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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 1 Breathing and the Nervous System ROGER P. SIMON •
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RESPIRATORY EFFECTS OF NERVOUS SYSTEM DYSFUNCTION Alteration of Gas Exchange Pulmonary Hydrostatic Pressure Capillary Permeability Central Effects on Ventilation Autonomic Dysfunction Extrapyramidal Disorders Forebrain Influences on Ventilation Apraxia of Ventilatory Movements Posthyperventilation Apnea Hindbrain Control of Ventilation Other Ventilatory Patterns Cheyne–Stokes Breathing Central Hyperventilation Alveolar Hypoventilation NERVOUS SYSTEM EFFECTS OF RESPIRATORY DYSFUNCTION Hypoxia Acute Hypoxia Hypercapnia Chronic Hypercapnia Acute Hypercapnia Hypocapnia Acute Hypocapnia Chronic Hypocapnia HICCUP SNEEZING YAWNING
The relationship between breathing and the nervous system can be considered from two perspectives, both of which are important to neurologists as well as to general physicians. First, neurological dysfunction can have effects on respiration that may be the most disturbing aspects of the underlying neurological disease. Second, primary respiratory dysfunction may affect the nervous system and lead to a request for neurological consultation. Both interactions are considered in this chapter. In revising this chapter for the current edition,
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many old but classic references were removed, but interested readers will find these cited in earlier editions, to which they are referred. RESPIRATORY EFFECTS OF NERVOUS SYSTEM DYSFUNCTION
Alteration of Gas Exchange One of the most dramatic and life-threatening effects of nervous system dysfunction on respiration is the impairment of alveolar gas exchange by a neurologically induced increase in pulmonary interstitial and alveolar fluid: the phenomenon of acute pulmonary edema. The fluid producing pulmonary edema originates in the pulmonary capillaries. Fluid movement from the pulmonary capillary bed into the alveolar air space is governed by the variables in the classic Starling equation. In its simplest form, the Starling equation expresses transcapillary fluid flux as a balance between intravascular pressures (tending to push fluid out of the vascular lumen) 1and plasma osmotic forces (which tend to retain fluid within the by which neurogenically induced vascular lumen) (Fig. 1-1). Although the mechanisms 2 pulmonary edema occurs remain uncertain, the major recognized factors are discussed in the following sections.
FIGURE 1-1 Relationships between microvascular hydrostatic pressure (PMV); perimicrovascular hydrostatic pressure, that is, within the interstitial space (PPMV); plasma colloid osmotic pressure (πMV); and perimicrovascular pericolloid osmotic pressure (πMv). Under normal conditions, the sum of forces is slightly positive, producing a small vascular fluid flux into the pericapillary interstitium of the lung, which is drained as lymph. (From Fein A, Grossman RF, Jones JG, et al: The value of edema fluid protein measurement in patients with pulmonary edema. Am J Med 67:32, 1979, with permission.)
Pulmonary Hydrostatic Pressure The main variable under the control of the nervous system affecting pulmonary capillary fluid flux is pulmonary intravascular pressure. A marked increase in this pressure can force fluid from the vascular compartment, flood the interstitial space (Fig. 1-1), produce pulmonary edema, and impair oxygenation. can unbalance the Starling equation and result in An elevation in intracranial pressure 2 neurogenic pulmonary edema. This early experimental observation in animals has been 3 confirmed in patients with traumatic head injury. Experimental studies have demonstrated that the effect of increased intracranial pressure on pulmonary vascular pressure and transcapillary fluid flux occurs as intracranial pressure approaches systemic pressure. An
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increase in systemic pressure (the Cushing response) then occurs to protect cerebral perfusion. In most studies, an increase in intracranial pressure alone, in the absence of the Cushing response, has no effect on transcapillary fluid flux in the lung. During the Cushing response, pulmonary vascular pressure increases in concert with systemic pressure, with a 4 resultant increase in pulmonary transcapillary fluid flux. Only one experimental study has shown an increase5in pulmonary transcapillary fluid flux in the absence of elevated pulmonary vascular pressure. Other classic models of induction of neurogenic pulmonary edema also appear to be those of centrally induced pulmonary vascular hypertension. These models include “sympathetic activation” induced by intracisternal veratrine and intracisternally 6–8 administered thrombin and fibrinogen with or without vagotomy in rabbits. Focal central nervous system (CNS) lesions can cause both an elevation of systemic vascular pressure and pulmonary edema. Although hemodynamic data in humans are lacking, there are many reports that the brainstem, particularly the medulla, is the site of focal 2,9–11 In unanesthetized small animals, brainstem CNS injuries that result in pulmonary edema. lesions in the region of the nucleus tractus solitarius produce marked systemic hypertension and fulminant pulmonary edema; pulmonary vascular pressure cannot be measured in these small animals. Following bilateral lesion placement in the ventral lateral nucleus tractus solitarius in sheep, however, pulmonary arterial pressures and transcapillary fluid flux in the lung can be measured and may increase significantly without a change in systemic or left 12 to a CNS injury is similar to that reported for atrial pressures. This pattern of response 2 neurogenic pulmonary edema in humans. Furthermore, a patient has been reported in whom a unilateral injury occurred to the tractus solitarius during a neurosurgical procedure and in whom the contralateral tractus solitarius was absent because of a congenital brainstem9 syrinx. The patient died of pulmonary edema and hypoxemia 34 hours postoperatively. The localization by magnetic resonance imaging (MRI) of a lesion at the obex (Fig. 1-2) in patients with recently diagnosed multiple sclerosis (MS) and acute pulmonary edema supports this 13,14 Recent corroborative data anatomical site as that inducing neurogenic pulmonary edema. come from a subset of patients with EV71 encephalitis in whom brainstem encephalitis and a polio-like acute flaccid paresis picture occur associated with neurogenic pulmonary edema. Brain MRI performed within hours of onset of pulmonary edema showed restricted diffusion in 15 the posterior medulla, anterior to the inferior aspect of the fourth ventricle (Fig. 1-3).
FIGURE 1-2 Rostral to caudal (A to C) schematic reconstruction of the medullary lesion in a patient with multiple sclerosis and pulmonary edema, based on magnetic resonance imaging, illustrating the major nuclear groups and tracts involved. AP, area postrema; 4th, fourth ventricle; LRN, lateral reticular nucleus; MLF, medial longitudinal fasciculus; MRN, medial reticular nucleus; NA, nucleus ambiguus; NTS, nucleus of the solitary tract; Ob, obex; ST, solitary tract; V, spinal trigeminal nucleus; X, dorsal motor nucleus of the vagus; XII, hypoglossal nucleus. (From Simon RP: Respiratory manifestations of neurologic diseases. p. 496. In Goetz CG, Tanner CM, Aminoff MJ [eds]: Handbook of Clinical Neurology. Vol 63. Elsevier, Amsterdam, 1993, with permission.)
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FIGURE 1-3 A, Diffusion magnetic resonance image at the level of the fourth ventricle, performed within hours of onset of neurogenic pulmonary edema, showing paired areas of restricted diffusion paracentrally in the region of the dorsal motor nucleus of the vagus, nucleus tractus solitarius, and medial reticular formation. Axial (B) and sagittal (C) T1-weighted images of same patient performed 4 weeks after onset of neurogenic pulmonary edema. Note the well-defined signal abnormality anterior to the inferior aspect of the fourth ventricle consistent with encephalomyelomalacia. (A kindly provided by Dr. P. Ian Andrews; B and C modified from Nolan MA, Craig ME, Lahra MM, et al: Survival after pulmonary edema due to enterovirus 71 encephalitis. Neurology 60:1651, 2003.)
Generalized seizures produce an abrupt, marked increase in sympathetic outflow from the 16 brain, and both systemic and pulmonary vascular pressures increase. The degree of systemic pressure elevation cor relates with the number of seizures and is maximal during status epilepticus. The magnitude of the pressure elevation in the pulmonary vasculature is independent of the number of seizures, however, although the duration of the elevation is maximal with status epilepticus (Fig. 1-4). The increase in transcapillary fluid flux resulting from this17transient pulmonary vascular hypertension persists for hours after the pressure transient and probably explains the phenomenon of pulmonary edema following seizures in humans.
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FIGURE 1-4 Vascular pressure changes that occur during seizures in sheep. Mean values have been plotted at 10-second intervals. Spinal cord refers to animals with cervical spinal cord transection prior to seizures. Single, 5, and 20 shocks refer to the number of electroconvulsive seizures induced; bicuculline refers to bicuculline-induced status epilepticus. LA, left atrial; PA, pulmonary arterial. (From Bayne LL, Simon RP: Systemic and pulmonary vascular pressures during generalized seizures in sheep. Ann Neurol 10:566, 1981, with permission.)
The development of postictal pulmonary edema requires an increase in pulmonary vascular pressures. If these pressure transients are aborted by a diversion of blood from the pulmonary artery and left atrium during experimental status epilepticus, pulmonary edema does not occur. As these peripheral vascular manipulations do not alter central sympathetic output during the seizure, the studies support a hydrodynamic mechanism for postictal pulmonary edema rather than the pulmonary edema being a manifestation of increased 18 activity of the sympathetic nervous system. Capillary Permeability Fulminant neurogenic pulmonary edema occurs in the setting of an alteration in pulmonary 5 19 capillary permeability, possibly independent of or in association with an imbalance of the forces in the Starling equation. The classic explanation for the pathogenesis of the altered permeability is that the rapid elevation of pulmonary vascular pressures and blood flow mechanically disrupts the pulmonary capillary bed, resulting in a pulmonary capillary leak 20 phenomenon and noncardiogenic pulmonary edema. Although this explanation is likely, some studies indicate the possibility that altered capillary permeability occurs in the absence 5 of altered intravascular pressure. Other studies in animals have demonstrated an inverse correlation between maximal pulmonary vascular pressures and altered capillary permeability, suggesting that a combination of “cardiogenic” and “noncardiogenic” factors 19 may be the most common cause of neurogenic pulmonary edema. A similar conclusion has been reached from the study of patients in whom the ratio of the protein concentration of edema fluid to plasma protein concentration has been used as an index of altered capillary 21 permeability.
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Central Effects on Ventilation Autonomic Dysfunction Neural pathways subserving volitional ventilation descend from cortex through the brainstem and spinal cord in the region of the corticospinal tract. The neuronal pools subserving rhythmic involuntary ventilation originate in the caudal medulla and give rise to descending pathways in the ventrolateral brainstem and spinal cord. Accordingly, appropriately placed focal lesions may interfere with voluntary or involuntary ventilation independently. Impairment of autonomic but not volitional ventilation produces the phenomenon of sleep apnea, or “Ondine's curse.” This term was taken from a 1956 play by Jean Giraudoux, who recreated a German mythical legend. The sea nymph Ondine cursed the unfaithful knight Hans with the necessity of voluntary control over all of his autonomic functions: “He died, they will say, because it was a nuisance to breathe.” In the brainstem, bilateral medullary 22 infarctions (Fig. 1-5A) have resulted in sleep apnea, as has unilateral medullary infarction (Fig. 1-5B). In the latter case, the lesion depicted in Figure 1-5B will have destroyed primary ventilatory nuclei in and about the nucleus retroambigualis and the nucleus tractus solitarius as well as fibers from these nuclear groups, which descend contralaterally. Transient 23 vertebrobasilar ischemia has also resulted in transient episodes of Ondine's curse. Congenital disorders of central alveolar hypoventilation may represent a primary defect in neural crest cell migration and function, resulting in altered central chemoreceptors. Accordingly neuroblastoma formation and Hirschsprung's disease sometimes occur in these 24 have lost patients. Patients with myotonic dystrophy and alveolar hypoventilation 25 catecholaminergic neurons in the medullary reticular formation. Incomplete and asymmetric involvement in the region of the dorsal and ventral ventilatory complex of the medulla at about the obex has been described in two patients with multiple sclerosis who died of sleep 26 apnea.
FIGURE 1-5 A, Location of bilateral brainstem infarcts in a patient with automatic respiratory failure. B, Brainstem section showing a unilateral lesion that resulted in failure of autonomic respiration. (A from Devereaux MW, Keane JR, Davis RL: Automatic respiratory failure associated with infarction of the medulla. Arch Neurol 29:46, 1973, with permission. B from Levin BE, Margolis G: Acute failure of automatic respirations secondary to a unilateral brain stem infarct. Ann Neurol 1:583, 1977, with permission.)
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Primary involvement of autonomic ventilatory nuclei was a common consequence of bulbar poliomyelitis (Fig. 1-6). As with lesions of the descending pathways from these nuclear groups, these lesions led to temporary or permanent sleep apnea. There are rare reports of 27,28 and pathological material from hypoventilation in patients with systems degeneration, such cases suggests that the causal abnormalities are located in the region of the solitary tracts in the caudal medulla. Vertebral artery dissection involving the dorsal medulla and 29 anterior spinal artery with resultant central ventilatory failure has been reported.
FIGURE 1-6 Medullary lesions found in 17 patients with bulbar poliomyelitis who died of respiratory failure. (From Baker AB, Matzke HA, Brown JR: Poliomyelitis. III: Bulbar poliomyelitis: a study of medullary function. Arch Neurol Psychiatry 63:257, 1950, with permission.)
Iatrogenic sleep apnea occurs in some patients following bilateral cervical tractotomy30 performed for intractable pain (6 of 112 patients reported by Tranmer and associates ). Figure 1-7 shows the most common site of the cordotomy lesion and the descending autonomic pathways in the reticulospinal tract. Descending pathways for voluntary ventilation are located in the corticospinal tract and thus are distant from the lesion site (Fig. 1-7).
FIGURE 1-7 Cervical spinal cord at the C1–C2 level showing the area commonly damaged in cervical cordotomies and the site of the descending autonomic pathway subserving ventilation. (From Tranmer BI, Tucker WS, Bilbao JM: Sleep apnea following percutaneous cervical cordotomy. Can J
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Neurol Sci 14:262, 1987, with permission.) Sleep apnea also occurs on an obstructive or mixed basis. Such patients are usually obese, hypertensive men older than 40 years. Excessive daytime sleepiness and sleep attacks are associated symptoms. Nocturnal breath cessation is associated with prominent snoring, snorting, and gasping sounds. Obstructive sleep apnea has been associated with neurodegenerative diseases, such as syringobulbia and olivopontocerebellar degeneration, 31 and miscellaneous unilateral lesions of the rostrolateral medulla, which may produce 32 oropharyngeal weakness. Nonobstructive ventilatory dysfunction may occur as well. 33 Treatment with continuous positive airway pressure (CPAP) during sleep is effective. Further discussion of this syndrome can be found in Chapter 32. Impairment of voluntary ventilatory efforts with preservation of autonomic ventilation may also occur. Cases have been reported from a demyelinating lesion in the high cervical cord and a bilateral pyramidal tract lesion in the medulla resulting from syphilitic arteritis. In another case, an infarct of the basal pons produced quadriplegia; autonomic ventilation was modulated normally by laughing, crying, and anxiety, supporting a nonpyramidal location of descending 27 pathways from limbic structures to medullary ventilatory nuclei. The most common cause, however, is a midpontine lesion that produces the “locked-in” syndrome. Patients may have a regular ventilatory pattern and a preserved response to CO2 stimulation, or a Cheyne–Stokes pattern that is volitionally unalterable. Extrapyramidal Disorders Symptomatic or asymptomatic ventilatory dysfunction is an infrequently recognized but relatively common manifestation of extrapyramidal syndromes34of multiple causes. Respiratory dysrhythmias were common in postencephalitic parkinsonism. Tachypnea, the most common abnormality, may be episodic or continuous during sleep or wakefulness; rates as high as 100 per minute are reported. Ventilatory dysrhythmias are less common and manifest as breath-holding spells, sighing, forced or noisy expiration, inversion of the inspiration/expiration ratio, or the Cheyne–Stokes pattern. Respiratory tics occur as well, manifesting as yawning, hiccupping, spasmodic coughing, and sniffing. In a study by Kim, all nine patients with postencephalitic parkinsonism had an increase in 35 respiratory rate, and the normal variation in respiratory amplitude did not occur. The most striking abnormality in these patients was their inability to alter the respiratory rhythm voluntarily so that, for instance, they were unable to hold their breath. Direct fiberoptic visualization of the upper airway in patients with extrapyramidal disease 36 (essential tremor, parkinsonian tremor, rigid parkinsonism, or dyskinesia) has disclosed rhythmic or irregular glottic and supraglottic involuntary movements. Symptomatic stridor and ventilatory failure that could be reversed by endotracheal intubation were described in a number of these patients and suggested upper airway obstruction. Abnormal flow-volume curves were commonly found. Such upper airway dysfunction may be a factor in the retention of secretions and respiratory infections that occur in many patients. Alternatively, a reduction in both maximal static inspiratory and expiratory pressures precluding the ability to rapidly 37 increase peak expiratory flow for maximally effective coughing may be an important factor. Respiratory distress and dyspnea are also described in patients with extrapyramidal dysfunction in whom no cardiopulmonary cause is found, but in whom respiratory rates are irregular owing to involuntary respiratory dyskinesias that are either levodopa induced or 38 related to a tardive dyskinesia. Respiratory dyskinesias, then, may be an accompaniment of choreiform movement disorders and may account for subjective complaints of dyspnea in 39 Parkinson's disease and dystonia. Forebrain Influences on Ventilation That the forebrain influences both ventilatory rate and rhythm is documented by the volitional acts of overbreathing and breath-holding as well as by the coordinated semivoluntary or involuntary rhythmic alterations in ventilatory pattern that occur as part of speaking, singing, laughing, and crying. Furthermore, during sleep, normal ventilatory patterns become more irregular, total ventilatory volume decreases, Paco2 is elevated, and the CO2 response curve shifts to the right. Cortical “readiness potentials” originating from supplementary motor and primary motor cortex can40be recorded from humans prior to volitional but not automatic inspiration or expiration. Using positron emission tomography of changes in regional cerebral blood-flow, areas of cortical activation during volitional inspiration and expiration 41 have been identified. Inspiration is associated with increased cerebral blood-flow in primary
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motor cortex bilaterally, the right supplementary motor cortex, and left ventrolateral thalamus. In expiration, the structures implicated are similar and overlapping but extend beyond those in inspiration and include the cerebellum. In the cortex, the identified regions activated during ventilation conform to the homuncular regions of thoracic and abdominal muscles. Diaphragmatic contraction induced from these cortical regions with magnetic stimulation does 42 not, however, affect automatic breathing. Hemispheric stroke results in attenuation of diaphragmatic excursion on the hemiplegic side but only during 43 volitional breathing; thus, the diaphragm lacks bilateral cortical 44 representation. The intercostal muscles are similarly affected by hemispheric stroke. Sleep-disordered breathing is common in acute supra- and infratentorial stroke but rarely has 45 localizing value. The cortical areas effective in inducing apnea in humans are similar to those in primates (Fig. 1-8) and include the anterior portion of the hippocampal gyrus, the ventral and medial surfaces of the temporal lobe, the anterior portion of the insula, and the anterior portion of the limbic gyrus. An episode of partial seizures with ictal apnea following encephalitis in humans has been studied with ictal-interictal subtraction single-photon emission computed tomography (SPECT), showing an abnormality in the left posterior lateral temporal region 46 consistent with the ictal electroencephalographic (EEG) findings. Respiratory changes have also been associated with paroxysmal abnormalities on the electroencephalogram. Such 47 episodes have been implicated in epileptic sudden death.
FIGURE 1-8 Points on the anterior lateral (top) and ventromedial (bottom)
cerebral cortex of Macaca mulatta where electrical stimulation elicited inhibition of respiration. C, cingulate gyrus; CC, corpus callosum; CF, central fissure; HG, hippocampal gyrus; IN, insula; LO, lateral orbital gyrus; OLF, olfactory tract; OT, optic tract; PO, posterior orbital gyrus; R, gyrus rectus; ST, superior temporal gyrus. (From Kaada BR: Somato-motor, autonomic, and electrocorticographic responses to electrical stimulation of “rhinencephalic”
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and other structures in primates, cat, and dog. Acta Physiol Scand 24:1, 1951, with permission.) Apraxia of Ventilatory Movements The inability to take or hold a deep breath despite normal motor and sensory function is termed respiratory apraxia. This phenomenon is noted most often in elderly patients with evidence of mild or moderate cerebrovascular disease. For example, in a patient with progressive supranuclear palsy, rhythmic breathing movements persisted during planned 48 volitional inspiration or breath-holding. As cortical magnetic stimulation of primary motor cortex produces diaphragmatic contraction but does not affect ongoing nonvolitional ventilation, cortical or subcortical regions other than primary motor cortex must be the site of respiratory apraxia in such patients. Posthyperventilation Apnea In 1867, Hering observed that brief periods of apnea followed hyperventilation in anesthetized 49,50 animals, and in 1908, Haldane reported apnea after voluntary hyperventilation in humans. Modern reanalysis of posthyperventilation apnea in awake normal human subjects shows that both hyperpnea and apnea of 10 to 30 seconds may occur in an individual subject; apneic pauses occur about 1 minute after cessation of hyperventilation; the apnea's length and occurrence, although variable among subjects, was reproducible in individual subjects; and 51 the occurrence of apnea was unrelated to the Pco2 during hyperventilation. In patients with brain injury, apnea occurred for more than 1052seconds with equal frequency in patients with unilateral (67%) and bilateral (70%) damage. No correlation was found between the decrease in end-tidal CO2 and the occurrence of apnea. A depressed level of consciousness in normal subjects, as during drowsiness, sleep, or anesthesia, also leads to posthyperventilation apnea. Posthyperventilation apnea has also been described in normal 53 patients engaged in an intellectual task. Hindbrain Control of Ventilation The concept that the hindbrain controls ventilatory function, rate, and rhythm has grown from the experiments of Lumsden (Fig. 1-9). These studies in anesthetized cats localized the brainstem ventilatory centers to regions below the inferior colliculus because transection at this level did not alter the ventilatory pattern when the vagi were intact. Transection at the medullary-cervical junction produced the cessation of all ventilatory functions. Accordingly, the neuronal centers responsible for ventilation are located between these levels. Transection at the pontomedullary junction resulted in rhythmic breathing with a gasping quality unchanged by vagal transection, demonstrating that the most primitive respiratory oscillator is located within the medulla. The higher brainstem “centers” play a modulatory role. A modern example of such experiments in anesthetized cats is found in Figure 1-10.
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FIGURE 1-9 A, The original illustration from Lumsden (1923) showing the level of “crucial sections” producing ventilatory alteration in cats. Ventilatory effects produced with lesions: 1, no alteration; 2, apneusis; between 3 and 4, uncoordinated inspiratory spasms and gasping; 4, gasping; between 5 and 6, cessation of all respiratory movements. B, Respiratory tracings from Lumsden (1923). a, normal animal; b, after vagotomy; c, apneusis (transection 2); d, gasping (transection 4). (From Lumsden T: Observation on the respiratory centres in the cat. J Physiol [Lond] 57:153, 1923, with permission.)
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FIGURE 1-10 Effects of brainstem and vagal transection on the ventilatory
pattern in an unanesthetized cat. APC, apneustic center; CP, cerebellar peduncle; DRG, dorsal ventilatory group; IC, inferior colliculus; PNC, pneumotaxic center; VRG, ventral ventilatory groups. Transections at different levels are indicated by roman numerals. Tracings on right represent the tidal volume with inspiration upward. (From Berger AJ, Mitchell RA, Severinghaus JW: Regulation of respiration. N Engl J Med 297:139, 1977, with permission.) Cerebellum
Classic studies of the role of the cerebellum in ventilation focused on the inhibitory effects of the anterior lobe induced by stimulation. Modern studies have extended these observations to the posterior lobe, showing stimulation-induced ventilatory inhibition from the fastigial nucleus and uvula. Stimulation of large regions of the cerebellum, however, produced no ventilatory alteration. Stimulation of the fastigial nucleus produced early termination of bursting in both 54 the inspiratory and the expiratory medullary neurons in the cat. Functional magnetic resonance imaging and positron emission tomography studies have also shown activation of the cerebellum along with other brainstem and basal forebrain structures during volitional 41,55,56 A breathing in humans. In some studies, expiration particularly involved the cerebellum. congenital syndrome associated with hypoplastic posterior cerebellar vermis (Joubert's syndrome) is characterized by prominent ventilatory abnormalities: episodic hyperpnea and 57 apnea. Pneumotaxic Center
Lumsden named the pneumotaxic center (pneumotaxy: normal rhythmic ventilation) and 58 localized it to the rostral pons in the parabrachial complex. Transection at this level results in regular breathing, and the rate of this breathing, but not the rhythm, is slowed by vagotomy. Destruction of this region or transection below it produces the phenomenon of apneusis (Fig. 1-9B), which is discussed in the next section. Modern electrophysiological and cytoarchitectural studies have localized respiratory-related neuronal activity to multiple nuclei 59 in the dorsal and ventral pons and its connections. Electrical stimulation within this region produces premature switching of respiratory phases. This off-switching is modified at least in 60 part by the classic Hering–Breuer (and possibly other) afferents carried within the vagus. 61 Glycinergic and GABAergic input is critical for off-switching. Neuroanatomical and neurophysiological studies in animals support the belief that the pneumotaxic center functions as a relay station, finely tuning the ventilatory pattern generator. Stimulation by glutamate injection of the parabrachial complex Kolliker–Fuse nucleus to include the margins of the sensory and motor trigeminal nuclei have identified functionally distinct cell populations producing specific but sometimes opposing ventilatory responses, which include both 62 respiratory facilitation and inhibition.
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Apneustic Center
The phenomenon of apneusis consists of prominent, prolonged end-inspiratory pauses that 58,63 Although the can be pro- duced by pontine transection in vagotomized animals (Fig. 1-9). phenomenon of apneusis is well recognized, anatomical definition of a neuronal aggregate that can reasonably be called the apneustic center is still lacking. Apneusis is defined operationally as a failure of activation of normal inspiratory off-switching. The phenomenon of apneusis may result from one of a number of lesions (Fig. 1-11) or pharmacological manipulations. Systemic, but not local, administration of antagonists of the N-methyl-d-aspartate (NMDA) subset of the glutamate receptor, but not non-NMDA 64 antagonism induces apneusis, thus defining the neurotransmitter system involved and the 65 lack of a specific inducing site. However, altered membrane66potentials in neurons of the ventral respiratory group are produced by NMDA antagonists.
FIGURE 1-11 Areas of the brainstem infarction in two patients with apneustic
breathing. (From Plum F, Alvord EC: Apneustic breathing in man. Arch Neurol 10:101, 1964, with permission.) Apneustic respiration is rare in humans. Children with brainstem damage from hypoxic-ischemic injury or other brainstem lesions may have apneustic breathing, with cyanosis during inspiratory pauses. Tandospirone or buspirone, serotonin-1A agonists, 67,68 Five patients with cervicomedullary compression from normalize breathing. achondroplasia had apneustic breathing patterns that were “reduced in the majority” following decompressive surgery. The absence of a compressive effect at the level of the pneumotaxic 69 center and the integrity of the vagus nerves are notable in this clinical description. Medullary Center
Rhythmic ventilatory excursions persist with brainstem transection at the pontomedullary level, and all ventilatory movements are abolished by transection at the medullary-cervical junction. Accordingly, attention has been focused on the medulla as the generator of rhythmic ventilatory movements. Medullary centers responsible for inspiration and expiration were identified and were held to explain both ventilatory function and ventilatory rhythmicity. Two major neuronal pools are responsible for ventilation. Primary inspiratory cells located in the ventrolateral nucleus tractus solitarius constitute the dorsal respiratory group, which receives all primary pulmonary afferents from the vagus nerves. GABAB receptors are the major 70 modulators. Inspiratory and expiratory neurons are found in a separate grouping within the nucleus ambiguus and the nucleus retroambigualis, which together constitute the ventral respiratory group (Fig. 1-12). Excitatory amino acid neurotransmitter function is necessary to modulate ventral respiratory group function. NMDA receptors are the major mediators of ventral respiratory group ventilatory drive, with modulation by non-NMDA glutamate 71 systems. Thus, ventilatory rhythmicity is mediated by the dorsal respiratory group, and projection to spinal respiratory motor neurons and vagally mediated auxiliary muscles of respiration occurs via the ventral respiratory group. Although rhythmic ventilatory responses occur from the medulla following ponto-medullary transection, this respiratory pattern has a rather gasping quality and is not normal rhythmic ventilation.72A gasping center has been found just rostral and ventral to the dorsal respiratory group. The primary ventilatory rhythm generator appears to reside in a limited region of the ventral medulla (the pre-Bötzinger
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complex) just rostral to the rostral ventilatory group (Fig. 1-12). Rhythm generation is eliminated by removal of this region, and medullary slices containing this region generate 73 complex responds to hypoxia, and this respiratory-related oscillations. The pre-Bötzinger 74 membrane response is modified by glutamate receptors. The network and intrinsic 75,76 properties of this region are an intensive area of current investigation.
FIGURE 1-12 A, Dorsal view of brainstem and cervical spinal cord indicating regions involved in control of breathing and progression of labeling with a viral tracer injected into the phrenic nerve. The percentage of labeled third-order neurons (propiobulbar neurons) in the pre-Bötzinger complex and adjacent regions is plotted in the set at right. Note that the pre-Bötzinger complex contains almost entirely third-order neurons, whereas adjacent regions, rVRG and BötC, contain 0 to 20 percent. BötC, Bötzinger complex; cVRG, caudal ventral respiratory group; KF, Kölliker-Fuse nucleus; NTS, nucleus tractus solitarius; PB, parabrachial nuclei; PGi, paragigantocellular reticular nucleus; preBötC, pre-Bötzinger complex; RTN, retrotrapezoid nucleus; rVRG, rostral ventral respiratory group. B, Sagittal and transverse view of the location of the pre-Bötzinger complex. cNA, caudal nucleus ambiguus; LRN, lateral reticular nucleus; rNA, rostral nucleus ambiguus; VII, facial nucleus. (From Rekling JC, Feldman JL: PreBötzinger complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation. Annu Rev Physiol 60:385, 1998, with permission.)
Other Ventilatory Patterns
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Cheyne–Stokes Breathing Periodic, or 77 Cheyne–Stokes, breathing suggests left ventricular failure or nervous system dysfunction. Its original description by Cheyne was in a patient who died of heart failure, but both CNS and cardiac dysfunction (or a combination of the two) can produce this ventilatory 78 pattern. The Cheyne–Stokes pattern is that of escalating hyperventilation followed by decremental hypoventilation and finally apnea, which recurs in cycles. Cycle lengths of 40 to 100 seconds 79 have been reported in humans. Arterial blood gas assays during Cheyne–Stokes breathing indicate a rising pH and a falling Paco2, which become maximal at the apnea point and never 80 return to normal values (Fig. 1-13). Cheyne–Stokes patterns are seen in 30 to 40 percent of patients in congestive heart failure, and Cheyne–Stokes breathing is associated with an 81–83 This ventilatory pattern also occurs in normal premature infants, increased mortality. during normal sleep, in subjects at high80,84 altitude, and with equal frequency in association with 85 Associated changes in arousal, pupillary size, supratentorial and infratentorial stroke. 86 cardiac rhythm, heart rate, blood pressure, muscle tone, and consciousness may occur cyclically in patients with Cheyne–Stokes breathing. The alterations in Paco2 also affect the cerebral vasculature, producing changes in the intracerebral volume of the vascular compartment with associated alterations in cerebral blood-flow and intracranial pressure. The periodicity80 of ventilation can be eliminated by intravenous theophylline or by oxygen inhalation.
FIGURE 1-13 Periodicity of arterial oxygen saturation (Sao2; upper trace), chest
wall motion (middle trace), and CO2 concentration in the expired air (lower trace) in a stroke patient with Cheyne–Stokes respiration. The phase shift between the upper and middle traces is due to the sampling time of the pulse oximeter of approximately 40 seconds. The drops in CO2 concentration during hypopnea are due to dead space ventilation. (From Nachtmann MD, Siebler M, Rose G, et al: Cheyne-Stokes respiration in ischemic stroke. Neurology 45:820, 1995, with permission.) Based on studies in patients with heart failure, the ventilatory oscillations result from Pco2
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87
fluctuations about the apneic threshold. The reciprocal fall in Po2 results from attenuated ventilatory drive. Cheyne–Stokes breathing is abolished by inhalation of CO2 (increasing the 88 Pco2 over the apneic point) but not by inhalation of oxygen. A host of factors that might explain Cheyne–Stokes ventilatory oscillations has been addressed experimentally and clinically. The possibility that a prolonged circulation time may itself produce ventilatory oscillations by creating a feedback loop delay to central receptors was classically considered as the factor responsible for the Cheyne–Stokes ventilatory pattern. However, Hoffman and associates, studying patients with cardiogenic pulmonary edema, found no differences in left ventricular ejection fractions in patients with or without 89 delay did correlate Cheyne–Stokes breathing. Hall and colleagues found that circulatory 90 with Cheyne–Stokes cycle length, but not with apnea length. Lorenzi-Filho and co-workers showed that CO2 inhalation blocked Cheyne–Stokes breathing in patients with heart failure and argued that reduction in Paco2 sensed by peripheral chemoreceptors triggered central 88 apneas. The issue of an abnormal feedback to91the CNS in the genesis of respiratory oscillations was studied in animals by Cherniack who used the normal phrenic nerve stimulus to trigger a mechanical ventilator that had been modified so that the gain could be varied to amplify or retard the induced tidal volume triggered by the phrenic stimulus. This model produced periodic ventilations when the gain was increased. Supporting the concept of abnormal feedback loops generating Cheyne–Stokes breathing, ventilatory periodicity was eliminated by destruction of peripheral chemoreceptors but was unchanged by vagotomy. Furthermore, all animals had a persistent respiratory alkalosis. Duplicating observed clinical phenomena, the oscillations were enhanced by hypoxia and eliminated by increasing the oxygen or CO2 content of inspired air. Hypoxemia (during sleep) also induces 92 Cheyne–Stokes breathing in humans. Originally described as a variant of Cheyne–Stokes breathing, Biot breathing is characterized by clusters of breaths having equal and regular inspiratory and expiratory phases, rather than the spindle characteristics of Cheyne–Stokes breathing. The similarity to Cheyne–Stokes breathing is in the separation of the ventilatory periods by apnea, which in Biot breathing occurs in end-expiration. Although first described in patients with meningitis, a ganglioglioma 93 and bihemispheric involving the cerebellum and pons was responsible in one patient, 94 infarction in another. Central Hyperventilation Hyperventilation was thought, at one point, to be the 95 respiratory pattern characteristic of midbrain dysfunction during transtentorial herniation. The exhaustion resulting from such hyperventilation may be fatal; morphine or methadone will suppress the abnormal ventilatory 96 drive. A specific midbrain localization for lesions pro-ducing this ventilatory pattern cannot be supported any longer. Cases of isolated brainstem tumors and sustained tachypnea offered the possibility of an unambiguous anatomical localization of the source of this ventilatory pattern. In some instances the pons or medulla was involved. Extra-axial medullary 97 compression has also caused central hyperventilation. Central hyperventilation has been associated with CNS lymphoma,98,99 the infiltrating nature of which has been suggested as the Table 1-1 shows the incidence of various abnormal common feature in such cases. ventilatory patterns associated with lesions at different CNS sites. Click here to view this table.... The possibility of central stimulation of medullary chemoreceptors due to local lactate production from tumors or stroke has been suggested to explain the lack of correlation between anatomical lesion site and ventilatory pattern. However, a markedly alkaline cerebrospinal fluid (CSF) pH was reported in a patient with central hyperventilation and a 100 pontine tumor. Pulmonary congestion of neurogenic cause (neurogenic pulmonary edema) might induce this respiratory pattern via stimulation of pulmonary receptors in the pulmonary interstitial space. At the San Francisco General Hospital, the author saw three patients with sustained tachypnea following stroke. Their in vivo lung water content was measured with a double indicator dilution technique (by Dr. Frank Lewis), and no elevation was found.
Alveolar Hypoventilation Hypoventilation, hypoxia, and apnea are major risks in diseases of the anterior horn cells,
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peripheral nerves, myoneural junctions, and muscles. Motor neuron disease, polyneuropathy, myasthenia gravis, and the muscular dystrophies are, respectively, the most common 101 examples of such diseases that cause ventilatory disturbances. In part because of the decreased exercise demands induced by the disease processes, dyspnea is often absent and arterial blood gases may show little alteration immediately prior to fatal ventilatory compromise. Furthermore, the amount of muscle weakness in extremity and girdle muscles is often a poor predictor of ventilatory muscle function. Vincken and associates examined this point and documented that maximal inspiratory (diaphragmatic, intercostal, and accessory neck muscles) and expiratory (abdominal and intercostal muscles) pressure measurements were required to assess 102 the risk of respiratory compromise in patients with chronic neuromuscular disease. Unsuspected ventilatory dysfunction was found in one half of the 30 patients studied, and in one third of patients, it was severe. In no case was the ventilatory dysfunction clinically suspected. Traumatic myelopathies or myelopathies resulting from infiltrative tumors produce ventilatory insufficiency with lesions above the cervical roots innervating the phrenic nerve (C3, C4, C5). Such patients' ventilatory dysfunction has been successfully managed without mechanical ventilation by electrical pacing of the diaphragm. In patients with lesions between C3 and C5, this treatment is feasible if the C5 root is preserved below the level of the lesion. Each of eight patients with traumatic tetraplegia reported by Vanderlinden and co-workers were successfully weaned from ventilator support using this 103 have been used to assess diaphragm technique. Cervical and cortical magnetic stimulation 104 strength in patients proposed for phrenic pacing. Although ventilatory compromise is often the terminal event in advanced motor neuron disease, isolated respiratory insufficiency may be the presenting feature of the disease. In patients with primary bulbar disease, sleep apnea or nocturnal hypoventilation occurs, manifesting itself by both obstructive and central apnea. Orthopnea may be the presenting symptom of motor neuron disease. Such patients have predominantly diaphragmatic weakness, and this may be unilateral or bilateral. Paradoxical chest wall and abdominal movements are seen during inspiration, and vital capacity is reduced, especially when the patient is tested in the supine position. In this group of patients with diaphragmatic weakness in the absence of bulbar impairment), symptomatic relief is obtained with ventilatory support (CPAP or nocturnal105 intermittent positive pressure ventilation) without unwarranted positive airway pressure (BiPAP) is now an prolongation of life. Continuous bimodal 105,106 important alternative to tracheostomy. Ventilatory failure requiring mechanical assistance has been reported in 10 to 80 percent of were needed in 43 percent patients with Guillain–Barré syndrome. Intubation and ventilation 104 of the 111 patients from the French plasmapheresis study and in 47 percent of the 123 107 patients in the American study. The mean duration of the assisted ventilation was 31 days in the French study, and it was reduced to 18 days by plasmapheresis. Intubation is usually required when vital capacity falls below 18 ml/kg. Sunderrajan and Davenport analyzed the presenting and early stages of their patients' illness and were unable to identify any 108 characteristics or neurological features that would predict the need for assisted ventilation. While the mean hospital day on which intubation was required was 4.4, the range was broad (0 to 21 days). The hospital day on which the patient was extubated had an equally wide range: hospital days 5 to 90. Two unusual cases required ventilatory support for more than a year. This experience suggests that extubation will be successful when vital capacities exceed 1 liter. A detailed study of diaphragmatic performance in patients with Guillain–Barré syndrome suggested that improvement in the maximal transdiaphragmatic pressure was the best predictor of recovery, and this measure was correlated with maximal inspiratory force, 109 but not forced vital capacity. The duration of mechanical ventilatory support required in patients with the Guillain–Barré syndrome was nearly halved by treatment with plasma 110 exchange; treatment with intravenous gamma globulin is equivalent. An acute, primary axonal degeneration of motor and sensory fibers occurs in the setting of 111 prolonged sepsis (approximately 2 weeks) with multiple organ failure. This syndrome has been termed critical illness neuropathy and is described in detail in Chapter 52. The neuropathy is characterized clinically by distal weakness with reduced or absent tendon reflexes; when it is severe, there is paralysis with areflexia. The syndrome is frequently recognized only because of unexpected difficulty in weaning patients from assisted ventilation. Phrenic nerve conduction velocities have been abnormal, and autopsy studies have shown axonal degeneration of112 the phrenic nerve, with denervation atrophy in the intercostal muscles and diaphragm. Complete recovery over a period of 6 months is the rule in mild and moderate cases, but patients with severe polyneuropathy may fail to improve and have a fatal outcome. A similar syndrome of critical care myopathy is recognized, with a 113,114 Neuromuscular blockade and corticosteroid treatment may be risk similar prognosis. 113 factors, especially in transplant patients.
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Temporary ventilatory support may be required in myasthenia gravis. Indications include the post-thymectomy period and failure of outpatient pharmacological therapy. Of 22 such patients seen at the Mayo Clinic, the duration of ventilatory support116required was 1 to 32 115 exchange days, with 1 to 41 days reported by O'Donohue and colleagues. Both plasma 117 and intravenous immunoglobulin treatments may be useful in myasthenic crisis. In patients with myopathy, ventilatory dysfunction may occur and may be disproportionate to the severity of the muscle weakness. Although the poor prognosis in the muscular dystrophies usually commits patients to ventilatory support for the remainder of their lives, two patients with Duchenne muscular dystrophy were weaned from39continual positive pressure ventilation with intermittent negative pressure techniques. Recurrent episodes of ventilatory failure independent of muscle weakness have been reported in patients with 118 mitochondrial myopathies. Patients have depressed respiratory responses to hypoxia and often to hypercapnia as well. Life-threatening hypoventilation often occurs in the setting of surgery, sedation, or infection. Reported cases include typical Kearns-Sayre syndrome, MERRF (myoclonic epilepsy and ragged-red fibers) syndrome, and familial mitochondrial myopathy. No specific biochemical defect has been found, although a defect in cytochrome-c 118 oxidase has been suggested. The cause of the hypoventilation may be central rather than 119 muscular. NERVOUS SYSTEM EFFECTS OF RESPIRATORY DYSFUNCTION
Hypoxia Acute Hypoxia The terms hypoxic and anoxic encephalopathy are frequently used to describe neurological syndromes that occur following cardiac arrest. The encephalopathy, however, is due primarily to cerebral ischemia. Acute hypoxia results in transient alterations of cognitive function similar to those due to intoxication with alcohol. Hallucinations and alterations in judgment and behavior are well known in mountain climbers at high altitudes. Climbers to the Mt. Everest summit, at 8,854 meters (29,000 feet) have been studied to determine the potential acute and long-term neurological deficits from hypoxia at these altitudes. The results of simple tests of short-term memory (number recall) and simple motor tasks (finger tapping) are shown in immediately after Figure 1-14. Significant reductions in performance in both tests were found 120 the expedition, and significant impairments persisted 12 months later.
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FIGURE 1-14 Results of finger-tapping and short-term memory tests performed
before, immediately after, and 1 year following an expedition to Mt. Everest. (From West JB: Do climbs to extreme altitude cause brain damage? Lancet 2:387, 1986, with permission.) Neuropathological studies of the CNS in primates subjected to hypoxia have revealed lesions only in the watershed distribution between major arterial territories. Thus, the effects of acute 121 Structural abnormalities do not hypoxia on the brain are those of cerebral hypoperfusion. 122,123 However, polymerase occur in the brain in the setting of hypoxia without ischemia, chain reaction (PCR) techniques to simultaneously amplify long random segments of DNA have shown that pure hypoxia for 30 minutes in vivo124 produces both nuclear and mitochondrial DNA damage, which have dissimilar repair kinetics.
Hypercapnia Chronic Hypercapnia A reversible syndrome of headache, papilledema, and impaired consciousness with “tremor 125 of the extremities” has been described in patients with chronic pulmonary insufficiency. Tremulousness is most prominent with the fingers outstretched and has the characteristics of an action tremor or the features of asterixis; in some patients, it resembles myoclonus. The headaches are attributed to the increased intracranial pressure. Arterial oxygen saturations in 125 one study ranged from 81 to 94 percent (but may be as low as 40%), and the Paco2 levels ranged from 39 to 68 mmHg (but can be higher). The electroencephalogram shows slowing in the theta or delta range. The etiology of such CO2 narcosis is probably multifactorial, including hypercapnia, hypoxia, and elevated intracranial pressure. 126 The increased intracranial pressure may produce papilledema that can progress to blindness. Ventilatory support and discontinuation of sedative drugs constitute effective treatment. Acute Hypercapnia Nervous system abnormalities from hypercapnia are related in significant measure to the rate of increase of Paco2. The rapid diffusibility of carbon dioxide across the blood–brain barrier produces a prompt fall in CSF pH in respiratory acidosis, a decrease that does not occur in + metabolic acidosis. A potent inhibitory effect of H upon the postsynaptic receptor for glutamate, the brain's major excitatory neurotransmitter, has been described and may be 127 responsible for the acute encephalopathy of hypercapnia.
Hypocapnia Acute Hypocapnia Acute hypocapnia occurs during hyperventilation. The symptom complex of dizziness, lightheadedness, faintness, paresthesias, and impaired consciousness can be reproduced in normal subjects during hyperventilation, supporting a cause-and-effect relationship between acute hypocapnia and the symptoms of the hyperventilation syndrome (Table 1-2), although 128 some have found hyperventilation as a consequence, rather than a cause, of the attacks. 129 Asthma was significantly associated in one series. This syndrome has its maximal incidence during the third decade. Distal paresthesias are notable and may be asymmetric, prompting evaluation for a more sinister cause. Alteration or loss of consciousness is common (31% in the series of Perkin and Joseph; Table 1-2), leading to an inappropriate diagnosis of epilepsy. Symptoms can often be reproduced by voluntary hyperventilation, and the electroencephalographic findings while the patient is symptomatic can help to exclude a diagnosis of seizure disorder. The effects of hypocapnia include cerebral vasoconstriction, alteration in the ionic balance of calcium, and a shift in the oxyhemoglobin dissociation curve with reduced delivery of oxygen to peripheral tissues. A combination of these events is responsible for the clinical symptoms. Click here to view this table.... Chronic Hypocapnia Fixed respiratory alkalosis is a common or even diagnostic finding in a number of metabolic disorders, the most prominent being hepatic encephalopathy; sepsis and salicylate poisoning are additional examples. However, the role of the alkalosis itself in causing CNS dysfunction
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is uncertain. Potential mechanisms by which alkalosis may affect the brain include a shift in the oxyhemoglobin dissociation curve (which decreases oxygen availability to tissues), a decrease in cerebral blood-flow resulting from cerebral vasoconstriction, and alkalosis-induced hypophosphatemia. Posner and Plum also found that control of the alkalosis by mechanical ventilation did not alter the encephalopathic manifestations in 130 patients with hepatic failure. Accordingly, alkalosis per se appears to have a minimal effect on the CNS. HICCUP 131
Persistent or intractable hiccup is an abnormality resulting from many133 systemic, 132 134 pharmacological, and CNS causes, including brainstem neoplasm, multiple sclerosis, 135 136,137 and thoracic herpes zoster. It may also occur with cortical pathology. Cases of 138 intractable hiccup are much more common in men than women. Hiccup results from CNS-induced synchronous contraction of the diaphragm and the external (inspiratory) intercostal muscles, followed rapidly by inhibition of expiratory intercostal muscles and glottal 139 closure. The glottal closure minimizes air exchange. However, with tracheostomy, the induced ventilatory movements of hiccup cause air exchange, and a respiratory alkalosis is 139,140 produced. The frequency, but not amplitude, of hiccuping is modulated by arterial Paco2. Hiccup 139 frequency is reduced with elevated Paco2 levels and increased with a fall in arterial Paco2. This observation is in keeping with the traditional cure for hiccups—breath-holding. Another common lay remedy for hiccup is swallowing or pharyngeal stimulation, maneuvers that may increase vagal tone. Thus, hiccups are most common at maximal inspiration because vagal afferents are inhibited by maximal lung inflation. High-frequency diaphragmatic flutter, 137 responsive to carbamazepine, is responsible for hiccups in some patients. Chlorpromazine remains the most141–143 popular pharmacological treatment, although baclofen and gabapentin are 144 ; a host of other approaches has been suggested. now also popular SNEEZING The coordinated act of sneezing arises from a caudal brainstem center near the nucleus 145 mass lesion or lateral medullary syndrome can prevent sneezing ambiguus. A medullary146–148 despite the urge to do so. Cortical input to sneezing has149 long been recognized. The central mediation of sneezing was noted by Penfield and Jasper in a patient during temporal lobe stimulation when both sneezing and chewing movements were induced. A common reflex that induces sneezing is 150 that which occurs on sudden exposure to bright light. This reflex was found in 80 percent of the families of medical students in whom the phenomenon of light-induced sneezing was reported.151 It has been suggested that this reflex is inherited in an autosomal dominant manner. YAWNING 152
Yawning is coordinated from brainstem sites near the paraventricular nucleus via 153 extrapyramidal pathways using a number of neurotransmitters and neuropeptides. This reflex may occur in patients “locked in” from pontine transection who have nonvolitional 154 mouth opening with spontaneous yawns. Yawning in the setting of a pyramidal lesion (capsular infarction) may be associated155 with arm stretching in the paretic limb, supporting the input also occurs, as reflected by the involvement of extrapyramidal circuitry. Cortical 156 Yawning has been seen to initiate a yawning related to boredom and somnolence. 149 temporal lobe seizure. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 2 Neurological Complications of Aortic Disease and Surgery DOUGLAS S. GOODIN •
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CLINICAL NEUROLOGICAL SYNDROMES DUE TO AORTIC PATHOLOGY Spinal Cord Ischemia Anatomy Ischemic Cord Syndromes Cerebral Ischemia Anatomy Strokes and Transient Ischemic Attacks Peripheral Neuropathy Mononeuropathies Radiculopathies Polyneuropathies Autonomic Neuropathies AORTIC DISEASES AND SURGERY Aortitis Syphilitic Aortitis Takayasu's Arteritis Giant Cell Arteritis Aortic Aneurysms Nondissecting Aneurysms Dissecting Aortic Aneurysms Traumatic Aortic Aneurysm Coarctation of the Aorta Surgery and Other Procedures Aortic Surgery Aortography and Other Procedures on the Aorta Intraoperative Adjuncts to Avoid Spinal Cord Ischemia
The aorta is the main conduit through which the heart supplies blood to the body, including the brain, brainstem, and spinal cord. In addition, this vessel is situated close to important neural structures. In consequence, both disease of the aorta and operations on it may have profound but variable effects on nervous system function. Often the neurological syndrome produced by aortic disease or surgery depends more on the part of the aorta involved than on the nature of the pathological process itself. For example, either syphilis or atherosclerosis may produce symptoms of cerebral ischemia if the disease affects the aortic arch or of spinal
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cord ischemia if the pathological process is in the descending thoracic aorta. Even when the nature of the pathological process is important in determining the resultant neurological syndrome, several diseases may result in the same pathological process. Thus, atherosclerosis, infection, inflammation, and trauma may each result in the formation of aortic aneurysms; similarly, coarctation of the aorta may be congenital, a result of Takayasu's arteritis, or a sequela of radiation exposure during childhood. The initial focus of this chapter is on the three major areas of neurological dysfunction resulting from aortic disease and surgery: spinal cord ischemia, cerebral ischemia, and peripheral neuropathy. Specific conditions that merit special consideration are then discussed individually. The normal anatomical relationships are also considered in order to provide insight into the pathogenesis of the resulting neurological syndromes. CLINICAL NEUROLOGICAL SYNDROMES DUE TO AORTIC PATHOLOGY Aortic disease may produce a variety of neurological syndromes. The specific syndrome depends to a large extent on the site of involvement along the aorta.
Spinal Cord Ischemia Anatomy Embryological Development
During embryological development, primitive blood vessels arise along the spinal nerve roots bilaterally and at each segmental level. Each of these segmental vessels then divides into anterior and posterior branches, which ramify extensively on the surfaces of the developing spinal cord. As development proceeds, most of these vessels regress and a few enlarge, so that by birth, the blood supply to the spinal cord depends on a small but highly variable 1–11 (Fig. 2-1). In the thoracic region, where the aorta number of persisting segmental vessels is situated to the left of the midline, the persisting vessels entering the spinal canal are those 5,6,8 from the left in 70 to 80 percent of cases.
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FIGURE 2-1 Extraspinal contributions to the anterior spinal arteries showing the three arterial territories. In the cervical region, an average of three arteries (derived from the vertebral arteries and the costocervical trunk) supply the anterior spinal artery. The anterior spinal artery is narrowest in the midthoracic region, often being difficult to distinguish from other small arteries on the anterior surface of the cord; occasionally it is discontinuous with the anterior spinal artery above and below. In addition, this region is often supplied by only a single small radiculomedullary vessel. The lumbosacral territory is supplied by a single large artery, the great anterior medullary artery of Adamkiewicz, which turns abruptly caudal after joining the anterior spinal artery. If it gives off an ascending branch, that branch is usually a much smaller vessel. This artery is usually the most caudal of the anterior radiculomedullary arteries, but when it follows a relatively high thoracic root, there is often a small lumbar radiculomedullary artery below. In this and subsequent illustrations, a indicates artery; m, muscle; n, nerve. Anterior Spinal Artery
The anterior spinal artery is formed rostrally from paired branches of the intracranial vertebral arteries that descend from the level of the medulla (Fig. 2-1). These two arteries fuse to form1 a single anterior spinal artery that overlies the anterior longitudinal fissure of the spinal cord. This artery is joined at different levels by anterior radiculomedullary arteries, which are branches of certain segmental vessels (Fig. 2-2). The number of these vessels is variable among5,6individuals, ranging from 2 to 17, although 85 percent of individuals have between 4 and 7.
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FIGURE 2-2 Anatomy of the spinal cord circulation, showing the relationship of the segmental arteries and their branches to the spinal canal and cord. The left rib and the left pedicle of the vertebra have been cut away to show the underlying vascular and neural structures.
The anterior spinal artery in the region that includes the cervical enlargement (C1 to T3) is particularly well supplied, receiving contributions from an average of three segmental 6 vessels. One constant artery arises from the costocervical trunk and supplies the lower segments; the others arise from the extracranial vertebral arteries and supply the middle 6 cervical segments. In addition, branches of the vertebral arteries have rich anastomotic connections with other neck vessels, including the occipital artery, deep cervical artery, and 6 ascending cervical artery. The anterior spinal artery in the midthoracic portion of the cord (T4 to T8) often receives only 6,8 a single contribution from a small artery located at about T7, most often on the left. The anterior spinal artery has its smallest diameter in this region, and it is sometimes 5,6 discontinuous with the vessel in more rostral or caudal regions. The anterior spinal artery in the region of the lumbar enlargement (T9 to the conus medullaris) is, as at the cervical enlargement, richly supplied, deriving its blood supply predominantly from a single large (1.0 to 1.3 mm in diameter) artery, the great anterior medullary artery of Adamkiewicz. This artery almost always accompanies a nerve root between T9 and L2,5,6usually on the left, although rarely it may accompany a root above or below these levels. Identification of the actual location of this great vessel has become an important part of the planning and execution of operations on the aorta such as repair of thoracoabdominal aortic aneurysms. Although digital subtraction angiography has been used for this purpose, the use of contrast-enhanced magnetic resonance angiography has recently 11 medullaris, the been proposed to offer a noninvasive alternative. Caudally, at the conus 6 anterior spinal artery anastomoses with both posterior spinal arteries. Posterior Spinal Arteries
The paired posterior spinal arteries are formed rostrally from the intracranial portion of the vertebral arteries. They are distinct paired vessels only at their origin,5,6however, and thereafter become intermixed with an anastomotic posterior pial arterial plexus (Fig. 2-3). This plexus is joined at different levels by a variable number (10 to 23) of posterior radiculomedullary 5 vessels that accompany the posterior nerve roots.
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FIGURE 2-3 Vascular anatomy of the spinal cord. The anterior spinal artery gives off
both peripheral and sulcal branches. The sulcal branches pass posteriorly, penetrating the anterior longitudinal fissure. On reaching the anterior white commissure, they turn alternately to 5the right and to the left to supply the gray matter and deep white matter on each side. Occasionally two adjacent vessels pass to the same side, and on other occasions, a common stem vessel bifurcates to supply both sides. Terminal branches of these vessels overlap those from vessels above and below on the same side of the cord. The peripheral branches of the anterior spinal artery pass radially and form an anastomotic network of vessels, the anterior pial arterial plexus, which supplies the anterior and lateral white matter tracts by penetrating branches. The posterior pial arterial plexus is formed as a rich anastomotic network from the paired posterior spinal arteries. Penetrating branches from this plexus supply the posterior horns and posterior funiculi. Intrinsic Blood Supply of the Spinal Cord
In contrast to the extreme interindividual variability in the extraspinal arteries that supply the spinal cord, the intrinsic blood supply of the cord itself is more consistent. The anterior spinal artery gives off central (sulcal) arteries that pass posteriorly, penetrating the anterior longitudinal fissure and supplying most of the central gray matter and the deep portion of the anterior white matter (Fig. 2-4). The number of these sulcal vessels is variable, with 5 to 8 vessels per centimeter in the cervical region, 2 to 6 vessels per centimeter in the thoracic 5,6 region, and 5 to 12 vessels per centimeter in the lumbosacral region.
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FIGURE 2-4 Intrinsic blood supply of the spinal cord. The vascular territories are depicted on the right half of the cord. The hatched lines indicate the territory supplied by the posterior spinal arterial system. The remainder is supplied by the anterior circulation, with the dark stippling indicating the area supplied exclusively by the sulcal branches of the anterior spinal artery.
The anterior spinal artery also gives off peripheral arteries that pass radially on the anterior surface of the spinal cord to supply the white matter tracts anteriorly and laterally. These arteries form the anterior pial arterial plexus, which is often poorly anastomotic with its 5 posterior counterpart. The posterior horns and posterior funiculi are supplied by penetrating vessels from the posterior pial arterial plexus. Ischemic Cord Syndromes Ischemia of the spinal cord may be produced either by the interruption of blood flow through critical feeding vessels or by aortic hypotension. The resulting neurological syndrome depends on the location of ischemic lesions along and within the spinal cord, which depends, in turn, on the vascular anatomy discussed previously. A wide variety of pathological disturbances of the aorta result in 12–15 spinal cord ischemia. They include both iatrogenic causes, and intrinsic aortic diseases, such as dissecting and 20 such as surgery and aortography, 16,17 6,18,19 inflammatory aortitis, occlusive atherosclerotic disease, nondissecting aneurysms, 21,22 6,23 infective and noninfective emboli, and congenital coarctation. Spinal cord ischemia is a 24 possibly due to aortic compression, which can occur toward rare complication of pregnancy, 25 the end of gestation. Some authors have suggested that the midthoracic region (T4 to T8) is particularly vulnerable to ischemia because of the sparseness of vessels feeding the anterior spinal artery in this 6 region and its poor anastomotic connections. Others have stressed the vulnerability of the watershed areas between the three anterior spinal arterial territories. Although the concept is theoretically appealing, documentation of the selective vulnerability of these regions is not 16,26–29 with respect to the completely convincing. For example, a review of 61 case reports distribution of ischemic myelopathies resulting from surgery on the aorta does not especially suggest that either of these areas is more vulnerable than other cord segments (Table 2-1). Even when the operation was performed on the thoracic aorta (and thus the proximal clamp was placed above the midthoracic cord feeder), the lumbosacral cord segments were the site of the ischemic damage more often than the supposedly more vulnerable midthoracic segments (Table 2-1). Similarly, the watershed area between these two arterial territories (T8 to T9) does not seem particularly vulnerable. In fact, the most frequently affected cord segment within each vascular territory in these 61 cases was centrally placed—T6 in the midthoracic territory and T12 in the lumbosacral territory—rather than at the borders, as would be anticipated with watershed vulnerability (Fig. 2-5). Click here to view this table....
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FIGURE 2-5 Upper segmental level of spinal cord involvement in 61 cases of spinal cord ischemia after surgery on the aorta (based on previously published 16,26–29 reports ).
Moreover, of the 25 cases of spinal cord infarction in an unselected autopsy series of 300 6 cases, two thirds were in cervical cord segments ; the most commonly affected segment was C6. Such a distribution would be unexpected if either the midthoracic or the watershed area was particularly vulnerable. Perhaps relating to such observations, it was recently found that, contrary to earlier reports, the anterior 9spinal artery is continuous along its length without interruption in all 51 cadavers studied. If this observation can be generalized, it may be the case that the poorly vascularized thoracic cord, which has much less gray matter than the cervical and lumbar enlargements, actually matches its sparse blood supply with its reduced 3,6,30 metabolic requirements. The site of aortic disease also plays an important role in the location of the lesion along the spinal cord. For example, distal aortic occlusion often presents with lumbosacral 6,20 whereas dissecting6,17,31,32 aneurysm of the thoracic aorta commonly presents with involvement, Similarly, cord ischemia following surgery on the infarction in the midthoracic region. abdominal aorta is essentially confined to the lumbosacral territory, whereas surgery on the thoracic aorta not infrequently involves the midthoracic segments (Table 2-1). Regardless of the pathological process affecting the aorta, however, it generally involves the suprarenal 6,33 because the important radiculomedullary arteries usually portion if there is cord ischemia originate above the origin of the renal arteries. Anterior Spinal Artery Syndrome
Ischemic injury of the spinal cord at a particular segmental level may present with a complete 6 transverse myelopathy. Within the spinal cord, however, there are certain vascular territories that can be affected selectively. In particular, the territory of the anterior spinal artery, 3,6 especially its sulcal branch, is prone to ischemic injury. This increased vulnerability probably relates to two factors. First, the anterior1,3,4,6 circulation receives a much smaller number Second, the posterior circulation is a of feeding vessels than the posterior circulation. 1,3,6 and therefore probably provides better collateral flow network of anastomotic channels than the single anterior artery, which in some6,34,35 patients is discontinuous along its length. The presumably reflects the relative constancy relative constancy of the resulting syndrome of the intrinsic vascular anatomy of the cord. As mentioned earlier, the anterior spinal artery supplies blood to much of the spinal gray matter and to the tracts in the anterior and lateral white matter. Ischemia in this arterial territory therefore gives rise to a syndrome of diminished pain and temperature sensibility with preservation of vibratory and joint position sense. Weakness (either paraparesis or quadriparesis, depending on the segments involved) occurs below the level of the lesion and
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may be associated with other evidence of upper motor neuron involvement, such as Babinski signs, spasticity, and hyperreflexia. Bowel and bladder functions are affected, owing to interruption of suprasegmental pathways. Segmental gray matter involvement may also lead to lower motor neuron deficits and depressed tendon reflexes at the level of the lesion. Thus, a lesion in the cervical cord may produce flaccid areflexic paralysis with amyotrophy in the upper extremities, spastic paralysis in the lower extremities, and dissociated sensory loss in all limbs. In contrast, a lesion in the thoracic cord typically presents with only spastic paraplegia and dissociated sensory loss in the legs. The syndrome usually comes on 36 abruptly, although occasionally it is more insidious and progressive. Motor Neuron Disease
On occasion, diseases of the aorta (e.g., dissecting aneurysms or atherosclerosis) that interfere with the blood supply to the anterior spinal artery result in more restricted cord ischemia, perhaps because of better anastomotic connections between the anterior and the posterior pial arterial plexuses in some individuals or because of greater vulnerability of the 6,14,36 The ischemic injury in these anterior horn cells with their greater metabolic activity. circumstances is limited to the gray matter supplied by the sulcal branches (Fig. 2-6). Clinical impairment is then confined to the motor system and is associated with amyotrophy. When 6 the ischemic nature of the lesion usually is apparent, but when the onset the onset is abrupt, 6,36 and especially when pyramidal signs are also present, it may mimic other is more gradual, diseases, such as amyotrophic lateral sclerosis or spinal cord tumors.
FIGURE 2-6 Area of infarction within the spinal cord over four adjacent spinal segments in a patient reported by Herrick and Mills (Herrick MK, Mills PE: Infarction of spinal cord. Two cases of selective gray matter involvement secondary to asymptomatic aortic disease. Arch Neurol 24:228, 1971). The infarction was extensive but limited to the gray matter, particularly the anterior horns. Posterior Spinal Artery Syndrome
In contrast to the anterior spinal artery syndrome, selective ischemia of the posterior circulation, characterized by prominent loss of posterior column function with relative sparing 2,14 and only occasionally reported of other functions, is rarely recognized clinically 10,20,37 For example, in a review of 27 cases 10 of nonsurgical spinal cord pathologically. ischemia, only 2 (7%) had posterior spinal artery patterns. The relative infrequency of this syndrome presumably relates to the more abundant feeding vessels and better anastomotic connections in this arterial system compared to the anterior spinal artery. Unilateral Cord Syndromes
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In some cases, the area of ischemic damage can be confined to only a small portion of the 10 spinal cord. For example, in the review cited previously, eight (29%) of the patients with nonsurgical spinal cord ischemia had unilateral syndromes involving either the anterior or posterior aspects of the spinal cord. Intermittent Claudication
Intermittent claudication (limping) refers to a condition in which a patient experiences difficulty in walking that is brought about by use of the lower extremities. Charcot initially described this syndrome in381858 and related it to occlusive peripheral vascular disease in the lower extremities. In 1906, Dejerine distinguished claudication39caused by ischemia of the leg muscles from that caused by ischemia of the spinal cord. In the latter condition, the arterial pulses in the legs tend to be preserved, pain tends to be dysesthetic or paresthetic in quality and may not occur, and neurological signs are frequently present, especially after exercise. In 1961, Blau and Logue identified another form of neurogenic claudication caused by ischemia or compression of the cauda equina and resulting from a narrowed lumbosacral canal (either 40 congenital or due to degenerative disease). This condition is similar to that produced by ischemia of the spinal cord; however, the sensory complaints tend to have a more radicular distribution, and signs of cord involvement (e.g., Babinski signs) are not present. The clinical distinction between various types of claudication, particularly between the two neurogenic varieties, is sometimes 6,41 difficult. The cauda equina variety, however, is far more Intermittent spinal cord ischemia, when it occurs, is common than the spinal cord form. often associated with intrinsic diseases of the aorta, such as coarctation or atherosclerotic 6 occlusive disease. Bony erosion through vertebral bodies from an abdominal aortic aneurysm with direct compression of the spinal nerve roots has also been reported to produce intermittent 42 neurological symptoms. The clinical details of the single reported case, however, are not sufficient to determine whether the symptoms resemble those of intermittent claudication.
Cerebral Ischemia Anatomy The aortic arch gives rise to all the major vessels that provide blood to the brain, brainstem, and cervical spinal cord (Fig. 2-7). The first major branch is the innominate (brachiocephalic) artery, which subsequently divides into the right common carotid and right subclavian arteries. The latter artery subsequently gives rise to the right vertebral artery, which ascends through the foramina of the transverse processes of the upper six cervical vertebrae to join with its counterpart on the left and form the basilar artery. The basilar artery provides blood to the posterior fossa and posterior regions of the cerebral hemispheres. The second major branch of the aortic arch is the left common carotid artery, and the third is the left subclavian artery, which, in turn, gives rise to the left vertebral artery.
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FIGURE 2-7 Vascular anatomy of the aortic arch and its branches.
Strokes and Transient Ischemic Attacks Diseases of the aortic arch, such as atherosclerosis, aneurysms, and aortitis as well as surgery on this segment of the aorta, may give rise to symptoms of6,13,18,32,43–47 cerebrovascular A young insufficiency, such as strokes or transient ischemic attacks (TIAs). woman has even been reported with a stroke secondary to an occlusion of the48aorta that was associated with the use of birth control pills and recurrent venous thromboses. Cerebral ischemia is produced either by occlusion of a major vessel or by embolization of atheromatous or other material to more distal arteries. The resulting neurological syndromes are not specific for any disease process but depend on the location and duration of the vascular occlusion. Atherosclerosis
Atherosclerosis of the aortic arch and its branches, compared with atherosclerosis at the origin of the internal carotid artery, is an infrequent cause of stroke or TIAs, probably for two reasons. First, atherosclerosis is much less common in this location than at the carotid 49 Second, the anastomotic connections between the major vessels in bifurcation (Table 2-2). 6,50 and an occlusion at their origin from the aortic arch is therefore the neck are extensive, less likely to be associated with symptoms of ischemia than a more peripheral obstruction. Click here to view this table.... Transient Emboligenic Aortoarteritis
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Transient emboligenic aortoarteritis has51been reported by Wickremasinghe and colleagues to be a cause of stroke in young patients. They described 10 patients (aged 16 to 36 years), all of whom had presented with pathologically verified thromboembolic strokes, and 3 of whom had a history of TIAs preceding the event by as much as 4 years. All these patients had both active and healed inflammatory lesions of the central elastic arteries, such as the aorta, innominate, common carotid, and proximal subclavian arteries. Active lesions were small (200 to 300 μm in diameter) and associated with a mural thrombus on the intimal surface. Healed lesions usually were associated with fibrous plaques but not with a mural thrombus. More peripheral arteries supplying the brain were normal. This condition seems to be distinct from segmental aortitis of the Takayasu type. Clinically it is an acute, intermittent disorder with an approximately equal sex incidence, whereas Takayasu's disease is more chronic and has a strong female predominance. The systemic symptoms of Takayasu's disease are absent, and occlusion of the central arteries does not occur in this condition. Subclavian (Cerebral) Steal
Disease of the aortic arch may result in occlusion of either the innominate artery or the left subclavian artery proximal to the origin of the vertebral artery. This, in turn, may result in the reversal of the usual cephalad direction of blood flow in the ipsilateral vertebral artery (Fig. 2-8), depending on individual variations in the collateral circulation and may result in ischemia 52–56 In some patients, this is particularly evident when the in the posterior cerebral circulation. metabolic52demand (and therefore the blood flow) of the affected arm is increased during exercise. If the innominate artery is blocked proximally, it may also cause a reversal of blood flow in the right common carotid artery, resulting in anterior circulation ischemia (Fig. 2-8).
FIGURE 2-8 Mechanisms producing subclavian steal syndrome in diseases of the aortic arch and its branches. A, Obstruction of the left subclavian artery at its origin, resulting in reversal of blood flow in the left vertebral artery. B, Obstruction of the right subclavian artery distal to the takeoff of the right common carotid artery, resulting in reversal of blood flow in the right vertebral artery. C, Obstruction of the innominate artery at its origin, producing reversal of blood flow in the right common carotid artery.
Killen and colleagues reviewed the clinical features of a series of patients with demonstrated reversals of arterial blood-flow in52a vertebral artery (i.e., with flow from the vertebral artery into the ipsilateral subclavian artery). The left subclavian artery was affected more than twice as often as the right subclavian and innominate arteries combined, probably as a result of the more frequent involvement of this artery by atherosclerosis (Table 2-2). Men were affected three times as often as women, probably reflecting the greater prevalence of atherosclerosis in men. Of the 87 patients in this series with symptoms that were adequately described, 75 (86%) had symptoms referable to the central nervous system (CNS). These symptoms were usually transient, lasting seconds to a few minutes, although the deficits were sometimes permanent. The neurological manifestations of steal were varied but most frequently included motor difficulties, vertigo, visual deficits, or syncope. Ischemic symptoms in the arms occurred in only a few patients, and precipitation of CNS symptoms by exercise of the arm ipsilateral to the occlusion was uncommon. Although reconstructive surgery relieved
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symptoms in most patients in this series, it was the frequent failure of surgery to correct such nonspecific symptoms that led to a more recent reassessment of the importance of 56 cerebral steal. Thus, when noninvasive techniques such as Doppler ultrasonography have been used to define the direction of blood flow in the great vessels in a large spectrum of patients with vascular disease, the majority (50% to 75%) of patients with documented subclavian steal are 53–55 When symptoms do occur, found to be asymptomatic, even when the steal is bilateral. they are suggestive of transient vertebrobasilar insufficiency in only 7 to 37 percent of 54,55 For patients with steal; the occurrence of infarcts in this vascular territory is distinctly rare. this reason, a recent review of this topic concluded that subclavian steal is a actually a marker of generalized atherosclerotic disease and that it is rarely a cause for symptoms of 56 cerebral ischemia.
Peripheral Neuropathy The peripheral nervous system is sometimes affected by aortic disease or surgery. The syndromes produced may be the presenting manifestations of aortic disease and may mimic less life-threatening conditions. Mononeuropathies Left Recurrent Laryngeal Nerve
The left recurrent laryngeal nerve descends in the neck as part of the vagus nerve and wraps around the aortic arch just distal to the ligamentum arteriosum (Fig. 2-7) before reascending in the neck to innervate all the laryngeal muscles on the left side except the cricothyroideus. It may be compressed by disease of the aortic arch, such as dissecting and 56 nondissecting aneurysms or aneurysmal dilatation proximal to a coarctation of the aorta. The resulting hoarse, low-pitched voice may be one of the earliest presenting symptoms of these conditions, although it is often overshadowed by other symptoms or57signs, such as chest pain, shortness of breath, congestive heart failure, or hypertension. Femoral Nerve
The femoral nerve arises from the nerve roots of L2, L3, and L4. It forms within the belly of the psoas muscle and then exits on its lateral aspect to innervate the quadriceps femoris, iliacus, pectineus, and sartorius muscles and the skin of the anterior thigh and medial aspect of the leg. The nerve is located considerably lateral to the aorta (Fig. 2-9) and hence is rarely involved by direct compression. It may, however, be compressed by a hematoma from a ruptured aortic aneurysm into the psoas muscle and thereby signal a life-threatening 6,58–60 condition that requires an urgent operation.
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FIGURE 2-9 Anatomy of the abdominal aorta showing its relationship to the femoral and obturator nerves, which form within the psoas muscle from branches of the L2, L3, and L4 segmental nerves.
The femoral nerve may also be injured as a consequence of aortic surgery. Boontje and Haaxma reported this complication in 3.4 percent of 1,006 abdominal aortic operations for atherosclerotic or aneurysmal disease, the left femoral nerve being involved unilaterally in two 61 thirds of the cases and jointly with the right femoral nerve in another 6 percent. The mechanism of injury in these cases was presumed to be ischemic and related to poor collateral blood supply to the intrapelvic portions of the femoral nerves, especially on the left. Obturator Nerve
The obturator nerve also forms within the belly of the psoas muscle by the union of fibers from the L2, L3, and L4 segments, but, in contrast to the femoral nerve, exits medially from this muscle (Fig. 2-9). It innervates the adductors of the leg and the skin on the medial aspect of the thigh. It too is lateral to the aorta and not usually involved by direct compression. Like the femoral nerve (and often together with it), the obturator nerve may be compressed by a 6 hematoma in the psoas muscle. Radiculopathies Nerve roots, particularly L4, L5, S1, and S2, which lie almost directly underneath the terminal aorta and iliac arteries (Fig. 2-10), may be directly compressed by an aortic aneurysm in this region. The syndromes produced are typical of radicular disease, with unilateral radiating pain 6 and a radicular pattern to the sensory and motor findings.
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FIGURE 2-10 Anatomy of the terminal branches of the aorta in relationship to
the nerve roots that subsequently join to form the sciatic nerve. Aneurysmal dilatation of the abdominal aorta often includes dilatation of these branch vessels, which can compress the nerve roots, particularly the L4, L5, S1, and S2 nerve roots, which lie directly underneath. Radiculopathies may also be produced by erosion of one or more vertebral bodies by an aortic aneurysm, with consequent compression of the nerve roots in the cauda equina or at the root exit zones. The syndrome produced is not necessarily associated with back pain; it 62–64 may result in multisegmental involvement on one side or even in paraplegia. Polyneuropathies Ischemic Monomelic Neuropathy
Ischemic monomelic neuropathy was described in detail by Wilbourn and co-workers, who reported 3 patients (and alluded to another 11) who had a distal “polyneuropathy” in one limb 65 after sudden occlusion of a major vessel. One of their patients had a saddle embolus to the distal aorta that occluded the right common iliac artery, another had a superficial femoral artery occlusion after placement of an intra-aortic balloon pump, and the third had upper-extremity involvement. The syndrome consists of a predominantly sensory neuropathy with a distal gradient. It affects all sensory modalities and is associated with a constant, deep, causalgia-like pain. The symptoms persist for months, even after revascularization or without evidence of ongoing ischemia. The results of nerve conduction studies and needle electromyography suggest an axonal neuropathy. There is no evidence of ischemic muscle injury, such as induration, muscle tenderness, or elevated serum creatine kinase levels. This condition is rare, 66 although a similar syndrome has been reported in the setting of an acute aortic dissection, and it may be that it is more prevalent than currently appreciated. Autonomic Neuropathies Anatomy
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The autonomic nerves, particularly the lower thoracic and lumbar sympathetic fibers that lie close to the aorta and its branches, may be injured by disease of or surgery on the aorta. The preganglionic efferent sympathetic finerve fibers originate in the intermediolateral cell column 67 in the spinal cord (Fig. 2-4) and exit segmentally between T1 and L2 with the ventral roots. The sympathetic fibers part company with the segmental nerves through the white rami communicantes (Fig. 2-2), which enter the paravertebral sympathetic ganglia and trunks to form bilateral sympathetic chains; these chains are situated lateral to and parallel with the vertebral column (Fig. 2-11). Some of these fibers synapse on postganglionic neurons in the ganglia of their segmental origin, whereas others ascend or descend in the trunk to different segmental levels before making such synapses. In the lumbosacral and cervical segments, where there are no white rami (i.e., below L2 or above T1), the segmental ganglia receive preganglionic contributions only from cord segments either above them (lumbosacral ganglia) 67 or below them (cervical ganglia). The postganglionic fibers rejoin the segmental nerves through the gray rami communicantes (Fig. 2-2) to provide vasomotor, sudomotor, and pilomotor innervation throughout the body.
FIGURE 2-11 Anatomy of the terminal aorta and pelvis in the male in
relationship to the sympathetic and parasympathetic nerves in the region. Some of the preganglionic fibers, in contrast, do not synapse in the paravertebral ganglia but pass through them to form splanchnic nerves, which then unite in a series of prevertebral ganglia and plexuses (many of which overlie the thoracic and abdominal aorta). These structures, in turn, provide sympathetic innervation to the viscera. The plexus that overlies the aorta in the region of its bifurcation, the superior hypogastric plexus (Fig. 2-11), is responsible (via the inferior hypogastric and other pelvic plexuses) for sympathetic innervation of the pelvic organs, including the prostate, prostatic urethra, bladder, epididymis, vas deferens, seminal vesicles, and penis in men (Fig. 2-12) and the uterus, bladder, fallopian tubes,
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vagina, and clitoris in women. This plexus is formed by the union of the third and fourth lumbar splanchnic nerves with fibers from the more rostral inferior mesenteric plexus. Its segmental contribution usually derives from T11 to L2.
FIGURE 2-12 Distribution of sympathetic (left) and parasympathetic (right) nerves to the pelvic viscera and sexual organs in the male.
The visceral afferent fibers accompany the efferent autonomic fibers and pass uninterrupted back through the trunk, ganglia, and white rami to reach their nerve cells of origin in the dorsal root. Postsympathectomy Neuralgia
Operations on the distal aorta to treat symptomatic aortic disease from atherosclerosis or other causes frequently include intentional sympathectomy as part of the effort to improve blood flow to the legs. This is usually done by dividing the sympathetic chain below the last white ramus at L2, thereby depriving the lower lumbar and sacral ganglia of their preganglionic innervation. Such an operation is often followed by a distinctive pain 68 68,69 which Raskin and associates termed postsympathectomy neuralgia. In their syndrome, experience with 96 such operations, this syndrome occurred in 35 percent of the patients. In each case, the sympathetic chain was interrupted at L3 by removal of the segmental ganglion. The pain was characterized as deep, boring, nonrhythmic, and nonradiating; it had an abrupt but delayed onset. The mean delay from sympathectomy to onset of pain was 12 days. The pain was located predominantly in the thigh, either medially or laterally, and was associated with tenderness in the area of pain. The course was always self-limited, with an average duration of 3 weeks.
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Disorders of Sexual Function
Normal male sexual function has two distinct components. The first, erection, is a response mediated predominantly through the parasympathetic nervous system by the pelvic splanchnic nerves (nervi erigentes) arising from segments S2, S3, and S4 (Fig. 2-12). Activation of 6,70 these nerves causes vasodilatation and engorgement of the penile musculature The blood supply to the penis is provided by the internal pudendal artery via and sinuses. have at the internal iliac artery (Fig. 2-10). The sympathetic nervous system, however, must 6,70 The least a modifying influence on erection because sympathectomy may disturb it. second component, ejaculation, can be divided into two phases. The first phase, expulsion of seminal fluid into the prostatic urethra, is a response mediated predominantly by the 6,70 The second phase, sympathetic nervous system through the superior hypogastric plexus. emission, is produced by the clonic contraction of penile musculature (bulbocavernosus and ischiocavernosus) innervated by somatic (pudendal) nerves (Fig. 2-12). 6,71–76
Female sexual Male sexual function may be disturbed by aortic disease or surgery. function has not been as well studied in77these circumstances, although it seems to be affected to a similar degree as in men. Because the superior hypogastric plexus lies close to the aortic bifurcation (Fig. 2-11), most preoperative and postoperative sexual disturbances occur with disease of this portion of the aorta, and most involve ejaculation (Table 2-3). The pelvic splanchnic nerves are not situated near the aorta (Fig. 2-11) and usually are not affected by aortic disease or surgery. Disturbances in erection, however, do occur, possibly because of sympathetic dysfunction, a71–76 reduction in blood flow to the internal pudendal artery To determine whether blood flow or sympathetic and penis, or cavernovenous leakage. function was more important in this regard, Ohshiro and Kosaki examined the outcome of (1) terminal aortic operations either done traditionally or designed to spare the superior 74 hypogastric plexus and (2) operations that did or did not preserve internal iliac blood-flow. Their results indicated that preservation of the hypogastric plexus appeared to be more important for maintenance of normal erection and ejaculation than was preservation of internal iliac artery blood-flow (Table 2-4). Other authors have also found that modification of operative technique to spare the superior hypogastric plexus considerably improves 6,71,73 postoperative sexual function. Click here to view this table.... Click here to view this table.... Despite the importance of operative technique in preserving sexual function, preservation of blood flow is probably also important. Thus, Nevelsteen and colleagues reported a clear relationship between the occurrence of preoperative impotence and the adequacy of blood 75 flow through the internal iliac arteries. In this study, however, no special attempt was made to improve blood flow in the internal iliac artery during surgery, so that it is unclear whether a different operative approach might have been beneficial in restoring postoperative sexual function. AORTIC DISEASES AND SURGERY Certain conditions affecting the aorta merit special consideration because of the variety of nervous system syndromes that each can produce.
Aortitis Injury to the aorta by a variety of infectious, toxic, allergic, or idiopathic causes may produce 18 similar inflammatory pathological changes in the elastic media (Table 2-5). Such aortic damage may lead to neurological syndromes either primarily through direct involvement of important branch arteries by the pathological process or secondarily through the development of aneurysms, aortic stenosis, or atherosclerosis. The neurological syndromes produced either primarily or secondarily by aortitis depend on both the nature and the location of the resulting aortic lesion. Click here to view this table.... Syphilitic Aortitis 18,78
During the prepenicillin era, syphilis was a common cause of aortitis, although by the 78 1950s, its occurrence had markedly declined. A report in 1958 on the relative occurrence of atherosclerotic and syphilitic thoracic aortic aneurysms showed cases of syphilis 79 outnumbering atherosclerosis by a ratio of 1.3:1.0. A similar report published in 1982 gave
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this ratio as 0.13:1.0. The pathological process in syphilitic aortitis is almost always in the 19,78 in contrast to the distribution of atherosclerosis, which is more prevalent in thoracic aorta, the abdominal aorta (Table 2-2). The aortitis78is accompanied by aneurysmal dilatation of the aorta in approximately 40 percent of cases. 6 Rarely, it presents with multiple arterial occlusions and mimics Takayasu's arteritis, although patients are generally older than those with Takayasu's arteritis and are usually men. Takayasu's Arteritis Takayasu's arteritis is an idiopathic inflammatory condition affecting the large arteries, 6,45,80,81 The pathogenesis seems to involve particularly the aorta and its branches. cell-mediated autoimmunity, although the responsible antigen is unknown. The onset of disease is typically between the ages of 15 and 30 years, and the condition seems most 6 prevalent in Asian and Hispanic populations. More than 85 percent of affected individuals are women. In the early (prepulseless) phase, the disease may be characterized by systemic symptoms such as fever, night sweats, weight loss, myalgia, arthralgia, arthritis, and chest pain. In some patients, however, the systemic symptoms are either inconspicuous or absent. The later (pulseless) phase of the disease is characterized by occlusion of the major vessels of the aortic arch, producing symptoms such as Takayasu's retinopathy, hypertension (secondary to renal artery stenosis, coarctation, or both), aortic regurgitation, and aortic aneurysms. Symptoms of cerebral ischemia can occur; however, they are typically reported in 6,45,81 Nevertheless, a report from South Africa on 272 patients who were only a few patients. diagnosed with Takayasu's arteritis, based on the criteria of the American College of Rheumatology, found that 20 percent of the cohort had symptoms of cerebrovascular 81 of this cohort experienced disease, including TIAs and stroke. In addition, 32 percent 81 Seizures and headaches have also intermittent claudication of either upper or lower limbs. 6 been reported but are uncommon. Involvement along the aorta is typically diffuse, although some patients (perhaps as many as 20%) present with symptoms related to more restricted 18,81 The disorder is discussed further in Chapter 29. aortic involvement. Giant Cell Arteritis Giant cell arteritis (GCA) seems to be a particularly important cause of aortitis in the 6,18,19,82 ; although it typically affects medium-sized vessels, as many as one fourth or elderly 83 more of affected individuals have large-artery involvement. For example, in18one series of eight consecutive patients with aortitis, GCA seemed to be its basis in many. Thus, four had definite GCA diagnosed based on their age at onset, the new onset of headaches, and an elevation in erythrocyte sedimentation rate. However, all these patients were older than 57 years, each of the eight had an elevation of some serum inflammatory marker (e.g., increase in Creactive protein levels, erythrocyte6 sedimentation rate, or fibrinogen levels), and three had symptoms of polymyalgia rheumatica. In another series of 45 patients undergoing aortic resection and who had microscopic evidence of active noninfectious aortitis, the majority had either unclassifiable aortitis (47%) or GCA (31%), two entities that were histopathologically 82 indistinguishable. The presenting symptoms in patients with GCA or unclassified aortitis are generally nonspecific and include exhaustion, night sweats, weight loss, chest and back pain, 19,82 Typically, all segments headache, fevers of unknown origin, TIAs, and arm claudication. of the aorta (ascending aorta, arch, and descending aorta) are involved in the inflammatory 6,18,19 Between 10 and 20 percent of process, although involvement can be more restricted. patients with unclassified aortitis or GCA will82,83 subsequently develop either dissecting or, more commonly, nondissecting aortic aneurysms.
Aortic Aneurysms Nondissecting Aneurysms Nondissecting aortic aneurysms can be caused by any pathological process that weakens the 6,15,18,53,60,84,85 In the past, arterial wall, such as inflammation, infection, or atherosclerosis. 86 syphilis was an important cause, but at present, almost all these aneurysms are caused by atherosclerosis. As a result, the distribution of aortic aneurysms essentially parallels the distribution of atherosclerosis within the aorta, with most occurring in the abdominal aorta (Tables 2-2 and 2-6). In a study from Sweden, it was found that the incidence of ruptured abdominal aortic aneurysms in men (but not women) had increased by more than 100 87 percent between 1971 to 1986 and 2000 to 2004. The reason for this increased incidence is unclear, and it is unknown whether a similar increase has occurred in other parts of the world. The prognosis of untreated aneurysms is grave, with 80 percent of patients dying of rupture 84 within 12 months of the onset of symptoms. Disturbances of neurological function in aortic
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aneurysms are uncommon, but when they occur, they are variable and depend in part on the location and extent of the lesion. Abdominal aneurysms may result in sexual dysfunction, 6,58–62,71–77 or, rarely, spinal cord ischemic syndromes, including compressive neuropathies, 88 ; descending thoracic intermittent claudication, asymmetric paraparesis, and paraplegia 16 arch aneurysms may result in aneurysms may produce spinal cord ischemia, and aortic6,57 Most commonly, neurological cerebral ischemia or recurrent laryngeal nerve dysfunction. symptoms are produced by either rupture or direct compression. Even when aneurysms result in paraplegia, the neurological deficit is often caused by bony erosion through the vertebral bodies and direct compression of the spinal cord or cauda equina rather than by 64,89 ischemia. Click here to view this table.... Dissecting Aortic Aneurysms Dissecting aortic aneurysms, in contrast to nondissecting aortic aneurysms, predominantly involve the thoracic aorta, either at the beginning of the6,17,32,57,66,89,90 ascending segment (type A) or Their etiology has not immediately distal to the left subclavian artery (type B). been established. Atherosclerosis is probably not a major factor because atherosclerosis is seldom found in the region of the intimal tear because the distribution of these aneurysms along the aorta is unlike that of atherosclerosis and because atherosclerosis is only 90–92 Nevertheless, hypertension probably is a factor as it is present in infrequently present. 91,92 Moreover, the large majority of patients with either type A or type B dissections. dissecting aortic aneurysms have been associated with cystic medial necrosis, a degenerative condition focally affecting the arterial media, which may itself be related to hypertension. This condition is increased in patients with Marfan's syndrome, as are dissecting aneurysms. Most aneurysms, however, do not occur in patients with Marfan's syndrome89,91,92 or other identifiable collagen disorders, and the pathophysiology remains Neurological involvement from dissecting aneurysms (due to the cutoff of unknown. important arteries by the dissection or by embolization) is well described but uncommon. It 91,92 and it usually involves either occurs more frequently with type A than type B dissections, spinal or cerebral ischemia. Neurological involvement may also occur during surgery to repair 57 the aneurysm. Thus, in one large series of 527 patients, preoperative stroke occurred in 4 percent, and paraparesis occurred in another 2 percent. Patients with aortic dissection usually present with acute chest or back pain, which generally leads to the proper 57,91,92 On6,66 occasion, however, pain is absent, and the neurological syndrome is the diagnosis. Moreover, the neurological deficit produced by the dissecting presenting feature. aneurysm is sometimes only transient, lasting for several hours, and thereby mimicking other 6 transient disturbances of neurological function. Traumatic Aortic Aneurysm Brutal deceleration injuries to the chest, especially from motor vehicle accidents, may result in traumatic rupture of the thoracic aorta, often just distal to the left subclavian artery. Many of 93–96 Still others these patients die immediately, but some present with an acute paraplegia. have a chronic aortic aneurysm that may present years later with acute spinal cord 93 94 ischemia or other neurological symptoms.
Coarctation of the Aorta 97
Coarctation of the aorta, a relatively common congenital condition, typically results in constriction of the thoracic aorta just distal to the origin of the left subclavian artery. Less commonly, it occurs as part of Takayasu's arteritis, and this condition should be suspected if 6,81 It may also follow radiation exposure during the location of the coarctation is atypical. 6,98 infancy ; in these cases, the pathological process is focal and limited to the segment of aorta that was in the field of irradiation. Coarctation can result in a variety of neurological 6,23,97,98 Cerebral infarcts probably result from embolization of symptoms (Table 2-7). 6 thrombotic material in the dilated aorta proximal to the obstruction. Click here to view this table.... Subarachnoid hemorrhage from ruptured saccular aneurysms can occur with coarctation. In the general population, aneurysmal hemorrhage has an annual incidence of approximately 8 6,99 6,99 and rarely occurs before the age of 20 years. Accordingly, the reported97 per 100,000 occurrence of ruptured aneurysms in 2.5 percent of patients with coarctation of the aorta suggests an association of these two disorders,6 although the coincidental occurrence of the two conditions cannot be completely excluded.
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Headache is a common accompaniment of coarctation, perhaps as a result of secondary hypertension, but, again, the incidental occurrence of two unrelated conditions cannot be excluded. Episodic loss of consciousness may also occur in patients with coarctation of the aorta. It6,97 may result either from syncope due to associated cardiac abnormalities or from seizures. It is unclear, however, whether seizures unrelated to cerebrovascular disease are more 97 prevalent in these patients than in the general population. Neurogenic intermittent claudication can result from aortic coarctation. In patients with coarctation of the aorta, blood flow to the legs is often provided by collateral connections between the spinal arteries and the distal aorta. In these situations, the blood 6,52 flow through the and the radiculomedullary and intercostal arteries distal to the obstruction is reversed, exercise-related spinal ischemia may be related to “steal” by the increased metabolic 6 demands (and thus increased blood flow) of the legs rather than aortic hypotension distal to the coarctation (Fig. 2-13). These collaterals are sometimes so extensive that they cause spinal cord compression and mimic (clinically and radiologically) vascular malformations of 6,14,98 the spinal cord.
FIGURE 2-13 Mechanism of steal in coarctation of the aorta. Obstruction of the
aorta at the isthmus causes dilatation of the anterior spinal artery and reversal of blood flow in anterior radiculomedullary arteries distal to the obstruction. In this circumstance, the blood flow to the lower extremities is provided by these (and other) collaterals, and use of the lower extremities may cause shunting of blood from the spinal circulation to the legs, which, in turn, sometimes results in spinal cord ischemia.
Surgery and Other Procedures Aortic Surgery
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As with diseases of the aorta, the risks of aortic surgery depend in part on the site of operation. Thus, operations on the aortic arch may produce cerebral ischemia either by intraoperative occlusion of major6,13,46,47 vessels or by embolization of material such as calcified Operations on the suprarenal aorta may result in plaque loosened13during surgery. on the distal aorta may result in sexual dysfunction or spinal ischemia, whereas operations 6,58–62,71–77 ischemia of the femoral nerve. The major complication of all aortic operations, however, is intraoperative spinal cord ischemia with resultant paraplegia or paraparesis. The occurrence of this complication varies with the location of the surgery and the nature of the pathological process affecting the aorta (Table 2-8). Thus, operations on dissecting or nondissecting aortic aneurysms that are entirely abdominal are associated with a lower incidence of this complication than operations 6,26,100–104 Surgery on aneurysms involving 100 the on aneurysms confined to the thoracic aorta. entire abdominal and thoracic aorta carries the highest risk of producing cord ischemia. Operations on the distal aorta for occlusive disease only rarely result in spinal ischemia, 26,33 This variability presumably occurs especially when confined to the infrarenal portion. because important feeding arteries to the spinal circulation are more likely to be ligated during surgery, included within the segment of the aorta that is cross-clamped, or subjected to distal hypotension when the aortic lesion is above the level of origin of the renal arteries. Click here to view this table.... Operations on the thoracic aorta for coarctation are much less frequently complicated by 23 spinal ischemia than thoracic operations done for other reasons. There are probably at least two reasons for this difference. First, the former patients are younger, and the extent of overall arterial disease is therefore less. Second, as mentioned earlier, 6,105 the flow in the so obstruction of radiculomedullary vessels below the coarctation is frequently reversed, blood flow in them (either by ligation or cross-clamping the aorta above and below their origin) may actually result in an increased blood supply to the spinal cord. Aortography and Other Procedures on the Aorta 16
6,106
Aortography may be associated with either spinal or cerebral ischemia, depending on the portion of the aorta visualized. This complication, however, is distinctly rare (Table 2-8). Paraplegia may also occur during intra-aortic balloon assistance after myocardial 6,107 revascularization. Intraoperative Adjuncts to Avoid Spinal Cord Ischemia Several adjuncts are commonly used during surgery in an attempt to avoid spinal cord injury. They include the use of deep hypothermia and circulatory arrest in addition to thiopental anesthesia and intraoperative corticosteroids, all of which are thought 57 to reduce the metabolic requirements of the cord or otherwise enhance tolerance to ischemia. In addition, many authors have reported that minimization of cross-clamp time results in a lower incidence of spinal ischemia. Other adjunctive methods such as the reattachment of intercostal arteries, the use of shunts to maintain distal perfusion pressure, and the use of cerebrospinal fluid drainage have not 7,46,49,108–114 although the more proved consistently effective at preventing cord ischemia, 7,49,113,114 Part of recent experience with such adjunctive techniques has been quite favorable. the difficulty with these procedures may relate to the extreme variability of the blood supply to the spinal cord. For example, if a crucial spinal artery leaves the aorta within the cross-clamped section, the preservation of distal blood-flow is irrelevant. Furthermore, because the important intercostal arteries are few and unpredictably situated, the random reattachment of a few intercostal arteries may be fruitless. There has been considerable interest in the use of somatosensory evoked potentials (SEPs) and motor94,115–125 evoked potentials (MEPs) for assessing spinal cord function during operations on The combined use of SEPs and MEPs may ultimately prove better than the aorta. 124 and, indeed, the most recent reports with both techniques have either technique alone, 7,46,123–125 An approach that seems particularly valuable is the use of been encouraging. intraoperative MEPs or SEPs to identify those vessels that perfuse the spinal cord and therefore need reattachment, should not be sacrificed, or should not be included within the 7,121,124 Another approach that has been reported to be useful is the use of aortic cross-clamp. intraoperative MEPs to monitor patients and to quickly increase both the123 distal aortic pressure and the mean arterial pressure in response to a drop in MEP amplitude. Nevertheless, although these reports are quite encouraging, the best method of monitoring intraoperative
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spinal cord function and how best to use the information to alter the operative technique so that postoperative spinal cord function is maintained are still being determined. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 3 Neurological Complications of Cardiac Surgery JOHN R. HOTSON •
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EXTRACORPOREAL CIRCULATION Technique Consequences During “Normal” Convalescence NEUROLOGICAL SEQUELAE OF CARDIAC SURGERY Brain Disorders Peripheral Nerve Disorders Neuro-ophthalmological Disorders NEUROCOGNITIVE DECLINE RISK FACTORS FOR STROKE PREVENTION OF NEUROLOGICAL COMPLICATIONS CARDIAC TRANSPLANTATION
Neurological complications are a potential consequence of cardiac surgery that can nullify or 1–8 limit any benefits of such surgery. The probability of these complications increases as coronary artery bypass graft surgery is used for treating ischemic heart disease in older patients,9 in patients with multiple comorbid conditions, and as heart transplantation programs expand. In spite of the increased use of catheter-based coronary revascularization, more than 400,000 people per year have coronary artery bypass graft surgery in the United 10 adverse cerebral outcome States. A substantial number of patients have a postoperative 6,11 Many more patients may develop such as stroke or hypoxic-ischemic encephalopathy. 8,12 Prevention of perioperative neurological loss of cognitive performance after heart surgery. complications remains an important medical problem. EXTRACORPOREAL CIRCULATION Cardiopulmonary bypass was first used successfully in cardiac surgery in 1953 and was the 13 pivotal development that led to modern cardiac surgery. Its early use in humans resulted in frequent complications, which restricted its employment to seriously ill patients with progressive heart failure. Although the safety of extracorporeal circulation has increased, it remains a potential cause of neurological complications independent of other heart surgery procedures.
Technique
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Open heart surgery with cardiopulmonary bypass begins with exposure of the heart, usually by a median13sternotomy, followed by cannulation of the ascending aorta and vena cava or material in a right atrium. Insertion of the aortic cannula can dislodge atheromatous 14 severely diseased aorta, thereby leading to cerebral embolization. In addition, this procedure can produce rotational torsion or compression of the brachial plexus, with 15,16 subsequent injury. Extracorporeal circulation is used in association with systemic heparinization, hypothermia, 13 and hemodilution. Anticoagulation is used to prevent clot formation when blood is exposed to the nonendothelial surfaces of the bypass pump oxygenator and microaggregation filtration system. Core hypothermia is often used in combination with selective cooling of the heart, or cold cardioplegia, in order to protect the heart, brain, and other vital organs from ischemic damage. Infusion of ice slush solutions into the pericardium is one technique for inducing 17–19 Normothermic cold cardioplegia, but it occasionally produces focal phrenic nerve injuries. cardiopulmonary bypass may also be used in patients with few risk factors for stroke because 20,21 it provides better hemodynamic function and decreases cardiopulmonary bypass time. Normovolemic hemodilution is used in part to conserve blood loss. It also compensates for the progressive hemoconcentration,13decrease in plasma vol ume, and reduced blood flow that is associated with hypothermia. During cardiac surgery with extracorporeal circulation, the ascending aorta is routinely cross-clamped; during valve-replacement surgery, congenital heart disease repair, or left ventricular aneurysm resection, the cardiac chambers are entered. These procedures may disrupt diseased tissue and produce emboli. Arterial systolic, diastolic, and mean pressure, pump pressure and flow rate, and central venous pressure are monitored during cardiopulmonary bypass. Mean arterial pressure13is usually maintained above 40 to 50 mmHg by vasodilators, pressors, or volume expanders.
Consequences During “Normal” Convalescence Extracorporeal circulation has predictable effects that result in a postperfusion syndrome and 13,22 This syndrome includes systemic inflammatory response during “normal” convalescence. the following conditions. Reduced Clotting Factors. Exposure of blood to an abnormal environment during cardiopulmonary bypass leads to consumption of platelets and coagulation factors. Platelets adhere to the unphysiological surface of the oxygenators and filtration system of the bypass pump. This clumping of platelets not only predisposes to platelet emboli but also can reduce the number of circulating platelets. The exposure to foreign surfaces also causes release and depletion of granule-stored aggregating proteins in 13,22 surviving platelets. Therefore, the remaining platelets have decreased adhesiveness. Coagulation factors are also consumed during cardiopulmonary bypass. A variety of carrier proteins and lipoproteins are denatured when blood passes through the bypass pump oxygenator. Even with adequate heparin levels, these damaged proteins can initiate a 22,23 The clinical significance of cascade in several coagulation and inflammatory systems. these hematological changes is usually minor. They may contribute, however, to the 24 intracranial hemorrhages that are occasionally observed after open heart surgery. Cardiovascular Response. During the early postoperative period, the degree of peripheral 13 vasoconstriction provides a clinical estimate of cardiac output. Transient atrial fibrillation, 25,26 A which carries a risk of cardiac emboli, is common during the convalescent period. metabolic acidosis is also common during the 2 hours immediately after operation and reflects a washout of lactic acid from regions of poor perfusion during extracorporeal circulation. Persistence of a metabolic acidosis may indicate inadequate tissue perfusion 13 secondary to low cardiac output. Red Blood Cell Fragmentation. Exposure of blood to nonendothelial surfaces during bypass surgery causes a breakdown of13red blood cells, with subsequent anemia, hemoglobinemia, and hemoglobinuria. Mild Mental Confusion. Transient mild disturbances of orientation, memory, and level of alertness that resolve13within the first few days after open heart surgery with cardiopulmonary bypass are frequent. Whether the changes in mentation are totally reversible events that accompany most major operations or whether they indicate long-term sequelae is an area of 8,11 sustained interest.
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Brain Swelling. Brain swelling is present when magnetic resonance imaging (MRI) is obtained immediately following coronary artery bypass surgery. When brain imaging studies are repeated 2 to 3 weeks after the surgery, the brain swelling has remitted. There are no 27 clinical findings associated with the brain swelling, and its cause is unknown. These expected consequences of cardiopulmonary bypass are functionally reversible and compensated for during convalescence. Firm evidence that extracorporeal circulation itself permanently harms the brain is lacking. Cardiopulmonary bypass, however, does create numerous potential hazards that, if augmented by procedural mishap, may lead to permanent injury of the central nervous system (CNS). Cardiac operations using extracorporeal circulation carry the risks of embolus formation (from platelets, fibrin, tissue or surgical 13,22 For these reasons, debris, air, or fat), cerebral hypoperfusion, and even hemorrhage. there is 28 interest in performing coronary artery surgery without the use of cardiopulmonary bypass. This off-pump technique can produce excellent cardiac outcomes. It is associated with fewer cerebral microemboli and29,30 less short-term neurocognitive decline when compared The short-term difference in cognitive performance, to on-pump coronary artery surgery. however, is limited, has not been consistently found across studies, and is not statistically 28,30,31 The off-pump technique does not lower the overall stroke rate, but significant at 1 year. may decrease stroke in a high-risk subgroup of patients with a severely atheromatous 32 aorta. Comparisons of performing coronary artery bypass grafting off-pump and28with cardiopulmonary bypass have not proven the overall superiority of either method. NEUROLOGICAL SEQUELAE OF CARDIAC SURGERY Diffuse or multifocal anoxic-ischemic damage, focal cerebral infarction, and brachial plexus injuries remain the main causes of permanent, disabling neurological complications after 1,6,15,33 Therefore, the common, obvious postoperative symptoms include cardiac surgery. diffuse impairment of cognition and level of consciousness, focal deficits from stroke, and isolated peripheral weakness and sensory loss in one arm and hand.
Brain Disorders Stroke, encephalopathy, coma, and seizures are the major brain disorders complicating 6,34 Stroke is reported in prospective studies to occur in 1 percent to more cardiac surgery. than 5 percent of patients following coronary artery bypass surgery, and the incidence 6,21,35–37 Stroke after cardiac increases in association with preoperative stroke risk factors. surgery increases hospital mortality approximately five- to sixfold, prolongs intensive care, 38,39 and typically requires inpatient rehabilitation or nursing home placement. 39The majority of stroke patients who survive to hospital discharge are substantially disabled. Most strokes occur in the first 2 to 3 days after coronary artery bypass surgery, but they may continue with 8,39,40 Stroke occurs more increased frequency during the first 2 postoperative weeks. frequently when valvular heart surgery is combined with coronary artery bypass graft 41,42 This increase is due to the additional risk of cerebral macroemboli with operations. operations that require opening a heart chamber and removal or repair of diseased mitral or aortic valves. Imaging and clinical studies, including cerebral arteriograms, suggest that the main cause of cerebral infarction with either coronary artery bypass surgery or valvular heart 40,43 Diffusion-weighted brain MRI is more surgery is embolization and not hypoperfusion. sensitive that computed tomography (CT) for detecting acute stroke after heart surgery and, when combined with measurements of the apparent diffusion coefficient, distinguishes acute 44 from chronic ischemic lesions. Intra-arterial thrombolysis for stroke occurring 1 to 14 days after heart surgery has been reported as a potential treatment option that merits further 45–47 study. Intracranial hemorrhage is an infrequent cause of stroke, but its rapid 40,48,49 identification is Hematomas may important so that surgical evacuation can be undertaken if necessary. be located in the brain parenchyma or in subdural or epidural spaces. Intracranial hemorrhage may be related to reduced platelet adhesion and coagulation factors during cardiopulmonary bypass. The global encephalopathy that can follow heart surgery varies from coma to confusion or delirium with impaired cognition. Stupor or coma after uncomplicated surgery is infrequent, 34 occurring in less than 1 percent of patients. It may be due to global anoxia-ischemia, massive stroke, or multiple brain infarctions. Postoperative hyponatremic encephalopathy is important to recognize and reverse because it can lead to brain damage and death, 50 Additional, rarely reported causes of encephalopathy or particularly in younger women. 51 52 a hypernatremic hyperosmolar state, and acute obstructive coma include hypoglycemia, 53 hydrocephalus.
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When anoxia-ischemia is the cause of coma, myoclonus, at times accompanied by seizures, may be prominent. Recurrent postanoxic myoclonus and seizures are often poorly responsive to anticonvulsant therapy. The outcome in these comatose patients is usually extremely poor, 54 with only a rare patient making a meaningful recovery. Clinical assessment55,56 identifies confusion or delirium after cardiac surgery in greater than 8 Its prevalence is even greater in patients57older than 65 to 70 years percent of patients. and in patients with known preexisting cerebrovascular disease. Confusion and delirium after cardiac surgery increase postoperative morbidity and prolong postoperative hospitalization. These encephalopathic patients may be slow to emerge from anesthesia, are often agitated, and have fluctuating moderate to severe impairment of cognitive function. Hallucinations may be present, and occasionally there are bilateral Babinski signs. Improvement often occurs during the first postoperative week. In comparison, patients who are matched for age and clinical condition but who have major surgery for peripheral vascular disease without 3 cardiopulmonary bypass rarely develop such transient impairment of intellectual function. Some confused patients have multiple, acute, small44ischemic brain lesions detected with diffusion-weighted MRI, suggesting multiple emboli. However, in many patients, the cause of confusion or delirium cannot be clinically defined. Coronary artery bypass grafting without the use of cardiopulmonary bypass results in less55frequent postoperative delirium, whereas prolonged operating time increases its frequency. Therefore, exposure to cardiopulmonary bypass appears to be a contributing factor to a transient encephalopathic state in otherwise uncomplicated cardiac surgery. Acute psychosis after open heart surgery has been attributed to a situational psychiatric 58 reaction if the level of alertness and memory remain intact. When the latter processes are also impaired, the psychotic behavior has been called an organic delirium. In patients undergoing cardiac surgery, this differentiation may be incorrect. When the psychotic response has cleared and neuropsychological testing is performed, both groups have similar, 59 multiple cognitive impairments compared to patients without neurobehavioral complications. The diagnosis of an intensive care unit psychosis is usually restricted to reactions that begin 2 to 5 days after surgery, are associated with preserved memory and alertness, and rapidly resolve after treatment with neuroleptic agents or discharge from the intensive care unit. Psychotic reactions that occur during the first 48 postoperative hours in a previously stable patient probably represent a behavioral response to an anoxic-ischemic insult associated with 58,60 cardiac surgery and cardiopulmonary bypass. Seizures may accompany coma, encephalopathy, or delirium, or they may occur 6,34 They occur in fewer than 1 percent of patients, usually independently after cardiac surgery. early in the postoperative period and often within the first 24 hours. Tonic-clonic or partial motor seizures are clinically apparent, but partial complex seizures in an encephalopathic patient may be difficult to recognize clinically. Choreoathetosis after heart surgery, a complication that occurs mainly in children, sometimes raises the question of a seizure 61 disorder. Nonconvulsive status epilepticus may occur with stroke complicating cardiac surgery and will then contribute to a prolonged confusional state that is treatable with 62 anticonvulsant drugs. Therefore, the electroencephalographic evaluation of patients with a persistent encephalopathy may be valuable.
Peripheral Nerve Disorders The brachial plexus and phrenic nerves are the most frequent peripheral nerves injured during cardiac surgery. A polyneuropathy may also occur under certain circumstances. A persistent brachial plexopathy after median sternotomy has been reported to occur in more 1,15,16 Transient and minor brachial plexus injuries may be even than 5 percent of patients. 63 more common. Most frequently, the lower trunk of the brachial plexus is injured. Therefore, the intrinsic hand muscles are often most severely impaired, and the triceps reflex may be decreased in the affected arm. Sensory loss is sometimes present in the affected hand. Pain is prominent in some patients, and a minority have Horner's syndrome. Injuries of the upper brachial plexus can also occur but are less frequent. Although not life-threatening and usually reversible in 1 to 3 months, a brachial plexus injury may produce permanent disability, particularly if it affects the dominant hand or produces intractable causalgia. The plexus injuries may be due to torsional traction or compression during the open heart 16,63 Intraoperative electrophysiological monitoring of upper extremity sensory nerve surgery. conduction reveals significant disturbances during sternal retraction in the majority of patients. This intraoperative monitoring technique can detect functional disorders of the
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brachial plexus during surgery, predict postoperative nerve injury, and identify intraoperative 64,65 Brachial plexus injuries may be reduced factors that predispose to brachial plexus injury. by minimizing the opening of the sternal retractor, placing the retractor in the most caudal 16 location, and avoiding asymmetric traction. Unilateral phrenic nerve injuries with hemidiaphragmatic paralysis occur in at least 10 percent 18,66,67 The location of the phrenic nerve adjacent to the of patients during open heart surgery. pericardium makes it particularly vulnerable to injury from hypothermia associated with topical cold cardioplegia, as well as injury from manipulation and ischemia. Unilateral phrenic nerve injury causes atelectasis and inspiratory muscle weakness, predisposing to postoperative respiratory complications. Phrenic nerve injury in patients with preoperative chronic obstructive pulmonary disease adds particularly to postoperative morbidity. In most patients, however, morbidity is low. Some recovery is usually evident by about 6 months after injury, but there may be a more protracted course consistent with axonal injury and regeneration. Severe, bilateral phrenic nerve injury is a rare complication of heart surgery and leads to 68 prolonged mechanical respiration. Mononeuropathies resulting from compression or trauma during surgery may involve the accessory, facial, lateral femoral15,69–72 cutaneous, peroneal, radial, recurrent laryngeal, saphenous, A recurrent laryngeal nerve injury with vocal cord long thoracic, and ulnar nerves. 15 Ischemia to the paralysis and a persistent peroneal neuropathy can be disabling. 73 cochlea-auditory nerve can result in severe hearing loss. Most compressive mononeuropathies, however, are transient. This reversibility, usually within 4 to 8 weeks, may reflect the focal selective injury to myelin, with relative sparing of nerve axons, which occurs 74 with compression neuropathies. Awareness of possible intraoperative compression sites helps to prevent these complications. Diffuse paralysis as a result of the Guillain–Barré syndrome may follow otherwise 75 uncomplicated cardiac surgery as well as other surgical procedures. Persistent paralysis also occurs after cardiac surgery in critically ill patients 76 who have renal failure and require days of vecuronium to facilitate mechanical respiration. If heart surgery is complicated by sepsis and multiorgan failure lasting for more than a week, a “critical illness” polyneuropathy and myopathy may develop, with difficulty in weaning from a respirator, distal weakness, and 77 reduced tendon reflexes.
Neuro-ophthalmological Disorders Visual disorders from cardiac surgery are frequent but usually asymptomatic and reversible. Retinal disorders include multifocal areas of retinal nonperfusion in almost all patients, cotton wool spots consistent with retinal infarctions in 10 to 25 percent of patients, and visualization of retinal emboli in fewer individuals. These retinal disorders are infrequently associated with 5,78 reduced visual acuity. An anterior ischemic optic neuropathy is an uncommon, disabling complication of heart surgery. It produces infarction of the optic nerve head, optic disc swelling with a painless and usually permanent decrease in visual acuity. An anterior ischemic optic neuropathy may 78 produce a monocular altitudinal, arcuate, or central scotoma. A retrobulbar or posterior 79 ischemic optic neuropathy due to infarct of the intraorbital nerve is even less common. It produces 80 acute blindness without optic disc swelling accompanied by impaired pupillary posterior ischemic optic neuropathies may produce reactions. Both the anterior and 79 unilateral or bilateral blindness. Homonymous visual field defects occur with focal ischemic injury of the visual cortex or retrochiasmal visual pathways. An occasional patient is found to be cortically blind after heart surgery, usually from bilateral ischemia of the occipital cortex. Retinal and pupillary examination are both normal in patients with cortical blindness. Some of these patients deny 5,78 any visual impairment. At least partial recovery from cortical blindness is possible. Horner's syndrome occurs in association with injuries to the lower brachial plexus and may result from concomitant injury to the preganglionic sympathetic fibers that travel through the 5 eighth cervical and first thoracic ventral roots. It also develops in the postoperative period in81 hypertensive and diabetic patients, presumably due to ischemic injury to sympathetic fibers. Gaze deviations, gaze paralysis, and dysconjugate gaze may occur in postoperative patients who have a brainstem or large hemispheric stroke involving eye movement systems. Intermittent gaze deviation with nystagmoid movements raises concerns about postoperative 82 focal seizures.
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Pituitary apoplexy resulting from acute hemorrhage or infarction of a pituitary adenoma is a 83 rare complication of cardiopulmonary bypass. The pituitary tumor is usually not recognized prior to surgery and is particularly susceptible to the ischemic and hemorrhagic risks associated with cardiopulmonary bypass. After heart surgery, patients awake with headache, ptosis, ophthalmoplegia, and visual impairment from compression of the adjacent cranial nerves and the anterior visual pathways. Transsphenoidal surgical decompression has been used safely in some patients. Infarction of a normal pituitary during coronary84artery bypass surgery also occurs, may initially be silent, and leads to panhypopituitarism. Visual hallucinations solely on eye closure have been reported following cardiovascular 85,86 Patients are otherwise fully alert and lucid and can stop the hallucinations simply surgery. by opening their eyes. Atropine or lidocaine toxicity and complex partial seizures have been associated with such hallucinations. NEUROCOGNITIVE DECLINE Neuropsychological studies of cognitive function before and after cardiac surgery have identified both a transient early and a subsequent late decline in cognitive function occurring 7,87–91 The early postoperative changes in cognition have been shown by after heart surgery. comparing repetitive neuropsychological test results in patients undergoing coronary artery surgery with extracorporeal circulation to nonsurgical control subjects. Performance declines on tests of attention, visuospatial ability, and memory 3 days after coronary artery bypass surgery compared to preoperative testing. A similar decline does not occur in age- and gender-matched nonsurgical control subjects. The impaired neurocognitive performance, 87,89–92 Although numerous however, typically returns to the preoperative level within weeks. factors may contribute to this transient postoperative cognitive impairment, direct evidence of 7 a specific etiology in individual patients is often lacking. A late decline in cognitive function occurs in the interval from 1 to 5 years after coronary 88,90,93 The cause of this late92decline is unproven, in part because few artery bypass surgery. of the longitudinal studies included control groups. One postulated etiology is that diffuse brain microemboli associated with extracorporeal circulation injure a neuronal reserve that is 94,95 Transcranial Doppler needed to compensate for brain aging and to prevent dementia. ultrasonography of the middle cerebral artery and carotid artery can detect microemboli during heart surgery. During cardiopulmonary bypass, there is a continuous dissemination of 78,94,96–98 The brain microemboli producing microvascular occlusions followed by reperfusion. washout of brain emboli 99 and reperfusion may be impaired if there is concurrent systemic or localized hypoperfusion. Patients with a high total microemboli count during heart surgery have a significantly higher frequency of neuropsychological test deficits than patients with low microemboli counts. Patients with long cardiopulmonary bypass durations also have a higher total microemboli 100–102 If extracorporeal circulation count and higher frequency of neuropsychological decline. does lead to a late decline in cognitive performance, then patients with off-pump coronary surgery on the beating heart should have less of a late decline. This comparative study is 103 pending. Evidence exists against the belief that disseminated brain microemboli from the extracorporeal circulation account for the late cognitive decline. Cognitive function 5 years after patients are randomly assigned to undergo either coronary surgery or angioplasty is 104 similar. Cognitive performance at 3 years is also similar in patients receiving on-pump coronary103 artery bypass surgery and a nonsurgical control group with coronary artery disease. One study with a small number of patients in which individuals with preexisting neurological or psychiatric diseases or impaired cognition were excluded showed no late decline in cognitive performance after 3 to 5 years. These patients also had very good 105 vascular risk factor control over the interval of neuropsychological testing. A case-control study found a similar incidence of coronary artery bypass surgery in control subjects and patients with dementia, including a subgroup with a diagnosis of Alzheimer's disease. 106 Coronary artery bypass surgery does not appear to be a major risk factor for dementia. A slow accumulation of microvascular brain ischemia due to vascular risk factors is an alternative explanation for the late decline in neurocognitive performance after cardiac surgery. Elderly subjects with asymptomatic ischemic lesions on brain imaging who have not had heart surgery have a greater decline 107–109 in cognitive function over a period of 3 to 4 years Similarly, subjects with symptomatic than individuals without ischemic lesions. cerebrovascular disease have increased progressive cognitive decline compared to control 110,111 Patients undergoing coronary artery bypass grafts typically have vascular risk subjects. factors for asymptomatic and symptomatic brain lesions that are associated with cognitive
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decline. It would be valuable to know whether very good control of vascular 7,105 risk factors eliminates the late decline in cognitive performance that follows heart surgery. RISK FACTORS FOR STROKE Several preoperative factors have been identified as placing a patient at a higher risk of a neurological complication (Table 3-1). Increasing older age is associated with increasing frequency of neurological and cognitive disorders following coronary artery bypass 6,113,114 A multicenter, prospective study of 5,000 patients found that the occurrence surgery. of stroke was 1 percent in patients younger than 50 years of age, almost 2 percent in patients aged 50 to 59 years, approaching 4 percent in patients aged 60 to 69 years, and greater than 115 5 percent in patients older than 70 years. With a growing elderly population, the number of patients older than 80 years who are evaluated for coronary artery bypass grafts may 116 increase. Click here to view this table.... Dislodgment of prothrombotic atheroma during instrumentation of the aorta is a risk factor for 14,32,117–120 Atheromatous aortic disease can be identified with intraoperative stroke. ultrasonographic scanning and transesophageal echocardiography. Approximately 25 to 50 percent of patients receiving a coronary artery bypass graft have atherosclerotic plaques in their ascending aorta identified by these techniques. The frequency of such aortic disease increases with age and is particularly prominent in patients older than 70 years. Identification 118,121 of a moderately to severely atheromatous aorta may alter surgical management. A preoperative history of hypertension, diabetes mellitus, stroke, severe stenosis of the carotid artery (>70%), and other markers 6,8,38,114,115,122 of vascular disease are also risk factors for stroke Cardiac surgery123 within 3 months of a following coronary artery bypass surgery. stroke may carry a risk of worsening preoperative neurological deficits. The greater the number of preoperative risk factors, the higher is the probability of a perioperative stroke. For example, a 65- to 75-year-old patient with a history of a stroke and hypertension has a risk of postoperative stroke that is three times greater than that of a patient of the same age without a history of stroke or hypertension. A patient older than 75 years with a history of stroke and hypertension has a probability for postoperative stroke that is 13 times greater than a patient younger than 65 years with no previous stroke or history of hypertension. Stroke risk indexes may identify patients124,125 prior to coronary artery bypass surgery who are at high risk of a perioperative stroke. Intraoperative factors also influence the frequency of stroke (Table 3-1). As noted previously, individuals who require coronary artery bypass surgery combined with a left-sided 38,126 Patients who require intracardiac procedure have a relatively high rate of stroke. cardiopulmonary bypass lasting more than 2 hours have a higher number of intraoperative cerebral microemboli detected by transcranial Doppler ultrasound monitoring and a higher 38,115,127,128 A large fluctuation in hemodynamic parameters during frequency of stroke. surgery, such as129 mean arterial pressure, has been associated with postoperative stroke and encephalopathy. The risk from sustained intraoperative hypotension with a mean arterial pressure below 40 to 50 mmHg during cardiopulmonary bypass remains unclear. Atrial fibrillation occurs in approximately one third of continuously monitored patients following cardiac surgery and is a risk factor for stroke. Its initial occurrence is most common during the first 3 postoperative days, and 20 percent of patients have more than one episode. Advancing age is a risk factor for atrial fibrillation, and patients older than 70 years are at high risk of arrhythmia. Withdrawal from β-adrenergic receptor–blocking agents or angiotensin-converting enzyme inhibitors is also associated with recurrent atrial fibrillation. Use of β-blocking drugs or angiotensin-converting enzyme inhibitors preoperatively and postoperatively and β-blockers postoperatively is associated with a reduced risk of atrial 25,115,122,130,131 fibrillation. PREVENTION OF NEUROLOGICAL COMPLICATIONS Attempts to prevent neurological sequelae after cardiac surgery have focused on improved 8,132,133 surgical and cardiopulmonary bypass techniques and neuroprotective drugs. Identification of surgical and technical factors that carry particular risks of neurological 8,13,132 An complications after cardiac surgery has led to the adoption of preventive measures. arterial line microfilter system has been incorporated into the extracorporeal circulation with the aim of reducing cerebral embolization. Improved surgical techniques reduce the bypass time and the total number of cerebral microemboli. Maintenance of the mean arterial blood pressure above 50 mmHg provides a safety margin against periods of relative hypoperfusion.
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The use of a membrane oxygenator decreases the magnitude of air emboli. Preoperative or early postoperative administration of β-blocking agents decreases the incidence of postoperative atrial fibrillation. Early postoperative use of aspirin decreases ischemic 134 complications of multiple organs including132,135 the brain. Perioperative monitoring and control Delaying heart surgery for 4 or more weeks of hyperglycemia may influence outcome. 132 after a recent stroke has been recommended if the cardiac condition allows such a delay. The benefit of combined carotid revascularization and coronary artery bypass surgery in patients with asymptomatic carotid stenosis awaits confirmation in a prospective clinical 114,136–139 Carotid endarterectomy for patients with severe (70% to 99%) internal carotid trial. stenosis that has been neurologically symptomatic in the past 6 months is of established 140 benefit independent of cardiac surgery. Performing a carotid endarterectomy before or simultaneous with coronary artery bypass surgery in such patients is an accepted 132,141,142 Carotid stenting has evolved as an alternative procedure for such practice.8,138,139,143,144 patients. An increased concern that an atheromatous aorta is a primary source of embolic stroke has led to intraoperative identification with transesophageal echocardiography and epiaortic 14 scanning. The presence of prominent aortic atheroma alters surgical techniques including the site of aortic cannulation, the aorta clamping technique, the use of intra-aortic filtration, and using off-pump coronary artery surgery to avoid manipulation of a severely diseased 28,32,118,132,145,146 aorta. The magnitude of cerebral microemboli and the frequent neuropsychological and anoxic-ischemic findings associated with cardiac surgery suggest a need and opportunity to study brain protective agents. Proposed mechanisms of pharmacological neuroprotection include decreasing cerebral oxygen consumption; decreasing cerebral blood-flow and, with it, the total number of microemboli; interrupting the cascade of cerebral ischemic events that are mediated via excitotoxins such as glutamate; and decreasing the inflammatory response 133,147–151 Clinical trials, and coagulation cascade associated with cardiopulmonary bypass. however, have yet to identify an effective pharmacological neuroprotective agent that has wide clinical application during coronary artery bypass surgery. CARDIAC TRANSPLANTATION Cardiac transplantation is an established treatment for selected patients with progressive, preterminal heart failure. Cardiac transplantation centers now report survival rates at 1 year of greater than 80 to 85 percent, at 5 years of 60152,153 to 80 percent, at 10 years of approximately The annual153 number of heart 50 percent, and at 15 years of 30 to 40 percent. transplantations worldwide is estimated to be greater than 4,000. Neurological sequelae occurring either in the perioperative period or as a late complication may negate an otherwise successful heart transplantation. The early identification of treatable complications offers the best opportunity to prevent severe disability. The perioperative neurological sequelae from cardiac transplantation are similar to the complications associated with valvular or bypass graft surgery, dis cussed previously, except 41 that neurological complications occur more frequently in transplant recipients. Postoperative encephalopathy, stroke, headaches, psychosis, seizures, and peripheral nerve disorders are 154–160 the most common problems. Vascular headaches accompanied by nausea and vomiting may occur in the first week after 156 transplantation. The headaches are associated with a rapid shift from low preoperative to high postoperative mean arterial pressures. Similar headaches may rarely precede an intraparenchymal hemorrhage. These vascular headaches respond to β-adrenergic receptor–blocking agents. 157
Seizures have been reported in as many as 15 percent of patients with cardiac transplants. They commonly occur during the perioperative period. They also occur as a side effect of cyclosporine or as a late complication of a brain infection or tumor. Seizures in the perioperative period are usually due to stroke and may not require long-term anticonvulsant therapy. When anticonvulsant drugs are indicated, phenytoin, phenobarbital, and carbamazepine are often avoided because they induce the hepatic metabolism of cyclosporine, tacrolimus, and sirolimus. When these antiepileptic agents are used, immunosuppression may be reduced. Levatiracetam and gabapentin have negligible hepatic 161 enzyme–inducing effects and few drug interactions and may be preferred anticonvulsants. Pregabalin, a newer antiepileptic drug, has similar characteristics. Psychotic behavior with hallucinations, delusional thought processes, and disorganized behavior can occur during the first 2 weeks after transplantation or as a late complication.
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When it occurs during the postoperative period, multiple causal factors may be present, but with time, the psychotic behavior usually resolves. When psychotic behavior occurs as a late complication, it is often a manifestation of an intracranial infection, most commonly viral. A thorough neurological evaluation is therefore indicated when a cardiac transplant recipient 154,155 develops an acute late psychosis. Immunosuppression remains a cause of late neurological complications after cardiac transplantation. Opportunistic infections can occur as early as 2 weeks after surgery and immunosuppression, but usually there is an interval of at least 1 month. Focal meningoencephalitis or brain abscess, meningitis, and diffuse encephalitis are three common 154,155,162 Aspergillus fumigatus, presentations of infections in cardiac transplant recipients. Toxoplasma gondii, Cryptococcus neoformans, Listeria monocytogenes, and herpesvirus infections are the more common causes of CNS infections in heart transplant 162,163 recipients. Aspergillosis is the most frequent fungal infection that produces a necrotizing 162 meningoencephalitis and single or multiple brain abscesses. Cerebral aspergillosis is almost always disseminated from a preceding pulmonary infection.164 The abscesses may have MRI ring, irregular, or no contrast enhancement on MRI and CT scans. Diffusion-weighted 165 may demonstrate restricted diffusion of water in the center of the abscess. Aspergillosis also causes an invasive necrosis of intracranial vessels that may lead to hemorrhagic infarction. Therefore, focal hemorrhage on brain imaging is suggestive of Aspergillus infection. The diagnosis is confirmed by direct needle aspiration or biopsy; cerebrospinal fluid studies and cultures usually are not helpful. If the diagnosis is made late, the disease is fatal; early diagnosis and treatment in an immunosuppressed patient, however, improve 166,167 survival. T. gondii is the second most common cause of focal162,168 or multifocal meningoencephalitis and abscess formation following cardiac transplantation. It can produce multiple ring-enhancing lesions, seen with contrast CT scans. MRI may demonstrate additional lesions not apparent on CT and may also show a rapid response to antibiotic therapy. Serological evidence of T. gondii is supportive evidence, particularly if there is seroconversion 168 after transplantation or an increase in titer compared to the preoperative baseline serology. While tissue diagnosis with material aspirated from a brain abscess is diagnostic, a presumptive diagnosis based on imaging and serological testing may lead to a therapeutic trial. Consideration of the diagnosis is mandatory because of the excellent therapeutic 169 cause an inflammatory response to antitoxoplasmic antibiotics. Toxoplasmosis may also170,171 myopathy in association with intracranial and multisystem infection. Other less frequent opportunistic infections that produce focal meningoencephalitis or brain abscess include the rhinocerebral phycomycotic organisms, Candida albicans in the setting of disseminated candidiasis, Nocardia infections, Klebsiella (abscess), and Rhodococcus 155,162,172–175 equi. Meningitis after cardiac transplantation is most commonly due to C. neoformans when the symptoms are subacute or chronic and the white blood count in the cerebrospinal fluid is mildly to moderately elevated with predominantly mononuclear cells. L. monocytogenes is the most common organism when the symptoms are acute and there is a prominent cerebrospinal fluid pleocytosis consisting of polymorphonuclear and mononuclear cells. Coccidioides immitis and Pseudoallescheria boydii, as well as previously mentioned fungi, 154,157,176,177 are less frequent causes of meningitis. Cytomegalovirus, herpes simplex, and herpes zoster encephalitis also occur, in association 157,163,178 with a disseminated viremia, in patients who have undergone cardiac transplantation. Immunosuppression, however, transforms the acute necrotizing focal herpes simplex encephalitis into a more diffuse and slowly progressive process. Progressive multifocal leukoencephalopathy after heart transplantation is thought to be due to reactivation of a JC 179 virus infection that is initially acquired during childhood. Pathogens can also be transferred from donor to transplant recipients, typically causing neurological deterioration during the first post-transplantation month. West Nile virus has been transferred from a donor heart to a 180 heart recipient causing an encephalitis shortly after transplantation. Rabies virus, lymphocytic chorimeningitis virus, and Trypanosoma cruzi are also reported donor-derived 181–183 infections. Immunosuppression for cardiac transplantation combined with Epstein–Barr virus infection can cause a post-transplantation lymphoproliferative disorder that leads to systemic 184 malignant lymphoproliferation including involvement of the brain. Post-transplantation lymphoproliferative disorders may regress with reduction of immunosuppressive therapy or
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they may require radiotherapy. The CNS can be the only site of malignant lymphoproliferation in association with Epstein–Barr virus in brain tissue. The response of this 184,187 post-transplantation primary CNS lymphoma to multimodal therapies is often poor. Glioma is another isolated brain tumor that can188occur after heart transplantation, although the relationship to immunosuppression is unclear. Immunosuppressive agents can also cause neurological side effects more directly. Prior to the use of cyclosporine, high-dose prednisone in combination with azathioprine was commonly used. The main side effect of the prednisone was weakness of the proximal lower extremities, osteoporosis 176 with lower thoracic and lumbosacral compression fractures, or psychiatric complications. With the use of calcineurin inhibitors, cyclosporine, and 189,190 tacrolimus, the dose of prednisone has been lowered, thereby reducing its side effects. Cyclosporine and tacrolimus themselves, however, may have neurotoxic side effects, including prominent tremor, headache, a lowered seizure threshold, paresthesias, mental confusion, acute mania, weakness, ataxia, dysarthria, visual hallucinations, and cortical blindness. Brain imaging may reveal a posterior leukoencephalopathy. Diffusion-weighted MRI studies suggest that the onset of neurotoxicity is due to vasogenic brain edema. Vasogenic edema is reversible, which is consistent with the typical remission of adverse effects and MRI findings following reduction of the cyclosporine or tacrolimus dose. Prolonged drug exposure at neurotoxic levels, however, may cause residual neurological 191–193 The newer immunosuppressive agent sirolimus has few reported impairment. neurotoxic effects and may be used as an alternative to cyclosporine or tacrolimus when 194 neurotoxicity occurs. 190
Cyclosporine also induces gout and produces chronic nephrotoxicity. When gout is treated with colchicines, the impaired renal function may lead to colchicine toxicity and a peripheral 195 neuromuscular disorder that improves when the colchicine is stopped. The monoclonal anti-CD3 antibody (OKT3) is used to prevent and treat graft rejection following cardiac transplantation. Aseptic meningitis with fever, headache, seizures, and a variable encephalopathy is reported to occur in 5 percent of patients as a reaction to it. This aseptic meningitis may occur during the course of OKT3 therapy or in the weeks immediately subsequent to it. The aseptic meningitis and encephalopathy resolve within days of 176,196,197 onset. As noted previously, most of the neurological complications of cardiac transplantation with immunosuppression may present with a confusional state in which headache and focal neurological findings may be present or absent. It is not uncommon, however, for more than one complication of 155 immunosuppression to cause symptoms in an individual cardiac transplant recipient. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 4 Neurological Complications of Congenital Heart Disease and Cardiac Surgery in Children CATHERINE LIMPEROPOULOS • ADRÉ J. DU PLESSIS •
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NEUROLOGICAL DYSFUNCTION BEFORE CARDIAC SURGERY Chromosomal Disorders Cerebral Dysgenesis Acquired Preoperative Cerebrovascular Injury MECHANISMS OF NEUROLOGICAL INJURY DURING CARDIAC SURGERY Intraoperative Brain Injury Focal or Multifocal Hypoxic-Ischemic Injury Global Hypoxic-Ischemic Injury Mechanisms of Postoperative Injury MANIFESTATIONS OF NEUROLOGICAL DYSFUNCTION IN THE POSTOPERATIVE PERIOD Delayed Recovery of Consciousness Postoperative Seizures Periventricular White Matter Injury Stroke Movement Disorders Spinal Cord Injury Brachial Plexus and Peripheral Nerve Injury NEUROLOGICAL COMPLICATIONS OF CARDIAC TRANSPLANTATION
Pediatric neurologists have become increasingly challenged by diagnostic and management decisions in children with congenital or acquired heart disease experiencing neurological dysfunction. Of the 30,000 infants born with heart defects in the United States each year, 1,2 approximately half require some form of surgical intervention within the first year of life. Since the late 1960s, there have been major changes in the clinical profile of neurological injury in children with congenital heart disease. In earlier years, the neurological complications of congenital heart disease were mediated for the most part by chronic hypoxia and polycythemia in cyanotic children, uncorrected right-to-left shunts, and the effects of 3,4 repeated palliative heart operations. Advances in surgical technique and intensive care management have allowed the anatomical correction of many heart lesions in early infancy. These early-life corrective procedures have resulted in major decreases in the mortality rate of congenital heart disease. Consequently, neurological sequelae are now increasingly seen
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in adult survivors of congenital heart disease. Heart defects considered inoperable in the mid-1980s are now successfully repaired with a very low mortality rate. More infants with critical congenital heart disease and profound hemodynamic disturbances in the newborn period are now rescued, only to manifest later the neurological consequences of this early-life morbidity. Furthermore, the same surgical support techniques responsible for advancing survival have, paradoxically, been associated5 with an incidence of neurological complications that approaches 25 percent in some centers. Consequently, mechanisms of brain injury during cardiac surgery have been the focus of intense investigation over the past two decades. Understanding of these intraoperative mechanisms has been advanced through 6,7 7–12 as well as by intraoperative animal experimental models and several large clinical trials, cerebral monitoring and perioperative magnetic resonance imaging (MRI). More recently, there has been increased recognition that both acquired and developmental brain disturbances in infants with congenital heart disease may have their origin prior to 13–22 It is expected that these surgical intervention, in many cases during the fetal period. mechanisms will receive particular attention over the next few years as the role of fetal 23,24 imaging expands and the potential for fetal interventions is explored. NEUROLOGICAL DYSFUNCTION BEFORE CARDIAC SURGERY Recent studies have demonstrated a high prevalence of neurological abnormalities prior to infant cardiac surgery, in some studies exceeding 50 percent. These abnormalities include 8,13,15,25 as well as microcephaly, hypotonia, behavioral dysregulation, and feeding difficulties 14,16 These preoperative neurological and abnormal electrophysiological studies. electrophysiological abnormalities are increasingly recognized as significant predictors of 14,16,25–28 The presence of these preoperative longer term neurodevelopmental sequelae. abnormalities in the early neonatal period strongly suggests a fetal onset of neurological impairment.
Chromosomal Disorders A number of chromosomal disorders have a phenotype that includes both cardiac and neurological malformations, including trisomies 11, 18, and 21. The most common neurological manifestation in children with trisomy 21, or Down syndrome, is cognitive dysfunction. Epilepsy develops in approximately 5 percent of children with trisomy 21. Congenital heart defects, most commonly endocardial cushion defects, are present in 40 percent of children with Down syndrome. Gross structural brain alterations in Down syndrome include a narrow superior temporal gyrus and a disproportionately small cerebellum and 29 brainstem. Trisomy 13 is associated with ventricular septal defects and patent ductus arteriosus; the associated cerebral dysgenesis in this syndrome is often severe, with holoprosencephaly and agenesis of the corpus callosum being the most common lesions. The most common cardiac lesions in infants with trisomy 18 are ventricular septal defects and patent ductus arteriosus, with neuronal migration defects the usual form of brain 30 dysgenesis. The phenotypic spectrum of specific chromosome 22 deletions, particularly in31the 22q11 region, includes a variety of cardiac malformations and neurological features. Recent population-based data suggest that at least 700 infants with chromosome 22 deletion 32 syndromes are born annually in the United States. The acronym CATCH 22 (cardiac defect, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia, chromosome 22q11 deletions) has been used to designate this group of apparently related syndromes. The two most common syndromes, DiGeorge and velocardiofacial (or Shprintzen) syndromes, have 33 neurological and cognitive manifestations in association with structural cardiac defects. The fundamental problem in DiGeorge syndrome is a developmental defect of the third and fourth pharyngeal pouches, manifesting with thymic and parathyroid hypoplasia and conotruncal cardiac malformations, which include interrupted aortic arch (type B), truncus arteriosus, and tetralogy of Fallot. A common neurological presentation in both DiGeorge and the velocardiofacial syndrome is hypocalcemic seizures due to hypoparathyroidism. In addition to the usual cardiac lesions (i.e., ventricular septal defect or tetralogy of Fallot), the velocardiofacial syndrome is associated with cleft palate or velopharyngeal insufficiency and a typical facial appearance, including a broad, prominent nose and retrognathia, and microcephaly in up to 40 percent. Neuroimaging and autopsy studies may show a small posterior fossa and vermis, small cystic lesions adjacent to the frontal horns of the lateral ventricles, dysgenesis of the corpus 34–42 Delayed opercular development callosum, and abnormal cortical gyrification patterns. and disproportionately enlarged sylvian fissures as well as white43matter abnormalities might underlie some of the developmental problems in these children, including nearly universal
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learning difficulties. The mean intelligence quotient (IQ) in this syndrome is around 70, with mild to moderate mental retardation in up to 50 percent of patients.
In recent years, a high rate of autism spectrum disorders and attention deficit/hyperactivity 45,46 disorder has been described in this group. 34,36Psychiatric disorders occur in up to 22 percent A peculiar and inappropriately blunt affect of patients with 22q11 deletion syndromes. 47 often evolving to frank psychosis during adolescence and may be evident during childhood, 48 adulthood. Altered prefrontal cortex-amygdala circuitry, reduced cerebellar and thalamic volumes, and increased basal ganglia and corpus callosal volumes, as shown by quantitative neuroimaging studies, may underlie the disrupted emotional processing and form the 38,39,44,49–51 neurobiological substrate for the psychiatric disturbances in these children.
Cerebral Dysgenesis The prevalence of brain dysgenesis in children with congenital heart disease approaches 30 29,52,53 The risk of cerebral dysgenesis appears related to percent in some autopsy studies. the underlying cardiac lesion. For example, infants with hypoplastic left heart syndrome may be at particular risk of associated developmental brain lesions, which range in severity from 52 microdysgenesis to gross malformations, including agenesis of the corpus callosum, holoprosencephaly, and immature cortical mantle. With advances in neuroimaging, the relationship between cardiac and brain dysgenesis is becoming more clearly defined. Clinically, these dysgenetic lesions may present in the newborn period with seizures, alterations in level of consciousness, and abnormalities in motor tone. Conversely, these lesions may remain clinically occult until later infancy and childhood, when they present with developmental delay, epilepsy, and cerebral palsy. For these reasons, it is important to consider cerebral dysgenesis in any child with congenital heart disease and neurological manifestations.
Acquired Preoperative Cerebrovascular Injury Infants with congenital heart disease are at increased risk of acquired antenatal or perinatal brain injury. During fetal life, congenital heart lesions may be associated with changes in cerebrovascular blood-flow distribution and resistance. Fetuses with hypoplastic left heart syndrome, whose cerebral perfusion is supplied retrograde through the ductus arteriosus, 19,20 Preoperative MRI studies have demonstrated that brain injury is may be at particular risk. common in infants with critical congenital heart disease and during invasive diagnostic 54,55 Preoperative findings detected by MRI procedures (e.g., balloon-atrial septostomy). include intracranial hemorrhage, cerebral venous thromboses, thromboembolic infarctions, dilation of the ventricles and subarachnoid spaces (suggestive of cerebral atrophy), 17,18,20,56,57 Elevated preoperative brain periventricular leukomalacia, and gray matter injury. lactate levels have been found by magnetic resonance spectroscopy in over half of 17,24,56 newborns. Complex corrective operations are performed in ever smaller and less mature newborn 58 infants. Consequently, the vascular lesions associated with less mature infants are now seen. Intraventricular/periventricular hemorrhage (IVH-PVH) is a common neurological 59 complication in the newborn. The risk of IVH-PVH is related to the severity of the vascular insult and inversely to the infant's gestational age. Prematurity predisposes to IVH-PVH because of the structural and physiological vulnerability of the immature periventricular germinal matrix. The hemodynamic instability commonly seen in more severe forms of congenital heart disease predisposes to the systemic hypotension or fluctuations in blood 59 pressure that trigger IVH-PVH. Compared with the incidence of 3.5 percent for IVH-PVH in term infants overall, the incidence in term infants with congenital heart disease is as high as 22 16 percent in some studies. At autopsy,6025 percent of infants with hypoplastic left heart syndrome have intracranial hemorrhage. Infants with coarctation of the aorta are also at increased risk of intracranial hemorrhage because of the intracranial vascular malformations 59,61 and hypertension associated with this condition. The detection of intraventricular hemorrhage in infants with congenital heart disease in the preoperative period creates a major management dilemma because the risk of extending such hemorrhage is increased by cardiopulmonary bypass and cardiac surgery. Specifically, cardiopulmonary bypass requires anti-coagulation to prevent clot formation in the bypass 62 circuit; in addition, it has been associated with enhanced systemic fibrinolytic activity. The more complex operations require periods of decreased perfusion to approach the cardiac defect. The requirement for anticoagulation and the potentially severe intraoperative perfusion changes increase the risk of extending any preoperative intracranial hemorrhage. The dilemma is further complicated by the fact that intracranial hemorrhage occurs most
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commonly in infants with the most critical cardiac lesions, that is, those in greatest need of early surgical repair. There are no prospectively tested protocols for managing the dilemma of preoperative intracranial hemorrhage in infants requiring cardiac surgery. At our center, we use the following guidelines. We perform preoperative cranial ultrasonography to exclude IVH-PVH in all premature infants with a birth weight less than 1,500 g and newborn infants with preoperative neurological dysfunction, coagulation disturbances, or hemodynamic instability causing significant metabolic acidosis. In those infants with IVH-PVH, surgical planning is based on the severity of the cardiac illness (which may directly affect the risk of hemorrhage extension), the likely complexity of surgery, and the severity of preoperative IVH-PVH. Minor 63,64 and should not delay cardiac subependymal hemorrhage carries a low risk of extension surgery. In infants with hemorrhage into the ventricles or the parenchyma, we delay cardiopulmonary bypass for at least 7 days if the cardiac condition permits. MECHANISMS OF NEUROLOGICAL INJURY DURING CARDIAC SURGERY Neurological dysfunction presenting during the early postoperative period is likely due in most cases to intraoperative hypoxic-ischemic/reperfusion injury. However, the risk of cerebrovascular injury extends into the postoperative period, when cardiorespiratory instability, together with cerebral autoregulatory dysfunction, predisposes to cerebral hypoxic-ischemic injury. Despite the remarkable advances facilitated by deep hypothermia and pharmacological agents, the persistent neurological morbidity in the postoperative period 65,66 attests to the incomplete neuroprotection offered by these strategies. The precise onset and evolution of hypoxic-ischemic/reperfusion injury may be difficult to establish. First, the mechanisms of both parenchymal and vascular hypoxic-ischemic/reperfusion injury are known to evolve over time. Second, during the early posthypoxic-ischemic period, cells that have sustained an insult may be at particular risk of irreversible injury from subsequent disturbances in oxygen supply. Consequently, it is difficult to ascribe with any certainty hypoxic-ischemic/re-perfusion injury to one of the preoperative, intraoperative, or postoperative periods. Rather, it is likely that in many cases the injury is multifactorial and cumulative.
Intraoperative Brain Injury There are multiple interrelated mechanisms by which brain injury may occur during cardiac surgery. However, hypoxic-ischemic/reperfusion injury is likely60,67 the principal mechanism, a that is, laminar cortical notion supported by the topography of injury seen at autopsy, 68,69 Animal models of deep hypothermic necrosis and periventricular white matter injury. circulatory arrest have also demonstrated selective neuronal necrosis in a distribution that70 corresponds closely to that seen after normothermic hypoxic-ischemic/reperfusion injury. Neuropathological studies of infants after deep hypothermic cardiac surgery suggest that cerebral white matter lesions tend to be the most prevalent and severe, followed by a 67 spectrum of gray matter lesions. The changes in cerebral perfusion and metabolism during cardiac surgery are complex, interrelated, and often extreme. When these changes exceed the brain's ability to maintain a balance between cerebral oxygen/substrate supply and utilization, a hypoxic-ischemic/reperfusion insult is triggered. The multiple factors determining intraoperative cerebral oxygen availability may be categorized as extrinsic, that is, related to the extracorporeal circulation (e.g., loss of pulsatility, low or no pump flow, hypothermia, emboli) or intrinsic (e.g., disturbances in cerebral blood-flow autoregulation). During deep hypothermic cardiac surgery, cerebral oxygen delivery may be impaired by focal or multifocal vaso-occlusive phenomena generated by 65,66 the bypass circuit or global hypoperfusion due to excessive attenuation of bypass flow rate. Focal or Multifocal Hypoxic-Ischemic Injury The relatively small intravascular volume of the young infant compared with the large blood volume required to “prime” the cardiopulmonary bypass circuit results in increased exposure 65,66 71 These may be either 72 embolic or inflammatory due to the to insults related to the bypass. extensive interface between blood and artificial surfaces. The replacement of bubble oxygenators with membrane devices has decreased but not eradicated the embolic “load” of bypass circuits. Both gaseous and particulate emboli may enter the circulation directly from the surgical field. Because the bypass circuit delivers oxygenated blood directly to the aorta, circulating emboli circumvent the normal pulmonary filtration bed and enter the systemic (and
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cerebral) arterial circulation directly. Earlier autopsy studies described cerebral embolic brain injury after cardiac surgery, and subsequent studies following cardiopulmonary bypass have 71 described a significant prevalence of cerebral capillary-bed aneurysmal dilatations. Cardiopulmonary bypass activates a host of inflammatory cascades that cause diffuse vascular injury, resulting in a postperfusion syndrome that in severe cases is associated with 73 and multiple organ failure. Pathways triggered include the eicosanoid, complement, 74 cause antioxidant kallikrein pathways. These pathways activate free radical generation, 75 depletion, and upregulate adhesion molecules on neutrophils and endothelial cells. These activated neutrophils appear to be potent mediators of reperfusion injury in the brain. Hypothermia delays and modifies the effect of these processes but does not completely 76 prevent them. Global Hypoxic-Ischemic Injury Several techniques used during neonatal cardiac surgery jeopardize cerebral oxygen delivery by altering cerebral perfusion, arterial oxygen content, and tissue oxygen delivery. Under deep hypothermic conditions, cerebral oxygen availability may be limited by cold-induced 77,78 impairment of cerebral pressure-flow increases in cerebral vascular resistance, 79,80 81 and increased oxygen-hemoglobin affinity. Normally, during periods of autoregulation, decreased perfusion pressure, cerebral oxygen delivery is maintained by an initial 82 However, both these vasodilatory response followed by an increase in oxygen extraction. 83 compensatory responses are compromised at deep hypothermia. To approach the often tiny cardiac defects, the bypass flow rate is decreased and often arrested for periods depending on the complexity of the lesion. Although there are general guidelines for “safe periods” of deep hypothermic circulatory arrest at different temperatures, these remain controversial and unpredictable in the individual infant. In addition, the safety of low-flow bypass compared with hypothermic circulatory arrest has been debated. Low-flow bypass prolongs exposure to bypass-related phenomena, as well as increasing the risk of incomplete ischemia. Conversely, deep hypothermic circulatory arrest (DHCA) allows more rapid completion of the intracardiac phases of the repair and reduces the exposure to bypass 65,66 Over the past perfusion; however, it exposes the infant to periods of complete ischemia. 15 years, a number of studies have focused on the relationship between DHCA and84–87 In the neurological outcome; most studies have reported a deleterious effect on outcome. first major clinical trial randomizing infants to a strategy of predominant hypothermic circulatory arrest or low-flow8 bypass, infants exposed to the former were at significantly 9 greater risk of perioperative and 1-year neurological sequelae. At age104 years, the DHCA group had significantly worse behavior, speech, and language function, but no difference in mean intelligence score. Furthermore, at 8-year follow-up, those assigned to DHCA scored worse on motor and speech domains, whereas those assigned to low-flow bypass had worse 11 scores for impulsivity and behavior. Therefore, the long-term follow-up of this large cohort has provided important insights into the evolution of neurodevelopmental outcome in this 88 complex population over time. Although it is now generally accepted that prolonged periods of uninterrupted DHCA may have adverse neurological effects, certain studies have shown 89–91 that shorter durations of DHCA are not consistently associated with adverse outcomes. In fact, available data suggest that the relationship between DHCA duration and neurodevelopmental sequelae is not linear and that the risk of brain injury increases 84,92 These studies have again emphasized that significantly after about 40 minutes of DHCA. the neurological dysfunction in this population is undoubtedly mediated by numerous interrelated preoperative and postoperative risk factors in addition to DHCA. In addition to the bypass flow rate, a number of other factors associated with cardiopulmonary bypass may affect cerebral perfusion and predispose to hypoxic-ischemic/reperfusion injury. Most centers in the United States use nonpulsatile bypass devices as well as hemodilution to reduce the magnitude of blood cell trauma. Deep hypothermia is widely used to suppress oxygen consumption during infant cardiac surgery. In addition to their intended beneficial effects, these techniques all have potential adverse effects on cerebral oxygen delivery. The nonpulsatile perfusion of cardiopulmonary93bypass, particularly at low-flow rates, may fail to maintain perfusion in distal capillary beds. Furthermore, nonpulsatile blood-flow may disrupt pressure-flow and metabolism-flow 77,80,94 Hemodilution is used during bypass to reduce rheologic injury to autoregulation. circulating red cells during deep hypothermia. However, because the concentration of oxygenated hemoglobin is the major determinant of oxygen-carrying capacity, hemodilution may limit cerebral oxygen delivery. In animal studies, extreme hemodilution (to hematocrit levels less than 10%) was associated with neurological injury, whereas hematocrit levels 6 above 30 percent improved cerebral recovery after DHCA. These experimental results were
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confirmed by a randomized clinical trial in which infants randomized to a hematocrit of 20 percent during cardiac surgery had significantly worse developmental scores at 1 year than 7 those randomized to a hematocrit of around 30 percent. Another important intraoperative factor is the management of acid-base status during cardiopulmonary bypass. In a randomized, single-center trial, infants undergoing cardiac operations were assigned12to the alpha-stat versus pH-stat strategy during deep hypothermic pH-stat management was associated with lower cardiopulmonary bypass. The use of 12 had no effect on overall early postoperative morbidity. Treatment assignment 95 neurodevelopmental outcome at 1, 2, and 4 years of age. Despite these equivocal findings, many centers are currently using pH-stat management during core cooling. After repair of the cardiac defect, bypass flow rates are increased using rewarmed and highly oxygenated blood. Rewarming aims to reactivate cellular enzyme function and oxygen utilization. During this period of reperfusion, a number of factors may predispose to free 65,66 Several studies have suggested a delay in recovery of mitochondrial 97 radical injury. 96 function, possibly by nitric oxide, which is generated in abundance during the bypass. The combination of a highly oxygenated reperfusion and98persistent mitochondrial dysfunction may after deep be a major source of injurious oxygen free radicals. Excessively rapid rewarming 100 99 hypothermia may be deleterious. Hyperthermia is a trigger for glutamate release, predisposing to excitotoxicity as well as further stressing the recovering cerebral metabolism.
Mechanisms of Postoperative Injury During the postoperative period of intensive care, a number of factors may predispose to brain injury. Cerebral perfusion pressure may be compromised by a combination of decreased cardiac output and elevated central venous pressure resulting from postoperative cardiac dysfunction. In addition to these systemic circulatory factors, there may be intrinsic cerebrovascular disturbances in the postoperative period. Specifically, elevated cerebral 3,66,79,101,102 and impaired vasoregulation vascular resistance, decreased cerebral blood-flow, have been described after deep hypothermic circulatory arrest. Together, these factors may render the brain vulnerable to injury in the postoperative period. MANIFESTATIONS OF NEUROLOGICAL DYSFUNCTION IN THE POSTOPERATIVE PERIOD 103
Recent studies suggest a decrease in acute neurological morbidity following surgery. However, intraoperative and postoperative insults may injure the neuraxis at any level. Because a detailed discussion of the entire spectrum of neurological manifestations is not possible in the current context, this review focuses on the more common clinical issues confronting the child neurologist.
Delayed Recovery of Consciousness Prolonged impairment of mental status after cardiac surgery, anesthesia, and postoperative sedation is a common reason for neurological consultation. The evaluation104should follow the well-established clinical guidelines for assessing impaired consciousness. Certain specific etiologies should be excluded, including postoperative hepatic or renal impairment, which may impair the metabolism or excretion of sedating drugs. Prolonged use of neuromuscular blocking agents in the preoperative or postoperative period may delay the recovery of motor 105 function (discussed later) and, if severe, may suggest impaired consciousness. This condition should be excluded at the bedside with a peripheral nerve stimulator or formal nerve conduction studies. Postoperative seizures are a common complication of cardiac surgery (as discussed in the next section), and not infrequently these seizures are clinically 8 silent. Such “occult” seizures or a prolonged postictal state should be considered in the evaluation of a depressed postoperative mental state. In spite of this approach, the precise cause of an impaired postoperative mental status is not established in most cases. Many of these children ultimately demonstrate features suggestive of hypoxic-ischemic/reperfusion injury.
Postoperative Seizures Seizures early in the postoperative period are among the most common neurological complications after open heart surgery. Postoperative clinical seizures have been reported to 106 occur in up to 19 percent of survivors of neonatal cardiac surgery, and in certain subgroups this risk may reach 50 percent. Clinical seizures are reported8,107 less frequently than those since postoperative seizures detected by continuous electroencephalographic monitoring
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may occur without typical motor correlates.
Postoperative seizures may be divided into two broad groups. First are those seizures with a readily identifiable cause, such as hypoglycemia, hypocalcemia, and cerebral dysgenesis. Postoperative seizures may also result from hypoxic-ischemic/reperfusion injury due to either generalized cerebral hypoperfusion (e.g., cardiac arrest) or focal vaso-occlusive insults. The second and more common category of postoperative seizures is that in which the etiology remains unknown. Although these cryptogenic seizures, commonly referred to as postpump seizures, are often assumed to relate to hypoxic-ischemic/reperfusion injury, their etiology is likely multifactorial8,108 with risk factors that include the use and duration of deep hypothermic circulatory arrest, younger age at106 surgery, the type of heart defect (e.g., aortic arch obstruction), and genetic conditions. Furthermore, postpump seizures differ in several respects from other forms of posthypoxic seizures. First, these seizures typically develop later than, for instance, those occurring after perinatal asphyxia. Second, although less 9 benign than previously believed, the prognosis of postpump seizures is significantly better than that 109 of asphyxial seizures, in which up to 50 percent of survivors are neurologically disabled. Both the delayed onset and more favorable outcome of postpump seizures may be due to the partial protective effect110of hypothermia at the time of intraoperative hypoxic-ischemic/reperfusion insult. The clinical course of postpump seizures is fairly typical. These seizures appear confined to a relatively narrow time-window, with onset between 24 and 48 hours after surgery. This is followed by several days during which serial seizures occur, often evolving to status epilepticus; thereafter, the tendency toward further seizures wanes rapidly. The clinical manifestations of these electrographic seizures are often subtle even in the absence of sedating and paralyzing drugs and may be confined to paroxysmal autonomic changes. When evident, convulsive activity is usually focal or multifocal. The therapeutic approach to postpump seizures should be based on their typical clinical course. After excluding reversible etiologies such as hypoglycemia, hypomagnesemia, and 111,112 the tendency toward repeated seizures and status epilepticus should be hypocalcemia, countered by rapid achievement of therapeutic anticonvulsant levels by an intravenous route. Most postpump seizures are controlled by lorazepam, followed by phenobarbital or phenytoin. Potential cardiotoxicity due to these agents in children recovering from cardiac surgery should be monitored carefully, particularly during the initiation of treatment. The apparently circumscribed window of susceptibility to postpump seizures often allows early withdrawal of anticonvulsants. Prospective studies have demonstrated a significant correlation between postoperative 8 9 seizures and9,106,113 risk of perioperative and 1-year neurological sequelae, as well as abnormal The longer term impact of postpump seizures may be less than MRI studies. 11,88,107 The development of subsequent epilepsy is rare; however, West previously thought. 114 syndrome (infantile spasms, mental retardation, and epilepsy) has been described after more intractable postpump seizures. When postoperative seizures have an identified cause, the long-term outcome is related to etiology. For instance, cerebral dysgenesis, which is increased in congenital heart disease, may present with seizures in the early postoperative period, and here the long-term outcome 106 to is usually poor, with epilepsy a common sequela. Infants with seizures due 115 postoperative stroke have a 20 to 30 percent risk of subsequent epilepsy.
Periventricular White Matter Injury Brain MRI of neonates following cardiac surgery has shown a prevalence of periventricular 116 leukomalacia in excess of 50 percent in some studies ; this is a rare finding in older infants. The precise onset of these lesions remains unclear, but the MRI features appear to be 56 transient in many cases. Reported risk factors for these MRI lesions include prolonged exposure to cardiopulmonary bypass (with or without DHCA), possibly related to inflammatory mechanisms activated by cardiopulmonary bypass. In addition, early postoperative hypotension (especially diastolic) and hypoxemia appear to increase the risk of periventricular 116,117 Magnetic resonance spectroscopy studies are leukomalacia in these MRI studies. beginning to provide insights into disturbed brain metabolism in the postoperative 17,118,119 Although significant decreases in brain N-acetyl-aspartate, a neuronal-axonal period. 118,119 marker, have been described, more recent data have shown an apparently improved cerebral oxidative metabolism postoperatively as evidenced by improved lactate/choline 17 ratios. The long-term significance of these acute structural and metabolic disturbances in children who survive cardiac surgery remains to be determined.
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Stroke The incidence of cerebrovascular accidents (strokes) in children ranges from 2.5 to 8 per 120 leading known association of childhood stroke 100,000. Congenital heart disease is the 120–122 In earlier autopsy studies, almost 20 and is present in 25 to 30 percent of cases. percent of children with congenital heart disease demonstrated features of cerebrovascular injury. Stroke associated with heart disease (cardiogenic stroke) may be classified on the basis of the likely embolic or thrombotic source as (1) cardioembolic (i.e., a probable intracardiac embolic source); (2) paradoxical (i.e., a cardiac anatomy that permits an embolus of systemic venous origin access to the cerebral circulation); or (3) venous (i.e., cerebral vein thrombosis due to central venous hypertension and venous stasis). Risk factors for cardiogenic stroke include the elements of Virchow's triad—altered vascular surface, stasis, and hypercoagulability—as well as the presence of “paradoxical” embolic pathways. Risk factors for cardiogenic stroke have changed over the years. In earlier studies, the risk of stroke was related to the effects of long-standing heart defects, such as chronic hypoxia and polycythemia, and uncorrected paradoxical pathways (e.g., right-to-left shunts). 1 The trend in recent decades toward earlier corrective surgery has reduced exposure to such stroke risk factors, shifting the focus to intraoperative and postoperative mechanisms for stroke. A number of intraoperative mechanisms related to cardiopulmonary bypass may predispose 71 to cerebral vascular occlusion. Embolic material (particulate/gaseous) generated during bypass avoids filtration by the pulmonary bed, gaining direct entry to the systemic arterial circulation. Earlier autopsy data demonstrated a substantial incidence of cerebral embolic infarction after surgery for congenital heart disease. Advances in bypass technique, including refinements in membrane oxygenators, in-line arterial filters, and anticoagulation, have 123 reduced the incidence of macroembolization and large-vessel occlusion. The impact of these advances on the incidence of microembolization and small-vessel disease is difficult to evaluate. The extensive interface between circulating blood and the artificial surface of the bypass circuit may trigger an inflammatory response, which in turn activates complex physiological 72 cascades, including endothelium–leukocyte interactions. This process further enhances the risk of ischemic injury during the intra-operative and postoperative periods. In the postoperative period, factors predisposing to stroke include stasis (intracardiac and extracardiac), altered vascular surfaces (native or prosthetic), and, in some situations, a 124 Intracardiac stasis may result potential procoagulant shift in the humoral clotting systems. 125 from localized areas of low flow or global ventricular dysfunction. Transient or sustained elevations of right heart and, hence, central venous pressure in the 126 early postoperative period predispose to local thrombosis in the right atrium and central veins. Prosthetic material in such areas of disturbed flow increases the likelihood of thrombus formation, and the presence of a right-to-left shunt (native or iatrogenic) compounds the risk of paradoxical embolization. Elevated right atrial pressure transmitted to the cerebral venous circulation predisposes to venous thrombosis, particularly in the dural venous sinuses. Elevated 127 impairment, and systemic venous pressure may cause a protein-losing enteropathy, liver124 pleural effusions, factors that may disturb the humoral coagulant systems. A number of the aforementioned stroke risk factors may be present after the Fontan operation, as highlighted 125,128 In one study, a 2.6 percent incidence of stroke was found in a in several reports. retrospective review of 645125patients after the Fontan operation; the risk extended over 3 a 20 percent incidence of years after the procedure. Rosenthal and co-workers found 128 thromboembolic complications after the Fontan procedure. Strokes originating during or immediately after cardiac surgery may escape clinical recognition for several days because of the effects of postoperative sedating and paralyzing 129 agents. In the young infant, stroke often presents with focal seizures or changes in mental status; focal motor deficits may be subtle. In older infancy and childhood, stroke usually presents with acute focal motor deficits, language disturbance, or visual dysfunction. The therapeutic approach to stroke in the child with heart disease includes (1) preventive and (2) “rescue” strategies. Experience with rescue therapies remains confined to adult and experimental stroke. These rescue therapies aim to salvage potentially viable brain using techniques designed to revascularize ischemic brain regions (thrombolytic therapy) or to 130 curtail injurious biochemical cascades. This discussion focuses on the principles of stroke prophylaxis using antithrombotic agents. Preventive stroke therapy may be categorized as
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primary or secondary. Primary stroke prevention aims to identify and treat high-risk patients before a stroke, whereas secondary prevention aims at minimizing the risk of stroke recurrence. Consistent and universally accepted guidelines for both primary and secondary stroke prophylaxis in children are lacking. Current guidelines are largely empirical, anecdotal, and derived from experience in adults. Established indications for primary stroke prophylaxis in children include prosthetic heart valves, dilated cardiomyopathy, or intracardiac thrombus on echocardiogram. The decision regarding whether and when to initiate secondary stroke prophylaxis with antithrombotic agents should aim to balance the risk of (1) recurrent cerebral embolization and (2) potentiating secondary hemorrhage into an area of cerebral infarction. Embolus recurrence risks after cardioembolic stroke are unknown in children. In adults (after myocardial infarction), this risk is highest in the early 132 poststroke period, at approximately 1 percent per day (10% to 20% over the first 2 weeks). Cardioembolic strokes are 133 particularly prone to hemorrhagic transformation, especially in the early poststroke period. Hemorrhagic transformation occurs (often silently) in 20 to 40 percent of adult cardioembolic 133 strokes. The risk of significant clinical deterioration after hemorrhagic transformation is greater in the anticoagulated patient. Although it is difficult to predict which infarcts will undergo hemorrhagic transformation, certain guidelines have been formulated. Among infarcts destined to83undergo hemorrhagic transformation, 75 percent do so within 48 hours after stroke onset. Large infarcts, particularly those larger than 30 percent, or one lobe, of a cerebral hemisphere, are at greater 134 risk of hemorrhagic transformation. Uncontrolled systemic hypertension and stroke due to septic emboli and cerebral venous thrombosis are additional risk factors for hemorrhagic infarction. The details of antithrombotic management are discussed elsewhere. The cerebrovascular disease associated with infective endocarditis warrants brief mention. The protean neurological manifestations of infective endocarditis include meningitis, brain abscess, and seizures. However, cerebrovascular injury, specifically septic embolism and hemorrhage, is the most common complication. Even with advanced antibiotic agents, neurological complications occur in one third of infective endocarditis cases in children; in 135 one half of such cases, the complications are embolic in origin. Cerebrovascular complications carry the highest mortality rate (up to 80% to 90%), primarily due to intracranial hemorrhage. The risk of and mortality rate of cerebral hemorrhage in this population contraindicates anticoagulant therapy. In all cases of cardiogenic stroke, the possibility of septic embolism should be considered before initiating anticoagulant therapy.
Movement Disorders 136
Reports of serious postoperative movement disorders go back to the early 1960s and the 137,138 Choreoathetosis is the most frequent early days of deep hypothermic cardiac surgery. form of dyskinesia complicating cardiac surgery; other rarer postoperative movement disorders include oculogyric crises and parkinsonism. The reported 139 incidence of 88 postoperative choreoathetosis reached 19 percent in earlier years ; fortunately, this complication has become rare in recent years. Despite their relative rarity, these movement disorders are often dramatic, frequently intractable, and, in severe cases, associated with a substantial mortality rate. Postoperative movement disorders have a fairly typical clinical course. The involuntary movements are preceded in most cases by a 2- to 7-day latent period during which postoperative neurological recovery appears to be uncomplicated. Thereafter, a subacute delirium (marked irritability, insomnia, confusion, and disorientation) develops, followed closely by the emergence of involuntary movements. Typically, these movements start in the distal extremities and orofacial muscles, progressing proximally to involve the girdle muscles and trunk. In severe cases, violent ballismic thrashing may develop. The abnormal movements are present during wakefulness, peak with distress, and resolve during brief periods of sleep. Oculomotor and oromotor apraxia are common, with loss of voluntary gaze as well as feeding and expressive language skills. The involuntary movements often intensify over a 1-week period, followed by a 1- to 2-week period during which movements remain relatively constant. The period of recovery is highly variable in duration. The long-term outcome of postoperative movement disorders depends largely on their initial severity. Mild cases tend to resolve within weeks to months, whereas severe cases have a mortality rate approaching 40 percent and a high incidence of associated, significant, long-term neurodevelopmental deficits, including diffuse hypotonia, persistent dyskinesia (47%), and 137,139 pervasive deficits in memory, attention, language, and motor abilities. The diagnosis of postoperative hyperkinetic syndromes is essentially clinical. Currently
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available neurodiagnostic studies are useful only for excluding other disorders. Cerebral changes by computed tomography (CT), MRI, and single-photon emission CT are137 nonspecific, seldom focal, and most commonly consist of diffuse cerebral atrophy and a high incidence of both cortical and subcortical perfusion defects. The electroencephalogram is usually normal or diffusely slow, with no ictal changes associated with the involuntary 140 movements. Descriptions of the neuropathological findings at autopsy are limited and inconsistent. Findings have ranged from normal to extensive neuronal loss and gliosis, 140 particularly in the external globus pallidus. Typical features of infarction are characteristically absent. Certain risk factors have been suggested, including (1) cyanotic congenital heart disease, particularly with systemic-to-pulmonary collaterals from the head and neck; (2) age at surgery older than 9 months; (3) excessively short cooling periods before attenuation of intraoperative blood-flow; (4) alpha-stat pH management strategy; 141–143 (5) deep hypothermia and extracorporeal Postoperative dyskinesias, usually circulation; and (6) preexisting developmental delay. 144,145 mild and transient, have been reported after prolonged use of fentanyl and midazolam. Once manifest, the involuntary movements are very refractory to treatment and generally respond poorly to a wide variety of conventional antidyskinetic medications, including dopamine receptor blockers (phenothiazines and butyrophenones), dopamine-depleting agents (reserpine, tetrabenazine), dopamine agonists (levodopa), GABAergic agents (benzodiazepines, barbiturates, baclofen), and other agents such as valproic acid, carbamazepine, phenytoin, diphenhydramine, and chloral hydrate. In general, successful movement control has been achieved only at the expense of excessive sedation. Given these limitations, the management of postoperative movement disorders should focus on the often severe agitation and insomnia. General measures, such as a decrease in the level of external (e.g., noise, light) and internal (e.g., pain) stimuli, are useful in decreasing the intensity of involuntary movements. Judicious use of sedation should aim to restore the fragmented sleep-wakefulness cycle. Oromotor dyskinesia is often severe enough to impair feeding and predispose to aspiration. Nasogastric or even gastrostomy tube feedings may be necessary to meet the high caloric demands of the constant involuntary movements.
Spinal Cord Injury 146,147
Spinal cord injury is a relatively rare complication of pediatric cardiac surgery and usually occurs after aortic coarctation repair, in which 0.4 to 1.5 percent of cases may be affected. Intraoperative spinal cord injury is mediated by hypoxic-ischemic/reperfusion injury to watershed territories in the cord, most commonly in the lower thoracic cord, where transverse infarction results in postoperative paraplegia. An additional watershed zone runs between the supply territories of the anterior and posterior spinal arteries; ischemia in this region results in predominant or selective anterior horn cell loss.
Brachial Plexus and Peripheral Nerve Injury Prolonged immobility during and after cardiac catheterization and surgery predisposes peripheral nerves to pressure and traction injury. Pressure palsies may occur at any dependent site, but most commonly involve the peroneal and ulnar nerves. Brachial plexus 148,149 Injury to the lower plexus results injury is not uncommon after cardiac catheterization. from prolonged traction during the extreme and sustained arm abduction required in some procedures. This neuropraxic lesion resolves gradually but usually completely. During cardiac catheterization, the insertion of indwelling central venous catheters through the internal jugular vein may injure the upper brachial plexus by direct physical trauma or extravasation of blood into the plexus. Phrenic nerve injury results from150 hypothermic injury by ice packed around the heart or from phrenic nerve injury has also been direct intraoperative transection. Postoperative 151,152 Intraoperative phrenic nerve injury presents described after malposition of chest tubes. with diaphragmatic palsy and prolonged postoperative ventilator dependence. The lesion may 153 be confirmed at the bedside by nerve conduction studies and electromyography. Most phrenic nerve injuries resolve spontaneously, but154 occasionally diaphragmatic plication or, in Younger infants are more likely than rare instances, diaphragmatic pacing is required. 151,152 older children to require diaphragm plication. Postoperative ventilation is commonly facilitated by the use of neuromuscular blocking agents. Prolonged use of nondepolarizing agents, especially vecuronium and pancuronium, 105,155–157 The concomitant use of has been associated with neuromuscular dysfunction. 157 steroids may increase the risk. The neuropathological spectrum in these conditions is
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highly variable, ranging from necrotizing myopathy to axonal motor neuropathy with variable 156 sensory involvement. These conditions may be difficult to distinguish from “critical illness polyneuropathy.” NEUROLOGICAL COMPLICATIONS OF CARDIAC TRANSPLANTATION Cardiac transplantation has become a rescue treatment for children with either primary (myocarditis/cardiomyopathy)158 or secondary (to associated congenital heart disease) 10-year survival rates from various pediatric end-stage myocardial failure. Reported 159 institutions range from 42 to 73 percent. More effective immunosuppression has advanced the survival of transplant recipients; however, long-term immunosuppression remains a major challenge and has well-recognized neurological complications. The passage to heart transplantation is itself fraught with risk of neurological injury, particularly hypoxic-ischemic, as is the transplantation procedure, which may be complex and involve long periods of bypass support. Adult autopsy studies have described brain injury in more than 80 percent of transplant recipients, consisting of vascular (up to 60%), infectious (20%), and lymphoproliferative disorders (13%). In a recent pediatric 160 autopsy study, brain injury was described in 87 percent of transplant recipients. In the first 2 weeks after transplantation, the most common complications are stroke, drug neurotoxicity, hypoxic-ischemic encephalopathy, and acute psychosis. In a recent report, 161 seizures occurred in 21 percent of children post-transplantation. Later, the complications of chronic immunosuppression, such as opportunistic 162 infections, lymphoma, drug neurotoxicity, and metabolic encephalopathy, are more common. Further discussion of these complications is provided in Chapters 3 and 46.
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 5 Neurological Manifestations of Acquired Cardiac Disease, Arrhythmias, and Interventional Cardiology COLIN D. LAMBERT • DAVID J. GLADSTONE •
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CARDIOGENIC EMBOLISM Clinical Features Investigations Causes Atrial Fibrillation and Flutter Cardioversion in Atrial Fibrillation or Flutter Chronic Sinoatrial Disorder Cardiomyopathies Myocardial Infarction and Left Ventricular Dysfunction Rheumatic Heart Disease Atrial Myxoma Marantic (Nonbacterial Thrombotic) Endocarditis Other Echocardiographic Abnormalities Linked to Stroke Acute Medical Treatment of Cardiogenic Embolism SYNCOPE INTERVENTIONAL PROCEDURES Coronary Catheterization Percutaneous Transluminal Coronary Angioplasty and Stenting Thrombolytic Therapy for Acute Myocardial Infarction
The neurological manifestations of acquired cardiac disease fall into several categories: 1. The sudden onset of a focal neurological deficit due to occlusion of a cerebral or retinal artery by an embolus that has developed within the heart (cardiogenic embolism) 2. Transient, self-limited episodes of generalized cerebral ischemia that occur as a consequence of brief failures of cardiac output, due to either rhythm disturbances or outflow obstruction, resulting in presyncope or syncope 3. The complications of invasive techniques for the investigation or management of cardiac disease
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The major exceptions to these generalizations occur with atrial fibrillation (AF), which is associated with embolus formation rather than syncope, and with chronic sinoatrial disorder, which predisposes to both syncopal and embolic disturbances. Topics that are the focus of other chapters are not considered here. In this chapter, the term stroke is used to mean the sudden onset of a focal neurological deficit of ischemic origin. Cerebral embolus is used where the deficit is thought to be of embolic origin. The term cardiogenic embolism is reserved for events in which the embolic occlusion is considered to be the result of a cardiac source of emboli. This chapter addresses three major situations: (1) cardiogenic embolism, (2) arrhythmias and their manifestations (syncope), and (3) interventional procedures. CARDIOGENIC EMBOLISM
Clinical Features Ischemic stroke or transient ischemic attack (TIA) may be classified into six major etiological 1 categories, which have implications for treatment and prognosis. This is the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification, the standard now for clinical studies. These categories are cardioembolism, large-artery atherosclerosis, small-artery (lacunar) occlusion, stroke of other determined etiology, stroke of undetermined etiology, and events of multiple possible etiologies. The first four categories are also subdivided into probable or possible. Strokes in the undetermined group are classed as either completely or incompletely evaluated. The last category accommodates those in whom more than one established cause is present. Cardiogenic brain embolism accounts for about 20 percent of acute ischemic strokes overall. Coexistent pathology (i.e., arterial and heart disease in the same patient) may be present in 2 up to one third of patients with a potential cardiac source of embolism. The most common 3 cardiac cause of ischemic stroke is AF, which accounts for about one sixth of all strokes. Other cardiac causes of stroke are listed in Table 5-1. Click here to view this table.... In the young stroke population (generally regarded as patients who have their first stroke 4 around the age of 15 to 45 years), 60 or so causes had to be considered in one study. In that study of 329 patients, cardioembolism was thought to be responsible in 64 (just under 20 percent). There were 13 diagnoses in these 64 patients, with the top three being paradoxical embolism and prosthetic or rheumatic valve disease. No patients had AF, a feature also 5 noted in a Swedish study. Strokes attributable to a cardiac source show striking differences in various studies. In a Persian study of 124 patients, 54 percent were thought to be of 6 cardiac origin. Rheumatic heart disease was the major culprit.7 In contrast, a French study of 296 patients attributed less than 9 percent to a cardiac cause. In Italy, the figure was 34 8 percent. This was a hospital-based study of 394 consecutive young adults with ischemic stroke submitted to a comprehensive diagnostic protocol. Of the 133 considered to be of cardiac origin, these were subdivided into two groups according to TOAST criteria. The smaller group (23) had a probable cause including recent myocardial infarction, AF, valvulopathy, patent foramen ovale (PFO) with deep vein thrombosis (DVT) and atrial myxoma. The much larger group (110 patients) had various possible causes: PFO with right to left shunt (60), atrial septal aneurysm (ASA) (22), and PFO plus ASA (16). Looked at another way, 23 of 394 patients (6%) had an established cardiac cause. Attribution was less certain in 28 percent. In Korea and Taiwan, around 18 percent of cases were attributed to a 9,10 Comparison of etiological factors in the occurrence of TIAs in younger, as cardiac cause. opposed to older, patients disclosed that only two cardiac sources were encountered 11 more frequently in the younger age group: valvular heart disease and mitral valve prolapse. Features suggesting cardioembolism are usually derived from analysis of the clinical presentation and neuroimaging features of acute ischemic strokes that occur in12–19 patients with Emboli cardiac abnormalities thought to predispose to thrombus formation (Table 5-2). may lodge in either the anterior (carotid) or the posterior (vertebrobasilar) circulation. The anterior circulation is affected four times more commonly than the posterior. Least likely to be affected are the20entire internal carotid artery, deep branches of the middle cerebral artery, and brainstem. Although the posterior circulation is less commonly affected, studies of the mechanism of infarction in specific territories (e.g., those of the posterior inferior cerebellar artery and superior cerebellar artery) implicate cardiogenic embolism in 50 percent of 21 with isolated cerebellar cases. A cardioembolic mechanism occurred in 67 percent of cases 22 infarcts (i.e., without concomitant brainstem or occipital infarcts). Embolism is also a
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common mechanism of infarction within the territory of the posterior cerebral artery. Click here to view this table....
Stroke recurrence rate and prognosis have been estimated in several studies. A meta-analysis showed that the 3-month risk of recurrent stroke was 12 percent if the etiology was cardioembolism, compared to 19 percent for large-vessel atherosclerosis, 3 percent for 24 small-vessel disease, and 9 percent for unknown cause. In a population-based study of first stroke in Bavaria, patients with cardioembolic stroke had the lowest 2-year survival rate (55%) and were three times more likely to be dead at 2 years compared to those with 25 small-artery occlusion.
Investigations The first neurological investigation for suspected stroke is usually a computed tomography (CT) scan of the head to exclude intracranial hemorrhage or other nonischemic pathological processes and to identify signs of acute infarction or vessel occlusion. In patients at high-risk of cardioembolism, cranial CT disclosed infarcts that were more likely to involve one half of a 12 lobe or more, or the infarcts involved both superficial and deep structures. Deep small infarcts were underrepresented and were considered to have a predictive value of 90 percent 12 for the absence of a major cardiac source. Similar conclusions were drawn in an earlier study, namely, that the mechanism underlying lacunes is infrequently embolic and that infarctions in26the pial (superficial) artery territory are usually indicative of an embolic mechanism. The potential for embolic infarcts to develop hemorrhagic transformation remains a concern, especially when anticoagulant therapy has to be considered. A hemorrhagic infarct was seen on the initial CT scan of 612percent of patients in a series of 244 cases, none of whom were In a series of scans performed within 48 hours of onset, the figure receiving anticoagulants. 27 rose to2824 percent ; on prospective follow-up scanning, a total of 40 percent was found at 1 month. With the more sophisticated technology of magnetic resonance imaging (MRI), the figure rose to nearly 70 percent at 3 weeks. Both of the latter studies showed that larger infarcts were more liable to demonstrate hemorrhagic3 transformation, with a figure of 90 29 percent for infarcts with a volume greater than 10 cm . Thus, the key factors that determine whether hemorrhagic transformation occurs appear to be the time of the study, size of the infarct, and technology applied. The age of the patient may also be a factor in that patients 28 older than 70 years may be more liable to hemorrhagic transformation. Because of concerns for the complications of acute stroke treatment by thrombolysis or anticoagulation, early pointers to hemorrhagic transformation have been sought. The only independent predictor identified in a study of 150 consecutive patients was focal hypodensity found by CT scanning within the first 5 hours after stroke onset. Mortality was twice as high in the hemorrhagic-transformation group owing to the larger size of infarcts in that group. Evolution29of the transformation process was similar in anticoagulated and nonanticoagulated patients. MRI is the most sensitive test for detecting 30 early infarction. Diffusion-weighted images are superior to T2-weighted images and to CT. The pattern of diffusion-weighted imaging abnormalities can help to determine the most likely etiological diagnosis. For example, a pattern of multiple acute lesions in more than one vascular territory (bilateral lesions or lesions in the anterior and posterior circulations) suggests a shower of cardiogenic emboli. Single cortical-subcortical lesions are also associated with a cardiac source of emboli. Conventional catheter angiography remains the definitive method for assessing structural abnormalities of the extra- and intracranial circulation. Use of this invasive procedure requires recognition of the associated risks. A review of 15 studies (8 prospective) concluded that the mortality rate was very low (less than 0.1%) but that the risk of a neurological complication (TIA or stroke) was approximately 4 percent and that of a permanent neurological deficit was 31 1 percent. The characteristic angiographic appearance of an embolic occlusion is of a proximal, meniscus-like filling defect in an artery that is otherwise normal and lacks evidence of atherosclerotic change. Emboli tend to fragment. In a study of 142 patients who underwent angiography, the initial procedure, performed at a median of 1.5 days after the precipitating event, revealed an occlusion in 82 percent. Follow-up angiography, at a median of 20 days, 28 showed reopening of the vessels in 95 percent. Distal branch occlusions are often also considered to be embolic manifestations. Conventional catheter angiography has now been largely replaced by noninvasive contrast-enhanced CT angiography or magnetic resonance angiography in many countries because of increased availability and lower complication rates.
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Echocardiography has come to occupy a preeminent place in the structural evaluation of the heart. Transthoracic echocardiography (TTE) is noninvasive but has limitations that can be overcome by using the transesophageal (transesophageal echocardiography [TEE]) route. For the latter procedure, the patient is usually mildly sedated and topical anesthetic is applied to the posterior pharynx. In experienced hands, the procedure was successfully 32 accomplished in 98 percent of instances. The complication rate was less than 1 percent. The technique employed (TEE or TTE) depends on the area to be visualized. The two procedures can be considered complementary; TTE images the left ventricle well, but TEE is required for adequate assessment of the left atrium and its appendage. TEE is also better for visualizing a PFO. TEE is the most sensitive and specific test for detecting a cardiac source of embolism. For patients with AF, TEE may assist in risk stratification and guide 3 cardioversion. A review of papers published between 1966 and 1998 evaluated the yield of TTE or TEE, or both, in various subgroups of patients with stroke. The figures reached were, for TTE, an overall yield of less than 1 percent in patients without clinical evidence of cardiac disease, rising to 13 percent in those with cardiac disease. The corresponding figures for TEE were 33 less than 2 percent and 19 percent. The recommendations reached highlight some uncertainties. It was concluded that there was fair evidence to recommend echocardiography in patients with stroke and clinical evidence of heart disease (grade B recommendation). Because the yield from TEE is higher than that for TTE, controversy arises as to whether this should be the first intervention. Some have preferred a sequential approach with TTE 34 but others have suggested that it is more cost-effective to followed by TEE, if indicated, 35 proceed directly to TEE. Clearly, the area to be visualized is a major consideration. Cardiac MRI is emerging as a new technology for noninvasive structural imaging of the heart. MRI is more sensitive than TTE and comparable to TEE for the detection of cardiac thrombi. Transcranial Doppler ultrasonography is a noninvasive tool that can be of value in the acute stroke setting for detecting acute intracranial vascular obstruction (e.g., due to an occlusive embolus in the middle cerebral artery) and can monitor recanalization following treatment with thrombolysis. It can also be used to detect right-to-left cardiac shunts due to PFO. By identifying microbubbles reaching the middle cerebral arteries, especially following the Valsalva maneuver, contrast-enhanced transcranial Doppler ultrasonography has shown near-perfect 36,37 correlation with contrast-enhanced TEE for the detection and quantification of such shunts. It remains necessary for the clinician to balance extensive investigation against its impact on patient management, usually the justification for lifelong anticoagulant therapy and its consequent risks. In several situations, there are no established guidelines for management. The onus remains on the clinician to determine the significance of potential sources of emboli and their implications for management.
Causes Atrial Fibrillation and Flutter Atrial fibrillation, the most common arrhythmia in medical practice, is a major risk factor for stroke and death. This arrhythmia accounts3 for nearly half of all cardiac causes of stroke and about one quarter of strokes in the38elderly. Strokes associated with AF are generally severe, and 1-year39,40 mortality is 50 percent. AF is also a risk factor for silent strokes and vascular dementia. The prevalence of AF is strongly age dependent, ranging from 0.1 percent among adults 38 older than 55 years to 9 percent in those 80 years38or older. Over 2 million individuals have AF in the United States, and prevalence is rising. AF typically occurs in patients with underlying cardiac disease (i.e., valvular heart disease, heart failure, coronary disease, hypertension, cardiomyopathy, mitral valve prolapse, mitral annular calcification, and cardiac tumors), but may also occur as “lone AF” in young patients who have no cardiac disease. It may be paroxysmal (self-terminating episode, lasting less than 7 days), recurrent (2 or more episodes), persistent (more than 7 days), or permanent (cardioversion failed or not attempted). Reversible or temporary causes include alcohol, surgery, hyperthyroidism, acute 3 myocardial infarction, pulmonary embolism, and pericarditis, among others. The average annual risk of stroke in individuals with AF is 5 percent and is heavily dependent on age and the presence of additional risk factors (Table 5-3). In the Framingham Study, stroke risk41was 1.5 percent in the age group 50 to 59 years and 23.5 percent in those 80 to 89 years.
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Click here to view this table.... It is well established that the risk of stroke in AF is related to the presence or absence of associated structural cardiac disease and other risk factors. For example, in the absence of rheumatic heart disease, there is a fivefold increase in stroke42incidence, but this increases to 17-fold when associated with rheumatic mitral valve disease. Only in lone AF (i.e., fibrillation in the absence of overt cardiovascular disease or precipitating illness) developing in middle age is the prognosis relatively benign. Follow-up at 1543years disclosed a rate of thromboembolic events of 0.55 per 100 person-years. This was equivalent to 1.3 percent of the patients experiencing a stroke on a cumulative actuarial basis. The most important predictor of stroke risk in patients with AF is a history of thromboembolism (i.e., previous TIA, stroke, or systemic arterial embolism). Other independent risk factors for stroke in AF are hypertension, heart failure, increasing age, and diabetes mellitus. Other factors that have been associated with increased stroke risk in some 3 studies include female sex, systolic hypertension, and left ventricular dysfunction. Echocardiographic features that have been used for risk stratification in patients with AF include left ventricular systolic dysfunction, atrial thrombus, dense spontaneous echo contrast or reduced blood flow velocity within the left atrium or left atrial appendage on 44 TEE, and aortic atheroma. Left atrial size does not appear to predict risk of thromboembolism. TEE is the method of choice for evaluating the left atrial appendage, the site at which most thrombi form, and the left atrium. In a prospective study of patients with AF considered on clinical grounds to be at high risk of stroke, risk was 18 percent per year in those with dense spontaneous echo contrast who were treated with low-dose warfarin (international normalized ratio [INR] 1.2 to 1.5) plus aspirin compared to 4.5 percent for those on dose-adjusted warfarin. Prevalence of thrombus in the left atrial appendage was similar initially in the two treatment groups (10% to 12%) when TEE was performed more than 2 weeks after study entry, but atrial thrombus was present in 6 percent of those on warfarin compared to 18 percent of those on combination therapy, and stroke rate was 13 percent per year in the latter group. Absence of thrombus predicted a low rate of ischemic events (2.3% per year); the presence 45 of thrombus predicted a high rate (18% per year). That the risk of stroke in AF can be significantly reduced by anticoagulation was clearly 46–49 A fifth, Canadian, study was terminated prior to established by four independent studies. 50 completion because the other studies51had shown clear evidence of benefit. A meta-analysis published in 1999 evaluated 16 trials. Six were of dose-adjusted warfarin versus placebo. The conclusions drawn from the original four studies were upheld. Warfarin reduced stroke risk by 62 percent overall. Absolute risk reductions were higher for secondary prevention (8.4% per year) than primary prevention (2.7%). These percentages translate into the numbers needed to treat (NNT) of 12 and 37, respectively. Although more intracranial hemorrhages (ICHs) occurred in the warfarin group (0.3% per year) compared to those on placebo (0.1%), this was not statistically significant. Major extracranial hemorrhage occurred in 0.6 percent per year of patients on placebo, with a relative risk of those on warfarin of 2.4 (absolute risk increase, 0.3% per year). The total number of patients in the six trials was 2,900, with an average follow-up of 1.7 years. The aforementioned risk reduction with warfarin was based on intention-to-treat analysis; the on-treatment analysis reveals more than 80 percent relative risk reduction in stroke. This meta-analysis also evaluated adjusted-dose warfarin compared to aspirin. There were five trials, all unblinded, totaling 2,837 individuals. Excluding one study because the range of the INR was wide (2.0 to 4.5), the relative risk reduction for warfarin compared to aspirin was 46 percent. 51
The issue of aspirin as an alternative to warfarin has also been addressed in several trials. Aspirin dose ranged from 25 to 1,200 mg daily. More than 3,000 patients were studied, with an average follow-up of 1.5 years. In patients receiving placebo, the stroke rate was 5.2 percent per year for primary prevention and 12.9 percent for secondary prevention. Aspirin reduced stroke risk by 22 percent, resulting in numbers needed to treat of 67 and 40, respectively. The trials showed only a trend toward reduced stroke in aspirin-treated patients. All-cause mortality was not reduced. The authors suggested that the benefit of aspirin is to prevent nondisabling stroke that is not of cardioembolic origin. Therefore, published guidelines strongly recommend warfarin52rather than aspirin for stroke prevention in individuals with AF who are at high risk. In practice, despite the clear benefit of warfarin in stroke prevention in patients with AF, this therapeutic intervention is frequently underused. Many studies from different countries have 53–55 demonstrated suboptimal rates of appropriate antithrombotic therapy for patients with AF.
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Several potential reasons account for underuse of warfarin, including physician factors, patient factors, and geographic practice variations. Warfarin is a difficult medication for patients because of the inconvenience of INR monitoring, drug and food interactions, and bleeding risks. However, physicians frequently overestimate the bleeding risks 56 but underestimate the benefits of warfarin and overestimate the benefits of aspirin. Although major adverse bleeding events associated with warfarin occur with a relatively low 57 58 incidence, they may profoundly bias physician prescribing behavior. There is often a bias against prescribing warfarin to patients of advanced age, especially elderly women, despite 59 the fact that safety in patients 80 years and older has been established. Individual patient preferences, knowledge, and attitudes affect compliance with long-term anticoagulation therapy. Among AF patients taking warfarin in one study, about one half did not know that AF was a risk factor for stroke and could not state why they were taking warfarin; ethnic differences in knowledge about their diagnosis and treatment were also 60 identified. Methods to encourage compliance with appropriate antithrombotic prophylaxis include use of a patient decision aid. One such tool is available for download at www.canadianstrokenetwork.ca/research.clinicians.php and is highly recommended for use by primary care physicians and specialists who are counseling AF patients about the benefits and risks of warfarin compared to those of aspirin for stroke prevention. A home INR finger-stick device for self-monitoring may increase the duration patients spend in the 61 therapeutic INR range. Bleeding is the major concern with anticoagulant therapy. The average risk of major bleeding in the clinical trials was 1.3 percent per year with warfarin compared to 1 percent with aspirin 62 rate of major or placebo. The Stroke Prevention in Atrial Fibrillation study had a higher 62 bleeding at 2.3 percent on warfarin and 1.1 percent per year on aspirin. Rates of ICH were 0.9 percent per year and 0.3 percent per year, respectively. Age older than 75 years increased the risk of major hemorrhage to 4.2 percent per year (relative risk = 2.6) compared to 1.7 percent per year in the younger population. Of patients on warfarin, 16 were in the therapeutic range, 4 were below, and 13 were above at the time of their bleed. All had had therapeutic levels on their last routine prothrombin time ratios. Intensity of anticoagulation was a risk factor for bleeding only in those older than 75 years. The other identified risk factor 62 was the use of more than three prescription drugs. Interestingly, in another study, patients with cerebral ischemia of presumed arterial origin had a substantially higher risk of ICH than 63 those anticoagulated for AF. Leukoariosis is a newly identified risk factor. Analysis of a cohort of patients attending five anticoagulation clinics documented the cumulative risk of bleeding over an 8-year period. Serious bleeds occurred at a rate of 7.5 events per 100 patient-years. Points that emerged were that the incidence of bleeding and thromboembolic complications remained approximately constant, with a prothrombin time ratio of 1.3 to 2.0, but it increased sharply above or below those limits (i.e., thromboembolism was much more likely with a prothrombin time ratio of less than 1.3). No increase in bleeding complication was found related to any specific indication for therapy, including cerebrovascular disease. Older patients did not have a greater risk of bleeding. The highest risk of bleeding was seen during the first 3 months of therapy, and then it tended to plateau somewhat. Of particular note was the high risk of recurrence (32%) in patients who experienced one serious bleed. It was also noted that patients who had more than four dose 64 adjustments per year bled 25 percent more often than those who had fewer adjustments. With the exception of some patients with lone AF, all patients with AF (regardless of whether this is paroxysmal, persistent, or permanent) require some form of antithrombotic therapy unless contraindicated. It remains necessary to individualize management strategies for specific patients, taking into account compliance, risk of bleeding complications, and other medical conditions. Risk stratification is essential to determine the optimal treatment, i.e., warfarin or aspirin. Many different schemes have been devised for identifying patients with AF unassociated with valvular heart disease that are at high, moderate, or low risk of stroke. According to the 2006 American Heart Association guidelines, high risk factors 3are previous stroke, TIA, or systemic embolism, mitral stenosis, and prosthetic heart valves. Moderate risk factors include age 75 years or older; hypertension; heart failure; left ventricular ejection fraction 35 percent or lower; and diabetes. Warfarin is recommended for patients with any high risk factor or more than one moderate risk factor. This means that all patients with a previous ischemic stroke or TIA are considered at high risk and require warfarin anticoagulation for secondary stroke prevention, unless contraindicated. Warfarin or aspirin (81 to 325 mg) is recommended for those with only one moderate risk factor. Aspirin alone (81 to 325 mg) is considered sufficient for patients without any of these risk factors. For patients receiving warfarin, the target INR should be 2.5 (range 2.0 to 3.0). The INR should be monitored closely: usually weekly initially and then monthly once stable. A
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minimum INR of 2.0 is recommended for stroke prevention; stroke risk increases 65 exponentially as the intensity of anticoagulation declines. In addition to protecting against stroke, antithrombotics attenuate stroke severity: patients taking warfarin at the time of stroke have less-disabling strokes compared to individuals taking aspirin or no antithrombotic therapy, and stroke severity is negatively correlated with 66,67 Table 5-4 gives a summary of the indications for warfarin in INR at stroke onset. secondary stroke prevention for patients with selected cardiac conditions. Click here to view this table.... For patients with a mechanical heart valve, the INR should be maintained above 2.5, and for 52 secondary stroke prevention, the target INR should be 3.0 (range 2.5 to 3.5) Dual antiplatelet therapy (aspirin plus clopidogrel) was investigated in a randomized trial and found to be inferior to warfarin for stroke prevention in AF and associated with a higher rate of 68 adverse bleeding events than warfarin. If warfarin therapy needs to be interrupted for surgical procedures, temporary discontinuation for up to 1 week is usually considered reasonable for patients without mechanical heart valves. However, this practice can be associated with increased stroke risk. Heparin may be substituted in high-risk patients. In addition to medical therapy for stroke prevention in AF, interventional techniques are being investigated. These include percutaneously implanted left atrial appendage occlusive devices and surgical resection of the left atrial appendage, given that 91 percent of thrombi are 69 localized at that site. Carotid artery endovascular devices to filter emboli are also under investigation. Cardioversion of AF to sinus rhythm (either pharmacological or electrical) does not reduce the risk of stroke and therefore does not obviate the need for continued anticoagulation 70,71 therapy for stroke prevention. AF occurring in the postoperative setting following cardiac surgery is fairly common and usually self-limited. Anticoagulation is reasonable if AF persists for more than 48 hours, but it may not need to be continued long-term if sinus rhythm is restored. Similarly, other conditions associated with transient AF (e.g., alcohol, thyrotoxicosis) usually do not need long-term 3 antithrombotic prophylaxis. In patients with atrial flutter, the risk of thromboembolism is thought to be less than that for AF but higher than for patients in sinus rhythm. These patients frequently go on to develop AF. For practical purposes, the antithrombotic treatment recommendations are similar to 3 those for AF. Cardioversion in Atrial Fibrillation or Flutter Cardioversion (electrical or pharmacological) undertaken to convert AF back to sinus rhythm is associated with an increased risk of thromboembolism. Review of7222 series published over a 30-year period showed an overall risk of embolism of 1.5 percent. Figures have changed 73 It appears that up to 3 weeks may be little in recent years, with an incidence of 1.3 percent. 74 required for atrial mechanical activity to recover. It is therefore recommended that warfarin (INR 2.0 to 3.0) be given for at least 3 weeks before elective cardioversion of patients who have been in AF for 2 days or more or when the duration of AF is unknown and that it be 3 continued until normal sinus rhythm has been maintained for 4 weeks. For patients requiring immediate cardioversion, intravenous heparin is recommended 3 concurrently followed by warfarin for at least 4 weeks. Alternatively, TEE prior to cardioversion can be performed; if no thrombus is detected, then cardioversion can occur as soon as the patient is anticoagulated and continue for at least 4 weeks. If a thrombus is detected on TEE, warfarin is recommended for at least 3 weeks before and may need to be continued for a longer duration afterward. 3
The recommendations for cardioversion in atrial flutter are the same as for AF. Atrial flutter has been studied less extensively than AF, but embolism can occur in relation to cardioversion or during subsequent months. The total incidence of acute and chronic events was found to be 7 percent over a period of 26 75 ± 18 months in a consecutive series of 191 unselected patients undergoing cardioversion. The same percentage was found in a smaller study of 86 patients who were followed for a longer period (mean,764.5 years). Annual risk was estimated at 1.6 percent, one third of the rate for those with AF. Prior
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transesophageal echocardiography is not an adequate predictor of those at risk. A total of 3 of 41 patients who had no left atrial77clot developed ischemic neurological syndromes within echo contrast was a more 48 hours of elective cardioversion. In another study, spontaneous 78 common finding than atrial thrombosis (34% versus 11%). Chronic Sinoatrial Disorder As with atrioventricular block, chronic sinoatrial disease (sick sinus syndrome) presents usually with syncope and dizziness but differs in predisposing to systemic embolism. In a study comparing age- and sex-matched control subjects with atrioventricular heart block to those having chronic sinoatrial disorder, prevalence of systemic embolism was found in 16 percent of those with 79 sick-sinus syndrome compared to 1.3 percent of those with patients with the atrioventricular block. Other studies have disclosed similar figures; 80,81 Insertion of a “brady-tachy” form of the disorder appear to be particularly at risk. pacemaker does not protect against embolic phenomena. In one series, 6 of 10 strokes developed after pacemaker insertion. Only one of these patients was anticoagulated at the 82 time. Concern was raised that, although ventricular pacing provides symptomatic relief, this modality may worsen the underlying disease process by increasing the rate at which AF, 83 congestive heart failure, and thromboembolism occur. Many studies relating to various pacemaker types have followed. A Cochrane review noted poor quality of reporting but concluded that physiological (primarily dual-chamber) pacing had a statistically significant 84 benefit in preventing the development of AF compared to ventricular pacing. A nonsignificant preference for stroke prevention was found. A large subsequent study, also comparing ventricular with dual-chamber pacing, concluded that clinical features were the 85 key predictors of stroke. In the same year, a Danish study showed single-chamber atrial pacing to be superior to dual-chamber pacing in the prevention of AF and 86 thromboembolism. Patients in the brady-tachy group were noted to be more at risk of developing AF and stroke. It was concluded that warfarin treatment should be considered for these patients. Cardiomyopathies This continues to be a rapidly changing field. A new definition and classification were 87 proposed in 2006. Cardiomyopathies are defined as “a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually ‘but not invariably’ exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of 87 causes that frequently are genetic.” Specifically excluded are those diseases of the myocardium secondary to congenital or valvular heart disease, systemic hypertension, or atherosclerotic coronary disease. The cardiomyopathies are then divided into two major groups based on predominant organ involvement. The primary cardiomyopathies are those solely or predominantly confined to heart muscle. Genetic, mixed, and acquired forms are recognized. Both hypertrophic and dilated cardiomyopathies are considered primary diseases. Also now included are the ion channel disorders, in which there is a primary electrical disturbance without structural cardiac pathology. These are further considered in the section devoted to syncope. The list of secondary cardiomyopathies is extensive. Neuromuscular or neurological causes listed are Friedreich's ataxia, Duchenne or Becker muscular dystrophy, Emery–Dreifuss muscular dystrophy, neurofibromatosis, and tuberous sclerosis. Surprisingly, the mitochondrial cytopathies, quintessentially multisystem disorders, are listed as primary cardiomyopathies. The secondary cardiomyopathy table classification does not include infective processes, such as Chagas' disease or infection with human immunodeficiency virus, although these are briefly mentioned in the text. In North America, the most common cardiomyopathy is hypertrophic cardiomyopathy, which 88 is an autosomal-dominant disease affecting 1:500 of the general population. The disorder is notorious as 89 a major cause of sudden cardiac death in athletes but is compatible with survival until old age. Mortality rates overall have been estimated at 1.0 to 1.5 percent for ages 16 to 65, 3.9 percent over the next decade, and 4.7 percent for ages older than 75 years. Risk was 90 risk in hypertrophic generally similar in Western and Asian populations. Stroke 91 cardiomyopathy has been studied in a group of 900 patients. Stroke occurred in 44 patients over a period of 7 ± 7 years. A small number (7) of other vascular events were noted. Age at first event ranged from 29 to 86 years, with a mean of 61 ± 14 years. Stroke was particularly associated with advanced age, congestive symptoms, and AF. The cumulative incidence of events was significantly higher in nonanticoagulated patients with AF compared to those receiving warfarin. Other studies confirm increased risk of stroke when AF develops in
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hypertrophic cardiomyopathy, but surprisingly also identified a subgroup in which the course 92 92,93 also increased the risk of stroke. The odds was largely benign. Outflow tract obstruction 92 ratio for stroke in patients with AF was 17.7. There are considerable geographic variations in the causes of cardiomyopathy. In Latin America, American trypanosomiasis (Chagas' disease) is a major cause. Stroke has been increasingly well documented as a complication. A study of 94 consecutive stroke patients with the cardiomyopathy of Chagas' disease compared these with 150 consecutive stroke 94 patients without Chagas' disease. A cardioembolic basis for stroke was considered present in 56 percent of the former compared to 9 percent of the controls. Most strokes in the group with Chagas' disease were in the anterior circulation (85%); the posterior circulation was rarely affected (5%) and less than 10 percent of the patients presented with lacunar syndromes. In Chagasic cardiomyopathy, the apical region of the left ventricle is the typical site for formation of thrombosis or aneurysm. Echocardiography in this study revealed an apical aneurysm in 37 percent and mural thrombosis in 12 percent, but the most common finding was left ventricular diastolic dysfunction (49%). The ECG was abnormal in 67 percent. The most common abnormality was a right bundle branch block pattern (35%), followed by left His fascicular block (17%), and AF (15%). A pacemaker had been inserted in 10. Oral anticoagulation has been recommended for all94individuals with Chagasic stroke who demonstrated risk factors for cardioembolism. In Africa, the major cardiomyopathy is the dilated type, but peripartum cardiomyopathy is 95 ubiquitous with an incidence ranging from 1:100 to 1:1,000. There are regional variations: endomyocardial fibrosis is restricted to the tropical regions of East, Central, and West 95 Africa. The incidence of human immunodeficiency virus (HIV)–associated cardiac disease, including cardiomyopathy, is increasing in contrast to developing countries where the availability of96highly active antiretroviral therapy has significantly reduced the incidence of myocarditis. In Japan, hypertrophic cardiomyopathy is the most97common cause of cardiomyopathy, followed closely by dilated cardiomyopathy (DCM). Cardiomyopathy associated with the prolonged QT interval syndrome came in a distant third, followed by mitochondrial disease, 97 arrhythmogenic right ventricular dysplasia, and Fabry's disease of the heart. In young adults arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is 98 another rare hereditary disorder causing sudden death. In a natural history study of 130 patients, 100 male, age at onset of symptoms was 32 ± 14 years. The annual 99 mortality rate Diagnosis was 2.3 percent; all patients who died had a history of ventricular tachycardia. 87 requires a high index of suspicion. In the dilated cardiomyopathies, a necropsy study showed a high incidence of embolic events (systemic or pulmonary) at 60 percent of 152 cases. In the living, once52a TIA or stroke has occurred, either warfarin or antiplatelet therapy should be considered. There is insufficient evidence to recommend warfarin or antiplatelet therapy for primary prevention, in the 100 absence of other indications. Myocardial Infarction and Left Ventricular Dysfunction 101
Patients with a history of coronary artery disease have a threefold increase in stroke risk. 102 This risk is particularly high within the first month after myocardial infarction (MI). Mechanisms include embolism from left ventricular 103 mural thrombosis and the development of AF (which occurs in up to 20% of patients after MI). A community-based study of 2,160 patients hospitalized between 1979 and 1998 found stroke risk during the 30 days after a first MI to be increased 44-fold, and it remained two to 102 three times higher than expected during the subsequent 3 years. Of note, the 20-year duration of the study enabled the conclusion to be drawn that acute MI treatment by 102 following MI is approximately 1 thrombolysis did not reduce stroke risk. Overall, stroke risk104,105 For a non-ST elevation percent during the first month and about 2 percent at 1 year. 106 acute coronary syndrome, the early stroke risk was found to be 0.7 percent at 3 months. In large randomized trials of aspirin versus the combination of aspirin and clopidogrel in patients 103 with MI or acute coronary syndrome, the stroke rate ranged between 0.9 and 1.7 percent. In a meta-analysis, predictors of stroke following MI included advanced age, diabetes,104 hypertension, previous stroke or MI, anterior MI, AF, heart failure, and nonwhite race. 107 Anterior wall MI has been a predictor of stroke in some, but not all, studies. Left ventricular
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thrombus develops in about one third of individuals in the first 2 weeks following an anterior 108 MI. A meta-analysis of 11 studies concluded that mural thrombus formation after an MI109 poses a significantly increased risk of embolization, which is reduced by anticoagulation. The current recommendation, in the absence of thrombolytic therapy, is that, after acute MI, heparin should be initiated and followed by warfarin for 3 months in patients considered to be at increased risk of embolism, either pulmonary or systemic. High-risk patients are those with severe left ventricular dysfunction, congestive heart failure, a history of pulmonary or systemic embolism, echocardiographic evidence of mural thrombosis, or the presence of AF. Because of the increased frequency of mural thrombosis in anterior as opposed to inferior myocardial infarcts, it is also recommended that patients with an anterior Q-wave infarction 110 receive heparin followed by warfarin. In patients with TIA/ischemic stroke related to an acute MI in which LV mural thrombus is identified, oral anticoagulation is recommended for at least 3 months and52up to 1 year (INR 2 to 3) in addition to aspirin for coronary artery disease (up to 162 mg/day). Stroke risk is inversely proportional to left ventricular ejection fraction (LVEF). In a study of 2,231 patients with LV dysfunction after an acute MI, those with LVEF less than 29 percent had a stroke risk nearly double that of patients with LVEF exceeding 35 percent: the annual stroke rate was 1.5111 percent overall. Thus, reduced LVEF is an independent risk factor for in risk of embolic events for subsequent stroke. Another study found a 58 percent increase 112 every 10 percent decrease in LVEF in women, but not men. Congestive heart failure carries a two- to threefold increase in the relative risk of stroke. Among patients enrolled into heart failure trials, the overall annual stroke 113 risk has ranged between 1.3 to 3.5 percent; most patients were taking aspirin or warfarin. In the absence of clinically overt heart failure or MI, the presence of asymptomatic left ventricular systolic 114 dysfunction, even of mild degree, is an independent risk factor for stroke. The optimal antithrombotic prophylaxis for patients with poor LV function remains uncertain; 115 the efficacy of warfarin versus aspirin is the subject of ongoing trials. Rheumatic Heart Disease Extensive experience has accumulated over several decades concerning the association of systemic embolism with rheumatic heart disease. A 1973 review concisely summarized 116 relevant features. A minimum of 20 percent of patients with rheumatic heart disease experience a thromboembolic complication at some time, and 40 percent of these arterial emboli involve the brain. Embolic events are the cause of death in 16 to 35 percent of adults dying of rheumatic heart disease, and subgroups of patients having a much greater frequency of embolic complication can be identified. The risk of embolism is substantially increased when atrial thrombus is present (risk increases from 16% to 41%) or AF develops (risk increases from 7% to 30%). The proportion of patients developing left atrial thrombus increases from 9 to 41 percent when AF is present; conversely, 80 percent of patients with atrial thrombus are in AF. Embolism is most likely to occur when the dominant valvular lesion is that of mitral stenosis, either alone or in combination with aortic valve disease or mitral insufficiency. Isolated aortic valve disease is rarely associated with embolic events. Older patients more frequently have AF, atrial thrombus, and embolic events. Studies of atrial thrombosis initially involved TTE, an insensitive method. Of 293 patients in one study who were to undergo open heart surgery, TTE disclosed thrombi in the left atrium in 33. At surgery, this was confirmed in 30 of the cases, but the study had missed 21 additional patients, including all 11 in whom thrombus was located in the left atrial 117 appendage. 118
Once embolization has occurred, recurrence rate is high, approaching 60 percent. Current recommendations are therefore strongly in favor of the use of long-term warfarin (to prolong the INR to 2.0 to 3.0) in patients with rheumatic mitral valve disease who have a history of systemic embolism or who develop AF, either chronic or paroxysmal. It is also recommended that the same treatment be given to patients in normal sinus rhythm if the left atrial diameter is in excess of 5.5 cm. Furthermore, if recurrent systemic embolism occurs despite adequate 119 warfarin therapy, addition of aspirin should be considered. The beneficial effect of adding aspirin,120 100 mg daily, to warfarin has been demonstrated in the context of prosthetic heart valves.
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Atrial Myxoma Atrial myxomas have long been recognized as a cause of cerebral embolism. They are uncommon. A French hospital reviewed experience with 112 cases collected over 40 121 years. Women outnumbered men 72 to 40; ages ranged from 5 to 84 years. The presenting symptoms were cardiac, constitutional, and embolic in 67, 34, and 29 percent, respectively. Younger and male patients were more liable to have embolic events.122 Neurological manifestations, in 113 patients, were evaluated in a literature review. Ischemic stroke was the most common at 83 percent, often at multiple sites. Syncope (28%), psychiatric presentations (23%), headache (15%), and seizures (12%) were all encountered. In a Spanish study of 28 patients, it was noted that in the 9 with stroke, TIA had preceded the 123 A rare delayed complication is that of distal multiple stroke in 7. Treatment is surgical. 124 cerebral aneurysm formation. Transient ischemic attacks led to this diagnosis 5 years after successful surgery in one person. Symptoms were controlled with clopidogrel. Marantic (Nonbacterial Thrombotic) Endocarditis Although there are several causes of nonbacterial thrombotic endocarditis, a review of 14 series, predating the era of echocardiography, found an underlying malignancy in half. The most common tumor was lung cancer. Cancers of gastrointestinal origin accounted for a similar number of cases. Breast cancer appeared underrepresented. The mitral valve was most commonly affected (43%), followed by the aortic valve (36%). Overall, embolism 125 cancers of the occurred in 42 percent of patients. An autopsy series (171 cases) found126 ovaries, biliary system, pancreas, stomach, and lung to be most common. The widespread availability of echocardiography has facilitated recognition of vegetations. A prospective study of 200 unselected ambulatory patients with solid tumors found vegetations in 19 percent compared to 2 percent in controls. Vegetations were seen in 50 percent of pancreatic cancers, 28 percent of lung cancers, and 19 percent of lymphomas. Only two 127 patients had cerebral events. On MRI, numerous lesions of various sizes may be found in multiple arterial territories. At one cancer center, 96 stroke patients were assessed. Echocardiography (TTE) was performed in 61; none had TEE. An embolic mechanism was thought to be causative in 52. The heart was implicated in 14, but nonbacterial thrombotic endocarditis in only 3. Stroke of embolic origin carried a dismal prognosis. Life expectancy was just over 2 months, and 128 treatment had no apparent influence. Other Echocardiographic Abnormalities Linked to Stroke Patent Foramen Ovale and Atrial Septal Aneurysm
A PFO is present in about one quarter of adults and represents a potential mechanism for 129 cardiogenic embolism. Case-control studies of young adults (younger than 55 years) with cryptogenic stroke found130a fivefold increase in prevalence of PFO compared to control subjects without stroke. In a French prospective study of individuals with stroke and an isolated PFO, the 4-year stroke recurrence risk was 2.3 percent. For those with both PFO and ASA, the rate was 15.2 percent compared to 0 percent for those with ASA alone. In the “control group” with neither 131 PFO nor ASA, the rate was 4.2 percent. All patients in this study were taking aspirin. In another study, the presence of a PFO (with or without ASA) did not confer a significant increase in stroke recurrence rate over a 2-year follow-up; furthermore, recurrence rate did 132 not differ between patients on aspirin or warfarin or in those with large or small PFO. 133
ASA was found in 2 percent of persons in a population-based study. In elderly patients undergoing cardiac surgery, the incidence was nearly 5 percent. No patient had a cerebrovascular event over a follow-up period of 70 months; most were receiving aspirin. It 134 was concluded that the risk of embolic stroke was low. The optimal management of patients with PFO is not currently known. Treatment options include (1) antiplatelet therapy, (2) anticoagulation, (3) percutaneous device closure, and (4) surgical closure. Opinions differ between specialists: neurologists are more likely to recommend medical management, whereas cardiologists are more likely to suggest device 135 closure. Randomized trials are currently under way to compare the efficacy and safety of medical therapy with percutaneous closure. For patients with cryptogenic stroke and isolated 136 PFO, antiplatelet therapy is usually recommended. For patients with PFO and ASA,
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anticoagulation or device closure may be considered, although evidence to support these treatments is lacking. Left Atrial Spontaneous Echo Contrast
Left atrial spontaneous echo contrast (smoke) may be detected by TEE and is thought to represent stasis of blood within the atrium. The finding may thus indicate a predisposition to thrombus formation. It is most commonly encountered in patients with either AF or mitral stenosis and has been found to be highly associated with previous stroke or peripheral 137 embolism in this context. Mitral Annular Calcification
Mitral annular calcification (MAC) has been suggested as a potential source of calcific or thrombotic emboli to the cerebral and retinal circulations, but the evidence has been conflicting on whether it is an independent risk factor for stroke. A Framingham study documented a doubled stroke risk in those with MAC compared to those without, but it was unclear whether this relationship is causal or a marker for other risk factors; for example, in 138,139 Although one study found MAC to MAC, the risk of developing AF is increased 12-fold. 140 141,142 did not. One of these involved be an independent predictor of stroke, two others 142 nearly 6,000 patients followed over 6 to 7 years. MAC appears to be a marker of generalized atherosclerotic disease including carotid stenosis, calcified aortic plaque, and 143,144 coronary disease. Mitral Valve Prolapse
Mitral valve prolapse (MVP) is the most frequent valve disease in adults, with146a prevalence of 145 a cause of stroke/TIA in the young, this has not about 2 percent. Initially postulated as 147,148 Stroke risk is increased with older age and the been confirmed in more recent studies. development of cardiac conditions: AF, mitral valve thickening, left atrial enlargement, and 149 diagnosis of MVP alone, confirmed by mitral regurgitation. In those with an auscultatory 150 significant echocardiography, no increase in risk was found. In the Framingham cohort, no151 difference was found in the prevalence of stroke/TIA in those with or without MVP. Treatment guidelines are therefore (1) no antithrombotic therapy151for primary prevention in individuals with MVP who have not experienced embolic events and (2) long-term antiplatelet therapy for secondary prevention in MVP patients who have had ischemic stroke 52 or TIA. If other cardiac abnormalities develop, these are treated according to their own merits. Aortic Valve Sclerosis and Stenosis
Systemic embolism in patients with aortic valve disease is uncommon in the absence of AF or other risk factors. Aortic sclerosis (valve thickening without outflow obstruction) is a common finding in the elderly and is associated 152 with generalized atherosclerotic vascular disease and increased cardiovascular mortality. A prospective study of patients with echocardiographically documented aortic valve calcification showed no statistically significant difference in stroke risk in patients with calcification without stenosis (8%) compared to those with stenosis (5%) or control subjects 153 (5%). Additionally, aortic valve disease was not associated with the presence of silent brain infarcts in this study. A larger study compared stroke risk in those with stenosis to those with sclerosis. Over a mean follow-up of 5 years, stroke risk was 12 percent in those with stenosis and 8 percent in those with sclerosis compared to 6 percent in those with a normal aortic valve. After adjusting for other variables,152 there was no statistically significant increase in stroke153 risk in those with aortic sclerosis. A similar conclusion was found in another cohort only if severe was it an independent predictor of study. With regard to aortic stenosis, 154 stroke in addition to age and AF.
Acute Medical Treatment of Cardiogenic Embolism The landmark study comparing thrombolysis of acute ischemic stroke with intravenous tissue plasminogen activator 155 (t-PA) against placebo showed improved clinical outcome at 3 months for all stroke subtypes. Cardioembolism accounted for 28 percent of the patients. Therefore, this acute intervention should be considered for stroke of cardioembolic origin. The two fundamental eligibility criteria are (1) treatment initiated within 3 hours of stroke
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onset (therefore the time of stroke onset must be clearly defined) and (2) absence of hemorrhage on CT brain scan. Prompt assessment and treatment are required because the odds of a favorable outcome with t-PA decline rapidly the longer the interval to t-PA injection time. 156
A series of inclusion and exclusion criteria exist. The purpose is to minimize the risk of intracerebral hemorrhage, the major complication of intravenous t-PA, and to avoid treating minor or rapidly resolving processes such as TIAs, or nonischemic events. The dose of t-PA for stroke thrombolysis (0.9 mg/kg) is lower than that for acute MI. The risk of intracerebral hemorrhage in the treated group (6.4%) was 10 times higher than that of the placebo group in 155 one report. This risk appears increased if the treatment window is extended beyond 3 hours. Patients treated with t-PA cannot receive heparin, warfarin, or aspirin for the first 24 hours after infusion. Subsequently, long-term anticoagulation for secondary stroke prevention must be considered. Other interventional approaches to achieve recanalization include direct intraclot lysis via a microcatheter and mechanical clot disruption, but availability of such procedures is limited. Mechanical clot removal devices may especially have a role in the acute treatment of patients 157 with severe stroke in whom thrombolysis is contraindicated (e.g., recent cardiac surgery). Some embolic infarcts undergo secondary hemorrhagic transformation, which may lead to clinical deterioration. Factors found to increase this possibility in one study were large infarct 158 size and initiation of early anticoagulation (less than 12 hours from presentation). The optimal timing of initiation of anticoagulation after cardioembolic stroke is not known. One recommendation is that nonhypertensive patients without evidence of hemorrhage on CT scan performed 24 to 48 hours after stroke can start anticoagulation. Anticoagulation is usually delayed for about 7 days in those with large infarcts. The American Stroke Association states that initiation of warfarin is generally recommended within 2 weeks after a stroke, but longer delays may be appropriate in patients with large infarcts or uncontrolled 52 hypertension. Decisions must be individualized. SYNCOPE Transient self-limited interruptions of cardiac output result in generalized cerebral ischemia, a 159 condition that is termed syncope when it results in a loss of consciousness. Syncope is discussed in Chapter 8 but is considered further here with particular regard to its occurrence in patients with acquired cardiac disease and arrhythmias. A study of syncope induced in 14 patients with pacemakers noted that consciousness was lost 9 or more160seconds after induction of a ventricular arrhythmia (fibrillation or tachycardia). Patients felt distant, dazed, or as if they were “fading out” before loss of consciousness. Motor activity was noted in 10 of 15 episodes, with generalized tonic contraction of axial muscles followed or accompanied by irregular jerking of the extremities, generalized rigidity without clonic activity, or irregular facial movement or eyelid flutter without tonic activity. None of the patients bit their tongue or was incontinent. During the recovery phase, tonic flexion of the trunk was seen in three patients. Patients remained dazed or confused for up to 30 seconds or more after restoration of the circulation. This study confirmed that motor phenomena occur in association with syncope without corresponding electroencephalographic (EEG) evidence of epileptic discharges. The authors noted 160 variability in EEG findings and poor correlation of these changes with the clinical ones. Videometric analysis of syncope lasting on average 12 seconds induced in 42 healthy volunteers showed that myoclonic activity occurred in 90 percent. Head turns, oral automatisms, and writhing movements were common. Upward eye deviation was also common, and eyes remained open in three quarters of the subjects. Visual hallucinations occurred in 60 percent and were associated with auditory hallucinations in 36 percent, 161 although never with intelligible speech. Focal neurological symptoms are rare with cardiac arrhythmia. Evaluation of 290 patients who required pacemaker insertion disclosed that only 4 had focal neurological symptoms or signs; among these,162 only 2 had focal symptoms that could be related to a specific episode of cardiac dysfunction. Rarely, features suggestive of complex partial seizures are seen. The clinical spectrum of abnormalities that occur with generalized cerebral hypoperfusion is thus an extended one, ranging from nonspecific “dizziness” through a variety of sensory disturbances, including paresthesias and alterations of vision to loss of consciousness, sometimes with convulsive features. This has long been recognized in the context of blood donation, where 12 percent of syncopal reactions were shown to have some convulsive
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163
features. Confusion may occur upon recovery. These observations highlight potential difficulties in distinguishing syncope from seizure. A collaborative study between cardiologists and neurologists identified historical criteria to identify seizure patients among those presenting with presumed syncope: waking with a lacerated tongue, loss of consciousness with emotional stress, head turning 164 to one side during loss of consciousness, and postictal confusion or abnormal behavior. Of note, syncopal events indistinguishable from seizures have been observed in the context of cardiac arrhythmias. Additionally, seizures may cause arrhythmias. 165
Syncope is common, especially in the elderly, who show a high recurrence rate. Of the many causes, it is important to identify those of cardiac origin because mortality is significantly increased in this group of patients. A cardiac basis, in different studies, ranged 159 from 1 to 8 percent for organic heart disease and 4 to 38 percent for arrhythmias. In addition to common structural causes, aortic tract outflow stenosis or intermittent obstruction to outflow may occur, for example, by a mobile thrombus or tumor in the left atrium. Echocardiography is the test of choice. In the case of arrhythmias, the prime objective is to document a relevant abnormality during an episode. In the past, no cause for syncope was found in about one third of patients, but diagnostic yields as high as 76 percent have been achieved,166 for example, in a Swiss study of 788 patients presenting to an emergency department. Evaluations were completed in 650 of those patients. History and clinical examination led to a diagnosis in 38 percent. In 10 percent, a possible cause for syncope was identified, and in about 3 percent this was refuted. In 21 percent, the cause of syncope was not initially determined, and the majority of this group underwent an extensive work-up. A probable cause of syncope was found in only 30 of the 122 patients in this group. Among the 650 patients, 69 (11%) were considered to have a cardiac cause, and arrhythmias were most prominent (44 patients). A sinus bradycardia or pause was seen in 15, as was atrial ventricular block, whereas 4 showed a supraventricular tachycardia and 1 had a pacemaker malfunction. Acute coronary syndromes were found in 9, aortic stenosis in 8, and pulmonary embolism in 8. The 18-month mortality in the cardiac group, noncardiac group, and group with unidentified cause was 26, 6, and 7 percent, respectively. A relatively common disorder predisposing to paroxysmal supraventricular tachycardia is the Wolff–Parkinson–White syndrome, usually a sporadic disorder, with a prevalence of up to 1 167 in 1,000 persons. AF may develop. Dizziness, syncope, and, rarely, sudden death may occur. The characteristic electrocardiographic (ECG) hallmarks are a short PR interval and a slowly rising prolonged QRS complex. It is those patients with an apparently normal heart that present a special challenge and raise 168 the possibility of disorders of the conducting tissues. The long QT syndrome is seen throughout the world. A recessive form is associated with deafness, whereas the more common form, without deafness, has autosomal-dominant inheritance. Acquired forms, often drug related, are more common. Exertion or emotion may trigger events. The characteristic feature, as the name implies, is a prolonged QT interval (corrected for heart rate) on a standard ECG. The disorder predisposes to87polymorphic ventricular tachycardia, which in turn predisposes to syncope and sudden death. 169
Recently, a short QT interval syndrome has been identified. Especially affected are the young, including infants. It is rare and predisposes to paroxysmal AF and episodes of ventricular fibrillation, which may lead to syncope and sudden death. It has been suggested 170 that the disorder may be responsible for some cases of sudden infant death. Sudden death in males from Southeastern Asia attributable to ventricular fibrillation has been recognized for more than 20 years. Episodes indistinguishable from generalized seizures 171 may occur in sleep, and the sudden death is presumed due to ventricular fibrillation. It is now known as SUNDS (sudden unexplained nocturnal death syndrome) and has been linked to the 172 Brugada syndrome, which is said to be phenotypically, genetically, and functionally the same. However, the Brugada syndrome has been described in Europe and in females. The Brugada syndrome is also characterized by sudden death due to malignant arrhythmias. The baseline ECG may be abnormal in showing ST elevation in leads V1, 2, and 3, together with the presence of a right bundle branch block pattern. However, this pattern may be concealed and require unmasking by the use of sodium channel blockers. Another disorder, but one in which the resting ECG is unremarkable, although it may show a sinus bradycardia and prominent U waves in some patients, is catecholamine-induced 173 polymorphic ventricular tachycardia. This is a disorder of childhood with an average age at symptom onset of 8 years. Syncope or events indistinguishable from seizures are triggered
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by exercise or emotional stress. Evaluation of syncope therefore requires attention to family history, age at onset, unexplained sudden deaths, note of apparent epileptic disorders, relation of events to exertion and distress, and effects of postural change. In the presence of an apparently normal heart, evaluation of the standard ECG may suggest a cause, as indicated previously. In the context of a normal ECG or with intermittent events, prolonged recordings may be required in order to capture an episode. With daily events, a Holter monitor may suffice. More prolonged recording techniques are available, as are sophisticated electrophysiological studies. Details are beyond the scope of this chapter;174 a useful modern overview of an approach to the investigation of syncope is available. Cardiac arrhythmias may also result from175 epileptic events. Tachycardia is the most atrioventricular commonly observed rhythm disturbance. Sinus bradycardia, complete176–178 Asystole block, and cardiac arrest all have been documented as epileptic effects. secondary to179 an epileptic event, often a partial seizure, has been documented to last for up to It should be noted that carbamazepine can cause heart block, especially in 60 seconds. 180 elderly women. INTERVENTIONAL PROCEDURES
Coronary Catheterization Coronary angiography carries a small (0.2%) risk of central nervous system (CNS) complications. An unexplained observation is the preponderance of embolic events within the 181 posterior circulation, regardless of the route of catheterization. The corresponding clinical features are visual disturbances that may be migrainous, transient, or persistent; confusion 182,183 For patients experiencing an iatrogenic ischemic stroke in the context may also occur. of coronary 184 catheterization, thrombolytic therapy is a potential treatment option that should be considered.
Percutaneous Transluminal Coronary Angioplasty and Stenting Percutaneous transluminal coronary angioplasty had an overall mortality of 0.1 percent in a large series of more than 12,000 patients. Of the 121 who died, low-output failure was the 185 most common cause (66% of deaths); stroke was responsible for 4 percent. Another study showed that in the presence of peripheral vascular186 disease the risk of any major complication (stroke included) was higher: 12 versus 8 percent. Angioplasty has187 also been compared to coronary stenting. Stroke rate (0.2%) was equal in the two groups. To prevent stent thrombosis, an antithrombotic regimen is required. The addition of clopidogrel188 to aspirin reduces stroke incidence both before and after percutaneous coronary intervention. In a study of more than 18,000 patients with a non–ST-segment elevation acute coronary syndrome, the 6-month stroke risk was 1.3 percent (1.1% for those not undergoing coronary189 artery bypass graft surgery) and the 6-month mortality in these patients was 27 percent. Independent predictors of stroke risk were coronary bypass surgery (especially when performed early), previous stroke, diabetes, and older age, among others. Percutaneous coronary intervention was not associated with an increased risk of stroke in this group. In a study of 12,407 percutaneous coronary interventions (1990190to 1999), the periprocedural risk of stroke and TIA was 0.38 and 0.12 percent, respectively. More than 90 percent of patients in this study underwent balloon angioplasty, and nearly half also underwent coronary stenting. Independent predictors of stroke were advanced age, use of an intra-aortic balloon 190 pump, and need for saphenous vein graft intervention. Primary angioplasty, compared to thrombolysis, has been noted to decrease significantly the 191 192 risk of stroke, but when used as a rescue therapy, stroke risk was marginally increased. In a review of 23 randomized trials involving more than 7,000 patients with acute MI and ST-segment elevation who were randomly assigned to either primary percutaneous transluminal coronary angioplasty or thrombolysis, the overall stroke rate was 1 percent with angioplasty compared to 2 percent with thrombolysis (a statistically significant reduction in 193 favor of angioplasty).
Thrombolytic Therapy for Acute Myocardial Infarction Concern that the introduction of thrombolytic therapy for MI would result in an increase in
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stroke was not substantiated by the results of the initial large Italian trial of nearly 12,000 patients. Stroke rate was 0.77 percent in the streptokinase group compared to 0.92 percent in the control group. An excess of stroke was evident only during the first day after randomization to streptokinase. After this time, patients in194 the control group had more stroke or TIA events. The study did not include CT scan results. Extended experience from this group, specifically stressing stroke risk, found that stroke occurred in 236 (1.14%) of 20,768 patients. Autopsy or CT scanning enabled the cause of stroke to be identified in 74 percent. Perhaps surprisingly, infarction was more common (42%) than hemorrhage 195 (31%). Patients receiving recombinant t-PA showed a small but significant excess of stroke. Comparison of four thrombolytic strategies confirmed a slight excess of hemorrhagic stroke in those receiving t-PA and in those receiving196 combined thrombolytic agents. This excess risk was on the order of 2 to 3 per 1,000 treated. In the four groups, stroke risk rate ranged from a low of 1.22 percent in those treated with streptokinase and subcutaneous heparin to 1.64 percent in those treated with intravenous heparin and both t-PA and streptokinase. These percentages are equal to or less than those documented in recent large prethrombolytic studies of acute MI. The risk of ICH following thrombolytic therapy has been linked to the intensity of heparin anticoagulation and timing of partial thromboplastin time (PTT) monitoring. Recent trials that have used reduced-dose heparin regimens and 3-hour PTT monitoring have reduced ICH 197 rates. When ICH does occur, it is likely to be large in size, supratentorial in site, and more often lobar than deep. Mass effect is common, and blood may extend into the ventricles or subarachnoid space. Of the 244 cases in the study referred to earlier, symptoms emerged within 8 hours of treatment in 55, after 30 hours in 58, and between these times in the 194 remainder. A small percentage (3%) of hemorrhages were subdural. Syncope within 48 hours of treatment, or facial or head trauma within 2 weeks of treatment were 198 disproportionately noted, but numbers were small (7). Review of risk factors in 150 patients with documented ICH identified four factors as independent predictors: age older than 65 years, body weight less than 70 kg, hypertension on hospital admission, and administration of alteplase. The same risk factors for ICH were identified in the GUSTO-I trial; additional predictors included a history of cerebrovascular 199 disease or hypertension, and elevated systolic and diastolic blood pressure on admission. If ICH is suspected, immediate brain CT scan and discontinuation or reversal of thrombolytic or antithrombotic therapy are recommended. Neurosurgical consultation should be 200 considered.
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 6 Neurological Manifestations of Infective Endocarditis LINDA S. WILLIAMS • BRADLEY L. ALLEN •
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HISTORICAL OVERVIEW EPIDEMIOLOGY OF NEUROLOGICAL COMPLICATIONS PATHOPHYSIOLOGY OF NEUROLOGICAL COMPLICATIONS RISK FACTORS FOR NEUROLOGICAL COMPLICATIONS Site of Infection Infecting Organism Acuteness of Infection Valvular Vegetations Hematological Risk Factors ISCHEMIC STROKE Clinical Presentation Seizures Evaluation of Patients Treatment of Ischemic Stroke Anticoagulation in Native Valve Endocarditis Anticoagulation in Prosthetic Valve Endocarditis Surgical Treatment HEMORRHAGIC STROKE Clinical Presentation Evaluation Treatment of Hemorrhagic Stroke Intraparenchymal Hemorrhage Mycotic Aneurysms CEREBRAL INFECTION Clinical Presentation Evaluation Treatment of Cerebral Infection OTHER NEUROLOGICAL COMPLICATIONS SUGGESTED MANAGEMENT ALGORITHM PROGNOSIS CONCLUDING COMMENTS
HISTORICAL OVERVIEW
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The relationship between infection of the heart valves and arterial embolization was first 1 recognized by Rudolf Virchow in the mid-1800s and the classic clinical triad of fever, heart murmur, and hemiplegia was described 30 years later by Osler in his Gulstonian Lectures of 2 1885. The understanding of infective endocarditis has evolved since these early descriptions to a concept of the disease having different predisposing conditions, different propensity for sites of valve infection, different infecting organisms, and different treatments, but the proportion of patients with neurological manifestations has remained relatively constant. It is important to recognize any neurological complications not only because they are frequent but also because they may require alterations in treatment and are often associated with increased morbidity and mortality in infective endocarditis. Although the key to treating neurological complications is appropriate antibiotic therapy, the presence of neurological manifestations often alters concomitant medical or surgical treatment of infective endocarditis. This chapter reviews the most common neurological manifestations of infective endocarditis, detailing their epidemiology and clinical presentations, suggesting appropriate diagnostic evaluations, and discussing treatment options. EPIDEMIOLOGY OF NEUROLOGICAL COMPLICATIONS Neurological events have long been recognized as frequent and severe complications of infective endocarditis. In series of patients from the 1950s onward, the overall frequency of neurological complications has remained relatively constant at approximately 20 to 40 3–15 One reason for the similarity of these reports is that cerebral emboli percent (Table 6-1). are almost always symptomatic; the only study to date that has systematically performed cerebral and abdominal imaging in patients with infective endocarditis regardless of symptoms showed that the overall proportion of cases with cerebral embolization was 34 9 percent and that more than 90 percent of these cerebral emboli were symptomatic. Nevertheless, because of the high overall incidence of stroke in the general population, infective endocarditis is an unusual cause of stroke. Neurological complications of infective endocarditis can be divided into three major types: ischemic stroke, hemorrhagic stroke, and cerebral infection (Table 6-1). Ischemic stroke is by far the most common, occurring in 20 to 30 percent of patients and accounting for 50 to 75 percent of all neurological complications. Primary cerebral hemorrhage, usually intraparenchymal or subarachnoid, is less common, reported in 2 to 17 percent of patients. Secondary hemorrhagic transformation of an ischemic stroke, however, is not uncommon and is estimated to occur in 20 to 40 percent of ischemic strokes. Cerebral infections may manifest without previous clinical evidence of ischemic or hemorrhagic stroke in less than 10 percent of cases; typical infections include cerebritis, meningitis, and microabscesses or macroabscesses. Other neurological symptoms, including seizures, headache, mental status changes, and neuropsychological abnormalities, sometimes occur but are usually secondary to one of the three major complications. Rarely, endocarditis has been associated with spinal cord infarction or abscess, discitis, retinal ischemia, and ischemic cranial and peripheral neuropathies. Click here to view this table.... PATHOPHYSIOLOGY OF NEUROLOGICAL COMPLICATIONS Almost all the neurological complications of infective endocarditis have embolization as their primary9cause. Although cerebral emboli are probably not more common than extracerebral emboli, they are more often symptomatic and thus more frequently reported, and they are associated with an increased morbidity and mortality compared to other systemic emboli. Cerebral emboli most often affect the middle cerebral artery (MCA) territory and may be septic or nonseptic; either type can cause ischemic stroke. Septic emboli may also lead to hemorrhagic stroke through the development of arteritis or mycotic aneurysm, to cerebral microabscess or macroabscess, usually by seeding of ischemic tissue, and to cerebritis or the term bacterial intracranial meningitis by seeding of the meninges (Fig. 6-1). Although 16 aneurysm has been suggested as more appropriate, the term mycotic aneurysm continues to be widely used and is therefore used here.
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FIGURE 6-1 Embolization to various cerebral structures is responsible for most of the neurological complications of infective endocarditis. Emboli that lodge in the lumen of cerebral vessels may lead to ischemic stroke and can lead to arteritis or mycotic aneurysm formation with resultant vessel rupture and cerebral hemorrhage. Emboli to the meninges may produce meningitis, and emboli to the brain parenchyma, especially when associated with cerebral ischemia, may result in meningoencephalitis or abscess. (Reprinted with permission from Solenski NJ, Haley EC Jr: Neurological complications of infective endocarditis. p. 331. In Roos KL [ed]: Central Nervous System Infectious Diseases and Therapy. Marcel Dekker, New York, 1997.)
Most primary intracerebral hemorrhages in infective endocarditis result from septic embolism, followed by septic necrosis and5,17,18,19 rupture of the vessel wall; less commonly, they result from Masuda and colleagues found that 10 of 16 patients rupture of mycotic aneurysms. with infective endocarditis and intracerebral bleeding had pyogenic arteritis, in 5 of whom rupture occurred without evidence of concomitant mycotic aneurysm; 13 of the 16 had either 18 septic emboli or arteritis, or both. Intracerebral hemorrhage may also occur owing to a secondary hemorrhage into an ischemic infarct. In one histopathological series of 17 patients, it was due to secondary transformation of ischemic infarction in 24 percent of cases, necrotic arteritis in 24 percent, mycotic aneurysm in 12 percent, and other causes in 11 percent; in 29 17 percent it was of unknown etiology. Mycotic aneurysm formation has been related to (1) septic embolization20to the arterial lumen, producing intraluminal wall necrosis and outward extension of infection, and (2) septic embolization to the adventitial layer of the artery, resulting in destruction of the adventitia and 21,22 Mycotic aneurysms are usually muscularis layers and subsequent aneurysmal dilation. small, located at distal arterial bifurcations, rather than on the circle of Willis, and can be single or multiple. Branches of the MCA are the most common location for mycotic aneurysms; in one series, almost 40 percent of all mycotic aneurysms involved distal MCA 23 vessels. Rarely, mycotic aneurysms involve extracranial vessels, including the internal carotid artery (Fig. 6-2).
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FIGURE 6-2 This patient with fungal endocarditis developed headache, confusion, and decreased level of consciousness without focal deficits. A, Head computed tomography (CT) showed subarachnoid hemorrhage (increased density) in the perimesencephalic cistern, left more than right, and dilatation of the temporal horns of the lateral ventricles. B, Digital subtraction angiography showed a large aneurysm of the cavernous portion of the left internal carotid artery. The aneurysm was treated with endovascular coils to occlude the carotid artery.
Brain macroabscesses account for less than 1 percent of all neurological complications of infective endocarditis and may occur secondary to ischemic infarction from a septic embolus or to extension of infection from adjacent arteritis or mycotic aneurysm. Brain microabscesses are more common than macroabscesses and usually occur in cases with multiple ischemic infarctions as a result of distal migration of septic embolic fragments. Microabscesses have been associated most commonly with Staphylococcus aureus infections. Meningoencephalitis is usually a result of embolization to meningeal vessels, with subsequent parenchymal or cerebrospinal fluid (CSF) invasion of the infecting organism. Aseptic meningitis may also occur with subarachnoid hemorrhage due to a necrotic arteritis or ruptured mycotic aneurysm. RISK FACTORS FOR NEUROLOGICAL COMPLICATIONS A variety of clinical and laboratory variables have been associated with an increased risk of neurological complications (Table 6-2), including site and type of valve infection, virulence of the infecting organism, acuteness of infection, presence of valvular vegetations, increased size and mobility of vegetations, and certain hematological factors. Click here to view this table....
Site of Infection Neurological 11,24,25 complications are more common with left-sided than with right-sided valve although some series have found increased embolism in patients with involvement, 26,27 Cerebral embolization in right-sided endocarditis may right-sided infective endocarditis. occur via embolization through a patent foramen ovale or a pulmonary arteriovenous 28,29 Mitral valve infection has been associated most commonly with neurological fistula. complications; in one series, mitral valve infection was found in 76 percent of cases with 30 < 0.005), and this neurological complications compared to 37 percent of other cases (P 3,10,31–33 association has also been reported by others. However, Wong and colleagues reported associations between aortic valve infection and stroke, with 44 percent of those with stroke having large aortic valve vegetations compared with a 9 percent prevalence in those 34 relationship between the site of infection and without stroke. Some authors have found no4,13,26,35 36,37 Although disagreement exists, most the occurrence of neurological complications. reports comparing native valve and prosthetic valve endocarditis indicate no significant difference in the proportion of patients with neurological complications. Among patients with prosthetic valve endocarditis, however, mechanical 38 valves may be associated with complications more often than bioprosthetic valves.
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Infecting Organism Several important changes in the type and characteristics of the infecting organism in infective endocarditis have become evident in the past few years. Although streptococci, staphylococci, and enterococci remain the three most prevalent infecting organisms, some recent studies report that staphylococcal is now more common than viridans group 12,39 More problematic than a shift in type of infecting streptococcal infective endocardi tis. organism is the growing prevalence of antibiotic resistance among these organisms, especially resistant viridans group streptococci and methacillin- and van-comycin-resistant S. 40,41 aureus. This changing resistance pattern is reflected in updated guidelines from the American Heart Association on diagnosis, antimicrobial treatment, and management of 42 complications in patients with infective endocarditis. It is unclear whether antibiotic susceptibility changes have an impact on the risk of embolic complications, although an infection with a resistant organism that takes longer to control might well be associated with an increased risk of embolization. Previous studies have linked 3,4,30,33,35,43 S. aureus, an increased3 risk of cerebral embolization to endocarditis due to 3 44 3 enterococci, Escherichia coli, Streptococcus bovis, various fungi, enterobacteriaceae, 3,45 and anaerobic bacteria. Several14studies have shown that, even after adjusting for other 14,15 and S. bovis were independently associated with embolism. In factors, S. aureus prosthetic valve endocarditis, specifically, Staphylococcus epidermidis has been associated 46 with more neurological complications than S. aureus. Endocarditis due to Streptococcus pneumoniae has been associated with an increased risk of meningitis (50% to 90% of 47,48 49 cases), and S. aureus endocarditis has been associated with brain abscess. The current summation of these varied reports is that the virulence of the organism, the availability of effective antimicrobial therapy, and the potential development of large, friable vegetations all contribute to the propensity for embolization.
Acuteness of Infection There is a higher risk of neurological complications with acute endocarditis than with subacute endocarditis. This probably relates to the typical etiological agents noted in acute disease (S. aureus and beta-hemolytic streptococci), the potential for large vegetations or valve damage, and the subsequent increased risk of cerebral embolization. Many authors have observed that the risk of cerebral embolization is highest in the first 1 to 2 weeks of infection, with most patients either presenting with a neurological3,5,10,13,14,33,50 complication or Similarly, the experiencing an acute event in the first 48 hours after diagnosis. risk of embolization decreases as the duration of effective antibiotic treatment increases, with 14,33,50 most events occurring in the first 2 weeks of therapy.
Valvular Vegetations Valvular vegetations are detected by two-dimensional echocardiography in 50 to 80 percent of patients with infective endocarditis and by transesophageal echocardiography (TEE) in 32,36,51–53 Because of its increased sensitivity and ability to more than 90 percent of cases. evaluate the more posteriorly located aortic valve, transesophageal echocardiography appears to be cost-effective as the initial study if clinical suspicion of infective endocarditis is 54,55 Although some older clinical series revealed no significant difference in the high. development4,8,50,56–58 of neurological complications between patients with and without most recent studies have linked either the presence of vegetations, vegetations, increased vegetation size, or vegetation mobility to an increased risk of 13,26,27,32,59–63 The emergence of this relationship may be related to greater embolization. access and improved technical capabilities of echocardiography in the more recent series. A prospective study of 384 patients with infective endocarditis, all of whom had transesophageal echocardiography, found that vegetation length greater than 10 mm and vegetation mobility increased the risk of embolism and that vegetation length greater than 15 14 mm independently increased 1-year mortality. The significance of changes in vegetations on serial echocardiography remains unclear: some investigators report that morphological 64 changes in vegetation size or consistency are not associated with complications, whereas others find that an increase in vegetation size during antibiotic treatment is associated with 33,65,66 A final echocardiographic variable that may be related to increased complications. complications is the presence of spontaneous echo contrast imaging. In a multivariate analysis, Rohmann and colleagues found that spontaneous echo contrast on transesophageal echocardiography was an independent predictor for embolization and 67 hypothesized that this finding signified increased spontaneous platelet aggregation. Current recommendations suggest that repeat echocardiography may be useful if clinical changes
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that suggest treatment failure occur during antibiotic therapy and that it should be performed urgently for unexplained42progression of heart failure, new heart murmurs, or the development of atrioventricular block.
Hematological Risk Factors In addition to spontaneous echo contrast, some reports also present evidence of an 13,68–71 In a series of association between coagulation system activation and embolic events. 91 patients with infective endocarditis, antiphospholipid antibodies were present in 62 percent of patients with embolic events compared to 23 percent of those without such events (P = 0.008) and were also positively correlated with69other markers of endothelial cell activation, have also been thrombin generation, and impaired fibrinolysis. Antiphospholipid antibodies 70 reported to decrease after successful treatment of infective endocarditis. Whether antiphospholipid antibodies independently increase the risk of embolism or this risk results from the association of these antibodies with increased numbers and size of vegetations remains to be determined. Similarly, soluble adhesion molecules have also been reported to 13,71 At present, however, these hematological independently increase the risk of embolism. studies do not clearly aid in risk prediction for patients with infective endocarditis. ISCHEMIC STROKE Ischemic stroke secondary to embolization of friable valvular material is the most common neurological complication of infective endocarditis. Most cerebral emboli are symptomatic, 9 stroke is the but they can be asymptomatic in as many as 35 percent of patients. Ischemic 3,30 and is most presenting symptom of infective endocarditis in up to 20 percent of cases common in the acute stage of the infection, that is, before antibiotic treatment is begun or 4,5,10 Because of this during the first several days of treatment (median time, 4 to 10 days). clustering of symptoms in the acute phase, transient focal neurological symptoms in a febrile patient, especially in the presence of a regurgitant murmur, should always raise suspicion for infective endocarditis.
Clinical Presentation In accordance with their embolic etiology, the majority of ischemic strokes involve the cortex, rather than being confined to subcortical brain tissue. One series found that 62 percent of strokes affected the cerebral or cerebellar cortex (with or without additional subcortical 5 Brainstem strokes account involvement), and only 16 percent were exclusively subcortical. 3 for 10 percent or less of all strokes in infective endocarditis. Because of their cortical involvement, ischemic strokes often present with aphasia, if the dominant hemisphere is involved, or visual or spatial neglect, if the nondominant hemisphere is affected. If the embolus lodges in the posterior cerebral artery, homonymous hemianopia can result. In addition to the more typical focal cerebral hemispheric or brainstem syndromes, 3 in more multiple microemboli are clinically manifest in as many as 11 percent of cases and 72 than 50 percent of cases systematically evaluated with neuroradiological studies. Patients with microemboli can present with nonlocalizing symptoms, including diminished level of consciousness, encephalopathy, or psychosis. Clinical worsening of ischemic stroke may result from a variety of mechanisms, including development of cerebral edema, recurrent embolization and stroke, secondary hemorrhage into the ischemic area, and development of cerebral abscess. Cerebral edema may occur regardless of ischemic stroke mechanism, is more likely to be symptomatic in larger strokes and younger patients, and is typically maximal between 72 to 96 hours after stroke. Recurrent embolization should be suspected if new focal deficits develop; this complication is most likely to occur early in the course of treatment or if infection is uncontrolled. Hemorrhagic transformation of an ischemic stroke occurs in 18 to 42 percent of all patients73with ischemic stroke and has been reported to be more common in cardioembolic strokes. An autopsy series of patients with neurological complications of infective endocarditis found hemorrhagic 18 transformation of an ischemic infarct in 9 of 16 patients. Hemorrhagic transformation of an ischemic stroke is often asymptomatic, although development of intrainfarct hematoma is 73 more likely to be symptomatic than is the development of petechial hemorrhage. The term septic infarction has been used when, several days to72weeks after an ischemic stroke, a cerebral abscess develops within the infarcted tissue (Fig. 6-3). The frequency with which this occurs is not known.
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FIGURE 6-3 This patient presented with left hemiparesis and mitral valve endocarditis. A, Noncontrast head CT showed a focal low-density lesion in the right internal capsule and lentiform nucleus with a central area of hemorrhage (increased density) and cortical hemorrhage in the insula. B, With contrast, large confluent areas of enhancement representing leaky blood–brain barrier can be seen in the right caudate and lentiform nuclei, the insula, and the temporal cortex. C, Fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). MRI 2 days after the head CT showed diffuse increased signal in the regions of CT enhancement and the right thalamus. D, After gadolinium, ring-like enhancement in the area of a previous infarct can be seen, representing possible secondary infection. This pattern is sometimes referred to as a “septic infarction.” This enhancement pattern resolved with antibiotic treatment and without development of a macroabscess.
Seizures Although seizures can occur in patients with infective endocarditis as a result of toxic or metabolic disturbances (e.g., hypoxia, antibiotic toxicity), most often seizures are secondary to ischemic or hemorrhagic stroke. The proportion of patients with seizure as the presenting symptom of infective endocarditis was 2 percent in one large series; 11 percent of patients 3 had seizures during the course of their illness. Seizures that are secondary to focal brain injury are usually focal in nature, with or without secondary generalization, whereas seizures due to metabolic or toxic factors are more often primarily generalized. The development of seizures during antibiotic treatment often signifies clinical worsening from either recurrent stroke, hemorrhagic transformation, or abscess formation. Thus, new onset of seizures
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should always prompt an urgent neuroimaging study. Rarely, seizures are secondary to antibiotic therapy, with imipenem the antibiotic having the greatest seizure proclivity.
Evaluation of Patients All patients with acute focal neurological deficits should have a noncontrast head computed tomography (CT) scan or brain magnetic resonance imaging (MRI). Noncontrast CT allows for the most accurate distinction between hemorrhagic and ischemic events and can be done more quickly than MRI in most settings. If infective endocarditis is known or suspected, head CT with and without contrast may be useful; areas of increased contrast enhancement, representing possible cerebral abscess may then be distinguished from areas of ischemia (Fig. 6-3). Although published radiological series are few, brain MRI appears to be more sensitive than CT in detecting the multiplicity of neurological lesions seen in infective endocarditis. In one series, multiple lesions were found in 10 of the 12 patients studied, with embolic branch infarction (8), multiple emboli and microabscesses (7), and hemorrhagic 72 stroke (4) being the most common findings. MRI findings have been categorized into four patterns: (1) embolic infarction, (2) multiple patchy infarctions (nonenhancing), (3) small nodular or ring-enhancing white matter lesions (probably microabscesses), and (4) 74 hemorrhagic infarctions (intraparenchymal or subarachnoid). Microabscesses usually develop several days75after the ischemic stroke and can be asymptomatic or associated with clinical deterioration. Multiple microabscesses are often responsible for nonfocal encephalopathy. MRI is superior to CT for symptoms referable to the brainstem or cerebellar regions. Once cerebral embolism has occurred, serial neuroimaging studies or subsequent angiography can be performed to assess the presence of secondary complications such as microabscess or macroabscess formation, hemorrhagic transformation of ischemic stroke, or development of a mycotic aneurysm. Most authors agree that patients without neurological symptoms do not require cerebral angiography and that those with intracerebral hemorrhage 76 do require angiography, but whether to perform cerebral angiography after ischemic stroke in patients with infective endocarditis is especially controversial. The 2005 AHA statement on diagnosis and treatment of infective endocarditis suggests that diagnostic pursuit of mycotic aneurysms should be considered in patients with severe headache, erythrocytes or 42 xanthochromia in CSF, or focal neurological signs. Based on the evidence that subarachnoid hemorrhage can occur without previous symptoms in more than 50 percent of patients with mycotic aneurysm, some authors recommend that all patients with cerebral embolism have arterial imaging performed at some time beyond 48 77 hours after the initial event. The basis for the timing of this recommendation is that mycotic aneurysm formation after septic embolization takes at least 48 hours to develop, and angiography immediately after embolization may therefore be negative. Although some studies suggest a more rapid angiographic evaluation based on78early mycotic aneurysmal rupture within 24 hours of the onset of neurological symptoms, others argue that a mycotic aneurysm develops in so few patients that angiographic complications present a greater risk. Using the published literature, van der Meulen and colleagues estimated the probability of 12-week survival in patients with infective endocarditis and ischemic stroke and found no added survival benefit for patients who had angiography, largely owing to the low prevalence of mycotic aneurysms and the low risk of their rupture in patients with adequate antibiotic 76 therapy. Since so few patients with infective endocarditis harbor mycotic aneurysms, the need to perform initial or serial angiography depends on the clinical presentation and proposed treatment. Patients with hemorrhagic stroke or hemorrhagic transformation of an ischemic stroke should have angiography to delineate mycotic aneurysm from arteritis because this distinction often influences subsequent evaluation and treatment. Patients with ischemic or hemorrhagic stroke who require long-term anticoagulation for mechanical valves or treatment of systemic thromboembolism, for example, may also benefit from angiography to exclude a mycotic aneurysm. Patients with ischemic stroke without hemorrhagic transformation or any indication for long-term anticoagulation probably do not benefit from repeated neuroimaging studies or conventional angiography. The diagnosis of infective endocarditis depends on the documentation of an infecting organism on serial42blood cultures and, in part, on the presence of valve abnormalities on echocardiography. Echocardiography is also important in assessing valve function and excluding conditions such as valve thrombosis or abscess formation that would change clinical management. Transesophageal echocardiography is more sensitive to mitral and aortic valve pathology and has been reported to change patient management in as many as 79 one third of cases. Whether serial echocardiography provides data that reliably predict risk of subsequent thromboembolism or otherwise influence management is not known.
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CSF examination is regarded by some authors as part of the standard evaluation of patients with infective endocarditis and neurological symptoms. The manner in which the CSF results will influence therapy, however, is not clear. The interpretation of CSF findings as a diagnostic tool for infective endocarditis in patients with acute stroke is complicated by the tendency for patients with cerebral embolism unrelated to endocarditis also to have mild to moderate increases in either white blood cells, red blood cells, or protein concentration in the 80,81 In one large series,3 CSF was abnormal in 48 of 69 patients with CSF shortly after stroke. infective endocarditis in whom it was examined. Of these, 28 percent had a purulent profile, 25 percent were aseptic, 13 percent were hemorrhagic, and 30 percent were normal. With the exception of purulent CSF in patients with meningismus, the type of neurological event in these patients did not correlate with the CSF pattern. For these reasons, CSF examination does not usually aid in the diagnosis or management of patients with neurological symptoms and infective endocarditis.
Treatment of Ischemic Stroke The cornerstone of treatment of infective endocarditis is appropriate antibiotic therapy directed at the infecting organism. Numerous studies have shown that the risk of either initial or recurrent thromboembolism decreases sharply after the first few days of adequate 4–7,33,51 Although this association may result in part from an ascertainment antibiotic therapy. bias, it is critical to ensure that antibiotics are begun empirically, immediately after drawing initial blood for cultures (preferably three sets from separate sites) in febrile patients with stroke in whom infective endocarditis is among the differential diagnoses. Since effective long-term antimicrobial therapy will be required to treat infective endocarditis, the isolation and susceptibility testing of the pathogen are of critical importance. Involvement of an infectious diseases consultant is recommended. Thorough discussion of a current approach to diagnosis and antimicrobial treatment in various clinical scenarios can be found in the 2005 42 AHA guideline statement. Recent studies have addressed the question of whether acute antiplatelet therapy is beneficial in reducing the risk of thromboembolism in infective endocarditis. In animal models of the disease, aspirin or aspirin plus ticlopidine has been found to reduce vegetation weight, echocardiographic evidence of vegetation growth, bacterial85titer of vegetations, or systemic 82–84 Although one pilot study confirmed this finding, a larger randomized controlled emboli. trial found no reduction of embolic events in patients treated with 325 mg aspirin compared to those given placebo, and there was a nonsignificant trend toward increased bleeding in the 86 aspirin-treated group. Based on this study, routine use of antiplatelet therapy for the purpose of decreasing embolic risk in patients with acute infective endocarditis is not 42 recommended. Anticoagulation in patients with infective endocarditis remains a controversial and complicated topic. Hemorrhagic complications are clearly more common in anticoagulated patients, with one retrospective study finding that 50 87 percent of the hemorrhages occurred in the 13 percent of subjects receiving anticoagulation. However, patients with mechanical prosthetic valves may be receiving long-term anticoagulation, and the decision as to whether and for how long to withhold anticoagulants in this setting is especially difficult. Given the divergent management strategies required, it is useful to consider anticoagulation in native and prosthetic valve endocarditis separately. Anticoagulation in Native Valve Endocarditis Many authors have documented an increased risk of hemorrhagic complications in anticoagulated patients with native valve endocarditis and ischemic stroke, and the risk of recurrent embolism is low in patients receiving appropriate antibiotic therapy. Accordingly, there appears to be little benefit to anticoagulating patients with native valve endocarditis. Whether lower-level anticoagulation (e.g., for prevention of deep venous thrombosis) is safe in patients with stroke and infective endocarditis is unknown. Because other strategies, such as using sequential compression devices, have been shown to be equally efficacious, a conservative approach is to use these nonpharmacological methods of prevention of venous thrombosis. Anticoagulation in Prosthetic Valve Endocarditis Patients with bioprosthetic valves are typically not on long-term anticoagulation and have a 38,46 ; thus, lower risk of stroke in infective endocarditis than patients with mechanical valves the same rationale applies to them as for patients with native valve endocarditis. Patients with
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mechanical prostheses who have endocarditis and stroke, however, present especially difficult management dilemmas. Most studies indicate that the proportions of patients with 4,5 native and prosthetic valves having endocarditis and cerebral embolism are similar ; initiating anticoagulation in a previously nonanticoagulated patient with infective endocarditis and a mechanical valve thus appears unwarranted. If a patient with a mechanical valve is receiving long-term anticoagulation and develops a cerebral embolus as a complication of infective endocarditis, the decision as to whether to continue anticoagulation or temporarily withhold it depends on several factors, including the size of the stroke and type of mechanical valve. Some authors have suggested that anticoagulation decreases the risk of cerebral embolism and87,88 should be instituted in all Because larger strokes, patients with newly diagnosed prosthetic valve endocarditis. especially those secondary to emboli, may be more likely to develop secondary hemorrhagic 76 complications, other authors favor withholding anticoagulation for several days in patients with acute cerebral embolism and mechanical valve endocarditis, especially when S. aureus 89,90 is the infecting organism. Regardless of the timing of anticoagulation, it is safer to convert the patient from oral anticoagulation to the more controlled intravenous route of therapy during the acute phase of infective endocarditis. Some authors have not found a decrease in cerebral emboli in patients 46 a with acute prosthetic valve endocarditis anticoagulated with warfarin or have documented 88 rate of hemorrhagic complications as high as 36 percent in this subgroup of patients, thus leading to the position that anticoagulants should not be initiated and perhaps should be temporarily discontinued in previously anticoagulated patients with prosthetic valve 5,91 If temporary discontinuation of anticoagulation is considered, determination endocarditis. of the patient's type of mechanical valve and consultation with a cardiologist or a cardiothoracic surgeon concerning the risk of valve thrombosis with that valve type will help guide the decision about how long the patient can safely remain off anticoagulation. Although the use of anticoagulants remains controversial, converting to the most controllable (i.e., intravenous) form of therapy and frequent monitoring of anticoagulation parameters (activated partial thromboplastin time or international normalized ratio [INR]) are recommended. Solenski and Haley recommend that large cerebral infarctions, hemorrhage on CT scan, presence of mycotic aneurysm, uncontrolled infection or infection with S. aureus, history of bleeding diathesis, and possibly advanced patient age are factors arguing against the use of anticoagulation in patients with neurological complications of mechanical valve 92 endocarditis.
Surgical Treatment Valve replacement is not usually recommended as a therapy for preventing initial or recurrent stroke, although multiple emboli, infection with a “virulent”26,61 organism, and the presence of Typically, surgery is reserved for large vegetations may be relative indications for surgery. patients with acute or refractory congestive heart failure, perivalvular abscess, unstable valve prosthesis, continued embolism, infection with a pathogen resistant to effective antimicrobial agents, or inability to clear the infection. If surgery is required, the timing of the procedure in a patient with ischemic or hemorrhagic stroke is controversial. If surgery is contemplated to prevent embolization, early surgery is associated with greatest benefit since the risk of embolization is greatest in the first 2 weeks of the infection. If stroke has occurred, the first 72 to 120 hours after stroke are the period of maximal risk of cerebral edema and disruption of cerebral autoregulation; thus, most authors recommend delaying cardiac surgery for at least 1 week after stroke if possible. One retrospective assessment of 247 patients operated on for left-sided native valve endocarditis found that operation at approximately 3 weeks after the neurological deficit appeared was as safe for patients with previous neurological 93 complications as for those without neurological manifestations of endocarditis. HEMORRHAGIC STROKE Intracerebral hemorrhage in infective endocarditis may be primary or secondary to ischemic stroke or other pharmacological or hematological conditions (Table 6-3; Fig. 6-4). Of the primary hemorrhages, intraparenchymal and subarachnoid hemorrhage are most common. Secondary transformation of an ischemic stroke is the most common form of intracerebral hemorrhage in17,18 infectious endocarditis, accounting for 24 to 56 percent of all hemorrhages in Intracerebral hemorrhage is a much less common complication than this condition. ischemic stroke, accounting for 2 to 17 percent of all neurological complications. In one recent series, only 8 cases of subarachnoid hemorrhage occurred among 489 patients with infective endocarditis; in 6 of these, no cause for the hemorrhage was identified by autopsy or 94 aneurysms in patients with infective angiography. The prevalence of asymptomatic mycotic 17 endocarditis is not known, but seems to be small.
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FIGURE 6-4 This patient had tricuspid valve endocarditis secondary to intravenous drug abuse. Initially, the patient had no neurological symptoms but left the hospital against medical advice after completing 6 days of antibiotic therapy. He returned 2 days later with a decreased level of consciousness and a right gaze preference. A toxicology screen was positive for cocaine. Noncontrast axial head CT at that time showed an approximately 3 × 4-cm hemorrhage in the right frontal lobe with intraventricular extension and subfalcial herniation. Cerebral angiography did not show a mycotic aneurysm. Echocardiography showed a large patent foramen ovale with right-to-left shunting and vegetations on the tricuspid valve. This case underscores several clinical points: (1) neurological complications of endocarditis are more common during uncontrolled infection; (2) neurologically asymptomatic patients may have silent cerebral emboli, particularly in the nondominant hemisphere; and (3) patients with right-sided endocarditis may develop cerebral embolization via a right-to-left shunt.
As described previously, in at least 40 percent of patients, septic embolization is the first 3,17,77 Depending on the location of the embolus, event leading to intracerebral hemorrhage. arteritis with secondary vessel rupture or development of a mycotic aneurysm may occur. Several series have documented that hemorrhagic complications are more common in anticoagulated patients, with one third of patients with endocarditis and subsequent 17 intracerebral hemorrhage either anticoagulated or having an underlying bleeding diathesis. In one series, 23 percent of all intracerebral hemorrhages occurred in the 3 percent of 3 50 percent of all such bleeds occurred in the 13 percent anticoagulated patients ; in another, 87 of patients who were anticoagulated. These observations have led to the consensus to avoid anticoagulation in native valve endocarditis and to a judicious approach to its use in
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prosthetic valve endocarditis. Other conditions that sometimes accompany infective endocarditis may also predispose to bleeding complications, including disseminated intravascular coagulation, thrombocytopenia, and vitamin K deficiency. Although mycotic aneurysms are most commonly found in the intracranial vessels, rarely these aneurysms may involve the extracranial carotid (Fig. 6-1), thoracic, or abdominal 95–97 Management in these cases should be individualized but may include surgical or vessels. endovascular interventions or vessel ligation.
Clinical Presentation Intracerebral hemorrhage usually presents with focal neurological symptoms as in ischemic stroke, but nonlocalizing symptoms, such as headache and decreased level of consciousness, may also predominate. Seizures may occur at the onset of the hemorrhage or later in its course. If subarachnoid hemorrhage occurs, either from rupture of an arteritic vessel or from a mycotic aneurysm, meningismus may be a prominent feature. Headaches 94 may be more diffuse and subacute than is typical with saccular aneurysm rupture. A transient ischemic attack (TIA) may precede intracerebral hemorrhage in as many as 25 98 percent of patients or may be the presenting symptom.
Evaluation As in ischemic stroke, noncontrast head CT is the best initial neuroimaging procedure. The hematoma appears as an increased-density signal on CT (Fig. 6-4) and can be localized to the intraparenchymal, subarachnoid, subdural, or intraventricular space. Hemorrhagic transformation of an ischemic infarct is most often patchy and may follow the contour of the gyri (Fig. 6-3A), but may appear as a homogeneous hematoma within an infarct. MRI is also useful and can better delineate stroke in the posterior fossa, although the signal change of blood products over time may make MRI more difficult to interpret in hemorrhagic stroke. A clue to the presence of an underlying mycotic aneurysm may be a focal area of cortical 99 enhancement adjacent to an area of hemorrhage. All patients with intracerebral hemorrhage complicating infective endocarditis should have imaging of the cerebral vasculature to visualize any underlying mycotic aneurysm. Since mycotic aneurysms tend to be small and to occur distally, rather than at the more proximal arterial branch-points as do saccular aneurysms, conventional cerebral angiography is preferred over magnetic resonance angiography (MRA) or CT angiography (CTA) for aneurysm detection. Although the resolution of these techniques continues to improve, at present they are adequate for screening in patients with infective endocarditis and ischemic stroke but should not be the primary diagnostic tool for evaluating patients with infective endocarditis and hemorrhagic stroke. They may be useful, however, for serial monitoring of aneurysm size following conventional angiography. One study reported the utility of monitoring mycotic aneurysms with serial thin-slice CT or MRI and found that all of six aneurysms identified with conventional angiography could be successfully followed for 6 to 8 100 weeks. Repeat angiography at the end of antibiotic treatment confirmed the resolution (in 2) or persistence (3 enlarged, 1 unchanged) of the aneurysms.
Treatment of Hemorrhagic Stroke Intraparenchymal Hemorrhage The mainstay of treatment for either primary or secondary intracerebral hemorrhage in patients with infective endocarditis is the same as that for cerebral emboli: effective treatment of the underlying infectious organism. This is especially true for patients with pyogenic arteritis but is also critical for the treatment of mycotic aneurysms. Some patients with intracerebral hemorrhage and progressive neurological deterioration, either from expanding hematoma or edema, may benefit from surgical evacuation of the clot, but no firm guidelines exist for assisting with management in these cases. Similarly, although recombinant factor VIIa has been used successfully to reduce hematoma growth and improve outcomes in 101 patients with intracerebral hemorrhage, no data are available for its use in patients with infective endocarditis and cerebral hemorrhage. The increased risk of thrombosis and stroke associated with its use would be of concern in this population. As discussed previously, patients with mechanical valves and receiving anticoagulation therapy may have their anticoagulant discontinued temporarily or converted to an intravenous form. All patients should have close neurological monitoring in an intensive care setting because deterioration from recurrent hemorrhage or edema is not uncommon.
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Mycotic Aneurysms The natural history of mycotic aneurysms is that approximately one third resolve with 6 to 8 weeks of antibiotic treatment, one third remain unchanged in size, and the remaining one third 17,78,100,102,103 are equally divided among those that increase and those that decrease in Because of their propensity to resolve with antibiotic therapy, the evaluation size. and treatment of mycotic aneurysms are controversial. Aspects of care that remain unclear are whether serial angiography is needed in patients with mycotic aneurysms and the indications for surgical therapy. Because more than one third of mycotic aneurysms either are unchanged in size or enlarge during antibiotic therapy, some authors recommend serial angiography every 2 weeks during 77,104,105 antibiotic treatment.104–106 If an aneurysm enlarges, surgical treatment to prevent rupture Late hemorrhage from a ruptured mycotic aneurysm in patients who may be advocated. have completed adequate 77 antibiotic therapy is rare, occurring in none of 122 patients with a 17,107 As discussed previously, the need mean 40-month follow-up, but it has been reported. for ongoing or subsequent long-term anticoagulation is another factor that may favor angiographic surveillance and surgical treatment, especially in patients with known cerebral embolization. Once an aneurysm is discovered, controversy also exists about its treatment. Asymptomatic aneurysms are often treated medically, with surgical intervention reserved for those that 105,106 Although either enlarge or do not resolve after antibiotic therapy is completed. symptomatic aneurysms may also resolve with antibiotic treatment and the risk of rebleeding is low, some authors105,106 favor surgical treatment of symptomatic mycotic aneurysms in addition This recommendation is usually based on the fear of recurrent to antibiotic therapy. bleeding, the associated increased morbidity and mortality, and the potential development of new aneurysms. Aneurysm accessibility and number are other features that influence the decision for surgical treatment; single aneurysms in a peripheral location are more likely to be treated surgically. Inaccessible aneurysms may be successfully treated endovascularly, 108–111 although the management and outcomes in these cases are highly individualized. Whether to undertake surgery at presentation or to wait until the completion of antibiotic therapy is debatable. For unruptured mycotic aneurysms, some authors have suggested 77,104,105 although the proportion of serial angiography every 2 weeks during antibiotic therapy, aneurysms that enlarge and thus may require urgent surgery is small. Since at least half of mycotic aneurysms persist after adequate antibiotic treatment and since new aneurysms can appear, it seems reasonable to repeat angiography, either conventional or MRA, at the conclusion of antibiotic therapy (usually 4 to 6 weeks) or to undertake serial imaging with a noninvasive procedure, such as MRA. Accessible aneurysms that persist after adequate antibiotic therapy or that enlarge during therapy are usually treated surgically. Because mycotic aneurysms often lack a defined neck amenable to clipping, other surgical techniques, including wrapping, excision, or endovascular obliteration, may be necessary. Because mycotic aneurysms are often difficult to locate at the time of surgery, new techniques, including stereoscopic brain-surface imaging 112 113 with MRA and stereotactic angiographic localization, are sometimes used to aid in aneurysm localization. CEREBRAL INFECTION Cerebral infection, most commonly abscess or meningitis, has been reported as a primary complication in 6 to 31 percent of cases, although these cases typically represent less than 10 percent of the entire population of patients with endocarditis and neurological complications (Table 6-1). These infections most typically occur after cerebral embolism; infection arising without clinical evidence of prior cerebral embolization is unusual. Encephalitis has also been reported, although the usual pathology in these cases is multiple emboli with microabscess formation. Meningitis accounts for 4 to 7 percent of all neurological manifestations of infective endocarditis and is reported to be more common with either S. aureus or S. pneumoniae 3,114,115 infections. When meningitis is associated with involvement of the cerebral cortex, evidenced by gyral enhancement on MRI, the terms cerebritis and meningoencephalitis are used. Rarely, cerebritis can lead to the development of a parameningeal abscess in the cortex. Meningitis typically results from septic emboli to the meningeal vessels with subsequent CSF colonization. Less commonly, meningitis is nonseptic, resulting from sterile inflammation of the meninges due to blood products or circulating immune complexes in the CSF.
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Cerebral abscesses are rare, accounting for approximately 2 percent of all neurological 116 Small “microabscesses,” often defined as complications in infective endocarditis. 3 abscesses smaller than 1 cm , are more common than “macroabscesses” but still account for less than 4 percent of all neurological complications. Cerebral abscess usually develops as the result of septic embolus and is not necessarily preceded by clinical symptoms. Radiographically, infarction-related abscesses are usually small and multiple and 72,74 demonstrate areas of nodular or ringlike enhancement in an area of prior ischemic stroke (Fig. 6-3D). Abscess has also been reported as a consequence of mycotic aneurysm or 117 septic arteritis.
Clinical Presentation Although the clinical diagnosis of meningitis is infrequent in infective endocarditis, symptoms of meningitis are not. In one series, meningeal symptoms or signs occurred in more than 40 31 percent of 84 patients with endocarditis. In addition to meningismus, headache, encephalopathy, cranial neuropathies, seizures, and increased intracranial pressure may occur. These symptoms may be subtle, especially in the elderly, and, when associated with fever, elevated white blood cell count, and regurgitant murmur should prompt an urgent evaluation for infective endocarditis.
Evaluation All patients with known or suspected infective endocarditis and neurological symptoms, whether focal or nonfocal, should have imaging with noncontrast head CT prior to lumbar puncture. This is critical because multiple embolic strokes, intracerebral hemorrhage, and abscess may all present with nonfocal symptoms and can also cause significant compartmental increases in intracranial pressure, thus increasing the risk of cerebral herniation. Lumbar puncture should not be done in any patient with a focal lesion and evidence of mass effect on neuroimaging studies. Because patients with endocarditis have a propensity toward hematological abnormalities, coagulation tests, including a platelet count and INR, are especially important before one performs a spinal tap.
Treatment of Cerebral Infection As for any type of meningitis, the goal of treatment is adequate antibiotic therapy to which the infecting organism is sensitive and that has good CSF penetration and activity in brain abscesses. Both microabscesses and macroabscesses usually respond to antibiotic treatment, although macroabscesses may occasionally produce significant mass effect and thus require stereotactic aspiration or surgical drainage. OTHER NEUROLOGICAL COMPLICATIONS Other extracerebral neurological complications may rarely occur. Although cerebral and 9 systemic emboli appear to occur with similar frequency, cerebral neurological complications predominate over extracerebral complications, probably because the brain receives more blood flow than peripheral neurological tissues and because cerebral complications are more likely to be symptomatic. Mononeuropathy simplex or multiplex has been reported in as many as 1 percent of patients 118 with infective endocarditis. Both peripheral and cranial nerves may be involved, and viridans streptococci appear to be an especially prominent infectious organism in these cases. Discitis, occasionally with associated abscess or osteomyelitis, has also been reported and is more common with S. aureus infection. Other rare sites of embolization include the spinal cord and the retina. SUGGESTED MANAGEMENT ALGORITHM The management of neurological complications of infective endocarditis is not standardized and substantial variations in care may be necessary based on the individual patient's characteristics. Nonetheless, it is helpful to consider a treatment algorithm that includes pathways for the major neurological manifestations of the disease (Fig. 6-5). This algorithm differs from some proposed previously in that cerebral angiography is not suggested for all patients with ischemic stroke, lumbar puncture is not recommended for all patients with 92,105 As many neurological complications, and serial angiography every 2 weeks is optional. other authors have suggested, the two keys to managing patients, regardless of any neurological complications, are (1) a high level of suspicion for the possibility of infective endocarditis and (2) prompt initiation of appropriate antibiotic therapy after obtaining multiple
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sets of blood cultures.
FIGURE 6-5 Suggested management algorithm for patients with focal neurological deficits and known or suspected infective endocarditis. Factors favoring either surgical or medical treatment of mycotic aneurysms are presented; management of these cases is highly individualized. Repeat angiography at the conclusion of medical therapy is suggested for all patients with known mycotic aneurysms and may be considered either for patients with intracerebral hemorrhage and a negative initial angiogram or for patients with ischemic stroke who require long-term anticoagulation. LP, lumbar puncture, MRA, magnetic resonance angiography.
PROGNOSIS Among patients with infective endocarditis, mortality is increased in those with neurological 3,4,9,10 Estimates of in-hospital mortality in various complications compared to those without. clinical series range from 16 to 58 percent compared with 14 to 20 percent for patients with and without neurological complications, respectively, although a population-based study from 12 France reported 16 percent in-hospital mortality in 1999. Mortality is higher in infections with more virulent organisms,14,15,39,119 with several large cohort studies showing an association between S. aureus and mortality. Intracerebral hemorrhage appears to confer added risk, as 17,30,119 mortality in these patients is reported to be 40 to 90 percent. Although rare, mycotic 106 aneurysm rupture is associated with even higher mortality. Mortality in patients with unruptured mycotic aneurysms appears no different from16the aggregate mortality rate in all patients with neurological manifestations of endocarditis. A multicenter, prospective study of 384 patients with infective endocarditis found that increasing age, female gender, serum creatinine greater than 2.0 mg/L, moderate to severe congestive heart failure, infection with S. aureus, increased medical comorbidity, and 14 vegetation length greater than 15 mm were all independently associated with 1-year mortality. Another study of factors related to in-hospital death also found an association with S. aureus infection and comorbidity as well 119 as embolic events and diabetes.
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The risk of recurrent neurological events, either embolic or hemorrhagic, is quite low.5 Recurrent ischemia has been documented in less than 0.5 percent of cases per day and 77 recurrent hemorrhage in less than 1 percent of all cases. Elimination of recurrent events 33,46,50 appears to depend more on effective antibiotic treatment than on other specific therapy. CONCLUDING COMMENTS Although infective endocarditis has evolved over the past several decades with regard to frequency of involvement of different valves and prevalence and susceptibility of infecting organisms, the proportion of patients with neurological manifestations and the type of neurological complications remain remarkably consistent. Most neurological complications are caused by embolization of friable valvular material resulting in either ischemic or hemorrhagic stroke. A high index of suspicion for infective endocarditis as the cause of stroke is critical because common treatments for acute stroke, such as thrombolysis or anticoagulation, are contraindicated in patients with native valve endocarditis and ischemic stroke. Management of patients with endocarditis and mechanical prosthetic valves is complicated, and decisions about continued anticoagulation in these patients must be individualized. Similarly, decisions about medical or medical plus surgical treatment of mycotic aneurysms must also be individualized because a number of clinical factors may influence treatment. Although many clinical decisions in patients with neurological manifestations of infective endocarditis must be individualized, it is clear that the cornerstone of prevention and treatment of all neurological complications is rapid delivery of appropriate antibiotic therapy. ACKNOWLEDGMENTS Dr. Williams is supported by grants from the Department of Veterans Affairs and the National Institutes of Health. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 7 Neurological Complications of Hypertension S. CLAIBORNE JOHNSTON • JACOB S. ELKINS •
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EPIDEMIOLOGY PATHOPHYSIOLOGY EVALUATION AND TREATMENT STROKE CEREBRAL ANEURYSMS Unruptured Cerebral Aneurysms Subarachnoid Hemorrhage INTRACEREBRAL HEMORRHAGE LACUNAR INFARCT PERIVENTRICULAR WHITE MATTER DISEASE BINSWANGER'S DISEASE CADASIL CAROTID ARTERY STENOSIS INTRACRANIAL ATHEROSCLEROSIS AORTIC ARCH ATHEROSCLEROSIS CARDIAC EMBOLUS DEMENTIA PERIPHERAL NEUROPATHY HYPERTENSIVE ENCEPHALOPATHY ECLAMPSIA IMMUNOSUPPRESSION
Blood pressure was first measured in 1707 by an English divinity student, Stephan Hales, 1 using a glass tube attached directly into the arteries of animals. Methods of measurement improved slowly over the next 200 years, with Nikolai Korotkoff describing the modern cuff-and-stethoscope technique in 1905. Hypertension was recognized as an indicator of poor prognosis by Theodore Janeway, who published a case series of 7,872 hypertensive patients gathered from 1903 to 1912, in which hypertension was defined as a systolic blood pressure greater than 160 mmHg. He found a mean survival of 4 to 5 years after the development of symptoms of hypertension, with stroke being an important cause of death. Hypertension was initially considered a compensatory phenomenon rather than a disease in itself. Even into the 1940s, physicians were concerned that lowering blood pressure would exacerbate end-organ damage, particularly in the kidneys. Treatment options were not
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available until 1925, when surgical sympathectomy was shown to reduce blood pressure without impairment in renal function. The first antihypertensive medication, tetraethylammonium, was used in a patient in 1946, but the agent was poorly tolerated because of severe anticholinergic side effects. A tolerable oral agent was not available until 1957, when chlorothiazide was shown to reduce blood pressure in patients with essential hypertension and rapidly became the most commonly prescribed medication. Both acute hypertension and chronic hypertension produce neurological disease. Acute hypertension is associated with hypertensive encephalopathy, an uncommon presentation since the widespread identification and treatment of hypertension. Chronic hypertension is associated with stroke, which is its most important neurological complication. All stroke subtypes are linked to hypertension, including ischemic infarction, intraparenchymal hemorrhage, and aneurysmal subarachnoid hemorrhage. Chronic hypertension is also associated with dementia and with peripheral neuropathy in those with diabetes. EPIDEMIOLOGY Both systolic and diastolic blood pressures are distributed approximately normally in the population. For convenience, physicians have defined pathological states such as hypertension based on specific blood pressure thresholds, typically a systolic blood pressure of 140 mmHg or greater or a diastolic blood pressure of 90 mmHg or greater, or both. Thus defined, hypertension is common, affecting2 approximately 50 million individuals in the United States and as many as 1 billion worldwide. In the Framingham study, individuals who were normotensive3at age 55 had an approximately 90 percent lifetime risk of developing hypertension. Despite the frequent division of blood pressure into diagnostic categories such as hypertension and normotension, there is no obvious threshold at which higher blood pressure begins affecting the risk of complications, and even patients with diastolic blood pressures of 80 to 90 mmHg are at increased risk of stroke compared with those with blood 4 pressures of 70 to 80 mmHg (Fig. 7-1). Reflecting a growing awareness of the continuous risk associated with blood pressure, blood pressures in the range of 120–140/80–90 mmHg, 2 once considered to be “normal,” are now labeled as “prehypertensive.” Throughout much of the twentieth century, blood pressure risk was assessed according to the diastolic blood pressure, and it was not until 1993 that systolic blood pressure was formally incorporated into 5 the definition of hypertension in U.S. guidelines. Since that time, however, it has been increasingly recognized that systolic blood pressure is somewhat more informative than 6 diastolic blood pressure at predicting future cardiovascular events.
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FIGURE 7-1 Relative risks of stroke. Estimates of the usual diastolic blood pressure (DBP) in each baseline DBP category are taken from mean DBP values 4 years after baseline in the Framingham study. Solid squares represent disease risks in each category relative to risk in the whole study population; sizes of squares are proportional to the number of events in each DBP category; and 95 percent confidence intervals for estimates of relative risk are denoted by vertical lines. (From MacMahon S, Peto R, Cutler J, et al: Blood pressure, stroke, and coronary heart disease. Lancet 335:764, 1990, with permission.)
PATHOPHYSIOLOGY In the brain, the primary pathophysiologic process of hypertension is related to increases in vasomotor tone and peripheral arterial resistance. Acute elevation in blood pressure results in constriction of small arteries in the brain in a compensatory response termed autoregulation. Brain blood-flow is maintained at a relatively constant level over a range of pressures. At high pressures, vasoconstriction is thought to be protective by reducing pressure at smaller, more distal vessels. Acute severe hypertension overwhelms normal autoregulation at a mean arterial pressure of approximately 150 mmHg, with increased cerebral blood-flow occurring above this pressure threshold. Vasoconstriction in acute hypertension is patchy, and some small vessels are exposed to high pressures, which may lead to endothelial injury and focal 7 breakdown of the blood–brain barrier. Acute hypertensive encephalopathy is a fulminant presentation of this process. Fibrinoid necrosis of small vessels may also occur, lowering the threshold for future ischemic and hemorrhagic events. Chronic hypertension results in8 cerebral vascular remodeling. The media hypertrophies, and the lumen becomes narrowed. These changes are protective, with reduction in wall tension 9 and shifting of the autoregulation curve to allow compensation at higher blood pressures. However, vascular remodeling is accompanied by endothelial dysfunction, with impaired relaxation and poor compensation for hypoperfusion. The result is greater susceptibility to 7 ischemic injury due to reduced collateral flow. Hypertension also predisposes to atherosclerosis. Hypertension is proinflammatory and is 10 accompanied by increased plasma oxygen free radicals. Free radicals induce vascular
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smooth muscle cell proliferation and may oxidize low-density lipoproteins, which in turn promotes macrophage activation and monocyte extravasation. Angiotensin II is elevated in many hypertensives and may play a direct role in atherogenesis independent of its effects on 11 blood pressure. It directly stimulates smooth muscle cell growth, hypertrophy, and 10 lipoxygenase activity, with resultant inflammation and low-density lipoprotein oxidation, thus accelerating atherosclerosis. Angiotensin II also stimulates the production of transforming growth factor β (TGF-β), a cytokine that is linked to fibrosis in a number of disease states. In animal models, transforming growth factor β appears12to play a causal role in the development of hypertension and pathological vessel remodeling. EVALUATION AND TREATMENT The gold standard of blood pressure measurement is auscultation using a mercury sphygmomanometer. Newer devices can provide accurate readings but require calibration. Blood pressure should be measured in the seated position after a 5-minute rest with the patient's feet resting on the floor and the arm supported at heart level during the measurement. Accurate readings depend on the use of an appropriate-sized cuff with the bladder covering at least 80 percent of the arm. The classification of blood pressure into specific diagnostic categories is based on the average of two or more readings on each of 13 two or more office visits. A complete history and physical examination with basic laboratory measurements are essential to evaluate for identifiable causes of hypertension and assess risk. Several patient characteristics may suggest an identifiable cause of hypertension including young age, severe hypertension, hypertension that is refractory to multiple interventions, and physical or laboratory findings suggestive of endocrinological disorders, such as truncal obesity or hypokalemia. Abdominal bruits or decreased 14 femoral pulses may also be an indicator of renovascular disease or coarctation of the aorta. Lifestyle modification is recommended as an initial therapy for patients with blood pressure of 2 120/80 mmHg or higher. Effective lifestyle interventions include weight loss, limited alcohol intake, aerobic physical activity, adequate potassium intake (approximately 90 mmol/day), reduction in sodium intake, and dietary regimens such as the Dietary Approaches to Stop 15 Hypertension (DASH) eating plan. Antihypertensive medications are recommended in addition to lifestyle measures for patients with blood pressure of 140/90 mmHg or higher, and when the blood pressure is 130/80 mmHg or higher in those with diabetes and chronic kidney disease. For subjects without a history of cardiovascular disease or other compelling indication, initiating therapy with a thiazide diuretic such as chlorthalidone, is generally recommended. In the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT), involving more than 33,000 participants, therapy with chlorthalidone was either equivalent or superior to lisinopril and amlodipine for the primary prevention of cardiovascular endpoints, with a 16 particular benefit for African American subjects both in terms of safety and efficacy. When the blood pressure is 160/100 mmHg or higher, initiating therapy with two-drug combinations 2 is generally recommended. There are many benefits to treating hypertension, especially reductions in myocardial infarctions, congestive heart failure, retinopathy, renal failure, and overall mortality. The focus of the remainder of this chapter is on specific neurological complications of hypertension and the unique aspects of treatment that they necessitate. STROKE Of all the identified modifiable risk factors for stroke, hypertension appears to be the most important, owing to its high prevalence and its associated three- to fivefold increase in stroke 17 percent of strokes could be risk. Based on epidemiological data, approximately 50 18 prevented if hypertension were eliminated (Table 7-1). Even small reductions in blood pressure result in large reductions in stroke risk. For example, in a meta-analysis of 37,000 hypertensive subjects from 14 studies, a reduction of 5 to 6 mmHg in diastolic blood pressure 19 with active treatment was associated with a 42 percent reduction in stroke risk. The benefits of blood pressure reduction on stroke risk extend similarly to the elderly with isolated elevations in systolic blood pressure. In the Systolic Hypertension in the Elderly Program (SHEP) trial of 4,736 subjects 60 years and older, a 36 percent reduction in stroke was seen with a20,21 12-mmHg decline in systolic pressure, a finding confirmed in other large randomized Although there is still some uncertainty surrounding the treatment of blood pressure trials. in the oldest old (>85 years), the best available data suggest that benefits will be comparable 22 with those seen in younger individuals. Stroke rates have generally declined worldwide, especially throughout the 1970s and 1980s, although more recently they appear to have 23 plateaued (Figs. 7-2 and 7-3). Although these historic trends are not entirely explained by
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better control of blood pressure, the rates of decline have roughly paralleled increased use of antihypertensive medications, suggesting that benefits of blood pressure therapy observed in 24 randomized trials have been at least partially realized in community practice.
FIGURE 7-2 Percent change in stroke mortality, men aged 35 to 74, 1972 to 1982. (From Thom TJ: Stroke mortality trends: an international perspective. Ann Epidemiol 3:509, 1993. Copyright 1993, with permission from Elsevier Science.)
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FIGURE 7-3 Age-adjusted death rates for stroke among men and women in the United States, 1900 through 1990. (From Higgins M, Thom T: Trends in stroke risk factors in the United States. Ann Epidemiol 3:550, 1993. Copyright 1993, with permission from Elsevier Science.)
Click here to view this table.... Hypertension contributes to each of the major intermediate causes of both ischemic and hemorrhagic stroke including carotid stenosis, intracranial atherosclerosis, small-vessel arteriosclerosis, and both macroscopic and microscopic aneurysms. Each of these conditions is considered separately in this chapter. In part because of the heterogeneity of its manifestations in the brain, there continues to be some uncertainty about the optimal management of blood pressure in both the acute and chronic phases after stroke. In the acute phase of cerebral ischemia, hypertension may play a compensatory role in 25 maintaining cerebral perfusion to viable but threatened areas of the brain. Loss of normal cerebral autoregulation has been demonstrated in areas of ischemic brain. When autoregulation is lost, blood flow to the brain becomes directly proportional to mean arterial pressure, and therefore, in theory, pharmacological increases in blood pressure could have 26 salutatory effects in preserving hypoperfused regions of the brain. In some small studies, rapid pharmacological reductions in blood pressure have predicted worse outcomes, and there are numerous anecdotal reports of the recrudescence of stroke symptoms after a 27,28 Therefore, most stroke guidelines recommend withholding decrease in blood pressure. pharmacological treatments of blood pressure in acute stroke in the absence of acute end-organ injury29or administration of thrombolytics, unless the blood pressure exceeds 220/120 mmHg. It is also possible, however, to make physiological arguments that would be supportive of acute blood pressure reduction, such as stabilization of an intra-arterial 30 thrombus or to reduce edema formation. Ongoing trials in this area will provide key data to help resolve this debate. Although historically there has been concern about lowering blood pressure even in the chronic phases after stroke, there is now overwhelming evidence to support the use of pharmacological interventions to lower blood pressure for secondary stroke prevention. In 6,105 subjects with a history of stroke, the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) demonstrated a 43 percent relative risk reduction for secondary stroke prevention when subjects were randomized to the combination of the angiotensin-converting 31 enzyme (ACE) inhibitor perindopril and the thiazide diuretic indapamide. Combination therapy with the ACE inhibitor and thiazide, which resulted in a mean blood pressure reduction of 12.3/5 mmHg, demonstrated a substantially more robust benefit for stroke prevention than monotherapy with ramipril (relative risk reduction 5%), which produced only a 4.9/2.8-mmHg average reduction in blood pressure (P for heterogeneity between treatments <0.001). Combination therapy with an ACE inhibitor and a thiazide is now commonly recommended for secondary stroke prevention, with benefits appearing to be similar
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regardless of whether measured blood pressure is above or below the traditional cut points 32 for hypertension. Although other studies have supported the finding that therapy with renin-angiotensin system antagonists and diuretics provides especially strong benefits for 33 stroke prevention, particularly when compared with β-blockers, the degree of hypertension control that is achieved is usually the best predictor of protection against recurrent stroke. Therefore, response to therapy and other comorbidities, such as heart failure, diabetes, asthma, and arrhythmia, should2 be considered when deciding on an appropriate antihypertensive drug regimen. There is still debate about how soon after stroke to initiate therapy, as the majority of patients in trials of blood pressure therapy after stroke have been randomized months after their qualifying event. Early initiation of therapy is increasingly practiced to improve patient compliance, and current guidelines recommend consideration of 32,34 treatment once the “hyperacute” period has ended. CEREBRAL ANEURYSMS Cerebral aneurysms are focal dilations of blood vessels. Subarachnoid hemorrhage, an important form of hemorrhagic stroke, occurs when a cerebral aneurysm ruptures (Fig. 7-4). Hypertension is associated with cerebral aneurysm formation and with subarachnoid hemorrhage. In a large sample of Medicare patients, hypertension was listed as a secondary diagnosis in 43 percent of patients admitted with unruptured aneurysms and in 34 percent of 35 of subarachnoid hemorrhage was hospitalized control subjects. In a meta-analysis, the risk 36 2.8 times greater in those with a history of hypertension.
FIGURE 7-4 A ruptured anterior communicating artery aneurysm producing
acute subarachnoid hemorrhage. A, Head computed tomography (CT) shows a large amount of blood at the base of the brain and a small amount of intraventricular blood. B, Angiogram reveals a complex saccular aneurysm. The cause of the development and rupture of cerebral aneurysms is probably multifactorial. Epidemiological studies have found several environmental risk factors for subarachnoid hemorrhage other than hypertension.36Cigarette smoking increases the risk of subarachnoid by increasing the release of proteolytic hemorrhage by 100 percent or more, perhaps 37 enzymes that affect blood vessel integrity. Heavy alcohol consumption increases subarachnoid hemorrhage risk with 36 a pooled odds ratio of 1.5 in case control studies and relative risk of 4.7 in cohort studies. Alcohol-induced37hypertension, relative anticoagulation, or increased cerebral blood-flow may be responsible. Oral contraceptives are associated with a small but significant38excess risk of subarachnoid hemorrhage, with a relative risk of 1.4 in current and past users. The source of the association is unknown. Genetic factors are also important to aneurysm formation and subarachnoid hemorrhage. The risk of subarachnoid hemorrhage is three to seven times greater in patients with an 39 of unruptured aneurysms is probably at affected first-degree relative, and the prevalence 40 least twice as high as without a family history. Females are twice as likely to have an aneurysm or present with subarachnoid41 hemorrhage. African Americans have twice the rate of subarachnoid hemorrhage as whites. Polycystic kidney disease, Ehlers–Danlos syndrome type 4, and α1-antitrypsin deficiency are also associated with increased risk. Marfan's syndrome has been considered a42risk factor for aneurysm formation, but this association has recently been questioned. The pathology of aneurysms reveals little about the underlying etiology. Two major morphological subtypes are recognized: fusiform and saccular or berry aneurysms. Fusiform aneurysms more commonly occur in children and in the elderly. The childhood form is 43 thought to represent a genetic or early developmental abnormality in vessel wall structure. 44 Fusiform aneurysms in the elderly are often associated with intracranial atherosclerosis.
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Saccular aneurysms commonly occur at vessel branch points at the base of the brain, with the middle cerebral artery bifurcation and origins of the anterior communicating artery and 45 posterior communicating artery representing the most frequent locations. Turbulent flow may be responsible for this tropism.
Unruptured Cerebral Aneurysms Estimates of the prevalence of unruptured aneurysms vary widely. A recent meta-analysis of prospective studies in adults reported463.6 percent prevalence in four autopsy series and 6.0 percent in nine angiographic studies. Prevalence was 2.3 percent in those without a known risk factor. Approximately 90 percent of these aneurysms were less than 10 mm in diameter, and 70 percent were less than 6 mm. Based on the prevalence from angiographic studies, an estimated 11 million American adults have an unruptured aneurysm, and these are being detected more frequently with advances in imaging studies. Annual cost for47unruptured aneurysms in the United States was estimated at $522 million in the 1980s and is probably significantly greater now. Unruptured aneurysms are often asymptomatic, discovered incidentally in a work-up for an unrelated problem. Some aneurysms produce symptoms by compressing neighboring structures. Presentation with a new cranial neuropathy is considered a worrisome sign for imminent rupture and often prompts urgent treatment. New headaches are also a presenting sign of unruptured aneurysm. Although migraine may simply represent an unrelated occurrence prompting head imaging, some headaches may be due to the aneurysm itself. A sudden, severe “thunderclap” headache may herald rapid aneurysm growth or a small leak 48 without evidence of subarachnoid hemorrhage. Catheter angiography is the gold standard for detection of aneurysms. Magnetic resonance (MR) angiography is approximately 85 percent sensitive for detecting aneurysms larger than 49 3 mm, with 85 percent specificity. Head computed tomography (CT) does not reliably detect unruptured aneurysms. Prognosis of unruptured aneurysms, as reflected in the rate of rupture, is a subject of controversy. In the largest prospective cohort study, the International Study of Unruptured Intracranial Aneurysms, 1,692 subjects with unruptured aneurysms who did not undergo surgery or endovascular treatment, were followed prospectively for an average of 4.1 years. The size of the aneurysm (≥7 mm in maximal diameter) and location at the basilar tip or posterior communicating artery were independent predictors of hemorrhage. Among 1,077 subjects with no history of subarachnoid hemorrhage, the annual risk of hemorrhage for an aneurysm less than 7 mm in diameter in the anterior circulation was500 percent; it was 0.5 percent when the aneurysm was located in the posterior circulation. The standard of care for treatment of aneurysms has historically been surgical clipping, in which a metal clip is placed over the neck of the aneurysm, isolating it from the circulation. Coil embolization is an alternative therapy and involves packing platinum coils into an aneurysm through a microcatheter in an angiographic endovascular procedure. The relative merits of the two procedures have been argued. Coil embolization appears to provide a safer 51 approach but may not reduce subsequent rupture rates as effectively as surgical clipping. Whether a given aneurysm requires treatment depends on the anticipated rupture rate. For asymptomatic aneurysms smaller than 7 mm with no history of subarachnoid hemorrhage, treatment may not be justified, particularly when in the anterior circulation, given the risks of 52 surgery and endovascular therapy. Treatment of unruptured aneurysms appears to be cost-effective when they are larger or symptomatic or when there is a history of subarachnoid hemorrhage from a different aneurysm. Controlling or eliminating risk factors, such as hypertension, smoking, and alcohol abuse, may reduce rupture rates, but this has not been systematically studied.
Subarachnoid Hemorrhage Subarachnoid hemorrhage accounts for approximately 5 percent of all strokes, but it tends to occur at a younger age than other stroke subtypes, with median age at death being 59 years for subarachnoid53hemorrhage, 73 years for intracerebral hemorrhage, and 81 years for ischemic stroke. Subarachnoid hemorrhage accounts for nearly one third of the years of potential life lost before age 65 due to stroke. Case fatality rates approach 50 percent, and 54 another 10 to 20 percent remain disabled and dependent at follow-up. Approximately 25,000 Americans present with subarachnoid hemorrhage each year, with total costs 55 estimated at $5.6 billion.
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Presentation with subarachnoid hemorrhage generally involves sudden onset of severe headache, sometimes accompanied by neck pain. Alteration of consciousness occurs in a minority of patients, but it may be severe enough to produce coma or sudden death outside the hospital. Head CT often shows blood surrounding the base of the brain. Intraventricular and intraparenchymal hemorrhage may be present and can provide clues as to the location of the ruptured aneurysm. Lumbar puncture may rarely show signs of hemorrhage when there is no evidence of it on head CT. Blood in the spinal fluid that does not clear is suggestive of subarachnoid hemorrhage. Xanthochromia is present in nearly all cases and may persist for more than 3 weeks, but its appearance is delayed by more than 12 hours in 10 percent of cases. Angiography is required for the characterization of the aneurysm and to plan treatment. Prognosis depends on the ability to treat the underlying aneurysm and on the patient's condition at presentation. Recurrent hemorrhage occurs in more than 4 percent of untreated patients during the first day and then in 1 to 2 percent per day for the next 2 weeks and is 45 associated with even greater fatality and morbidity than primary rupture. Regardless of treatment and recurrent hemorrhage, the level of consciousness is the major predictor of 56 mortality (Table 7-2). The World Federation of Neurological Surgeons developed a Universal Subarachnoid Hemorrhage Grading Scale, similar to the older Hunt and Hess scale, which has been widely adopted but offers little advantage over determinations of level 57 of consciousness alone. Click here to view this table.... To reduce the risk of recurrent hemorrhage, aneurysms are generally rapidly identified and repaired with surgical clipping or endovascular coil embolization. Controversy continues about optimal timing of treatment in high-risk patients. Early surgery may be technically more challenging when a large amount of subarachnoid clot is present, but early surgical treatment reduces the risk of recurrent rupture more quickly than45does later surgery. Most neurosurgeons therefore recommend early treatment. Hydrocephalus from obstruction of the cerebral aqueduct or the meninges by blood clot may require external drainage. Vasospasm is a common complication that produces cerebral ischemia due to blood vessel constriction in areas with aneurysmal subarachnoid clot. It becomes symptomatic in one third of cases, usually 3 to 58 14 days after hemorrhage, and results in cerebral infarction or death in 15 to 20 percent. Transcranial Doppler ultrasonography can59detect vasospasm before it becomes symptomatic and is helpful in monitoring patients. Oral nimodipine, a calcium-channel antagonist, reduces poor outcomes from vasospasm and should be given as soon as possible after the initial bleed in all cases. Hypertension induced with pressors and hydration with intravenous fluids may reduce the risk of infarction, but these measures have never been studied in trials. They should not be used in patients with untreated ruptured aneurysms because of the risk of precipitating further episodes of bleeding. Vasodilatation through angioplasty or intra-arterial verapamil (or other vasodilators) immediately reverses angiographic vasospasm in many cases, but it requires further study before clinical benefits are proven. INTRACEREBRAL HEMORRHAGE Bleeding directly into the substance of the brain is termed intraparenchymal or intracerebral hemorrhage (Fig. 7-5). It may occur as a complication of ischemic stroke, termed hemorrhagic conversion, or as the primary injury without preceding ischemia. Hypertension is the most important identified risk factor for intracerebral hemorrhage. More than 70 percent of patients with intracerebral hemorrhage have a history of hypertension, and the risk of hemorrhagic stroke is elevated 9.5-fold in the highest compared with the lowest quintile of 60 systolic blood pressure.
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FIGURE 7-5 Head CT of an acute basal ganglia intracerebral hemorrhage with mass effect compressing the ventricles.
Intracranial hemorrhage is responsible for 10 to 15 percent of all stroke deaths but for more than one third of the years53of life lost before age 65 due to the younger age distribution of 50 percent dead at 1 intracerebral hemorrhage. Case fatality rates are high, with 35 to 61 month and only 20 percent returning to independence at 6 months. In the United States, an estimated 37,000 cases of intracerebral hemorrhage55occur each year, with the total estimated cost of care exceeding $6 billion annually. Other risk factors for intracerebral hemorrhage include age, race, substance abuse, anticoagulation, platelet dysfunction, and vascular and structural anomalies. Rates of intracerebral hemorrhage increase with age. African Americans have 40 percent higher rates 41 than those of whites, with larger differences at younger ages. Cocaine and amphetamines are associated with increased risk, particularly acutely, possibly because of transient severe 60 hypertension. Abnormalities in clotting may account for an increased incidence of intracerebral hemorrhage with heavy alcohol use. Excessive warfarin anticoagulation and 62,63 Thrombolytic antiplatelet therapy also increase the risk of intracerebral hemorrhage. agents used for ischemic stroke and myocardial infarction cause intracerebral hemorrhage in some cases. It may also occur with severe thrombocytopenia and platelet dysfunction. Intracerebral hemorrhage may result from and occur in brain tumors, such as glioblastoma multiforme and metastatic melanoma, choriocarcinoma, renal cell carcinoma, and bronchogenic carcinoma. Congophilic amyloid angiopathy, a vasculopathy common in the elderly, is associated with lobar hemorrhages, often centered at the gray-white junction. Other punctate hemorrhages may be apparent on gradient-echo MR images (Fig. 7-6), supporting the diagnosis. Arteriovenous malformations, abnormal complexes of arteries and veins in 60 brain parenchyma, account for 5 percent of intracerebral hemorrhage. Cavernous malformations are dense collections of thin-walled vascular channels and appear to be the 63 cause of intracerebral hemorrhage in 5 percent of autopsies ; they are not apparent on
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angiography but have a “popcorn” appearance in T2-weighted MR images, with a hyperintense core surrounded by hypointense hemosiderin from previous small hemorrhages (Fig. 7-7). Aneurysms may produce intracerebral hemorrhages when blood is directed into the brain, and these rarely are mistaken for primary hypertensive hemorrhages.
FIGURE 7-6 Imaging findings of amyloid angiopathy, with no evidence of hemorrhage on CT (A) but multiple punctate hypointensities at the gray-white junction on T2-weighted multiplanar gradient-recalled (MPGR) magnetic resonance imaging (MRI) (B), suggesting old hemorrhage (two lesions are apparent on this image in the parieto-occipital region).
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FIGURE 7-7 A cavernous malformation with a small amount of acute, intracerebral hemorrhage surrounding it on CT (A). T2-weighted MRI (B) shows a lesion with a focal area of high signal intensity surrounded by a thick rim of hypointense siderin. T1-weighted MRI (C) showing the typical “popcorn” appearance. The high signal intensity represents methemoglobin.
Primary hypertensive intracerebral hemorrhage was thought to be caused by chronic vascular injury, resulting in formation of microscopic aneurysms, first characterized by Charcot and Bouchard in 1868. Advances in pathological tissue preparation have raised doubts about the frequency and64importance of microscopic aneurysms, attributing the appearance to complex vascular coils. More recently, fibrinoid65necrosis of small arteries has been proposed as the initial step in intracerebral hemorrhage. When acute hypertension or clotting abnormality precipitates rupture, blood dissects into the brain parenchyma, sometimes producing a hematoma. Brain injury occurs because of compression of surrounding tissue and from the direct toxic effects of blood. Mass effect from the hematoma may lead to uncal, subfalcine, tonsillar, or transtentorial herniation, depending on location, and death may ensue. Clinical presentation depends on the location and size of the hemorrhage (Table 7-3). Nearly all intracerebral hemorrhage is characterized by sudden onset of neurological deficits, progressing over minutes and accompanied by headache, often with alteration of consciousness. Deterioration due to surrounding edema, hydrocephalus, or continuing or recurrent hemorrhage often occurs within the first 24 hours but may be delayed by days. Click here to view this table.... Prognosis is multifactorial. Hemorrhage volume, most easily measured by halving the product of the length, width, and depth on axial head CT images, is a powerful predictor of mortality, with 80 percent 30-day mortality in those with volumes greater than 60 ml and 22 percent 66 mortality in hemorrhages less than6730 ml. Mortality is much greater in those with intraventricular extension of blood. Hydrocephalus due to intraventricular extension or cerebrospinal fluid (CSF) outflow obstruction predicts in-hospital mortality: 51 percent of 68 those with and 2 percent of those without hydrocephalus died in one series. Lower Glasgow Coma Scale scores, greater age, location, and blood pressure or pulse pressure are other independent predictors of69,70 mortality. Simple multivariable prediction models have been developed and validated. Urgent head CT is required in patients with suspected intracerebral hemorrhage. MR imaging (MRI) is probably as sensitive as CT for detecting hemorrhage and is more sensitive for detecting an underlying structural etiology, but the rapidity, availability, and ease of interpretation of CT favor its initial use. Contrast-enhanced head CT scan may show evidence of71persistent hemorrhage at the time of presentation, a sign associated with poor prognosis. Urgent catheter angiography is required whenever aneurysmal subarachnoid hemorrhage is possible, such as in cases with a large amount of subarachnoid blood, and should be considered for all patients without a clear etiology who would be surgical candidates. Early MRI may be indicated if a structural etiology is suspected, but findings are often obscured by the hemorrhage, and a scan delayed by 4 to 8 weeks may provide more useful information if urgent diagnosis is unnecessary. MRI is useful in diagnosing cavernous malformations and may suggest congophilic amyloid angiopathy. Treatment is generally supportive, although surgical intervention is indicated in some cases. Severe hypertension is common after intracerebral hemorrhage, in part because it is a response to elevated intracranial pressure and brain injury. No clinical studies are available for determining optimal blood pressure control after intracerebral hemorrhage. Theoretically, persistent hypertension could increase the risk of ongoing hemorrhage, but antihypertensive treatment may reduce blood72flow to ischemic brain surrounding a hematoma or reduce cerebral perfusion pressure. Consensus guidelines have recommended antihypertensive medications for systolic blood pressure greater than 180 mmHg or diastolic blood pressure greater than 105 mmHg, and fluids or pressors for systolic blood pressure less than 90 61 mmHg, but these thresholds for treatment are frequently debated. Increased intracranial pressure may lead to coma and is treated with extraventricular drainage, osmotherapy, or hyperventilation. Surgical evacuation of primary intracerebral hemorrhages is commonly performed when there is posterior fossa hemorrhage with a risk of brainstem compression or when there is evolving neurological deterioration in patients with lobar hemorrhages and other prognostic signs are favorable. A large, international trial randomized 1,033 subjects with supratentorial hemorrhage to receive early surgical evacuation of the hematoma or initial conservative treatment followed by surgical evacuation only if it was necessitated by neurological
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deterioration. There was a favorable outcome at 6 months in 26 percent of those allocated to early surgery as compared with 24 percent in those allocated to initial conservative treatment (P = 0.89). In subgroup analysis, it appeared that early surgery was more effective than conservative therapy when the hematoma was 1 cm or less from the cortical surface. Additional trials will be needed to resolve the issue of early surgical benefit for superficial 73 hematomas. After the acute period, aggressive treatment of hypertension is indicated. In addition to reducing cardiovascular disease and ischemic stroke, one study has shown that treating 74 hypertension reduces the risk of intracerebral hemorrhage by more than 50 percent. LACUNAR INFARCT The term lacune was first introduced in 1843 by M. Durand-Fardel to describe small, subcortical areas lacking gray and white matter. These lesions were attributed to infarct and associated with particular clinical presentations by P. Marie and J. Ferrand more than 50 75 years later. In the 1950s C. Miller Fisher reintroduced the term into modern neurology. In a rapid succession of articles, he described the clinical and pathological presentation, recognized the importance of hypertension as an etiology, and developed a theory of pathogenesis that survives today. Less than 2 cm in diameter, lacunes are small infarcts that result from occlusion of small penetrating branches arising from large arteries (Fig. 7-8). There is general agreement about the definition of lacune, but much argument about the interrelationship between lacunar infarcts, lacunar strokes (symptomatic lacunes), lacunar syndromes (symptom complexes often associated with lacunar strokes), and lacunar disease (lacunes due to intrinsic small-vessel changes). Arguments arise from imperfect correlations between these entities. First, not all lacunes produce lacunar strokes because some are silent. Second, lacunar syndromes are sometimes associated with large-vessel strokes. Third, lacunes are produced by intrinsic small-vessel disease and by other etiologies. These issues are discussed in greater detail later.
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FIGURE 7-8 An acute right thalamocapsular lacunar stroke producing left sensorimotor syndrome. The lesion was hypodense in noncontrast head CT (A). With MRI, it was hyperintense on T2-weighted images (B), inconspicuous on T1-weighted images (C), and hyperintense on diffusion-weighted images (D).
More than 50 percent of lacunes are located in the basal ganglia and thalamus, with the remainder in the internal capsule, pons, cerebellum, and subcortical white matter. Approximately 20 to 30 percent of ischemic strokes are due to lacunes. In a recent study, 23 percent of randomly selected subjects 65 years or older had a lacune on MR scanning, and 76 89 percent of those with a lacune denied a history of stroke or transient ischemic attack. These “silent” lacunes were associated with impairment in cognitive and functional tasks, suggesting that the overall clinical burden of lacunes may be greater than previously suspected. Hypertension is an important risk factor for development of lacunes, ranking as the most 76,77 However, the strength of78the important identified risk factor in multivariable models. association may be no greater for lacunes than for other forms of ischemic stroke, and 79 hypertension is not always present. Nonetheless, since other risk factors are less important for lacunes, eliminating hypertension would be expected to have a greater impact on the occurrence of lacunar infarction than other forms of ischemic stroke. Elevation in the level of serum creatinine is independently associated with lacunar76infarction, perhaps because it is a marker for chronic end-organ damage from hypertension. Diabetes mellitus is a risk factor for symptomatic lacunes, approximately doubling the risk. However, the influence of diabetes 78 on lacunar stroke does not appear to differ from its effect on other ischemic stroke subtypes. This is also true for cigarette smoking, which doubles the risk of all ischemic strokes, including lacunes. Carotid artery stenosis is associated with an increased risk of lacunar stroke, with76more than twice the risk of a symptomatic lacune above a 50 percent or greater stenosis. Cardiac disease is less common in patients with
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lacunes (20%) than in those with other ischemic stroke types (47%).
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The etiology of lacunes has been argued bitterly. Some have suggested that the vast majority of lacunes is due to changes within small penetrating vessels, primarily because of chronic 80 hypertension, but others have argued that emboli to small vessels79and intracranial atherosclerosis are responsible for a significant number of lesions. Fisher produced much of the data supporting intrinsic small-vessel disease. He found degenerative changes in small vessels he termed lipohyalinosis and fibrinoid degeneration, characterized by layers of 81 connective tissue within the vascular media, obstructing the lumen. These changes were proximal to infarcts in some cases. Atherosclerosis at the origin appeared responsible for 81 other infarcts. Fisher recognized that emboli may be responsible for some lacunes. Animal models have shown that particles may embolize to small penetrating arteries, producing 82 lacunes. Risk factor profiles have been used to argue against hypertension and intrinsic small-vessel 79 disease as the sole etiology of lacunes. As discussed previously, the risks imparted by hypertension, diabetes, and cigarette smoking are similar for lacunes and for other forms of ischemic stroke, and carotid and cardiac disease appear to be independent risk factors for lacunes. However, carotid and cardiac disease are much more commonly associated with 83 large-vessel infarctions than with lacunes. The etiology of lacunes is almost certainly multifactorial. Intrinsic small-vessel disease may predominate, but emboli and intracranial atherosclerosis almost certainly account for a significant minority of cases. Several classic presentations of lacunar strokes have been described, termed the lacunar syndromes. Pure motor hemiparesis is the most common, accounting for 45 percent of cases. Motor functions involving face, arm, and leg are impaired, but other neurological functions are spared. The appearance is different from that with cortical strokes, in which deficits in sensation or cognition often accompany motor changes. Pure motor hemiparesis is not always due to a lacune, with 10 to 20 percent of cases attributed to a cortical stroke. When a lacune is responsible, it is most often located in the posterior limb of the internal capsule or in the basis pontis, but any other site along the path of corticospinal fibers can produce the syndrome. Sensorimotor syndrome is the second most common lacunar syndrome, accounting for 20 78 percent of cases. Weakness and numbness are present in varying degrees, usually involving the face, arm, and leg. Other neurological deficits are absent. The syndrome is most commonly produced by a lacune involving the lateral thalamus and internal capsule, but 78 13 percent of cases are not due to lacunes. 78,84
Ataxic hemiparesis accounts for 10 to 18 percent of lacunar syndromes. In the affected limbs, pyramidal weakness is combined with elements normally attributed to cerebellar ataxia. Intention tremor, exaggerated rebound, and irregular rapid alternating movements are superimposed on ipsilateral weakness.78The findings are highly suggestive of a lacunar stroke, with 95 percent attributable to lacunes. Infarct locations are identical to those that cause pure motor hemiparesis. 78,84
Among patients with lacunar syndromes, 7 percent have a pure sensory stroke, characterized by impaired sensation without other accompanying neurological deficits. When the face, arm, and leg are involved, the lesion is nearly always a lacune in the contralateral thalamus. A lesion in the medial lemnicus in the midbrain or rostral pons may occasionally produce an identical syndrome. Pain and dysesthesia in the affected region may accompany the lesion acutely or may be delayed by weeks to months. Many other lacunar syndromes have been described, including clumsy-hand dysarthria, hemiballism, and pure motor hemiparesis combined with various eye movement 81 abnormalities. Although lacunes occur more commonly in certain regions79of the brain, they can occur anywhere, producing an infinite number of potential syndromes. Even signs generally attributed to cortical lesions may be produced by lacunes, including aphasia, abulia, confusion, and neglect. Prognosis for recovery after a lacunar stroke is generally more favorable than for ischemic 85 Recurrent stroke and mortality rates are also strokes due to occlusion of major vessels. 86 lower than for other stroke subtypes. Lacunar syndromes may be produced by cortical strokes or even by small hemorrhages. Also, some lacunes may be associated with carotid disease or intracranial atherosclerosis, and knowledge of this could alter treatment decisions. Therefore, diagnostic imaging has been recommended for all those presenting with lacunar syndromes. An immediate head CT scan will rule out hemorrhage as an etiology but may not distinguish lacunes from
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large-vessel infarctions. The absence of changes on a head CT scan delayed by more than 6 hours has been used as confirmatory evidence of lacunar infarction. MRI provides more definitive confirmation, and MR angiography may suggest intracranial atherosclerosis. For lacunar strokes in the internal carotid distribution, duplex ultrasonography or neck MR angiography should be performed because a stenosis proximal to the lacune would generally be considered symptomatic. Acute therapy for lacunes has not been well studied. Most studies of ischemic stroke have not examined this subtype separately, except in post hoc analyses with numbers too small to find significant treatment effects. There has been much debate about whether lacunar strokes should be treated with tissue plasminogen activator (t-PA). Some have argued that the predominant etiology of lacunar syndromes is intrinsic small-vessel disease, which would not be expected to respond to thrombolytics, so that patients would be exposed to an increased risk of hemorrhage without a good chance for benefit. In the National Institute of Neurological Disorders and Stroke t-PA trial, t-PA was effective in the85subgroup of patients judged to have small-vessel occlusive strokes prior to randomization. In fact, absolute differences in favorable outcomes were greater for small-vessel strokes than for large-vessel occlusive and cardioembolic strokes, and differences in two indices reached statistical significance despite small numbers. Some have argued that the final stroke occurs suddenly, implying that acute thrombosis in a diseased small vessel may account for a lacunar infarction and that this explains the efficacy of thrombolysis. Others have argued that the correlation between lacunar stroke and lacunar syndrome is so poor that a diagnosis of nonthrombotic small-vessel occlusion cannot be made with accuracy and that all patients with stroke should receive t-PA because of its overall benefit in ischemic stroke. The American 87 Heart Association guidelines do not recommend avoiding t-PA in lacunar syndromes. Although treatment is not recommended for patients with mild neurological deficits, including isolated hemisensory deficits, a patient with a pure motor hemiparesis is considered an appropriate candidate for thrombolysis. Other acute treatment for lacunar strokes is supportive. Aspirin appears to reduce the risk of subsequent ischemic strokes, regardless of etiology. Although differences in effectiveness in stroke subgroups have not been carefully studied, the Chinese Acute Stroke Trial found that aspirin's effect on stroke recurrence was similar in 88 patients with lacunar strokes and those with other ischemic stroke subtypes. Clopidogrel and the combination of dipyridamole/aspirin are alternatives for secondary prevention in those who cannot tolerate aspirin or who have recurrent strokes despite aspirin. Control of hypertension reduces subsequent ischemic stroke risk, and risk reduction may be even greater for lacunes. Treatment of isolated systolic hypertension in elderly patients halved the 74 risk of lacunar stroke, a more dramatic effect than that seen for other ischemic strokes. A lacune89was considered evidence that a carotid stenosis was symptomatic in previous studies. Whether the risk–benefit ratio for endarterectomy in patients with lacunes is different from that in those with large-vessel strokes is not known. PERIVENTRICULAR WHITE MATTER DISEASE With improvements in head imaging, changes in the white matter surrounding the lateral ventricles were recognized frequently in the elderly, prompting Vladimir Hachinski to coin the term leukoaraiosis for the finding. Head CT shows a periventricular mantle of hypodensity, often most profound at the frontal and occipital horns, which is hyperintense on T2-weighted 96 percent of those older than 65 MRI (Fig. 7-9). Age is the most important risk factor, with 90 years showing at least some evidence of such change. Clinically, the changes are most frequently associated with insidious declines in cognitive and motor performance, particularly 90,91 on tests that depend on reaction time and speed.
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FIGURE 7-9 Imaging findings of periventricular white matter disease, with
hypodensity on head CT (A) and T2-weighted hyperintensities on MRI (B). The etiology of white matter lesions is believed to be related to several distinct pathological processes, including hypoperfusion injury, cerebral amyloid angiopathy, dilated perivascular spaces, axonal loss, astrocytic gliosis, and loss of ependymal integrity with resulting cerebrospinal fluid extravasation. Lesions contiguous with the ventricles show fewer histological and molecular markers of ischemia than lesions in the deep subcortical92areas, where they resemble areas of “incomplete” infarction on pathological examination. Loss of vasomotor reactivity and autoregulation due to93small-vessel vasculopathy is hypothesized to be a frequent cause of the ischemic changes. Leukoaraiosis may be an important clinical indicator of end-organ injury from hypertension, integrating information about cumulative exposure to high blood pressure as well as susceptibility to injury. Individuals with white matter lesions in the brain are at high risk of incident stroke and other clinical cardiovascular 94 is also one of strongest predictors of incident brain infarction events. White matter burden 95 defined by serial cranial MRI. BINSWANGER'S DISEASE In 1894, Otto Binswanger described a form of early dementia distinguishable from 96 syphilitic general paresis and large-vessel vascular dementia by its subcortical involvement. Hypertension is an important risk factor for the disease, existing in 94 percent of cases in one 97 series. Diabetes also appears to be a risk factor. Multiple lacunar infarctions are combined with diffuse and focal myelin loss, particularly in periventricular areas, producing a pathological picture consistent with a combination of multiple lacunes and periventricular white matter disease. Patients present with a stepwise and gradual progression of motor, cognitive, and behavioral deficits, generally over 5 to 10 years. Periods of symptom stabilization or improvement may occur. Imaging studies show patchy periventricular white matter hypodensity or hyperintensity on T2-weighted MRI, with superimposed focal, subcortical lesions consistent with lacunes. Aspirin and control of hypertension are expected to slow progression, but this has not been shown systematically. CADASIL Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently recognized dementing illness caused by mutations in the NOTCH3 98 gene, which encodes a transmembrane receptor protein of unclear function. Clinical presentation is similar to that of Binswanger's disease, with stepwise decline in cognitive and motor functions. However, onset is earlier, beginning at 30 to 50 years of age, and it is often preceded by migraines with aura. Hypertension and diabetes are not associated. Head 99 imaging shows multiple lacunes superimposed on periventricular white matter disease. Degeneration of vascular smooth muscle cells and granular deposits characterize vessels in the brain and in other regions. Involvement of the dermis allows confirmation by skin biopsy. No treatment is available. CAROTID ARTERY STENOSIS The first comprehensive description of carotid occlusion and stroke is attributed to J. R. Hunt, who in 1914 described a patient with decreased carotid pulsation contralateral to a 100 hemiparesis. Autopsy confirmed a hemispheric infarct and showed patent intracranial vessels. With the advent of angiography and surgical exploration, internal carotid artery
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occlusion with recent thrombus was confirmed in the 1940s. The importance of internal carotid artery stenosis as a cause of stroke is unclear because it is difficult to definitively attribute a stroke to the stenosis. The Stroke Data Bank of the National Institute of Neurological Disorders and Stroke classified 69 of 1,273 ischemic stroke cases as 101,102 Based atherothrombotic and 41 as embolic due to severe carotid stenosis or occlusion. on these numbers, approximately 9 percent of ischemic strokes are due to internal carotid stenosis or occlusion. In the Atherosclerosis Risk in Communities Study, 34 percent of randomly selected subjects aged 45 to 64 years had evidence of carotid plaque on 103 60 percent is found in ultrasonography. An asymptomatic carotid stenosis of more than 104 approximately 5 percent of 65-year-olds and increases with age. Hypertension is an important risk factor for carotid stenosis. In the Framingham study, systolic hypertension was a powerful predictor of subsequent105 carotid stenosis, with twice the pressure is also a odds for each 20-mmHg increase in systolic blood pressure. Systolic 106 predictor of progression in patients with asymptomatic stenoses. Cigarette smoking, high serum cholesterol level, and increased homocysteine are other risk factors for carotid 105 stenosis. Internal carotid artery stenosis is produced by atherosclerosis just distal to the common carotid bifurcation. The pathophysiology of carotid artery stenosis is complex. Hypertension induces vascular remodeling, resulting in medial thickening, luminal narrowing, and impaired 8 smooth muscle relaxation. These changes are concentrated in areas of nonlaminar flow, such as the common carotid bifurcation. Atherosclerotic plaques are thought to develop in these areas as a response to10injury produced by hypertension, blood-flow abnormalities, lipids, and possibly infection. This initiating injury induces endothelial cell expression of cell adhesion molecules that mediate local extravasation of mononuclear cells. Vessel wall inflammation results, with foamy, lipid-laden macrophages and T lymphocytes. Chronic injury leads to intimal hyperplasia and formation of complex plaques that may include a lipid core. When a plaque ruptures into the vessel lumen, thrombosis is induced, which may produce local occlusion, distal embolus, or, after organization, progressive luminal stenosis. Shear forces associated with a severe stenosis may induce platelet activation and thrombus formation without plaque rupture. Clinically, symptomatic patients present with large-vessel ischemic strokes or transient ischemic attacks in the distribution of the ophthalmic, middle, or anterior cerebral artery. Transient monocular blindness (amaurosis fugax), weakness, numbness, aphasia, or neglect may occur, depending on the affected region of the anterior circulation. Border-zone ischemia due to distal hypoperfusion in the anterior and middle cerebral artery territories presents with proximal upper and lower extremity weakness and numbness (“man-in-the-barrel” syndrome) and may indicate a critical stenosis or occlusion with inadequate collateral blood-flow. Artery-to-artery emboli classically appear as cortical wedge-shaped infarcts, indistinguishable from emboli from other sources. Lacunar infarcts, often attributed to intrinsic small-vessel disease, probably represent embolic events from carotid artery stenoses107 in some instances because endarterectomy appears to reduce the risk of ipsilateral lacune. A cervical bruit may be a sign of carotid stenosis, but it is absent in 25 to 40 percent of cases later confirmed to have a greater than 70 percent stenosis and is present in 25 to 40 percent 108 of those without a severe stenosis. Therefore, carotid imaging studies are generally indicated for patients with anterior circulation ischemic strokes or transient ischemic attacks. Carotid Doppler ultrasonography, neck MR angiography, or catheter angiography is required for the determination of whether an internal carotid stenosis is present. All three tests are 109 good predictors of the degree of stenosis determined at surgery. Catheter angiography is considered the gold standard but is limited to producing two-dimensional projections and carries a 1 percent risk of stroke. Therefore, it is generally preferable to perform carotid Doppler ultrasonography or neck MR angiography first. Carotid Doppler ultrasonography is more widely available and usually less expensive. MR angiography provides three-dimensional views and can incorporate the intracranial vasculature. When the findings on either Doppler ultrasonography or MR angiography are positive, performing the other study provides confirmation of degree of stenosis and may obviate the need for catheter angiography. From the perspective of society,104 it does not appear cost-effective to screen patients for asymptomatic carotid stenoses. Because of the limited benefit of surgery and the costs of carotid ultrasonography, the pretest probability of finding a stenosis must be greater than 40 percent before it is cost-effective to screen those without symptoms. Carotid ultrasonography probably is not cost-effective even in asymptomatic elderly patients with bruits because the pretest probability of finding a high-grade stenosis is only approximately 15 percent, given the
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5 percent prevalence of a high-grade stenosis in those older than 65 years and a threefold 108 increased likelihood of stenosis in those with a bruit. Aspirin has been shown to reduce risk of stroke and myocardial infarction in patients with 110 ischemic stroke or transient ischemic attacks, with a risk reduction of about 20 percent. Some clinicians use anticoagulation with heparin or warfarin to treat symptomatic carotid stenosis, but there are no reliable data supporting this approach. Based on results in coronary artery disease, a process with similar pathophysiology, and on overall risk reduction of ischemic stroke, treatment with cholesterol-lowering agents may be of benefit even in those without hypercholesterolemia. Surgical removal of the obstructing plaque by endarterectomy is the established standard of therapy for symptomatic patients with carotid artery stenosis of at least 70 percent (Table 89,111 7-4). Endarterectomy also reduces recurrent stroke rates in patients with symptomatic carotid stenoses of 50 to 69 percent, but the number needed to treat (NNT) to prevent one recurrent stroke is considerably higher in this group when compared with those with stenoses exceeding 70 percent (∼15.4 to prevent one stroke over 5 years in those with 50% to 69% ∼5.8 to prevent one stroke over 2 years in those with 70% to 99% stenosis versus 107 stenosis). Endarterectomy is not beneficial in patients with stenosis less than 50 percent and is generally impractical in those with carotid artery occlusion. The risk of stroke with medical therapy is greater in those with cerebral events compared with ocular events, with plaque surface irregularity consistent with ulceration, with a symptomatic event within 2 112 weeks of presentation, and with greater degrees of stenosis. The risk of surgery is greater in females, in those with severe hypertension, and in those with peripheral vascular disease. These prognostic factors may be useful in fine-tuning patient selection for endarterectomy. Click here to view this table.... For patients with asymptomatic carotid artery stenosis, endarterectomy also prevents stroke when there is stenosis of at least 60 percent as assessed by carotid ultrasonography, but again the number needed to treat to prevent one stroke over 5 years remains large (∼20), and, therefore, current guidelines recommend consideration of endarterectomy for asymptomatic stenosis for patients with a surgical risk less than 3 percent and life expectancy 32,113 of at least 5 years. Endovascular angioplasty and stenting are an evolving approach to treatment of carotid stenosis, and stenting has been shown to be not inferior to endarterectomy in patients with both symptomatic and asymptomatic stenoses who have comorbidities associated with high surgical risk during endarterectomy. Large-scale trials comparing endarterectomy and stenting in more representative patient populations are ongoing. High-grade stenoses of the carotid arteries could impair distal cerebral blood-flow in some patients without adequate collateral supply. When endarterectomy is planned for the near future, physicians will routinely allow higher than normal blood pressures to reduce the risk of symptomatic hypoperfusion. Whether such a practice is truly justified when compared to the risk of plaque rupture associated with hypertension has not been addressed in clinical trials. INTRACRANIAL ATHEROSCLEROSIS Atherosclerosis involving the large intracranial vessels causes about 8 percent of ischemic 114 strokes. African Americans, Hispanics, and Asians have a higher prevalence of intracranial atherosclerosis, and relatively low prevalence of extracranial carotid artery stenosis 114,115 Extracranial carotid atherosclerosis is associated with a higher compared with whites. prevalence of peripheral vascular and coronary artery disease, but intracranial 114 atherosclerosis is not. Given racial and risk factor distribution differences, it seems appropriate to consider intracranial atherosclerosis an entity distinct from carotid artery disease rather than as an additional manifestation of widespread atherosclerotic changes. Hypertension is an important risk factor for intracranial atherosclerosis,116with a two- to threefold higher risk of disease in those with a history of hypertension. Smoking may be the most important risk factor, with a 50 percent increase in odds of disease for every 10 years of smoking. Diabetics have about three times the risk of developing intracranial atherosclerosis. Hypercholesterolemia also increases risk, but probably to a lesser degree. The relative contribution of these factors to intracranial atherosclerosis as opposed to other stroke subtypes is unclear. Distribution of known risk factors probably accounts for some of 114 the racial differences. There are intriguing differences in the pathophysiology of intracranial atherosclerosis and other forms of vascular disease. Intracranial arteries are less susceptible to
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117
hypercholesterolemia than are extracranial arteries, and atherosclerotic plaque rupture 118 appears to be less common. Release of endothelial adhesion molecules is greater with intracranial atherosclerosis than in other ischemic stroke 119 subtypes, suggesting that inflammation is particularly important in its pathogenesis. There is no accepted unifying theory on the etiology of intracranial atherosclerosis. Clinical presentation is characterized by large-vessel or penetrating artery ischemia. The middle cerebral artery is most commonly involved, followed in order by the basilar, 114 intracranial internal carotid, anterior cerebral, and posterior cerebral arteries. Thrombosis at the site of the stenosis may lead to hypoperfusion in the entire distal territory or artery-to-artery embolus indistinguishable from events caused by extracranial carotid artery stenosis or cardiac embolus. Basilar thrombosis may result from underlying atherosclerosis in the basilar or vertebral arteries or after cardiac embolus. It is a life-threatening, often delayed diagnosis characterized by coma, quadriplegia, and cranial nerve findings. Involvement of the origin of penetrating small vessels may produce lacunar infarctions. Presentation with transient ischemic attack prior to infarction is more common with intracranial atherosclerosis than with other stroke subtypes. Intracranial MR angiography may reveal narrowing or occlusion of large vessels. However, artifacts may suggest a stenosis where none is present, and sensitivity is low for medium-sized and smaller vessels. Transcranial Doppler ultrasonography shows increased blood flow velocities in large stenotic vessels. Its sensitivity and specificity are also low, so it may be most useful as an adjunct to MR angiography. Catheter angiography is the gold standard for establishing the diagnosis, but it is associated with a 1 percent stroke risk that is probably even higher in the population being evaluated for intracranial atherosclerosis. Given the risk of angiography, it is only justified if results will alter treatment decisions. Prognosis in symptomatic patients is poor. Stenosis generally becomes more severe with time, but regression in some segments may occur. In the largest randomized trial of treatment for symptomatic intracranial atherosclerosis, the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial, 569 subjects were randomized to aspirin (1,300 mg/day) 120 and warfarin (target international normalized ratio, or INR, of 2.0 to 3.0). The trial was stopped early because of safety concerns among subjects randomized to warfarin, and there was no significant difference in the primary endpoint of stroke, brain hemorrhage, or vascular death (P = 0.83). The 2-year rates of ischemic stroke were 19.7 percent in the aspirin group and 17.2 percent in the warfarin group (P = 0.29), indicating that intracranial atherosclerosis is a high-risk condition for recurrent stroke. For comparison, the 2-year risk of ischemic stroke was 26 percent among individuals with symptomatic carotid stenosis between 70 and 99 percent assigned to medical therapy in the North American Symptomatic Carotid Endarterectomy Trial and approximately 11 percent among those assigned to aspirin in the Warfarin-Asprin Recurrent Stroke Study (WARSS), in which more than 75 percent of 121 subjects had a lacunar or cryptogenic etiology for stroke. In part because of the high recurrent stroke risk, intracranial angioplasty and stenting are sometimes considered for patients who have failed medical therapy because of recurrent ischemic symptoms. Given the current lack of efficacy data, such an approach remains investigational, but historical case-series data are encouraging, and122 as techniques and devices improve, the indications for endovascular treatment may broaden. Patients with intracranial atherosclerosis also have a theoretical risk of hypoperfusion distal to the stenosis when blood pressure is lowered. Since these lesions are less commonly corrected compared with those in the carotid artery, some physicians may be less aggressive about treating hypertension in these patients. Newer imaging modalities provide a way to assess whether there is sufficient vascular dilatory capacity distal to a stenosis to preserve blood flow in response to systemic changes in arterial resistance, but the integration of this 123 information into clinical practice has not been fully resolved. There is currently no evidence to justify higher long-term blood pressure thresholds in patients with intracranial atherosclerosis or to support the belief that lower blood pressures could in fact increase the 124 risk of infarction distal to a stenosis. It would be prudent, however, to consider lower initial doses, slower titration schedules, and more frequent monitoring for orthostasis and other adverse effects of antihypertensive therapy in such patients. AORTIC ARCH ATHEROSCLEROSIS The aortic arch has only recently come to be appreciated as a source of emboli to the 125 brain. An autopsy study found a 28 percent prevalence of ulcerated plaque in the aortic arch of patients with ischemic stroke compared with a 5 percent prevalence in a control 125 of a thickened aortic arch population. Transesophageal echocardiograms show evidence126 in 14 percent of stroke patients and 2 percent of control subjects. In those with no other
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identified etiology, a thickened aortic arch is present in 28 percent. Aortic arch atherosclerosis 127 is more strongly associated with peripheral vascular disease than with carotid stenosis. Epidemiological studies have been small, and only cigarette smoking has been identified as an important risk factor. Hypertension, diabetes, and hypercholesterolemia may be risk factors, but this has not been confirmed. Strokes and transient ischemic attacks produced by aortic atherosclerosis are identical to those produced by cardiac sources of emboli. Large-vessel territories are generally affected, producing weakness and numbness in similar distributions or cortical signs, such as aphasia and neglect. Stroke patients with atherosclerotic plaque 4 mm thick or larger in the aortic arch have a 127 fourfold increase in the risk of recurrence after correcting for other risk factors. Optimal treatment is not known but should include an antiplatelet agent or anticoagulation. Aortic endarterectomy has been performed in some patients who have failed medical therapy, but it has not been systematically studied. CARDIAC EMBOLUS Hypertension increases the risk of myocardial infarction and atrial fibrillation. These diseases are associated with increased stroke risk from cardiac embolus, as discussed in Chapter 5. DEMENTIA There is evidence from multiple cohort studies that cardiovascular risk factors, including hypertension, are risk factors for the development of dementia and cognitive 128–130 The biological basis for these associations remains unresolved. Although impairment. there are some data to support a direct association between hypertension and Alzheimer 131 individuals with dementia have a pathology, there is increasing recognition that most 132 mixture of neurodegenerative and vascular pathology. The association between hypertension and dementia is likely to be mediated in part by the accumulation of subclinical vascular injury in the brain, including infarct and leukoaraiosis, that results in the interruption of cognitive networks. Whether this process is simply additive to the cognitive effects of Alzheimer's pathology or whether there is synergism between the two processes remains unresolved. There is currently no convincing evidence that treatment of hypertension will make a large impact on the occurrence of dementia outside of its established benefits for stroke prevention. Although one large primary prevention trial using the calcium blocker nitrendipine found that the risk of dementia was reduced by 50133–135 percent in those receiving active therapy, In the PROGRESS trial, which the finding has not been confirmed in other trials. included subjects exclusively with a history of stroke, active therapy with perindopril and indapamide reduced the risk of dementia overall, but the benefit was not statistically 136 significant when the analysis was restricted to those without recurrent stroke. Although it hardly seems necessary to define additional benefits of treating hypertension, the recognition that cognitive decline may be an important manifestation of end-organ injury from hypertension has important implications for testing new treatments for cerebrovascular 137 disease, assessing risk of stroke, and encouraging adherence to treatment. If hypertension therapy is proven to prevent dementia among those without stroke, the cost–benefit ratio for more aggressive screening and therapy could also be substantially improved, an important issue, given that the elderly, who are at highest risk of dementia, are also the least likely to have their hypertension adequately treated. Some have suggested that aggressive blood pressure reduction could worsen cognition, particularly among those with loss of cerebral 138 autoregulation due to small-vessel arteriopathy. Therefore, the benefits of blood pressure therapy for cognition will need better definition in order to optimize treatment regimens. PERIPHERAL NEUROPATHY In diabetics, hypertension appears to be a risk factor for the development of peripheral neuropathy. One recent prospective study found a fourfold increased risk of distal symmetrical sensorimotor polyneuropathy with hypertension among insulin-dependent 139 diabetics. Hypertension probably increases the risk of peripheral neuropathy in non–insulin-dependent diabetics as well, but not all studies have found an effect. Hypertension is thought to accelerate small-vessel changes in diabetics, producing microvascular ischemic injury to peripheral nerves. In the absence of diabetes, hypertension has not been demonstrated as a risk factor for peripheral neuropathy. HYPERTENSIVE ENCEPHALOPATHY
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Hypertensive encephalopathy is one of several forms of reversible posterior leukoencephalopathy, a syndrome also encompassing other etiologies, including renal failure, 140 immunosuppressive therapy, and eclampsia. Hypertensive encephalopathy is an uncommon disease. There are no recent measurements of its incidence, but it is thought to have declined with greater use of antihypertensives. It tends to occur with a sudden elevation in blood pressure rather than with chronic hypertension. A number of medical conditions are known precipitants. Hyperadrenergic states may be responsible, including pheochromocytoma, tyramine ingestion with monoamine oxidase inhibitors, abrupt antihypertensive discontinuation, lower gastrointestinal 141 irritation in paraplegic patients, and stimulant medications. Structural precipitants include aortic coarctation and renal artery stenosis. Acute or chronic renal failure is another cause, probably through volume overload in addition to hypertension, and human recombinant 142 erythropoietin may be a precipitant. In patients in the postoperative period after endarterectomy, changes ipsilateral to the surgery may be identical to those seen with hypertensive encephalopathy, even in the absence of blood pressure elevation, probably because vessels compensate for chronic hypoperfusion above a severe stenosis and sudden return of blood flow produces relative hypertension. Hypertensive encephalopathy is associated with vasogenic cerebral edema, particularly severe in the posterior regions of the cerebral hemispheres, which is sometimes sufficient to result in herniation. The pathophysiology linking hypertension and cerebral edema has been argued. At mean arterial pressures greater than 120 to 170 mmHg, cerebral blood-flow increases linearly with blood pressure, and some have argued that this is the threshold for 140,143 hypertensive encephalopathy, when a “breakthrough of autoregulation” occurs. Angiotensin II may contribute to the formation of edema by increasing cerebrovascular 144 permeability through oxygen free radicals. A predilection toward involvement of the posterior hemispheres may be due to differential vascular innervation by the sympathetic 143 nervous system. Hypertensive encephalopathy is a neurological emergency that can lead to death if untreated. Diagnosis may be delayed when the connection between acute neurological dysfunction and hypertension is not obvious. High blood pressure may be attributed to an underlying neurological condition or agitation rather than identified as the causative agent. Headache is a common early complaint, sometimes accompanied by nausea and vomiting. Confusion with either agitation or lethargy may proceed to obtundation and coma if the process is untreated. Visual disturbance is frequent due to involvement of the retina and occipital lobes, with 140 papilledema and subjective blurred vision, hemianopia, or cortical blindness. Other cortical deficits may occur, including neglect, aphasia, and weakness. Focal or generalized seizures may complicate the course. Head imaging should be performed to exclude hemorrhage or a structural etiology for both the encephalopathy and the hypertension. Since increased intracranial pressure can result in severe hypertension, which may be required to maintain cerebral perfusion, an urgent study is necessary. Head CT may show hypodensity in subcortical white matter, often most obvious in the occipital lobes (Fig. 7-10). MRI can be dramatic, with multifocal T2-weighted hyperintensities particularly apparent in fluid-attenuated inversion recovery images. These changes are distinguished from infarcts by sparing of the cortex and absence of reduced 145 diffusion, as expected with vasogenic edema. Because cerebral edema may be severe, lumbar puncture should be avoided.
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FIGURE 7-10 A patient with eclampsia. Typical findings in hypertensive
encephalopathy are identical and include normal or subtle hypodensity on CT (A), subcortical hyperintensities on MRI fluid-attenuated inversion recovery (FLAIR) (B), enhancement with gadolinium on T1-weighted images (C), and no abnormality on diffusion-weighted MRI (D). Once a structural etiology has been excluded, treatment of hypertension must be initiated. Target blood pressures are tailored to individual patients, with the goal of returning patients to their recent baseline. For patients without a history of hypertension, normal blood pressure parameters are appropriate, but for those with chronic hypertension, an abrupt return to 140/90 mmHg may result in hypoperfusion owing to chronic vascular compensatory changes. Close observation and intravenous antihypertensives are generally indicated. Nitroprusside is a good choice because of its effectiveness, rapid onset, and ease of adjustment. It produces some cerebral vasodilation, but there is no clinical evidence that this elevates the risk of herniation. Intravenous ACE inhibitors are also effective and easy to titrate and may have less-profound effects on cerebral vessels. Further, animal studies suggest that these agents may have more dramatic effects144 on cerebral edema by blocking increased vessel permeability from angiotensin II. Anticonvulsant therapy may also be indicated. The underlying cause of the hypertensive episode should be sought. Prognosis in treated patients is generally excellent. Neurological deficits usually recover completely within 2 weeks. ECLAMPSIA Eclampsia is a form of reversible posterior leukoencephalopathy. Occurring during the second half of pregnancy or the puerperium, eclampsia presents with proteinuria and clinical
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and imaging manifestations identical to hypertensive encephalopathy. Hypertension may not be severe, so additional effects on brain endothelial cell permeability are probably important. There is evidence of generalized endothelial cell dysfunction with abnormal vascular 146 reactivity. An underlying inflammatory response may be causative, but other potential etiologies have also been hypothesized. Cerebral venous sinus thrombosis is another complication of pregnancy and delivery and can present with findings similar to those seen with eclampsia. MRI and venography are usually adequate to distinguish the two diseases, showing obstructed venous sinuses or ischemia with cytotoxic edema on diffusion-weighted images in cerebral venous sinus thrombosis. 147
Treatment includes delivery of the fetus and intravenous magnesium. Other antihypertensive medications and anticonvulsants can also be used. Prognosis is good if treatment is initiated quickly. IMMUNOSUPPRESSION Several immunosuppressive agents produce a reversible posterior leukoencephalopathy identical to hypertensive encephalopathy. Cyclosporine is the most commonly identified, and it may produce neurological symptoms at therapeutic levels and without evident hypertension. Tacrolimus,140 FK-506, interferon-alpha, cytarabine, and fludarabine have also been associated. An alteration in the permeability of cerebral endothelial cells has been postulated. Lowering blood pressure and discontinuing immunosuppression generally reverses the process. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 8 Postural Hypotension MICHAEL J. AMINOFF •
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NON-NEUROLOGICAL CAUSES OF POSTURAL HYPOTENSION Cardiovascular Disorders Alterations of Effective Blood Volume Drugs Endocrine and Metabolic Disorders Inadequate Postural Adjustments Age AUTONOMIC REGULATION OF THE HEART AND BLOOD VESSELS NEUROLOGICAL CAUSES OF POSTURAL HYPOTENSION Central Lesions and Spinal Injury Root and Peripheral Nerve Lesions Toxic Exposure Primary Degeneration of the Autonomic Nervous System Miscellaneous Disorders SYMPTOMS OF DYSAUTONOMIA Syncope Postural Hypotension Vasovagal Syncope Deglutition Syncope Micturition Syncope Carotid Sinus Syncope Syncope With Valsalva Maneuver Cardiac Syncope Hyperventilation EVALUATION OF AUTONOMIC FUNCTION Postural Change in Blood Pressure Postural Change in Heart Rate Valsalva Maneuver Other Cardiovascular Responses Digital Blood-Flow Cold Pressor Test Norepinephrine Infusion Response to Tyramine Norepinephrine Response to Edrophonium
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Sweat Tests Other Studies Pupillary Responses Radiological Studies PATIENT MANAGEMENT Treatment General Precautions in Management of Dysautonomic Patients
When a normal person stands up after being recumbent, approximately 500 ml of blood (or more) pools in the vessels of the legs and abdomen, causing a reduction in filling pressure of the right atrium and thus a decrease in cardiac output and systemic blood pressure. This leads to changes in baroreceptor activity and thus to changes in impulse traffic in the ninth and tenth cranial nerves. These changes affect the activity of the brainstem vasomotor center, which, in turn, influences the autonomic neurons in the intermediolateral cell columns of the thoracolumbar spinal cord, producing reflex peripheral vasoconstriction and an increase in force and rate of myocardial contraction (Figs. 8-1 and 8-2). Cardiopulmonary reflexes, subserved by vagal afferent fibers from mechanoreceptors in the heart and stretch receptors in the lungs, contribute to maintenance of the blood pressure, acting synergistically with the baroreceptor reflexes. The venoarteriolar axonal reflexes may also be important in limiting blood flow to the skin, muscle, and adipose tissues. Standing up also leads to release of norepinephrine. Venous return is aided during maintenance of the upright posture by mechanical factors, such as the tone in the leg muscles and the pumping action of these muscles during walking, and by maneuvers that1 increase intra-abdominal pressure. This has important therapeutic implications (see p. 155). In addition, there is secretion of antidiuretic hormone (arginine vasopressin) and activation of the renin-angiotensin-aldosterone system, so that salt and water are conserved and blood volume increases. These, however, are typically longer term rather than immediate control mechanisms.
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FIGURE 8-1 Anatomy of the autonomic pathways involved in maintaining the blood pressure on standing.
FIGURE 8-2 Sequence of events that ensure maintenance of the blood
pressure after adoption of the upright posture. Only the immediate cardiovascular changes are shown. As indicated in the text, a variety of other humoral mechanisms are also activated. Postural hypotension is defined as a decrease of at least 20 mmHg in systolic pressure or 10 mmHg in diastolic pressure on standing. It occurs when there is a failure of the autoregulatory mechanisms that maintain the blood pressure on standing. It may therefore occur with any neurological disorder that impairs baroreceptor function, disturbs the afferent input from these receptors, directly involves the brainstem vasomotor center or its central connections, or interrupts the sympathetic outflow pathway either centrally or peripherally. It may also occur with a number of non-neurological disorders, and it is important to consider these disorders if patients are to be managed correctly. NON-NEUROLOGICAL CAUSES OF POSTURAL HYPOTENSION
Cardiovascular Disorders A variety of cardiac disorders may lead to postural hypotension or even syncope. Pathological processes such as mitral valve prolapse, aortic stenosis, or hypertrophic cardiomyopathy may limit cardiac output. Cardiac outflow may also be blocked in rare instances by a thrombus or myxoma when the patient is in the upright position. Certain paroxysmal cardiac dysrhythmias (bradycardias or tachycardias) may occur with activity or on standing and produce episodic hypotension or syncope; however, disturbances of cardiac rhythm are common in
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asymptomatic elderly persons, and their presence must be interpreted with caution. In patients with congestive heart failure, the heart rate and level of sympathetic tone may be such that compensatory adjustments cannot be made when the patient stands, and postural hypotension therefore results.
Alterations of Effective Blood Volume Postural hypotension can occur because of loss of effective blood volume. Normal adults can withstand the loss of 500 ml of blood or bodily fluids with few if any symptoms, but greater volume depletion may occur acutely for a variety of reasons (e.g., hemorrhage or burns) and cause a postural drop in blood pressure. Hyponatremia and Addison's disease may also lead to an absolute reduction in blood volume. Postural hypotension may occur owing to venous pooling in patients with severe varicose veins or congenital absence of venous valves or because of poor peripheral resistance and reduced muscle tone in patients with paralyzed limbs. Similarly, it may occur during the late stages of pregnancy owing to obstructed venous return by the gravid uterus. Marked vasodilatation, such as occurs in the heat or with the use of certain drugs or alcohol, sometimes causes postural hypotension.
Drugs Numerous drugs may produce postural hypotension, including those given to treat neurological disorders (e.g., dopamine agonists and levodopa) and2 psychiatric disturbances (e.g., tranquilizing, sedative, hypnotic, and antidepressant agents). Antihypertensive drugs, diuretics, and vasodilators commonly lead to postural hypotension as a side effect. Insulin may cause nonhypoglycemic postural hypotension in diabetic patients with autonomic neuropathy, possibly because of vasodilatation and reduced venous return in the absence of functioning compensatory mechanisms or because of impaired baroreceptor responses to changes in arterial pressure. Iatrogenic and toxic autonomic neuropathy is considered later.
Endocrine and Metabolic Disorders Autonomic neuropathy, with consequent postural hypotension, is a major and common complication of diabetes. Postural hypotension may be a feature of Addison's disease, hypopituitarism, myxedema, thyrotoxicosis, pheochromocytoma, carcinoid syndrome, and hypokalemia. It may also occur with anorexia nervosa. Anemia may exacerbate or cause postural hypotension. A patient who had marked postural hypotension and extreme lability of 3 the blood pressure in association with severe hypophosphatemia has been described.
Inadequate Postural Adjustments Prolonged bed rest may result in postural hypotension when patients first begin standing again, but this problem is self-limited. Its cause is poorly understood, but it may be multifactorial. Carotid baroreceptor function is impaired, cardiac vagal activity is reduced, blood pooling is increased in the legs because of greater venous compliance, the total circulating blood volume and central venous pressure are reduced, and the red cell mass 4–6 may decline. Prolonged bed rest also leads to an increased incidence of cardiac dysrhythmias. In otherwise healthy subjects, vigorous exercise to the point of exhaustion may also cause a postural decline in blood pressure, possibly because of marked peripheral vasodilatation and venous pooling.
Age Many patients older than 70 years have a decline in systolic pressure of 20 mmHg or more on standing. 7Several causes for reduced orthostatic tolerance with advancing age have been identified. Baroreflex sensitivity declines with age and certain adrenoreceptors exhibit reduced sensitivity. Loss of preganglionic neurons also occurs with age and becomes symptomatic when approximately 50 percent of the cells are lost. Diuretics (which are commonly taken by the elderly) reduce blood volume and may lead to postural8 hypotension. Finally, structural, mechanical, and functional changes in the vascular system, such as loss of vascular elasticity and the occurrence of varicose veins, may be contributory, as may a reduction in the skeletal muscle mass. Prolonged bed rest, intercurrent illness, and adverse reactions to medication may also be important. Postural hypotension appears not to have an 9 impact on mortality, at least among patients discharged from an acute geriatric ward. Syncope is a common problem in the elderly. Often no precise explanation for it can be found, but postural hypotension is probably responsible in many instances. Nevertheless, it is
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best not to ascribe patients' symptoms to postural hypotension unless they can be reproduced by a demonstrable fall in blood pressure on standing. Many of the homeostatic mechanisms that maintain intravascular volume and blood pressure may be impaired with advancing age, as discussed earlier, so that syncope is more likely to occur. Indeed, in many elderly patients a number of factors can be found to account for syncope, and it is then difficult to determine which of these factors is responsible in any individual instance. AUTONOMIC REGULATION OF THE HEART AND BLOOD VESSELS The central nervous system (CNS) is important in regulating cardiovascular function. Various lower brainstem centers receive inputs from both the periphery and other central structures such as the cerebral cortex, temporal lobe, amygdala, hypothalamus, cerebellum, 10,11 The nucleus tractus solitarius is the site of periaqueductal gray matter, and pontine nuclei. termination of baroreceptor, chemoreceptor, and cardiopulmonary afferent fibers; it connects with the nucleus ambiguus and dorsal nucleus of the vagus and with neurons in the lateral reticular formation that 12,13 project to the cord in the bulbospinal pathway, thereby influencing the cardiovascular system. The vagus nerve has a major role in regulating the heart rate responses to various maneuvers. The sympathetic nervous system is important in influencing vasomotor tone and peripheral vascular resistance, but the sympathetic outflow to different regions and structures is regulated separately. The sympathetic nervous system causes a vasoconstriction in response to the release of norepinephrine. The occurrence of vasodilatation in the limbs probably depends on reduced sympathetic activity, and, to a lesser extent, on axon reflexes and antidromic conduction, but some of the vessels in limb muscles are probably also supplied by sympathetic vasodilator cholinergic fibers. Microneurographic studies in humans have shown that bursts of impulses occur rhythmically in sympathetic efferent vasomotor fibers to the skin and muscles and are time-locked to the pulse. This rhythmic activity depends on supraspinal mechanisms and is not seen below the level of a complete cord transection. Such sympathetic impulse traffic to vessels in the limb 14 muscles is markedly affected by baroreceptor activity, but not by brief mental stress, whereas the traffic in human cutaneous nerves is markedly increased by mental stress. High-pressure arterial baroreceptors are located primarily in the carotid sinus and aortic arch, from which afferent fibers pass to the brainstem in the glossopharyngeal and vagus nerves, respectively. Sympathetic efferent activity is inhibited by an increase in the pressure in the carotid sinus and aortic arch, whereas a reduced pressure causes increased sympathetic activity and a peripheral vasoconstriction. The heart rate is also influenced by the baroreceptors and cardiopulmonary stretch receptors, so that a bradycardia occurs when the pressure is increased and a tachycardia when the blood pressure declines. Change from recumbency to an erect posture causes blood to pool in the legs and lower abdomen. There is a slight fall in systolic blood pressure; this leads to baroreceptor activation, a peripheral vasoconstriction, and an increase in heart rate and contractile force. Compensatory changes in the splanchnic vasculature, constriction of venous beds, and activation of the renin-angiotensin system also occur. The carotid baroreceptor reflexes seem to be more important in responding to the immediate changes in blood pressure that occur on standing, whereas the aortic baroreceptors assume a greater role with maintenance of the upright posture. The cardiopulmonary stretch receptors act synergistically with the baroreceptor reflexes. The venoarteriolar axon reflex, which is activated by venous distention in the legs and an associated increase in transmural venous pressure, is also important in ensuring an increase in limb vascular resistance with change to an erect posture. During activity, the baroreceptors are reset by an uncertain, probably neural, mechanism to allow the blood pressure to increase with exercise. 15 Unmyelinated chemoreceptor afferent fibers from skeletal muscles are also activated, thereby increasing blood pressure and correcting any deficiency in muscle perfusion pressure during moderate to heavy exercise. In addition, activation of mechanically sensitive muscle receptors (muscle mechanoreflex) occurs, and these exercise pressor reflexes (peripheral neural reflexes originating 16 in skeletal muscle) contribute significantly to cardiovascular regulation during exercise. At the initiation of exercise, “central command” from higher brain centers leads to17,18 an immediate increase in heart rate and output as well as in blood pressure and respiration. NEUROLOGICAL CAUSES OF POSTURAL HYPOTENSION
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Central Lesions and Spinal Injury The autonomic consequences of spinal cord injuries depend on the level and severity of the lesion. In quadriplegic patients, the period of spinal shock that follows injury is associated with a dysautonomia in which the resting blood pressure and heart rate are typically low and postural hypotension is marked. This mandates that the patient be kept flat, without elevation of the head of the bed, and that any loss of blood volume be avoided or treated vigorously. A few weeks after transection of the cervical cord, activity returns to the isolated spinal segment, but the brain is no longer able to control the sympathetic nervous system. Loss of regulation during postural change leads to orthostatic hypotension, whereas overactivity occurs if spinal sympathetic reflexes are activated and leads to the syndrome of autonomic hyperreflexia, which occurs in patients with cervical or high thoracic lesions. It is characterized by episodic hypertension, bradycardia, headache, and hyperhidrosis above the level of the lesion, with pallor and piloerection distal to it. Anxiety, confusion, nasal congestion, and facial flushing may also occur. Treatment of this syndrome thus requires avoidance of stimuli that activate spinal sympathetic reflexes (e.g., a distended bladder), elevation of the head of the bed, and, if necessary, use of short-acting antihypertensive agents such as calcium-channel blockers. In general, spinal cord transection produces postural hypotension if the lesion is above about the T6 level. Intramedullary and extramedullary tumors, transverse myelitis, and syringomyelia involving the cord above T6 may also produce dysautonomia. A variety of brainstem lesions can19,20 impair autonomic function and 21 affect control of the blood and posterior22fossa tumors. Chiari malformation with pressure, including syringobulbia tonsillar herniation may lead to syncopal episodes. Impairment in Wernicke's encephalopathy may relate to central or peripheral involvement. The extent to which autonomic reflex function, and particularly cardiovascular regulation, is impaired in Parkinson's disease is disputed. Several recent studies have indicated that many patients 23 with Parkinson's disease have postural hypotension from cardiac sympathetic denervation. 24 In such patients, responses to the Valsalva maneuver are also abnormal. Other dysautonomic symptoms, such as disturbances of bladder or gastrointestinal function, and excessive salivation, are relatively common. The findings in certain other disorders with parkinsonian features (e.g., Shy–Drager syndrome, olivopontocerebellar atrophy, and striatonigral degeneration) are discussed on p. 147. Mild postural hypotension occurs occasionally in progressive supranuclear palsy, but cardiovascular reflexes are preserved or show only minor abnormalities of dubious 24–26 27 A variety of dysautonomic symptoms may occur in Huntington's disease, significance. 28 but any abnormalities of blood pressure regulation are usually mild and subclinical, except when related to neuroleptic medication taken for chorea or behavioral disturbances. Postural hypotension or other disturbances of cardiovascular autonomic function occur occasionally in 29,30 but disturbances of bladder and bowel function are much patients with multiple sclerosis, more common dysautonomic features of that disorder. Wallenberg's syndrome or bilateral brainstem strokes may lead to bradycardia and hypotension that may exacerbate the 31 underlying neurological problem.
Root and Peripheral Nerve Lesions Postural hypotension may occur in patients with tabes dorsalis because of interruption of circulatory reflexes. In patients with polyneuropathies, autonomic involvement is not uncommon. It is particularly frequent in diabetic neuropathy, although usually relatively mild in 32 is the most common cause of autonomic neuropathy in the more severity ; indeed, diabetes 33 developed countries. Postural hypotension occurs in approximately 25 percent of patients with diabetic neuropathy. In addition to postural lightheadedness, the dysautonomia of diabetes may be manifest by impotence, postprandial bloating, early satiety, gastrointestinal motility disturbances, abnormalities of bladder control, and alterations of sweating. Cardiac vagal control is usually impaired early, before the development of postural hypotension; the quantitative sudomotor axon reflex test is commonly abnormal and indicates involvement of 34 distal postganglionic sympathetic fibers. Other polyneuropathies associated with postural hypotension include those of alcoholism, Guillain–Barré syndrome, malignant disease, idiopathic small-fiber neuropathies, and acute porphyria. In many patients with chronic alcoholism, however, there is no excessive decline in blood pressure on standing, although the cardiovascular responses to various maneuvers are 35 often abnormal and indicate chronic vagal damage. Primary amyloidosis and familial amyloid polyneuropathy of Portuguese type (FAP type 1) are
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often accompanied by dysautonomia consequent to the loss of predominantly unmyelinated and small myelinated peripheral fibers and of cells in the intermediolateral columns of the cord. Postural hypotension and impotence are early manifestations; episodic constipation and diarrhea, distal anhidrosis, impotence, urinary retention, and cardiac arrhythmias may36also be conjoined. Tests of sympathetic and parasympathetic function are typically abnormal. Autonomic dysfunction with abnormal cardiovascular responses occurs in some patients with chronic renal failure on intermittent hemodialysis, but the site of autonomic involvement is unclear. Vitamin B12 deficiency may lead to autonomic neuropathy and postural hypotension 37,38 Autonomic that improves or resolves completely after vitamin supplementation. involvement, with impairment of sweating and cardiovascular responses, may occur in 39,40 leprosy, sometimes without conspicuous features of peripheral nerve involvement. Symptoms of autonomic impairment, including postural hypotension, may be a presenting 41 feature of systemic autoimmune disorders. In Fabry's disease, disturbed sweating, reduced saliva and tear production, impaired pupillary responses, and gastrointestinal symptoms are common, but postural hypotension does not 42 usually occur, and postural cardiovascular reflexes are normal. Autonomic involvement in Guillain–Barré syndrome is usually mild, but paroxysmal cardiac arrhythmias or asystole or episodic hypertension may lead to a fatal outcome. Postural 43 hypotension is common. It has a number of possible causes including inactivity and bed rest, baroreceptor deafferentation, efferent sympathetic denervation, hypovolemia, cardiac abnormalities, or some combination of these and other factors. The severity of autonomic involvement in Guillain–Barré syndrome is not related to the degree of sensory or motor disturbance, and a wide variety of autonomic abnormalities is found if patients are studied in detail. The hypertensive episodes may relate to catecholamine supersensitivity or denervation of baroreceptors. Treatment of Guillain–Barré syndrome is by supportive measures or with plasmapheresis or intravenous immunoglobulin therapy depending on disease severity. Patients with autonomic instability require close observation and management in an intensive care unit. Further aspects of treatment are given on page 155. Curiously, postural hypotension is uncommon in chronic inflammatory demyelinating polyneuropathy, although 44,45 mild impairment may be found in many patients on tests of autonomic function. Autonomic neuropathy of acute or subacute onset, possibly on an autoimmune basis, sometimes occurs as a monophasic disorder in isolation or with associated sensory or motor involvement. It has occurred in the context of antecedent viral infections, malignancy, 46,47 and Hodgkin's disease, infectious mononucleosis, certain connective tissue diseases, 48 ulcerative colitis. In approximately 50 percent of patients, high titers of ganglionic acetylcholine receptor (AChR) antibody are found. In patients with a paraneoplastic etiology, other autoantibodies may be present, including antineuronal nuclear antibody 1 (ANNA-1 or anti-Hu) or 2 (ANNA-2), Purkinje cell antibody 2 (PCA-2), and collapsin response-mediator 49 protein 5 antibody (CRMP-5). The presence of such antibodies may suggest the likely site of an underlying primary tumor. Both sympathetic and parasympathetic fibers are usually involved, leading to marked postural hypotension accompanied by a fixed heart rate, anhidrosis or hypohidrosis, heat intolerance, sphincter disturbances, gastroparesis, ileus, and dryness of the eyes and mouth, but occasionally abnormalities are confined to postganglionic cholinergic neurons (acute cholinergic neuropathy), in which case postural hypotension does not occur. Pure adrenergic neuropathy has also been described. Autonomic function tests reflect the clinical findings. Nerve conduction study results are typically normal, but sensory abnormalities are sometimes found. Treatment is supportive; immunomodulating therapy may have a role in those with severe disease. Paraneoplastic dysautonomia may remit if the underlying malignancy is treated. The prognosis of patients with acute or subacute autonomic neuropathies is guarded: approximately one third of patients do well, but the remainder either fail to improve or are left with a major residual deficit, including marked postural hypotension. Autonomic involvement may occur in a variety of hereditary polyneuropathies. In familial dysautonomia, or Riley–Day syndrome, many parts of the nervous system are affected. Presentation during infancy may be with inability to suck, but episodic vomiting, recurrent pulmonary infections, hypertension, tachycardia, and diaphoresis occur, especially after 3 years of age. There may also be emotional outbursts, difficulty in swallowing, hypothermia or hyperthermia, poor flow of tears, postural hypotension, and syncope. Sensory abnormalities include impaired pain and temperature appreciation, and the tendon reflexes are depressed. The tongue is smooth and lacks fungiform papillae. Cardiac arrest may occur on tracheal 50,51 Postural hypotension usually is not a intubation. Treatment is essentially supportive. feature of the other hereditary sensory and autonomic neuropathies, whereas sudomotor function is often markedly impaired.
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Autonomic symptoms or signs may occur in patients with hereditary motor and sensory 52 neuropathy type 1, and abnormal vascular reflex responses may be present. Postural hypotension is usually not a conspicuous feature of the disorder. A familial disorder characterized by progressive distal weakness and muscle atrophy, distal53 sensory loss, pyramidal and visual pathway lesions, and dysautonomia has been reported. Patients had a sensorimotor polyneuropathy. The dysautonomia consisted of postural hypotension, lack of normal sinus arrhythmia, an abnormal response to the sweat test, abnormal pupillary responses with denervation supersensitivity, and low serum norepinephrine levels in both the recumbent and upright positions. 54
Iatrogenic postural hypotension is common in the elderly and relates most often to the use of antihypertensive agents or diuretics. Iatrogenic polyneuropathies may be responsible in 55 other instances, as reviewed elsewhere ; postural hypotension may be conspicuous in patients with the neuropathy caused by perhexiline maleate, cisplatin, paclitaxel (Taxol), vinca 55 alkaloids, or amiodarone.
Toxic Exposure Autonomic dysfunction may result from occupational or other exposure to certain neurotoxins but does not usually lead to postural hypotension. One study suggested that long-term occupational exposure to a mixture of organic solvents causes subtle disturbances of peripheral parasympathetic nerves as well56as sensorimotor peripheral neuropathies, as reflected by cardiovascular reflex studies, but other reports of autonomic involvement in this context are few. Intentional inhalation of n-hexane or methyl-n-butyl-ketone for recreational purposes may lead to a rapidly progressive neuropathy with associated postural 55 hypotension. Acrylamide neuropathy is usually accompanied by hyperhidrosis and cold, cyanotic extremities; in intoxicated rats, but not in humans, there is evidence that acrylamide 57 alters common measures of cardiovascular function. A variety of autonomic symptoms (in-cluding tachycardia, hypertension, and disturbances of sweating) may occur with thallium, arsenic, or mercury poisoning, but postural hypotension is not usually a feature. McFarlane and associates described a patient with severe postural hypotension and 58 neurological signs that were attributed to styrene intoxication. The rodenticide N-3-pyridylmethyl-N'-p-nitrophenyl urea (Vacor) has caused severe dysautonomia with 59 disabling postural hypotension, as well as sensorimotor peripheral neuropathy and encephalopathic states. Iatrogenic postural hypotension was considered earlier.
Primary Degeneration of the Autonomic Nervous System Postural hypotension resulting from primary degeneration of the autonomic nervous system is well described. The postural hypotension is often exacerbated postprandially, and the normal circadian rhythm is reversed so that the blood pressure is highest at night and lowest in the morning. In addition, blood pressure typically declines with activity rather than increasing as in normal subjects. Other symptoms of dysautonomia in these patients include impotence, disturbances of bladder and bowel function, impaired thermoregulatory sweating, and xerostomia. Two distinct groups of patients are now recognized. In one, primary or pure autonomic failure leads to idiopathic orthostatic hypotension and other evidence of dysautonomia without peripheral neuropathy or CNS involvement. In the other, autonomic failure is associated with more widespread neurological degeneration (i.e., with evidence of multisystem atrophy) such that there may be clinical features of parkinsonism (or striatonigral degeneration), and often of pyramidal, cerebellar, and lower motor neuron lesions as well (Shy–Drager syndrome). A disorder similar to olivopontocerebellar atrophy may also occur. The autonomic deficit may precede the somatic neurological one, or vice versa, but within a 60 short period there is clinical evidence of both. Occasionally there is a family history of dysautonomia. The time course and pattern of the dysautonomia reportedly differ between these two disorders. In pure autonomic failure, syncope and sudomotor dysfunction may precede the onset of constipation, bladder dysfunction, or respiratory disturbances whereas in multisystem atrophy, urinary complaints occur early and are then followed by abnormalities of 61 sweating or by postural hypotension. Patients61with pure autonomic failure had a slower functional deterioration and a better prognosis. The ingestion of water temporarily increases the seated blood pressure by uncertain mechanisms in patients with chronic autonomic 62 failure. This occurs earlier in pure autonomic failure than multisystem atrophy, perhaps reflecting differing lesion sites in these two disorders. In patients of both groups, plasma renin activity is usually subnormal. There are, however, a
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number of reported pharmacological differences between them. Patients with pure autonomic failure have low plasma norepinephrine levels when lying down, and these levels fail to increase appropriately on standing; they also have a lower threshold for the pressor response 63 to infused norepinephrine. The increase in plasma norepinephrine level in response to tyramine64(see p. 154) is significantly less than in normal subjects or patients with multisystem atrophy. Extensive cell loss occurs in the intermediolateral cell columns of the thoracic cord, and the autonomic dysfunction has been attributed primarily to loss of these preganglionic sympathetic neurons. However, the pharmacological studies described previously indicate that loss of postganglionic noradrenergic neurons also occurs, and norepinephrine may be depleted from sympathetic nerve endings. By contrast, in multisystem atrophy, in which lesions are situated at multiple sites in the CNS, circulating norepinephrine levels are normal, suggesting that peripheral sympathetic neurons are intact, but plasma norepinephrine fails to63,64 increase appropriately with standing, implying There is also an exaggerated pressor that these neurons have not been activated. response to infused norepinephrine, but only patients with idiopathic orthostatic hypotension show a shift to the left in their dose–response curve, reflecting true adrenergic receptor 64 supersensitivity. Some investigators have not found any clear pattern in the resting level of plasma norepinephrine that distinguishes between these two types of autonomic failure. They have emphasized that low levels probably indicate the severity of sympathetic dysfunction rather 65 than the site of lesions. Endogenous arginine vasopressin is a powerful vasoconstrictor; it also acts on the kidney to control urinary concentrating mechanisms. The cardiovascular responses usually associated with arginine vasopressin are reduced cardiac output, heart rate, and plasma renin activity 66,67 Arginine vasopressin helps and increased vascular resistance and blood pressure. maintain arterial pressure in certain hypotensive situations such as hemorrhage or volume depletion, but increased levels of arginine vasopressin do not normally affect the blood pressure significantly because the acute vasoconstrictor effects are buffered by the baroreceptor reflex. The chronic effects of vasopressin on renal function do not produce sustained retention of sodium and water, and so produce only minimal changes in mean arterial pressure. Vasopressin release is influenced by the plasma's osmotic pressure and by the activity of vascular stretch receptors. In normal people, plasma arginine vasopressin increases in response to standing, presumably because a decrease in venous return influences afferent activity from these stretch receptors. In patients with progressive autonomic failure or with multisystem atrophy, plasma levels similar to control values are found in 68 the horizontal position, but the postural rise is only 10 percent of that in normal people. If hypertonic saline is infused intravenously into such patients, plasma arginine vasopressin increases in a 69 manner comparable with that in normal control subjects. This suggests normal function of the efferent connections from the osmoreceptors within the hypothalamus and implies that in this clinical context, the loss of vasopressin response with head-up tilt is due to lesions in 69 ascending pathways from cardiovascular receptors. A vulnerability has been suggested of the noradrenergic neurons of the caudal ventrolateral medulla that are involved in activating 70 hypothalamic neurons involved in vasopressin secretion. However, in multisystem atrophy, loss of vasopressin neurons occurs in the posterior region of the hypothalamic paraventricular nucleus and may contribute to sympathetic failure, whereas loss of catecholaminergic input from the brainstem to the magnocellular vasopressin neurons may 71 contribute to impaired vasopressin secretion following orthostatic stress.
Miscellaneous Disorders Patients with Holmes–Adie syndrome may present with or develop postural hypotension or abnormalities of thermoregulatory sweating. Postural hypotension may occur in botulism; however, blurred vision, dry mouth, and constipation are much more common autonomic manifestations. In rare instances, it relates to excessive amounts of endogenous bradykinin (a vasodilator) or a congenital defect of norepinephrine release. In patients with dopamine β-hydroxylase deficiency, norepinephrine and epinephrine cannot be synthesized, and 72,73 dopamine is released from central and peripheral adrenergic nerve terminals. Severe postural hypotension is accompanied by other autonomic disturbances in association with absent norepinephrine and excessive dopamine levels in the plasma. Orthostatic symptoms may develop in association with a significant tachycardia (an increase of 30 beats per minute 74,75 or more), but in the absence of consistent postural hypotension or an The designation postural tachycardia syndrome (POTS) is applied autonomic neuropathy.
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to this disorder, which is more common in women than men and tends to occur in patients between 20 and 60 years of age. Symptoms on standing include tremulousness, lightheadedness, palpitations, visual disturbances, weakness, fatigue, anxiety, hyperventilation, nausea, postprandial bloating, and sweating, and may occur cyclically. Thus, orthostatic symptoms are accompanied by symptoms of sympathetic activation. A preceding viral infection can sometimes be recognized, and the syndrome may also occur in association with mitral valve prolapse or a more specific dysautonomia. Its etiology remains uncertain. A reduced or redistributed blood volume of uncertain cause has been proposed. Partial sympathetic denervation in the legs may be responsible, as suggested by studies of norepinephrine spill-over into the venous circulation of the limbs in response to various 76 vasoconstriction on the Valsalva maneuver, but stimuli. There is impaired peripheral 77 cardiovagal responses are normal. The optimal therapy for the disorder is not clear, but treatment may include volume repletion, fludrocortisone, β-blocking agents, midodrine, and phenobarbital. SYMPTOMS OF DYSAUTONOMIA Postural hypotension is usually the most disabling feature of autonomic failure. Symptoms induced by postural hypotension reflect cerebral hypoperfusion and include faintness, lightheadedness, blurred vision, and syncope. They may be particularly troublesome after exercise or a heavy meal or in the morning when the blood pressure tends to be at its lowest (in contrast to healthy subjects). However, in some patients, marked postural hypotension may be clinically asymptomatic or may be accompanied by symptoms not usually regarded as suggestive of postural hypotension, such as nausea, breathlessness, heaviness or weakness of the limbs, episodic confusion, falling, staggering, and generalized weakness. Constipation may precipitate syncopal attacks during straining. Symptoms may also worsen in the heat because of vasodilatation and volume loss due to sweating. The symptoms of idiopathic postural tachycardia syndromes (discussed earlier) may be mistakenly attributed to postural hypotension, but occur without a significant decrease in blood pressure. Impotence is a common initial symptom of autonomic dysfunction in men, often preceding other symptoms by several months or years. Bladder involvement may manifest by urinary frequency, urgency, incontinence, retention, and increased residual urine; urinary infections and renal calculi may occur in some patients with urinary stasis. Bowel dysfunction may lead to constipation, fecal incontinence, and diarrhea. Thermoregulatory sweating may be impaired. Pupillary abnormalities include Horner's syndrome and anisocoria. Lacrimal dysfunction may lead to inadequate or excessive production of tears. Other symptoms of dysautonomia include night blindness, nasal congestion, and, sometimes, supine hypertension. Vocal abnormalities and respiratory disturbances (especially involuntary inspiratory gasps, cluster breathing, airway obstruction, and sleep apnea) sometimes occur, especially in patients with multisystem atrophy.
Syncope Syncope refers to a sudden, transient loss of consciousness due to diffuse cerebral ischemia or hypoxia. It is usually associated with flaccidity, but a generalized increase in muscle tone sometimes occurs with continuing cerebral ischemia/hypoxia, and there may be arrhythmic transient motor activity as well. Postictal confusion is usually brief (less than 30 seconds) when it occurs at all, unlike the marked postictal confusion that often follows a convulsion. Several causes of syncope have been recognized. Postural Hypotension In patients with orthostatic hypotension due to autonomic dysfunction, there is a fall in blood pressure on standing, without adequate compensatory change in total peripheral resistance or heart rate, and syncope may result. When postural hypotension occurs because of one of the non-neurological causes discussed earlier, it may also lead to syncope if autonomically mediated compensatory mechanisms fail to limit the decline in blood pressure. Vasovagal Syncope During vasovagal syncope, there is an initial increase in heart rate, blood pressure, total peripheral resistance, and cardiac output, followed by peripheral vasodilatation, increased blood flow to the muscles, decreased heart rate, and a decrease in venous return to the heart. Blood pressure falls owing to failure to increase the heart rate and cardiac output sufficiently, a decrease in systemic vascular resistance, or both. The vasodilatation and decline in systemic vascular resistance have been related to depressor Bezold–Jarisch
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reflexes arising from cardiac sensory receptors and subserved by vagal unmyelinated afferent fibers, perhaps in consequence of a decrease of central blood volume and 78,79 Recordings from nerve fibers reveal that impulse traffic decreased ventricular filling. ceases in the sympathetic outflow to skeletal muscle during syncope and gradually builds up 80 again over the following 5 minutes or so. Syncope of this sort may be precipitated by pain, fear, emotional reactions, injury, and surgical manipulation. It may occur in association with missed meals, heat, or crowds; it usually occurs while subjects are standing. Warning symptoms include weakness, sweating, pallor, nausea, yawning, sighing, hyperventilation, blurred vision, impaired external awareness, and dilatation of pupils. Lying down or squatting at this time may abort actual loss of consciousness. Deglutition Syncope Swallowing precipitates syncope in some subjects (deglutition syncope). In such instances, 81 there may be associated esophageal disorders. The syncope has usually been attributed to atrioventricular heart block or cardiac arrhythmia. It is presumed that the prime factor is clinical or subclinical disease of the conducting system of the heart and that disturbances of cardiac rhythm are then triggered by reflexes originating in the esophagus. A pacemaker may 81,82 prevent further episodes. Micturition Syncope Micturition syncope occurs after urination, particularly when the patient has arisen from bed at night. It may relate to sudden release of the reflex vasoconstriction elicited by a full bladder. Assumption of the upright posture, the peripheral vasodilatation resulting from the warmth of the bed, and, particularly in elderly men, straining to micturate may also contribute to the drop in blood pressure. Occasionally, syncope occurs in response to cardiac dysrhythmia induced by a full bladder before micturition. Carotid Sinus Syncope Carotid sinus syncope may be provoked by neck-turning or a tight collar in susceptible 83 subjects. Certain drugs have also been shown to predispose toward it, especially propranolol, digitalis, and α-methyldopa. A hypersensitive carotid sinus reflex is defined by a slowing in heart rate of more than 50 percent or a decline in systolic pressure by more than 83 40 mmHg during carotid sinus massage. However, less than 50 percent of patients with carotid hypersensitivity have syncope as a result. Conversely, in many patients with syncope of unidentifiable cause, the carotid sinus syndrome may have been overlooked. Syncope With Valsalva Maneuver Vigorous coughing or straining at stool may lead to syncope because of the reduced cardiac output and the peripheral vasodilatation caused by a high intrathoracic pressure. Cerebral perfusion may also be reduced by an increase in intracranial pressure. Cardiac Syncope As discussed earlier, postural hypotension may have a cardiac basis. In addition, atrioventricular conduction block may lead to sudden loss of consciousness, regardless of the position of the body (Adams–Stokes attacks). Further discussion of this topic is provided in Chapter 5. Exertional syncope suggests obstructive valvular disease or a right-to-left shunt. Coronary artery disease may lead to arrhythmias that cause syncope. Hyperventilation Hyperventilation, with consequent hypocapnia and reduced cerebral perfusion, is a common cause of presyncopal symptoms, but actual loss of consciousness is uncommon. EVALUATION OF AUTONOMIC FUNCTION After neurological, cardiological, and metabolic causes of syncope have been excluded, a number of patients remain in whom the diagnosis is unclear. The utility of autonomic studies 84 in these circumstances was examined by Mathias and colleagues. They found that screening autonomic function tests revealed postural hypotension and confirmed chronic
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autonomic failure in 5 percent, and neurally mediated syncope was diagnosed in 43.5 percent based on clinical features and autonomic studies. Thus, in recurrent syncope or presyncope, autonomic studies are worthwhile as they may clarify the diagnosis. In patients with unexplained syncope, the implantable 85 loop recorder is an important diagnostic tool that may clarify the underlying pathophysiology.
Postural Change in Blood Pressure In investigating patients with suspected autonomic dysfunction or postural hypotension, the blood pressure should be measured with the patient supine for at least 10 (preferably 20) minutes. The patient then stands up, and the blood pressure is measured again after 5 to 10 seconds, and again after 1, 2, and 5 minutes. There is normally an increase in pulse rate on standing, but the pulse rate may not change if there is already a high resting pulse or in patients with dysautonomia; furthermore, the change in heart rate may be blunted in the elderly. As for the blood pressure, there is normally a slight decline in systolic pressure, whereas diastolic pressure increases slightly. The response of the blood pressure is regarded as abnormal if systolic pressure decreases by at least 20 mmHg or diastolic pressure by 10 mmHg on standing. In some instances, postural hypotension develops only after exercise; it is therefore worthwhile to record the postactivity blood pressure if clinically feasible. It may be necessary to record the blood pressure on a number of occasions before the diagnosis of postural hypotension can be confirmed. In other instances, prolonged tilt (for up to 60 minutes) may be required to detect abnormalities. The effect of postural change on blood pressure can be evaluated more accurately if the blood pressure is measured using an intra-arterial cannula or a noninvasive plethysmographic device with the patient resting quietly on a tilt-table; measurements are made continuously while the patient is supine and then at a 60-degree head-up tilt. The response to head-up tilt may differ from that obtained by standing because less enhancement occurs of the venous return to the heart by contraction of leg and abdominal muscles, and thus there is greater peripheral pooling of blood. Mann and co-workers monitored ambulant intra-arterial blood pressure in six patients with 86 autonomic failure and postural hypotension. They found a consistent circadian trend in blood pressure that was the inverse of the pattern in normal subjects, with the highest pressures found at night and the lowest in the morning. Such temporal variation in blood pressure implies that physiological testing should be carried out at a standard time of day, especially if comparative studies are to be performed, and potentially harmful hypertension in response to treatment should be looked for especially during the early part of the night.
Postural Change in Heart Rate A simple, noninvasive test of autonomic function consists of evaluating the response in heart rate to change from a recumbent to a standing position. There is typically a rapid increase in heart rate that is maximal at approximately the fifteenth beat after standing, with a subsequent slowing from the initial tachycardia (i.e., a relative bradycardia) that is maximal at approximately the thirtieth beat (Fig. 8-3). This response is mediated by the vagus nerve. For testing purposes, the R-R interval at beats 15 and 30 after standing can be measured to give 87 the 30/15 ratio. Values greater than 1.03 occur in normal subjects, whereas in diabetic patients with autonomic neuropathy (who typically show only a gradual increase in heart rate), values are 1.00 or less. Some prefer to measure the ratio of the absolute maximum to absolute minimum heart rate after standing, which may not coincide with the heart rates at 88 beats 15 and 30. This test does not depend on the resting heart rate and correlates well with the Valsalva ratio and the beat-to-beat variation in heart rate, described later. Studies 88,89 suggest that the value for the 30/15 ratio declines with age in normal subjects.
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FIGURE 8-3 Heart rate responses to standing in a normal subject. Immediately on standing, there is a rapid increase in heart rate that is maximal at approximately the fifteenth beat after standing.
In some patients, an excessive and sustained tachycardia develops in response to standing or head-up tilt, without significant drop in blood pressure. A prolonged tilt (for up to 60 minutes) may be necessary to elicit the abnormality. The mechanisms underlying this postural tachycardia have not been clearly established.
Valsalva Maneuver The Valsalva maneuver consists of a forced expiration maintained for at least 10 seconds (preferably 15 seconds) against a closed glottis after a full inspiration. Intrathoracic pressure should be increased by 30 to 40 mmHg. Clinically, this can be ensured by requiring the patient to blow into a mouthpiece connected to a manometer. The response can be recorded with an intra-arterial needle (Fig. 8-4), a noninvasive photoplethysmographic recording device (Finapres), or an electrocardiograph (ECG) (Fig. 8-5).
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FIGURE 8-4 Cardiovascular responses to the Valsalva maneuver, as recorded with an intra-arterial needle. A, Normal response. B, Abnormal response in a patient with Shy–Drager syndrome. (From Aminoff MJ: Electromyography in Clinical Practice. 3rd Ed. Churchill Livingstone, New York, 1998, p. 206, with permission.)
FIGURE 8-5 Valsalva maneuver as recorded using an electrocardiograph (ECG) or heart rate monitor in a normal subject. The tachycardia that occurs during the forced expiratory maneuver is clearly evident, as is the compensatory bradycardia that occurs when the maneuver is released.
The cardiovascular response is usually divided into four stages. Stage 1 is characterized by a transient increase in blood pressure at the onset of the forced expiration, reflecting the increased intrathoracic pressure. In stage 2, there is normally a gradual decrease in systolic and diastolic pressures, pulse pressure, and stroke volume for several seconds because of a reduction in venous return to the heart, with an associated reflex tachycardia. Reflex vasoconstriction arrests the decline in blood pressure after about 5 to 7 seconds. Stage 3
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occurs when the patient releases the expiratory maneuver and is characterized by a transient fall in the blood pressure because of pooling of blood and expansion of the pulmonary vascular bed with the abrupt decline in intrathoracic pressure. In stage 4, there is an overshoot of the blood pressure above baseline value as a result of the peripheral vasoconstriction, with a compensatory bradycardia. The Valsalva maneuver is an accurate indicator of baroreceptor reflex sensitivity. Abnormalities are found in patients with dysautonomia (Fig. 8-4) and may consist of loss of the overshoot in systolic blood pressure and compensatory bradycardia in stage 4, a fall in mean blood pressure in stage 2 to less than 50 percent of the previous resting mean pressure, and loss of the tachycardia in stage 2 or a lower heart rate in stage 2 than stage 4. However, abnormalities may also be found in patients with severe congestive heart failure and in those with cardiac lesions other than primary myocardial dysfunction. If the response is recorded noninvasively using an electrocardiograph, the ratio of the shortest R-R interval (the tachycardia) during the maneuver to the longest R-R interval (bradycardia) after it is determined and expressed as the Valsalva ratio. A value of 1.1 or less was arbitrarily defined by Ewing and associates as 90 an abnormal response, 1.21 or greater as a normal response, and 1.11 to 1.20 as borderline. Using such criteria, these authors found that the Valsalva maneuver was abnormal in 62 percent of diabetic patients with symptoms and signs suggestive of autonomic neuropathy. When more generous criteria for abnormality were used, with a lower limit for normal of 1.50, the value was abnormal in 86 percent of these patients, and such an abnormality correlated well with the presence of a significant postural drop in blood pressure.91,92 Subsequent studies have shown that age- and gender-based normal values should be used.
Other Cardiovascular Responses Other cardiovascular responses can also be measured noninvasively (e.g., the beat-to-beat variation in heart rate and the heart rate responses to deep breathing and sustained hand grip). Such tests of parasympathetic function appear to give abnormal results more often and earlier than tests of sympathetic function, at least with the dysautonomia that occurs in 87 diabetes. A particularly useful test is to measure the heart rate variation during deep breathing (Fig. 8-6). In normal subjects, there is considerable heart rate variation, which is accentuated during deep breathing. This variation is reduced or absent in diabetic patients with autonomic neuropathy. The optimal breathing rate for this test is six breaths per minute (i.e., inspiration = expiration = 5 seconds). Heart rate variation scores can be calculated by measuring the difference between the maximal and minimal heart rates in inspiration and expiration, taking the average from 10 breaths in and 10 breaths out. Normal subjects usually have a score greater than 9, and autonomic neuropathy is probably absent if scores greater than 12 are 93 89,91,94,95 Thus, Freeman indicated obtained ; the normal range, however, is age dependent. that heart92rate variability may decline by 3 to 5 beats per minute per decade in normal subjects. The use of a single normal value regardless of age may therefore limit the utility of the test. Physical fitness, body weight and position, time of testing, and concomitant medication may affect the test results.
FIGURE 8-6 Normal variation in heart rate that occurs in response to deep
breathing.
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An increase in heart rate and blood pressure should also occur in response to startle, such as occurs with a sudden loud noise, and to mental stress, as is produced when the patient attempts to subtract 7 serially from 100 while constantly being distracted.
Digital Blood-Flow Blood flow to a finger can be measured by conventional plethysmography or photoplethysmography. A sudden inspiratory gasp causes reflex digital vasoconstriction as a spinal reflex, and this is easily measured plethysmographically (Fig. 8-7). The response is impaired or absent in patients with a lesion of the cord or sympathetic efferent pathway, as in peripheral neuropathy. In entrapment neuropathy, such as carpal tunnel syndrome, the vasoconstrictor response may be 96 abolished in fingers supplied by the affected nerve but not in those supplied by other nerves.
FIGURE 8-7 Variation in blood volume after a deep inspiration in a normal subject, measured photoplethysmographically by means of an infrared emitter and detector placed on the pad of the index finger. The bottom trace represents the sensor output after it has been amplified by the photoplethysmographic module of a computerized autonomic testing system; it is a function of the absolute blood volume in the finger. Each peak represents a heartbeat, and the amplitude of each wave reflects blood volume in the area about the sensor. The apparent shift of the direct-current signal component is due to the long time constant that is necessary so that signal information is not lost. The relative voltage, representing the amplitude of each pulse, is shown in the upper trace. It is evident in both traces that after the deep inspiration there is a reduction in digital blood flow (i.e., reduced amplitude of the waveforms in the lower trace and a corresponding decline in the upper trace).
Cold Pressor Test In the cold pressor test, one hand is immersed in ice water at 4°C, and this normally produces an increase in systolic pressure of 15 mmHg or more within 1 minute. The afferent pathway involves the spinothalamic tract, and if this tract is intact, the lack of a pressor response suggests a lesion centrally or in the sympathetic efferent pathway. A normal response in a patient with an abnormal Valsalva response and intact pain and temperature sensation suggests an afferent baroreceptor lesion.
Norepinephrine Infusion The plasma norepinephrine level can be used as an index of sympathetic activity. Perhaps of greater value, the blood pressure can be measured in64response to intravenous infusion of norepinephrine at several dose rates up to 20 μg/min. In this way, a dose–response curve can be constructed. In normal subjects, it is usually necessary to administer 15 to 20 μg/min
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to increase systolic blood pressure to 40 mmHg above baseline. A similar increase in blood pressure results from doses of 5 to 10 μg/min in Shy–Drager syndrome and less than 2.5 64 μg/min in patients with idiopathic orthostatic hypotension.
Response to Tyramine Tyramine, an indirectly acting sympathomimetic drug, can be used to test neuronal uptake and release of norepinephrine. Bolus injections ranging from 250 to 6,000 μg are administered and blood pressure measured at 1-minute intervals. The amount of norepinephrine released into plasma by tyramine can be quantified by obtaining a blood 64 sample shortly after the rise in blood pressure.
Norepinephrine Response to Edrophonium Intravenously administered edrophonium (10 mg) normally leads within 8 minutes to the postganglionic release of norepinephrine and thus to an increase in plasma norepinephrine levels. In patients with central dysautonomias (and intact postganglionic function), a normal response is obtained, whereas patients with more peripheral disease have absent or 97 attenuated responses. The sensitivity and specificity of the test remain to be established.
Sweat Tests Cutaneous blood vessels and sweat glands are supplied by sympathetic fibers intermingled in 14 the same fascicles but of different size and conduction velocity. Commonly used tests of sweating are messy and require application of heat, which is time-consuming. A heat cradle placed over the trunk is used to produce an increase of 1°C (from a resting level of 36.5° to 37.0°C) in the oral temperature over the course of 30 to 60 minutes, and the presence of sweat over selected regions of the trunk and limbs is detected by the change in color of quinizarine powder or a starch-iodide mixture that it produces. Changes in hand blood flow can also be measured with a plethysmograph. The pattern of any impairment of sweating may be helpful in suggesting the underlying cause. For example, impairment is usually distal in the limbs in patients with polyneuropathies. The volume of sweat produced by axon-reflex stimulation either electrically (faradic sweat response) or with parasympathomimetic drugs under specified conditions indicates the state of sudomotor innervation in the tested limb. After a short latent period, sweating occurs in an area that is approximately 4 to 5 cm in diameter about the site of stimulation. The reflex is subserved by sympathetic postganglionic fibers; impulses pass centripetally along these fibers until they reach a branch point and then pass distally again. The receptor involved in 98 the reflex has not been defined. Rather than detecting a sweat response by a color change, as described previously, it may be necessary to quantify the volume of sweat. Recordings can then be made of the humidity 98 change of an air stream of defined flow. Using such an approach, the group at the Mayo Clinic have quantified the sudomotor response to axon reflex stimulation using electrophoresed acetylcholine to stimulate the receptors involved in the axon reflex. Another simple technique for evaluating sudomotor function is to measure changes in skin resistance. With sweating, there is a reduction in skin resistance. This is the so-called galvanic skin response, which can be elicited by painful or emotional stimuli or by deep inspiration. Sudomotor function has also been evaluated in patients with polyneuropathies by recording the change in voltage measured from the skin surface after deep inspiration or startle or after electrical stimuli applied to the skin of the wrist or ankle (sympathetic skin response). Responses are recorded from a pair of electrodes placed on the palm and dorsum of the 99 hand or the sole and dorsum of the foot. The sympathetic skin response is simple to record, but responses tend to habituate and are affected by the recording technique and a number of other factors. The absence of a response, and not the absolute values of latency or amplitude, is regarded as significant for determining abnormality. The normal latency in the upper limb is in the order of 1.5 seconds and in the lower limb is about 2 seconds, reflecting the slow conduction velocity of postganglionic C fibers (approximately 1 m/sec) Abnormalities of the sympathetic skin response reportedly correlate well with the quantitative sudomotor 100 axon reflex test.
Other Studies
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Pupillary Responses Pupillary constriction with 2.5 percent methacholine applied locally indicates denervation supersensitivity due to interruption of postganglionic parasympathetic fibers, as in the Holmes–Adie syndrome. Local instillation of 1:1,000 epinephrine hydrochloride (one or two drops) produces little or no response unless there is postganglionic sympathetic denervation, in which case marked pupillary dilatation occurs. A 4 percent solution of cocaine hydrochloride applied to the conjunctival sac dilates the normal pupil, but fails to do so if sympathetic innervation has been interrupted outside the CNS. Radiological Studies Radiological studies may be helpful in characterizing gastrointestinal and bladder function but are beyond the scope of this chapter. PATIENT MANAGEMENT The initial investigative approach to patients presenting with syncope or other symptoms suggestive of postural hypotension or autonomic dysfunction is to exclude reversible causes such as hypovolemia or certain medications (see pp. 142 to 143). The history must include a detailed account of illnesses and drug intake. Simple laboratory investigations should include a full blood count and erythrocyte sedimentation rate as well as determination of plasma urea, electrolytes, glucose, morning and evening cortisol levels, and lying and standing catecholamine concentrations. Urinary screen for porphyrins; serum protein electrophoresis and immunophoresis; hepatic, renal, and thyroid function tests; chest radiograph; and electrocardiogram (to exclude recent cardiac infarction or cardiac ischemia, heart block, or persisting cardiac dysrhythmia) are also performed, as are serological tests for syphilis and nerve conduction studies. Neuroimaging studies may be helpful if a structural intracranial lesion is suspected. An echocardiogram may help when evaluating patients with suspected structural lesions of the heart predisposing to syncope. Prolonged tilt-table evaluations and invasive cardiac electrophysiological studies may be necessary when an arrhythmia is likely. In patients with symptoms of uncertain etiology in whom general medical causes have been excluded, more detailed evaluation of autonomic function in the manner suggested earlier may be helpful.
Treatment If a specific reversible cause, such as a metabolic or endocrinological disturbance, can be recognized, it must be treated appropriately. The need for continuing with drugs likely to be responsible should be reviewed and, if feasible, treatment discontinued. Patients should be advised against using alcohol. Treatment with antiarrhythmic agents, cardiac pacemaker, or surgery may be indicated in patients with a cardiac cause of syncope or postural hypotension. Pacemaker therapy may also help patients with syncope due to carotid sinus 83 hypersensitivity. If no specific cause can be identified, treatment should be directed to the minimization of symptoms (Table 8-1). The actual extent to which the blood pressure falls on standing, for example, is of less significance than the occurrence of symptoms. Patients with dysautonomia should avoid extreme heat, alcohol, large meals, rapid postural changes, prolonged periods of recumbency, and excessive straining (e.g., during micturition or defecation), each of which may exacerbate symptoms. Diuretics should be stopped, if possible, and salt intake liberalized. Click here to view this table.... When standing, patients often find it helpful to work the leg muscles because this aids the venous return to the heart. Symptoms may also be reduced if patients stand up gradually (e.g., by first adopting the seated position and, after a short pause, getting up from this position). Other physical maneuvers that may be helpful include standing with legs crossed, bending forward, squatting, or placing a foot on a chair, thereby slightly increasing the mean arterial pressure so that cerebral blood flow remains adequate. The underlying common mechanism is held to be1 an increase of thoracic blood volume by transfer from below the diaphragm to the chest. Resistance exercise may increase orthostatic tolerance, plasma volume, and baroreflex gain. Waist-high elastic stockings may be helpful in alleviating postural symptoms but are often difficult to put on (especially for elderly patients) and may be uncomfortable in hot weather.
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To be effective, the stockings must extend at least as high as the waist. Antigravity suits have been used in the past but are awkward, restrictive, impractical, and not generally available. Many dysautonomic patients have a disturbance in the regulation of body fluids. In particular, there is defective sodium conservation, especially during recumbency at night, associated 101 with, but not entirely due to, low aldosterone levels ; there are also abnormal posture-dependent changes in urine volume (Fig. 8-8) accompanied by an alteration in the 102 secretion of antidiuretic hormone. This leads to relative hypovolemia and postural hypotension that are worse in the morning and improve during the day. The disturbed regulation of body fluids could be due, at least in part, to diminished adrenergic activity in the renal nerves, which affects tubular reabsorption and renin release (and thus angiotensin formation). The effect of recumbency can be minimized by elevating the head of the bed by 5 to 20 degrees, which leads to reduced renal artery pressure, thereby stimulating the renin-angiotensin system and promoting sodium retention. Head-up tilt at night reduces nocturnal shifts of interstitial fluid from the legs into the circulation; furthermore, such interstitial fluid may exert hydrostatic force, opposing the tendency of blood to pool in the legs 103 on standing. Head-up tilt at night also reduces supine hypertension.
FIGURE 8-8 Renal responses of five dysautonomic patients and four parkinsonian
(control) subjects to fluid deprivation for 36 hours, commencing at 6 p.m. Average results are presented for urine osmolality and volume as well as potassium and sodium excretion for each successive 4-hour period. Subjects were lying down (white bars) during the night (10 p.m. to 10 a.m.) and were up and about (black bars) during the day (10 a.m. to 10 p.m.). (From Wilcox CS, Aminoff MJ, Penn W: Basis of nocturnal polyuria in patients with autonomic failure. J Neurol Neurosurg Psychiatry 37:677, 1974, with permission.) If these measures are unsuccessful, the mineralocorticoid fludrocortisone can be tried. This agent seems to exert its effect in part by temporarily increasing plasma volume and also by increasing vascular sensitivity to norepinephrine and improving the vasoconstrictor response to sympathetic stimulation. Treatment is usually commenced with a daily dose of 0.1 mg, which can then be increased by 0.1 mg every 2 weeks or so until benefit occurs or there are intolerable side effects. Some patients may require as much as 1.0 or 2.0 mg daily, but usually a dose of 0.5 mg or less is sufficient. During treatment with fludrocortisone, a positive sodium balance should be ensured, with a sodium intake of at least 150 mEq/day. Side effects include pedal edema, weight gain, recumbent hypertension, cardiomegaly, hypokalemia, and retinopathy; coexisting diabetes mellitus may also be exacerbated. Prostaglandin synthetase inhibitors should expand plasma volume and inhibit vasodilator prostaglandin synthesis. Indomethacin (25 to 75 mg three times daily with meals) increases peripheral vascular resistance, promotes fluid retention, and may increase the sensitivity of 104 It is said to be helpful in the peripheral vasculature to norepinephrine and angiotensin II. 105 some patients with postural hypotension, especially if they are also on fludrocortisone, but, in general, the results with it have been disappointing despite the theoretical advantages of its use. Ibuprofen (200 to 600 mg four times daily before meals) can also be tried and is sometimes helpful. Side effects include gastric irritation, nausea, constipation, and skin rashes.
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Dihydroergotamine is a relatively selective constrictor of peripheral veins. Its action may be mediated partially through α-adrenoreceptors, and enhanced synthesis of a vasoconstrictor prostaglandin may also be important. It is sometimes helpful for treating postural hypotension, but may cause recumbent hypertension. Although it is effective when administered intravenously, its efficacy when taken orally (5 to 10106 mg three times daily) is Cafergot (caffeine and more limited and variable. Inhaled preparations may be effective. 107 ergotamine) suppositories have sometimes been effective. Sympathomimetic drugs that either act directly to constrict blood vessels (e.g., phenylephrine) or that have an indirect action, preventing the destruction of norepinephrine at sympathetic nerve terminals (e.g., ephedrine and amphetamines), have been used to treat postural hypotension. These drugs can sometimes be helpful, but any benefit is often mild and temporary, and they may cause severe recumbent hypertension. Other side effects include nervousness, anxiety, restlessness, tachycardia, and tachyphylaxis. Midodrine is a direct α-adrenergic agonist that causes constriction of arterioles and venous vessels. It is started in a low daily dose (2.5 mg three times daily) that is built up gradually to 10 mg three times daily) depending on response and tolerance. Side effects include supine hypertension, 108,109 Pyridostigmine bromide may reduce postural hypotension by piloerection, and pruritus. enhancing ganglionic transmission without aggravating or precipitating supine hypertension. A recent clinical trial showed that its greatest effect was on diastolic blood pressure, 110 suggesting that improvement is due to increased total peripheral resistance. Its role merits further study. Propranolol may help the postural hypotension associated with postural tachycardia syndrome and also reduces sodium excretion, leading to an increase in blood volume. Furthermore, it has been said to help the hypotension of both idiopathic orthostatic hypotension and the Shy–Drager syndrome; this action has been attributed to the β-blockade correcting an imbalance of α- and β-adrenoreceptor activity in the peripheral nervous 111 system. It can be initiated at a dose of 10 mg four times daily and built up to 40 mg four times daily. Pindolol, a β-blocker with intrinsic sympathomimetic activity, has also been helpful 112 in some instances, but more often it produces no benefit and may lead to cardiac failure. Clinical benefit and an increase in blood pressure on standing in patients with sympathetic 113–115 However, in a patient with more severe efferent failure may occur with cardiac pacing. sympathetic 115 involvement, Goldberg and colleagues failed to show any benefit with atrial tachypacing. Bannister and associates reported a patient with selective impairment of sympathetic cardiovascular reflexes but relative sparing of cardiac parasympathetic 48 function. Because of accentuation of bradycardia and the risk of dysrhythmia with any elevation in blood pressure, it was thought that the use of pressor agents would be especially hazardous. A demand pacemaker was therefore introduced, and, although it did not improve postural hypotension, it enabled blood pressure to be readily and safely controlled by drugs. Atrial tachypacing may thus prove helpful in patients with selective sympathetic autonomic neuropathy by protecting against vagal overactivity. Vasopressin responses to upright posture are often defective in autonomic failure, and patients are hypersensitive to exogenous vasopressin. The long-term therapeutic utility of vasopressin is unclear. Kochar studied the effect of lysine vasopressin nasal spray in 10 patients with chronic orthostatic hypotension and found no significant alteration in the effect of tilt on heart rate, stroke volume, or cardiac output; there was, however, an increase in blood 116 pressure and total peripheral resistance. In five patients with chronic autonomic failure who were not receiving treatment with drugs, Mathias and associates found that the vasopressin analogue desmopressin (given intramuscularly) reduced nocturnal polyuria, raised supine 117 blood pressure, and reduced postural drops in blood pressure. Intranasal desmopressin administered once at night in patients with multisystem atrophy118 and nocturnal polyuria has led to an improvement in nocturia without serious adverse effects. If this approach is to be used, serum sodium should be monitored, especially during the first 4 to 5 days of treatment and then at monthly intervals. Recombinant erythropoietin helps the mild anemia that is common in dysautonomic patients and also reduces postural hypotension. It is expensive, may require concomitant iron supplementation, and sometimes leads to supine hypertension, but can be tried in cases that are otherwise difficult to manage. It is given subcutaneously, with the dose and frequency of administration individualized. There have been a variety of other experimental therapeutic approaches. Yohimbine, a centrally acting α2-antagonist, increases mean arterial pressure and plasma norepinephrine 119 120 levels in normal subjects and dysautonomic patients, but its clinical utility is not clear.
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The use of a dopamine receptor antagonist, metoclopramide, was suggested because 121 dopaminergic drugs (e.g., bromocriptine) may depress the blood pressure. It is probably most helpful in patients with a diabetic dysautonomia, particularly if gastroparesis is also conspicuous. It is given in a dose of 5 to 10 mg three or four times daily, before meals, but long-term use may lead to tardive dyskinesia. In a few patients with pure autonomic failure, 122 the selective partial α-agonist clonidine may be helpful, but it has caused profound hypotension in a patient with baroreceptor dysfunction123 due to irradiation of the neck; it may reduce supine hypertension and nocturnal natriuresis. It is probably most likely to help in patients with an efferent sympathetic lesion. It is started in a dose of 0.1 mg taken in the morning, and the dose is then built up gradually to 0.2 to 1 mg twice daily. Side effects include xerostomia, constipation, drowsiness, and supine hypertension; hypotension may be exacerbated in patients with non-neurological causes of postural hypotension. Administration of caffeine with meals may markedly reduce postprandial hypotension and is worthy of trial 115 brain when symptoms are particularly troubling after meals. A possible role for deep 124 stimulation of the periventricular/periaqueductal gray region has been suggested. Patients with vasovagal syncope require reassurance coupled with advice about ensuring adequate fluid and salt intake and about sympathetic activation techniques (such as isometric 125 hand exercises) to increase the blood pressure ; sitting or lying down or sitting with head between the knees may help to abort attacks.
General Precautions in Management of Dysautonomic Patients Patients may show postprandial falls in blood pressure because blood is diverted to the hepatic and splanchnic beds. Vasoactive substances may also contribute to the hypotensive response. To avoid or minimize this postprandial hypotension, it is helpful to eat smaller meals and to avoid excessive activity during the immediate postprandial period. Dysautonomic patients often have low circulating catecholamine levels and denervation supersensitivity to sympathomimetic amines. Medications containing such substances should therefore be avoided, even though they are often available without prescription in over-the-counter preparations. Patients with dysautonomia pose special problems during anesthesia. They are unable to tolerate hemodynamic stresses normally because of impaired cardiovascular reflexes. Maintenance of fluid balance is more difficult because of the abnormal manner in which they handle salt and water, and their enhanced sensitivity to volume changes influences blood pressure control. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 9 Neurological Complications of Cardiac Arrest W.T. LONGSTRETH JR •
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VIEW OF THE PAST OUTCOMES OF CARDIAC ARREST Insults Consequences Complications PREDICTING OUTCOMES OF CARDIAC ARREST General Issues and Physical Examination Ancillary Tests Application of Prognostic Information ALTERATION OF OUTCOMES Minimizing Insult Brain Resuscitation Hypothermia VIEW TO THE FUTURE
VIEW OF THE PAST Not long ago, cardiac arrest was an irreversible event that meant certain death. 1 Mouth-to-mouth resuscitation, described since biblical times, or other types of artificial ventilation alone may save a victim of respiratory arrest but not cardiac arrest. The understanding of the causes and treatment of cardiac arrest is intriguingly intertwined with the study of electricity. By the middle of the nineteenth century, investigators knew that electrical currents caused the ventricles of animals to be thrown into a state of Herzdelirium or fibrillation. A series of experiments by Prevost and Battelli in dogs in 1899 established that 2 electrical current could not only induce ventricular fibrillation but also reverse it, leading Jex-Blake to conclude in the 1913 Goulstonian lectures: “It is more than probable that the same treatment—a hair of the dog that bit them—could be applied with success to human 3 beings apparently killed by electric currents.” Progress was interrupted by World War I, and interest was not rekindled until the 1920s in 4 the United States. Concern about accidental death among linemen led Consolidated Edison Company of New York City to request help from the Rockefeller Institute. Several investigations were initiated, including in 1928 work at Johns Hopkins5University by Kouwenhoven, an electrical engineer, and Langworthy, a neurologist. They confirmed earlier
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works indicating that lower voltage shocks induced ventricular fibrillation and higher voltage shocks caused respiratory arrest. However, they were unable to reverse the ventricular fibrillation with various treatments. In 1930, a colleague pointed out to them the 1899 works by Provost and Battelli, which they subsequently confirmed. The Johns Hopkins investigators returned to Edison Electric Institute to have them create a portable defibrillator. One of the defibrillators subsequently developed had paddles that had to be pushed against the chest before the current could be discharged. Investigators noted that forceful application of the paddles to the chest wall of dogs led to a rise in blood pressure while the heart was still fibrillating. This serendipitous observation led to closed chest compressions. Now the stage was set to treat effectively a common cause of sudden cardiac death—ventricular fibrillation. Closed chest compression and mouth-to-mouth respiration would keep the patient viable long enough for the portable defibrillator to be brought to the patient and applied. Progress was again interrupted by World War II, and it was not until 1956 that Zoll and colleagues reported 6 the first successful external defibrillation in humans. In 1960, Kouwenhoven and co-workers reported a series of successful resuscitations in hospital with closed chest cardiac massage 7 and external defibrillation. Several epidemiological aspects of8sudden cardiac death led to the application of these same techniques outside the hospital. First, the importance of heart disease as a cause of death was increasingly recognized. Second, sudden cardiac death was the presenting feature in up to one third of people with heart disease. Finally, many people dying of heart disease, especially in the setting of myocardial infarction, were doing so outside the hospital. 9–11
One of the first prehospital emergency medical systems was developed in Belfast, Ireland. In their 1967 report, Pantridge and Geddes describe the out-of-hospital resuscitation of a 55-year-old man who had collapsed while dancing. A bystander performed chest compressions, and personnel from the mobile unit applied cardioversion to restore 10 brain damage. A spontaneous circulation. Unfortunately, the patient died a week later with12,13 and systems similar emergency medical system began in Seattle, Washington, in 1970, rapidly proliferated throughout the United States and elsewhere. Meanwhile, selective application of cardiopulmonary resuscitation in hospital had become common as patients, families, and clinicians tried to decide who was likely to benefit from this technique. Over these decades, the realization has grown that the outcome among those in whom spontaneous circulation can be restored is often dominated by brain damage suffered during 14–16 the arrest.
Between 400,000 and 450,000 people are estimated to experience sudden17cardiac death out of hospital or in the emergency department each year in the United States. The numbers treated by emergency medical systems is lower and estimated to be 155,000 people for all rhythms based on an incidence of 55 per 100,000 person-years and 60,000 for ventricular 18 fibrillation based on an incidence of 21 per 100,000 person-years. In this review including studies from 1980 to 2004, survival was 8.4 percent for all rhythms and 17.7 percent for ventricular fibrillation. In many regions of the United States, cardiac arrest has become a leading cause of coma, along with head trauma and drug overdose. The goal of this chapter is to review the neurological sequelae of cardiac arrest (outcomes) and address linked issues of predicting outcomes (prognostication) and improving outcomes (treatment). The focus is on adults, and extreme caution should be used in extrapolating to 19 children. OUTCOMES OF CARDIAC ARREST
Insults To understand the outcomes of cardiac arrest, the insults must be understood. Interruption of cardiac function, as evidenced by an absent pulse, causes insufficient blood flow to the brain leading to global brain ischemia and global brain dysfunction, as evidenced by an absence of consciousness. The dysfunction can be transient or permanent, depending in large part on the duration and severity of the ischemia. At the extreme, the ischemia may be complete where the initial electrocardiogram (ECG) reveals ventricular fibrillation or asystole. With other pulseless conditions, such as rapid ventricular tachycardia or pulseless electrical activity, the ischemia may be incomplete or unknown. During the resuscitation of individuals with cardiac arrest, the inability of medical personnel to detect a pulse or blood pressure does not preclude the possibility of severe hypotension, which could be detected if more sensitive means of measuring blood pressure were available. In most cardiac arrests, both incomplete (low flow) and complete global brain ischemia (no flow) contribute to the brain dysfunction and possible injury. For example, a patient with myocardial ischemia may have hypotension (low flow) preceding deterioration to ventricular fibrillation (no flow). During cardiopulmonary
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resuscitation and basic life support, severe hypotension can exist (low flow). Finally, with restoration of spontaneous circulation, hypotension and cardiogenic shock (low flow) can complicate the hospital course. The duration and severity of these components of global brain ischemia probably determine the degree of brain damage and outcome. Unfortunately, duration and severity are usually unknown. Cardiac arrest most commonly results from a primary problem with the heart. Although the list of potential cardiac problems is long, coronary artery disease and myocardial ischemia 20 are the most likely culprits. Cardiac arrest can also occur secondary to other toxic and metabolic problems. With the possible exception of hypothermia and overdoses of sedative drugs, these other problems can augment the insult to the brain, especially when a respiratory arrest precedes a cardiac arrest. The respiratory arrest may occur in many settings and is often not a simple event in itself, as with drowning, decompensation of chronic lung disease, drug overdoses, hanging, strangulation, trauma, asphyxia, and carbon monoxide poisoning. In the absence of a cytotoxic agent, such as carbon monoxide, the 21 hypoxia of respiratory insufficiency can be surprisingly well tolerated by the brain. However, if a cardiac arrest ensues, the resulting brain damage can be devastating. Primary neurological problems, such as focal brain ischemia, hemorrhage, and trauma, can lead to a cardiac arrest, which most commonly results from an initial respiratory arrest. Rarely will the first rhythm be ventricular fibrillation. Some neurological events can result in cardiac arrest without intervening respiratory arrest. Brain–heart interactions are detailed in Chapter 22 10. Their importance is supported by experiments in pigs. When pigs were placed under psychological stress, occlusion of the left anterior descending coronary artery resulted in ventricular fibrillation. Functional blockage with cryoprobes of pathways from the frontal cortex through the posterior hypothalamus to the brainstem prevented or delayed the development of ventricular fibrillation. Such pathways may play a role in the sudden death experienced by some patients with epilepsy in whom a fatal arrhythmia may be the terminal 23 event. Thomas mused on the possibility that mechanisms have evolved to ensure sudden death 24 when the end of an animal's life is near. If such mechanisms exist and are triggered inappropriately, premature sudden death could result. Psychological factors may be important in triggering these responses. Richter presented an experimental model in rats of the influence of psychological factors on sudden death and proposed that deaths in humans due 25 to hexing could represent the same phenomena. All such theories assume a strong interaction among cardiac, psychological, and neurological factors.
Consequences The consequences of global brain ischemia have intrigued investigators since well before resuscitation from cardiac arrest was a reality. In 1836, Cooper, an English physician, carried 26 out experiments on rabbits. After surgically occluding both common carotid arteries, he noted that pinching of the vertebral arteries led to sudden unconsciousness. If the blood flow to the brain was not interrupted for too long, the rabbit regained consciousness rapidly upon release of the vertebral arteries. These seminal observations were extended by Brown-Séquard, who27introduced the concept of a rostral-caudal deterioration of brain function with global ischemia. Simply put, cerebral cortical function was lost before brainstem function. In turn, upper brainstem function, such as the pupillary light reflex, was lost before lower brainstem function, such as spontaneous respiratory efforts. The clinical stimulus for these early investigations is uncertain, given that the only examples of global brain ischemia recognized in humans at the time were conditions like beheading and hanging. Confirmation that cerebral cortical function was lost before brainstem function with global ischemia came from additional studies in the 1940s. These studies entailed rapid inflation of a cuff about the neck of human volunteers, with interruption of blood flow to the brain. 28,29 In a 1957 study in which they recorded Subjects were rendered rapidly unconscious. electroencephalograms (EEGs) on 100 patients with syncope, Gastaut and Fischer-Williams attempted to induce transient cardiac arrest with vagal stimulation induced by ocular 30 compression. “When cardiac arrest lasted more than about 14 sec., one or two generalized clonic jerks appeared without affecting the E.E.G., followed by generalized tonic contraction resembling decerebrate rigidity and accompanied by complete ‘flattening’ of the E.E.G.” More recent examples include observations made during induction of ventricular arrhythmias to test 31,32 33 and head-up tilt testing for syncope. Although the automatic implantable defibrillators electrocerebral accompaniments of global ischemia may be more complex than suggested in the earlier studies, all studies agree that motor activity early in the course of global brain ischemia is common and not related to cerebral cortical hyperactivity. Careful video observations have also been made in patients rendered unconscious following
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hyperventilation, orthostasis, and the Valsalva maneuver to induce global brain ischemia. In addition to the motor activity, various eye movement abnormalities, including downbeat nystagmus, were documented. The cerebellum, in addition to the cerebral cortex, was held to be sensitive to brief global ischemia. Given the observations that the cerebral cortex is more sensitive than the brainstem to global 36,37 Based on experiments of global ischemia, the major clinical outcomes can be anticipated. ischemia in primates, Nemoto and colleagues proposed S-shaped curves relating the 38 duration of ischemia with the degree of brain damage and thus with neurological deficits. Assuming that similarly shaped curves exist for the human brain and that for any duration of ischemia, except at extremes, damage to the cerebral cortex is greater than damage to the The outcomes predicted are similar to those brainstem, Figure 9-1 can be constructed. 39 defined in the Glasgow Outcome Scale. At extreme durations of cardiac arrest, both the cerebrum and brainstem will be totally destroyed and brain death will result. Such an outcome after a primary cardiac arrest, as with ventricular fibrillation or asystole, is uncommon and probably reflects the inability to resuscitate individuals whose arrest has such a long duration. In a study of 459 consecutive patients admitted to one hospital in Seattle after out-of-hospital cardiac16arrest and resuscitation, only about 1 percent had an outcome consistent with brain death. With shorter durations of arrest, the cerebral cortex may still be entirely destroyed, but without as complete a devastation of the brainstem. Such individuals will not be brain dead in that they retain some brainstem function, but 40 they may have evidence of forebrain failure, such as electrocerebral inactivity on the EEG. Various terms have been applied to this type of brain damage, including cortex death, neocortical death, partial brain death, death of the forebrain, and acute failure of forebrain with sparing of brainstem function. Although this condition is well described after cardiac arrest, it also is unusual.
FIGURE 9-1 Hypothetical relationship between duration of ischemia and brain damage, assuming that cerebral cortex is more vulnerable to global ischemia than 36–38 brainstem. For example, in a study of 459 patients admitted to a single hospital in Seattle after out-of-hospital cardiac arrest, 279 (61%) awakened, of whom about two 16 thirds regained independence.
More commonly, the cerebral cortex is severely damaged but not completely destroyed. The damage is extensive enough to preclude the patient ever regaining consciousness even though evidence of cerebral cortical activity may exist on the EEG. Evaluation of brainstem function may reveal some deficits or no abnormality. Spontaneous eye opening is common, 41,42 In one survey of four nursing 43 and such patients are said to be in a vegetative state. homes in Milwaukee, Wisconsin, about 3 percent of patients were in a vegetative state. In about 20 percent, the vegetative state resulted from a respiratory or cardiac arrest. A 44 vegetative state that has lasted at least 1 month can be termed persistent. The time at which it can be considered permanent is a topic of debate, as detailed in a subsequent section. Some aspects of conscious behavior may be difficult to judge, but at a minimum, vegetative patients should not follow commands or have comprehensible speech.
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With a shorter duration of ischemia, the damage to the cerebral cortex is less and recovery of consciousness or awakening can occur, as evidenced by the patient following commands or 45 having comprehensible speech and entering a minimally conscious state. Typically, brainstem function is normal. These patients can be severely disabled because of their neurological impairments, which can include spastic quadriparesis, cortical blindness, severe ataxia, bowel and bladder incontinence, and severe memory deficits. For these survivors, independence in activities of daily living is not possible. In the series of 459 consecutive patients with out-of-hospital cardiac arrest in Seattle, 18 (4%) had such an outcome, including 16 cortical blindness in 4 patients. With still shorter duration of ischemia, less cerebral cortex is damaged and impairments are thought to relate to the parts of the brain most sensitive to ischemia. Nonetheless, in one study of 17 survivors of out-of-hospital cardiac arrest, memory impairments were related more to global cerebral atrophy on magnetic resonance imaging 46 Memory problems can be seen with subtle (MRI) than to selective hippocampal injury. 47 48–50 The memory problems can range from severe motor findings or can occur in isolation. dementia to mild forgetfulness, and some of these patients may be independent in many of their activities of daily living. Finally, if the duration of ischemia is brief and the resuscitation swift and effective, the brain may escape serious injury. Upon awakening, such patients commonly have severe memory impairments, which clear over days. Those patients who have a complete cardiac51arrest remain amnestic for the event and typically do not report near-death experiences. In a prospective study of 509 successful resuscitations, 12 percent of patients reported at least some recollection of the event and 8 percent described core experiences, including most commonly positive emotions, awareness of being dead, meeting with deceased persons, and 52 moving through a tunnel. Depending on the cardiac status and other comorbidities, patients may be able to return to their previous level of neurological function and are typically independent in their activities of daily living. Neuropsychological testing was performed on 68 long-term survivors of cardiac arrest as part of53a clinical trial and showed no deficits or only was in delayed mild ones in approximately one half at 1 year. The most common deficit 54 memory. Improvement in scores on the Mini-Mental State Examination, a simple cognitive measure familiar to most clinicians, occurs mostly in the first 3 months after the arrest, with results at 1 year being comparable to those at 3 months (Fig. 9-2). Quality of life and the level of function have also been assessed and, for many, are comparable to those of similar 55 patients who have suffered a myocardial infarction without a cardiac arrest.
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FIGURE 9-2 Scores on the Mini-Mental State Examination
at certain times after out-of-hospital cardiac arrest in patients enrolled in a randomized trial of nimodipine versus placebo. Because results did not differ by treatment status, combined results are presented. Patients whose scores were zero are included. (Data from Roine RO, Kajaste S, Kaste M: Neuropsychological sequelae of cardiac arrest. JAMA 269:237, 1993.)
After cardiac arrest, any individual patient may pass through all of the stages illustrated in Figure 9-1. At the initiation of the resuscitation, these patients may lack all evidence of brain function and, with time, move toward complete recovery. As with other forms of ischemic brain injury, most of the recovery occurs in the first 3 to 6 months, for example, as shown in Figure 9-2 for the Mini-Mental State Examination score. In the study from Seattle of 459 patients, 61 percent awakened after out-of-hospital cardiac arrest and about two thirds of 16 those awakening were left without gross neurological deficits. Unfortunately, recovery can become stalled at any stage short of complete recovery, with the best recovery for many 42 being a vegetative state or minimally conscious state. Assessment of 39 outcomes after cardiac arrest has most commonly involved the Glasgow Outcome Scale or a variation on it such as56the Cerebral Performance Category (CPC) developed by investigators from Pittsburgh. Certain dichotomous outcomes, as in the top part of Figure 9-1, are important but vary in the ease with which they can be determined and timed. Death is clear-cut. Awakening is defined by the ability to produce comprehensible speech or follow commands, or both. The reliability of its components has been studied in 57 detail as part of the Glasgow Coma Scale. In addition, the timing of its occurrence can be determined with relative ease, like that of death. Many legal and judicial guidelines concerning limitation of medical support address the probability of awakening. Regaining independence is of great importance to patients, families, and clinicians but lacks a uniform
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definition. It takes longer to achieve, it is more susceptible to the effects of comorbidity than awakening, and the timing of its occurrence can be problematic. 21
The pathology of global brain ischemia has been well described. It confirms what is seen clinically, namely, that some cell types and some regions of the brain are more vulnerable than others. The explanation for selective vulnerability remains incompletely understood. Rather than destroying multiple cell types, as may occur with focal brain ischemia or infarct, damage after cardiac arrest may be limited to the neurons. Ischemic neurons are seen most prominently in certain layers of the cerebral cortex, parts of the hippocampus, and the Purkinje cells of the cerebellar cortex. In the neocortex, layer 3 is the most sensitive, followed by layers 5 and 6. Layers 2 and 4 are the most resistant. In the allocortex, the parts of the hippocampus most sensitive are the Sommer sector (CA1) and the end folium (CA3 to CA4). The region between these two areas (CA2) is the most resistant. At least in rats, the initial loss of hippocampal CA1 neurons after global ischemia 58 can be followed by their reappearance and by recovery of learning and memory. Whether this capacity to form new neurons occurs in humans and explains delayed recovery of memory after cardiac arrest remains to be established. The gross appearance of the brain of a person autopsied following a brief comatose survival after cardiopulmonary resuscitation can look surprisingly unremarkable. Microscopic examination reveals ischemic changes as described, but quantification of these changes is not readily available. The number of neurons that need to survive to result in the clinical outcomes described Figure 9-1, except at the extremes of all or none, remains poorly defined.
Complications Seizures and myoclonus complicate the clinical course in 30 percent or more of patients 59–61 They tend to occur in the immediate following cardiac arrest and resuscitation. postresuscitation period, and long-term epilepsy is rare. Myoclonus is common and can be diffuse and multifocal, as with myoclonus status epilepticus. Alternatively, the patient may have little clinical manifestation of seizure activity beyond some subtle abnormalities of eye 62,63 movements, yet the EEG can show evidence of ongoing electrical seizure activity. Regardless of the manifestations, seizures and myoclonus can be difficult to control in this setting, and treatment does not seem to affect the outcome. Brain swelling is common, as evidenced by the results of imaging and lumbar puncture, but it rarely leads to herniation and deterioration. Exceptions are patients in whom a respiratory arrest precedes the cardiac arrest. These patients sometimes develop brain swelling severe enough to result in herniation, neurological deterioration, and brain death. In such circumstances, the swelling probably reflects a severely damaged brain, and treatments aimed at controlling increased pressures do not seem to affect outcomes. After cardiac arrest, patients are also at risk of numerous cardiac and general medical complications, which are beyond the scope of this discussion. All these, especially recurrent cardiac arrest and hypotension, tend to worsen the initial injury and thus the outcome. A number of other rare complications can occur in the setting of a mixture of brain insults, sometimes including cardiac arrest. The greater the proportion of incomplete compared with complete global ischemia, the greater is the risk of preferential damage to border-zone regions of the brain and spinal cord. In the brain, this can result in injury between the anterior and middle cerebral artery distributions and a clinical picture of a brachial diplegia. With the upper extremities being more involved than the lower 64 extremities, this clinical picture has been referred to as the “man-in-the-barrel” syndrome. A similar border-zone phenomenon in the spinal cord has been proposed as an explanation for the paraplegia that can complicate cardiac arrest, although a retrospective pathological study of patients dying after global65ischemia found the lumbosacral spinal cord more commonly affected than the thoracic and less commonly from bone marrow secondary to cord. Emboli may arise from the heart 66 the trauma of chest compressions. Interestingly, patients with focal ischemia of the cerebral cortex may have symmetric neurological examinations upon presentation after cardiac arrest. Their examination reflects a level of function below their focal insult. If the level rises, focal abnormalities may become evident. Given the masking capability of global brain ischemia and the elevated risk of cardiac emboli in many of these patients, cardioembolic infarcts may be missed in this setting. Two well-described but rare complications seem to be more a function of respiratory failure mixed with cardiovascular insufficiency than simply of68cardiac arrest: delayed postanoxic 67 encephalopathy and posthypoxic action myoclonus. Many of the cases of delayed encephalopathy have occurred in the setting of carbon monoxide exposure. A period of
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improvement69and sometimes return to seemingly normal function is followed by marked deterioration. Diffuse demyelination is the apparent cause of the deterioration in those who have died. An70association with a partial deficiency of arylsulfatase A has been described in some cases. Those with posthypoxic action myoclonus awaken soon after their respiratory arrest, often 71 with normal cognitive function but with severe action myoclonus. Attempts at movement are interrupted by myoclonic jerks. These can also be triggered by loud noises and other sensory stimuli. The pathological substrate for the condition is uncertain. Treatment with valproic acid or benzodiazepines is sometimes successful. Clinicians not familiar with posthypoxic action myoclonus may confuse it with myoclonus status epilepticus. Early after the insult, the two conditions can look similar but carry very different prognoses. The confusion usually arises when soon after the inciting insult the action myoclonus is treated aggressively with benzodiazepines. If the benzodiazepines are reduced, the patient lightens but the myoclonus returns. Consequently, the benzodiazepines are reinstituted. What may not be appreciated is that the unresponsive state is more a result of the medications than the original insult. Table 9-1 contrasts the two conditions with the goal of minimizing the risk of a clinician confusing the two. Click here to view this table.... Other movement disorders, including akinetic, dystonic, and hyperkinetic syndromes, have also been described, but not always clearly following sole cardiac arrest with complete global 71 brain ischemia. Imaging and neuropathological examination can reveal injury in the basal ganglia. This topic is discussed further in Chapter 59. PREDICTING OUTCOMES OF CARDIAC ARREST
General Issues and Physical Examination Key to making clinical decisions is information on prognosis. In patients with a poor prognosis, the decisions may range from initiation of potentially dangerous treatments aimed at brain resuscitation to limitations in the intensity of medical support. The outcomes to be predicted include death, awakening, and independence. For the reasons discussed earlier, independence can be difficult to determine and time. Death is easily determined and timed but may relate to cardiac problems and need not reflect the degree of neurological recovery. Consequently, awakening is often used as a simple, easily determined, and timed outcome for identifying important predictors. The accurate delineation of prognosis after cardiac arrest 72,73 and has been the topic of many reports and comprehensive presents74,75 several challenges Some of the major findings of these studies are summarized in this section. reviews. The severity and duration of global brain ischemia are probably the most important predictors of outcome but are usually unknown or, at best, crudely estimated. The cardiac rhythm identified at the start of the resuscitation is a predictor of outcome. The probability of restoring a spontaneous rhythm is higher when the initial rhythm is ventricular fibrillation rather than 76,77 A similar finding holds for survival and awakening. asystole or pulseless electrical activity. Demographic factors such as age and gender are not important predictors of restoration of 78,79 African Americans are more spontaneous circulation or survival to hospital discharge. 80,81 Comorbidity may be an important factor with respect to likely to have poor outcomes. outcome and probably explains why resuscitation rates for out-of-hospital cardiac arrest in 82,83 some regions of the country are better than those for in-hospital cardiac arrest. The amount of brain dysfunction as indicated by the physical examination reflects the severity of the insult. In general, the greater the function at any particular time after the arrest, the better is the eventual outcome. Nonetheless, complete loss of neurological function at the time that the resuscitation is initiated is still compatible with awakening and good recovery. The duration of arrest that is incompatible with recovery is uncertain and, as a practical matter, is often difficult to estimate. The human brain can probably not fully recover from more than 5 to 10 minutes of complete global brain ischemia, as with ventricular fibrillation or 84 asystole. Patients with some degree of neurological function at the start of the resuscitation, such as the presence of pupillary light reflex or spontaneous respiratory efforts, have a better 85–87 As discussed earlier, neurological function is outcome than those without that capacity. lost in a rostral-caudal manner when blood ceases flowing to the brain, with spontaneous respiratory efforts being the last to go. Thus, the presence of neurological function at the start of the resuscitation indicates that the cardiac arrest is likely less than a few minutes old. The physical examination performed once the patient has been stabilized with respect to
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cardiovascular status gives the clinician the next chance to assess prognosis. Evaluation 39 but should be augmented by further evaluation of includes the Glasgow Coma Scale 56 brainstem function to include pupillary light reflex, corneal reflex, cough, gag, spontaneous respiratory efforts, and eye movements elicited by vestibulo-ocular and cervico-ocular 88 reflexes (Table 9-2). Click here to view this table.... Agreement across clinical studies is remarkable, given the diversity of populations studied and the statistical methods applied. For instance, two studies examined prognostication after cardiac arrest. One study included 389 consecutive unconscious patients admitted to a single 89 hospital in Seattle after out-of-hospital cardiac arrest with ventricular fibrillation or asystole. The other was a multicenter study of 21090patients with a mixture of hypoxic-ischemic insults occurring both in and out of the hospital. The studies used different multivariable techniques to identify independent early predictors of outcome, but both found that pupillary light reflex, motor response, and eye movements were the most important predictors. The other independent predictor of outcome in the study from Seattle was the admission blood glucose, which is discussed later. Figure 9-3 shows a simplification of the multivariable rule from the Seattle study and its performance in predicting outcome based on information collected at the time of admission. By using this rule, the clinician can rapidly form an initial prognostic impression.
FIGURE 9-3 Performance of a simple rule applied at admission to predict awakening after out-of-hospital cardiac arrest due to ventricular fibrillation or asystole. (Data from Longstreth WT Jr, Diehr P, Inui TS: Prediction of awakening after out-of-hospital cardiac arrest. N Engl J Med 308:1378, 1983.)
As would be surmised from Figure 9-1, the finding of persistent brainstem dysfunction suggests a poor prognosis, given that the cerebral cortex, being more sensitive, has suffered an even worse injury. In a detailed review, the clinical signs most strongly related to a poor outcome, which could include patients who regained consciousness but not independence, were absent corneal response at 24 hours, absent pupillary response at 24 hours, absent withdrawal response to pain at 24 hours, no motor response at 24 hours, and no motor 91 response at 72 hours. Unfortunately, preservation of brainstem function does not ensure a good outcome in that the cerebral cortex may still have been damaged to a degree that
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precludes ever awakening. The pupillary light reflex and the motor function, as assessed in 57 the Glasgow Coma Scale shown in Table 9-2, have emerged as important prognostic factors in a number of studies. In a systematic review of factors that predict a poor outcome after cardiac arrest, which was defined as death or survival in a vegetative state (i.e., never awakening), the absence of a 74 pupillary light reflex on admission had a specificity that ranged from 69 to 100 percent. Specificity is the percentage of all patients with a good outcome who lack the finding. Only when patients were tested on day 3 after the arrest did absence of a pupillary light reflex have 100 percent specificity in all studies. A specificity of 100 percent means that the positive predictive value must be 100 percent and that the false-positive rate must be 0 percent, namely, that all those with the finding (absence of a pupillary light reflex on day 3) have a poor outcome and never awaken. Unfortunately, the sensitivity of this finding was low, ranging from 22 to 55 percent. Sensitivity is the percentage of all patients with a poor outcome who demonstrate the finding. The Glasgow Coma Scale has been used by itself as a predictor of outcome but is dominated by the motor findings. Most of these patients are intubated as part of their resuscitation, so that the verbal response cannot be assessed. Eye opening is an uncertain predictor, with some patients having spontaneous eye opening soon after resuscitation and never regaining consciousness. In a systematic review, the worse the motor response, the worse was the 74 outcome, with the accuracy of predictions improving over time. Thus, a score of 1 on the motor scale (absent motor response to pain) on day 3 after the arrest had a specificity of 100 percent for a poor outcome, but the sensitivity ranged from 11 to 58 percent. In a subsequent large prospective study of 407 patients, specificity92was 95 percent and the false-positive rate was 5 percent for no motor response at 72 hours. 93
As J⊘rgensen and Malchow-M⊘ller first demonstrated and others have confirmed, the longer the delay in the return of neurological function, the worse is the prognosis. For example, recovery of pupillary light reflex within 12 minutes was compatible with a good 93,94 outcome, whereas its absence for more than 28 minutes predicted a poor outcome. Ultimately, duration of unconsciousness itself becomes a predictor of the likelihood of consciousness ever returning. For example, in the study from Seattle, although overall 61 percent of the 459 patients awakened, the probability of ever awakening fell precipitously 16 during the first 3 days after admission from out-of-hospital cardiac arrest. More than 90 percent of those destined to ever awaken did so by 3 days. All those awakening after 4 days had some persistent neurological deficits, and all those awakening after 14 days had persistent severe neurological deficits. Interestingly, in that study as well as a subsequent 95 one, about one in five of those still unconscious 1 week after the arrest eventually awakened. 72
a basic, unavoidable one is the Although these studies are replete with potential problems, 96 where reliability of the information on which prognosis is based. Even in research settings 91 the question of agreement between examiners has been evaluated systematically, it is not 100 percent and is likely lower in a practice setting. In addition, many of the medications administered to these patients may alter the findings on the neurological examination and adversely affect the accuracy of predictions based on them. Consequently, a certain degree of random error or noise will always exist in predictive models based on the neurological examination. In the large prospective study 92 of 407 patients, physical examination findings were inferior to other tests to be discussed. Perhaps the best that can be expected from the neurological examination is to provide an early indication of prognosis, such as with the awakening score provided in Figure 9-3, and to monitor neurological recovery.
Ancillary Tests Laboratory tests typically have greater reliability or precision than that of findings from the physical examination, and several tests have been evaluated for their potential to predict outcome after cardiac arrest. To be clinically useful, such a test must improve on the good, but not perfect, prediction of outcome already available from the physical examination. Several ancillary tests have been used for prognostication after cardiac arrest. Results of most routine laboratory tests are not related to outcome after cardiac arrest, the possible exceptions being thyroid function tests and admission blood glucose levels. For 89 example, admission values for arterial blood gas or hematocrit are not related to outcome. By contrast, in one study, lower total thyroxine, total triiodothyronine, and thyrotropin from 97 In addition, blood collected at the end of resuscitation were associated with a poor outcome. 98 after as predicted from animal experiments, elevated admission blood glucose levels 89,99,100 In cardiac arrest have been shown to be associated with poor neurological outcome.
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one study that attempted to explain this association, analyses were done of blood glucose levels determined during cardiopulmonary resuscitation in patients with out-of-hospital cardiac arrest and suggested that the admission blood glucose level simply reflected the 101 duration of resuscitation. Because a small detrimental effect of glucose could not be excluded in these observational studies and because of102data from experimental studies in animals, a randomized trial in humans was performed. During resuscitation of patients with out-of-hospital cardiopulmonary arrests, emergency medical services personnel randomized patients to receive either the fluid that had been routinely used, 5 percent dextrose in water, or a glucose-free alternative, 0.5 normal saline. Results indicated that awakening was not related to the glucose content of the fluids that were given (Fig. 9-4), although the amount of fluid administered by emergency medical services personnel was small. An unexpected and not easily explained finding in the clinical trial was that the relationship between blood glucose level and awakening was reversed in patients whose cardiac arrest was not due to ventricular fibrillation or asystole on a presumed cardiac basis. For these other patients, most of whom had pulseless electrical activity, a high blood glucose level on admission was associated with a favorable outcome. Overall, these studies suggest that the admission blood glucose level after cardiac arrest depends on the duration of certain aspects of the arrest and resuscitation. level is not as Although it is an independent predictor of outcome (Fig. 9-3), the blood glucose 89 powerful as certain aspects of the physical examination already discussed.
FIGURE 9-4 Presentation of results on survival and awakening after cardiac arrest from clinical trial of brain-cardiopulmonary resuscitation. This randomized trial examined whether the type of fluids (5% dextrose in water versus 0.5 normal saline) administered in the field by emergency medical services personnel affected outcome. Shown in the graph is the proportion of 291 admitted patients, all of whom were initially comatose after out-of-hospital cardiopulmonary arrest, who went on to awaken or to die without awakening. Solid lines represent the experience among those who received 5 percent dextrose in water (n = 141); dashed lines represent those who received 0.5 normal saline (n = 150). A vertical line from the horizontal axis at any particular time indicates the proportion who had awakened (from the 0.0 horizontal line to the lower pair of curves), who were still comatose (from lower to upper pair of curves), and who had died without awakening (from the upper pair of curves to the 1.0 horizontal line). For example, a vertical line at 3 days indicates for the entire cohort that about 34 percent had awakened regardless of treatment group (34% minus 0%), that about 37 percent were still comatose (71% minus 34%), and that the remaining 29 percent (100% minus 71%) had died without awakening. Of the 117 patients who awakened, 15 subsequently died during hospitalization and are classified in this figure as having awakened. (From Longstreth WT Jr, Copass MK, Dennis LK, et al: Intravenous glucose after out-of-hospital cardiopulmonary arrest: a community-based randomized trial. Neurology 43:2534, 1993, with permission.)
Another study that is typically available in these patients is the EEG. In addition to electrocerebral inactivity and a burst-suppression pattern, other specific patterns have been described, such as spindle coma, theta-pattern coma, and alpha-pattern coma, although no 75 universally accepted EEG classification scheme exists. Both electrocerebral inactivity and a
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burst-suppression pattern are associated with a poor prognosis. In a systematic review, electrocerebral inactivity and a burst-suppression pattern had a specificity for a poor outcome 74 of never awakening of 100 percent in all but one study. Interestingly, the only study not to 103 show a specificity of 100 percent was also the only study in which blinding was employed. Of note, alpha-pattern coma was not necessarily associated with a poor prognosis. Part of the difficulty in assessing the prognostic utility of the EEG relates to its typically being obtained early in the hospital course on patients who are having uncontrolled seizures or myoclonus or later in those who remain unconscious. Thus, confounding by indication may be present, with the seizures and prolonged unconsciousness being markers of a poor prognosis. Whether the EEG provides additional independent prognostic information is uncertain. The prognosis with myoclonus status epilepticus in the first 24 hours following the arrest is especially poor, leading some to equate myoclonus status61,75,92,104 epilepticus with an agonal brain In one review, myoclonus phenomenon indicating severe cerebral cortical damage. status was defined as spontaneous, repetitive, unrelenting, generalized multifocal myoclonus involving the face, limbs, and axial musculature in comatose patients after primary circulatory 75 104 arrest, and it can be associated with abnormal but variable EEG findings. A meta-analysis yielded a specificity of 100 percent and a false-positive rate of 0 percent with 95 percent confidence interval of 0 to 8.8 percent, 75 suggesting that the true percentage is 95 percent likely to fall somewhere within the interval. Sensitivity has varied across studies. In the largest study that included 407 patients, only 4 percent of those who never awakened had 92 status from myoclonus status. Extreme caution is needed in distinguishing myoclonus 105 action myoclonus (Table 9-1), given the marked differences in prognosis. Evoked potential studies have been investigated thoroughly, and bilateral median nerve somatosensory evoked potentials have become the dominant prognostic test after cardiac 74,75 Bilateral absence of a short-latency cortical response (N20) is associated with a arrest. 74,75,92,106 In a systematic review, bilateral absence of the short-latency cortical poor prognosis. response was 100 percent specific, with none of the 187 patients with this finding after cardiac arrest achieving a good outcome. Of note, exceptions exist if the somatosensory 107 evoked potentials are performed within 24 hours of arrest. In a subsequent prospective cohort study, serial somatosensory evoked potentials were performed at 24, 48, and 72 hours after resuscitation. Among the 301 patients still alive and unconscious at 72 hours, all 136 (45%) with bilaterally absent N20 at any of these times died or remained unconscious after 1 92 month. Interestingly, in nine patients, N20s were present on an initial test but lost on follow-up, and in five patients, the reverse was seen. All these patients had a poor outcome. Although treating physicians were blinded to results of the testing at 24 and 48 hours, they were informed of the results of the tests at 72 hours and advised that chances for survival or recovery of consciousness were virtually nil with bilaterally absent N20. An exception has 108 evoked been reported, which may reflect that although the reliability of somatosensory 109 potentials may be better than that for the physical examination, it is not perfect. Recommendations to improve the reliability of the test have been offered (Table 9-3). A meta-analysis based on these and other studies yielded a specificity of 99.3 percent and75a false-positive rate of 0.7 percent with 95 percent confidence interval of 0 to 3.7 percent. Unfortunately, the presence of N20 does not ensure a good outcome. Preliminary studies 110 suggest that cognitive evoked potentials hold promise in predicting good outcomes. Click here to view this table.... Imaging of the head with computed tomography (CT) and MRI may show loss of gray-white matter75differentiation, evidence of swelling, and other changes suggesting diffuse cortical injury. In one study, agreement about111the presence or absence of gray-white matter differentiation on CT was problematic. The abnormalities, especially on MRI, may be 75 dramatic (Fig. 9-5), but more work is needed to clarify the prognostic utility of such tests. Interestingly, evidence of swelling is more common among those who experienced 112 respiratory failure prior to their cardiac arrest. Later in the course, these studies may show atrophy in patients who remain unconscious. Other types of brain imaging have been studied, but only in a small number of patients, precluding any firm conclusions about their prognostic value.
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FIGURE 9-5 Magnetic resonance imaging (MRI) after cardiac arrest. The patient was a 49-year-old woman with respiratory arrest followed by cardiac arrest. Paramedics found her cyanotic and asystolic. Initial neurological examinations showed her to be comatose with extensor posturing but intact brainstem function. MRI was performed about 32 hours after cardiac arrest. Cerebral cortical abnormalities are less obvious on fluid-attenuated inversion recovery (FLAIR) sequences (A, bright) than on diffusion-weighted imaging (B, bright) and apparent diffusion coefficient (ADC) maps (C, dark). 75,113
Several serum and cerebrospinal fluid (CSF) enzymes have been evaluated. Caution must be exercised in the interpretation of enzyme results when a mixture of brain insults has occurred because elevations are not specific to cardiac arrest, having been described with other types of injury. The highest quality evidence of predictions of outcomes after cardiac arrest exists for serum neuron-specific enolase (NSE). In the prospective cohort study 92 mentioned earlier, serial NSE was assayed at 24, 48, and 72 hours after resuscitation. Among the 231 patients still alive and unconscious at 72 hours, all 138 (60%) with an elevation above the prespecified cutoff of 33 μg/L at any time died or remained unconscious after 1 month. With this cutoff, a meta-analysis yielded a specificity of 100 percent and a false-positive rate of 0 percent with 95 percent confidence interval of 0 to 3 percent. 92,114,115 and serum NSE is often not available on Exceptions using this cutoff are now known, a timely basis, especially in the United States. Finally, NSE is present in platelets so 75 hemolysis can lead to increased serum values. Assays of creatine kinase (CK) and its isoenzymes, including the BB isoenzyme, which116 is present 117 in high concentration in the brain, are readily available, and studies in humans and animals suggest that the enzymes peak in the CSF 48 to 72 hours following global brain ischemia. The higher the value, the greater is the damage to the brain and the worse the outcome. In one retrospective study, 351 patients had CSF CK BB isoenzyme activity determined in a single laboratory. No complications from the lumbar punctures were encountered. The median CK BB isoenzyme activity in those who awakened was 4 U/L, 118 whereas in those who never awakened, it was 191 U/L. No one with a value greater than 204 U/L ever awakened, and no one with a value greater than 50 U/L ever regained independence. The assay was subsequently modified in this laboratory allowing reversibly inactivated CK BB isoenzyme to be reactivated. The revised cutoffs were 363 U/L for awakening and 89 U/L for independence. As with the somatosensory evoked potentials, the sensitivity of the CSF CK BB isoenzymes was low at 48 percent. Another study has shown that specificity can be119 maintained at 100 percent and sensitivity increased to 69 percent by increased by combining the results of several employing both tests. That sensitivity can be 92,114,120 tests has also been demonstrated by others.
Application of Prognostic Information These and other studies on prognostic tests raise several issues: some ethical, some legal, 72 and some statistical. Often when the prognosis for awakening is extremely poor, family members and clinicians will agree that the best course of action is to limit artificial life-sustaining treatments and allow the patient to die, with appropriate attention being given to end-of-life care as outlined in Chapter 63. Given that such actions, which121 can include discontinuation of artificial nutrition and hydration, uniformly result in death, a danger exists that prognostic information creates a self-fulfilling prophecy. One option to avoid this possibility is to treat maximally all patients until they die of some other cause, an option
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unacceptable to most families and clinicians. Nevertheless, support is maintained in some patients, particularly younger ones, and late awakenings have been documented. For example, in the series of 459 consecutive patients from one hospital in Seattle, the last 3 individuals to awaken after cardiac arrest did so at about 56, 75, and 100 days after their 16 cardiac arrest. Of note, all these patients were severely impaired and totally dependent in their activities of daily living, as has been described in other patients who awakened late after 122,123 Another option in the evaluation of a new predictive test is to collect data cardiac arrest. without making them available to the clinicians who will make decisions about support. After outcomes have been determined, performance of the test can be evaluated without fear of its results having influenced decisions. Unfortunately, prognostic tests are correlated so findings on the physical examination may influence decisions about support even though the results of the other prognostic tests are kept secret. So despite the blinding of the treating physician to the results of the NSE in the longitudinal study already described, sup- port was more often 92 limited in those with elevated NSE compared to those without. A final option is to require some independent gold standard to assess the degree of brain damage. A quantitative neuropathological examination would serve such a purpose but is currently not readily available in humans. If a treatment is being evaluated, such as in a clinical trial, it is essential that decisions concerning the limitations of treatments are made in as standard a fashion as 37 possible and without the knowledge of treatment status so as to avoid biasing results. A standardized approach is also warranted in vegetative patients being considered as 124 non–heart-beating donors. Based on these considerations, a practical approach to prognostication after cardiac arrest is suggested. It involves serial neurological examinations to document baseline function and change. Using the simple rule in Figure 9-3, clinicians can use the initial examinations to formulate an initial impression about prognosis. These examinations should include the 57 Glasgow Coma Scale and assessment of brainstem function (Table 9-2). EEGs should be reserved for those in whom seizure activity is suspected. If the patient is not awake by 48 to 72 hours following the arrest, additional testing may help to clarify the prognosis. The tests that seem the most useful are somatosensory evoked potentials and biochemical markers of brain damage. Assays of CSF CK isoenzymes may be more widely available than assays of serum NSE, but cutoffs may not be sufficiently standardized for either. When the results of these tests are available, a meeting should be held with the patient's surrogate to review the results and to proffer a prognosis (Table 9-4). The patient's surrogates are typically family members, legal next-of-kin, or other legally appointed representatives for the patient. If the physical examination suggests a poor prognosis, especially with persistence of no pupillary light reflex and no motor responses to pain, and the results of the ancillary tests are consistent, an option of limiting medical support should be discussed. Typically, surrogates insist on limiting support when they learn that their loved one faces the prospects of a prolonged unconscious state and when they know the patient would not want aggressive treatment in such circumstances. Most surrogates, especially of elderly patients, strongly resist delaying decisions, especially for several months to a year, as has been 72,125 suggested. Click here to view this table.... These considerations raise several statistical issues about the confidence of predictions of 72 outcome. The discussion by Shewmon and De Giorgio is particularly enlightening. We strive for a prognostic model with both a specificity for predicting a poor outcome and a positive predictive value of 100 percent and a false-positive rate of 0 percent. This goal is often claimed to have been achieved when a certain number (N) of patients have a particular test result, and all (N/N = 100%) have a poor outcome, or, alternatively, none (0/N = 0%) has a good outcome. A simple rule of three (3/N) allows a reader to estimate the upper 95 percent 126 confidence interval rapidly for the proportion in which the numerator is zero. For example, none of 187 patients with bilateral absence of the short-latency cortical response of the somatosensory evoked potentials after cardiac arrest had a good outcome in a systematic 74 review. We can estimate the upper 95 percent confidence interval as 3/187 = 0.02. The lower confidence interval will always be zero. We may conclude that the results are consistent with up to 2 percent of the patients with this finding achieving a good outcome. If we want a prognostic model to exclude even remote possibilities of errors, huge numbers of patients fully supported for prolonged periods are required. Using Bayesian methodology, Shewmon demonstrated that, given N patients with a particular test result, none of whom 127 awakened, the risk of the very next patient awakening is approximately 1/(N + 2). Also, the risk of at least one person breaking the rule in the next N + 1 patients studied is approximately 50 percent. All this information suggests that the search for some infallible rule is quixotic, and exceptions will probably be found if enough patients are studied. The literature on prognostication may become less interesting for large series in which problems with self-fulfilling prophecies cannot be avoided than for reports of patients who break the
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rules and awaken despite absence of motor responses at 72 hours, bilateral absent N20 108 or serum NSE greater than 33 responses on somatosensory evoked potentials, 92,114,115 μg/L. In discussions with a patient's surrogate decision-maker concerning withdrawal of artificial life-sustaining treatments, the inherent uncertainty need not be masked. Uncertainty does not preclude decisions to limit support nor does certainty ensure such decisions. These concepts have been illustrated previously with decision analysis incorporating probabilities and utilities 128 of outcomes after cardiac arrest. The care provider brings to the surrogate the probabilities based on the prognostic tests described. The surrogate must estimate the utility or value of certain outcomes, especially the vegetative state. Ideally, such estimates of utility are based on the patient's previously stated opinions about living in severely neurologically impaired states and whether such states are better or worse than death. If the utility of an outcome such as a vegetative state is judged as not being worse than death, the best decision will be to continue full support even in the face of near certainty that the patient will never awaken. At the other extreme, if the utility of an outcome such as a vegetative state is judged as much worse than death, the best decision will be to limit full support even in the face of substantial uncertainty that the patient will never awaken. Many people would choose to give up the chance of awakening, especially awakening with neurological deficits, to avoid being trapped in a prolonged vegetative state. Challenges arise when the probabilities and utilities lead to a close call or when care providers and surrogates disagree about what is best for the patient because they disagree about probabilities, utilities, or both. The use of decision analysis allows a quantitative deconstructed view of what most clinicians already know, namely, that decisions can be made in the setting of uncertainty, but preferences of patients or their surrogates about outcomes are key considerations, as discussed in Chapter 63. None of these approaches incorporates the societal view, with concerns about resources. Requiring prolonged support for unconscious patients results in extensive resources being devoted to 72 these patients. Scarcity of resources may someday force society to mandate that the vegetative state is valued at worse than or equal to death. ALTERATION OF OUTCOMES
Minimizing Insult Many strategies exist to reduce brain damage from cardiac arrest. Most effective is to prevent cardiac arrest from occurring in the first place. Prevention requires delineation of the risk factors for cardiac arrest. The most common cause of cardiac arrest is atherosclerotic cardiovascular disease; thus, the two share risk factors. With identification and control of these risk factors in recent years, the incidence of cardiac arrest may be expected to decrease. Assuming that efforts at prevention fail and a patient suffers a cardiac arrest, another strategy is to limit as much as possible the severity and duration of global brain ischemia. Such is the aim of what currently is the most effective treatment for brain damage following cardiac 129 arrest, namely, cardiopulmonary resuscitation with basic and advanced life support. The most treatable condition leading to cardiac arrest is ventricular fibrillation, and the necessary treatment is electrical defibrillation. Consequently, in patients with ventricular fibrillation, the outcome is determined in large part by how quickly the patient and defibrillator can be 130 brought together. In-hospital cardiac arrests require code teams and the availability of necessary equipment, especially in areas where cardiac arrests are known to occur more frequently, such as intensive care units, operating suites, and the emergency department. For out-of-hospital cardiac arrest, success requires an emergency medical system capable of a rapid response and early defibrillation. Automatic defibrillators made available to care 131 132 made available to the public, and especially providers, automatic defibrillators 133 implantable defibrillators have led to a reduction in the time from the onset of the arrest until delivery of the first defibrillatory shock. Patients with other rhythms, such as asystole and 76–78 pulseless electrical activity, are less likely to have spontaneous circulation restored,134,135 and have efforts to improve the proportion resuscitated, such as with high-dose epinephrine, been disappointing.
Brain Resuscitation Even when cardiopulmonary resuscitation leads to restoration of spontaneous circulation, many patients will die without ever awakening. Currently, hypothermia is the only therapeutic intervention initiated after restoration of spontaneous circulation that has been shown to improve neurological outcomes after cardiac arrest in humans. Efforts to identify such treatments, which constitute brain resuscitation, have been substantial. Safar and Bircher
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suggested that brain resuscitation includes both specific measures and general 136 brain-oriented intensive care. The general measures are essential and are the approach taken for any critically ill comatose patient. As mentioned, the occurrence of seizures and myoclonus tends to indicate a worse prognosis, which is not clearly improved with treatment. Brain swelling is rarely a serious problem when the mechanism of arrest is primarily cardiac, and treatments aimed at reducing swelling, such as hyperventilation, use of osmotic agents, and administration of corticosteroids, have no clear role. The efficacy of corticosteroids has not been studied in a randomized clinical trial. In two cohort studies, both of which had 137 138 concurrent nonrandomized controls, one retrospective and one prospective, outcomes were not related to the use of corticosteroids. Perhaps duration and severity of complete and incomplete global brain ischemia determine the outcome, and no manner of treatment after the insult will alter outcome. Evidence against such a nihilistic view has come from the use of experimental treatments in animal models of global brain ischemia and an expanding knowledge of the brain's response to ischemia, reperfusion, and repair. Several reviews address these topics and their implications for 139–141 In many ways, patients resuscitated from cardiac arrest represent an ideal treatment. group to evaluate treatments for brain ischemia. The condition is common, good outcomes are not rare in subgroups such as those with ventricular fibrillation, treatments can be initiated very early after restoration of spontaneous circulation, and relevant outcomes are easily determined and timed. What follows is a brief overview of this field from the perspective of a clinician. Under normal circumstances, intracellular calcium is kept quite low relative to extracellular calcium, a 10,000-fold concentration difference. During ischemia, the ability of a cell to maintain this gradient is lost, and the increase in intracellular calcium triggers a number of destructive events that lead to the cell's death, including activation of calcium-dependent enzymes. Calcium can enter the cell via a number of pathways. The initial hope was that most of the calcium entered through voltage-sensitive calcium channels and could be stopped with calcium entry blockers. As a testimony to the popularity of the hypothesis, it was subsequently tested 142 in at least four143–145 randomized clinical trials of calcium entry blockers, 146 and flunarizine. In humans, none of these agents including lidoflazine, nimodipine, has been shown to be effective in altering outcome. The 144 study of nimodipine reported by Roine and colleagues set a high standard for such trials. It included only patients with out-of-hospital cardiac arrest with ventricular fibrillation. The treatment was initiated in the field upon restoration of spontaneous circulation. Finally, the follow-up of the patients and 53 documentation of outcomes were superb. Unfortunately, no overall benefit could be detected from the drug, although patients with delayed resuscitation of more than 8 minutes 145 may have benefited. The lack of efficacy of the calcium entry blockers may be explained by calcium also entering cells by agonist-operated channels, specifically those activated by glutamate. It is an excitatory neurotransmitter that in this setting is proposed to be an excitatory neurotoxin or excitotoxin. Glutamate acts at several receptors named for the more specific agonists that bind to them, including AMPA (αamino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and NMDA (N-methyl-d-aspartate). The AMPA sites mediate fast synaptic transmission, opening a channel for sodium and potassium, but not calcium. The NMDA channels are gated by magnesium and allow the flux of cations, including calcium. Despite hopes that blockage of the NMDA sites would reduce the influx of calcium and protect the brain, experimental studies of global brain ischemia have not consistently shown benefit. Interestingly, the glutamate antagonists that block the AMPA sites have been effective after global brain ischemia. By preventing rapid changes in sodium and potassium and thus excitatory synaptic transmission, these agents may prevent the cell from depolarizing. Without depolarization, calcium does not enter through the voltage-sensitive calcium channels. In addition, depolarization is necessary for clearance of magnesium from NMDA channels. Thus, even in the presence of excess glutamate, if the cell is not depolarized, magnesium blocks the channel and calcium cannot enter. Currently, none of the agents that block the AMPA receptors has been systematically studied in humans after cardiac arrest. One randomized trial of humans with a factorial design using magnesium to reduce excitation 87 and diazepam to increase inhibition showed no benefit of either agent or their combination. Barbiturates also prevent cells from depolarizing by increasing the inhibitory effects of γ-aminobutyric acid. Thiopental was studied in a randomized trial of humans and was not 147 found to be effective. This landmark study was the first major clinical trial that evaluated a treatment whose purpose was brain resuscitation. The sequence of events following ischemia and during reperfusion continues to be clarified. Free radicals probably play an important role in the brain injury following cardiac arrest. A
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number of strategies exist for dealing with oxygen free radicals, including reducing their production, increasing their removal, and blocking their effects. How nitric oxide fits into these theories of excitotoxins and free radicals remains to be defined. Coagulation may play a role in microcirculatory reperfusion disorders in animals, and a randomized trial of thrombolysis 148 during cardiopulmonary resuscitation is pending. Also, attention has turned in recent years to the reparative mechanisms and the possibility that some of the damage following global brain ischemia is a consequence of defective repair. The production of growth factors such as nerve growth factor and insulin-like growth factor, the induction of stress proteins such as heat shock proteins, and the transcription of immediate early genes such as c-fos and c-jun all are under investigation. Although necrosis has been the focus in the past, apoptosis also 149 likely plays a role. How the genetic make-up of patients who suffer cardiac arrest may modify the response to injury and thus prognosis remains largely unstudied. A better understanding of the pathophysiology of ischemic brain injury may lead to novel ways of improving the outcomes of patients after cardiac arrest.
Hypothermia To date, induced hypothermia represents the sole success in the many efforts to make brain 150 to protect resuscitation a reality. The idea is not novel, having first been used in the 1950s 151–153 The the brain initially during cardiac surgery and subsequently after cardiac arrest. precise mechanism by which hypothermia confers protection is unknown, but results in experimental animals for both global and focal brain ischemia are consistent. In 2002, two randomized clinical trials both showed improved outcome after ventricular fibrillation with 154,155 In one trial of 275 patients, external cooling with a external cooling to 32° to 34°C. specialized blanket did not begin until after hospitalization at a median of 105 minutes from return 154 of spontaneous circulation, and the target temperature was achieved at a median of 8 hours. Hypothermia was continued for 24 hours with concomitant use of midazolam, fentanyl, and pancuronium. Cooling was associated with an increased percentage of patients discharged alive without severe neurological deficits, namely from 39 percent to 55 percent, for an absolute difference of 16 percent. In the other trial of 77 patients, external cooling was initiated in the field with paramedics applying cold packs and continued in the hospital, and target temperature was achieved by about 120 minutes after return of spontaneous 155 circulation. Hypothermia was continued for 12 hours with concomitant use of midazolam and vecuronium. Again cooling was associated with an increased percentage of patients discharged alive without severe neurological deficits, specifically from 26 to 49 percent, for an absolute difference of 23 percent. Experience in patients whose initial rhythms were asystole or pulseless electrical activity is limited. In one study of 33 such patients, external cooling with a specialized helmet did not begin until after hospitalization at a median of 102 minutes from return of spontaneous circulation, and the target temperature was achieved at a median of 154 180 minutes. Hypothermia was continued for 4 hours with concomitant use of midazolam, fentanyl, and pancuronium. Cooling was associated with an increased percentage of patients discharged alive without severe neurological deficits, from 0 percent to 19 percent, for an absolute difference of 19 percent. In a meta-analysis of these three studies, benefit was 156 substantial despite delays in each of these studies in achieving the target temperature. The estimated number needed to treat with cooling to yield one more person who would survive cardiac arrest without severe neurological deficits was 6, with a 95 percent confidence interval of 4 of 13 people. No serious side effects of cooling were identified, although the trend was for an increased risk of bleeding and sepsis with cooling. Also potassium150 can decrease, and glucose can increase with cooling, both deserving special attention. Although this and other evidence was deemed sufficient for therapeutic hypothermia after cardiac arrest to earn the approval of the Advancement Life Support Task Force of the 157 International158,159 Liaison Committee on Resuscitation, such treatment is still used A common excuse for not cooling patients is that it is technically too infrequently. difficult to accomplish. Several methods that go beyond external cooling have been explored to cool patients rapidly. Appealing for its simplicity and effectiveness is the rapid infusion of cold intravenous fluids. Results from three studies have been remarkably consistent with patients having low temperatures on admission after resuscitation from out-of-hospital cardiac arrest (35.5°, 35.4°, and 35.6°C) and having them drop substantially (1.7°, 1.7°, and 160–162 In two studies, the fluids were 1.8°C) after the infusion of cold intravenous fluids. 160,161 In two studies, 4°C lactated161 administered with a pressure bag over 20 to 30 minutes. 160,162 whereas in161,162 the other, 4°C normal saline was infused. Ringer's solution was infused, 160 In two studies the amount infused was 2 liters, and in the other, it was 30 ml/kg. All protocols included paralytic agents and sedatives. The infusions have been well tolerated without deterioration noted on clinical examination, blood tests, or echocardiogram. In these patients, hypothermia in the target range of 32° to 34°C was maintained for 12 to 24 hours using cooling blankets or a more complicated endovascular device, which allowed for easy
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External cooling devices are also available that allow for easy
Given that 164–166 hypothermia may be more effective if achieved early after return of spontaneous intravenous infusion of cold fluids is also appealing for its ability to be circulation, initiated in the field in patients resuscitated from out-of-hospital cardiac arrest. Will cooling be more effective if initiated in the field rather than being delayed until after hospital admission? This question and many others remain unanswered. Will patients with initial rhythms other than ventricular fibrillation benefit from cooling? What is the best method to induce hypothermia? What is the optimal duration of cooling? What is the best protocol for rewarming? More randomized trials are needed to answer these and other questions about 87 brain resuscitation. A factorial design is particularly appealing, given the desire to alter more than one of the many proposed pathophysiological mechanisms. Decisions about artificial life-sustaining treatments should be standardized as much as possible in clinical trials and made without knowledge of randomized treatment status. Analyses should include comparison of randomized treatment groups for various outcomes, but especially death and awakening. The times of occurrence of death and awakening can easily be determined, and time-dependent analyses should be performed and presented (Fig. 9-4). VIEW TO THE FUTURE Brain damage after cardiac arrest is the result of an imperfect technology. Prior to the advent of cardiopulmonary resuscitation and especially electrical defibrillation, virtually all patients died after cardiac arrest. With the proliferation of in-hospital code teams and prehospital emergency medical systems, an increasing proportion of these patients are resuscitated. As a consequence, patients, families, and clinicians are faced with issues of brain damage after cardiac arrest. The ability to predict outcomes has improved but will never be perfect, a fact that should not prevent clinicians from working with families to make decisions about artificial life-sustaining treatments. Currently, induced hypothermia can improve neurological outcomes after cardiac arrest, but more needs to be learned about how best to employ this treatment. Given the increasing understanding of the brain's response to ischemia, reperfusion, and repair, other treatments should follow and become an integral part of brain-cardiopulmonary resuscitation. Such treatments will find immediate use in the thousands of patients who are resuscitated from cardiac arrest each year. In the meantime, and for all time, prevention of cardiac arrest and efficient cardiopulmonary resuscitation are essential. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 10 Cardiac Manifestations of Acute Neurological Lesions NERISSA U. KO • JONATHAN G. ZAROFF •
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HISTORICAL PERSPECTIVE ISCHEMIC AND HEMORRHAGIC STROKE Anatomy and Physiology: The Insular Cortex The Electrocardiogram QT Prolongation Repolarization Abnormalities Q Waves and U Waves Cardiac Arrhythmias Cardiac Injury and Dysfunction Plasma Markers EPILEPSY AND OTHER NEUROLOGICAL disorders CARDIAC EVALUATION CLINICAL MANAGEMENT CONCLUDING COMMENTS
Cardiac abnormalities are common after acute neurological injury. Disturbances can range in severity from transient electrocardiographic (ECG) abnormalities to profound myocardial injury and dysfunction. Evidence from animal models and clinical observations indicate that the central nervous system (CNS) is involved in the generation of cardiac arrhythmias and dysfunction even in an otherwise normal myocardium. Many studies demonstrate how neurological lesions can influence cardiovascular function and affect cardiac prognosis. Recent evidence from patients with subarachnoid hemorrhage (SAH) also suggests an association with cardiac dysfunction and adverse neurological outcomes. A better understanding of cardiac abnormalities after acute neurological injury can improve the clinical management of patients and may also have important prognostic implications. This chapter briefly outlines the cardiac manifestations after acute neurological injury, summarizes the neurophysiology and neuroanatomy of cardiac control, and discusses the clinical implications and treatment recommendations for the most common cardiac complications. HISTORICAL PERSPECTIVE At the turn of the previous century, Cushing first described hemodynamic changes after acute
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intracerebral hemorrhage (ICH). Subsequent clinical observations began to identify the importance of the brain–heart interaction in patients with cerebral lesions. Cardiac abnormalities were described with various CNS diseases including seizures, trauma, ischemic stroke, and ICH and less commonly with tumors, electroconvulsive therapy, and 2 meningitis.3–5More recently, an emotion- and stress-induced cardiomyopathy has been described. To date, hemorrhagic and ischemic stroke remain the best described clinical models of neurocardiogenic injury. The anatomy and physiology of the pathways involved in brain–heart interactions have been elucidated in both animal and human studies. During World War I, a series of animal experiments were conducted to identify the cause of unexpected deaths of patients undergoing surgery with chloroform anesthesia. The frequent ventricular tachyarrhythmias that occurred in cats under light chloroform anesthesia could be aborted by cardiac sympathetic denervation. The ability to reproduce the arrhythmia by6,7activation of the sympathetic nervous system suggested a neurogenic mechanism. The medulla has been described as the principal site of vagal parasympathetic and 8,9 sympathetic areas involved in cardiac control. In addition, both anatomical and 10 physiological evidence exists to implicate the hypothalamus in cardiac control. Electrical stimulation experiments suggest a posteriorly located area of cardiovascular sympathetic 11 and colleagues first control and an anterior parasympathetic control region. Beattie 12 described cardiac arrhythmias after hypothalamic stimulation. Arrhythmias from 13,14 hypothalamic stimulation were subsequently confirmed in other animal models. Areas of the cerebral cortex with connections to the autonomic nervous system can also elicit cardiac responses. The autonomic-emotional interactions with cardiovascular function have 15,16 Stimulation of the orbitofrontal, been linked to the central nucleus of the amygdala. cingulate, and temporal regions can elicit a cardiac response, but with much less frequency 17–19 The majority of evidence suggests that compared to the hypothalamus and brainstem. the insular cortex has a pivotal role in integrating autonomic responses and is strongly associated with adverse cardiac events after neurological injury. ISCHEMIC AND HEMORRHAGIC STROKE Clinical observations in patients with stroke have greatly advanced the understanding of interactions between20the brain and heart. Cardiac abnormalities occur in 60 to 70 percent of patients after stroke. The most common disturbances include ECG abnormalities, cardiac arrhythmias, and myocardial injury and dysfunction. Distinguishing cardiac abnormalities directly caused by stroke, however, remains difficult because the prevalence of preexisting 21,22 However, cardiac disease is high, particularly among patients with ischemic stroke. substantial evidence exists supporting the occurrence of cardiac disturbances after stroke even in the absence of significant coronary artery disease (CAD). More importantly, cardiac disturbances are the most common cause of death after stroke, accounting for up to 6 23 percent of unexpected deaths during the first month. Understanding the mechanisms of cardiac disturbances may prevent future cardiac complications and improve survival in these patients.
Anatomy and Physiology: The Insular Cortex The insular cortex has widespread connectivity with other areas of the brain that are known to 24 be involved in autonomic control. Both experimental and clinical evidence strongly suggests a role for the insula in cardiovascular function. Oppenheimer and colleagues first identified the insular cortex in rats as a site from which lethal cardiac arrhythmias and myocardial damage could be produced, resembling changes seen in patients after stroke and sudden death in patients with epilepsy. These microstimulation experiments in the rat posterior insular cortex produced stereotyped ECG changes from progressive atrioventricular block leading to complete heart block, interventricular block, QT interval prolongation, ST segment depression, ventricular ectopy, and finally death in asystole. These ECG changes were directly correlated with pathological changes in the myocardium called myocytolysis that were 25 thought to be induced by excess activation of intrinsic cardiac sympathetic nerves. Animal models of stroke have provided further evidence of involvement of the insula in the autonomic regulation of the heart. In a rat model of cerebral ischemia, insular infarction was associated with increased renal sympathetic nerve activity, prolongation of the QT interval, 26,27 Pathologically, cardiac myocytolysis was and elevated norepinephrine levels. 28 demonstrated only if the insular cortex was involved. Furthermore, stroke involving the insular cortex in humans abolished the normal nocturnal decline in blood pressure, prolonged the corrected QT interval, increased ventricular tachyarrhythmias, and resulted in higher
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plasma norepinephrine levels. Clinical observational studies among stroke patients 31 also 30 loss of nocturnal vagal dominance, and suggest a loss of cardiac parasympathetic tone, 32 increased sympathetic tone. This evidence collectively supports the belief that stroke can alter cardiovascular tone by directly damaging the insular cortex or other interrelated areas and shifting the balance toward a predominance of sympathetic activation. Although there is considerable evidence suggesting lateralization of cardiac control in animal models, the clinical impact of the laterality of insular strokes in humans has proven to be more complicated. In a rat model comparing the effects of left and right middle cerebral artery occlusion on sympathetic tone, right-sided lesions were associated with elevated plasma norepinephrine levels and prolongation of the QT interval, whereas left-sided lesions led to 26 more hypotension during urethane anesthesia. With more selective posterior insular lesions, elevated baseline heart rate and blood pressure were noted after right-sided33injury, and significantly increased baroreflex sensitivity was observed after left-sided injury. Clinical observations and more recent systematic studies have addressed the effect of lateralization in humans. In patients undergoing temporal lobectomy for the control of intractable seizures, stimulation of either insula resulted in alterations of blood pressure and heart rate, but bradycardia and decreased blood pressure occurred with greater frequency from the left anterior insular34cortex, suggesting a greater sympathetic cardiovascular representation on the right. Similarly, stimulation of the right temporal lobe tip in a schizophrenic patient induced elevations in blood pressure that were greater than with 35 stimulation on the left. Other observations during infusion of amylobarbital during the Wada test describe tachycardia after left carotid infusion and bradycardia with right internal carotid 36 infusion. Collectively, these observations support a greater sympathetic cardiovascular representation on the right and greater parasympathetic regulation on the left. However, observational stroke studies in humans have reported conflicting results. An observational study of 62 acute stroke patients indicated an increased incidence of sudden 37 death among patients with right insular strokes. In addition, right middle cerebral artery strokes were associated with a significantly increased incidence of supraventricular 38 tachyarrhythmias compared with similar left-sided strokes. When anterior left insular lesions were specifically isolated, there was increased cardiac sympathetic and decreased cardiac 39 parasympathetic tone. In contrast, left parietoinsular stroke was associated with an increased incidence 40 of new-onset atrial fibrillation, often considered a parasympathetically derived abnormality. In a prospective study of patients with stroke and transient ischemic attacks (TIAs), left insular strokes were an41independent risk factor for adverse cardiac outcome in patients without heart disease. Similarly, in a secondary analysis of the North American Symptomatic Endarterectomy Trial (NASCET), 42 long-term risk of sudden death was significantly increased in patients with left brain infarction. These observations highlight the complex interactions of the insular cortex and other autonomic centers of the brain. The relative balance of excitatory and inhibitory pathways involved in cardiovascular control can vary with the state of arousal as well as with involvement of adjacent inhibitory pathways in the frontoparietal cortex. Evidence suggests that in humans, a stroke isolated to the left anterior insula or the right frontoparietal cortex 43 sparing the insula will have similar effects on cardiovascular outcomes.
The Electrocardiogram 44
ECG abnormalities are common, occurring in 92 percent of patients with acute stroke. In 1947, Byer and colleagues first described marked QT prolongation with large T and U waves 45 on the ECG of four patients with acute stroke. Subsequently, Burch and colleagues described an ECG pattern after acute stroke consisting of large inverted T waves, prolonged QT intervals, and large septal U waves that has become distinctive of cerebrovascular injury 46 (Fig. 10-1). In the 17 abnormal ECGs reported in their study, the abnormalities were most frequently observed after SAH, followed by ICH and ischemic lesions. These early studies did not control for the incidence of concomitant or preexisting ischemic cardiac disease, but subsequent case-control studies suggest that repolarization abnormalities on ECGs are not present prior to the stroke event. Overall, there was a significantly increased incidence of ST depression, prolongation of the QT interval, T-wave inversion, and ventricular premature beats among stroke patients compared to age- and sex-matched controls. Although patients with known cardiac disease were excluded, limitations of these studies were the lack of detailed cardiac evaluations and comparison to44,47,48 antecedent ECG tracings that may not have completely excluded coexistent heart disease.
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FIGURE 10-1 Typical “neurogenic” electrocardiographic (ECG) changes with symmetric
deep T-wave inversions in a patient with acute subarachnoid hemorrhage. These abnormalities were transient and not associated with myocardial infarction. QT Prolongation The most common stroke-related ECG abnormality is QT prolongation, a myocardial repolarization abnormality associated with an increased risk of a characteristic 49 life-threatening cardiac arrhythmia, known as torsade de pointes (Fig. 10-2). Interestingly, congenital forms of long QT may be related to imbalance of sympathetic innervation of the 50 heart. Among acute stroke patients, prolonged QT interval is more frequently observed after hemorrhagic strokes, occurring in 45 to 7144,47,51,52 percent of patients with SAH or ICH compared to Ventricular tachyarrhythmias including 38 percent of those with ischemic strokes. sudden death and torsade de pointes are often preceded by QT prolongation in patients with 51,53 QT prolongation, accompanied by U waves and T-wave changes, often correlates SAH. 44,51 Assessment of common causes of with elevated systolic blood pressure on admission. acquired QT abnormalities accompanied by U waves and T-wave changes, such as hypokalemia, hypomagnesemia, and medication toxicity, is recommended before attributing these changes to the underlying stroke.
FIGURE 10-2 ECG changes can precede pathological arrhythmias in patients with
severe neurological injuries. A, Prolongation of the QT interval is common after subarachnoid hemorrhage. Electrolyte abnormalities or medications can also prolong the QT interval. B, Torsade de pointes is a polymorphic ventricular tachycardia associated with QT prolongation. (Courtesy of Byron Lee, MD, University of California, San Francisco.)
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Repolarization Abnormalities The similarities between ECG changes due to acute myocardial ischemia and infarction and those associated with stroke are most striking with the repolarization abnormalities involving the ST segment, leading many investigators to hypothesize coexisting cardiac disease as the primary cause. ST segment changes (including ST elevations) occur in 22 to 35 percent of patients with ischemic stroke, which is complicated by the increased prevalence of cardiac 48,54 However, new T-wave abnormalities appear disease in this subgroup of stroke patients. in approximately 15 percent of patients with acute stroke, even in the absence of electrolyte 48 disturbances or primary ischemic heart disease. Inverted or flat T waves have also been reported in up to 55 percent of patients with SAH, the stroke subgroup with the lowest 55,56 More direct evidence comes from an autopsy prevalence of coexistent cardiac disease. study of five patients with ECG changes who57died after SAH. None of the autopsied patients had evidence of epicardial coronary disease. Kono and colleagues performed detailed cardiac assessments on 12 patients with acute SAH and ST elevations on the ECG. Although patients were found to have apical wall motion abnormalities on the echocardiogram, there 58 was no evidence of coronary artery stenosis or vasospasm on cardiac angiography. These findings, along with the observation that stroke-induced ECG changes are evanescent, resolving over a period of days to months with little residuum, argue against myocardial ischemia or infarction as the only cause of repolarization changes on ECG. Q Waves and U Waves New Q waves similar in morphology to those observed in acute myocardial infarction are also common after acute stroke, reported in approximately 10 percent of patients with acute 47,52 To complicate matters, Q waves may be transient or ischemic or hemorrhagic stroke. 44,48 Further cardiac proceed through the evolutionary changes seen in myocardial infarction. evaluation may be necessary in patients with Q waves and ST segment alterations, particularly if they are older than 65 years with coronary risk factors such as diabetes 59 mellitus. New U waves occur in isolation or with T waves and QT abnormalities in approximately 13 to 44,60 Isolated U waves were 15 percent of patients with acute ischemic stroke and SAH. equally distributed between ischemic and hemorrhagic strokes, but the combination of U 44 waves and QT prolongation was more common among patients with hemorrhagic strokes. There is no relationship between the presence of U waves and stroke mortality, suggesting that this ECG change should not require any specific treatment or evaluation.
Cardiac Arrhythmias Nearly every type of cardiac arrhythmia has been reported after acute stroke including bradycardia, supraventricular tachycardia, atrial flutter, atrial fibrillation, ectopic ventricular beats, multifocal ventricular tachycardias, torsade de pointes, ventricular flutter, and ventricular fibrillation. Most arrhythmias occur within the first week after stroke, occurring in 25 to 61,62 40 percent of patients with ischemic stroke or ICH, and 98 percent of patients with In retrospective case-control studies of the ECG after acute stroke, the most SAH. common arrhythmia was atrial fibrillation (14% to 21%), followed by ventricular arrhythmias 44,47 40 Transient atrial fibrillation is much more common after ischemic stroke. (5% to 13%). Without controlling for preexisting cardiac disease in these studies, rhythm disturbances may have preceded the stroke event and, in the setting of atrial fibrillation, may be causally related to the ischemic stroke. Not surprising, because the ECG is a relatively insensitive test for arrhythmia, a prospective study of ischemic stroke patients with cardiac telemetry monitoring found a higher incidence of ventricular extrasystoles, followed by atrial extrasystoles, 59 supraventricular tachycardia, and atrial fibrillation. In similar studies of hemorrhagic strokes, the incidence of ventricular arrhythmias was 10 63 percent after ICH. Location of hemorrhage appears to correlate with the rhythm disturbances. Yamour and colleagues52reported a correlation between the occurrence of brainstem bleeds and atrial fibrillation. Ventricular arrhythmias correlated with temporoparietal location, whereas sinus bradycardia and supraventricular tachycardias were seen more commonly with traumatic frontal lobe hemorrhage. Patients with SAH have even more profound rhythm disturbances that may be related to the diffuse nature of the injury and the degree of monitoring in the intensive care unit. Stober and associates described multifocal ventricular ectopy (54%), asystolic intervals (27%), sinus 64 bradycardia (23%), and atrial fibrillation (4%). Because the frequency and severity of 53,65,66 we arrhythmias are significantly higher in patients studied within 48 hours of SAH onset,
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recommend continuous cardiac monitoring in an intensive care setting for all patients with acute SAH. In one study of monitored patients, rhythm disturbances occurred in one third of patients, including asystole55and ventricular fibrillation, with 5 percent of patients suffering a life-threatening arrhythmia. In addition, torsade de pointes, a polymorphic ventricular 67,68 tachyarrhythmia that is difficult to treat, was detected in about 4 percent of SAH patients. Unlike ischemic stroke, a significant proportion of patients with SAH have normal cardiac function even though they have the highest incidence of cardiac arrhythmias. Increasing evidence supports a catecholamine-mediated myocardial injury after SAH. As previously described, the type and location of the stroke can determine the type of arrhythmia, with vasodepressor effects more common with injury to the right insula and tachycardia and 26,37,38 However, even a hypertension more common with injury of the left insular region. diffuse neurological injury like SAH can influence cardiac function and generate cardiac arrhythmias. After SAH, the most common ECG change is QT prolongation that often precedes pathological arrhythmias. More importantly, the 69 presence of arrhythmias after stroke is significantly associated with increased mortality.
Cardiac Injury and Dysfunction Evidence from autopsy series in both ischemic and hemorrhagic stroke indicate that cardiac 57,70,71 When myocardial tissue injury dysfunction can occur in the absence of underlying CAD. is present, suspicion of underlying cardiac disease increases, but pathological and functional studies of the heart suggest a mechanism distinct from coronary artery–induced ischemia. Subendocardial hemorrhages were initially described in patients dying after acute strokes and seizures. Further studies suggested that these pathological changes were secondary to 72–75 Offerhaus and Van Gool showed convincingly that 76 excessive sympathetic stimulation. following intracranial hemorrhage, there was an increase in cardiac tissue catecholamines. A broader description of these catecholamine-induced subendocardial lesions included scattered foci of swollen myocytes surrounded by infiltrating monocytes, interstitial 77 hemorrhages, and myofibrillar degeneration. Collectively, the characteristic pathological changes have been called contraction band necrosis, coagulative myocytolysis, or myofibrillar degeneration (Fig. 10-3). The pattern of myofibrillar necrosis localizing near cardiac nerves is identical to other lesions thought to be of sympathetic origin such as catecholamine infusion, “voodoo death,” hypothalamic stimulation, or reperfusion of transiently ischemic cardiac 78 muscle. In patients with CAD, myocardial necrosis typically follows a vascular distribution. The timing of the injury is also distinct from the necrosis seen in CAD, which typically occurs in a delayed fashion after progressive ischemia and muscle cell death. Neurogenic myocardial injury can be visible within minutes of onset, with appreciable differences observed on a cellular level. In myocytolysis, mononuclear infiltration predominates, 78 with early calcification, and myocardial cells in a hypercontracted state with contraction bands.
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FIGURE 10-3 A representative cross section of myocardium after
hematoxylin–eosin stain showing marked myocyte hypertrophy with nucleomegaly and myocytolysis. (Courtesy of Philip Ursell, MD, University of California, San Francisco.) Further evidence of a neurogenic mechanism of cardiac injury comes from studies of cardiac function after SAH, which typically affects younger patients without a history of coexistent cardiac disease. Global or regional left ventricular systolic dysfunction on echocardiogram 58,79,80 The has been described after SAH with an approximate incidence of 10 to 28 percent. severity of neurological injury is strongly associated with the presence of left ventricular 81 dysfunction. Similarly, diastolic dysfunction is also common after SAH, is associated with the severity of neurological injury, and may be the cause of pulmonary edema seen in83,84 these 82 In patients. The onset of left ventricular dysfunction occurs early in the course of SAH. the largest study to date, a regional wall motion abnormality was most likely to be present 84 within the first 2 days. The prevalence then declined during days 3 to 8 after hemorrhage. In this same study, the authors demonstrated complete or partial resolution of left ventricular dysfunction in the majority of patients during the acute hospitalization. Cardiac dysfunction 85–88 appears to be reversible in most cases and normalizes over time. There is a well-demonstrated, unique, apical-sparing pattern of regional wall motion abnormality that differentiates SAH patients from those with the typical patterns seen in CAD. The most frequently affected segments are the basal and mid-ventricular portions of the anteroseptal and anterior walls and the mid-ventricular portions of the inferoseptal and 84,89 A retrospective study of SAH patients demonstrated reversibility and anterolateral walls. both global and regional left ventricular dysfunction,90most commonly affecting the anterior and anteroseptal walls that do not involve the apex. 91Younger age and anterior aneurysm position were independent predictors of this pattern. This apical-sparing pattern of left
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ventricular dysfunction argues against an obstruction or vasospasm of coronary arteries and provides indirect evidence of neurally mediated mechanism of injury. Experimental and clinical studies have addressed a neurogenic catecholamine-mediated 92–95 In a cohort of mechanism of injury or “catecholamine hypothesis” of cardiac dysfunction. patients with SAH, we found an association between regions of contractile dysfunction and abnormalities in myocardial sympathetic innervation while demonstrating normal cardiac perfusion. We measured the degree of cardiac innervation with a scintigraphic evaluation 123 ([99m I]metaiodobenzylguanidine or MIBG), cardiac perfusion (using [ Tc]sesta-methoxyisobutylisonitrile or MIBI) and regions of myocardial dysfunction with echocardiography simultaneously in SAH patients. Patients with functional cardiac denervation had worse regional wall motion scores (RWMS) and more troponin release than patients without evidence of cardiac denervation (Table 10-1). Figure 10-4 illustrates normal perfusion and global denervation in an SAH patient whose echocardiogram showed global left ventricular systolic dysfunction. All study subjects had normal perfusion imaging, 89 excluding significant CAD and supporting a neurogenic mechanism of cardiac injury. In addition, recent data suggest that genetic polymorphisms of the adrenoceptors are 96 associated with an increased risk of cardiac abnormalities after SAH. These data support the hypothesis that cardiac dysfunction after SAH is a form of neurocardiogenic injury. Click here to view this table....
FIGURE 10-4 Normal myocardial innervation (A) and perfusion (B) in a 71-year-old man with subarachnoid hemorrhage. Global functional denervation (C) and normal perfusion, except for a nonspecific apical irregularity (D), in a 41-year-old woman with subarachnoid hemorrhage. (From Banki NM, Kopelnik A, Dae MW, et al: Acute neurocardiogenic injury after subarachnoid hemorrhage. Circulation 112:3314, 2005, with permission.)
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Plasma Markers In addition to pathological data and measurements of cardiac function, elevations in cardiac enzymes provide evidence of myocardial injury after stroke. Creatine kinase (CK) and specifically the cardiac isoenzyme CK- MB are released from damaged myocardium. Elevated serum levels are seen in 10 to 45 percent of stroke patients, and there is a good correlation between elevation in CK-MB and stroke-induced ECG changes or cardiac 62 arrhythmias. Unlike acute myocardial infarction, a stroke-induced increase in serum CK-MB levels occurs more slowly and peaks at a much lower value at approximately day 4 after a 97 stroke. Elevated serum CK levels have been associated with increased mortality after stroke, but unfractionated CK levels are not specific for myocardial injury and we cannot accurately attribute the increased mortality to cardiac injury in these studies. Cardiac troponin I is a specific and more sensitive marker of myocardial damage. Elevations 98–100 The degree in troponin I have been described in 20 to 25 percent of patients with SAH. of neurological injury and female gender are strong predictors of myocardial necrosis after 100 SAH (Table 10-2). Acute troponin I elevation after SAH is associated with ECG abnormalities, left ventricular dysfunction, pulmonary edema, hypotension, and delayed 101 cerebral ischemia from vasospasm. Peak troponin I levels were associated with increased mortality and poor functional outcome at hospital discharge, providing more direct evidence of the role of cardiac injury in adverse outcomes. Click here to view this table.... Serum B-type natriuretic peptide is often used as a marker of heart failure. Elevated B-type natriuretic peptide levels after SAH have been independently associated with hyponatremia, 102 delayed ischemic neurologi cal deficits, and poor Glasgow Coma Scale score at 2 weeks. In our prospective study, we found that elevated levels were significantly correlated with systolic and diastolic dysfunction, pulmonary edema, elevated troponin I levels, and lower cardiac ejection fractions (Fig. 10-5). The predominance of cardiac abnormalities similar to heart failure suggests that although B-type103natriuretic peptide is found in heart and brain, elevated levels are likely of cardiac origin. Moreover, elevated troponin I and B-type natriuretic peptide levels are independent and strong predictors of inpatient mortality after 104 SAH. These data provide additional evidence that the degree of myocardial injury has significant implications for prognosis in these patients.
FIGURE 10-5 Plasma B-type natriuretic peptide (BNP) levels and cardiac outcomes. The
column height indicates the mean BNP level, and the error bars indicate 95 percent confidence intervals. Probability values indicate results of Wilcoxon rank-sum tests. cTi, cardiac troponin I more than 1.0 μg/L; EF, left ventricular ejection fraction less than 50 percent; RWMA, regional wall motion abnormality. (From Tung PP, Olmsted E, Kopelnik A, et al: Plasma B-type natriuretic peptide levels are associated with early
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cardiac dysfunction after subarachnoid hemorrhage. Stroke 36:1567, 2005, with permission.) EPILEPSY AND OTHER NEUROLOGICAL disorders Similar cardiac arrhythmias and ECG findings have been described in patients with epilepsy, brain tumors, head trauma, meningitis, multiple sclerosis, and spinal lesions. In all cases, a common mechanism of neurogenic cardiac injury is supported by increased sympathetic nervous system discharge, increased adrenomedullary catecholamine production, and 105 reduced parasympathetic activity. In studies of intensive cardiac monitoring after severe closed head injury, the hyperdynamic cardiac state was correlated with increased arterial 106 levels of epinephrine and norepinephrine. Autopsy case reports in young patients who died suddenly of seizures and brain tumors describe cardiac pathology identical to myocardial 43 injury from excessive sympathetic activation and catecholamine infusion. Clinical observations as well as experimental work also suggest that sympathetic activation may be important in the pathogenesis of cardiac arrhythmia and sudden death in epilepsy, which is another well-studied model of brain–heart interactions. Experimental evidence from animal models of epilepsy has elucidated the mechanism by which cortical activity can lead to cardiac arrhythmia and death. Lathers and colleagues were able to induce cortical spike activity while recording from107,108 the cardiac vagus nerve and from In their cat model of epilepsy, two different branches of the cardiac sympathetic nerve. they described ECG changes similar to those found in clinical observational studies. Their most significant finding, however, was an increase in cardiac arrhythmias that corresponded with desynchronization of firing between the vagus and sympathetic nerves and with an increase in ictal cortical discharges. With sustained cortical activity, the animals died either in asystole or in ventricular fibrillation. Furthermore, electrical stimulation studies in both animals and humans have provided direct evidence of cardiac autonomic activation from specific 34 regions of the insula. Clinical observations and more recent controlled studies of patients with epilepsy also support neurocardiogenic mechanisms of injury. More importantly, advances in cardiac monitoring have enabled better prospective studies of the changes in heart rate accompanying seizures to better understand the phenomenon of sudden unexpected death in epileptic patients. Sinus tachycardia and ECG changes are commonly associated with seizures. In studies using simultaneous ambulatory electroencephalographic (EEG)/ECG monitoring, sinus tachycardia occurring at the time of the seizure was seen in 90 percent of patients. Cardiac arrhythmias were identified in 52 percent of all seizures and most frequently comprised a marked beat-to-beat variation in the R-R interval accompanied by changes in P-wave shape. 109,110 Of note, interictal ECGs Sinus bradycardia or asystole was rare, seen in 0.5 percent. were often normal in these patients. Ambulatory ECG studies suggest that there is more sympathetic tone during seizures and 109 that no significant cardiac disturbances occur during the interictal period. However, measurements of cardiac innervation suggest baseline dysfunction in cardiac sympathetic 111 innervation in patients with chronic temporal lobe epilepsy. In 22 subjects with chronic temporal lobe epilepsy, there was a significantly lower cardiac MIBG uptake and greater heart rate variability compared to controls. All subjects had MIBI with normal myocardial perfusion. These results suggest an increase in parasympathetic activity during the interictal period. Increased parasympathetic activity has been described previously, affecting variation in blood 112 pressure and heart rate after sympathetic challenge. Ictal bradycardia and asystole were considered rare,113,114 with only two cases of sinus arrest Long-term cardiac monitoring using associated with the ictus reported in earlier studies. implantable loop recorders, however, suggests that bradyarrhythmias may be more common. Sinus tachycardia remained the most common abnormality seen in all patients. Of the 20 patients with focal epilepsy monitored over a 2-year period, more than one third had ictal bradycardia,115 and more than one half required pacemaker insertion for clinically significant arrhythmias. The association of these pathological arrhythmias with seizures has important implications for understanding the mechanisms of sudden unexpected death in epilepsy. Epilepsy is associated with an increased mortality rate compared to the general population, 116–118 The and approximately one half of seizure-related deaths are sudden and unexplained. incidence of119 sudden unexpected death in epilepsy has been estimated at between 0.05 and 0.2 percent. Risk factors for sudden unexpected death include increased seizure frequency, generalized seizures, younger age, lower concentration 118–120 of antiepileptic The etiology for medications, use of multiple medications, and duration of epilepsy. sudden death in these patients remains elusive. Cardiac arrhythmia is a potentially treatable
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cause of sudden death, but direct evidence of increased mortality with ictal arrhythmias is lacking. Recent studies have focused on ictal bradyarrhythmias and asystole as well as 121 interictal heart rate variability that may represent high risk of sudden death. Improvements in cardiac monitoring and early intervention with cardiac pacing could improve outcomes if arrhythmias are found to be a significant risk factor for sudden death. CARDIAC EVALUATION Despite the growing evidence of neurocardiogenic mechanisms for cardiac injury after acute neurological insults, proper evaluation of cardiac injury and dysfunction remains important for both cardiac and neurological prognosis. Ischemic stroke patients, in particular, are more 22 likely to have concomitant significant CAD. A strong association between cerebrovascular disease and CAD has been established in a number of clinical studies. In the longitudinal Framingham study, similar risk factors predicted both stroke and heart disease. The presence of carotid atherosclerosis had similar rates of cerebral and cardiac ischemic events 122 (annual rates of 6% and 7%, respectively). After transient ischemic attacks, the risks of myocardial infarction and sudden death (21%) and stroke (23%) were similar, but cardiac 123 events were more likely to be fatal (63%) than stroke (16%). Coronary angiography of stroke patients identified that 40 percent had significant narrowing of their coronary arteries 124 that was asymptomatic at the time of stroke presentation. Using functional testing with thallium stress imaging, significant 21 CAD was present in 45 to 60 percent of patients with transient ischemic attack or stroke. Given the higher probability of CAD, several diagnostic evaluations are recommended in the acute period for all patients with ischemic stroke including an echocardiogram and serum troponin I levels. Further functional testing with echocardiography and continuous cardiac monitoring are often initiated to determine the risk of cardiogenic source of embolic ischemic strokes. Exercise or pharmacological stress test (nuclear or echocardiographic) and coronary angiography should be performed based on the patient's risk level and functional status. The majority of patients with acute stroke would not be eligible for acute treatments for myocardial infarction, but coronary angiography may be indicated if there is a strong clinical suspicion of plaque rupture or thrombus formation that may be safely treated endovascularly. As previously described, distinguishing cardiogenic from neurogenic causes of myocardial injury can be problematic in this patient population. Integration of clinical signs of heart failure, such as cardiogenic pulmonary edema and hypotension, careful analysis of the ECG, assessment of cardiac function by echocardiography, and evaluation of myocardial necrosis by cardiac markers may help to determine the need for cardiac catheterization. The CK-MB levels are insensitive and should not be used for differentiation between neurogenic injury and cardiogenic injury. A large increase in serum troponin I levels with a significant temporal trend, along with ECG changes that correlate with the location of left ventricular systolic 125 dysfunction on the echocardiogram may be more helpful. In contrast, common “neurogenic” ECG changes, including T-wave inversion, QTc prolongation, a shorter PR interval, and the presence of U waves, may aid in differentiating neurogenic injury from 126 myocardial infarction. In hemorrhagic strokes, the frequency of cardiac arrhythmias is high and often correlates with ECG changes. Baseline ECG and continuous cardiac monitoring in this population are often performed in the intensive care unit. Patients with SAH pose a greater challenge when the complication of cerebral vasospasm arises. The typical management of these patients includes induced hypertension with pressors, hypervolemia, and hemodilution to improve 127–130 The reduction of cardiac output from cerebral blood-flow through narrowed vasculature. normally elevated levels may increase the risk of cerebral ischemia related to vasospasm and 131 increase the risk of cardiopulmonary complications. SAH patients could potentially benefit from measurement of serum troponin I and B-type natriuretic peptide levels as well as transthoracic echocardiography as part of their initial management. Moreover, a close independent relationship has been established between the severity of SAH and the probability of troponin release and could be used to anticipate greater risk of cardiac 100 abnormalities in these patients. We do not recommend coronary angiography after SAH because most patients with left ventricular dysfunction following an SAH who undergo cardiac catheterization have normal epicardial coronary arteries and no evidence of coronary 58 vasospasm. For patients with epilepsy, sudden unexpected death is the most feared complication. Growing evidence suggests that neurogenic cardiac arrhythmias may contribute to the risk of sudden death. Identifying patients at highest risk of sudden death has been challenging. In addition to identifying clinical risk factors and promoting better medication compliance, advanced cardiac monitoring with ambulatory ECG and long-term implantable loop recorders 115 could help identify patients with pathological arrhythmias. In addition, other methods for
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measuring cardiac autonomic input such as heart rate variability and spectral analysis could 132 be potentially useful. CLINICAL MANAGEMENT After identification of the common cardiac abnormalities, management should be initiated to prevent their detrimental effect on patient outcomes. The most common ECG changes generally do62not require specific treatment, but may prompt further testing and continuous monitoring. Identification of other causes or contributors to ECG changes can lead to rapid resolution. In particular, specific treatment of hypokalemia, hypomagnesemia, and medication toxicity may correct a prolonged QT interval. Antiarrhythmic (e.g., quinidine, sotalol, amiodarone) or antipsychotic (e.g., haloperidol) drugs known to affect the QT interval should be avoided in these patients, especially if their neurological injury exacerbates underlying hereditary long QT syndrome. When repolarization abnormalities occur, excluding acute myocardial infarction may be necessary. Common electrolyte abnormalities such as hyperkalemia can produce tall T waves, whereas hypokalemia is the most common cause of U waves. Correction of electrolyte abnormalities can reduce the risk of arrhythmias. It is important to recognize that cardiac rhythm disturbances after neurological injury can be complex, requiring cardiology consultation. The most important aim is to identify patients who may be hemodynamically unstable in the presence of an arrhythmia. This is a medical emergency and should be managed immediately by appropriate personnel in the intensive care unit, with the involvement of a cardiac team. In a stable asymptomatic patient, identifying the type of arrhythmia can guide management. Atrial or ventricular premature contractions generally do not require specific treatment. For sinus bradycardia or tachycardia, identification and treatment of the common underlying conditions such as fever, thyroid dysfunction, anemia, pain, sepsis, and anxiety will often correct the rhythm disturbance. Specific pharmacological treatment may be required if the patient develops stable tachyarrhythmias. A trial of adenosine can terminate supraventricular tachycardia and assist in determining the underlying rhythm disturbance. Rate control with an intravenous β-blocker, calcium-channel blocker, or amiodarone can be used in patients with atrial fibrillation or flutter, most common after ischemic stroke and ICH. Stable ventricular tachyarrhythmias can also be managed with intravenous amiodarone or lidocaine. Specific treatment of torsade de pointes includes intravenous magnesium. Any arrhythmia more complex than ectopic beats or sinus bradycardia or tachycardia should prompt a cardiology consultation. When more significant cardiac dysfunction or injury is identified from elevated serum markers or dysfunction on the ECG, several steps can be taken to improve cardiac prognosis. If CAD is present, management of atherosclerosis risk factors (diabetes, hyperlipidemia, hypertension, and smoking) and treatment with antiplatelet agents and lipid-lowering agents may help both the ischemic stroke and heart disease. β-Blockers reduce the risk of vascular events after myocardial infarction, but their role in the prevention of cardiac events in other high-risk patients with stroke is unclear. Finally, revascularization by angioplasty or coronary artery bypass grafting is beneficial for patients with symptomatic CAD, but the decision to treat must balance the risk to the patient with an acute neurological injury. The value of 22 revascularization in patients with asymptomatic CAD is less clear. In the rare event of coronary plaque rupture in a patient with SAH, coronary angioplasty along with stenting may be considered once the aneurysm is secured and the necessary anticoagulation regimen can be tolerated safely. Although further studies are needed to determine the safety of percutaneous coronary intervention and anticoagulation after successful aneurysmal intervention, patients with unsecured aneurysms should not undergo any coronary intervention given the unacceptably high risk of rebleeding. In SAH patients, the presence of cardiac injury and dysfunction often directly affects management. The decision to treat a ruptured aneurysm should not be delayed because of concerns regarding cardiac injury. Because the mechanism of neurogenic cardiac injury is likely catecholamine mediated, treatment should focus on correcting or improving the underlying neurological process. For patients with SAH, prevention of rebleeding with early aneurysm clipping or endovascular coiling has proven benefit and does not appear to affect cardiac outcomes. In our patient cohort, there was no significant difference in cardiac 133 morbidity between surgical and endovascular therapies. Management of cerebral vasospasm in the setting of significant neurocardiogenic injury is challenging and directly affects neurological prognosis. Permissive hypertension requiring pressors to improve cerebral blood-flow often leads to increased myocardial wall stress and oxygen consumption, whereas hemodilution will decrease oxygen delivery to the myocardium, predisposing to further injury. Although most patients tolerate treatment for
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cerebral vasospasm, our recent study found that phenylephrine, the most commonly used 104 pressor, is relatively ineffective in patients with a poor cardiac ejection fraction. Other studies have also suggested the use of alternative agents such as dobutamine and milrinone, 134 which may be more effective in this setting. In those patients with diastolic dysfunction, iatrogenic hypervolemia may cause increased filling pressures leading to pulmonary edema. We recommend continued aggressive therapy for vasospasm, but consider more effective pressors and volume repletion strategies in patients with concomitant cardiogenic injury. In patients with severe neurogenic cardiac injury and evidence of heart failure who are unable to tolerate medical therapy for vasospasm, placement of an intra-aortic balloon pump to 85,135,136 increase cerebral perfusion pressure has been successful. Given the potential role of excessive catecholamines in neurocardiogenic injury, β-blockers may have a role in providing cardioprotection if administered early in the hospital course. Limited evidence from two small studies has demonstrated clinical efficacy. The first study demonstrated resolution of abnormal ECG changes associated with SAH after administration 126 of 80 mg propranolol. The second study was a randomized, double-blind, placebo-controlled trial of 12 patients comparing propranolol (80 mg) and 20 mg 137 phentolamine (20 mg) with placebo given within the first 48 hours. Although there was no mortality benefit in the treatment group, necrotic myocardial lesions were present in all six patients who died in the placebo group, whereas the six patients who died in the treatment group had no necrotic myocardial lesions. The pathological correlation suggests that β-blockade may protect myocytes from the hostile environment caused by massive levels of catecholamines released from cardiac sympathetic nerve terminals following SAH. Larger studies will help to determine the role of early administration of β-blockers in patients with cardiac dysfunction following SAH. Calcium-channel blockers targeting the calcium overload preceding contraction band necrosis has not been well studied. There does not appear to be a significant cardiac benefit from nimodipine, the calcium-channel blocker already administered to patients for vasospasm prophylaxis. CONCLUDING COMMENTS Cardiac disturbances are diverse and frequent in the setting of acute neurological injury. More importantly, the presence of cardiac abnormalities has significant impact on clinical management and affects cardiac and neurological outcomes adversely. Understanding of the underlying pathophysiology and localization of the important autonomic regulatory centers involved in brain–heart interactions has progressed significantly in recent years. Animal models have been translated into important clinical research studies that have revealed further complexity in the brain regulation of cardiac function. It is widely accepted that acute brain injuries most often lead to an increase in sympathetic tone, leading to a potential role for β-blockade in these patients. Understanding certain aspects of neurocardiogenic injury has already affected clinical management. Early detection of asymptomatic CAD in ischemic stroke patients will likely improve outcomes. Prioritizing treatment of the underlying neurological condition, even in the setting of cardiac dysfunction, has led to timely aneurysm treatment after SAH and prevention of rebleeding. Close cardiac monitoring for cardiac arrhythmias after acute injuries and screening for elevated serum levels of cardiac enzymes and for echocardiographic abnormalities in high-risk patients may lead to better treatment strategies. The knowledge that the cardiac injury that occurs following SAH appears to be reversible will likely prevent unnecessary invasive testing for CAD. Echocardiography and screening for elevated troponin and B-type natriuretic peptide levels may help prognosticate and guide treatment of stroke and optimize treatment of vasospasm after SAH. In most cases, treatment of cardiac injury should be supportive. β-blockers may provide cardioprotection from the hyperadrenergic milieu around myocytes but to date have no proven mortality benefit. Improved diagnostic techniques with ECG spectral analysis should help to detect the effect of the parasympathetic and sympathetic nervous systems on the heart. These techniques may help to identify patients with epilepsy at risk of cardiac arrhythmias and sudden death. Improved biomarker assays and screening for genetic susceptibility for neurocardiogenic injury will eventually be possible. Last, for brain-dead patients, cardiac evaluation under optimal conditions may help to increase the organ donor pool. According to the United Network for Organ Sharing, in 1998 138 only 42 percent of potential donor hearts were transplanted. One main reason for this low yield was left ventricular dysfunction; in 1995,139 918 of 2,199 potential donor hearts were unused because of poor ventricular function. Current guidelines help to determine which donor hearts will have the greatest success and recommend careful evaluation and assessment of cardiac anatomy and systolic function by echocardiography and cardiac
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catheterization in patients who are at higher risk of CAD. Because it is likely that left ventricular dysfunction following SAH is reversible and unrelated to CAD, initial cardiac evaluation that is obtained under suboptimal conditions may not be an accurate reflection of long-term contractile function of the left ventricle. One study demonstrated that donor hearts with left ventricular dysfunction defined by hemodynamic criteria could be functionally resuscitated in 92 percent of cases, resulting in a 30 percent increase in donor-retrieval 141 rate. Proposed guidelines that suggest evaluation during optimized conditions and more liberal criteria for cardiac catheterization, among other changes in recommendations, are being established to help increase the donor pool without compromising success following 140 transplantation. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 11 Neurocutaneous Syndromes BRUCE O. BERG •
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NEUROFIBROMATOSIS TUBEROUS SCLEROSIS VON HIPPEL–LINDAU DISEASE STURGE–WEBER SYNDROME ATAXIA-TELANGIECTASIA
The diseases usually considered in the category of neurocutaneous syndromes are characterized by their dysplastic nature and tendency to form tumors. Although the skin and central nervous system (CNS) are primarily affected, other organ systems may be involved. Several of the diseases in this group were described during the nineteenth century, but in 1914 Bielschowsky first associated neurofibromatosis and tuberous sclerosis because of 1,2 their dysplastic and neoplastic features. In describing the ocular findings in these two diseases, Van Der Hoeve suggested the neologism phakomatosis (Gr. phakos, lentil, mole, birthmark)—an inappropriate term—to epitomize these diseases; he later added von 3–5 Hippel–Lindau disease and Sturge–Weber syndrome to this group. In 1941, Louis-Bar reported the clinical features of a syndrome now recognized as ataxia-telangiectasia and 6 suggested that it too belonged in this disease category. During the last several decades, a variety of other disorders, all unusual and some lacking the typical features of the neurocutaneous syndromes, have been added to the group. Some of them are summarized in Table 11-1. The five most important syndromes are discussed in detail in this chapter. Click here to view this table.... Except for Sturge–Weber syndrome, these major neurocutaneous syndromes are genetically determined, although sporadic cases can occur. They are distinct clinical entities, and although there are reports of double “phakomatoses” or “overlap,” reliable documentation of any combination of these diseases is rare, and such a combination occurs no more 7 frequently than by chance. NEUROFIBROMATOSIS Neurofibromatosis, an inherited disease transmitted as an autosomal-dominant trait, is noted for its heterogeneity of clinical expression. It may involve the peripheral and central nervous systems as well as skin and bone, and the endocrine, gastrointestinal, and vascular systems.
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Although von Recklinghausen is credited for the initial clinical description of the disease, it 8–11 had been described earlier. Three distinct forms of neurofibromatosis have been recognized: type 1 (NF1), the most common type, is widely known as von Recklinghausen disease and is characterized by multiple hyperpigmented macules (café-au-lait spots) and neurofibromas; type 2 (NF2) is characterized by eighth-nerve tumors (schwannomas), but other intracranial and intraspinal tumors are common; and type 3 (NF3), schwannomatosis, is characterized by the occurrence of schwannomas on cranial and spinal nerves with the exception of the vestibular nerves. The diagnosis of NF1 neurofibromatosis can be made in patients with two or more of the following clinical findings: six or more café-au-lait spots with a maximum diameter of more than 5 mm during prepuberty and more than 15 mm in postpubertal patients; two or more neurofibromas of any type or one plexiform neuroma; freckling of the axillary or inguinal regions; optic glioma; two or more Lisch nodules; typical bony lesions; and a first-degree relative with the disorder diagnosed by these criteria. The diagnosis of NF2 neurofibromatosis can be made if the patient has bilateral vestibular schwannomas. The diagnosis can also be made if the patient has a first-degree relative with unilateral schwannoma before the age of 30 years or any two of the following findings: neurofibroma, meningioma, glioma, 12 schwannoma, or juvenile subcapsular lenticular opacity. The skin changes associated with neurofibromatosis are characterized by focal or diffuse lesions, or both, that are usually present before the appearance of any neurological abnormality. They include café-au-lait spots, fibroma molluscum, patchy or diffuse areas of hyperpigmentation, hypopigmented spots, and angiomas. Café-au-lait spots are usually present at birth. The number of spots and the degree of pigmentation tend to increase during the first year of life, but after that time the number of spots remains relatively stable. These spots can appear anywhere on the body (Fig. 11-1) except probably the scalp, palms, and soles. They are typically flat, with discrete borders, and vary in size from millimeters to centimeters. Crowe and associates observed that patients with six or more café-au-lait spots with a diameter of 1.5 cm have a presumptive diagnosis of neurofibromatosis; Crowe later reported that axillary freckling was also an important feature 13,14 The presence of café-au-lait spots does not necessarily establish the of the disease. diagnosis of neurofibromatosis, however, since at least 10 percent of the population have one or more hyperpigmented cutaneous macules.
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FIGURE 11-1 Typical café-au-lait spots of neurofibromatosis, located primarily on the
trunk. Fibroma molluscum, a prominent skin lesion found in the dermis or adjacent to it, consists of discrete, soft or firm papules ranging in size from a few millimeters to several centimeters. They are flat, sessile, or pedunculated and can be readily impressed into the subjacent skin. Hypopigmented spots, similar to those found in tuberous sclerosis, are sometimes present, as are discrete areas of skin hypoplasia and angiomas. Neurofibromas can occur anywhere from the dorsal root ganglion to the terminal peripheral nerve branches and can affect any organ system. They vary in size and are more often found on the trunk than on the limbs (Fig. 11-2). Plexiform neuromas are made up of interwoven elements of tumor and connective tissue that infiltrate normal tissue. They can be superficial, involving skin and subcutaneous tissues, or deep, affecting visceral and adjacent tissues. Diffuse areas of skin hyperpigmentation may overlie the plexiform neuroma. Neurofibromas are composed of a variety of cell types including Schwann cells, fibroblasts, perineurial cells, 15–18 with an incidence and mast cells. Malignant transformation of neurofibromas may occur, of 2 to 7 percent in different series. Pain, an increasing neurological deficit, and enlargement of a preexisting peripheral nerve sheath tumor indicate the need for surgical biopsy to 19 exclude such transformation.
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FIGURE 11-2 Multiple subcutaneous neurofibromas in a young adult.
Other intracranial tumors commonly found in neurofibromatosis include astrocytomas involving the cerebrum, cerebellum, or brainstem, and there is an increased frequency of 20,21 Other cranial nerves can be affected by neurofibromas or optic nerve gliomas. schwannomas, and bilateral acoustic neuromas are a characteristic feature of NF2. Although meningiomas, both solitary and multiple, are found with increased frequency in the major type of neurofibromatosis (NF1), they are more typically observed in NF2. Medulloblastomas, ependymomas, and hamartomas also occur more17frequently in patients with neurofibromatosis than in the general population. Intraspinal tumors are single or multiple, intradural or extradural. They can be accompanied by spinal anomalies such as syringomyelia. Some intraspinal tumors assume a dumbbell shape, extending through the intervertebral foramen. They are17sometimes associated with enlargement of that foramen or defect of the contiguous bone. Lisch nodules, a typical finding in neurofibromatosis, are melanocytic hamartomas found in the iris. Age-dependent and bilateral, they are found in about 10 percent of patients younger than 6 years, 50 percent of patients younger than 30 years, and almost all patients by age 50. Other ocular findings in neurofibromatosis include optic nerve gliomas (the most common CNS tumor) and congenital glaucoma. The frequency of optic gliomas in neurofibromatosis 17,18 Patients usually have symptoms of decreased visual has ranged from 15 to 20 percent. acuity or visual field defects but may initially appear with signs and symptoms of increased intracranial pressure. The tumor mass can involve the optic chiasm or hypothalamus and 20,22 Although rarely manifests as the diencephalic syndrome of infancy or precocious puberty. there is some controversy regarding the nature of the tumor, optic gliomas in children are probably congenital hamartomas, indolent and slow-growing. They are reportedly rare after the age of 6 years and progression of preexisting tumors in children with NF1 has been held to be uncommon after this age; nevertheless, late-onset or late-progressive21,23 lesions may certainly occur, mandating careful monitoring of all patients into adulthood. Congenital glaucoma, a known complication of neurofibromatosis, is commonly associated with a neurofibroma of the superior eyelid. The mechanisms underlying its cause include angle obstruction by neurofibromas, angle narrowing from neurofibromatous thickening of the ciliary body and choroid, fibrovascularization and synechial narrowing of the angle, and developmental anomalies of the angle.
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A variety of bony changes can occur in neurofibromatosis, including a ballooning of the middle fossa, an enlarged sella turcica, a J-shaped sella, and abnormalities of the sphenoid wing. The optic foramina are enlarged in some patients with optic glioma; bony defects of the orbit, the area of the lambdoid sutures, and other cranial bones are not uncommon. Scoliosis is reported in 10 to 40 percent of patients, although usually it is not reported before the age of 6 years; kyphosis, anterior meningocele, enlarged intervertebral foramina, bowing of the tibia and fibula, and bony overgrowth have also been reported. Pseudarthrosis is a characteristic feature of neurofibromatosis and usually involves the junction of the middle and distal third of 24,25 The bony defects associated with the tibia, although other tubular bones can be affected. neurofibromatosis are secondary to developmental abnormalities of mesenchymal tissue and are usually not the result of bone erosion by tumor. Magnetic resonance imaging (MRI) of the head may show focal areas of increased signal intensity in T2-weighted images that are associated with increased myelin water content and gliosis. The lesions are seen primarily in the basal ganglia, internal capsule, brainstem,26,27 cerebellum, and subcortical white matter and tend to involute spontaneously with age. Other features of neurofibromatosis include macrocephaly and short stature, which are reported to occur in 10 to 40 percent of patients. Mental retardation and seizures, though not necessarily related, occur in about 10 percent of patients, and about 50 percent of patients 17 have specific learning disabilities and hyperactivity. Precocious puberty has been observed in patients with a hypothalamic glioma or hamartoma or in some optic chiasmal gliomas that involve the hypothalamus. It should not be presumed, however, that precocious puberty without hypothalamic involvement by mass lesion is an integral part of the disease. Hypertension can develop from stenotic lesions or aneurysm formation at all levels of the renal arteries including intimal proliferation and fibromuscular changes of the media in parenchymal branches of the arteries, and stenotic28,29 changes of the internal carotid artery can result in moyamoya disease and ultimately stroke. A variety of tumors occur more frequently in patients with neurofibromatosis than in the general17,30–33 population, including pheochromocytoma, leukemia, neuroblastoma, and Wilms' There is an increased frequency of multiple endocrine neoplasia and medullary tumor. thyroid carcinoma. Among patients with pheochromocytomas, a significant number (4% to 23%, depending on the series) have neurofibromatosis, whereas only 1 to 2 percent of 30–33 patients with neurofibromatosis have pheochromocytomas. The frequency of neurofibromatosis, inherited as an autosomal-dominant trait, is about 1 in 12 4,000 persons for NF1 and about 1 in 50,000 persons for NF2. About one half of the cases are said to be spontaneous mutations. The factors behind the risk of developing the varied 34 complications of the disease are yet to be determined. The gene for NF1 has been mapped to a locus on chromosome 17q11.2, and it encodes a 3818 amino-acid protein, neurofibromin, which is expressed in a variety of cell types, particularly Schwann cells, 35–39 The protein contains a guanosine triphosphatase oligodendrocytes, and neurons. (GTPase) activating40–42 protein (GAP) that appears to regulate conversion of RAS-guanosine Neurofibromin is a tumor suppressor gene with respect to formation diphosphate (GDP). 43 of neurofibromas. Conversion to malignancy requires additional genetic alterations, but it is not known whether dysplasia results from tumor suppressor mechanisms or whether the expression of haploinsufficiency of neurofibromin causes the lesion. The gene for NF2 has been44,45 localized to a mutation at 22q12.2 and the protein is referred to Schwannomas are clonal tumors and the NF2 gene acts as a as schwannomin or merlin. tumor suppressor, whereas merlin is a cytoskeletal protein that functions in the control of cell growth. Schwannomatosis is characterized by the occurrence of schwannomas affecting cranial or spinal nerves except for the vestibular nerve. The disease is sporadic, and the responsible 46 gene has been localized to chromosome 22, near the NF2 locus but distinct from it. The treatment of patients with neurofibromatosis is symptomatic. Peripheral neurofibromas are generally indolent lesions that do not require surgical removal unless they are subjected to repeated trauma or show rapid growth. On occasion, plexiform neuromas are removed for cosmetic reasons. Intracranial and intraspinal tumors are treated with appropriate surgical techniques, irradiation, or chemotherapy. Optic gliomas in children are generally thought to be hamartomas; some authors recommend that they be managed conservatively by following their growth and documenting visual function, rather than by immediate surgery or radiation 47,48 therapy. TUBEROUS SCLEROSIS
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Tuberous sclerosis complex, inherited as an autosomal-dominant trait, is characterized by a wide spectrum of clinical findings, including seizures, varying degrees of mental subnormality, and dysplastic and neoplastic changes of the skin, nervous system, and other organs. It was probably first described by von Recklinghausen in 1862,49–52 although Bourneville is appropriately Bourneville thought that cerebral credited for the initial clinical description of the disease. “scleroses” and renal tumors were associated findings but paid little attention to the facial skin lesions. Only later did he and Brissaud suggest an association of cerebral scleroses and renal tumors. In 1908, Vogt believed there was a typical triad of findings: adenoma 53 sebaceum, seizures, and mental retardation. The clinical expression of the disease depends on the patient's age and the extent of organ involvement. Seizures, the most common symptom occurring in 75 to 90 percent of patients, can appear at any time after birth. Generalized and, less commonly, partial54–58 seizures occur, The early and infantile spasms are often present during the first several years of life. onset and severity of recurring seizures is correlated with mental subnormality, and patients who have numerous cerebral tubers are prone to have greater impairment of higher cortical function. There is, however, notable variability of mental function in patients with tuberous sclerosis, and about 30 to 50 percent of patients have normal intelligence. Some affected children may develop normally during the first few years of life, but mental function deteriorates later in the first decade; between 25 and 50 percent manifest symptoms and 59,60 signs of autism spectrum disorder. Adenoma sebaceum, commonly considered to be the characteristic skin lesion in tuberous sclerosis, consists of angiofibromas that appear in patches or in a butterfly distribution about the nose, cheeks, and chin (Fig. 11-3). Observed in more than 50 percent of patients, they are rarely apparent at birth and are usually first observed between the ages of 1 and 4 years, 54,55 Hypopigmented spots can be visualized in a variety of forms: tending to enlarge with time. polygonal or “thumb-print”–shaped, in an ash-leaf configuration, or as confetti-like hypopigmented spots. The hypopigmented spots vary in size from millimeters to several centimeters (Fig. 11-4). They may be present at birth but become more prominent with time. Visualization of these hypomelanotic macules is enhanced by using a Wood light because melanin absorbs light of that frequency (360 nm), so areas deficient in melanin are accentuated.
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FIGURE 11-3 Adenoma sebaceum of tuberous sclerosis.
FIGURE 11-4 Leaf-shaped hypopigmented macule (left arrows) and adjacent small fibroma (right arrow) commonly seen in tuberous sclerosis.
In some patients, a patch of white or gray hair precedes the appearance of hypopigmented 61 spots. Other skin changes that may occur include the shagreen patch (a “leathery” cutaneous hamartomatous plaque) usually found over the lumbosacral or gluteal area), 55 café-au-lait spots, fibromas, and angiomas. Subungual or periungual fibromas (Koenen tumors) are found in about 20 percent of patients and affect the toes more than the fingers. They are usually first noted during adolescence. 62 Gingival fibromas may also occur, as may dental enamel pits. Although retinal tumors (hamartomas) are commonly present, affecting about 50 percent of patients, visual complaints are few (Fig. 11-5). These astrocytic, nodular lesions tend to calcify and may be solitary or multiple. Gray-yellow glial patches are sometimes present. Additional ocular findings include iritic hypomelanotic spots, cataracts, and colobomas of the iris, lens, and choroid.
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FIGURE 11-5 Typical retinal (mulberry) lesion observed in tuberous sclerosis.
Renal tumors are found in about 25 percent of patients with tuberous sclerosis and include angiomyolipomas and cystic lesions that are embedded in the renal parenchyma. These 63 lesions are relatively benign and only rarely require surgical intervention. Cardiac rhabdomyomas are found in at least 50 percent of patients and are solitary, multiple, or infiltrative, diffusely affecting the myocardium. They may be the cause of obstructive outflow or abnormalities of valvular function.64–66 Their demonstration has been notably improved with They are often identified prenatally and are most echocardiography and angiography. apparent during the first few years of life, subsequently undergoing spontaneous regression. Other associated abnormalities include pulmonary abnormalities that occur almost entirely in female subjects and may be manifested as lymphangioleiomyomatosis or pulmonary cysts. They may be asymptomatic or become apparent because of dyspnea, spontaneous 67–69 Hamartomas can be present in other organ pneumothorax, or pulmonary hypertension. 70–72 systems, and a variety of endocrine abnormalities have been reported. Radiographic studies can be effectively utilized to confirm the diagnosis. Intracranial calcifications, commonly observed in the region of the foramen of Monro or the periventricular region, are present on skull radiographs in about 60 percent of affected patients. Computed tomography (CT) may demonstrate cerebral hamartomas, subependymal nodules, ventriculomegaly, and areas of diffuse demyelination (Fig. 11-6). The CT findings may be abnormal in patients without clinical features of the disorder; less commonly, the findings are 73 normal in clinically affected patients. The most reliable finding on CT head scan is the demonstration of mineralized subependymal nodules. Periventricular calcification is less specific and may not be distinguishable from toxoplasmosis, cytomegalic inclusion disease, and Fahr's syndrome. MRI demonstrates with great clarity not only uncalcified subependymal 74 nodules but a marked distortion of normal cortical cytoarchitectonics (Fig. 11-7).
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FIGURE 11-6 Computed tomography (CT) scan (unenhanced axial view) of
patient with tuberous sclerosis, showing calcified tubers.
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FIGURE 11-7 Magnetic resonance imaging (MRI) of the head (axial view),
demonstrating multiple cortical and subcortical foci of increased signal intensity in tuberous sclerosis. Other typical radiographic findings include cystic rarefaction of phalanges and metacarpals, sclerotic areas of long bones, areas of increased or decreased bony density of the skull, and cerebellar calcification. Patients with pulmonary involvement may have a fine reticular infiltrate or multicystic changes on chest radiographs. Brain weight and configuration are usually normal except for the presence of cortical tubers, which may be noted anywhere in the cerebral hemisphere. Tubers are often found within the cortical gyri, although smaller nodular lesions can be observed in the region of the sulcus terminalis or basal ganglia, protruding into the ventricle. Tubers located about the foramen of Monro or the aqueduct of Sylvius may grow sufficiently to obstruct the normal circulation of cerebrospi-nal fluid (CSF), resulting in increased intracranial pressure. The microscopic appearance of the tuber is characterized by a decreased number of neurons with scattered large, bizarre, sometimes vacuolated “monster” neurons. Sections of cortex show proliferation of fibrillary astrocytes, demyelination, and abnormalities of cortical 75,76 cytoarchitectonics. The walls of some vessels may show hyaline degeneration. Subependymal nodules are fibrocellular, with round or oval cells and whorls of fibrillary glial tissue. Amyloid or calcium deposits may be present within the tuber or subependymal nodule; cerebellar calcification occurs rarely. Tuberous sclerosis is inherited as an autosomal-dominant trait with variable penetrance; the estimated frequency of the disease is 1 in 58,000. The reported sporadic rate, ranging from 50 to 75 percent is probably an overestimate because it is likely that a diagnosis of tuberous sclerosis could be established in some of the “asymptomatic” parents of children with the 77 disease if they were examined with current diagnostic techniques. It is thought that two genes are responsible for the tuberous sclerosis complex; one gene is located at chromosome 9q34, with its protein product being hamartin, and the other at chromosome
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16p13.3, with the gene product being tuberin. Hamartin and tuberin interact and function as 78,79 tumor suppressor molecules. Convulsive disorders are treated by administration of appropriate anticonvulsant medications; the ketogenic diet and vagus nerve stimulator have also been used. Unfortunately, the control of seizures cannot be assured. There is no specific treatment for the skin lesions unless they are subjected to frequent irritation; selected lesions can be surgically removed or treated with other dermatological measures. When the diagnosis of tuberous sclerosis is established, genetic counseling is required for all family members. Patients with tuberous sclerosis must be afforded thoughtful medical and emotional support and guidance. VON HIPPEL–LINDAU DISEASE Von Hippel–Lindau disease, inherited as an autosomal-dominant trait, is characterized by retinal and cerebellar hemangioblastomas. Other manifestations include cysts of the pancreas, liver, and spleen as well as malignant renal tumors. There are no associated skin lesions, as are found in other neurocutaneous syndromes. The retinal lesion was first80described, though not recognized as a hemangioblastoma, by Panas and Remy in 1879. In 1882, Fuchs thought the lesion was an arteriovenous malformation, and Collins in 1894 believed it originated from capillaries and had a hereditary 81,82 Von Hippel decided that83the retinal lesion was a hemangioblastoma but attached basis. the name of angiomatosis retinae. In 1926, Lindau established the association of retinal and cerebellar hemangioblastomas, but he was also aware that these patients may have other lesions, including spinal cord angiomas and cystic tumors of the pancreas, kidney, and 84 epididymis. The retinal hemangioblastoma is one of the earliest manifestations of the disorder. Though reported to occur during childhood, it is usually found initially during the third decade. The early appearance of the lesion is similar to an aneurysmal dilation of a peripheral retinal vessel; later, there are typical tortuous vessels, with an afferent arteriole and venule leading 85,86 to a small, raised retinal lesion (Fig. 11-8). Some lesions are small and easily overlooked. The retinal lesions have been divided into three categories: (1) a pinkish red vascular lesion located in the midperiphery, with visible dilated “feeder” vessels and variable exudate; (2) a pale gray lesion, with “feeder” vessels observed only on fluorescein retinal angiography; and (3) retinal lesions that are similar to diabetic microaneurysms but that are not observed to have retinal vascular connections. Patients with peripheral retinal lesions may have no significant visual impairment, but if the lesion involves the macula or optic disc, there is 87–90 progressive visual loss.
FIGURE 11-8 Typical round, white-red retinal hemangioblastoma observed in
von Hippel–Lindau disease. The diagnosis of cerebellar hemangioblastoma is usually first made during the third or fourth decade, but there are rare reports of its occurrence before puberty. The initial signs and symptoms are primarily those of cerebellar dysfunction and increased intracranial pressure.
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Hemangioblastomas can also occur in the medulla and the91–93 spinal cord, where in about 80 Supratentorial percent of patients they are associated with syringomyelia. hemangioblastomas are uncommon but have been reported in the pituitary, third ventricle, and cerebral hemispheres. Renal lesions may be found in von Hippel–Lindau disease and include benign cysts, 94,95 Hypernephromas occur in more than half of patients angiomas, and hypernephromas. and are a prominent cause of morbidity and mortality. Benign cysts are also found in the pancreas, adrenal gland, and epididymis and are usually asymptomatic. There is an increased frequency of pheochromocytoma in patients with von Hippel–Lindau disease, 96 ranging from 3 to 17 percent. The retinal lesions are recognized by ophthalmological examination, and fluorescein retinal angiography can demonstrate the vascular characteristics of the lesion. CT and MRI delineate the structural characteristics of the cerebellar or spinal cord lesions. Intra-abdominal lesions can be demonstrated by CT, MRI, and ultrasonography. The red blood cell count may be elevated because of increased concentration of erythropoietin in the hemangioblastoma cyst fluid; the absence of polycythemia, however, does not exclude the diagnosis. Patients with CNS tumors have an elevated protein concentration in the cerebrospinal fluid. Urine collection (24-hour) for assay of epinephrine, norepinephrine, and vanillylmandelic acid is performed to screen for pheochromocytoma. The most frequent site of the tumor is the cerebellum, usually in the paramedial aspect of the cerebel lar cortex, and the tumor is associated with prominent vessels. The microscopic features of the tumor are characterized by large numbers of thin-walled, closely packed blood vessels that are lined by plump endothelial cells and separated by large, pale cells 94 incorporated into an elaborate network of reticulin fibers. Von Hippel–Lindau disease is inherited as an autosomal-dominant trait with variable penetrance. There is no sex predominance. The incidence of sporadic cases is not known. The tumor suppressor gene that causes von Hippel–Lindau has been localized to chromosome 3p26–25 by linkage analysis and encodes a protein that senses and responds 97–101 to hypoxia. Posterior fossa hemangioblastomas are treated by neurosurgical techniques to remove the cyst and associated fluid and mural nodule. Radiation therapy is of little benefit in the treatment of this tumor. Retinal hemangioblastomas are treated by a variety of methods, including laser photocoagulation and cryotherapy. STURGE–WEBER SYNDROME Sturge–Weber syndrome is characterized by a facial angioma (nevus, port-wine stain) associated with signs and symptoms of a leptomeningeal venous angioma. In 1860, Schirmer described a patient with a facial nevus and buphthalmos, but Sturge is credited with the first clinical description in 1879 of the syndrome in a102,103 young child who had a facial angioma, He suggested that the patient had an buphthalmos, and contralateral partial seizures. underlying104 cerebral nevus, but it was not until 1897 that pathological studies confirmed his prediction. Weber subsequently described the associated intracranial calcifications noted on skull 105 der Hoeve radiographs and introduced the term encephalofacialangiomatosis, and Van 106 inappropriately suggested that the disorder was the “fourth phakomatosis.” Sturge–Weber syndrome has no clear pattern of inheritance. The estimated incidence is approximately 1 in 50,000 persons. The facial angioma is congenital and unilateral (though it may be bilateral) and involves at least the upper face, superior eyelid, or periorbital region (Fig. 11-9). It may involve the nasopharynx, palate, lips, gingiva, and tongue. Although the facial angioma is commonly thought to conform to the sensory distribution of the first and possibly second or third divisions of the trigeminal nerve, there is reason to consider such a relationship fortuitous. Rather, the distribution of the facial nevus may be determined by 107 embryological development of the face. Angiomas may also be found on the neck, trunk, or extremities. Meningeal venous angiomas may occur in the absence of any facial angioma; although secondary cerebral signs and symptoms are similar to those of the Sturge–Weber syndrome, these patients are more appropriately thought to have a separate disorder, 108 referred to as meningeal angiomatosis.
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FIGURE 11-9 Facial angioma (port-wine stain) of Sturge–Weber syndrome
primarily involving the left upper face (arrows). In addition the patient manifests contralateral hemiparesis and hemiatrophy. During early infancy, most patients with Sturge–Weber syndrome experience seizures that are primarily partial motor in type, although some patients have generalized tonic-clonic seizures. There is usually a relentless progression of severity and frequency of the convulsive disorder, and any postictal Todd's paralysis often requires increasingly longer periods of time to resolve, until eventually there is a permanent hemiparesis. Other types of seizures, including infantile spasms, myoclonic seizures, and atonic attacks, occur less commonly. In earlier studies, the frequency of seizure disorders has varied from 70 to 90 percent. In a retrospective study of 102 patients evaluated between 1942 and 1986, 88 patients had one cerebral hemisphere affected and 14 patients had bilateral hemispheric involvement. Seizures occurred in 75 percent of these patients. Among 88 patients with unilateral hemispheric disease, 63 had seizures, with the mean age at seizure onset being 24 months; 13 of 14 patients with bilateral hemispheric lesions had seizure disorders, with a mean age at 109 onset of 6 months. Hemiparesis contralateral to the facial angioma occurs in about 30 percent of patients and is sometimes apparent during infancy, before the onset of seizures. The weakness is generally exacerbated by increasingly severe recurrent seizures and may be accompanied later by hemiatrophy. Bilateral hemipareses may be present in patients with meningeal angiomas affecting both cerebral hemispheres. Hemisensory deficits are less frequently documented because reliable sensory examinations are difficult to carry out in very young and in mentally subnormal patients. Homonymous hemianopia is present in about one third of patients, and glaucoma secondary to choroidal angioma is found in about one fourth. Other ocular findings include iritic heterochromia with the hyperpigmented iris ipsilateral to the facial angioma, optic atrophy, and strabismus. At least 50 percent of patients are mentally subnormal, and behavioral problems are common. As seizures of early onset increase in frequency and severity, mental function and behavior often regress. In the retrospective study noted previously, 25 of 88 patients with unihemispheric leptomeningeal involvement who did not have seizures were of average intelligence; 1 of 14 patients with bilateral hemispheric109involvement was unaffected by seizures and that patient was of average intelligence. These observations are important considerations in patient management. Electroencephalographic (EEG) studies may show decreased amplitude and frequency of electrocerebral activity over the affected hemisphere. Diffuse multiple and independent spike
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110
Intracranial calcification, demonstrated on skull radiographs, is present in more than 90 percent of patients. It is rarely observed in infants but has nevertheless been reported in the neonate and is present in most patients by the end of the second decade. The calcifications, which are usually in the occipital or parieto-occipital regions, assume a linear, parallel configuration (“tram sign”). CT scans of the head demonstrate calcifications and cerebral atrophy more readily than plain radiography and may show the calcific deposits during the first few months of life. Cerebral angiography shows decreased cerebral venous drainage and dilated deep cerebral veins. About one third of patients have a variety of vascular abnormalities, including thrombotic lesions, dural venous sinus abnormalities, and arteriovenous malformations. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) provide a measure of the extent of cerebral metabolic impairment, and serial PET scanning can be useful with other neuroimaging techniques to document the progression of 111,112 The extent and amount of glucose asymmetry as detected by PET 112 the disease. scanning are reported to be sensitive markers of seizure severity and cognitive decline. SPECT detects asymmetries in cerebral blood-flow in infants with Sturge–Weber disease, and these asymmetries may shift with age. In particular, the cortex involved in the vascular malformation is hyperperfused during the first year of life, becoming hypoperfused 113 thereafter. Typical pathological features include thickened, hypervascularized leptomeninges involving primarily the occipital, parietal, or temporo-occipital lobes. Meningeal vessels are small and tortuous, lending a dark, purplish blue color to the cerebral surface. These abnormal vessels rarely enter the underlying atrophic hemisphere. Calcific deposits of varying size are found in the walls of some small cerebral vessels but are located primarily in the molecular and outer pyramidal cortical layers. Although some iron associated with calcific deposits has been reported, the iron content of gray and white matter is normal, whereas the calcium content is greatly increased. The pathogenesis of intracortical calcium deposition is not fully understood. Good management requires careful attention to every aspect of the patient's medical and emotional well-being. The seizure disorder is managed with anticonvulsant drugs. Adrenocorticotropic hormone (ACTH) may be required for patients with infantile spasms. It is not unusual for seizures to be recalcitrant to medical management; in selected cases, consideration must114,115 be given to the surgical removal of an affected lobe or lobes or to but there is no agreement as to the optimal time for such an hemispherectomy, 116 approach. There has been some measure of success in treating the facial angioma with administration of pulse-dye laser. Management of mental subnormality and behavioral problems requires the skilled support of the physician, psychologist, and social worker. ATAXIA-TELANGIECTASIA Ataxia-telangiectasia is a multisystem disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasis, proclivity to sinopulmonary infections, and immunoincompetence associated with lymphoreticular neoplasia. The disease is transmitted as an autosomal-recessive trait, affecting male and female subjects equally. 117
Although this condition was initially described by Syllaba and Henner in 1926, Louis-Bar believed that her 1941 report of ataxia and notable cutaneous telangiectasis in a 9-year-old boy described a118 hitherto unrecognized disease and suggested that it was one of the phakomatoses. Three independent reports of the disease were published in 1957: Boder and Sedgwick described the clinical features of the disease and named it 119 ataxia-telangiectasia ; Biemond described the clinical and pathological findings of the 120 disease and emphasized the recurring sinopulmonary infections and extrapyramidal signs ; and Wells and 121 Shy reported the disease as “familial choreoathetosis and cutaneous telangiectasis.” Affected patients appear normal until the time they begin to walk independently, usually at 12 to 18 months, at which time truncal ataxia first becomes apparent. Normal motor development continues despite the ataxia, but within several years there is little question that the child is inordinately clumsy. Abnormalities of ocular motility characterized by slow, involuntary ocular movements with erratically interspersed vertical components are common. There is a defect in the initiation of voluntary and involuntary saccades; associated eye blinking and head thrusts or jerks, 122,123 consistent with congenital oculomotor apraxia, are usually present.
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Patients are generally hypotonic, and there is a paucity of muscle bulk. Stretch reflexes, usually normal in the younger child, are decreased or lost within a few years; plantar responses are nonreactive or flexor. Choreoathetosis is common in most patients and may increase in severity. There are generally no sensory abnormalities of note, although older patients may have posterior column dysfunction. Affected patients appear rather apathetic, if not sad, but they usually have a pleasant disposition. Although dysarthria and drooling may convey the impression of dullness, mental subnormality is not a typical feature of the disease. There appears to be a “leveling off” of the acquisition of cognitive skills rather than a deterioration of mental function. Telangiectasias become apparent later than ataxia and are usually first observed between the ages124 of 3 and 5 years, although they have been observed at birth or as late as the second decade. They are generally first noted in the lateral bulbar conjunctiva but gradually involve its entirety (Fig. 11-10). Exposed areas of skin are also affected, including the nasal bridge, ear, and antecubital and popliteal spaces. Telangiectasias become more prominent following exposure to sun. Progeric changes of skin and hair are common and are manifested by sclerodermoid and atrophic areas of skin and patches of gray or white hair.
FIGURE 11-10 Characteristic conjunctival telangiectasias seen in
ataxia-telangiectasia. Chronic blepharitis is often present. Recurring sinopulmonary infections, affecting 90 percent of patients, usually result in chronic bronchitis or bronchiectasis. Hypogonadism is frequently present, and growth retardation is notable despite normal levels of serum growth hormone. The incidence of malignant neoplasms in patients with ataxia-telangiectasia has been reported as 10 to 15 percent. Most of these neoplasms are lymphomas, reticulum cell sarcomas, histiocytosarcomas, Hodgkin's disease, or leukemias; other associated neoplasms include brain tumors, gastric adenocarcinomas, ovarian dysgerminomas, gonadoblastomas, cystadenofibromas, uterine leiomyomas, thyroid adenomas, and basal cell carcinomas. Abnormalities of both humoral and cellular immunity have been demonstrated. Most patients have absent or low serum levels of immunoglobulin A (IgA) or IgG2; serum IgE and IgM 125 levels may also be decreased. Serum levels of IgM, IgG1, and IgG3 have also been
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reported as normal or elevated. The humoral deficits can result in impaired antibody response to some bacterial and viral antigens. The most consistent biochemical findings, 126–128 however, are elevated serum α-fetoprotein and carcinoembryonic antigen. Impaired cellular immunity is common in older children as a consequence of abnormally developed or absent thymus gland, tonsils, adenoids, and lymphoid tissue. Other cellular features of ataxia-telangiectasia include cytoskeletal abnormalities, decreased cell life in culture, an increased incidence of spontaneous or irradiation-induced chromosomal breakage and rearrangement, defective radiation checkpoints at G1, S, and G phases of the cell cycle, and abnormalities of signal transduction pathways. A large gene found on chromosome 11q22–23 has been associated with ataxia-telangiectasia, and many different mutations in patients with 129–132 the disease have been described. Pathological studies show notable cerebellar atrophy with particular involvement of Purkinje and granular cells, although basket cells may be affected as well. Neuronal degeneration of the dentate and olivary nuclei has been described, as has neuronal loss in the substantia nigra and nuclear changes in cells of the oculomotor complex and hypothalamus. In many cases of long duration, there is degeneration of the posterior columns of the spinal cord; degenerative changes of anterior horn cells have also been observed. Bizarre dystrophic changes and nucleomegaly of satellite cells in the dorsal root ganglia and Schwann cells of peripheral nerves have been described. No characteristic vascular pathology of the nervous system has been reported. Specific treatment is not available. Patients must therefore receive vigorous supportive care, with particular attention directed to recurrent infection and pulmonary function. Attempts to improve the immunological status of patients by plasma transfusion, administration of thymosin, and fetal thymus transplants have thus far not altered the course of the disease. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 12 Dermatological–Neurological Interactions KEVIN C. WANG • TIMOTHY G. BERGER •
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NEUROPATHIC PRURITUS Brachioradial Pruritus Notalgia Paresthetica Anogenital Pruritus Prurigo Nodularis ERYTHROMELALGIA NEUROPATHIC ROSACEA IDIOPATHIC SUDOMOTOR FAILURE
Many patients are referred to dermatologists for complaints that are primarily if not entirely neurological in nature. These include such symptoms as pruritus, pain, and paresthesias. Although dysesthesias, paresthesias, and anesthesia are common features of disorders such as postherpetic neuralgia and diabetic neuropathy (Chapter 21), they may occur as a component or as the sole symptom of various cutaneous syndromes. Characteristically, these sensations, especially pruritus, when induced by neurological disorders, cause patients to rub, scratch, or pick at their skin. A number of disease entities that are closely associated with involvement of pathways within the nervous system are discussed here. These diseases share common clinical features and have an underlying neurological basis. The term neurocutaneous dermatoses—defined as a dermatitis that arises secondary to disease located at any point along the circuitry of the nervous system—can be used to encompass these conditions. They can be further classified into three subgroups (Table 12-1): anatomical, neurovascular, and primary sudomotor, according to the underlying mechanism presumed to be responsible primarily for producing their clinical features. Click here to view this table.... NEUROPATHIC PRURITUS Persistent picking and scratching result in stereotypical changes that are easily recognized clinically. The presence of these characteristic features on physical examination should suggest an underlying neurological etiology for the cutaneous complaints. Lichenification and prurigo papules/nodules are two of the most common manifestations of the unrelenting cycle
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of itching and scratching. These lesions are often accompanied by skin thickening and dyspigmentation. “Lichenification” refers to hyperplasia of the skin in response to constant rubbing or scratching. The skin becomes leathery, and the normal lines in the skin become exaggerated, giving it a bark-like appearance referred to as “increased skin markings.” Lichenification occurs in patients with cutaneous conditions such as atopic dermatitis, where chronic itching causes repeated scratching and rubbing of the affected area. A related entity is lichen simplex chronicus, a condition in which one or more slightly erythematous, scaly, well-demarcated, lichenified, firm, rough plaques with exaggerated skin lines are noted (Fig. 12-1). Pigmentary changes (especially hyperpigmentation) are seen. As is the case with lichenification, rubbing plays a key role in formation of lichen simplex chronicus and is evidenced by linear scratch marks, erosions, and ulcerations from deeper scratching.
FIGURE 12-1 Lichen simplex chronicus, scrotum. Chronic persistent rubbing
and scratching resulting in a plaque of thickened and leathery skin. The lichenified plaque is often unilateral, well-circumscribed with marked accentuation of the skin creases. Pigmentary abnormalities are common, especially in patients with darker skin. Intractable localized or segmental pruritus without evidence of a primary dermatological process has been reported under various names, depending on the affected area of the body. Brachioradial pruritus, notalgia paresthetica, and anogenital pruritus are three of the more common conditions. This group of diseases is frequently a manifestation of injuries (often mechanical in nature) affecting the vertebral column or nerve roots, and the anatomical distribution of each disorder corresponds to the respective levels of injury—brachioradial pruritus to the cervical, notalgia paresthetica to the thoracic, and anogenital pruritus to the lumbosacral region. Knowledge and understanding of the anatomical pathogenesis enables the clinician to correctly diagnose and treat these disorders.
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Brachioradial Pruritus Brachioradial pruritus is an entity of localized pruritus characterized by severe, refractory, intractable itching and secondary skin changes such as lichenification. The skin overlying the proximal heads of the brachioradialis muscles is affected, usually in association with clinical1 evidence of chronic sun damage; occasionally, the pruritus extends across the upper back. Heyt demonstrated radiographic evidence of cervical vertebral osteoarthritis in four of five patients and hypothesized that nerve injury, resulting from either lesions of the cervical spine 2 or from mechanical compression by nearby structures, was of etiological importance. Goodkin and colleagues provided further support for the belief that cervical spine disease may be an important contributing factor, since 50 percent of their patients had radiologically 3 verified cervical spine disease that correlated with the location of pruritus in each patient. Cervical root compression as a mechanism was further supported by report of a spinal cord 4 tumor causing pruritus in the C5–C6 dermatomes. Of note, none of the published reports have included magnetic resonance images (MRIs) of the cervical spine, although this is the current definitive diagnostic means of determining nerve root impingement. On the basis of these observations, brachioradial pruritus is now thought to represent a form 5 of neuropathic pruritus related to cervical disease. However, sunlight can be an eliciting factor and compression of cervical nerve roots a predisposing factor in these patients. Wallengren and Sundler compared the cutaneous innervation in biopsies from the affected skin of patients with brachioradial pruritus to normal skin from age-matched controls. Cutaneous innervation was visualized by antibodies to protein gene product 9.5, a general neuronal marker; calcitonin gene-related peptide, a marker for thin sensory nerve fibers; and 6 the VR1-receptor, a marker for capsaicin-sensitive nerve fibers. They found that pruritus was seasonal in most of their patients, and histologically the biopsy specimens displayed changes similar to those seen in skin affected by ultraviolet light. The number of nerve fibers in diseased skin, as detected by the previously mentioned nerve markers, was significantly reduced compared with controls. Interestingly, fiber counts from some patients, who served as their own controls, normalized as they became symptom free. Wallengren and colleagues argue that spinal disease alone cannot explain the symptoms of brachioradial pruritus, on the basis of their observations of symptom-free periods interspersed with relapses. Familial occurrence has suggested the presence of a hereditary form of brachioradial pruritus, with 7 either autosomal-dominant or possibly X-linked inheritance. To relieve the burning and stinging quality of their itch, patients often apply ice packs to the affected 8arm. Since sunlight is a cofactor, sunscreen may be of partial benefit in some patients. The most effective treatments, however, are those directed at the neurological cause of the disease. Significant relief has been achieved from application of topical 9,10 10 capsaicin ; amitriptyline was effective in capsaicin-refractory cases. Other treatments reported—sometimes purely anecdotally—to be effective for brachioradial15pruritus include 11–13 14 resection of a16cervical rib. Cervical gabapentin, 2,15carbamazepine, and surgical 2 and cervical manipulation and acupuncture have also been reported as physiotherapy an effective treatment. Tait and colleagues described a group of patients who were treated with cervical spine manipulation and found that 71 percent reported resolution of symptoms following manipulative treatment, including all those with documented cervical spine disease, 14 as well as some with no previous history of neck symptoms.
Notalgia Paresthetica Notalgia paresthetica is usually a unilateral sensory neuropathy found mainly in older patients 17 characterized by infrascapular pruritus, burning pain, tenderness, or hyperalgesia ; other neurological symptoms such as numbness, tingling, and formication have been described as well. Its distribution is usually in that of the T2 through T6 dermatomes. There is often no evidence of an accompanying primary dermatological lesion, although pigmented patches 18 and frictional amyloidosis (macular amyloidosis; Fig. 12-2) may arise with rubbing. The fact that the posterior rami of these five thoracic roots traverse a 90-degree course through the multifidus spinae muscle may contribute to their increased susceptibility to mechanical 19 injury.
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FIGURE 12-2 Macular amyloid. A chronic, pruritic eruption of small brown macules
distributed in a rippled, symmetric fashion on the interscapular region of the back with nonuniform pigmentation resulting in a rippled, “salt-and-pepper” appearance. It is hypothesized to result from rubbing of dysesthetic areas of notalgia paresthetica. 20
Pathogenesis is thought to involve musculoskeletal compression and resultant spinal nerve impingement of the posterior primary rami of the aforementioned spinal nerves. Thus, Raison-Peyron and associates have presented evidence of dorsal arthrosis in spinal 18 radiographs of patients with notalgia paresthetica, and Savk and colleagues offered striking correlation of the localization of notalgia paresthetica with degenerative changes in the 21 spine. In both sets of patients, the observed structural abnormalities matched precisely the expected dermatomal localization of pruritus. Some hereditary cases have occurred, mainly in young patients, associated with multiple endocrine neoplasia type 2A (MEN 2A). The associated cutaneous lesions are hypothesized 22 to be secondary to pathology in the neural crest–derived dorsal sensory nerves. To date, treatments for notalgia paresthetica for which some efficacy has been claimed 23 24 paravertebral local anesthetic blocks, cervical epidural steroid include capsaicin, 25 26 anesthetic cream (2.5% lidocaine and 2.5% prilocaine), and injection, topical 18 physiotherapy. Most of these treatment modalities act either directly or indirectly on the nervous system, lending support to the theory of a neurological etiology.
Anogenital Pruritus Anogenital pruritus is a general term used to describe itching that is virtually always limited to a defined area—the perianal or genital skin, with few or no symptoms at other anatomical sites. Cutaneous manifestations are identical to those of lichen simplex chronicus elsewhere Attacks are characterized by paroxysms of violent itching. Nocturnal on the body (Fig. 12-1). 27 pruritus is common. Specific terms used to describe chronic itching in the anogenital region include pruritus ani, pruritus vulvae, and pruritus scroti. Usually pruritus is restricted to one anatomical region with limited migration to closely adjacent sites. For example, patients with scrotal itch have no or very limited perianal itch, and vice versa. These conditions are common and are often poorly managed. Anogenital itching may be a manifestation of preexisting pathology or an idiopathic, primary condition, in which case a more severe and 27–30 A thorough and careful search for specific anatomical persistent itch is experienced. etiologic factors should always be conducted, such as for hemorrhoids or anal/genital neoplasia. 28,31
In chronic Acute anogenital pruritus is usually caused by infections or contact dermatitis. pruritus, inflammatory dermatoses and rarely malignancies are found in a significant number of cases. In idiopathic anogenital pruritus, where no demonstrable cause can be identified, the skin findings are frequently entirely absent or limited to erythema, lichenification, and
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excoriations. Depression, anxiety disorder, and obsessive-compulsive traits must be 32,33 Recent studies have considered in patients with intractable pruritus resistant to therapy. speculated on a possible neuropathic origin for idiopathic anogenital pruritus, with a mechanism akin to that suggested for brachioradial pruritus and notalgia paresthetica. One study of a group of patients with “idiopathic” anogenital pruritus suggested such an 34 association. Patients with anogenital pruritus were observed to have lumbosacral radiculopathy, representing nerve or nerve root compression at the level of L4 to S2 vertebrae, as evidenced by degenerative changes of the lower spine by radiography. In addition, the location of the pruritus was 34 correlated with that of the neuropathic changes observed with electrodiagnostic studies. More definitive studies are clearly needed. Treatment of anogenital pruritus usually begins with elimination of apparent exacerbating factors such as irritants and potential sensitizers, as well as modification of cleansing and toilet habits. Short courses of high-potency topical steroids, with adjunctive sedating antihistamines, can bring moderate to complete relief and limit night-time symptoms by 27 cream (0.006%) is effective in some breaking the itch–scratch cycle. Dilute capsaicin 35 cases, mostly in the pruritus ani subgroup. In cases of neuropathic anogenital pruritus (i.e., those cases possibly attributable to lumbosacral radiculopathy), paravertebral injections of corticosteroids and lidocaine may alleviate pruritus and other associated cutaneous 34 symptoms. Psychotropic agents may be required to achieve adequate sedation. Selective serotonin reuptake inhibitors such as fluoxetine, paroxetine, sertraline, and citalopram36may be required in patients refractory to treatment or with underlying psychiatric disorders.
Prurigo Nodularis Prurigo nodularis is a chronic condition occurring mainly in adults. It is characterized by numerous excoriated firm nodules, the majority of which are situated symmetrically on the extremities (with a predilection for the anterior surfaces of limbs, trunk, and other 37–39 Individual lesions or nodules, which may vary from a few to easy-to-reach areas). hundreds, are firm, several millimeters to 2 cm in diameter, often in a linear arrangement with prominent excoriations, crusting, and postinflammatory hyper- and hypopigmentation as a result of repeated scratching (Fig. 12-3). The lesions evolve slowly over time. Severe itching is the hallmark of the disorder and is characteristically paroxysmal and usually confined to the lesions themselves.
FIGURE 12-3 Prurigo nodularis. Persistent picking and scratching, usually on
the extensor aspects of the limbs, upper trunk, and buttocks, result in formation of firm, pea-sized, dome-shaped nodules, often with an eroded surface with scale and crusts. The intervening skin may be normal, or it may show changes such as erythema, scales, excoriations, lichenification, postinflammatory pigmentary changes, or scars. The etiology is unknown, although multiple factors such as atopic dermatitis, hepatic dysfunction including hepatitis C, human immunodeficiency virus infection, lymphoproliferative diseases, renal failure, pregnancy, venous stasis, insect bites, and stress
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38,39,40–42
have been postulated as possible contributors.37,38 Some authors have suggested that whereas others believe that it represents prurigo nodularis is related to neuronal factors, an induced reaction to particular stimuli. There is evidence to suggest that the disorder is, at least at some level, a neural-mediated entity. For example, proliferation of peripheral nerves with some disorganization, axonal swelling, and axonal dystrophy as well43as newly formed nervous tissue resembling neuromas have been observed in the lesions. Nerve bundles from the lesions show increased immunoreactivity to neuropeptides such as substance P and 44,45 when compared to normal unaffected skin. It has calcitonin gene-related peptide (CGRP) been hypothesized that neuropeptides serve as mediators of cutaneous neurogenic inflammation and pruritus by liberating histamine through interactions with mast cells and 46 nerve growth factor (NGF) receptors. Harris and colleagues demonstrated an increase in the number of nerves in the papillary dermis (so-called “hypertrophy of dermal nerves”), advocating a pathogenic neurocutaneous component with NGF as a major contributor to the 47,48 Extreme pruritus in chronic lesions can presumably be related to the neurohyperplasia. increased number of dermal nerves. Prurigo nodularis is notoriously difficult to treat. Spontaneous regression is rare, and relapse 49 37 is common. Once the cycle of pruritus–excoriation–pruritus begins, it is difficult to stop. Topical or intralesional glucocorticoids are the initial treatment but are often ineffective. Anecdotal reports support the use of liquid nitrogen cryotherapy, presumably through its 50 damaging properties on the sensory nerves. 51–53
Topical capsaicin treatment has resulted in clearing of the lesions. The mechanism is thought to involve release and prevention of the reaccumulation of neuropeptides in the unmyelinated, polymodal C and small myelinated A-delta cutaneous nerves. Unfortunately, how capsaicin modulates the interaction between the peripheral nervous system and the proinflammatory cytokines at the molecular level remains unclear. Other treatments such as 54 55 56 topical vitamin D3, cyclosporine, and phototherapy have been demonstrated to relieve pruritus and lead to resolution of skin lesions in selected patients. There has been one clinical study and many reports on the use of thalidomide, a derivative of glutamic acid, for cases of prurigo nodularis refractory to conventional treatment. Most report resolution of the pruritus within 1 to 2 months and involution of the nodular lesions in several 57–60 The mechanism of action of thalidomide is still unclear61,62 but is believed to be months. —thus, patients are at through a direct destructive effect on the proliferated neural tissues increased risk of developing a dose-dependent neuropathy. The improvement of pruritus, however, may not be totally explained by nerve damage and may be attributed 59 to the numerous immunomodulatory and anti-inflammatory properties of thalidomide. Alternatively, clinical improvement may be secondary 49,63 to thalidomide's central sedative effects and consequent interruption of the that result in reduction in peripheral stimuli perception itch–scratch cycle. ERYTHROMELALGIA Erythromelalgia, also known as erythermalgia and acromelalgia, is an extraordinary pain syndrome first described by S. Weir Mitchell in 1878. It is a rare form of paroxysmal vasodilation characterized by episodes of severe localized burning pain affecting the feet (usually bilaterally and symmetrically) and, rarely, the hands, accompanied by striking redness and warmth of the skin, often precipitated by heat or activity and terminated only with cooling of the64affected extremity. The burning spells may last anywhere from a few minutes to several days. Two forms have been described. The primary form is either a sporadic or an 65 autosomal-dominantly inherited disorder. In these cases, symptoms begin in childhood. Secondary erythromelalgia is seen in association with an underlying disease process such as diabetes mellitus, hypertension, neurological disorders (myelitis, multiple sclerosis, and peripheral neuropathy), collagen-vascular diseases, use of certain drugs, and especially myeloproliferative disorders (polycythemia, thrombotic thrombocytopenic purpura, and 66 throm-bocythemia). Treatment with pharmacological agents and targeted neurological surgery have been found to be most effective in patients with secondary erythromelalgia, in which treatment of the 67 associated disorder generally results in remission. Symptoms in the primary group may be minimized by appropriate environmental control with cooling and avoidance of heat-producing situations that would raise skin temperature above a critical thermal threshold. Calcium-channel blockers and cyclosporine have been68,69 utilized as treatments but in some cases can actually exacerbate or induce the condition. The pathophysiology is poorly understood, but there is evidence that primary and familial
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erythromelalgia are secondary to disorders of peripheral small-fiber (C-fiber) neurotransmission. Layzer hypothesized that erythromelalgia is a disorder of hypersensitized polymodal C-fiber receptors in the skin, in which the threshold to heat activation is lowered 66 (from 36° to 32°C). The activated C-fibers then cause vasodilation through axonal reflexes, resulting in redness, heat, and swelling; cooling brings the nociceptors below the temperature activation threshold. Along the same lines, secondary erythromelalgia may occur as a result of injuries to C-fibers, either directly in cases of neuropathy or indirectly from humoral factors released by platelets or ischemic tissues. Davis and his group have provided further support for this mechanism by noting that a high proportion of their patients with erythromelalgia had severe postganglionic sudomotor impairment, as well as 70 evidence of peripheral, especially distal, denervation without generalized autonomic failure. Their neurological assessments included electromyography, nerve conduction studies, and autonomic reflex screening, all of which demonstrated a consistent relationship between erythromelalgia and small-fiber 70 neuropathy. The presence of voltage-gated sodium channels in sensory neurons may play a crucial role in several chronic painful neuropathies. Recently, several groups have demonstrated mutations in SCN9A (or Nav 1.7), a sodium channel that is selectively expressed within nociceptive dorsal root ganglion and71,72 sympathetic ganglion neurons, in families with autosomal-dominant primary erythromelalgia. In fact, erythromelalgia is perhaps the first inherited painful neuropathic disorder to be understood at a molecular level. Similar to the concept of modulating C-fiber receptor thresholds described previously, shifts in activation/deactivation as well as an enhanced response to small stimuli in the mutant sodium channels act to 72 Furthermore, the decrease the threshold for impulses in pain-sensing neurons. 73 74 observations that sympathetic ganglion block and epidural bupivacaine can bring effective symptomatic relief for secondary erythromelalgia support the role that region-specific ion-channel disturbances play in the disorder. Erythromelalgia may resemble post-traumatic painful neurological syndromes involving the somatosensory, sympathetic, and somatomotor systems such as reflex sympathetic dystrophy 75 (RSD) and causalgia (collectively classified as complex regional pain syndromes, or CRPS). Distinguishing among the three conditions can be difficult, since patients with these conditions may all have hot, swollen, and painful limbs. Erythromelalgia has also been reported to coexist with Raynaud's phenomenon, an interesting association given that one is 76 a problem of vasodilation and the other of vasoconstriction. Erythromelalgia may be primarily a neuropathy that results in vascular phenomena, or a vasculopathy with hypoxia that results in a similar neurological phenotype. The real pathophysiological mechanism is likely distinct in individual patients, as evidenced by therapeutic success that has been reported with medications used for both neuropathy (such as gabapentin, tricyclic antidepressants, and selective serotonin reuptake inhibitors) and vasculopathy (such as 67,77 beta-blockers and calcium-channel antagonists). NEUROPATHIC ROSACEA There is a clear subset of patients seen by both neurologists and dermatologists, whose main complaints are facial pain and dysesthesias. These patients often have a history of prominent facial flushing and blushing in response to various stimuli such as emotional stress, hot beverages, alcohol, spicy foods, exercise, heat, and sun exposure. They may also have erythematous papules and pustules. This cluster of features is most consistent with a diagnosis of rosacea but, when combined with the78pain and dysesthesias, a form of complex regional pain syndrome must also be considered. In addition, some patients may have concurrent erythromelalgia and Raynaud's disease, suggesting that the etiology is perhaps more complex. 79–81
Rosacea is primarily believed to be a result of abnormalities of the facial vasculature. Histopathological studies have demonstrated that all major symptoms (erythema, 82 telangiectasia, and inflammatory papules) are likely to be vascular in origin. The vasculature is likely to be hyper-responsive, secondary to an increased excitability of its modulation by the nervous system, to both internal and external stimuli, resulting in chronic vasodilatation. It is not unreasonable to presume that a hyperexcitable neuroregulatory mechanism plays a significant role in the flushing/blushing patient with facial pain and dysesthesias. This is 79,83,84 especially in supported by reports of an85association between rosacea and migraine, postmenopausal patients. A “migraine diathesis” should be considered by those taking care of these patients. Recognition of the underlying pathophysiology in these patients is a prerequisite for a mechanism-oriented therapeutic strategy. Treatment is difficult. In patients whose major complaints center around the flushing/blushing component of the disorder, a beta-blocker
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such as propranolol may be tried for symptomatic relief. In patients suffering from facial 87 pain and dysesthesias, neuroactive agents such as gabapentin may be effective. Surgical approaches can include laser ablation of the vessels, although care must be taken with the latter option as some patients have experienced worsening of their pain after laser procedures. IDIOPATHIC SUDOMOTOR FAILURE Hypohidrosis or anhidrosis is an acquired disorder of sweating characterized by a decrease in or complete loss of sweat 88 production in response to an appropriate thermal or pharmacological stimulus. It can be generalized or segmental. Symptoms may include heat intolerance, tingling pain, nausea, and palpitations. The condition can result from poral occlusion, absence of sweat glands, sweat gland dysfunction, or impaired autonomic function 89 (Chapter 8) found in certain neurological disorders. Hypohidrosis or anhidrosis due to impaired sweat glands can be observed in patients with90Sjögren's syndrome, progressive systemic sclerosis, and systemic lupus erythematosus. Hypohidrosis or anhidrosis due to impaired autonomic function has been associated with cases of congenital insensitivity to pain; central nervous system (CNS) disorders such as Parkinson's disease, multiple sclerosis, and Shy–Drager syndrome; and peripheral neuropathies including diabetes mellitus, amyloidosis, Guillain–Barré syndrome, Fabry's disease,91and Ross syndrome (a triad of segmental progressive anhidrosis, tonic pupils, and areflexia). Occasionally, no underlying cause can be92–94 found and the condition is then termed “acquired idiopathic generalized anhidrosis.” Patients with acquired idiopathic generalized anhidrosis, usually young adults who are otherwise healthy, present with the complaint of severe prickling pain and itch whenever they are warm enough to sweat—usually when their body temperature is raised by approximately 0.5°C. The sensation is intolerable, and patients are often unable to exercise or work. When patients are given a heat stress, they develop transient, fine, skin-colored papules resembling “goose bumps” centered around eccrine orifices. The cutaneous sensations appear with the skin lesions. Cooling immediately resolves the symptoms. The pathogenesis of acquired idiopathic generalized anhidrosis is still unclear but is probably heterogeneous. Findings from skin biopsies have been inconsistent, ranging from normal eccrine glands in some to atrophic or degenerated glands in others,91,94,95 with a few showing A decrease in the infiltrates of lymphocytes and mast cells around the duct or glands. number of nerve terminals and unmyelinated axons associated with histologically normal eccrine glands has led some to implicate degeneration of postganglionic sympathetic 95 cholinergic nerves as responsible for anhidrosis. Even though an association of acquired idiopathic generalized anhidrosis with cholinergic 91 urticaria has been documented in the literature, there are clear and distinct differences between the two diseases. Patients with cholinergic urticaria, believed to be produced by actions of acetylcholine on mast cells, often complain of itching wheals surrounded by areas of erythema that appear within minutes of exertion, with increased environmental 96 temperature, after emotional disturbances, or after ingestion of spicy foods, whereas patients with acquired idiopathic generalized anhidrosis do not report identifiable triggers except heat. In patients with cholinergic urticaria, systemic symptoms of flushing, 97,98 ; however, unlike those with acquired hypotension, faintness, or asthma may occur idiopathic generalized anhidrosis, patients with cholinergic urticaria are not anhidrotic and usually enjoy a refractory period with no lesions for up to 24 hours following a provoked attack. A useful way to avoid confusion between the two is to think of acquired idiopathic generalized anhidrosis as a neurologically mediated entity and cholinergic urticaria as a nerve-stimulated mast cell phenomenon. Treatment of acquired idiopathic generalized anhidrosis is limited, and nonresponders are not uncommon. Corticosteroids produce dramatic effects in some patients, although clinical studies are93,99 difficult to evaluate because adequate control subjects have not been It is likely that the effects of corticosteroids depend on the nature of the examined. 95 pathogenetic process or the disease stage.
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 13 Neurological Manifestations of Hematological Disorders G.A.B. DAVIES-JONES • JON D. SUSSMAN •
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ANEMIA Iron-Deficiency Anemia Vitamin B12 Deficiency Peripheral Neuropathy Myelopathy Encephalopathy Optic Neuropathy Disordered Eye Movements Extrapyramidal syndrome Infantile Vitamin B12 Deficiency Imerslund-Graesbeck Syndrome Folate Deficiency Sickle Cell Disease Thalassemia Hereditary Spherocytosis Paroxysmal Nocturnal Hemoglobinuria Cold Agglutinin Disease Cryoglobulinemia Kernicterus RARE NEUROLOGICAL SYNDROMES AND RED CELL ABNORMALITIES PROLIFERATIVE DISORDERS Leukemia Meningeal Leukemia Localized Leukemic Deposits Chloromas (Granulocytic Sarcoma) Intracranial Hemorrhage Cellular Hyperviscosity Infections Leukoencephalopathy and Other Encephalopathies Myelomatosis Spinal Myeloma Nerve Root Compression Cranial Myeloma
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Peripheral Neuropathy Neurological Effects of Metabolic Complications Neurological Effects of Immunological Complications Macroglobulinemia (Waldenström's Disease) Paraproteinemias Lymphoma Spinal Cord and Meningeal Involvement Intracranial Involvement Paraneoplastic Syndromes Other Neurological Complications Burkitt's Lymphoma Primary Intracerebral Lymphoma Intravascular Lymphoma Lymphomatoid Granulomatosis Polycythemia Cerebellar Hemangioblastoma Pseudopolycythemia Essential Thrombocythemia Myelofibrosis Eosinophilic Syndromes HEMORRHAGIC DISORDERS Hemophilia Von Willebrand's Disease Christmas Disease Other Clotting Factor Deficiencies Acquired Hemophilia Hemorrhagic Disease of the Newborn Thrombocytopenia Disorders of Platelet Function Disseminated Intravascular Coagulation Thrombotic Thrombocytopenic Purpura Hemolytic-Uremic Syndrome Gaucher's Disease COAGULATION DISORDERS Antiphospholipid Antibodies Hereditary Thrombophilia Antithrombin Deficiency Protein C Deficiency Protein S Deficiency Factor V Leiden (RQ506Q) Prothrombin G:A 20210 Mutation Hyperhomocysteinemia Factor VIII Interactions Between Inherited Thrombophilias Interactions Between Inherited and Acquired Risk Factors Thrombophilic Disorders and Arterial Thrombosis Patent Foramen Ovale
Hematological disorders can affect the central and peripheral nervous systems in a number of different ways, producing a wide range of neurological disturbances. Some of these neurological complications are well described, but others are less clearly defined. In the present chapter, neurological aspects of each of the main groups of hematological disorders are discussed. For brevity, a number of the older references have been deleted, but they can be found in earlier editions of this book. ANEMIA
Iron-Deficiency Anemia Nonspecific neurological symptoms of tiredness, fatigability, weakness, poor concentration, irritability, faintness, dizziness, tinnitus, and headache are commonly associated with anemia. Occasionally, more concrete neurological syndromes arise, and a number of case reports have drawn attention to the association of benign intracranial hypertension and cerebral 1,2 venous sinus thrombosis with iron-deficiency anemia. The benign intracranial hypertension 2 may resolve and recur with resolution and recurrence of the iron-deficiency anemia. In some patients with iron-deficiency anemia, thrombocytosis may be marked and may be so high as to suggest a myeloproliferative disorder. The increased platelet mass may be accompanied by signs and symptoms of cerebrovascular insufficiency, either as transient cerebral ischemic
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attacks (TIAs) or as cerebral infarction or amaurosis fugax. Profound anemia, particularly if associated with thrombocytopenia, may produce a retinopathy comprising papilledema, cotton-wool exudates, flame-shaped hemorrhages, retinal edema, and even retinal detachment. Blindness is a rare but long-recognized complication of massive hemorrhage; swelling of the optic discs is followed within a few weeks by optic atrophy. Focal neurological signs may arise from severe anemia in conjunction with severe cerebral atherosclerosis. Symptoms may resolve completely over hours as the hemoglobin is 3 increased. 4 Severe anemia may produce signs and symptoms that mimic Guillain–Barré syndrome. Transient erythroblastopenia of childhood has been noted to present with papilledema and 5 may be associated with iron-deficiency transient hemiparesis. Restless legs syndrome 6 anemia including frequent blood donation. Iron deficiency and a strong family 7history (present in 72%) are characteristic of childhood-onset restless legs syndrome.
Vitamin B12 Deficiency Vitamin B12 deficiency may result in lesions affecting the peripheral nerves, spinal cord, optic nerves, and brain. Addisonian pernicious anemia is an important cause of vitamin B12 deficiency, but the neurological complications may also result from vitamin B12 deficiency secondary to malabsorption syndromes, gastric and ileal resections, terminal ileal removal for 8 lower urinary tract reconstruction, blind loops, infestation with fish tapeworm, and dietary deficiency, particularly in vegans. It is essential to realize that all the neurological complications of vitamin B12 deficiency may occur with no appreciable alteration in the peripheral blood picture. There may be no anemia, and erythropoiesis may even be normoblastic. Lindenbaum and colleagues confirmed that neuropsychiatric disorders due to vitamin B12 deficiency occur commonly in the absence of anemia or macrocytosis and suggested that measurements of serum methylmalonic acid and total homocysteine both 9 before and after treatment are useful in the diagnosis of these disorders. Peripheral Neuropathy The frequency of peripheral neuropathy as a complication of vitamin B12 deficiency is difficult to determine accurately, since the sensory symptoms of peripheral neuropathy may be identical to those of vitamin B12 myelopathy. However, the findings of muscle wasting and absent reflexes confirm the presence of neuropathy. Electrophysiological studies indicate that the neuropathy is secondary to a dying-back type of axonal degeneration, and neuropathological studies have demonstrated the loss of large myelinated fibers in distal sensory nerves as well as axonal degeneration in teased-fiber preparations. Paresthesias and numbness appear first in the feet and legs, accompanied by loss of reflexes, superficial sensory impairment in a stocking distribution, and impairment of vibration sense. Later, there are similar sensory changes in the hands, together with wasting and weakness of the distal leg muscles. Myelopathy Demyelination followed by axonal degeneration seems to affect the most heavily myelinated fibers first, which may explain why lesions appear first in the posterior columns and later in the lateral columns. They tend first to appear at the mid-thoracic level. The term subacute combined degeneration is appropriate for describing this process in most cases because symptoms and signs usually progress over several weeks and months. However, progression may be rapid, resulting in severe clinical disability within a week or two; or it may be much more chronic, developing over a year or more. Sensory symptoms appear first in the feet, accompanied by early and severe impairment of proprioception and vibration sense. The ankle reflexes are usually absent, owing to the invariable concomitant peripheral neuropathy, but the knee reflexes become exaggerated sooner or later, and subsequently the plantar responses become extensor. Severe sensory ataxic spastic paraparesis may be virtually the sole manifestation of vitamin B12 myelopathy. Bladder symptoms of urinary urgency leading to incontinence occur later. Pseudoathetosis of the fingers, hands, or toes due to severe loss of joint position sense can be a rare but prominent feature. Encephalopathy
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The pathological changes in the brain are similar to those in the spinal cord. Multiple foci or diffuse areas of demyelination in the white matter occur with little evidence of glial cell proliferation or axonal degeneration. Changes appear most marked in the corpus callosum and in the frontal and parietal white matter. A variety of symptoms occur, consisting of disorders of mood, mental slowing, poor memory, confusion, agitation, delusions, visual and auditory hallucinations, aggression, dysphasia, and incontinence. Shorvon and associates assessed the neuropsychiatric state of 50 patients with megaloblastosis due to vitamin B12 deficiency and that of 34 patients due to folate deficiency 10 presenting to hematologists or general physicians. One third of each group had no neuropsychiatric complications. Peripheral neuropathy was the most common complication of vitamin B12 deficiency (40%). Eight patients (16%) had evidence of subacute combined degeneration of the cord, and one (2%) had optic atrophy. Organic mental change of unspecified nature occurred in 26 percent, and affective disorders in 20 percent. Response to vitamin B12 therapy is variable. Healton and associates confirmed that all 11 patients respond to some extent to treatment, and recovery was complete in virtually half. The severity score was reduced by 50 percent in 91 percent of instances. Residual long-term moderate or severe neurological disabilities were observed in 6.3 percent. The degree of neurological disability remaining after treatment was related to two factors—the nature of the neurological disability and the duration of symptoms before treatment. Optic Neuropathy Optic neuropathy due to vitamin B12 deficiency is rare. It is reputedly more common in men. It may precede, coincide, or follow the anemia or the myelopathy. The characteristic visual abnormality is a centrocecal scotoma, usually appearing earlier to red than to white, which may be associated with constriction of the periphery of the visual field leading to optic atrophy. With early and adequate treatment, recovery may be complete. Disordered Eye Movements 12
13
14
Downbeat nystagmus, paralysis of upward gaze, and internuclear ophthalmoplegia been attributed to vitamin B12 deficiency and have responded to vitamin B12 therapy.
have
Extrapyramidal syndrome Kumar described the rapid onset of a typical parkinsonian syndrome over 10 days in a man found to have vitamin B12 deficiency that showed a dramatic response to parenteral vitamin 15 B12. At 5-year follow-up there were no residual neurological signs. Infantile Vitamin B12 Deficiency Infantile vitamin B12 deficiency may result from maternal vitamin B12 deficiency causing 16 encephalopathy, epilepsy, and microcephaly. Imerslund-Graesbeck Syndrome Vitamin B12 malabsorption in the ileum has been suggested to be the underlying cause of this syndrome, which consists of megaloblastic anemia, proteinuria, and multiple neurological abnormalities. A young Saudi child with spasticity, truncal ataxia, cerebral atrophy, 17 megaloblastic anemia, and proteinuria completely recovered following vitamin B12 therapy.
Folate Deficiency In the study of Shorvon and colleagues previously mentioned, affective disorders (mostly depression) and organic mental change were the most common neuropsychiatric 10 complications of folate deficiency. Peripheral neuropathy was seen in a few patients, but there was no instance of optic atrophy or myelopathy. Subacute combined degeneration of the cord and optic atrophy occurred only in the patients with vitamin B12 deficiency. However, diet-induced folic acid deficiency with subacute combined degeneration 18 of the spinal cord that improved significantly after treatment with folic acid has been recorded. Mental and physical retardation, hypotonia, cerebral atrophy, seizures, ataxia, and athetoid movements are associated with congenital folate malabsorption; calcification of the basal
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ganglia has also been reported. Allen and colleagues have associated the Kearns–Sayre syndrome—progressive external ophthalmoplegia, conduction heart block, atypical pigmentary degeneration of the retina, calcification of the basal ganglia, white matter hypodensities on cranial computed tomography (CT), and “ragged red fiber” myopathy—with 19 low cerebrospinal fluid (CSF) folate levels.
Sickle Cell Disease Most if not all of the clinicopathological complications of sickle cell anemia (Hb SS) or of sickle C disease (Hb SC) relate to the formation of sickle cells; these cells form because of the insolubility of deoxygenated hemoglobin S polymers, and they produce vascular occlusion by adhering to various receptors on the vascular endothelium, producing aggregates and thrombotic vessel occlusion. The neurological complications also result from a point mutation 20 that causes vasculopathy of both large and small vessels. In circumstances of severe hypoxemia, even patients with sickle cell trait (Hb SA) may develop vaso-occlusive disease. Factors exacerbating the sickling phenomenon include hypoxia, dehydration, acidosis, and infection. Children with sickle cell disease have a reduced level of the majority of endothelial coagulation inhibitors, which further enhances the 21 adhesive interactions between sickle cells with injured cell membranes and endothelial cells. As sickling occurs in the venous circulation, central venous Po2, not arterial Po2, is the critical factor. There is a trace of sickling in homozygous disease even when hemoglobin is 100 percent saturated with oxygen, whereas at 65 and 50 percent oxygen saturation there is 75 and 100 percent sickling, respectively. In heterozygous disease with 40 percent hemoglobin S (Hb S), sickling starts at 40 percent saturation. The critical Po2 is 30 mmHg for sickle cell disease and 20 to 30 mmHg for sickle cell trait. In the presence of circulatory stasis or reduced cardiac output, oxygen extraction may be so high that venous Po2 is reduced to dangerously low values despite normal arterial oxygen tension. In sickle cell trait, the severity of sickling depends on the actual amount of Hb S rather than the proportions of hemoglobin A (Hb A) and Hb S. The percentage of Hb S in sickle cell trait can vary from 25 to 45 percent. In vitro studies suggest that in carriers who have a high concentration of Hb S, the risk of 22 sickling is not much less than in patients with sickle cell disease. The incidence of neurological manifestations in patients with sickle cell disease approximates 25 percent, with cerebral infarction and hemiparesis being most common. Cerebral infarction tends to occur in young children, and transfusion greatly reduces the risk of a first stroke in affected children 23 who have abnormal high-velocity flow on transcranial Doppler ultrasonography. Intracranial hemorrhage is much rarer; it tends to occur more often in adults and is more commonly subarachnoid. In adults, the subarachnoid hemorrhage is usually associated with ruptured aneurysms, which frequently are multiple and commonly involve the posterior circulation. In children, it tends to be primary and possibly related to fibrotic endarteritis and fragmentation of the internal elastic lamina of the larger proximal 24 intracranial arteries. Stenosis of large extracranial or intracranial vessels may occur secondary to a vasculopathy and fibrous proliferation of the intima. Other neurological manifestations of sickle cell disease include aphasia, cranial 25 26 neuropathies, radiculopathy, ischemic mononeuropathy, radiculomyelopathy from vertebral crushing as a result of successive bone infarction, paraplegia, spinal cord infarction, hypopituitarism, ischemic optic neuropathy, optic atrophy, transient ischemic attacks, and seizures. Prengler and colleagues suggested that vasculopathy and 27 focal hypoperfusion cord infarction might be relevant to the seizures associated with sickle cell disease. Spinal 28 Subcortical is rare, and there has been only one autopsy report of this complication. 29,30 as has cerebral venous cerebral infarction31has also been described in sickle cell trait, sinus thrombosis. In contrast to homozygous sickle cell disease, cerebrovascular complications are relatively uncommon in Hb SC disease. The association of proliferative retinopathy with Hb SC disease is well known. Fabian and Peters found a significant increase in retinopathy, stupor, coma, 32 and seizures in patients with Hb SC disease compared with matched control subjects. Recurrent transient impairment of vision due to occlusion of major retinal vessels is an unusual manifestation of Hb SS disease. It is important to remember that patients with sickle cell disease may develop neurological disorders unrelated to their hemoglobinopathy and so should be investigated to exclude unrelated but treatable conditions. This is illustrated by the patient of Caprioli and colleagues who developed acute monocular visual loss with no retinal or vitreous abnormalities but who 33 had a large aneurysm of the anterior communicating artery compressing the optic nerve.
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Thalassemia Chronic anemias such as thalassemia are associated with extramedullary hematopoiesis, usually in the liver, spleen, or lymph nodes. There have been a few reports of extramedullary hematopoiesis in thalassemia producing spinal cord compression and paraparesis, the hematopoietic tissue presumably arising from embryonal rests in the extradural areolar tissue of mesodermal origin. Most commonly the lesion is situated in the middle to lower thoracic region of the spinal canal, and surgical decompression plus radiotherapy is curative. Treatment with corticosteroids or repeated blood transfusions together 34 with local radiotherapy to the tumor without surgical decompression has also been successful. Transfusion alone to maintain the hemoglobin level above 12.5 g/dl has been reported to relieve the signs of spinal 35 cord compression, with near-complete resolution of the extradural hematopoietic suprasellar extramedullary hematopoiesis in mass. Visual failure secondary to 36 β-thalassemia has been described. In one study, 20 percent of β-thalassemic patients were found to have clinical and 37 electrophysiological findings of a predominantly motor sensorimotor neuropathy. Severe forms of β-thalassemia are associated with an increased risk of cerebral thrombosis as well as portal and deep vein thrombosis and pulmonary 38 embolism.
Hereditary Spherocytosis There has been an isolated report of two patients with hereditary spherocytosis associated 39 with a mild spastic paraparesis for which no cause was found. Although it may have been an entirely fortuitous association, the authors deliberated about a possible common mechanism for the neurological and red blood cell abnormalities. This association has not been described since.
Paroxysmal Nocturnal Hemoglobinuria Paroxysmal nocturnal hemoglobinuria is a rare acquired hematopoietic stem-cell disorder characterized by deficiency of glycosyl phosphatidylinositol (GPI)–anchored protein. This results in deficiency in the binding of several protective red cell membrane proteins and leads to hypersensitivity to complement and hemolysis. It may occur de novo or in association with marrow hypoplasia. It is characterized by intravascular hemolysis and manifested by episodes of hemoglobinuria and venous thrombosis. Increased intravascular destruction of red cells occurs at night, which results in hemoglobinuria seen when the first urine is passed in the morning. One of the commonest complications of this disorder is large-vessel thrombosis, and its occurrence in the brain and portal system accounts for the death of 50 percent of patients. The thrombotic tendency is thought to arise from deficiency in GPI-linked proteins in platelets. Although thrombosis has been reported in most organs, it has not been detected in the vessels of the spinal cord; most of the neurological complications of paroxysmal nocturnal hemoglobinuria relate to thrombosis of intracranial vessels. Cerebral 40 arterial and venous thrombosis occurs, resulting in hemorrhagic infarction. During the crises of paroxysmal nocturnal hemoglobinuria, an occasional patient suffers TIAs that have been attributed to the hypercoagulable state induced when excess thromboplastin is released from lysing red blood cells. Increased sensitivity of the red cells to lysis by complement stimulates platelet aggregation and hypercoagulability. In the study of Hillmen and associates, a neurological cause of death was found in 10 percent of patients, including cerebral venous 41 thrombosis, subarachnoid hemorrhage, and intracerebral hemorrhage.
Cold Agglutinin Disease Cold agglutinin disease is usually associated with IgM antibodies (rarely IgG and IgA cold-reactive autoantibodies) directed against erythrocytes with binding activity that increases as the temperature approaches 0°C. Characteristically, the disease presents as anemia and a cold-induced rash. A case is reported of a man with purpura, anemia, cold agglutinins, and a sensory and autonomic polyneuropathy that resolved on treatment with corticosteroids and 42 plasma exchange.
Cryoglobulinemia Cryoglobulins are serum proteins or protein complexes that undergo reversible precipitation at low temperatures. Three main types of cryoglobulin are recognized. Type I consists of monoclonal proteins seen in association with multiple myeloma, Waldenström's macroglobulinemia, and other lymphoproliferative disorders. Type II consists of mixed immunoglobulin complexes in which the monoclonal antibody has specificity for polyclonal
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IgG, and is described in association with lymphoproliferative diseases, autoimmune disorders, and hepatitis. Type III cryoglobulin is composed of polyclonal immunoglobulin and is found in infections and autoimmune disorders. Neurological complications are not unusual, with peripheral symmetric sensorimotor axonal or demyelinating polyneuropathy being the most common finding. More rarely, acute mononeuritis or cerebral ischemia or vasculitis may occur.
Kernicterus With the virtual elimination of hemolytic disease of the newborn, kernicterus is now uncommon in developed countries. It may be produced by any hemolytic process of sufficient severity in neonates and in premature infants by “physiological jaundice.” Whenever the serum unconjugated bilirubin level exceeds 20 mg/dl during the first few weeks of life, kernicterus may occur. Unconjugated bilirubin is highly lipid soluble; it enters the brain and binds to neurons, resulting in neuronal necrosis particularly in the basal ganglia and cerebellum. The neurological features include opisthotonos, convulsions, rigidity, involuntary movements, athetosis, deafness, nystagmus, and psychotic behavior. RARE NEUROLOGICAL SYNDROMES AND RED CELL ABNORMALITIES Hallervorden–Spatz disease of dystonia, dementia, and spasticity in childhood43,44 or adolescence has been associated with acanthocytosis in occasional patients. Bassen–Kornzweig disease (neuroacanthocytosis with abetalipoproteinemia) is a well-defined, recessively inherited syndrome characterized by acanthocytosis, retinitis pigmentosa, increasing cerebellar ataxia, peripheral neuropathy, steatorrhea, and complete or almost complete lack of serum β-lipoproteins, with onset during childhood. Treatment with vitamins A and E as early as possible is helpful. Chorea-amyotrophy-acanthocytosis is another rare neurological syndrome associated with peripheral blood acanthocytosis. The neurological features consist of adult-onset progressive choreiform movements of the limbs, lip and tongue biting, orofacial dyskinesia, high serum creatine kinase levels, peripheral neuropathy with amyotrophy, and normal serum 45,46 This neurological lipoproteins. These patients may also develop features of parkinsonism. syndrome without acanthocytosis but with47chronic spherocytic hemolytic anemia was seen in two brothers by Spencer and associates. At autopsy the striatum was atrophic, with iron deposition and spheroid bodies. There was degeneration of the substantia nigra and anterior horn cells of the spinal cord. These features provide an anatomical basis for the parkinsonism and motor neuron disease associated with chorea-amyotrophy-acanthocytosis. Hardie and associates reviewed 19 cases of neuroacanthocytosis in which progressive chorea, dystonia, akinetic rigidity, orofaciolingual movements, pseudobulbar dysphagia and 48 dysarthria, and lip and tongue biting occurred. Cognitive impairment and organic personality changes occurred in more than half of the cases, more than one third of patients had seizures, and frontal subcortical-type dementia was also described. Depressed or absent tendon reflexes occurred in 13, and axonal neuropathy was often found electrophysiologically. The investigators emphasized that mild acanthocytosis can easily be overlooked and that scanning electron microscopy may be helpful. A benign X-linked myopathy with acanthocytosis has also been described and is referred to as McLeod's syndrome. A progressive spinocerebellar syndrome and a sideroblastic anemia segregating together in 49 an X-linked recessive fashion was described by Pagon and co-workers. Cerebellar ataxia and dysarthria develop at an early childhood, and there is motor delay. The neurological signs 50 tend to be stable until the 40s, when slow progression may occur. A case of primary acquired sideroblastic anemia with a predominantly motor polyneuropathy responsive to 51 vitamin B6 has been documented. An autosomal-recessive axonal hereditary sensory-motor 52 neuropathy has ben associated with sideroblastic anemia. Sideroblastic anemia and mitochondrial myopathy is a rare autosomal recessive disorder of oxidative phosphorylation 53 and iron metabolism; the gene responsible maps to chromosome 12q24.33. Triosephosphate isomerase deficiency is a rare disorder characterized by chronic hemolytic anemia, progressive neurological dysfunction, and usually an increased susceptibility to infection. The neurological features consist of a dystonic-dyskinetic syndrome; gross intention tremor and rhythmical, jerky movements of the proximal parts of the limbs; generalized weakness; amyotrophy and hypotonia of the trunk and limbs; and sometimes pyramidal signs. There are electromyo-graphic (EMG) signs of denervation with normal nerve
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conduction velocities, suggestive of anterior horn cell impairment. It has been suggested that low triosephosphate isomerase activity leads to a metabolic block in the glycolytic 55 pathway and hence to an impairment of the cellular energy supply. PROLIFERATIVE DISORDERS
Leukemia The increased frequency of central nervous system (CNS) involvement in leukemia is related to the increased survival of patients. It is estimated to occur in between 2 and 4 percent of leukemic patients per month. CNS involvement is a poor prognostic sign if it is evident on presentation and even more so if it develops later. Involvement of the CNS in leukemia is often due to infiltration with leukemic cells, but neurological complications may occur as the result of hemorrhage, infection, drug- and radiation-induced neurotoxicity, electrolyte disturbance, and impairment of cerebral circulation from leukostasis. Leukemic cells enter the nervous system by direct seeding of circulating leukemic cells, lymphatic spread, or direct invasion from overlying meninges, or from cells with hematopoietic potential lying in relationship to arachnoidal vessels. Meningeal Leukemia The most common presenting symptoms of meningeal leukemia are headaches, nausea, and vomiting, sometimes associated with lethargy and irritability, drowsiness, coma, convulsions, and neck stiffness. Diffuse meningeal infiltration impairs the circulation of CSF and can result in obstructive or communicating hydrocephalus. Papilledema is the commonest sign, with separation of the skull sutures in young children. The leukemic deposits may compress or infiltrate the cranial nerves or spinal nerve roots and spread between the nerve fibers. The second, third, sixth, seventh, and eighth cranial nerves are the most commonly affected, but the lower cranial nerves are occasionally involved. Oculomotor palsy with pupillary sparing 56 has been described secondary to chronic lymphocytic leukemic infiltration of the meninges. The diagnosis of meningeal leukemia is confirmed by finding leukemic cells in the CSF. Increased CSF leukocyte counts are found in approximately 90 percent of cases, and cytocentrifuge preparations enable both blast cells and mitotic figures to be identified. The CSF pressure is usually elevated, but in approximately 10 percent of cases with unequivocal clinical evidence of meningeal involvement, the CSF is normal in every respect. Reduced CSF glucose and elevated protein concentrations are frequently seen but are unreliable characteristics of meningeal disease. Although meningeal leukemia is predominantly associated with acute lymphocytic leukemia and occasionally with acute nonlymphocytic leukemia, meningeal leukemia as the initial 57 presentation of B-cell chronic lymphocytic leukemia has been described. In their review of chronic lymphocytic leukemia with neurological complications, Cramer and co-workers pointed out that invasion of the CNS may produce meningitis 58 with cranial nerve palsies, confusional states, optic neuropathy, and cerebellar dysfunction. Symptomatic involvement of the CNS was comparatively rare, although infiltration of the brain and spinal cord was common at autopsy. By contrast, clinical involvement of the peripheral nervous system, including the cranial nerves, was more common. Acute myelomonocytic leukemia accompanied by pericentric inversion of chromosome 16 is a unique subtype associated with a high incidence of CNS involvement in the form of leptomeningeal deposits and granulocytic sarcoma (chloroma). Localized Leukemic Deposits Leukemic deposits may involve any part of the CNS. The symptoms and signs are therefore numerous and varied, and they depend on the extent of infiltration and the area of localization. The complete range of cranial nerve palsies has been described, as has hemiplegia, aphasia, hemianopia, ataxia, convulsions, and cortical blindness. Blindness may 59 and visual impairment from also occur from leukemic infiltration of the optic nerve head, 60 with visual blurring may be the retinal infiltration. Bilateral serous macular detachment 61 presenting symptom of acute lymphoblastic leukemia. One of the authors (GDJ) has seen
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three patients with mental nerve involvement that produced sensory impairment of the lower lip and painless traumatic ulceration of the buccal mucosa, and three further cases of the numb chin syndrome as an initial symptom of acute lymphatic leukemia have been 62 reported. Hypothalamic and pituitary dysfunction are not uncommon, resulting in the hypothalamic obesity–somnolence syndrome, with excessive eating, headache, weight gain, somnolence, vomiting, and a change of behavior, usually to a more aggressive pattern. Histological examination of the hypothalamus in these cases shows diffuse infiltration by leukemic cells. This syndrome may also be associated with hydrocephalus, the hypothalamic pituitary dysfunction arising from the pressure effects of a distended third ventricle. Diabetes insipidus may occur alone or as part of the hypothalamic obesity syndrome. Clinically significant spinal cord involvement is unusual in leukemia, in contrast to intracranial, especially meningeal, involvement. The clinical syndromes relating to spinal cord involvement range from a complete cord syndrome (transverse lesion of the spinal cord with paraplegia, sensory loss below the involved segment, and urinary retention) to partial cord syndromes: anterior or posterior cord syndromes or the Brown-Séquard syndrome. Back pain, frequently with root involvement, and progressive paraparesis or quadriparesis over days or weeks is another manifestation of progressive spinal cord compression from extradural deposits, usually in the thoracic area. Cervical cord, cauda equina, and conus medullaris compression occur rarely. In their review of spinal cord leukemia, Petursson and Boggs found acute myeloid leukemia to be the most common type, followed by acute lymphoblastic and chronic 63 myeloid leukemia, with only one instance of chronic lymphatic leukemia. Cord syndromes arise from compression by extradural deposits; direct infiltration of the spinal cord and nerve roots; vascular occlusion by thrombus, leukemic cells, or a mixture of leukemic cells and thrombus; or hemorrhage. Exceptionally, an acute paraneoplastic necrotizing myelopathy may occur. Peripheral neuropathy complicating leukemia is rare. It usually results from diffuse leukemic infiltration, hemorrhage, or infarction, and it manifests by either individual or multiple nerve involvement. Proven examples of paraneoplastic neuropathy are exceptionally uncommon. Adult T-cell leukemia found among subjects born in Kyushu, Japan, may be complicated by a 64 peripheral neuropathy. Chloromas (Granulocytic Sarcoma) Chloromas are solid tumors of nonlymphatic leukemia. Occasionally, extramedullary chloromas occur in patients without any evidence of leukemia, which these tumors may precede by many months. Histologically, they are composed of poorly differentiated blast cells, almost invariably myeloblasts but occasionally monoblasts. Macroscopically, they have a distinctive green color that fades on exposure to light. Most occur subperiosteally, usually in the cranial and facial bones, especially the paranasal sinuses, mastoid air cells, or orbits; they are usually attached to the dura mater. More common in children than adults, they may present with ophthalmoplegia and exophthalmos, if orbital in origin, or with facial palsy, if they arise from the mastoid air cells. As a result of dural involvement, they may produce headaches, nausea, vomiting, papilledema, hemiplegia, or multiple cranial nerve palsies. They rarely invade cerebral tissue. Chloromas associated with the spinal dura mater result in spinal cord compression. Decompression together with radiotherapy or65chemotherapy produces resolution of the paraplegia and disappearance of the tumor. Chloromas are radiosensitive. Intracranial Hemorrhage Intracranial hemorrhage usually occurs at presentation or during relapse when the leukemic patient is unresponsive to chemotherapy. Thrombocytopenia is an almost constant concomitant of intracranial hemorrhage. It is possible, at least in some cases, that it is the result of platelet consumption due to disseminated intravascular coagulation (DIC) rather than to reduced platelet production by the bone marrow secondary to leukemic infiltration. Platelet production may also be impaired as a result of myelotoxic effects of the chemotherapy. In the absence of any other abnormality of coagulation, intracranial hemorrhage is unusual if the 3 platelet count is greater than 20,000/mm . Bleeding in the CNS is usually multifocal, affecting the meninges as well as the brain or spinal cord. Characteristically, the hemorrhages vary in size from multiple petechial hemorrhages to large, confluent ones. DIC is a prominent feature of promyelocytic leukemia. In other forms of leukemia, DIC is particularly marked in patients with high peripheral white cell counts, and it appears soon after the beginning of chemotherapy, presumably occurring because tissue thromboplastins are released from
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destroyed leukocytes. The widespread distribution of hemorrhage in acute leukemia usually results in deep coma from the outset, rapidly progressing to death. If the bleeding is localized and not multifocal, the resultant syndromes depend on the part of the neuraxis involved. The cerebral hemispheres are most frequently implicated, particularly the white matter. Both acute and chronic subdural hematoma may occur; and cisternal, cervical, or lumbar puncture in a thrombocytopenic patient with acute leukemia may cause a spinal subdural hematoma and spinal cord or cauda equina compression. Cellular Hyperviscosity The hyperviscosity syndrome embraces a symptom complex of neurological dysfunction, visual disturbances, and a hemorrhagic tendency. Marked elevation of the white cell count may produce a significant increase in whole blood viscosity. All types of leukemia, acute or chronic, may produce this syndrome, but neurological symptoms may occur more readily at lower leukocyte counts in patients with myeloid leukemia than in patients with lymphocytic leukemia. This finding is probably a reflection of the larger cell size in the myelogenous leukemias. The signs and symptoms of cellular hyperviscosity are varied and include auditory and visual disturbances, headache, ataxia, profound lethargy, somnolence, impairment of consciousness, and TIAs (Fig. 13-1). It is important to recognize the possibility of this 9 syndrome in patients with massively elevated white cell counts (in excess of 200 × 10 /L), since treatment with leuka-pheresis may abolish the symptoms. It is important also to remember that blood transfusions may be hazardous in patients with high leukocyte counts because the additional red blood cells may further elevate the blood viscosity to clinically significant levels, sufficient to produce coma and even death. Hyperleukocytosis in chronic 66 myeloid leukemia may also result in deafness.
FIGURE 13-1 Cellular hyperviscosity in leukemia. Virtually complete occlusion of
cortical vessel with leukemic cells. (Hematoxylin and eosin. Original magnification 504×.) (From Davies-Jones GAB, Preston FE, Timperley WR: Neurological Complications in Clinical Haematology. Blackwell Scientific Publications, Oxford, UK, 1980, with permission.) Infections
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In all leukemias, but particularly in the lymphoblastic leukemia of childhood, viruses (especially mumps, measles, and varicella) are the most common infective organisms of the CNS. Bacterial and fungal infections, especially aspergillosis, also occur. The increased incidence of involvement of the CNS with rare organisms or organisms that are normally nonpathogenic is contributed to by widespread use of corticosteroids, +chemotherapy, and broad-spectrum antibiotics. Autoimmune myositis with extensive CD8 T-cell infiltrates without any evidence of microbial infection has been described in association with large 67 granular leukocytic leukemia. Leukoencephalopathy and Other Encephalopathies Progressive multifocal leukoencephalopathy may complicate a variety of chronic diseases, including leukemias, lymphomas, carcinomas, sarcoidosis, and acquired immunodeficiency syndrome (AIDS) (Chapter 45). It is a progressive demyelinating infection caused by the ubiquitous, usually nonpathogenic JC virus in immunocompromised patients. Lysis of oligodendrocytes causes foci of myelin breakdown, which coalesce to form large areas of demyelination. Progressive disturbance in mental status, motor function, vision, and coordination results, as may focal sensory deficits. It is generally rapidly fatal, but very rarely spontaneous remission has occurred, and it may respond to treatment with cytarabine and interferon-α. Another disseminated leukoencephalopathy appears in patients with acute lymphoblastic leukemia treated with cranial irradiation and intrathecal methotrexate or in those treated with craniospinal irradiation followed by intravenous methotrexate. High-dose intravenous methotrexate produces an encephalopathy in less than 2 percent of instances; with either cranial irradiation or intrathecal methotrexate, encephalopathy develops in less than 1 percent of children. After combined intravenous methotrexate and cranial irradiation or intrathecal methotrexate and cranial68irradiation, however, the incidence increases to 15 percent and 5 percent, respectively. Pathologically, the leukoencephalopathy is characterized by demyelination, axonal degeneration, gliosis, coagulation necrosis with or without fibrinoid vascular change, mineralizing microangiopathy, and calcification. The periventricular white matter seems to be preferentially involved, but the lesions may occur anywhere in the white matter of the brain and spinal cord. The clinical manifestations of this form of encephalopathy may be delayed until several months after treatment is finished. The symptoms and signs may be varied and diffuse, reflecting the disseminated neuropathological process. Clinical features include irritability, agitation, confusion, drowsiness, ataxia, dementia, hemiplegia, quadriplegia, aphasia, and hemianopia. Cranial irradiation may produce signs of mild encephalopathy within hours of the initial dose. This usually results in somnolence but may be associated with signs of increased intracranial pressure, cranial nerve palsies, convulsions, ataxia, signs of cerebral herniation, coma, and death, especially if the patient has been given one or more injections of intrathecal chemotherapy. Cranial irradiation alone may also produce a “somnolence syndrome,” which generally occurs several weeks after treatment. Leukoencephalopathy following radiotherapy and intrathecal methotrexate may result in learning difficulties, cognitive dysfunction, and seizures in long-term survivors of childhood leukemia. Brouwers and associates showed that leukoencephalopathic patients with CT scan abnormalities of any type—calcification and cerebral atrophy—exhibited poor memory (more so for long-term retention than immediate recall) and difficulty in word-finding as compared 69 with patients who had normal CT scans. Patients with CT calcification showed greater deficits than those with cortical atrophy. Green and colleagues studied 17 adult patients with acute lymphoblastic leukemia, assessing them by neurological examination, electroencephalography (EEG), auditory evoked 70 potentials, CT scans, and magnetic resonance imaging (MRI). They concluded that there was little evidence of major CNS sequelae to the prophylactic use of cranial irradiation and intrathecal methotrexate in adults. Only minor abnormalities were found in the neurophysiological tests, psychometry, and scans in a few of the patients. Relling and associates, however, have emphasized the high incidence of malignant brainstem tumors following prophylactic craniospinal irradiation and antimetabolite treatment of acute lymphatic 71 leukemia. They stated that prophylactic radiotherapy should be given only to patients with a high risk of CNS relapse. Reddick and co-workers found that smaller white matter volumes were associated with larger deficits in attention and learning among long-term survivors of acute lymphoblastic leukemia of childhood. Those who had received chemotherapy alone had significantly larger volumes of white matter than those who had also received cranial irradiation, but their volumes
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remained significantly smaller than those in the control group.
Acute encephalopathy during induction therapy for acute lymphoblastic 73 leukemia occurred in 21 children in the Medical Research Council UKALL VIII study and trial. This was attributed to drug toxicity, probably from l-asparaginase, although vincristine may also have contributed. Convulsions (sometimes focal) and coma were the major features.
Myelomatosis Myelomatosis is the best-recognized expression of the plasma cell dyscrasias. These include Waldenström's macroglobulinemia, monoclonal gammopathy of unknown significance (MGUS), paraproteinemias, plasmacytoma, and plasma cell leukemia. These conditions commonly involve the nervous system. The major neurological complications can be placed into four categories: (1) compression of spinal cord, cauda equina, or solitary nerve roots; (2) cranial nerve involvement; (3) intracranial myeloma; and (4) peripheral neuropathy. Pure meningeal myeloma is rare (Fig. 13-2) and presents with confusion, altered consciousness, 74 and cranial nerve palsies. In 20 percent of cases, it is associated with plasma cell leukemia.
FIGURE 13-2 Section of hypothalamus showing meningeal infiltration by
myeloma cells. This patient had diffuse meningeal involvement by myeloma cells without parenchymatous infiltration of the brain or spinal cord. (Hematoxylin and eosin. Original magnification 504×.) (From Davies-Jones GAB, Preston FE, Timperley WR: Neurological Complications in Clinical Haematology. Blackwell Scientific Publications, Oxford, UK, 1980, with permission.) Spinal Myeloma The vertebrae are commonly infiltrated by myeloma cells, which may extend into the extradural space to form an extradural tumor and cause spinal cord compression. As a cause of cord compression, myeloma comes second to metastatic carcinoma in frequency. Vertebral body fragmentation and collapse may also produce neurological deficits from spinal cord and nerve root compression. Acute paraplegia with sensory loss due to spontaneous epidural hematoma secondary to bleeding from myeloma deposits in the thoracic vertebrae 75 has been described. Extradural myeloma tumor may occur without local bone involvement, and intradural deposits
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of myeloma may arise by spread along nerve roots via intervertebral foramina. Spinal cord compression has infrequently been caused by amyloid deposits. Infiltration of the spinal cord by myeloma cells, and paraneoplastic myelopathy are rare complications. The lower thoracic area of the spinal cord is the most commonly affected area, followed by lumbar and cauda equina involvement. Cervical cord compression is relatively rare. Patients with IgA myeloma seem to be at greater risk of spinal cord compression. The neurological symptoms usually develop comparatively slowly but may do so over a week or two. Usually, back pain of several months' duration precedes any evidence of spinal cord compression, although occasionally the interval is a few weeks only. Syndromes typical of spinal cord or cauda equina compression occur, with sensory impairment below the lesion and a spastic or flaccid paraparesis progressing to complete paraplegia with urinary retention and incontinence. Nerve Root Compression Nerve root compression is produced by direct infiltration or compression by myeloma cells or by compression from vertebral collapse. The result is progressive brachialgia accompanied by sensory impairment and weakness or lumbosacral pain with sensorimotor dysfunction. Cranial Myeloma Cranial myeloma is rare. The predominant sites of occurrence are the region of the sella and cavernous sinus, the body of the sphenoid, and the apex of the petrous bones. Orbital myeloma is well recognized and presents as an orbital mass with proptosis and ophthalmoplegia. Total ophthalmoplegia may occur from amyloid infiltration of the extraocular muscles secondary to myeloma. Myeloma may infiltrate the intracranial cavity from the oropharynx or paranasal sinuses. Primary plasmacytomas may originate in the cranial vault or the dura. Direct infiltration of the brain by myeloma cells is exceptionally rare, as is diffuse meningeal involvement. Bilateral optic neuritis producing painless progressive impairment of visual acuity over 12 months and bilateral central scotomas has been described in relation to IgA lambda myeloma. The optic neuritis recovered virtually to normal over 2 months, suggesting that the optic nerve involvement was unlikely to be due to infiltration and was 76 possibly secondary to binding of IgA to myelin. Headaches and signs of raised intracranial pressure are the earliest indications of intracranial myeloma. Other signs and symptoms depend on the site of the lesion and can vary from a palpable lump over the skull vault to convulsions, hemiparesis, hemianopia, diabetes insipidus and hypopituitarism, cranial nerve palsies, brainstem syndromes, and symptoms of generalized cerebral impairment, such as confusion, disorientation, drowsiness, and coma. The pathogenesis of the latter in the setting of myelomatosis is complicated, and undoubtedly factors such as renal failure, anemia, hypercalcemia, and hyperviscosity play a part. Benign intracranial hypertension has been observed in occasional cases of IgG myeloma. 77 None of the patients showed evidence of hyperviscosity or of intracranial myeloma. Peripheral Neuropathy Four types of neuropathy have been described in association with myelomatosis: 1. Paraneoplastic neuropathy producing demyelination and axis cylinder degeneration 2. Ischemic neuropathy due to amyloid deposition in the vasa nervorum 3. Amyloid infiltration of the peripheral nerves (Fig. 13-3) 4. Infiltration of the peripheral nerves by myeloma tissue
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FIGURE 13-3 Amyloid neuropathy in myeloma. Electron micrograph shows fibrillary deposits of amyloid adjacent to an axon. (From Davies-Jones GAB, Preston FE, Timperley WR: Neurological Complications in Clinical Haematology. Blackwell Scientific Publications, Oxford, UK, 1980, with permission.)
Neuropathy occurring in myelomatosis results in a chronic, progressive, symmetric sensorimotor disturbance that affects the legs first and, later and to a lesser extent, the arms. This is particularly so of the paraneoplastic variety, whereas infiltration by myeloma or amyloid tissue may produce an asymmetric or mononeuritic picture. Although it is a complication of the established disease in diffuse myelomatosis, the paraneoplastic type of neuropathy is usually the presenting feature of a solitary, commonly sclerotic plasmacytoma. This combination has a distinct male predominance. The neuropathy is usually sensorimotor, with the motor component predominating. The solitary sclerotic tumor may arise in the vertebrae, ribs, clavicles, scapulae, or long bones. The CSF protein concentration is increased, but the peripheral blood and bone marrow are normal; the erythrocyte sedimentation rate (ESR) is usually normal, and there is typically no identifiable paraprotein unless serum immunoelectrophoresis or immunofixation is performed. Localized radiotherapy to the bone lesion effectively arrests and usually alleviates the neuropathy. The outlook for survival is good. A progressive, symmetric sensorimotor neuropathy in patients with monoclonal gammopathy, characteristically osteosclerotic bone lesions, and circulating light-chain paraprotein has been described predominantly from Japan. It is sometimes called POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes). This syndrome has also been described in association with 78 extramedullary plasmacytoma and occasionally with isolated dysproteinemia only.
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Osteosclerotic myeloma is a plasma cell dyscrasia characterized by sclerotic bone lesions, progressive demyelinating polyneuropathy, and bone marrow containing less than 5 percent plasma cells (in multiple myeloma, the bone marrow contains more than 10% plasma cells). Miralles and associates suggested that the distinction of osteosclerotic myeloma and the 79 POEMS syndrome is artificial. In their study, 84 percent of patients who fulfilled the criteria for osteosclerotic myeloma had multiorgan involvement: skin change (58%), lymphadenopathy (42%), papilledema (37%), peripheral edema (29%), hepatomegaly (24%), splenomegaly (21%), and ascites (11%). Five patients fulfilled the criteria for the POEMS syndrome, and these patients had the same clinical outcome as those with the incomplete forms. There seemed to be no benefit in differentiating POEMS syndrome and osteosclerotic myeloma. Plasma cell dyscrasia with polyneuropathy is a better all-embracing term for including the variables of these two conditions. Dispenzieri et al have proposed new criteria 80 for the diagnosis of POEMS syndrome. A particularly localized form of neuropathy due to infiltration of the carpal tunnel by amyloid deposits is well recognized. Jowitt and associates described a 81 patient who developed polymyositis 18 months after multiple myeloma was diagnosed. The stiff limb syndrome with anti-GAD antibodies has been described in a patient with multiple myeloma undergoing treatment with thalidomide by 82 Schiffer and colleagues. Neurological Effects of Metabolic Complications Neurological complications may result from hypercalcemia, uremia, and hyperviscosity (Fig. 13-4). The hyperviscosity syndrome occurs most commonly in IgA myeloma to the extent that 25 percent of patients with this form of myeloma attending the authors' hospital have at one time or another developed this complication. It occurs because the IgA myeloma molecule has an inherent tendency to form high-molecular-weight polymers.
FIGURE 13-4 Plugging of a cerebral vessel by hyperviscous protein with seepage into
the perivascular space secondary to vessel ischemia, from a case of hyperviscosity syndrome in myeloma. (Original magnification 504×.) (From Davies-Jones GAB, Preston FE, Timperley WR: Neurological Complications in Clinical Haematology. Blackwell Scientific Publications, Oxford, UK, 1980, with permission.) Hypercalcemia and uremia cause increasing headaches, confusion, disorientation, somnolence, stupor, coma, uremic convulsions, and myoclonic twitching. The hyperviscosity syndrome of myeloma is identical to that of Waldenström's macroglobulinemia. Neurological Effects of Immunological Complications
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Immunological incompetence is often a feature of myelomatosis. In the CNS, this is reflected by the development of meningitis (bacterial, viral, fungal) and cerebral abscess. Pneumococcal infection is particularly implicated, as is herpes zoster and, more rarely, cryptococcosis and toxoplasmosis. Profound septicemia may be complicated by cerebral DIC. Progressive multifocal leukoencephalopathy may also occur.
Macroglobulinemia (Waldenström's Disease) It has been estimated that peripheral or CNS symptoms occur in 25 percent of patients with macroglobulinemia. Although peripheral neuropathy may be associated with the hyperviscosity syndrome, this is unusual; it is unlikely, therefore, that the hyperviscosity syndrome is the cause of the neuropathy in most patients with macroglobulinemia and paraproteinemia. The neuropathy may be related to antibody binding (see later). Other mechanisms such as lymphocytic infiltration of the peripheral nerves, amyloidosis, and bleeding tendency have also been suggested as an explanation for the neuropathy. Abad and colleagues reported four patients with lymphoplasmacytic cells infiltrating meninges and nerve roots, producing progressive leg weakness from lumbar radiculopathy. Chemotherapy 83 and irradiation of the involved nerve roots led to significant improvement. Complete unilateral ophthalmoplegia has been described as the presenting manifestation 85 of 84 Waldenström's macroglobulinemia, as has an isolated lesion of the fourth cranial nerve. MRI in the latter case demonstrated an orbital apex lesion, which was not biopsied. There were no other neurological lesions. Four months after initiation of treatment with prednisolone and chlorambucil, MRI revealed complete resolution of the orbital lesion, which was probably a lymphoid infiltrate. The other neurological complications relate to hyperviscosity and bleeding tendency. Any part of the CNS may be involved, with complications presenting as strokes or other focal brain syndromes, dementia, diffuse encephalopathy, subarachnoid hemorrhage, and spinal cord symptoms from hemorrhage or infarction. Patients frequently complain of profound fatigue, lethargy, and headaches, and they develop confusion, stupor, coma, and convulsions. Visual disturbances and deafness occur and may be irreversible. Congestion, tortuosity, segmental dilation of retinal veins and bilateral central retinal venous occlusion occur, as do hemorrhages, exudates, and papilledema. The bleeding tendency results in spontaneous bruising, purpura, epistaxis, gastrointestinal hemorrhage, and oozing from venipuncture sites. Dramatic relief is frequently achieved by plasmapheresis. A case of progressive myelopathy 86 from Waldenström's disease showed a marked response to rituximab, and a 87 polyneuropathy due to it was also effectively treated with chemotherapy and rituximab. Exceptionally, Waldenström's disease is complicated by the development of primary 88 intracerebral lymphoma, progressive multifocal leukoencephalopathy, or a humorally mediated immune myopathy from IgM-kappa antibodies directed against muscle surface 89 protein.
Paraproteinemias Monoclonal gammopathy of unknown significance (MGUS), formerly termed benign monoclonal gammopathy, is characterized by low-titer (<3 g/dl) bands of IgM, IgG, or IgA. Immunoelectrophoresis or immunofixation may be required to detect smaller bands. Urine light chains are detected only rarely. The marrow contains less than 5 percent plasma cells; blood counts are normal; and lymphadenopathy, organomegaly, and skeletal lesions do not occur. Investigation may identify primary systemic amyloidosis, myeloma, macroglobulinemia, cryoglobulinemia, lymphoma, or lymphoproliferative disorder. Approximately one third of patients with MGUS will develop myeloma, macroglobulinemia, amyloidosis, or a lymphoproliferative disorder over 20 years; this is sometimes indicated by an unusually 90 rapidly progressive course of the neuropathy. Kyle and associates found the risk of progression of MGUS to multiple myeloma or related disorders to be about 1 percent per 91 year. Approximately 5 percent of patients with MGUS will develop a polyneuropathy, associated in 92 the majority with an IgM band. The median age of onset is in the sixth decade with a slowly progressive, distal, symmetric sensorimotor polyneuropathy or, less commonly, a predominantly sensory neuropathy. A presentation resembling chronic inflammatory demyelinating polyneuropathy (CIDP) is well recognized, although this condition differs from typical CIDP with more dominant sensory symptoms, a greater age at onset, and a slower, 93 more progressive course. Neurophysiological studies commonly demonstrate a mixed axonal and demyelinating picture. Predominant axonal degeneration is uncommon; pure demyelination is particularly associated with IgM MGUS. CSF protein levels may be markedly
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elevated. Antibody to myelin-associated glycoprotein (MAG) may be identified in paraprotein 94 neuropathy and in as many as half of the cases of IgM MGUS. Other binding specificities are described, including GM1 ganglioside, disialosyl gangliosides, and sulfatide; however, the 95 pathogenic role of these antibodies is unclear. IgG and IgA MGUS are less likely than IgM MGUS to be associated with identifiable antineuronal antibodies. They are comparatively less 92 common, less likely to be demyelinating96or sensory, but more likely to respond to plasmapheresis than IgM neuropathies. Sural nerve biopsies in MGUS neuropathy demonstrate neuronal loss, segmental demyelination, and axonal degeneration. The characteristic changes in IgM anti-MAG neuropathy are widening of myelin lamellae at the minor dense line in the outer half of the sheath, and IgM light-chain binding to MAG, with co-localized complement components. The bound IgM is usually kappa type. The mechanism of nerve injury in many cases of MGUS neuropathy is unclear, although immune-mediated injury is probable in the presence of 96 anti-MAG disease.
Lymphoma Hodgkin's disease and the non-Hodgkin's lymphomas affect the nervous system with equal frequency, but only rarely. This usually occurs by direct spread from primary nodal and extranodal sites. Occasionally, primary Hodgkin's disease and primary non-Hodgkin's lymphoma (microglioma, reticulum cell sarcoma, histiocytic lymphoma) of the CNS are seen. Although as many as 25 percent of all non-Hodgkin's lymphomas present in extranodal sites, at most 1 percent present in the CNS. Primary lymphoma of the CNS represents about 10 97 percent of all primary tumors of the CNS. The neurological complications result from compression and direct invasion of the nervous system or from secondary paraneoplastic syndromes. Within the CNS, the cerebral hemispheres are the most frequent sites of involvement, followed by the cerebellum and brainstem. Primary lymphomas of the spinal cord are rare. CNS involvement occurs most commonly with lymphoblastic lymphoma, followed by diffuse undifferentiated lymphoma and diffuse histiocytic lymphoma. Spinal Cord and Meningeal Involvement Spinal cord and meningeal involvement are relatively common neurological complications of the lymphomas. In one study, 38 percent of patients with systemic lymphoma and CNS 98 involvement had spinal cord tumors. Extradural deposits arise as the result of direct spread from the retroperitoneal or postmediastinal spaces via the intervertebral foramina from tumor growth along nerve roots, or by direct invasion from an affected vertebral body. The tumor often extends around the lateral aspect of the spinal cord and may encircle it completely. Although the dura mater usually prevents invasion of the cord itself, intramedullary 99 metastases of lymphoblastic lymphoma is a rare but recognized complication. The segmental arterial supply may be compressed by the tumor to produce an ischemic myelopathy. Rarely, an acute necrotizing myelopathy appears as a remote paraneoplastic effect of a lymphoma. This is universally progressive. A less acute paraneoplastic myelopathy developed in a patient with pathological stage 1A Hodgkin's disease before treatment was 100 begun; it resolved substantially with intrathecal dexamethasone. With compressive lesions, back pain, frequently worse on lying down and often associated with radicular spread, is accompanied by progressive spinal cord dysfunction, producing a spastic paraparesis, sensory impairment below the lesion, and sphincter problems resulting in incontinence. Spinal cord segments C5 to T8 are most commonly implicated, although compression of the cauda equina may occur. Brown-Séquard syndrome secondary to extradural compression has been described. Nerve roots may be invaded and enlarged by the lymphoma, causing pain and sensorimotor segmental syndromes (e.g., cervical or lumbosacral radiculopathy). Intracranial Involvement Intracranial involvement usually arises from infiltration via the skull base, by direct extension from involved cervical lymph nodes as well as by lymphatic spread. On rare occasions, lymphoma of the skull bones has been known to spread to form an intracranial mass. Tumor is usually found extradurally but may occur within the dura as a subdural mass that sometimes invades underlying brain; it may even be purely intracerebral. Typically, widespread disseminated meningeal lesions occur and characteristically produce multiple cranial nerve palsies, headaches, meningism, and papilledema. The seventh cranial nerve
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seems to be involved most commonly. Patients with T- and B-cell surface markers are at increased risk of cranial nerve involvement, factors also associated with increased incidence of CNS relapse. Almost all cases of lymphomatous meningitis are found in patients with diffuse non-Hodgkin's lymphoma. Lymphoblastic lymphoma, diffuse histiocytic lymphoma, diffuse undifferentiated lymphoma, and diffuse lymphocytic poorly differentiated lymphoma have a high incidence of meningeal disease. Meningeal lymphoma may have a protracted course with spontaneous remission of clinical and neuroimaging signs. A patient with spontaneous remission of a third cranial nerve palsy subsequently developed meningeal lymphoma that produced multiple lumbosacral radiculopathies a year after initial presentation. Nerve root biopsy revealed a B-cell lymphoma. Serial CSF analyses over the intervening year showed occasional atypical cells 101 that were later found to resemble closely the biopsy cell type. Intracranial deposits produce signs and symptoms of increased intracranial pressure with focal disturbances as a result of infiltration of the cerebral hemispheres, cerebellum, or brainstem. Convulsions may occur. Painful ophthalmoplegia with proptosis, together with sensory impairment of the cornea and ophthalmic division of the trigeminal nerve owing to cavernous sinus infiltration, is a recognized intracranial complication and usually occurs by invasion from the ethmoid or sphenoid bones or sinuses. Intracranial deposits seem to be associated more often with histiocytic lymphoma, and orbital deposits more commonly with lymphocytic lymphoma. Intracranial deposits are rarely seen in lymphocytic lymphoma unless leukemia has supervened. Zaman and associates reported anterior visual system involvement in non-Hodgkin's lymphoma due to lymphomatous infiltration of the optic chiasm in one patient and bilateral optic neuropathy in another who later developed progressive multifocal 102 leukoencephalopathy. 103
Younger and colleagues studied nine patients with motor neuron disease and lymphoma. They described upper and lower motor neuron signs in association with lymphoma, often accompanied by paraproteinuria. Signs suggestive of amyotrophic lateral sclerosis may also be accompanied by conduction block in peripheral nerves. Paraneoplastic Syndromes The paraneoplastic syndromes of peripheral neuropathy, encephalomyelopathy, cerebellar cortical degeneration, polymyositis, progressive multifocal leukoencephalopathy, and an acute necrotizing myelopathy have been described in association with the lymphomas (see Chapter 27). Acute dysautonomia as the only neurological association of systemic Hodgkin's 104 neuromyotonia and peripheral neuropathy, myasthenia disease has been observed, as has 105 106 opsoclonus-myoclonus, and progressive external gravis, the Guillain–Barré syndrome, 107 ophthalmoplegia. Other Neurological Complications Other neurological complications may occur as the result of radiotherapy or chemotherapy, including opportunistic infections of the CNS due to bacteria, fungi, or viruses, or from hemorrhage due to thrombocytopenia.
Burkitt's Lymphoma Burkitt's lymphoma is frequently complicated by nervous system involvement, the most common complications being paraplegia, cranial neuropathies, and pleocytosis of the CSF. Tumor spreads through the bones of the face, skull, and orbit and along cranial nerves. Spinal cord compression from extradural deposits arises from direct extension from the vertebral bodies or from paravertebral tumors infiltrating through the intervertebral foramina. Patients with facial tumors are likely to develop orbital involvement and ophthalmoplegia, or infiltration of the skull base that produces cranial nerve palsies and pleocytosis of the CSF. Ischemic myelopathy can result from compression of radicular arteries by retroperitoneal and retropleural tumor.
Primary Intracerebral Lymphoma Primary CNS lymphomas are rare, accounting for about 10 percent of primary brain tumors. Although all cytological types are observed, the most common types belong to the high-grade category of non-Hodgkin's lymphoma, the majority being clonal and of B-cell origin, as
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evidenced by their monotypical expression of either kappa or lambda light-chain immunoglobulin. The tumor masses are usually multicentric and ill defined. They occur in individuals given prolonged immunosuppressive therapy, patients in receipt of organ allografts, and those with inherited immunodeficiency disorders, such as ataxia-telangiectasia and the Wiskott–Aldrich syndrome. There is a clear association between primary cerebral non-Hodgkin's lymphoma and the HIV-associated acquired immunodeficiency syndrome (AIDS) (see Chapter 45). The incidence of these tumors is increasing, and their association with AIDS only partly accounts for this. Primary CNS 108 lymphoma in immunodeficient patients is universally associated with the Epstein–Barr virus. These tumors most commonly present as discrete lesions of the cerebral cortex, corpus callosum, septum pellucidum, basal ganglia, suprasellar region, and, to a lesser extent, the cerebellum. Bilateral cerebral involvement via the corpus callosum is a feature and presents with increasing intracranial pressure, dementia, papilledema, long-tract signs, and convulsions. A case of corticosteroid-responsive primary malignant lymphoma of the optic chiasm documented by MRI and MRI-directed stereotactic biopsy was described by Gray and 109 colleagues, and Patrick and associates described a 30-year-old woman with primary cerebral lymphoma who had diabetes insipidus and otherwise minimal abnormality of 110 to metastasis from a hypothalamic pituitary function. Isolated radial nerve palsy secondary 111 primary malignant lymphoma of the brain has been described. Neuroimaging displays discrete, often large tumors with bilateral hemispheric involvement in most cases, striking enhancement with contrast media, and surrounding edema. Despite the fact that these tumors are highly radiosensitive, late morbidity and mortality may occur from radiation necrosis. Without biopsy confirmation, radiation necrosis cannot be reliably distinguished 112 from recurrent tumor. Cerebral radiation necrosis seems to be related to radiation dose and the bulk of residual tumor following diagnostic neurosurgery. Primary lymphoma of the spinal cord is exceptionally rare, as is primary lymphoma of the nerve roots. One of the authors (GDJ) has 40 investigated and cared for a patient with primary lymphoma of the cauda equina (Fig. 13-5).
FIGURE 13-5 Marked nodular thickening of the nerve roots of the cauda equina
from infiltration by primary lymphoma of the central nervous system (CNS). (From Davies-Jones GAB, Preston FE, Timperley WR: Neurological Complications in Clinical Haematology. Blackwell Scientific Publications, Oxford, UK, 1980, with permission.) Peripheral neuropathy of the paraneoplastic type has been described in association with 113 primary lymphoma of the brain.
Intravascular Lymphoma Intravascular lymphomatosis is a rarely diagnosed generalized lymphoma, usually of large B-cell type producing vascular occlusion of arterioles, capillaries, and venules. More than 50 percent of cases present with neurological symptoms, usually diffuse or focal, and suggestive of vascular disease. Dementia, stroke-like episodes, and brainstem and spinal cord syndromes predominate. Imaging demonstrates multifocal lesions in the brain suggestive of microvascular or demyelinating disease. Angiography may show a beaded appearance reminiscent of vasculitis. The CSF findings are nonspecific. Cerebral biopsy should be 114 undertaken in suspected cases.
Lymphomatoid Granulomatosis Lymphomatoid granulomatosis frequently involves the nervous system. The usual presenting symptoms are fever, weight loss, malaise, cough, dyspnea, and neurological complications.
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The latter include encephalopathy, seizures, hemiparesis, cranial polyneuropathy, optic neuropathy, peripheral neuropathy, and mononeuritis multiplex. Pathologically, there is extensive infiltration of T lymphocytes and histiocytes in the meninges and cerebral vessel walls within the brain parenchyma and along nerve roots and peripheral nerves mimicking true vasculitis and resulting in vascular occlusion. Lymphomatoid granulomatosis progresses to an angiocentric T-cell lymphoma in many cases.
Polycythemia An increased incidence of thrombotic and hemorrhagic complications is a well-recognized phenomenon in polycythemia, not least in the nervous system. Approximately 15 percent of patients with polycythemia die of cerebral thrombosis, 87 percent of them after repeated episodes. Thromboembolism often continues to be a major clinical problem even after hematological control has been achieved. The high incidence of thrombosis is attributed to the increased blood viscosity, reduced perfusion, vascular engorgement, and atheromatous degeneration of vessel walls, and possibly to chronic DIC. Hemorrhage may be related to imperfect clot retraction, abnormal thromboplastin generation, and abnormalities of platelet count and function. It may be cerebral, extradural, subdural, or subarachnoid. Most of the intracranial lesions are thrombotic and involve arteries, veins, or venous sinuses. The risk of developing cerebral infarction is proportional to the hemoglobin level. Nonspecific symptoms of fullness in the head, vertigo, tinnitus, and lack of concentration are common. More specific signs such as hemiparesis, hemianesthesia, hemianopia, and aphasia depend on the site of infarction or hemorrhage. Brainstem vascular syndromes occur, as do bulbar and pseudobulbar palsy, convulsions, and coma. Amaurosis fugax, blindness, scotomas, and transient cerebral or brainstem ischemic attacks are features as well. More rarely, signs and symptoms of a progressive cerebral lesion arise because of a subdural hematoma, an expanding intracerebral blood clot, or cerebral infarction and edema. Distention and congestion of the retinal veins, central retinal venous or arterial occlusion, and papilledema may be present. Idiopathic intracranial hypertension has been reported. Aseptic cavernous sinus thrombosis associated with internal carotid artery occlusion may occur. Treatment with repeated phlebotomies and heparin resulted in resolution of the proptosis, pain, periorbital edema, lacrimation, venous congestion, ptosis, and ophthalmoplegia, and it restored the patient's sight. The one-and-a-half syndrome due to polycythemia was described 115 by Lousa and associates. Spinal cord infarction is an exceptionally rare complication; although spinal cord compression due to spontaneous subdural hematoma and extramedullary hematopoiesis 116,117 in the Chorea is proliferative phase of polycythemia have been described, this is uncommon. another rare complication. It may be of sudden onset and tends to occur in women older than 50 years. It may resolve before any significant reduction of the red cell count, but more often it resolves with the correction of the polycythemia. The chorea is generalized, with predominant involvement of the face, mouth, tongue, and arms. It is not apparently related to the rare finding of a small infarct in the caudate nucleus. Some have suggested that it may result from excess dopamine presentation to the basal ganglia by the increased number of sluggishly circulating platelets. It is discussed further in Chapter 59. Although paresthesias are not uncommon symptoms in the extremities, peripheral 118 neuropathy due to polycythemia was thought to be rare. However, Poza and co-workers in a prospective clinical and electrophysiological study of 28 patients with polycythemia identified 46 percent with clinical features of neuropathy and 71 percent with neurophysiological evidence of polyneuropathy. Oculomotor nerve paresis as a presenting sign of acute myeloblastic leukemia complicating polycythemia has been reported.
Cerebellar Hemangioblastoma Cerebellar hemangioblastoma may be associated with erythrocythemia, which arises as a response119 to erythropoietin secretion by the tumor. An incidence of 15 percent has been reported. The symptoms are those of increased intracranial pressure and “dizziness,” with either truncal and gait ataxia or ataxia of one or the other side with nystagmus. Neck stiffness and, rarely, cerebellar “fits” may occur. On examination, the symmetric or lateralized cerebellar ataxia is associated with papilledema, hemiparesis, bilateral pyramidal signs, or any combination of deficits from fifth, sixth, seventh, or eighth cranial nerve involvement. Recurrence many years after surgical treatment is typical of hemangioblastoma.
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Pseudopolycythemia Pseudopolycythemia is a condition in which an increased packed cell volume (hematocrit) is associated with normal red cell mass, although plasma volume may be reduced in the absence of apparent fluid loss. It is associated with hypertension, obesity, and stress, especially in middle-aged men who are smokers. In this condition, as in polycythemia, there is an increased risk of thromboembolism because the increased packed cell volume is associated with an increase in whole blood viscosity and reduced cerebral blood-flow, which predispose to vascular occlusive episodes. In patients with a packed cell volume greater than 54 percent, regular small venisections of 100 to 250 ml are recommended to reduce the packed cell volume to around 46 percent.
Essential Thrombocythemia Essential thrombocythemia is a rare disorder characterized more frequently by thrombotic than hemorrhagic complications. The condition is diagnosed on the basis of a persistently elevated platelet count without evidence of trauma, inflammation, hemorrhage, hyposplenism, or any other condition known to be associated with thrombocytosis. Amaurosis fugax, transient hemiparesis or hemianesthesia, recurrent 120 vertigo, and confusion were the characteristics of the patients studied by Preston and others. Most had evidence of circulating platelet aggregates or spontaneous platelet aggregation, and three had reduced platelet survival. Considerable clinical improvement was achieved by antiplatelet drugs and, where appropriate, by reduction of platelet count. Jabaily and colleagues have also confirmed a high incidence of121TIAs of both the anterior and the posterior cerebral circulation in essential has thrombocythemia. The incidence of cerebral ischemia in essential thrombocythemia 122 been estimated to be 180 times greater than that in a control population. It has been suggested that there is no correlation between the severity of the thrombocythemia and the 123 incidence of TIAs and completed strokes, but the numbers studied are insufficient to warrant this conclusion. Neurological complications occurred in 25 percent of 70 patients with 124 essential thromocythemia.
Myelofibrosis Myelofibrosis is an uncommon myeloproliferative disorder arising predominantly in patients older than 50 years. It is characterized by replacement of the bone marrow by fibrous tissue associated with extramedullary hematopoiesis and marked hepatosplenomegaly. The patients are anemic, may be slightly jaundiced, and have a leukoerythroblastic blood picture. Neurological complications are rare. Rutman and colleagues described a woman 125 with advanced myelofibrosis who developed a left hemiparesis and left-sided agnosia. At postmortem there were bilateral intracranial masses of hematopoietic tissue compressing both frontoparietal areas and arising from the meninges. Spinal cord compression and paraplegia from extramedullary hematopoiesis due to myelofibrosis is also very 126 uncommon. Essential thrombocythemia, polycythemia vera, and myelofibrosis with myeloid metaplasia constitute the “classic” bcr/abl-negative myeloproliferative disorders. Each represents a stem cell–derived clonal myeloproliferation. A Janus tyrosine kinase127mutation (JAK2V617F) is found in all three disorders and may be diagnostically helpful.
Eosinophilic Syndromes Eosinophilia is defined as an increase in peripheral blood eosinophil count to greater than 450 cells/μl blood, and eosinophilic infiltration is particularly observed in the tissues affected by the condition—muscle, nerve, or CSF. Eosinophilia may be observed in a wide range of conditions: connective tissue disorders; vasculitides; malignancies; allergic reactions, particularly drug reactions; infectious diseases, particularly helminth but not protozoan parasites; and the hypereosinophilic syndrome (Table 13-1). Click here to view this table.... Eosinophilic myositis is a pathological diagnosis characterized by eosinophilic infiltration of the muscle. In idiopathic eosinophilic myositis no systemic cause for the eosinophilia is apparent. Eosinophilic infiltration into skeletal muscle, although rare, has been described in a diverse group of conditions. It occurs most commonly in parasitic infection as focal eosinophilic myositis but can be a feature of systemic hypereosinophilic conditions such as eosinophilia-myalgia syndrome and idiopathic hypereosinophilic syndrome.
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There are three main forms of eosinophilic neuromuscular disease. Diffuse fasciitis or Shulman syndrome can be limited to the fascia or associated with perimyositis. Eosinophilic myositis corresponds to focal muscle involvement. It is associated with skin lesions in approximately 40 percent of cases, including deep subcutaneous induration, erythema, angioedema, urticaria, and papular lesions. The overall prognosis of eosinophilic myositis/polymyositis is good, particularly when 128 muscle lesions are focal and the principal histopathological finding is perimysial infiltrates. Compound heterozygous or homozygous CAPN3 mutations have been found in a subgroup of children in the first decade with autosomal-recessive inheritance, variable peripheral eosinophilia, and elevated serum creatine kinase, but with little or no weakness. The CAPN3 gene encodes calpain-3, a muscle-specific intracellular nonlysosomal protease. Mutations in this gene are responsible for the commonest autosomal-recessive limb-girdle muscular dystrophy, calpainopathy (LGMD2A). Eosinophilia has not been identified in adults with calpainopathy. Whether this represents the well-known 129 inflammatory feature of muscular dystrophy or is a true eosinophilic myositis is uncertain. Eosinophilic polymyositis is a manifestation of the hypereosinophilic syndrome and is life-threatening. In the idiopathic hypereosinophilic syndrome there are at least 1500 eosinophils/μl in the blood for at least 6 months without any recognizable cause after a careful workup. There is evidence of multiorgan infiltration by eosinophils. Cardiac disease is common with valvular disease resulting in embolization. The systemic manifestations include eosinophilia, anemia, hypergammaglobulinemia, vascular involvement (subungual petechiae, livedo reticularis, Raynaud's phenomenon), skin rash and subcutaneous edema, pulmonary infiltrates and pleuritis, cardiac involvement (congestive heart failure, arrhythmias, heart block, pericarditis, myocardial and endocardial fibrosis), and peripheral neuropathy. One third of the patients have neurological symptoms such as encephalopathy, multiple cerebral infarcts (possibly embolic in origin), peripheral neuropathy, and mononeuropathy multiplex. The prognosis is poor, average survival being only 9 months after the onset of symptoms, although patients may respond well to corticosteroids. HEMORRHAGIC DISORDERS
Hemophilia The severity of bleeding in hemophilic patients correlates with the factor VIII level. Severely affected hemophiliacs with levels of less than 1 percent commonly have spontaneous bleeding into muscles and joints. With factor VIII levels of 1 to 5 percent, spontaneous bleeding may occur but is much less frequent. Excessive bleeding is precipitated by minor trauma, but patients with factor VIII levels greater than 10 percent can nowadays lead normal lives, as excessive blood loss occurs only after more severe trauma and surgery. Intracranial bleeding is the leading cause of death among hemophiliacs. The incidence of intracranial hemorrhage ranges from 2.2 to 13.8 percent. Bleeding tends to occur predominantly in young hemophiliacs. The most common factor associated with bleeding is trauma (53%), with hypertension an important factor in older patients. Delay in the onset of 130 symptoms following trauma is common (50%), with a mean duration of 4 ± 2.2 days. This long latent interval is most commonly associated with subdural hematoma. Bleeding may occur into the subdural, extradural, or subarachnoid spaces or into the cerebral hemispheres, cerebellar hemispheres, and brainstem. The symptoms and signs depend on the site of the hemorrhage and its extent. Prognosis in intracranial hemorrhage has been considerably improved by the early use of factor VIII concentrates, and there is now no contraindication to surgical intervention, provided that adequate control of coagulation factors is maintained. Subdural or subarachnoid bleeding carries a better prognosis than does intracerebral hemorrhage. Seizures occur in 25 percent of survivors of intracranial hemorrhage and increase the risk of further bleeding. Other sequelae include hemiparesis, aphasia, hemianopia, ataxia, and mental retardation. MRI imaging of the brain in males aged 7 to 19 with moderate to severe hemophilia 131 reportedly shows abnormalities in 20 percent of subjects. In one study, the most common acquired findings, in 11 percent of subjects, were single or multifocal nonhemorrhagic areas of high signal intensity in the white matter on T2-weighted images; cerebral atrophy and 131 hemorrhagic lesions were also be noted in some instances. Bleeding into the spinal canal is rare. With epidural hemorrhage, radicular symptoms, especially pain, are accompanied by progressive paraparesis or quadriparesis, depending on the site of the bleeding. Patients with small epidural hemorrhages and only minimal nonprogressive signs of spinal cord dysfunction may recover completely with intensive factor
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VIII replacement therapy alone. With signs of more severe cord compression, surgical decompression with evacuation of the clot is also necessary. Peripheral nerve lesions are the most frequent neurological complication of hemophilia. In most instances, nerve involvement is a complication of intramuscular hemorrhage, most commonly into the iliac muscle and leading to femoral neuropathy. Median, ulnar, and radial neuropathies result from hemorrhage into the arm or forearm muscles. Nerve compression by pseudotumors (subperiosteal hemorrhages producing expanding lesions) also occurs. Severe hemophilic arthropathy of the elbow may result in ulnar nerve palsy. Intraneural hemorrhage as a cause of peripheral nerve palsy is exceptional but has been described as 132 affecting the ulnar nerve in the cubital tunnel. On exploration of the ulnar nerve, free blood escaped when the epineurium was divided; recovery was rapid and complete. In one study of 126 hemophiliacs, 34 peripheral nerve lesions were identified in 24 patients. The frequency of nerve lesions correlated with the severity of the hemophilia and with increasing age. It was not133 apparent that all mononeuropathies were caused by identifiable episodes of hemorrhage.
Von Willebrand's Disease Von Willebrand's disease consists of a family of related disorders characterized by deficiency or malfunction of von Willebrand factor, which is a carrier for factor VIII and is also required for normal platelet adhesion. Most cases are inherited as an autosomal-dominant trait. The bleeding complications of von Willebrand's disease are relatively mild, and spontaneous hemorrhage into joints and muscles does not occur. Acute onset of neurological dysfunction is not a feature of this disease. Nevertheless, serious hemorrhage may result from trauma, and patients who sustain head injuries should receive immediate factor VIII replacement therapy. The rare types 2N and 3 are inherited as autosomal-recessive traits and result in more significant hemorrhage.
Christmas Disease The neurological complications of Christmas disease are identical to those of hemophilia. Thus, peripheral nerve compression occurs as a consequence of spontaneous intramuscular hemorrhage; and intracranial hemorrhage, an important cause of death in both disorders, may occur spontaneously in severely affected patients or following trauma in less severely affected individuals. Clotting factor IX is the deficient factor requiring replacement.
Other Clotting Factor Deficiencies Spontaneous and post-traumatic hemorrhages are features of disorders resulting from deficiencies of other clotting factors. Surgical evacuation of any intracranial hemorrhage must be done under cover of replacement therapy with the relevant deficient factor or with plasma or cryoprecipitate if the specific factor is not available. Similarly, replacement therapy should probably be given routinely following head injuries.
Acquired Hemophilia Acquired hemophilia is a rare condition resulting from the production of autoantibodies in middle age that inactivate factor VIII. Both sexes are affected. Cutaneous purpura and internal hemorrhage are common, whereas extensive bleeding into the joints is not a prominent feature. The condition is associated with systemic autoimmune disorders such as systemic lupus erythematosus; rheumatoid arthritis; malignancy such as lymphoma, acute or chronic lymphocytic leukemias, and solid tumors; and pregnancy. Drugs such as the 134 penicillins, phenytoin, phenylbutazones, or chloramphenicol have also been implicated. Neurological involvement in this rare disorder is not well recognized, but a case of ulnar neuropathy has been described in association with bleeding that resulted in a compartment syndrome in an elderly woman with organ-specific autoimmunity in the form of 135 hypothyroidism associated with antithyroid antibodies. Diagnosis is based on the identification of a low factor VIII level associated with the presence of a time-dependent inhibitor in the plasma. Treatment of bleeding episodes requires the use of an activated prothrombin complex concentrate or recombinant activated factor VIII. Immunosuppression with steroids is usually effective 136 at reducing inhibitor production and bringing about a sustained rise in the factor VIII level.
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Hemorrhagic Disease of the Newborn Intracranial hemorrhage represents the most serious complication of hemorrhagic disease of the newborn and occurs particularly after breach deliveries. Bleeding appears to occur from capillary lesions rather than major vessels. Subdural and subarachnoid hemorrhages are the most frequent form of intracranial bleeding, and intracerebral hemorrhage is rare. CNS bleeding appears to occur earlier and with greater frequency in infants born to mothers receiving anticonvulsant therapy. This is due to interference of anticonvulsant medication with vitamin K–dependent clotting factors, as discussed in Chapter 35. Occasionally, a bleeding syndrome related to vitamin K deficiency occurs in infants beyond the neonatal period, and this is associated with a greatly increased incidence of intracranial hemorrhage. Blanchet and associates described 93 infants who developed this condition between the ages of 2 weeks and 1 year. Intracranial bleeding, particularly subdural and 137 subarachnoid hemorrhage, occurred in 63 percent.
Thrombocytopenia If platelet function9is normal, satisfactory hemostasis may be achieved with a platelet count spontaneous hemorrhage does not usually occur if as low as 80 × 10 /L. Clinically significant 9 9 the platelet count exceeds 25 × 10 /L, but below 20 × 10 /L spontaneous hemorrhage is not uncommon. Cerebral, subarachnoid, and subdural hemorrhage constitutes the most serious neurological complication of thrombocytopenia. In patients with idiopathic thrombocytopenic purpura, the risk of spontaneous intracranial hemorrhage appears to be greatest during the first 2 weeks of the onset of the disorder. Severe spontaneous intracranial hemorrhage may also occur in patients with thrombocytopenia due to aplastic anemia, DIC, and acute leukemia. The risk of cerebral hemorrhage appears to be greater in DIC and leukemia than in uncomplicated idiopathic thrombocytopenic purpura, almost certainly because of other hemostatic defects also present in these conditions. In aplastic anemia, bleeding becomes a much greater problem when infection supervenes, presumably because of the superimposed hemostatic defect or intravascular coagulation. An uncommon complication of bleeding, superficial siderosis, has been described in association with repeated intraventricular and 138 subarachnoid bleeding of a newborn infant with neonatal alloimmune thrombocytopenia. Drug-induced immune thrombocytopenias arise when the drug functions as a hapten, binding to platelets and resulting in complement fixation and intravascular lysis or removal by the reticuloendothelial system. The platelet count falls within 7 or more days after a new drug is taken or within 2 to 3 days of a repeat exposure. Commonly involved drugs include quinine, quinidine, gold salts, phenytoin, valproic acid, carbamazepine, sulfonamides, and certain cephalosporins. Heparin-induced thrombocytopenia is the commonest disorder of this type. Type I heparin-induced thrombocytopenia is characterized by a moderate reduction in platelet counts, usually 9within the first 1 to 3 days of heparin therapy. The platelet count rarely drops below 100 × 10 /L and normalizes in spite of continued heparin therapy. Type II heparin-induced thrombocytopenia is immunologically mediated. It is defined as a platelet 9 count below 100 to 150 × 10 /L for no apparent reason other than heparin administration. Up to 30 to 60 percent or more develop serious thrombotic complications, including ischemic 139 damage to limbs, CNS, myocardium, and lungs. A study of neurological complications in 120 cases of immune-mediated heparin-induced thrombocytopenia showed that 9 percent of patients developed neurological complications, including ischemic cerebrovascular events (6%), cerebral venous thromboses (2.5%), and a transient confusional state in one case. Primary intracerebral hemorrhage was not observed. Importantly, in three cases, neurological 140 complications preceded the onset of thrombocytopenia. In severe thrombocytopenia, massive intracranial hemorrhage may be instantaneous and treatment of no avail. The onset of intracranial bleeding is often heralded by headaches of varying severity. In these circumstances, platelet transfusion should be instituted without delay, as it also should be after head injury in patients who have significantly reduced platelet counts.
Disorders of Platelet Function Regardless of the platelet count, abnormal bleeding states may result from abnormalities of platelet function, that is, disorders of platelet adhesion, aggregation, secretion, and procoagulant activity, or a combination of abnormalities of number and function.
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Bernard–Soulier syndrome is a disorder of platelet adhesion caused by deficiency of the surface glycoprotein Ib/IX. As a result, platelets fail to stick and clump together at the site of the injury. In Glanzmann's thrombasthenia, platelets lack glycoprotein IIb/IIIa, which prevents fibrinogen bridging from occurring and thus prevents clot retraction and significantly prolongs bleeding time. The gray platelet syndrome, delta storage pool deficiency, and abnormalities of the granule secretion mechanism all result in malfunction of platelet secretion of substances required for platelet adhesion and aggregation. In Scott's syndrome, platelets fail to promote activation of the blood-clotting factors. A variety of hereditary disorders may be associated with low platelet counts or platelets of abnormal size, including Wiskott–Aldrich syndrome and Alport's syndrome. These disorders are rare, and there is a paucity of data on the risk of intracranial hemorrhage. Fatal cerebral hemorrhage has however been described in Glanzmann's thrombasthenia. In the main, bleeding due to these disorders is treated primarily with platelet transfusions. The commonest acquired disorders of platelet function arise from drugs such as aspirin, nonsteroidal anti-inflammatory drugs, and ticlopidine. A wide range of other drugs may affect platelet function, including antihistamines, some antibiotics, antidepressants, and anesthetics. Platelet function may also be affected by chronic renal failure, the use of blood-bank platelets, the leukemias, and cardiopulmonary bypass. In myelomatosis or macroglobulinemia, abnormal platelet function results from interference by circulating paraproteins, and bleeding may be readily controlled by plasmapheresis.
Disseminated Intravascular Coagulation Disseminated intravascular coagulation should not be considered as a distinct disorder but rather as indicative of the presence of an underlying disorder. The coagulation system is activated by the rapid release of thromboplastic substances into the circulation to form either soluble or insoluble fibrin. Clotting factors and platelets are consumed, and there is defective and activated fibrinolysis and impairment of the coagulation inhibition system. The clinical syndromes produced are many and varied and result from vascular obstruction giving rise to tissue ischemia or necrosis with dysfunction of organs and tissues. The overwhelming consumption of α2-antiplasmin and platelets together with the anticoagulant properties of fibrin degradation products may also result in a bleeding tendency that can vary in severity from slight oozing at venipuncture sites with purpura and spontaneous bruising, to massive uncontrollable gastrointestinal, genitourinary, or postoperative hemorrhage. Simultaneous hemorrhage and thrombosis may occur. Pathologically, fibrin-rich thrombi are seen in arterioles, capillaries, and venules. The brain, kidneys, gastrointestinal tract, and lungs are usually the most frequently and severely affected. Globules of fibrin are occasionally seen free in the circulating blood, and some are large enough to obstruct the microcirculation. In many cases, red blood cells can be forced through fine networks of fibrin strands and, in the process, become damaged and fragmented, resulting in microangiopathic hemolytic anemia. Some of the most florid cases of DIC, particularly in young people who usually have a vigorous fibrinolytic response, show only a hemorrhagic picture with little or no evidence of fibrin in vessels. In some instances, the hemorrhagic complication may be so marked that massive cerebral, intraventricular, or subarachnoid hemorrhages result. Two mechanisms underlie the association of intravascular coagulation and neurological disorder. Primary brain damage releases powerful thromboplastins into the circulation that may precipitate DIC, and already established DIC may affect the nervous system. All patients with evidence of brain damage are at risk of developing DIC. It has been described in association with status epilepticus, possibly related to widespread endothelial injury 141 secondary to seizure-induced hyper-pyrexia. When DIC affects the nervous system, the symptoms and signs are related to the thrombotic and hemorrhagic complications (Fig. 13-6) as well as the primary disorder triggering the DIC (Table 13-2). Any part of the brain may be affected, producing focal or generalized encephalopathic manifestations or a combination of the two. The symptoms and signs may fluctuate markedly with time, presumably because of the continuing deposition and lysis of fibrin, which results in intermittent obstruction of vessels and blood flow. There seems to be a level of cerebral perfusion that is sufficient to maintain the viability of neurons but, nevertheless, may produce marked neurological abnormalities, including coma. It should be noted that patients may remain in a coma for several days, but, provided that the circulation is reestablished, they may subsequently make a complete recovery.
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FIGURE 13-6 Disseminated intravascular coagulation (DIC). This section of the
cerebral cortex shows multiple thrombosed small blood vessels surrounded by areas of hemorrhage. (Original magnification 220×.) (From Davies-Jones GAB, Preston FE, TimperleyWR: Neurological Complications in Clinical Haematology. Blackwell Scientific Publications, Oxford, UK, 1980, with permission.) Click here to view this table.... In DIC secondary to carcinoma, microvascular obstruction of the brain may produce signs indistinguishable from those of metastatic deposits. Neurological complications due to DIC may antedate the clinical presentation of the underlying malignancy. In the absence of a definite metabolic, infective, paraneoplastic, or metastatic cause for an encephalopathy, especially if accompanied by fleeting and fluctuating focal neurological abnormalities, DIC should be thoroughly excluded. With such a generalized and focal process, the neurological signs are numerous and varied, comprising confusion, disorientation, delirium, lethargy, stupor, coma, hemiparesis, aphasia, cortical blindness, focal or generalized seizures, cerebellar ataxia, and focal brainstem disease. The spinal cord may also be affected, for example by subdural or epidural hematoma. 142
Ischemic myelopathy due to DIC has been reported in a 39-year-old man with AIDS. He died of diffuse encephalopathy within 9 weeks of onset of the neurological syndrome. Neuropathological examination revealed multiple, usually small, frequently hemorrhagic infarcts of various ages, with fibrin thrombi in medium and small penetrating vessels and capillaries of the brain and spinal cord, characteristic of DIC. There were no inflammatory changes. No single test is available that is sufficiently sensitive or specific to permit a diagnosis of DIC. The presence of soluble fibrin in plasma has high sensitivity but low specificity for the diagnosis. The diagnosis may frequently be made using a combination of platelet count, measurement of global clotting times, measurement of one or two clotting factors and inhibitors (e.g., antithrombin), and a test for fibrin degradation products. Serial coagulation tests are often helpful and a reduced platelet count or a clear downward trend is a sensitive if not specific sign of DIC.
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It is important to note that at the onset of the neurological disorder, the coagulation profile may be normal and that during pregnancy, postoperatively, following trauma, and in association with malignancy, plasma fibrinogen, an acute-phase reactant, is invariably elevated. Therefore, increased fibrinogen consumption serves only to reduce plasma fibrinogen to normal. For this reason the only laboratory evidence of DIC in this situation may be thrombocytopenia and an elevated level of fibrin degradation products. If DIC is suspected, coagulation studies should be performed at frequent intervals, and falling concentrations of the various clotting factors should be accepted as evidence of a consumptive coagulopathy. D-dimer test is the most specific and sensitive test for DIC, although inflammation and surgery may elevate levels, and false-positive results may arise in patients with elevated IgM rheumatoid factor. The International Society 143 on Thrombosis and Haemostasis has proposed a useful algorithm for the diagnosis of DIC.
Thrombotic Thrombocytopenic Purpura Thrombotic thrombocytopenic purpura is a microangiopathic hemolytic anaemia. The only consistent abnormalities are red cell fragmentation and thrombocytopenia, which are also found in other conditions. It is most common between the ages of 20 and 50 but may affect individuals of all ages. It probably affects women more commonly than men. Before the introduction of plasma exchange when the mortality rate was up to 90 percent, the diagnosis was based on the pentad of microangiopathic hemolytic anaemia, thrombocytopenia, renal and neurological abnormalities, and fever. Neurological deficits, however, may not be 144 present. As the presence of renal and neurological abnormalities and fever are no longer a requirement for the diagnosis, plasma exchange may be introduced earlier with a 145 corresponding decline in the mortality rate to less than 20 percent. There may be complete recovery. A chronic relapsing form has been described. With use of the less restrictive diagnostic criteria, care must be taken to exclude conditions that may mimic thrombotic thrombocytopenic purpura, such as DIC, disseminated malignancy, Evans syndrome, HELLP syndrome (found in 10% of cases of eclampsia and pre-eclampsia), sepsis, accelerated hypertension, eclampsia, and the catastrophic form of the antiphospholipid antibody syndrome. Thrombotic thrombocytopenic purpura results from a severe deficiency of a von Willebrand factor–cleaving protease during acute episodes, thereby causing exceptionally large multimers of von Willebrand146factor to be secreted by endothelial cells. These multimers cause platelet aggregation. Pathologically, there is hyperplasia of endothelial and adventitial cells in arterioles, capillaries, and venules associated with platelet-rich and hyaline thrombi in these vessels, in which microaneurysms may also form. Neurological features are the most frequent presenting manifestations, occurring in 60 percent of cases. As the result of involvement of any part of the CNS, there is an endless variety of neurological syndromes. However the more common neurological manifestations are headache, organic brain syndromes, coma, paresis, aphasia, dysarthria, syncope, vertigo, ataxia, visual symptoms, paresthesias, seizures, and cranial nerve palsies. These symptoms are typically transient and fluctuating and, in147 some instances, resemble TIAs. Permanent neurological complications may also occur. Involvement of the visual pathways commonly results in homonymous field defects, but ocular changes of exudative retinal detachment, retinal and choroidal hemorrhages, papilledema, anisocoria, and diplopia may occur. Prolonged coma without evidence of major structural lesions in the CNS in patients with thrombotic thrombocytopenic purpura should be treated vigorously with daily repeated plasma exchange, antiplatelet drugs, corticosteroids, and vincristine, because full recovery is possible. Exceptionally, the neurological abnormalities may precede the full syndrome by months or even years. In a typical case, there may be a variety of prodromal symptoms, including fatigue, weakness, headaches, anorexia, nausea, vomiting, abdominal distress, fever, cough, hematuria, arthralgia, tachycardia, mental change, numbness, paralysis, and gastrointestinal or vaginal bleeding. At the time of presentation, the patient is usually pale, icteric, and febrile; has petechial hemorrhages in the skin; exhibits mental changes and neurological abnormalities; and has splenomegaly, hepatomegaly, lymphadenopathy, arthropathy, and some degree of hypertension and renal insufficiency. The main laboratory abnormalities are microangiopathic hemolytic anemia, thrombocytopenia, hyperbilirubinemia, uremia, and erythroid and myeloid hyperplasia of the bone marrow with increased megakaryocytic activity. Although laboratory evidence of DIC may be present, it occurs in only a few patients.
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Hemolytic-Uremic Syndrome The hemolytic-uremic syndrome is a disease of children that is characterized by renal impairment, thrombocytopenia, and microangiopathic hemolytic anemia, typically preceded by abdominal pain and diarrhea. Involvement of the nervous system is found in around 30 percent of children. As with thrombotic throm-bocytopenic purpura, the diagnosis may be made on the basis of microangiopathic hemolytic anemia and thrombocytopenia. Despite its similarities to thrombotic thrombocytopenic purpura, there are important differences. Deficiency of von Willebrand148 factor–cleaving protease has not been shown in hemolytic-uremic syndrome. Furthermore, 91 percent of children with hemolytic-uremic149 syndrome survive with supportive care, and plasma exchange treatment is not indicated. Most cases arise as a complication of infection by organisms producing Shiga toxins such as Escherichia coli O157:H7 or Shigella. Sporadic, noninfectious causes resulting from idiopathic, familial, or autoimmune diseases, drugs, or tumors also occur. The non–diarrhea-associated cases occur predominantly in adults and may be idiopathic; associated with HIV, bone marrow transplant, cancer, and autoimmune diseases; or associated with use of cyclosporine, mitomycin, and other forms of chemotherapy. Familial hemolytic-uremic syndrome constitutes 5 to 10 percent of cases and is associated with deficiency of plasma factor H, which protects the host by promoting C3b cleavage. The most common neurological manifestations150 are seizures, predominantly generalized tonic-clonic convulsions but occasionally focal. Behavioral changes, diplopia, dizziness, irritability, obtundation, coma, decerebrate posturing, cerebellar ataxia, hemiparesis, hemianopia, cortical blindness, cranial nerve palsies, vitreous hemorrhages, and retinal infarction may occur. Axonal neuropathy has been151 described in a patient with E. coli serotype O157:H7–associated hemolytic-uremic syndrome. Striatal involvement due to small areas of infarction of the basal ganglia, with resultant involuntary movements, has been 152 Changes of described. MRI of the brain may show features of infarction or hemorrhage. 153 reversible posterior leukoencephalopathy have also been described. A hemorrhagic component within an acute lesion most reliably predicted residual pathological findings on follow-up imaging. Prognosis was favorable for clinical outcome and resolution of 154 imaging findings, even in patients with severe CNS involvement on acute imaging studies. There is a risk of residual hypertension and chronic renal failure, which is greatest in those children with neurological complications. Seizures, alone or as part of155 neurological involvement, were associated with mortality or long-term neurological sequelae.
Gaucher's Disease Gaucher's disease is the commonest lipid storage disorder. An autosomal-recessive disorder, it is characterized by a deficiency of glucocerebrosidase and an accumulation of glucocerebroside in lipid-laden macrophages (Gaucher cells) in various organs. Type 1 is the non-neuronopathic type. It results from accumulation in bones, liver, spleen, and lungs and is characterized by hepatosplenomegaly, bone pain and fractures, thrombocytopenia, and bleeding diathesis. It may develop at any time in childhood. It occurs worldwide in all populations, but 60 percent of cases are found in the Ashkenazi Jewish population. Type 2, the acute neuronopathic form, shows no ethnic predilection, Hepatosplenomegaly arises in the first few months of life. Characteristic brainstem abnormalities then develop with strabismus, horizontal supranuclear palsy, and opisthotonic posturing and trismus in response to noxious stimuli. There is diffuse spasticity and developmental regression, and it is usually fatal during the first 3 years of life. Type 3 Gaucher's disease, the chronic neuronopathic form, is also without ethnic predilection and is estimated to occur in 1 in 50,000 live births. The neurological symptoms are slowly progressive and appear later in childhood than the symptoms of type 2 disease. It has a more chronic course, with variable hepatosplenomegaly and the progressive development of incoordination, myoclonic seizures, and mental deterioration. The cognitive disturbance ranges from a mild memory disorder to severe dementia, which is most frequent. The seizures may be tonic-clonic, partial complex, or myoclonic. Progressive myoclonic jerking of the face, limbs, or palate may be prominent, as may pyramidal signs, cerebellar ataxia, and 156 cranial nerve palsies. Oculomotor apraxia has been described as the presenting feature. In addition, thrombocytopenia and prolonged prothrombin and partial thromboplastin times may cause a bleeding tendency. The patient may be anemic, and Gaucher cells may be found on bone marrow examination. The symptoms vary between individuals, so that some children may have cirrhosis with portal hypertension, varices, pulmonary interstitial involvement, and heart disease. Type 3 Gaucher's disease has been classified further as types 3a and 3b based on the extent of neurological involvement and the presence of progressive myotonia
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and dementia (type 3a) or isolated supranuclear gaze palsy (type 3b). Norbottnian Gaucher's disease, a genetic form identified in Sweden, has features of types 2 and 3. The slowly progressive neurological symptoms may not occur until early adulthood. Bone marrow transplantation can reverse the non-neurological effects of type 1 Gaucher disease but has a high mortality rate and has been supplanted by enzyme replacement therapy. Enzyme replacement with a recombinant form of macrophage-targeted acid β-glucosidase is beneficial for types 1 and 3 Gaucher's disease, reducing liver and spleen size, improving blood counts, and reducing skeletal anomalies. It does not cross the blood–brain barrier and is not effective in the management of neuronopathic symptoms. Substrate reduction therapy with N-butyldeoxynojirimycin is available for patients unable to take enzyme replacement therapy. This compound inhibits the enzyme glucosylceramide synthase, a glucosyl transferase responsible for the first step in the synthesis of glycosphingolipids. Unlike enzyme replacement therapy, this drug does cross the blood–brain barrier, but no data are yet available on whether it has a role in neuronopathic Gaucher's disease. COAGULATION DISORDERS Thrombosis may arise from abnormalities of the blood-vessel wall, alterations in blood composition, and abnormalities in the dynamics of blood flow—Virchow's triad. The intact vessel wall modulates thrombin activity, platelet reactivity, and the release of vasodilators, and it promotes local fibrinolytic activity. Injury of a vessel wall may therefore lead to the exposure of the prothrombotic subendothelium as well as interfering with its antithrombotic properties. A number of blood components exhibit prothrombotic and antithrombotic effects, so that under normal circumstances platelet degranulation and aggregation and thrombin generation occur only at sites of tissue injury. Thrombin production is the major step in thrombosis that results in fibrin deposition. The fibrinolytic system prevents the deposition of excess fibrin, a negative-feedback process that is catalyzed by fibrin through plasmin production and that also breaks down platelet-adhesive glycoproteins, thus reducing further platelet recruitment. The balance between prothrombotic and antithrombotic activity determines the degree of thrombus progression. There are a number of well-recognized circumstances under which this balance may be altered; tissue injury may lead to increased synthesis of plasminogen activator inhibitor type 1 (PAI-1), with an increased risk of thrombosis. Congenital deficiencies in an ever-increasing range of anticoagulant proteins are also now well recognized. Antiphospholipid antibodies are associated with venous and arterial thrombosis. Pregnancy is associated with a variety of changes in hemostatic components giving rise to thrombosis or hemorrhage; increased fibrinogen production and placental production of a plasminogen activator inhibitor (PAI-2) leads to increased risk of thrombosis in the later stages of pregnancy. Cigarette smoking, estrogen use, tissue injury, infection, and inflammation result in increased production of components of the cascade, particularly fibrinogen. Diminished blood flow may lead to the local accumulation of platelets and thrombin, and if the stasis is sufficient, endothelial hypoxia may result in impairment of the antithrombotic properties of the endothelium. Blood viscosity is a significant determinant of blood flow. Under low-flow conditions, platelets have a minor role in the generation of thrombosis; stasis is the dominant factor in the pathogenesis of venous thrombosis in which activated clotting factors circulate to areas of venous stasis, where fibrin is generated. This process is exacerbated by defects in the innate anticoagulant mechanisms. In the arterial system, thrombosis usually arises from endothelial damage, commonly in association with atherosclerosis. Procoagulant mechanisms may be involved in the initiation and progression of atherosclerosis, but local platelet degranulation results in plaque growth. Plaque rupture or ulceration exposes procoagulant material with rapid formation of platelet thrombus, which may break up and embolize or become consolidated and enlarged by fibrin deposition. It follows from the physiology of thrombosis that differing risk factors are responsible for the generation of venous and arterial thrombosis. Furthermore, the multifactorial nature of thrombophilia is becoming increasingly apparent, and individuals with more than one inherited thrombophilia risk factor or those with an inherited and an acquired risk factor are particularly prone to thrombosis. The risk factors for venous thrombosis are distinct from those for arterial thrombosis and ischemic stroke. Routine evaluation for hypercoagulability such as assays for deficiencies of
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coagulation inhibitors, or genetic analysis for factor V Leiden or prothrombin 20210 mutation, are not helpful in identifying risk factors for adult patients with stroke, other than in the context of a patent foramen ovale (see later). New genetic polymorphisms continue to be discovered and evaluated as risk factors for stroke.
Antiphospholipid Antibodies Lupus anticoagulant and anticardiolipin are members of a group of antiphospholipid antibodies that are directed against epitopes on phospholipid-bound proteins and are associated with venous and to a lesser degree arterial thrombosis. β2-Glycoprotein is the target for anticardiolipin antibodies, and prothrombin is thought to be the target for most lupus anticoagulant antibodies. Cardiolipin is a component of mitochondrial membrane and has been used as the antigen in solid-phase assays. The term antiphospholipid does not fully describe the target of anticardiolipin antibody assays. All assays for anticardiolipin antibodies require a source of plasma proteins to facilitate phospholipid binding. In many cases, the required plasma factor is β2-glycoprotein I. Affinity for coagulation-active negatively charged lipids is the basis for phospholipid-dependent coagulation assays for lupus anticoagulant. In systemic lupus erythematosus, predisposition to thrombosis is associated with the presence of antinuclear antibodies and antiphospholipid antibodies. The primary antiphospholipid syndrome is the association between arterial and venous thrombosis with lupus anticoagulant, anticardiolipin or other phospholipid antibodies, or both, and a history of recurrent early miscarriage and sometimes thrombocytopenia, in the absence of systemic lupus erythematosus or other connective tissue disorders. Antiphospholipid antibodies may arise de novo or may be associated with a variety of underlying disorders (Table 13-3). The risk of thrombosis is variable; antiphospholipid antibodies associated with infections and a variety of drugs are associated with a smaller risk of thrombosis than those of primary or secondary antiphospholipid syndromes. In a cohort of 1,000 patients with the antiphospholipid syndrome, 82 percent were female, primary antiphospholipid syndrome was present in 53 157 percent, and SLE was associated in 36 percent. Click here to view this table.... Patients with clinical manifestations may have lupus anticoagulant or anticardiolipin antibodies, or both, and some have antibodies that do not react in all phospholipid-dependent coagulation assays. Testing must therefore include at least two sensitive coagulation assays, usually the kaolin-cephalin clotting time (KCCT) and the dilute Russell's viper venom time (DRVVT) with a platelet neutralization step or kaolin clotting time, as well as solid-phase assays for IgG and IgM anticardiolipin antibody. Long KCCTs may arise from coagulation factor deficiency, and false-negative antiphospholipid antibody testing may arise from binding of the antibodies to platelets in samples not processed rapidly and appropriately. Antibody isotype (IgG or IgM) may be important in pathogenicity, with low titers and IgM antibody most likely to be nonpathogenic; since transient positive antibodies, particularly IgM, may follow a variety of infections, positive tests should be repeated after at least 6 to 12 weeks. Assays of β2-glycoprotein may distinguish between the β-glycoprotein–dependent anticardiolipin antibodies that are associated with infection and the β-glycoprotein–independent antibodies that are more likely to be associated with thrombosis. Anti–β2-glycoprotein I antibodies (Aβ2A) are found in approximately 30 percent of patients with systemic lupus erythematosus and are an independent risk factor for arterial and venous thromboses. Approximately 20 percent of patients with systemic lupus erythematosus who test negative for anticardiolipin antibodies will test positive for Aβ2A; Aβ2A may be more specific than anticardiolipin antibodies in predicting thrombosis, especially in adult patients 158,159 with systemic lupus erythematosus. Antiprothrombin antibodies are found in a higher percentage (50% to 60%) of patients with 160 systemic lupus erythematosus than are anticardiolipin antibodies and Aβ2A, and they also 161,162 The simultaneous constitute an independent risk factor for venous thrombosis. presence of antiprothrombin antibodies is also associated with a higher risk of thrombotic 163 events in patients with primary antiphospholipid syndrome. Annexin V is a natural anticoagulant with a high calcium-dependent binding affinity for negatively charged phospholipids, one that acts competitively with coagulation factors with inhibition of the prothrombin complex. High levels of anti-annexin V antibodies have been 164,165 but it is not yet found in 20 to 30 percent of patients with systemic lupus erythematosus, clear whether they are associated with an increased risk of thrombosis. Of the various antiphospholipid and anticofactor antibodies, anti-annexin V antibodies prove to be the greatest, if not the only, risk factor associated with recurrent pregnancy loss in women with
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systemic lupus erythematosus and in women without autoimmune disease or other risk 166 the antiphospholipid syndrome have been updated, giving factors. The Sapporo criteria for 167 diagnostic significance to Aβ2A. At least one clinical and one laboratory criterion should be met. Clinical criteria include (1) one or more clinical episodes of arterial, venous, or small-vessel thrombosis, confirmed by imaging or histopathology, without significant evidence of inflammation in the vessel wall; and (2) pregnancy morbidity following defined criteria. The laboratory criteria are (1) lupus anticoagulant present in plasma on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis; (2) anticardiolipin antibody of IgG or IgM isotype in serum or plasma, present in medium or high titer (i.e., >40 GPL or MPL, or >99th percentile), on two or more occasions, at least 12 weeks apart, measured by a standardized enzyme-linked immunosorbent assay (ELISA); and (3) Aβ2A of IgG or IgM isotype in serum or plasma (in titer >99th percentile), present on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA, according to recommended procedures. Depression, cognitive dysfunction, psychosis, seizures, chorea, and transverse myelitis have been associated with the presence of antiphospholipid antibodies, although there is evidence that not all arise from ischemia. An interaction between antibodies and CNS cellular elements may account for some of these manifestations. Sneddon's syndrome of cerebral thrombosis in association with livedo reticularis is strongly associated with the presence of antiphospholipid antibodies. In systemic lupus erythematosus, the risk of168thrombosis is increased two- to fivefold in subjects who have the lupus anticoagulant. Venous thrombosis is seen most commonly, 169,170 but arterial thrombosis may also occur in the absence of other recognized risk factors. A study of epilepsy in patients with the antiphospholipid syndrome reveals a prevalence of 8.6 percent. Multivariate logistic regression analysis found CNS thromboembolic events as the most significant factor associated with epilepsy, with an odds ratio of 4.05 (95% confidence interval, 2.05 to 8), followed by systemic lupus erythematosus (OR 1.4, 95% CI 1.2 to 4.7), 171 and valvular vegetations (OR 2.87, 95% CI 1 to 8.27). The cumulative clinical features during the evolution of the disease have been described in 157 1,000 patients with antiphospholipid syndrome. Neurological manifestations included migraine (20.2%), stroke (19.8%), transient ischemic attack (11.1%), epilepsy (7.0%), amaurosis fugax (5.4%), multi-infarct dementia (2.5%), retinal artery thrombosis (1.5%), chorea (1.3%), acute encephalopathy (1.1%), optic neuropathy (1.0%), retinal vein thrombosis (0.9%), transient amnesia (0.7%), cerebral venous thrombosis (0.7%), cerebellar ataxia (0.7%), transverse myelopathy (0.4%), and hemiballismus (0.3%). Many studies have examined the association between antiphospholipid antibodies and stroke, but with inconsistent conclusions as a result of the use of differing patient groups and a selective range of test methods. A study of unselected adults presenting with stroke suggested that the 172,173 but does presence of anticardiolipin antibodies is an independent risk factor for stroke not predispose to subsequent thrombotic events, although other studies failed to confirm 174 this. Another study showed that presence of an antiphospholipid antibody (either lupus anticoagulant or anticardiolipin) among patients with ischemic stroke did not predict either increased risk of subsequent vascular occlusive events over 2 years or a differential response to aspirin or warfarin therapy. Routine screening for antiphospholipid175 antibodies in unselected adults with ischemic stroke has therefore not been recommended. With the introduction of assays for antibodies directed specifically against β2-glycoprotein I, however, a 176 relative risk of stroke of 2 to 3 has been suggested. Studies of a wider range of antiphospholipid antibodies in the pathogenesis of cerebral ischemia suggest a relevant role for a combination of antiphosphatidylserine IgG and anti–β2-glycoprotein I IgA in stroke 177 etiology. A consensus is forming that one or a number of the antiphospholipid antibodies have an association with stroke in adults. Whether this is a risk factor for recurrent vascular events is uncertain, and whether specific treatment is required is quite unclear. Among younger patients, the association appears stronger, with antiphospholipid antibodies present in 46 percent of subjects younger than 50 years who present with stroke or a transient ischemic attack (TIA) compared with 8 percent in matched control subjects with 178 nonthrombotic neurological disease. In young adults, the presence of antiphospholipid antibodies, particularly lupus anticoagulant, has been identified as an independent risk factor 179 for first and possibly also for recurrent ischemic stroke, although a prospective study of young patients with recent TIAs or ischemic stroke suggested that antiphospholipid 180 antibodies are not a strong risk factor for recurrent stroke or TIA. Prothrombotic abnormalities181have been identified in 20 to 50 percent of children presenting with acute ischemic stroke.
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Hereditary Thrombophilia The inherited thrombophilias are a group of disorders in which a defect or deficiency in the natural anticoagulant mechanisms predisposes to the development of venous thrombosis. Within the cerebral venous system, the superior sagittal and transverse sinuses are frequently involved, whereas cavernous sinus thrombosis is much less common. Antithrombin, protein C, and protein S deficiencies, factor V Leiden, the G20210A prothrombin gene mutation and MTHFR C677T mutation resulting in hyperhomocysteinemia predispose to thrombosis, although it is uncertain whether other inherited disorders, such as deficiency of heparin cofactor 2, plasminogen, tissue plasminogen activator, factor XII, or prekallikrein, also result in thrombosis. In homocystinuria, homozygotes are susceptible to arterial and venous thromboses. Genetic or acquired predisposing factors can be identified in 182 as many as 80 percent of patients who develop cerebral venous sinus thrombosis. A genetic risk factor is now identifiable in up to 50 percent of unselected patients with venous 183 thromboembolism, although a lower incidence of inherited thrombophilia of 15 to 19 percent is reported in patients with cerebral venous sinus thrombosis in studies undertaken 184,185 Investigation in before the identification of the 20210A prothrombin gene mutation. potentially inherited disorders must include assessment of family members. Antithrombin Deficiency Antithrombin is a plasma glycoprotein that inhibits thrombin and other activated serine proteases, including factors IXa, Xa, XIa, XIIa, and kallikrein. Heterozygous antithrombin 186,187 and may arise as a new deficiency affects 1 in 2,000 to 5,000 of the population mutation. Deficiency of antithrombin is associated with sagittal sinus and cerebral venous 188 189 thrombosis, and is an under-recognized cause of neonatal seizures. A rarer disorder is recognized in which a nonsense mutation results in a dysfunctional variant of antithrombin 190 causing recurrent venous thrombosis. Acquired antithrombin deficiency associated with cerebral thrombosis may also arise from reduced antithrombin synthesis in liver disease or 191 increased loss in nephrotic syndrome, oral contraceptive use, DIC, protein malnutrition, and heparin therapy. A retrospective cohort family study that assessed the risk of venous thromboembolism in individuals with thrombophilia suggested that individuals with antithrombin deficiency might have a higher risk of thrombosis than that with the other genetic 192 defects. Protein C Deficiency Protein C is a vitamin K–dependent protein that binds to thrombomodulin, an endothelial cell surface protein, and is converted to an active protease by the action of thrombin. In conjunction with protein S, protein C proteolyses factors Va and VIIIa, thereby reducing thrombin formation as well as promoting fibrinolysis. Inheritance of protein C deficiency is usually autosomal dominant, although in some families, heterozygotes with plasma concentrations of less than 50 percent of normal remain asymptomatic, giving an autosomal recessive–like pattern of inheritance. Dysfunctional molecules present in normal levels have been described. Sagittal sinus and cerebral venous thromboses are recognized in 193 association with deficiency of protein C. Population studies suggest that 1 in 200 to 300 subjects have levels of protein C consistent with congenital deficiency, although the incidence of protein C deficiency and venous thromboembolism suggests a prevalence of 1 in 194 30,000. This represents 4 percent of subjects with venous thromboembolism presenting before the age of 45 and demonstrates that other inherited and acquired risk factors are frequently required for thrombosis to occur. Protein S Deficiency Protein S is a vitamin K–dependent glycoprotein that acts as a cofactor for activated protein C. Approximately 60 percent of it is protein bound, so that total and free protein S must be measured. Only the unbound protein is biologically active, and since its level may fall in acute disease, repeat measurement and the demonstration of a persistently reduced level is required to prove association with disease. In the presence of factor V Leiden, functional assays of protein S may give a falsely low reading. Sagittal sinus and cerebral venous 195 thromboses are reported in association with deficiency of protein S. Factor V Leiden (RQ506Q) Factor V Leiden is a point mutation in factor V at Arg 506, where protein C cleaves and
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inactivates the Va procoagulant. This results in a poor response to the anticoagulant activity of activated protein C, a key enzyme in the downregulation of blood coagulation, resulting in a predisposition for a hypercoagulable state. It is the most common inherited prothrombotic 196 accounting for at least 90 percent of the cases with resistance to activated protein state, 197 C. The mutation is inherited as an autosomal-dominant trait and has a prevalence of 2 to 10 percent in the general white population. A number of clinical studies, using different inclusion criteria, show a prevalence of activated protein C resistance of 20 to 60 percent among patients with venous thromboembolism at any site, and 20 to 25 percent for cerebral venous thrombosis. The actual thrombotic risk is moderate, with an odds ratio of 5:7, but its high prevalence makes it by far the most important inherited risk factor known today, exceeding184,197–199 the sum of contributions from inherited deficiencies of antithrombin, protein C, and protein S. Activated protein C resistance, which is not due to factor V Leiden and which appears to be acquired, is also a risk factor for venous thrombosis. A decreased response to activated protein C is common during pregnancy and during the use of oral contraceptives, although the clinical relevance of these findings remains unclear. Thrombotic events often occur in the presence of inherited and circumstantial risk factors. Noninherited factors predisposing to cerebral venous thrombosis (e.g., oral contraceptive intake, pregnancy, puerperium, trauma, or prolonged immobilization) were reported in 72 percent of cases of cerebral venous 199 thrombosis with factor V Leiden. Prothrombin G:A 20210 Mutation Prothrombin is a precursor of the serine protease thrombin, a key enzyme in the production of fibrin from fibrinogen. A single nucleotide substitution (G to A) at position 20210 in the 3′-untranslated region of the gene encoding prothrombin is associated with elevated plasma prothrombin200,201 and an increased risk of deep venous thrombosis and cerebral venous The mutation is found in 18 percent of selected patients with a family thrombosis. history of venous thrombosis, 6 to 7 percent of unselected patients with deep vein thrombosis, and 1 to 2 percent of control subjects, making it the second most common cause 201–203 The prevalence of the prothrombin of hereditary thrombophilia after factor V Leiden. gene mutation is 20 percent in patients with cerebral vein thrombosis in comparison with 3 199 percent in healthy control subjects.
Hyperhomocysteinemia Hyperhomocysteinemia is a risk factor for venous thrombosis. A C-to-T mutation at position 677 in the methylene tetrahydrofolate reductase gene (MTHFR) gives rise to a thermolabile variant with reduced activity and to elevated plasma homocysteine. Homozygosity for the thermolabile form is found in 5 to 15 percent of the general population, who have significantly elevated plasma homocysteine levels. Some studies suggest that being a homozygote for 204,205 Others have found that although MTHFR-T is a risk factor for venous thrombosis. homozygotes have consistently elevated plasma homocysteine concentrations, this is not a 206–208 Moderate risk factor for deep-vein thrombosis, regardless of factor V Leiden genotype. hyperhomocysteinemia209is now recognized as a risk factor for arterial disease, including 210 carotid artery stenosis and stroke. This mutation has not yet been systematically investigated in cerebral venous sinus thrombosis. Further discussion of hyperhomocysteinemia is provided in Chapter 61.
Factor VIII Levels of factor VIII are associated with the risk of venous thrombosis, and factor VIII gene 211 variations do contribute to both levels of factor VIII and the risk of thrombosis. Elevated levels of factor VIII coagulant activity within families is associated with an increased risk of 212 both arterial and venous thromboses. Cerebral venous sinus thrombosis has been 213 described in hyperthyroidism, which may be associated with elevated factor VIII levels.
Interactions Between Inherited Thrombophilias The multifactorial nature of thrombophilia, both circumstantially and at a genetic level, is increasingly well recognized. Among 162 patients and 336 control subjects investigated for thrombophilia after documented venous thromboembolism, two or more polymorphisms were detected in 16.7 percent of patients and 0.9 percent of control subjects; the odds ratios for joint occurrence of factor V and prothrombin G20210A was 58.6, compared with 35.0 for
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factor V and MTHFR polymorphisms, and 7.7 for prothrombin G20210A and MTHFR 205 protein S polymorphisms. Coexistence of additional antithrombin III, protein C, or 214 deficiency is reported in 14.5 percent of patients with the Leiden mutation. A combination of prothrombin gene G20201A variant and factor V Leiden is associated with an increase in the prevalence of more unusual sites of venous thrombosis, such as the cerebral venous 215 system. A case has been reported of massive thrombosis of cerebral venous sinuses in a 2-year-old 216 boy with a combined inherited deficiency of antithrombin III and protein C. Concomitant inferior vena cava, iliac, femoral, and cerebral venous thromboses were reported in a woman with combined protein C deficiency and protein C–activated resistance commencing 10 days 217 after she had started using an oral contraceptive.
Interactions Between Inherited and Acquired Risk Factors The incidence of inherited thrombophilia exceeds the incidence of venous thrombosis, suggesting that additional factors are required for thrombosis to occur. The use of oral contraceptives is strongly and independently associated with cerebral vein thrombosis. The presence of both the prothrombin gene mutation and oral contraceptive use further raises the 199 risk of cerebral vein thrombosis. In women who use oral contraceptives and also carry factor V Leiden mutation, protein C, protein S, or antithrombin deficiency, the odds ratio for cerebral sinus thrombosis is about 30 relative to women who had neither risk factor. A combination of these factors appears to interact in a multiplicative way in the development of 185 cerebral sinus thrombosis. In a study of the interaction between various risk factors for cerebral venous thrombosis in children, 56.4 percent had at least one prothrombotic risk factor compared with 20.8 percent of controls. An underlying predisposing condition was found in 70.5 percent of 149 patients. On univariate analysis, factor V, protein C, protein S, and elevated lipoprotein(a) were found to be significantly associated with cerebral venous thrombosis. However, in multivariate analysis, only the combination of a prothrombotic risk factor with an underlying condition (OR 3.9, 95% CI 1.8to 8.6), increased lipoprotein(a) (OR 4.1, 95% CI 2.0 to 8.7), and protein C deficiency (OR 11.1, 95% CI 1.2 to 104.4) had 218 independent associations with cerebral venous thrombosis.
Thrombophilic Disorders and Arterial Thrombosis Although there are numerous220reports of cerebral arterial thrombosis and infarction occurring 219 221,222 223 deficiencies, and 224 factor V Leiden, the in antithrombin, protein C, and protein S risk is extremely small compared with the risk of venous thrombosis. A stroke in the presence of a strong risk factor for venous thrombosis should therefore always raise the suspicion of paradoxical venous embolism. Only rarely has familial thrombophilia been conclusively diagnosed following arterial thrombosis, by demonstrating that the deficiency persists after the acute event is over. This is particularly important in the case of protein S, since it binds to an acute-phase reactant (C4bBP), resulting in an acquired reduction in free or functional protein S. Low protein S levels are also found in acute nonvascular illness and during pregnancy, and protein C levels may fall in liver disease, postoperatively, and in association with DIC. Mayer and colleagues, in a case-controlled study, concluded that acquired deficiency of protein S is not a major risk 225 factor for226 stroke. The degree of reduction in protein C levels correlates with the severity of demonstrate that it may take 3 months for levels a stroke. Serial protein C measurements 227 studies have failed to identify an to return to normal following a stroke. Case-control 228,229 association between factor V Leiden and stroke. A number of reports suggest that hereditary thrombophilia may be associated with stroke in childhood, 230 but reference ranges are lower than for adults, so the association may be erroneous. Ethnic differences have also been noted in the levels of markers of 231 thrombophilia in stroke, emphasizing the need for care in interpreting these investigations. In a comparative study of 191 patients with arterial disease and 296 unmatched control subjects, 19 percent of those with arterial disease were homozygous for the mutated MTHFR-T allele compared with 4 percent of controls (odds ratio, 5.52). These data support the hypothesis that204,232 being a homozygote for the MTHFR-T is a risk factor for the development of arterial disease. A possible relationship has been described between the presence of prothrombin gene variant and233atrial fibrillation although not with thromboembolism in the context of atrial fibrillation.
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Patent Foramen Ovale Inherited prothrombotic states, such as the factor V Leiden and prothrombin gene G20210A mutations, elevated levels of factor VIII, and decreased activity of protein C, protein S, and antithrombin are linked to an increased risk of venous thromboembolism. There is still a lack of evidence supporting an association between these states and brain infarction in general. In patients 55 years or younger with cryptogenic brain infarction, patent foramen ovale has been shown to be a more common finding (56%) than in controls (18%) and in patients with brain infarction of undetermined cause (17%), suggesting paradoxical embolism as the mechanism 234,235 A strong association has been shown between the presence of coagulation for stroke. abnormalities, especially factor V Leiden and prothrombin G20210A mutations, and a history of Valsalva maneuver–like activity at stroke onset. Such activity was more common at stroke onset in patients with than without patent foramen ovale. Coagulation abnormalities have been found in 30 percent of patients with cryptogenic infarction who also had patent foramen 236 ovale. In another study in young adults, the PTG20210A variant and, to a lesser extent, the FVG1691A mutation, appeared to represent risk factors for cerebral infarcts related to patent foramen ovale. No significant association was found in the distribution of the MTHFR 237 genotype. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 14 Hepatic Encephalopathy ALAN H. LOCKWOOD •
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HISTORY TERMINOLOGY FULMINANT HEPATIC FAILURE PORTAL SYSTEMIC ENCEPHALOPATHY Neuropathology Pathophysiology Cerebral Blood-Flow and Glucose Metabolism Ammonia Abnormalities of Neurotransmission GABA-Benzodiazepine Complex Mercaptans and Short-Chain Fatty Acids Summary Therapy General Measures and Diet Lactulose Neomycin Lactitol Transjugular Intrahepatic Portosystemic Shunts Outcome
The liver occupies a complex central position in the gastrointestinal system. The central nervous system (CNS) is absolutely dependent on the liver for (1) maintaining normal blood glucose levels; (2) the intermediate metabolism of a variety of other nutrients, vitamins, and trace elements, required for normal brain function; and (3) removal of toxic metabolic wastes. Hepatic encephalopathy is a common manifestation of liver disease in adults and is due primarily to a failure of this third function of the liver. Liver disease is an important contributor to morbidity and mortality in the United States. Data from the National Institute of Diabetes and Digestive and Kidney Diseases indicate that each year about 25,000 Americans die of cirrhosis of the liver, making cirrhosis a leading cause of death by disease. As cirrhosis reaches its terminal phases, neurological impairment becomes a problem of increasing importance. Other diseases of the liver may express themselves via secondary CNS dysfunction. Fulminant hepatic failure, Wilson's disease, and other metabolic disorders may have an important secondary impact on the neurological symptoms.
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HISTORY Descriptions of what was probably hepatic encephalopathy appear in the writings of early authors, including Galen, Hippocrates, and perhaps even Shakespeare. However, clear, 1 contemporary descriptions follow Frerichs's treatise on liver disease. Frerichs wrote (as translated by Murchison): In most cases we can distinguish two stages, that of excitement and depression…characterized by delirium and convulsions and…progressively increasing coma.…In most cases, the nervous system derangements appeared simultaneously with jaundice; and they usually attracted the attention of the observer sooner than the slight jaundiced tint of the conjunctivae. Frerichs noted that it is common for hepatic encephalopathy to be recognized first by someone other than the patient or physician—that is, the “observer,” who may be a family member or other associate. He further noted: Toward the termination of the disease the delirium and convulsions, as a general rule, gave place to stupor, which in a short time has merged into the deepest coma, from which no shaking could rouse the patient. Frerichs was undoubtedly describing what we would now call fulminant hepatic failure. This condition was invariably fatal at that time and is still associated with a high mortality rate in the absence of transplantation. As Frerichs did not describe remissions or recoveries, he was probably not describing portal systemic encephalopathy. This latter condition, now the most common form of hepatic encephalopathy, undoubtedly existed at that time, as suggested by this quote from Shakespeare's “Twelfth Night.” Sir Andrew Aguecheek: But I am a great eater of beef and believe that does some harm to my wit. The failure to differentiate portal systemic encephalopathy from acute hepatic failure may have been due to high mortality rates associated with both conditions. Frerichs also had excellent insight into the pathophysiological mechanisms causing encephalopathy: Abnormal nervous symptoms… must be referred to changes in the blood. I attribute the cause of the blood-intoxication to the complete arrest of the hepatic functions…[and] also [to] the cessation of the powerful influence which the liver exerts over the processes of metamorphosis of matter. Most of the progress in defining the pathophysiology of hepatic encephalopathy consists of nothing more than refinement of this broad but accurate statement. TERMINOLOGY Some of the current confusion in the literature is the result of terminology that is poorly defined and used. The term hepatic encephalopathy, which is often used synonymously with portal systemic encephalopathy, refers to a syndrome of reversible cerebral dysfunction associated with chronic liver disease (usually cirrhosis) that is often associated with portal hypertension and shunts that divert hepatic portal blood into the systemic circulation; chronic portal systemic encephalopathy implies a sustained condition with a potential for reversibility. This term should not be used synonymously with hepatocerebral degeneration. Other misused terms include subclinical hepatic encephalopathy, abbreviated as SHE, and latent hepatic encephalopathy. These terms refer to a condition of apparent clinical normality with impaired function detected by specialized testing. These tests include neuropsychological evaluations, the most reliable method, but may include electrophysiological tests, such as the electroencephalogram (EEG) or event related potentials. Minimal hepatic encephalopathy is the term advocated by a World 2 Gastroenterology consensus panel to describe these patients. FULMINANT HEPATIC FAILURE Fulminant hepatic failure is a condition in which patients with a previously normal liver develop encephalopathy within 8 weeks of the onset of their liver disease. Viral hepatitis and toxin exposure are frequent causes. Ingestion of excessive quantities of acetaminophen, a drug that is particularly hepatotoxic, is common as a suicide attempt or gesture or as an accident by children. A recent review indicates that there were nearly 400,000 reports to poison control centers of ingestions of analgesics, cough remedies, or cold preparations, i.e.,
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compounds that are likely to contain acetaminophen. This condition is associated with a mortality rate of about 85 percent. Death is often due to cerebral edema and may occur within days of the onset of the disorder. The features that differentiate fulminant hepatic failure from portal systemic encephalopathy are shown in Table 14-1. Click here to view this table.... Because the initial signs and symptoms of fulminant hepatic failure are frequently referable to the brain, neurologists may be among the first to be involved in the care of these patients. Nausea, vomiting, and abdominal pain associated with delirium or mania are common in the initial stages. These symptoms evolve rapidly to a comatose state associated with generalized seizures. The goal of therapy is to support patients so that they recover or remain candidates for orthotopic liver transplantation. This requires specialized care, preferably in a transplant center, and admission to an intensive care unit. Depending on the signs and symptoms and the tempo of evolution, computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain should be done to evaluate the size of the cerebral ventricles, an indicator of the presence of cerebral edema and an increase in intracranial pressure. The edema is due to an increase in brain water that is the result of an increase in astrocytic glutamine 4 content. The decision about whether to place an intracranial-pressure monitoring device must be made. These devices are not without risk, and their use is somewhat controversial. 5 Among 324 patients in a recent series, 28 percent had intracranial pressure monitored. In a subset of these, 10.3 percent had radiographic evidence of an intracranial hemorrhage. Of these hemorrhages, half were incidental findings. However, any cerebral hemorrhage, particularly in a patient who is likely to have clotting factor abnormalities, is a cause for concern. The authors concluded that patients who did not undergo intracranial-pressure monitoring were treated less aggressively, even though they were placed on transplant lists. Neurological treatments involve the use of hyperventilation, to reduce cerebral blood volume, and osmotic diuretics, to control increased intracranial pressure that is due to the combined effects of edema and changes in blood flow and volume. In a study of cerebral blood-flow in patients with fulminant hepatic failure, Strauss and co-workers. found that hyperventilation 6 appears to have no effect on the pattern of blood flow. In these patients, who had grade 4 hepatic encephalopathy, the relative reduction in blood flow in frontal and basal ganglionic regions that was found before the initiation of hyperventilation persisted and was not aggravated by hyperventilation. Among survivors, the pattern of flow returned to normal, suggesting that this therapy does not predispose to the development of hypoxic-ischemic damage. In addition to these measures, exchange transfusions may be performed to reverse clotting abnormalities and preserve neurological function. In some centers, experimentation with 7 hepatotrophic agents and artificial livers may serve as a bridge to transplantation. Since there are more candidates for transplantation than organs available, it is important to screen patients properly so that patients who do not require transplantation are not subjected to this therapy (i.e., those who do not have severe and worsening encephalopathy) and to avoid transplantation when the prognosis for neurological recovery is hopeless. Among children, the development of radiographic evidence of cerebral edema is an indicator of a very poor 8 prognosis. A better understanding of the pathophysiology of fulminant hepatic failure may lead to the development of better medical 9treatment that will reduce or obviate the need for orthotopic 10 transplantation. Studies by Blei and Norenberg and their associates have been particularly important in this regard. Blei and his colleagues have studied rats with portacaval shunts 11 during ammonia infusions. They found that the infusion led to an increase in glutamine, as might be expected, and an increase in blood flow. This led to a significant increase in brain water, i.e., brain edema. Treatment with the glutamine synthetase inhibitor, methionine sulfoximine, reduced the brain glutamine concentration and blood flow while increasing blood ammonia levels. Along with the decrease in glutamine, there was a decrease in edema, leading to the speculation that ammonia-induced glutamine formation plus the cerebral hyperemia that attends the increase in blood flow are important mechanisms for the production of brain edema. They suspect that nitric oxide synthase may mediate the blood flow increase and could be a target for future therapy. The work of Norenberg and co-workers is discussed later. PORTAL SYSTEMIC ENCEPHALOPATHY Alterations in the level and the content of consciousness are the hallmarks of hepatic encephalopathy. Most clinical grading systems are based on the level of consciousness, as
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shown in Table 14-2. There is a substantial amount of variation in the severity of these abnormalities, which may be so subtle that they are unrecognized. The onset may be slow and insidious, making early diagnosis and treatment difficult, or rapid, with progression to death within days. This early stage is a classic delirium, defined as a disturbance of consciousness with a reduced ability to focus, sustain, or shift attention. Delirious hypervigilant states are less common. As this is a disorder that affects the entire brain to varying degrees, all systems may be affected as the clinical condition worsens. Wernicke's encephalopathy should be suspected in patients with delirium, particularly if they have alcoholism. This disorder is more common than generally believed and usually presents without the full triad of delirium, disordered ocular motility, and ataxia. In some autopsy series, pathological evidence of unsuspected evidence of Wernicke's encephalopathy has been found in more than 2 percent of cases. Click here to view this table.... For over 20 years, some clinicians have recognized that many patients with cirrhosis will score in the impaired range on neuropsychological tests in spite of the fact that they do not have any overt evidence of encephalopathy. This association was first recognized by Rikkers 12 and colleagues in their evaluation of patients with portacaval shunts. They found impairment in 60 percent of their 30 patients. They attributed this impairment to hyperammonemia, and they reported that treatment led to improvement. They coined the unfortunate term subclinical hepatic encephalopathy, abbreviated as SHE by some, to describe this association. Since then, numerous studies, conducted under a variety of circumstances, have expanded on this finding. In a study of alcohol-induced cirrhosis that used alcoholics without liver disease as a control, Gilberstadt and 13 associates concluded that it was the liver disease itself that caused the cerebral dysfunction. Tarter and his colleagues performed one of the earliest, highly detailed neuropsychological investigations of patients with cirrhosis of several etiologies unrelated to alcohol consumption and found that measures of visuopractic 14 capacity, visual scanning, and perceptual-motor speed were impaired. The impairment was not global, in that intellectual, language, memory, attentional, motor, and learning abilities were intact. In that same study, an impact on daily life was found by use of the Sickness Impact Profile (SIP). The findings and the use of patients with Crohn's disease as a control for chronic disease suggested strongly that it was cirrhosis itself that caused these abnormalities. Other and larger studies have extended these findings. In a large, multicenter study performed in Germany, almost 300 different physicians administered a number connection15 and line drawing test to 783 patients: of the 771 valid results, 71.5 percent were abnormal. In a Dutch study of 179 patients, encephalopathy was defined as an abnormal result on the 16 Trailmaking A test, digit symbol test, or slowing of the EEG using automated analysis. The 48 encephalopathic patients whom they identified had significantly more impairment on the basis of the total SIP score as well as on all 12 scales of the SIP, the psychosocial subscore, and the physical subscore. Should patients with minimal hepatic encephalopathy drive an automobile? Recognizing that human error is the leading cause of automobile accidents, this question has been addressed by several groups. Schomerus and co-workers suggested that cirrhosis impacts daily life in a 17 was study that reported a large proportion of cirrhotics were unfit to drive. This finding 18 disputed by Srivastava and associates, who observed actual on-the-road driving. Wein and collaborators studied 14 cirrhotics with minimal encephalopathy, defined by neuropsychological testing, and compared their driving ability to 34 cirrhotics without encephalopathy and 49 patients with stable gastroenterological disease not affecting the 19 liver. They employed a blinded driving instructor who rated performance on a 22-mile 90-minute road test. The performance of encephalopathic patients was significantly worse in terms of handling, adaptation to road conditions, and cautiousness. Accident prevention required active intervention by the instructor in 5 of the 14 encephalopathic patients. These and other data show clearly that there are groups of cirrhotic patients whose lives are impacted by their condition. Several caveats are important. As with all forms of delirium, attentional mechanisms and the level of consciousness are likely to vary substantially over relatively brief periods of time. In employing neuropsychological tests, it is important to use age-defined normals, since performance on some tests changes as a function of aging. The use of young normal control values when testing an older patient is likely to generate a false-positive outcome. This problem is most likely to occur when poorly trained individuals administer the tests. A test battery consisting of Trailmaking tests A and B, serial dotting, line tracing, and the digit-symbol subtest of the Wechsler Adult Intelligence Scale (Revised) has
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been recommended for evaluation of patients who may have hepatic encephalopathy because it is sensitive and relatively specific for the disorder compared to other metabolic 2 encephalopathies. Taking these caveats into account, patients with cirrhosis should be evaluated in an attempt to determine whether their functional status is impaired, based on the best estimates of the premorbid state. If impairment is found, or even suspected, it is reasonable to treat these patients, preferably in a prospective manner, and re-evaluate their status at appropriate intervals. If improvement is found, treatment should continue. Since these patients are impaired by many measures, and because many improve, it is not appropriate to use the term subclinical hepatic encephalopathy, or SHE, to describe them. The problem is of clinical importance. The use of the term SHE and the related misnomer latent encephalopathy risks trivializing the importance of diagnosis and treatment for a condition that has a measurable and significant impact on the quality of life. The function of the cranial nerves in patients with hepatic encephalopathy is almost invariably intact unless the patient is near death, as may be the case for patients with cerebral edema complicating fulminant hepatic failure. Reliable assessment of the visual fields may be impossible (but visual evoked potentials usually indicate intact pathways). Frequently the pupils are smaller than normal, and pupillary constriction in response to light may be slower than normal. Oculovestibular and caloric responses are usually intact, and passive head moving typically produces eye movements that indicate functional integrity of the third and sixth cranial nerves. If a disorder of ocular motility is found, Wernicke's encephalopathy should be suspected, and the patient should be treated with thiamine. The corneal reflex is usually preserved. Motor responses may be varied, but the characteristic flapping tremor, or asterixis, is frequently encountered in patients well enough to be tested. Asterixis was originally thought to be pathognomonic for hepatic encephalopathy. However, experience has shown that this physical sign may be associated with other metabolic encephalopathies, such as uremia, and structural brain lesions. Electrophysiological studies have shown that the postural lapses are associated with sudden and unexplained periods of complete electrical silence in muscles. The sign may be elicited from a variety of voluntary muscles, including arm and hand extensors, flexors of the leg, and protruders of the tongue. Increased muscle tone, hyperreflexia, and extensor plantar responses are common and may be the source of some confusion when excluding a structural lesion of the brain, such as an occult chronic subdural hematoma. Abnormal involuntary movements may be observed transiently. The sensory examination may not be helpful and is probably best used to evaluate the depth of coma. Patients with liver disease may have peripheral neuropathies that can result in reflex loss or altered sensation. Although in many cases the ultimate decision concerning the diagnosis is clinical, laboratory tests are frequently helpful. Liver function tests are usually abnormal, but derangements may not be as drastic as expected on the basis of the clinical examination. Chronic, severe liver disease may be associated with relatively normal serum enzymes and a modest level of hyperbilirubinemia. In these cases, however, hypo-albuminemia and clotting factor deficiency may be substantial and a more reliable guide to the severity of the liver disease. The arterial blood ammonia level, when measured properly in the fasting state, is a useful test and provides an excellent correlation with the clinical state and the rate of ammonia uptake and metabolism by the brain. Several precautions must be taken to ensure that the results of the test are valid. The blood must be arterial. Venous blood is unacceptable because of the release of ammonia by muscle made partly ischemic by a tourniquet and the unpredictable ammonia uptake by muscle itself. Because of the phenomenon of toxin hypersensitivity, discussed later, a so-called normal or slightly elevated arterial ammonia level may still be compatible with encephalopathy that is severe. Electrophysiological studies, especially the EEG and perhaps visual evoked potentials, may be helpful in establishing the diagnosis and evaluating the response to therapy. Three phases in the evolution of the EEG abnormalities can be recognized: a theta stage with diffuse 4- to 7-Hz waves, a triphasic stage with surface-positive maximum deflections, and a delta stage with random, nonrhythmic slowing without much bilateral synchrony. Brenner in his review described bursts of moderate- to high-amplitude waveforms (100 to 300 20 μV) with low frequencies (1.5 to 2.5 Hz) as being the most characteristic abnormality. Weissenborn and colleagues have reported that the auditory oddball P300 event-related potential is abnormal in a fraction of patients with cirrhosis similar to the frequency of abnormal Trailmaking test 21 results. These tests are somewhat cumbersome to administer and require equipment and expertise not found in typical gastroenterology clinics. They may be helpful in the evaluation
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of some patients. Neuroimaging studies 22 have limited usefulness in the diagnosis of hepatic encephalopathy (as is reviewed elsewhere ). They are most useful in excluding structural lesions of the brain, such as a subdural hematoma. MRI has demonstrated abnormalities in the pallidum on 23–25 The abnormality was correlated with the T1-weighted images as shown in Figure 14-1. 26 blood ammonia level and may regress or disappear after successful liver transplantation. Although the increases in the pallidal T1 signal intensity are the most typical and easily observed abnormality, the T2 signal intensity is also abnormal. This shortening is more difficult to detect visually because of the already short T2 values seen in typical image sets. In addition to the pallidal abnormalities, T1 signals are increased in other brain regions including the pyramidal and extrapyramidal systems and limbic regions of the brain. The MRI 27–29 Similar abnormalities appear to be due to increased manganese levels in the brain. abnormalities have been observed in patients with increased manganese loads due to parenteral hyperalimentation, 30–32 after manganese exposure, and in monkeys after the administration of manganese.
FIGURE 14-1 T1-weighted transaxial plane magnetic resonance imaging (MRI)
of a patient with cirrhosis, showing an increase in signal intensity in the pallidum. Arrowheads define the abnormality on the right side of the image. This abnormality is thought to be the result of an increase in manganese content. The abnormality may regress or disappear after successful liver transplantation. (Courtesy of the Department of Radiology, Cleveland Clinic Foundation.) Proton MRI spectroscopic studies of cirrhotics have revealed a relatively consistent pattern of increases in the glutamate–glutamine 22,33–35 complex, reductions in choline and myoinositol, and With magnets of very high field strength, it is preservation of N-acetyl-aspartic acid. possible to separate the glutamate and glutamine signals. Although these spectroscopic findings are relatively specific, MR spectroscopy has no advantages over other testing methods, particularly neuropsychological testing, at the present time and is cumbersome and expensive.
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Neuropathology The Alzheimer type II astrocyte is the neuropathological hallmark of patients with hepatic encephalopathy. Adams and Foley provided a translation of the original description in their 36–38 These abnormal astrocytes are found in many locations, including the classic paper. cortex and the lenticular, lateral thalamic, dentate, and red nuclei. Adams and Foley speculated that the duration of coma might correlate with the severity of the abnormality. 39 Ammonia was shown to produce the Alzheimer II transformation by Cole and associates. In rats with portacaval shunt–induced hyperammonemia, Alzheimer II cells become evident after 5 weeks, a time course that parallels the development of the low blood flow and low oxygen metabolism in response to chronic hyperammonemia. Ultrastructurally, these astrocytes appear to be metabolically hyperactive, and immunohistochemical staining techniques have shown increases in the activity of glutamic acid dehydrogenase and glutamine synthetase, leading Norenberg to speculate that hepatic encephalopathy is a 10 syndrome due to astrocyte dysfunction.
Pathophysiology Improvements in the care of patients with hepatic 1encephalopathy have been substantial since the rather dismal account given by Frerichs. These improvements have been linked closely to improvement in our understanding of the pathophysiology of the disorder. Because of the complexity of the metamorphosis of matter that attends normal hepatic function, to use Frerichs's analysis, it is no surprise that a number of hypotheses have been advanced to explain the development of hepatic encephalopathy. Suspected factors include hyperammonemia and the effects of ammonia on neural function, altered amino acid and neurotransmitter function, elevated mercaptan concentrations, high levels of short-chain fatty acids, and altered function of the GABA-benzodiazepine complex. These abnormalities may then have further effects on cerebral metabolism. Cerebral Blood-Flow and Glucose Metabolism Cerebral blood-flow and metabolism studies in patients with hepatic coma have shown the reductions that would be expected in patients with reduced levels of consciousness. 40–42 Successful treatment normalizes flow and metabolism. Animal studies of flow and metabolism have been helpful in elucidating possible mechanisms related to ammonia intoxication. Gjedde and colleagues measured blood flow and oxygen metabolism in normal rats and in rats 4 and 8 weeks after portacaval shunting; measurements were made under baseline conditions and serially after an ammonia 43 challenge. The ammonia challenge had little effect on the control animals and in the rats at 4 weeks after shunting. However, after 8 weeks, the ammonia challenge caused a significant reduction in flow and metabolism. This increase in toxin sensitivity emerges during the same time interval that the Alzheimer II astrocyte transformation becomes apparent. These experimental data support the clinical observations and the hypothesis that toxin 44 hypersensitivity develops as liver disease advances. Studies of cerebral blood-flow and glucose metabolism in patients with minimal levels of 45 encephalopathy have shown a characteristic pattern. In patients with chronic liver disease and grade 0 to 1 encephalopathy, the pattern of blood flow and glucose metabolism, as shown by positron emission tomography (PET), is abnormal even though global rates are unaffected. In a study of patients with cirrhosis and minimal encephalopathy that used more sophisticated statistical methods to evaluate glucose metabolism, reductions were found in the cingulate46gyrus, a part of the anterior attentional center, the frontoparietal cortex, and the cerebellum. These regions may be functionally impaired and contribute to the expression of clinical symptoms. More recent PET studies have shown significant correlations between low glucose metabolic rates in distinct frontal and parietal 47 brain regions and impaired performance on a variety of neuropsychological tests. Additional studies are likely to clarify the relationships between cerebral metabolism and neuropsychological test performance and clarify the pathophysiology of minimal encephalopathy. Ammonia Ammonia is the most completely studied of the neurotoxins implicated in the pathogenesis of hepatic encephalopathy. Early investigators thought that ammonia in the blood was an artifact, produced by the breakdown of proteins as the blood stood at room temperature. However, after the perfection of suitable methodology, it was realized that ammonia is indeed
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present in normal blood. The beginnings of the link between ammonia and encephalopathy are best dated to the studies of Gabuzda and associates, who reported the development of encephalopathy in patients treated with resins that exchanged serum sodium ions for 48 resin-bound ammonium ions. Further studies correlated the changes in mental status with the development of hyperammonemia and led to recommendations that ammonia-containing compounds be avoided in patients with liver disease. Later, Sherlock correlated the fasting 38 a number of publications arterial ammonia level with the severity of coma. Subsequently, 37,49 The evidence that supports the and reviews supported and strengthened this correlation. ammonia hypothesis can be summarized briefly. First, there is a good correlation between the degree of hyperammonemia and the depth of coma. The metabolites of ammonia, notably glutamine and its transamination product, α-ketoglutaramate, are elevated in the brain and cerebrospinal fluid (CSF) of patients with hepatic encephalopathy. Second, patients with encephalopathy have higher rates of ammonia uptake and metabolic trapping by the brain than do nonencephalopathic controls. Third, ammonia reproducibly precipitates episodes of coma, along with compounds that form ammonia in the gastrointestinal tract, such as blood from a hemorrhage or protein meals. Fourth and finally, the most effective treatments for hepatic encephalopathy act to reduce blood ammonia levels. Ammonia is a gas that is highly soluble in water, where it forms a weakly basic solution. At physiological pH values, 1 to 2 percent of the ammonia is present as the gas, with the remainder present as the ammonium ion. Ammonia is normally produced in the gastrointestinal tract and carried to the liver by the hepatic portal vein (Fig. 14-2). In the liver, ammonia is converted to urea by the enzymes of the urea cycle, and the urea is excreted by the kidneys. A portion of the urea enters the gastrointestinal tract and is hydrolyzed to form ammonia in an enterohepatic circulation of nitrogen. In the rest of the body, ammonia is taken up by skeletal muscle to form glutamine, which is then transported to the liver, where the amide nitrogen is used in urea synthesis. Ammonia is released by skeletal muscle and the kidney. About 7 percent of the ammonia in the systemic circulation is trapped by the brain. Liver disease leads to the shunting of ammonia-rich blood from the portal into the systemic circulation.
FIGURE 14-2 Human ammonia metabolism. Most ammonia is formed in the colon,
although other organs make a contribution as well. Ammonia in the hepatic portal vein is normally detoxified by the enzymes of the urea cycle in the liver. Portal-systemic shunts cause excessive amounts of ammonia and probably other toxins to enter the systemic circulation and reach the brain. About 7 percent of the ammonia in the
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systemic circulation is taken up and metabolized by the brain. Skeletal muscle also is an important organ for ammonia homeostasis, taking up ammonia and converting it to glutamine, which is subsequently converted to urea in the liver. Data suggest a complex interaction between hyperammonemia, its effects on cerebral satiety centers, and the development of cachexia. (From Lockwood AH, McDonald JM, Reiman RE, et al: The dynamics of ammonia metabolism in man: effects of liver disease and hyperammonemia. J Clin Invest 63:449, 1979, with permission.) Cerebral ammonia metabolism studies 13 have been facilitated by the use13of the cyclotron-produced radioactive isotope N, which is easily made into [ N]ammonia. The first of these quantitative studies of ammonia metabolism was performed by Lockwood and associates. Their initial studies showed that about 1 mol of37ammonia is removed from the systemic circulation each day by the various body organs. Somewhat surprisingly, skeletal muscle was shown to be a major organ in ammonia homeostasis. In patients with end-to-side portacaval shunts, skeletal muscle becomes the single most important organ for maintaining 13 ammonia homeostasis. Subsequent studies using [ N]ammonia have shown that the blood–brain barrier is highly permeable to ammonia, despite the fact that it is highly ionized at physiological pH values and that the permeability of the barrier to ammonia is such that, at normal blood flow and pH values, about half the ammonia presented to the brain is extracted by the brain and trapped metabolically as glutamine. Two studies of cerebral ammonia metabolism have shown that the rate of ammonia uptake and metabolic trapping is disproportionately high in patients with hyperammonemia and 37,50 This may be due to51an increase of the permeability–surface area product of the cirrhosis. blood–brain barrier to ammonia. This observation was challenged in a more recent paper in which the blood–brain barrier to ammonia was reported to be less permeable to ammonia in 52 patients with hepatic encephalopathy. In correspondence that followed the publication of this paper, the authors indicated that an arithmetic error had occurred, and there was no difference between the controls and the patients with hepatic encephalopathy. Although this issue is unresolved, an increase in the ease with which ammonia in the arterial blood gains access to the brain would explain why some patients with minimal hyperammonemia become symptomatic and develop toxin hypersensitivity with the passage of time. The mechanisms by which ammonia affects brain function are still a matter of substantial interest. Virtually every aspect of neuronal function appears to be affected by ammonia. In addition to affecting glucose metabolism, ammonia affects brain energy metabolism, disrupts amino acids profiles in the brain (particularly that of glutamate), and alters the physiology of neural membranes by affecting the chloride pump, producing a reversible depolarizing shift in the inhibitory postsynaptic potential toward the resting potential. The subject is reviewed in 49 detail elsewhere. The studies of Norenberg and his collaborators suggest strongly that at least part of the effect 10 of ammonia is due to astrocytic dysfunction. These studies show that ammonia reduces the ability of astrocytes to remove glutamate from the extracellular space. This excess of glutamate may cause excitotoxic cellular injury. In addition, ammonia causes an increase in the peripheral type of benzodiazepine receptor and an associated increased production of neurosteroids that, in turn, modulate neuronal GABAA receptors. The increase in glutamine has osmotic effects on astrocytes and may contribute to the development of edema. 53
The response of the hypothalamic satiety center is of special interest. This center, like other hypothalamic regions, is sensitive to exogenous ammonia and is stimulated by relatively small amounts of ammonia delivered to the brain. Electrical stimulation of this brain region causes satiety. Thus ammonia-induced satiety may explain appetite loss and the development of cachexia in susceptible patients. Loss of muscle bulk, particularly in patients with portacaval shunts, may then facilitate the development of hyperammonemia. It has been hypothesized that the effects of ammonia on the hypothalamus, the loss of skeletal muscle bulk, and the development of toxin sensitivity may be important in the emergence and 53 perpetuation of terminal symptoms in patients with liver disease. Abnormalities of Neurotransmission Neurotransmitters and their role in normal brain function are among the most important characteristics that differentiate the brain from other organs, and abnormalities of neurotransmitter function are proved or implied in a variety of diseases ranging from parkinsonism to schizophrenia. It is therefore not surprising that neurotransmitter abnormalities have been proposed as being of potential importance in the pathogenesis of hepatic encephalopathy.
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Glutamate was the first of the amino acid transmitters to be implicated, and this led to unsuccessful attempts to treat patients with glutamic acid infusions. Hindfelt and associates 54 observed small reductions in brain glutamate levels in animals challenged with ammonia. The anatomical locus of the depleted glutamate could not be determined from that study. Glutaminase inhibition and reduced hippocampal glutamate release have also been suggested. As indicated earlier, Norenberg has suggested that disruptions of the glutamate–glutamine relationship take place at the astrocytic level and that this may have secondary effects on glutamate neurotransmission. Biogenic amines and false neurotransmitters, notably octopamine, were the source of considerable interest after Fischer and Baldessarini proposed the false neurotransmitter 55 hypothesis in 1971. Their observations and similar ones by others were buttressed by uncontrolled trials suggesting that some patients awoke in a near-miraculous fashion after the administration of levodopa. These observations were combined with new and existing data on the plasma amino acid profile associated with liver disease to produce a new hypothesis. This hypothesis stated that the ratio of the sum of the concentrations of valine, leucine, and isoleucine divided by the sum of the phenylalanine and tyrosine concentration is a useful predictor and index of the severity of encephalopathy, and that normalization of the ratio by the infusion of amino acid mixtures rich in the branched-chain amino acids of the numerator is therapeutic. A subsequent refinement of the hypothesis suggested that the high level of glutamine in the brain acts as the driving force behind the uptake of the deleterious 56,57 aromatic amino acids. The amino acid hypothesis was supported by uncontrolled clinical trials of branched-chain amino acids. Controlled trials were disappointing. Two of the controlled studies of 58,59 60 branched-chain amino acids showed no effect, 61 one showed worsening, and a fourth showed improved survival and cerebral function. In all these studies it was reported that the amino acid ratio was improved, but there was no correlation with electroencephalographic or clinical improvement. Thus, the potential benefit of this therapy for the treatment of encephalopathy is not defined. However, amino acid infusions may be useful as a safe way to maintain positive nitrogen balance in cirrhotics. 62
Michel and associates found levodopa to be ineffective. The dopaminergic agonist bromocriptine has been63evaluated and found to be no better than standard treatment with enemas and neomycin. In addition to the disappointing results of the branched-chain amino acid trials, the false neurotransmitter hypothesis has been weakened on other grounds. Zieve and Olsen injected octopamine directly into the brains of animals at concentrations 20,000 times those 64 encountered in life, with no effect on behavior. Similarly, monoamine oxidase inhibition and imipramine therapy both led to increases in brain octopamine without the induction of 65 encephalopathy. GABA-Benzodiazepine Complex The hypothesis that excessive GABAergic tone causes hepatic encephalopathy generated a great deal of attention. Normally, the brain is protected from numerous compounds in the blood, including GABA, by the impermeable blood–brain barrier. According to this hypothesis, excess GABA is produced in the gastrointestinal tract and enters the brain through a damaged, or permeable, blood–brain barrier. The GABA then binds to GABA receptors, which are present in excess numbers, and the increased inhibitory tone is expressed as coma. Experimental evaluation of the GABA hypothesis has made it less credible. Improved analytical methods have shown that early reports of elevated blood GABA levels were erroneous, GABA probably does not cross the blood–brain barrier to any appreciable 66 extent, 67GABA levels in the brains of patients who have died in hepatic encephalopathy are normal, and inhibition68of GABA transaminase (which increases brain GABA levels) does not cause encephalopathy. As interest in GABA waned, more attention was directed at benzodiazepines. Patients with cirrhosis have a heightened sensitivity to this class of drugs, suggesting to some that they, or an endogenous ligand with benzodiazepine activity, may cause hepatic encephalopathy. Reports of rapid recovery after the administration of the benzodiazepine antagonist flumazenil (RO 15-1788, or Anexate) led to increased interest in the benzodiazepines. Although there is no reason to doubt the validity of these anecdotal reports and open trials, the evidence that these responders had not taken benzodiazepines is often incomplete. Despite reports of elevated levels of endogenous benzodiazepines in some
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comatose patients, the levels are lower than those associated with anxiolytic activity in normal subjects. Benzodiazepine receptors are present in normal numbers69and exhibit normal kinetics in the brains of patients with fatal hepatic encephalopathy. Controlled trials of flumazenil have shown that more patients responded in the flumazenil group than in the 70,71 However, there was evidence of the presence of exogenous control group. benzodiazepines in some the responders and a history of benzodiazepine administration. The action of this drug may relate, in part, to its general ability to activate the brain rather than simply to the displacement of a benzodiazepine. Among patients who improve after flumazenil, complete recovery is unusual, suggesting that any benzodiazepine effect is probably augmented by other pathophysiological mechanisms. Albrecht and Jones presented a synthesis of data concerning deranged neurotransmitters in 72 hepatic encephalopathy. Their analysis suggests that an excess of extracellular glutamate, caused by hyperammonemia, leads to downregulation of glutamate receptors and a reduction in excitatory tone. This is associated with an increase in GABAergic inhibitory tone due to multiple factors including an increase in the release of GABA and stimulation of GABAA receptors, increased levels of a natural benzodiazepine, a direct effect of ammonia on the GABAA-benzodiazepine receptor, and an ammonia-induced increase in peripheral benzodiazepine receptors in astrocytes. The hypothesis that abnormalities of neurotransmission cause all or part of the hepatic encephalopathy syndrome is likely to be modified as new data emerge and as investigators gain a better understanding of this complex area of research. Mercaptans and Short-Chain Fatty Acids Mercaptans are thio alcohols containing–SH groups, in contrast to the–OH groups in conventional alcohols. Because of the–SH group, these compounds are malodorous and are responsible for the fetor hepaticus that is occasionally encountered in patients with hepatic encephalopathy. Methanethiol is the principal mercaptan in humans and is formed by the catabolism of methionine in the gastrointestinal system. Methanethiol levels are elevated in the blood and end-tidal air samples of patients with hepatic encephalopathy, and levels have been 73 correlated with the severity of the encephalopathy. Mercaptans also appear to act in a synergistic fashion with other toxins, notably ammonia and fatty acids, 75 to produce coma in 74 animals. Clinically, mercaptan levels correlate poorly with symptoms. Abnormalities in short-chain fatty acid concentrations affect a variety of metabolic reactions or processes directly or indirectly in a fashion that may cause or contribute to the development of encephalopathy. Coma can be produced in animals by the intraperitoneal injection of shortand medium-chain fatty acids. Deficiency of medium-chain acyl-coenzyme A (CoA) dehydrogenase appears to be a common condition that may present as coma and often 76 mimics other conditions, such as Reye's syndrome or sudden infant death syndrome. Summary A variety of compounds have been implicated in the pathogenesis of the encephalopathy associated with portal-systemic shunting of blood and fulminant hepatic failure. A similarly large number of experimental models have been used to study these conditions. It is not presently possible to create a unifying hypothesis that explains all aspects of this encephalopathy, but certain general comments can be made. First, ammonia is probably of central importance in the pathogenesis of portal systemic encephalopathy. Second, the actions of ammonia appear to be affected by the development of toxin hypersensitivity and synergism with other toxins. Third, endogenous benzodiazepine ligands may contribute to the development of the disorder. Fourth, many models of liver disease are most appropriately considered as models of fulminant hepatic failure, and the mechanisms causing brain dysfunction in this disorder are poorly understood, as is witnessed by the poor therapies available to treat this condition.
Therapy The management of liver failure accompanied by neurological disturbances may be a difficult task. Many patients have a variety of complicating problems, including severe infections, abnormalities of renal function, cardiovascular collapse, hemorrhagic disorders due to clotting factor deficiencies and hypersplenism, or other medical-surgical problems. Thus, it is unusual to encounter patients with relatively uncomplicated hepatic encephalopathy.
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In planning therapy, it is critical to differentiate patients with fulminant hepatic failure from patients with portal systemic encephalopathy. For the former, supportive care and evaluation for potential transplantation are urgent issues. For patients with portal systemic encephalopathy, supportive measures should be supplemented by specific treatment strategies including the elimination of precipitating factors, cleansing enemas, and the use of lactulose or neomycin (or both). In evaluating the results of the many reported therapies for encephalopathy associated with liver disease, it is critical to remember that mere inclusion in a therapeutic trial is likely to be beneficial because investigators are then better able to control diet, alcohol consumption, and other precipitating factors that are critical to the success of treatment. Because of this, open trials and placebo-controlled trials of almost any therapy for portal systemic encephalopathy are likely to be associated with improvement in clinical and laboratory measures designed to evaluate a response to therapy. Although lactulose and neomycin are mainstays of therapy, the clinical trials supporting their use would have difficulty meeting current standards for drug approval required by the U.S. Food and Drug Administration. However, clinical experience with these compounds is extensive, and they remain a mainstay in the therapy of hepatic encephalopathy. Most of the therapies that are clearly effective in the treatment of portal systemic encephalopathy are believed to work by influencing ammonia metabolism. These therapies are considered in some detail. General Measures and Diet Much of the body burden of ammonia is due to the action of urease and amino acid oxidases in the colon, and so a variety of successful measures designed to reduce colonic ammonia production have been evaluated. Much of the ammonia formed in the colon is derived from protein, and control of protein is therefore critical. This control can be achieved by several means, each of which should be considered. During acute exacerbations, complete elimination of dietary protein may be required. During this phase, the altered level of consciousness increases the risk of aspiration associated with any attempts at oral feeding. Prolonged protein restriction is unwarranted and contributes to acceleration of catabolic reactions that may interfere with hepatic regeneration and impair ammonia detoxification by nonhepatic tissues. Bleeding in the gastrointestinal tract must be stopped as quickly as possible, and elimination of blood must be facilitated by the judicious use of purgatives and enemas. These measures should be considered in every patient, especially when a history of constipation is obtained. Constipation maximizes the dwell-time for nitrogenous compounds in the colon and thereby the potential for conversion to ammonia. More aggressive measures such as surgery to remove or bypass the colon have been evaluated, but the morbidity and mortality of the surgery are high and obscure any possible therapeutic benefit. In patients with chronic liver disease, it is important to maintain adequate nutrition to optimize hepatic regeneration and prevent the development of cachexia. This may be an indication for the use of the branched-chain amino acid mixtures that have been developed for both intravenous and oral use, but further evaluation of this approach is required. Uribe and associates compared various diets, including 40 g of meat protein plus neomycin, 4077g of vegetable protein without neomycin, and 80 g of vegetable protein without neomycin. Both vegetable protein diets were found to be superior to the diet containing meat protein plus neomycin. However, two patients receiving the vegetable protein diet had episodes of hypoglycemia, and most patients found it difficult to eat the large volumes of food required to ingest 80 g of vegetable protein. These forms of therapy may work by reducing dietary methionine and its subsequent conversion to methanethiol and ammonia and by the cathartic effect of the fiber in diets that are high in vegetable protein. Dietary issues related to the treatment of patients with cirrhosis have been reviewed by 78 Kondrup and Müller. They point out that most patients with cirrhosis are malnourished. Energy and protein balance can be maintained in most patients by a diet providing 30 to 40 kcal/kg per day containing 0.8 to 1.3 g protein/kg. This may require frequent feedings, including nocturnal feedings. A recent randomized trial compared a progressive low protein diet (0 g on days 1 to 3, with progressive increases every 3 days to a target of 1.2 g/kg daily) 79 with a diet containing 1.2 g/kg daily. The two groups fared equally well, in terms of their encephalopathy, but the higher protein diet group suffered less protein breakdown. Micronutrients and vitamins should be supplied, as 10 to 50 percent of cirrhotics are deficient in these compounds. Lactulose Lactulose, a synthetic disaccharide, is currently the mainstay in the treatment of portal
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systemic encephalopathy and has largely replaced neomycin, since it is not associated with renal toxicity or ototoxicity. Effective lactulose therapy is associated with reductions in the arterial ammonia concentration that are paralleled by normalization of the EEG and improvements in mental status. Its therapeutic efficacy is therefore thought to be related to its effect on ammonia. The history of lactulose is of considerable interest. It was first given to patients with the expectation that it would acidify the colon, leading to repopulation of the colon with bacteria that did not contain urease and trapping ammonia as the less diffusible ammonium ion. Subsequent studies demonstrated that this hypothesis, although attractive from a theoretical perspective, was not correct. Lactulose appears to exert its effect by favoring nitrogen fixation 80 in several clinical in the gastrointestinal tract. The efficacy of lactulose has been established 81 trials and is a mainstay in the therapy of hepatic encephalopathy. The dose of lactulose varies from patient to patient, but 20 to 30 g four times daily is a typical effective regimen. The dose should be adjusted until two to three bowel movements per day are produced without unacceptable side effects. Patients with coma require more aggressive initial therapy, with hourly doses of 20 to 30 g of lactulose until a catharsis is produced, after which the dose is reduced. Adverse reactions most commonly include abdominal bloating and diarrhea. These symptoms are dose-related, and adjustments in the therapeutic regimen usually allow continuation of therapy. Care must be taken to prevent diarrhea and secondary electrolyte abnormalities. Patients with liver disease may be particularly susceptible to the development of central pontine myelinolysis. This condition may occur when hyponatremia is corrected too rapidly. This complication must be avoided. Neomycin Although the efficacy of neomycin was widely accepted, proof of 81 its utility did not come until the same cooperative study that proved the efficacy of lactulose. Neomycin is also effective in the management of acute encephalopathy. For this condition, the usual daily dose ranges between 4 and 12 g taken in divided doses, whereas chronic therapy is usually accomplished with 2 to 3 g daily. When chronic neomycin therapy is required, monitoring of drug levels and otological and renal function is mandatory to detect early toxicity. Lactitol 82
Another synthetic disaccharide, lactitol, has been reported to be as effective as lactulose. It remains to be seen whether this drug will find widespread acceptance. It is used as a sugar substitute in low-energy and low-fat foods, but it is not currently available for the treatment of hepatic encephalopathy in the United States. Transjugular Intrahepatic Portosystemic Shunts Transjugular intrahepatic portosystemic shunts (TIPS) may be created to control ascites. A meta-analysis of this procedure has shown that it controls ascites more effectively than large-volume paracentesis but carries the penalty of inducing encephalopathy without 83 the degree of shunting, increasing survival. Endovascular techniques, designed to reduce 84 may be effective in controlling encephalopathy in selected cases.
Outcome Patients with fulminant hepatic failure have an 80 to 85 percent expected mortality rate, and treatment has been of little help. The ultimate prognosis depends on the severity of the liver disease, the presence of complications, and in some cases the availability of livers for transplantation. Patients with portal systemic encephalopathy fare much better than patients with fulminant hepatic failure. Most patients with relatively uncomplicated encephalopathy can be expected to make a full recovery, at least after the initial episode. Again, complications and the nature of the precipitating factor have an impact on survival. Severe hepatic coma carries a substantial risk of death or permanent neurological disability. Levy and colleagues encountered 51 patients with 85 hepatic coma in their prospective analysis of nontraumatic coma of at least 6 hours' duration. In that group, 49 percent showed no sign of recovery over the first year after diagnosis, whereas 27 percent regained the ability to live independently and made a good neurological recovery. Among the remainder, 2 percent developed a persistent vegetative state, 14 percent were left with severe disability, and 8
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percent remained with moderate disability over a 1-year period. These patients probably represent a worst-case group because of the requirement for very deep and prolonged coma that had to be satisfied prior to enrollment in the study. Orlandi and associates studied a less severely affected population and reported a mortality rate of 6.1 percent for patients with 86 grade 1 encephalopathy, rising to 27 percent in patients with grade 2 or higher. An identifiable precipitating factor and a short duration were favorable indicators, whereas hyperbilirubinemia, prolongation of the prothrombin time, ascites, and cachexia predicted an unfavorable outcome. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 15 Other Neurological Disorders Associated With Gastrointestinal, Liver, or Pancreatic Diseases VINAY CHAUDHRY • WILLIAM J. RAVICH •
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NEUROLOGICAL COMPLICATIONS OF GASTROINTESTINAL DISORDERS Malabsorption Syndromes Celiac Disease Chronic Idiopathic Inflammatory Bowel Disease Infectious Diseases Campylobacter Enteritis and Guillain–Barré Syndrome Whipple's Disease Liver and Neurological Disease Peripheral Neuropathy Acquired Hepatocerebral Degeneration Pancreas and Neurological Disease GASTROINTESTINAL MANIFESTATIONS OF NEUROLOGICAL DISEASES Dysphagia Neurological Diseases With Dysphagia Evaluation of Dysphagia Management of Dysphagia Motility Disorders
Neurological disorders associated with gastrointestinal (GI), liver, or pancreatic diseases are poorly recognized. In consequence, their diagnosis and treatment are often unnecessarily 1–3 delayed and costly. Neurological manifestations may be secondary to the presence of a known GI disorder. Conversely, GI disturbances may complicate known neurological disorders. These two aspects are discussed separately, but there is a considerable overlap between the two, so that patients with undiagnosed GI disease may first be seen by a neurologist, and vice versa. NEUROLOGICAL COMPLICATIONS OF GASTROINTESTINAL DISORDERS
Malabsorption Syndromes The term malabsorption is used to describe a variety of disorders in which ingested nutrients are not absorbed. These disorders in turn are commonly divided into disturbances of
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digestion (maldigestion) in which ingested foods are inadequately broken down into absorbable components and disorders of absorption proper (malabsorption) in which there is a failure of the normal transport of the nutrients through the intestines. Malabsorption syndromes can cause neurological abnormalities both through specific nutritional deficiencies 4 and through multisystem involvement associated with specific disorders. Table 15-1 summarizes the neurological manifestations of nutritional deficiencies of vitamins and electrolytes caused by various malabsorption syndromes. A detailed discussion of individual vitamin deficiencies can be found in Chapter 17. The manifestations of deficiency of a specific nutrient are the same whether the deficiency occurs from reduced dietary intake, impaired intraluminal digestion, or disorders of intestinal transport. Unexplained confusion, memory changes, numbness, weakness, and gait ataxia should lead to a suspicion of malabsorption, especially if associated with diarrhea or weight loss. Glossitis, cheilosis, and stomatitis may also be noted. Laboratory studies demonstrating deficiencies of minerals and vitamins, including determination of serum iron, ferritin, vitamin B12, vitamin D (25-OH vitamin D), vitamin E, thiamine, folic acid, calcium, and phosphorus, may suggest but are not specific for malabsorption. Deficiency of water-soluble vitamins (thiamine, riboflavin, niacin, and pyridoxine) is more likely to result from dietary deficiencies than from malabsorption syndromes, whereas deficiency of fat-soluble vitamins (vitamins D, E, and B12) is more likely to be the result of absorptive problems. Click here to view this table.... The differential diagnosis of malabsorption disorders is quite broad and can be divided into the following, often overlapping, groups: 1. Mucosal disorders, such as celiac disease, collagenous sprue, nongranulomatous ulcerative jejunoileitis, eosinophilic gastroenteritis, immunoproliferative small intestinal disease, lymphoma, lymphangi ectasia, Crohn's disease, radiation enteritis, and chronic mesenteric ischemia 2. Infectious disorders, such as bacterial overgrowth, tropical sprue, Whipple's disease, parasitic diseases (e.g., Giardia, Cryptosporidium, tapeworm infestations), and Mycobacterium avium-intracellulare infection 3. Maldigestive disorders, such as pancreatic exocrine insufficiency, hepatic or biliary tract disease with bile acid deficiency, Zollinger–Ellison syndrome, and drug effects (cholestyramine, colchicine, laxatives) 5
4. Postoperative malabsorption, such as following gastric surgery or extensive intestinal resection (short gut syndrome) 5. Lymphatic obstruction from disorders such as lymphoma and tuberculosis 6
6. Other disorders, including abetalipoproteinemia, malabsorption in the elderly, diabetic 7 8 collagen vascular disease, and acquired immunodeficiency diarrhea, amyloidosis, 9 syndrome (AIDS) Unexplained confusion, memory changes, numbness, weakness, and gait ataxia should lead to a suspicion of malabsorption, especially if associated with diarrhea or weight loss. Common symptoms of malabsorption include foul-smelling, greasy stools, weight loss, 10 flatulence, and bloating. Glossitis, cheilosis, and stomatitis may also be noted. Most patients with malabsorption describe a change in their stools. The hallmark of malabsorption is steatorrhea, loss of excessive fat in the stool. Most patients with steatorrhea have diarrhea, but about 10 percent of patients have steatorrhea without diarrhea. Typical characteristics of steatorrhea include a pale color, excessive bulk, greasiness, a tendency to float (due to incorporated fat), and stool that leaves a greasy film on the toilet bowl surface after flushing. A spot qualitative assay of fecal fat using Sudan staining may be used. The presence and severity of steatorrhea is confirmed by fecal fat collection, usually over a 3-day 11 period. The patient must be ingesting an adequate amount of fat. Commonly, the patient is placed on a high (100 g) fat diet for a number of days before collection begins, but the test can be satisfactorily performed during ingestion of lower amounts of fat (e.g., 70 g). The important issue is to make sure that the fat is ingested. With an adequate fat diet and with moderate to marked malabsorption, the test usually correlates fairly well with a quantitative assay of fat malabsorption and can provide rapid data that can direct subsequent diagnostic testing. Steatorrhea is defined as the loss in the stool of more than 7 percent of ingested fat. Once steatorrhea is confirmed, a d-xylose test in which the blood or urine level of d-xylose is
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measured helps to determine whether the malabsorptive process is due to a mucosal 12 disease or intraluminal digestion. A positive test, showing low levels of d-xylose absorption, indicates either an abnormality of mucosal processing or bacterial overgrowth (bacteria compete for d-xylose), whereas a normal test indicates an abnormality of intraluminal digestion, most often due to pancreatic disease. Other laboratory tests that may suggest malabsorption are not specific; they include determination of serum iron, ferritin, vitamin B12, vitamin D (25-OH vitamin D), vitamin E, thiamine, folic acid, calcium, and phosphorus. A small bowel biopsy may be needed for a definitive diagnosis of a mucosal, infective, or infiltrative cause of malabsorption. Celiac Disease Celiac disease (nontropical sprue, gluten-sensitive enteropathy) is a malabsorptive condition in which an allergic reaction to the cereal grain protein gluten causes small bowel injury resulting in malabsorption. Celiac disease deserves to be discussed separately given its numerous neurological manifestations that may occur even without clinically evident 13,14 malabsorption of nutrients. The age at onset of celiac disease is bimodal, being either in the first decade of life or between 40 and 50 years of age. Women are affected more often than men (2:1). The clinical presentation is with the symptoms of malabsorption described earlier. Some patients may 14 have minimal GI symptoms or none at all at the onset of their neurological illness. Although neurological symptoms are rare in children, as many as 36 percent of adult patients have 15 been reported to have neurological manifestations. Dementia, cerebellar ataxia, myelopathy, brainstem encephalitis, progressive leukoencephalopathy, seizures, vasculitis, and occipital calcification make up the central nervous system (CNS) manifestations of celiac 2,13 Hadjivassiliou and associates reported the presence of antigliadin antibodies in disease. 16 41 percent of patients with idiopathic ataxia. Neuropathological examination has shown Purkinje cell loss in the cerebellum and in the brainstem nuclei. The deep gray matter and 17 spinal cord may also show pathological changes. This pattern of involvement is not influenced by nutritional therapy and differs from the changes seen in alcohol-related cerebellar degeneration and from subacute combined degeneration due to vitamin B12 deficiency. Epilepsy manifesting as partial seizures has been reported in as many as 5.5 18 percent of patients with celiac disease. Some of these cases were refractory to antiseizure medications until a gluten-free diet was initiated. The neuromuscular manifestations of celiac disease include polymyositis, dermatomyositis, 14 and inclusion-body myositis. All the myopathies described have the classic features of a primary inflammatory process, with proximal muscle weakness, high serum creatine kinase (CK) levels, the electromyographic (EMG) features of a myopathy, and necrotizing features with primary inflammation on muscle biopsy. A sensory-motor axonal peripheral neuropathy with length-dependent features affecting lower limbs more than upper limbs has also been reported with celiac disease as an independent association, again even without malabsorption or nutritional deficiencies. In a study by Chin 19 and co-workers, 5 percent of 400 screened patients with neuropathy had celiac disease. Of 9 patients described by Hadjivassiliou and colleagues, 3 had peripheral neuropathy, and 1 each had axonal motor neuropathy, mononeuropathy multiplex, inclusion-body myopathy, 14 and neuromyotonia. These authors emphasize that gluten sensitivity is common and should be searched for in all patients with neurological disease of unknown cause, including peripheral neuropathy, mononeuritis multiplex, and myopathy. By contrast, a study of 27 patients with cerebellar ataxia and 32 with peripheral neuropathy concluded that the presence of food antibodies is a nonspecific finding, casting doubt on 20 the nosological status of “gluten ataxia” and “gluten neuropathy” as discrete disease entities. The diagnostic test for celiac disease is a small intestinal biopsy that reveals loss of villi and flattening of the mucosa, which is composed of cuboidal cells in place of the normal columnar cells. In addition, the crypts are elongated, and there is an increase in inflammatory cells in the intestinal biopsy specimen. Laboratory tests for circulating IgA anti–tissue transglutaminase and anti-endomysial antibodies in the serum are relatively sensitive and specific for the diagnosis of celiac disease. A falsely negative test may result from IgA deficiency, which is more common in celiac disease than in the general population. Despite the high degree of test specificity, most authorities would require confirmation of celiac disease by small intestinal biopsy. A gluten-free diet, which consists of removal of all substances containing wheat, rye, and barley, is the mainstay of treatment. Even small amounts of dietary gluten will sustain the mucosal injury. Once a gluten-free diet is initiated, malabsorptive symptoms usually improve
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within 1 to 2 weeks, but the mucosal architecture may take 1 to 2 months to return to a near-normal state. It is not clear, however, whether neurological symptoms are necessarily improved, stabilized, or even prevented by a gluten-free diet. Overall, convincing evidence of a causal association of celiac disease with specific neurological conditions has not been established. Routine screening for celiac disease in 20 patients with idiopathic neurological syndromes cannot be recommended. Chronic Idiopathic Inflammatory Bowel Disease Ulcerative colitis and Crohn's disease are the two main diseases in this category. Ulcerative colitis is a chronic disease characterized by inflammation of mucosal and submucosal portions of the rectum, extending proximally for a variable distance along the colon. It generally presents with symptoms of bloody and urgent diarrhea. Crohn's disease is also a chronic disease that, unlike ulcerative colitis, can result from inflammation of any region of the GI tract. Also unlike ulcerative colitis, Crohn's disease generally affects all layers of the involved region of the bowel. It presents as abdominal pain, with nonbloody and less urgent diarrhea. Neurological involvement is uncommon in inflammatory bowel disease (3%) and either is due to21–23 malabsorption (Table 15-1) or is a part of the extra-intestinal complications. Neurological manifestations of ulcerative colitis include the acute inflammatory demyelinating 24 25 polyneuropathy form of Guillain–Barré syndrome (GBS) and polymyositis. 21A patient with myasthenia gravis was also reported in the series by Lossos and associates, although this association may have been coincidental. The diarrhea that occurs in ulcerative colitis may cause symptoms due to potassium deficiency (Table 15-1). Crohn's disease has been associated with sensorimotor axonal neuropathy independent of 26 Myopathy has also been associated with Crohn's any deficiency of specific nutrients. 21 disease. In most cases, the myopathy is thought to be inflammatory with an immune basis 27 and, in about half the cases, seems to be correlated with the activity of the bowel disease. Crohn's disease may also lead to neurological symptoms from malabsorption of nutrients resulting in hypokalemia, hypocalcemia, hypomagnesemia, and vitamin B12 deficiency. The malabsorption may relate to length of mucosal involvement or surgical resection, loss of the terminal ileum, or bacterial overgrowth. Peripheral neuropathy in Crohn's disease is often associated with vitamin B12 deficiency due to the disease or to resection of the intestine. Gondim and colleagues reported peripheral neuropathy unassociated with nutritional26 deficiency in 18 patients with Crohn's disease and 15 patients with ulcerative colitis. Axonal sensory (small- or large-fiber), axonal sensorimotor, and demyelinating neuropathies responsive to immunotherapies were noted by these authors. Treatment of the disease often requires corticosteroids or metronidazole, each of which has potential neurological side effects. Thromboembolic complications are well-known complications of both ulcerative colitis and 28,29 Transient Crohn's disease and may manifest neurologically as cerebral vein thrombosis. ischemic attacks, ischemic strokes, and cerebral hemorrhage also occur. Cerebral arterial occlusions have been described as affecting the internal carotid, middle cerebral, or posterior cerebral vessels. In a prospective study, magnetic resonance imaging (MRI) of the brain showed hyperintense focal white matter changes in 40 to 50 percent of patients with 30 inflammatory bowel disease compared with age-matched control subjects. None of the patients, however, had neurological symptoms. Lossos and colleagues noted 5 patients with 21 slowly progressive myelopathy.
Infectious Diseases Campylobacter Enteritis and Guillain–Barré Syndrome Campylobacter jejuni is a leading cause of acute gastroenteritis in humans and is now recognized to be the most frequent antecedent pathogen leading to Guillain–Barré syndrome (GBS). GBS is the most common cause of acute generalized paralysis and is characterized by an acute polyneuropathy, with areflexia and albuminocytological dissociation in the cerebrospinal fluid (CSF). The epidemiological link between preceding C. jejuni infection and 31 GBS has been confirmed in many parts of the world, occurring in between 15 and 75 percent of GBS cases in different places. Patients developing GBS after C. jejuni infection 32 have autoantibodies to GM1 ganglioside in the acute phase of the illness. The C. jejuni and GBS association represents an example of molecular mimicry between C. jejuni lipopolysaccharides that carry ganglioside-like epitopes and ganglioside-like moieties present
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on nerve fibers. Infection by C. jejuni that bears the GM1-like lipopolysaccharides associated with the serotypic determinant of PEN 19 induces high production of IgG1 and IgG3 anti-GM1 antibodies with the help of T cells. IgG anti-GM1 antibody binds to motor nerve terminal axons, inhibits motor neuron excitability, and leads to development of GBS. The bacterial 31 gene responsible for this has been determined (cst-II). Whipple's Disease Whipple's disease is a rare, chronic, multisystem infectious disease that is caused by Tropheryma whippelii infection, a weakly gram-positive actinomycete. Whipple's disease is more common in men (80%) than in women, with the mean age of onset being 50 years. Although the disease can affect any organ, its predominant manifestations are in the GI tract and are characterized by abdominal pain, diarrhea (steatorrhea), and weight loss. Variable fever, relapsing-remitting arthralgia, arthritis, and lymphadenopathy may also occur. Neurological involvement occurs in 4 to 11 percent of patients with Whipple's disease. Among neurological symptoms, mental status changes including dementia, confusion, and behavioral and personality changes are the most frequent manifestations. Abnormalities of eye movements are the next most frequent presentation and may include supranuclear (vertical more than horizontal) ocular palsy, conjugate gaze paresis, and nystagmus. Oculomasticatory myorrhythmia and oculofacial-skeletal myorrhythmia (slow convergent-divergent nystagmus combined with rhythmic33movements of the jaw, mouth, and limbs) are said to be pathognomic for Whipple's disease. Other movement disorders, including myoclonus of the extremities, twitching of the facial muscles, and bruxism, have been described. Seizures and hypothalamic, cerebellar, spinal cord, and basal ganglia involvement may also occur and lead to a wide range of reported manifestations, such as polydipsia, hyperphagia, hypersomnolence, seizures, cerebellar ataxia, myelopathy (spastic quadriparesis), parkinsonism, aseptic meningitis, stupor, and coma. Ocular involvement may be manifested by uveitis, vitritis, keratitis, optic neuritis, or papilledema. Peripheral manifestations include myopathy, peripheral neuropathy, and compressive neuropathy. The multifocal involvement resembles cerebral vasculitis or CNS sarcoidosis. The CSF is generally normal, although pleocytosis and mild elevations in protein concentration have been reported. Spinal fluid or tissue (duodenum) assay by polymerase chain reaction for Tropheryma whippelii is important for confirming the diagnosis. Magnetic resonance imaging of the brain can reveal atrophy, hydrocephalus, and multiple areas of abnormal signal intensity in deep white matter, hypothalamus, medial temporal lobes, basal ganglia, and 34 pons. If the disease is suspected, a duodenal biopsy is necessary. The presence of PAS-positive foamy macrophages on light microscopy and of the characteristic morphology of the bacilli on electron microscopy establishes the diagnosis. The availability of polymerase chain reaction (PCR) assays has made diagnosis easier. Treatment of Whipple's disease should be with antibiotics that can cross the blood–brain barrier. At present, the favored method of treatment is the daily parenteral administration of 1.2 million units of benzylpenicillin (penicillin G) and streptomycin, 1 g, for a period of 2 weeks. This is followed by treatment with cotrimoxazole35,36 (trimethoprim, 160 mg, and Ceftriaxone parenterally for 1 sulfamethoxazole, 800 mg) twice daily for 1 to 2 years. 37 month, followed by oral cefixime for 2 years, has also been recommended. Symptomatic treatment of seizures and movement disorders may be required. PCR assays of the CSF are helpful in monitoring treatment. The response to treatment has been variable. Established neurological manifestations are difficult to reverse, and a relapse may occur once antibiotics are discontinued.
Liver and Neurological Disease Fulminant acute hepatic failure and reversible hepatic encephalopathy (also called portal systemic encephalopathy) are discussed in Chapter 14. This section, therefore, focuses on the peripheral neuromuscular manifestations of liver disease. Acquired hepatocerebral degeneration, a topic not covered in Chapter 14, is also discussed. Peripheral Neuropathy Although peripheral neuropathy may occur in patients with liver disease, there is controversy 38 regarding a causal relationship. Some authors doubt the existence of hepatic neuropathy, 39–41 whereas others report an incidence ranging from 19 to 100 percent. A prospective study
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of 58 patients with end-stage liver disease found that peripheral neuropathy was frequent, 41 occurring in 71 percent of these patients. In most patients, the neuropathy was either subclinical or associated with minimal symptoms. Examination showed distal sensory loss and loss of distal reflexes consistent with a length-dependent neuropathy. Quantitative sensory testing revealed abnormalities of small-fiber function (cooling threshold) more than large-fiber function (vibration threshold). Nerve conduction studies showed length-dependent loss of sensory and motor response amplitudes with relatively preserved conduction velocities, confirming that axonal loss was responsible. Median neuropathy at the wrist (carpal tunnel entrapment) was common, occurring in one third of patients. Some authors have reported that the neuropathy is predominantly demyelinating in 39,40,42 On careful analysis of these reports, the conduction velocities were rarely in the nature. range suggestive of demyelination and can be explained by large-fiber axonal loss. Furthermore, entrapment neuropathies were not excluded as possible explanations for the reduced conduction velocities. Similarly, a few pathological studies have suggested that the neuropathy is associated with demyelination on the basis of sural nerve biopsies showing 40 thinly myelinated fibers and short internodes. However, no active demyelination or inflammatory cells were reported, and the thinly myelinated fibers and small internodes may have been a reflection of axonal degeneration followed by regeneration. The causal relationship between liver disease and neuropathy has been questioned because certain systemic illnesses that cause liver dysfunction are also independent causes of peripheral nerve dysfunction. This applies to alcohol-induced cirrhosis, porphyria, polyarteritis nodosa, certain intoxications, primary biliary cirrhosis, and amyloidosis. However, the severity of neuropathy correlates with severity of liver disease independently of its etiology, suggesting 39 that the peripheral neuropathy is caused by the liver disease. Moreover, patients with cryptogenic liver disease also develop peripheral neuropathy of varying severity. In addition to hepatocellular damage, portosystemic shunting has been incriminated in the genesis of 43 hepatic neuropathy. However, others have found no differences between cirrhotic patients related to portacaval shunt, and an experimental study of portacaval anastomosis in rats also 44 favored hepatocellular failure as the principal cause of hepatic neuropathy. Reports are increasing that hepatitis C may be associated with neuromuscular complications. Two groups of patients with hepatitis C may develop peripheral neuropathy. Patients with cryoglobulinemia may have a fulminating vasculitic syndrome and develop a mononeuropathy 45,46 Patients with chronic liver disease in the absence of cryoglobulinemia may multiplex. 39 develop a length-dependent oligosymptomatic distal peripheral neuropathy. Both acute neuropathy (GBS) and chronic demyelinating neuropathies sometimes occur in the setting of 47–49 Myalgia is a common symptom of unknown cause in infectious hepatitis; viral hepatitis. muscle weakness is rarely present. Polymyositis is increasingly being reported as an immune 50 response to hepatitis C, although a clear causal relationship remains to be established. In addition, interferon therapy for hepatitis C infection may precipitate or aggravate the 51 myopathy. Patients with chronic liver disease secondary to primary biliary cirrhosis form a separate group. These 52 patients have pure sensory neuropathy with or without xanthomatous infiltration of the nerves. 53
Autonomic neuropathy occurs frequently in chronic liver disease. In one study, autonomic 41 dysfunction was found in 48 percent of patients. Abnormalities of heart-rate variation with deep breathing and with the Valsalva maneuver are more likely than an orthostatic decline in blood pressure, suggesting predominant parasympathetic dysfunction. Most patients with autonomic dysfunction have evidence of a somatic neuropathy. The prevalence and severity of autonomic dysfunction relates to the severity of hepatic dysfunction and is independent of 54 its etiology. Acquired Hepatocerebral Degeneration Acquired (non-Wilsonian) hepatocerebral degeneration occurs in the setting of 2,55 The decompensated acquired liver disease or extensive portosystemic shunts. characteristic clinical presentation resembles Wilson's disease and includes dysarthria, ataxia, tremor, choreoathetosis, and altered mental status. Parkinsonism may occur (p. 1113). Typically, patients experience several episodes of hepatic encephalopathy before developing the extrapyramidal manifestations. Tremor of the outstretched arms is followed by gait ataxia, dysarthria, and rigidity. Intention myoclonus, nystagmus, varying degrees of dementia, and spastic myelopathy may also be noted. Wilson's disease needs to be excluded if an acquired etiology for chronic liver disease is not obvious. Unlike Wilson's disease, patients with acquired hepatocerebral degeneration will have normal serum and urinary
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copper levels, normal serum ceruloplasmin, and absence of Kayser–Fleischer rings. T1-weighted magnetic resonance imaging sequencing shows hyperintensity in the lenticular 56 nucleus, although this is not a specific finding. The pathogenesis is poorly understood, although it is presumed to be secondary to toxic metabolites bypassing the liver circulation. Increased manganese deposition in the basal ganglia has been documented. Histologically, prominent astrocytic hyperplasia, white matter spongy degeneration, and pseudolaminar cortical necrosis have been found. The disorder is not responsive to conventional therapy for hepatic encephalopathy and tends to be irreversible. A few case reports of patients improving with liver57transplant have been described, although the improvement has not been sustained.
Pancreas and Neurological Disease Pancreatic encephalopathy is a term used to describe a range of neuropsychiatric symptoms 2,58 associated with acute pancreatitis. These symptoms are similar to those of any other metabolic encephalopathy and may include fluctuating mental status, hallucinations, decreased attention span, restlessness, delirium, anxiety, slurred speech, spasticity, and seizures. In a59prospective study of 17 cases of acute pancreatitis, encephalopathy was found in 6 patients. A direct relationship was found between the pancreatic encephalopathy and an increase in CSF lipase. The electroencephalographic (EEG) changes were nonspecific. The encephalopathy was not related to severity of the pancreatitis, did not affect the course of the pancreatitis, and showed no relationship to type of treatment. Several hypotheses have been proposed to explain the pathogenesis of cerebral dysfunction in acute pancreatitis, but 60 none has been proved. Fat embolism, intravascular coagulation, hyperosmolarity, and hypoxia all have been regarded as etiopathogenic mechanisms of pancreatic encephalopathy. Wernicke's encephalopathy should be included in the differential diagnosis in the setting of pancreatitis. Treatment with thiamine (100 mg/day) should be considered even if the classic triad (nystagmus, ataxia, and confusion) of Wernicke's encephalopathy is lacking. Chronic pancreatitis from any cause, including cystic fibrosis, may cause neurological symptoms due to malabsorption, as noted earlier. Alcoholism is a common etiology of chronic pancreatitis and may independently cause peripheral neuropathy (from nutritional deficiency of thiamine) and myopathy. Diabetes mellitus occurs in as many as 30 percent of patients with chronic pancreatitis and in up to 70 percent of patients with diffuse pancreatic calcifications. In this setting, neuropathy is as frequent as in other patients with diabetes. Hypoglycemic neuropathy is an entity that is encountered in relation to insulinoma or the accidental or deliberate injection of insulin. Although the predominant manifestation of this is 61 an encephalopathy, distal paresthesias and weakness have been reported. GASTROINTESTINAL MANIFESTATIONS OF NEUROLOGICAL DISEASES
Dysphagia Swallowing involves a coordinated act that has oral, pharyngeal, and esophageal phases. In the oral phase, the tongue partitions the bolus and pushes a portion into the pharynx. In the pharyngeal phase, the nasopharynx closes so that food does not go into the nasal passages, the epiglottis tilts downward, the larynx elevates, and the vocal cords approximate to prevent entry of food into the airway, and the upper esophageal sphincter relaxes to allow unimpeded bolus passage. In the esophageal phase, a progressive contraction of the circular muscle layer is coordinated with relaxation of the lower esophageal sphincter to push the swallowed food bolus down the length of the esophagus and into the stomach. Patients with oral and pharyngeal dysphagia often complain of difficulty in controlling the oral bolus, difficulty in initiating swallowing, coughing during swallowing, or the feeling of food sticking in the throat. Associated symptoms of facial, tongue, jaw, and pharyngeal weakness, such as nasal regurgitation, coughing during swallowing, and dysarthria (nasal speech) are usually present. Patients with oral and pharyngeal dysphagia often localize the sensation of food-stick to the lower neck. Neurological Diseases With Dysphagia Oral- and pharyngeal-phase dysfunction is often due to neurological diseases (Table 15-2). Neurogenic dysphagia may result from cortical (generally bilateral) lesions; lesions of the pyramidal tracts; movement disorders; cerebellar disorders; lesions of the brainstem nuclei of cranial nerves V, VII, IX, X, and XII; and lesions of these cranial nerves, their neuromuscular
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junctions, or the oral, pharyngeal, or esophageal striated muscles that they innervate (Table 62 15-2). Dysphagia may be the first or presenting symptom of the neurological disorder or may develop during the course of the neurological disease. Click here to view this table.... Cerebrovascular disease is the most common cause of neurogenic dysphagia, which occurs 63 in up to 50 percent of patients with stroke. Brainstem strokes and bilateral anterior circulation strokes are more likely to result in dysphagia, although swallowing dysfunction 63 may also occur in unilateral hemispheric strokes involving either side. Isolated dysphagia is uncommon from stroke, although it has been reported with lacunar infarcts in the 62 periventricular white matter and with discrete brainstem lesions. The mechanism of dysphagia is an upper or lower motor neuron disturbance involving the bulbar muscles, with oral masticatory and transit phases of swallowing being affected. Video radiography using barium contrast often shows premature leakage of oral contents into the pharynx, delayed initiation of swallowing, asymmetric weakness of the pharyngeal constrictor mus cles, nasopharyngeal incompetence, incomplete laryngeal closure, or poor opening of the pharyngo-esophageal segment. The consequence of these abnormalities includes nasal regurgitation, penetration of barium into the larynx, and pharyngeal retention. The risk of aspiration is high when the patient's sensorium is altered and may necessitate intubation to protect the airway. Dysphagia as a result of a stroke is usually transient, with most patients able to swallow within 2 weeks. Movement disorders such as Parkinson's disease, progressive supranuclear palsy, Huntington's disease, Wilson's disease, and spasmodic torticollis have all been associated with dysphagia, although it is rarely severe enough to affect nutrition or warrant a feeding tube. Reduced tongue motility, delayed initiation of swallowing reflex, and decreased peristaltic movement have been described in Parkinson's disease. Dysphagia in Parkinson's disease is often associated with tongue tremor, pharyngeal peristaltic dysfunction, and 64 impaired opening of the upper esophageal sphincter. Drooling and difficulty in handling the secretions are manifestations of dysphagia, rather than secondary effects of increased secretions, even though treatment is often directed at the latter. As many as one third of parkinsonian patients experience coughing, choking, or nocturnal dyspnea due primarily to the dysphagia. Abnormal swallowing is also common in multiple sclerosis, although it is often asymptomatic 65 and does not compromise nutrition. It is associated with disordered brainstem or cerebellar function, bilateral pyramidal tract disease, overall disability, depressed mood, and low vital capacity. Multiple sclerosis impairs the oral and pharyngeal stages of swallowing by spasticity, ataxia, and weakness. palsy and Dysphagia in amyotrophic lateral sclerosis (ALS) is due to bulbar or pseudobulbar 66 occurs in as many as 25 percent of patients at the onset of the disease. Eventually almost all patients with ALS have at least some degree of dysphagia. The oral and pharyngeal components of swallowing are predominantly affected. Weakness of oral muscles (orbicularis oris, buccinator, pterygoids, masseter, and tongue) results in poor lip seal, reduced ability to chew (poor bolus formation), food particles collecting in the buccal sulcus, poor secretion control, poor propulsion of food, coughing, and choking before swallowing. Pharyngeal constrictor muscle weakness along with impaired laryngeal elevation results in symptoms of aspiration, such as choking or coughing during or immediately after swallowing. Symptoms are progressive and rapidly affect nutritional intake, and the risk of aspiration pneumonia is high. Dysarthria, either flaccid or spastic, frequently accompanies the dysphagia. Although clinical distinction between bulbar and pseudobulbar palsy is often made, the findings are often mixed. Sialorrhea (drooling), often resulting from impaired pharyngeal clearance rather than an increase in salivation, also accompanies bulbar symptoms in patients with ALS. A percutaneous endoscopic gastrostomy (PEG) tube should be considered early in ALS, before vital capacity declines to less than 50 percent, as an alternative or supplemental route for nutrition. The indications for PEG include inadequate oral intake (with weight loss) because of either difficulty in swallowing or fear of choking. Two studies suggested that PEG 66,67 placement prolongs survival, although there has been some debate on this issue. Patients with ALS also show delayed colonic transit times compared with healthy control subjects and a prolonged gastric emptying time. Bowel dysfunction does not occur, but constipation is common as the result of altered dietary intake, medications, and reduced mobility. Dysphagia due to infection of the bulbar neurons (brainstem lower motor neurons) during acute paralytic poliomyelitis is now rare, but after several years survivors may develop
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dysphagia as part of the postpolio syndrome. Dysphagia is slowly progressive and is severe in patients who initially had acute bulbar poliomyelitis. Sonies and Dalakas found clinical or subclinical evidence of dysphagia in most (31 of 32 patients examined) patients with the 68 postpolio syndrome (defined by onset of new weakness in the limbs). Aspiration is rare, and simple modifications of swallowing position, a change to soft food, and introduction of compensatory techniques were sufficient to control symptoms in all patients. Many postpolio patients are unaware of any difficulty with swallowing, since they have learned to68make gradual compensations in the way they swallow and take longer to finish a meal. Approximately 33 percent of patients with myasthenia gravis will have significant fatigable 69,70 Patients dysphagia, with oral and pharyngeal phases of swallowing being affected. typically do not have chewing or swallowing difficulty at the beginning of a meal, but tire easily as the meal progresses. They should be instructed to time the dosing of their cholinesterase inhibitors so that they are taken approximately 30 minutes prior to food intake. Botulism 71,72 presents with prominent bulbar symptoms of dysphagia and dysarthria, associated with blurred vision, diplopia, ptosis, descending paralysis, constipation, and autonomic symptoms, including ileus. Dysphagia for both solids and liquids is prominent in polymyositis and 62,73 inclusion-body myositis. The pharyngeal and esophageal phases of swallowing are affected. Nasal regurgitation is rare, and dysarthria and chewing difficulties are not primary complaints. To avoid aspiration, patients spend a long time in chewing their food. Oculopharyngeal muscular dystrophy is an autosomal-dominant myopathy that usually manifests itself with bilateral symmetric ptosis. Dysphagia usually occurs subsequently, although this symptom first brings the patient to seek medical attention. The dysphagia is at the upper sphincter level, at the junction of pharynx and esophagus, and is usually accompanied by pharyngo-oral and pharyngo-nasal regurgitation, which often causes social embarrassment to the point that patients no longer enjoy eating. Tracheal aspiration occurs frequently. Patients with myotonic muscular dystrophy may also have prominent dysphagia with myotonia; ptosis; facial weakness; and atrophy and 74 weakness of temporalis, sternocleidomastoid, masseter, and distal limb muscles. Cataracts, frontal balding, testicular atrophy, cardiac conduction defects, mental dullness, and sleep apnea are associated features. Pharyngeal and palatal weakness in myotonic dystrophy also lead to nasal dysarthria. Dysphagia occurs in as many as 25 to 85 percent of patients in different series. There is a high incidence of aspiration pneumonia. Involvement of the smooth muscle at several levels of the GI tract can occur (Table 15-3). Some of these patients have “unexplained abdominal pain,” which may lead to unnecessary laparotomy and even cholecystectomy. Click here to view this table.... Evaluation of Dysphagia Dysphagia should always be a concern in neurological patients with weight loss, since patients with mild to moderately severe dysphagia may not be aware of their symptoms. Drooling, aspiration, interrupted sleep, and change of diet to softer foods may suggest the presence of dysphagia. Patients with neurogenic dysphagia tend to have difficulty in the early phases of swallowing in contrast to patients with mechanical obstruction that localizes to mid-sternum or the xiphoid process. Also in contrast to mechanical causes of dysphagia, liquids are often harder to swallow than solids. A simple bedside slurp test consists of timing the patient as754 oz. of water in a cup are sucked through a flexed straw. Normal adults take 7 to 9 seconds. The patient should be observed for nasal regurgitation, aspiration, choking, effortful swallowing, leakage from the mouth, and apraxia. A video pharyngoesophagogram, in which the structure and movement of the oral cavity, pharynx, larynx, and esophagus are 76 visualized during swallowing, is the gold standard. The basic diagnostic study is often performed by a radiologist. A modification of the video study (the modified barium swallow) determines the impact of differing volumes and viscosities as well as the timing and head position during swallowing on swallowing safety and the efficiency of oral and pharyngeal function. The study is often performed jointly by a speech pathologist with specialized training in swallowing therapy and a radiologist. The impact of different food types, different food consistencies, and various therapeutic maneuvers on pharyngeal clearance and severity of aspiration can be determined. During the radiographic examination, the patient is also asked to flex the neck, extend the neck, and turn the head to one side in order to design postural strategies (e.g., chin down to prevent aspiration) to provide compensation for dysphagia. Management of Dysphagia
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Management depends on the results of the video study, diet modifications, postural strategies, and teaching supraglottic swallow (see later), which can be used to improve the efficiency and safety of swallowing. Diet modifications are based on observations during the video fluoroscopic swallowing study as to whether liquids, semisolids, or solids are safer and easier for the patient. Adjustment of the head position (“chin tuck”) during chewing and swallowing can help patients with difficulty in moving the food from mouth into the pharynx, and with premature leakage of the oral contents into the pharynx. Finally, some patients, especially those who retain food in anatomical spaces, may benefit from a supraglottic or safe-swallow procedure. The patient is instructed to inhale prior to swallowing, swallow the food (cough if needed), and then exhale immediately after swallowing. Sedatives should be avoided. Drooling in parkinsonian and ALS patients is due to dysphagia rather than to excessive production of saliva. Although anticholinergics may help reduce the saliva output, they may aggravate the dysphagia by making the secretions thicker and forming a mucous plug. Suction machines are often helpful. Other helpful measures include avoiding dry and 62 sticky foods and eating foods of uniform consistency. Cricopharyngeal myotomy, a surgical procedure in which the cricopharyngeal muscle (the major contributor to the upper esophageal sphincter) is cut, may be useful but only in an extremely well-selected group of patients with dysphagia due to neuromuscular disorders. It is likely to be more helpful if the video study shows failure of relaxation of the upper esophageal sphincter. It has been used successfully in oculopharyngeal muscular dystrophy and is reported to be useful in dysphagia with other neuromuscular disorders. In our experience, however, the procedure is not useful for most patients with neuromuscular diseases causing oral or pharyngeal weakness. Weight loss, malnutrition, and aspiration pneumonia are the feared complications of dysphagia. To avoid these complications, enteral feeding is often required by either nasogastric tube or PEG and jejunostomy tubes. A PEG is placed under local anesthesia (and sedation) by an endoscopist or a radiologist. The tube is placed through a small incision into the skin overlying the stomach on the anterior abdominal wall. Verification of the tube's position in the stomach lumen is obtained endoscopically and radiologically. Although it is thought by most neurologists that a PEG tube will prevent aspiration, the risk of aspiration remains high in patients with neurogenic dysphagia even after tube placement.
Motility Disorders Gastric and bowel motility is controlled by parasympathetic and sympathetic nerves that stimulate or inhibit the enteric neurons of the gut, which are organized as ganglionated plexuses and innervate the smooth muscles of the GI tract. The parasympathetic control of GI motility is from vagal and sacral nerves (S2, S3, S4) and the sympathetic outflow is from the intermediolateral column of the spinal cord (T5 to L3) through superior and inferior mesenteric ganglia. Neurological lesions affecting the sympathetic or parasympathetic pathways, or the smooth muscle, may affect the motility of the GI tract, resulting in gastroparesis, symptoms of small bowel obstruction, diarrhea, or constipation. These disorders are discussed in detail in Chapter 16, and brief comment here is made about only certain of them. Chagas' disease, also known as American trypanosomiasis, causes GI disease due to 77 intrinsic lesions of bowel innervation. Megacolon, megarectum, and mega-esophagus are common in rural areas of central Brazil, where the disease is endemic. Chronic constipation, abdominal distention, and dysphagia, at times so severe as to produce cachexia, are the clinical manifestations of intestinal dilatation. Loss of esophageal myenteric neurons occurs in this condition. Patients complain of dysphagia with the bolus being “stuck” or “hung up” at the level of the suprasternal notch, even though the level of obstruction is well below that. Hollow visceral myopathy is a term used to describe the motility disorder ascribed to 78 myopathic processes affecting the smooth GI muscle. Acute gastric dilatation has been described in patients with muscular dystrophy. Abdominal pain, tenderness, and distention, followed by vomiting, dehydration, gastric perforation, and peritonitis, have all been reported to occur, rarely with a fatal outcome. It is thought that dystrophic changes in the smooth muscle of the stomach wall may be responsible, but these have yet to be convincingly demonstrated. Myotonic muscular dystrophy can affect all levels of the GI tract (Table 74 15-3). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by ophthalmoparesis, peripheral neuropathy, leukoencephalopathy, and gastrointestinal symptoms of recurrent nausea, vomiting, or diarrhea due to intestinal dysmotility, and 79 histologically abnormal mitochondria are present in the muscle. Two defects of innervation also need to be considered under the heading of motility
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disorders. Achalasia is a disorder of esophageal motility characterized by aperistalsis and failure of the lower esophageal sphincter to relax. It presents with dysphagia and regurgitation. It is diagnosed by manometry or barium esophagogram. Although the esophageal findings are similar to those of Chagas' disease, the abnormalities in achalasia are restricted to the esophagus. Good long-term symptomatic relief can be achieved with pneumatic dilatation and Heller myotomy, although intrasphincteric injection of botulinum 80 toxin is also an effective treatment. Hirschsprung's disease is a motility disorder of the colon due to absence of autonomic ganglia that may involve the rectum only or variable lengths of the colon. The lack of ganglion cells results in a condition in which the affected area of colon fails to relax. This results in the development of megacolon and severe constipation beginning soon after birth. Genetic factors are involved in some cases.
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 16 Disturbances of Gastrointestinal Motility and the Nervous System MICHAEL CAMILLERI • ADIL E. BHARUCHA •
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INTERACTIONS BETWEEN THE EXTRINSIC NERVOUS SYSTEM AND THE GUT COMMON GASTROINTESTINAL SYMPTOMS IN NEUROLOGICAL DISORDERS Dysphagia Gastroparesis Chronic Intestinal Pseudo-obstruction Constipation Diarrhea Fecal Incontinence EXTRINSIC NEUROLOGICAL DISORDERS CAUSING GUT DYSMOTILITY Brain Diseases Stroke Parkinsonism Head Injury Autonomic Epilepsy and Migraine Amyotrophic Lateral Sclerosis Postpolio Dysphagia Brainstem Tumors Autonomic System Degenerations Pandysautonomias or Selective Dysautonomias Idiopathic Orthostatic Hypotension Postural Orthostatic Tachycardia Syndrome Shy–Drager Syndrome Spinal Cord Lesions Spinal Cord Injury Multiple Sclerosis Peripheral Neuropathy Acute Peripheral Neuropathy Chronic Peripheral Neuropathy GENERAL MUSCle DISEASES CAUSING GUT DYSMOTILITY IDENTIFICATION OF EXTRINSIC NEUROLOGICAL DISEASE IN PATIENTS WITH GASTROINTESTINAL SYMPTOMS OF A MOTILITY DISORDER MANAGEMENT OF GASTROINTESTINAL MOTILITY DISORDERS CONCLUDING COMMENT
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The nervous system modulates normal gut function through the extrinsic neural supply and the enteric nervous system of the gastrointestinal tract. Disorders of the nervous system affecting gastrointestinal tract function are manifested primarily as abnormalities in motor, rather than absorptive or secretory, functions or other digestive processes. The normal neural–gut interactions, common clinical manifestations of gut dysmotility encountered in neurological disorders, and the assessment of gastrointestinal functions that might be used to assess extrinsic autonomic control of viscera are reviewed in this chapter. Finally, the main features in the diagnosis and treatment of neurological diseases affecting the gut are discussed. INTERACTIONS BETWEEN THE EXTRINSIC NERVOUS SYSTEM AND THE GUT Normal motility and transit through the gastrointes-tinal tract result from an intricately balanced series of control mechanisms (Fig. 16-1): the electrical and contractile properties of the smooth muscle cell; control by the intrinsic nervous system through chemical transmitters, such as acetylcholine, biogenic amines, gastrointestinal neuropeptides, and nitric oxide; and regulatory extrinsic pathways (sympathetic and parasympathetic nervous systems). The neuropeptides may act as circulating hormones or at the site of their release (paracrine or neurocrine functions).
FIGURE 16-1 Control of gut motility: interactions between extrinsic neural
pathways and the intrinsic nervous system (“enteric brain”) modulate contractions of gastrointestinal smooth muscle. Interactions between transmitters (e.g., peptides and amines) and receptors alter muscle membrane potentials by stimulating bidirectional ion fluxes. In turn, membrane characteristics dictate whether the muscle cell contracts. (From Camilleri M, Phillips SF: Disorders of small intestinal motility. Gastroenterol Clin North Am 18:405, 1989, by permission of Mayo Foundation.) The electrical properties of gut smooth muscle cells result from transmembrane fluxes of ions; as in other excitable muscular organs, these fluxes alter the membrane potential and result in muscle contraction or relaxation. In some parts of the digestive tract, such as the stomach and small bowel, a contraction occurs once a threshold potential is exceeded by a spike potential. In other regions (e.g., internal anal sphincter), no such spike occurs, but contractions are nevertheless observed and associated with altered basal electrical rhythm. Infiltrative or degenerative processes that affect the excitability of the smooth muscle cells of the gut are typically manifestations of myopathic disorders and prevent normal contractions, resulting in gastrointestinal dysmotility. In the mammalian digestive tract, the intrinsic (or enteric) nervous system contains about 100 million neurons, approximately the number present in the spinal cord. This integrative system is organized in ganglionated plexuses (Fig. 16-2), which include the interstitial cells of Cajal (the gastrointestinal pacemakers), and is separate from the sympathetic and parasympathetic portions of the autonomic nervous system. It has several components: sensory mechanoreceptors and chemoreceptors; interneurons that process sensory input and control
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effector (motor and sensory) units; and effector secretor or motor neurons involved in secretory or motor functions of the gut. Preprogrammed neural circuits serve to integrate motor function within and between different regions and thereby control the coordinated functions of the entire gastrointestinal tract, such as the peristaltic reflex and probably the interdigestive migrating motor complex (Fig. 16-3). The synaptic pathways in the gut wall are capable of autonomous adjustment in response to sensory input. They can also be modulated by the extrinsic nervous system at prevertebral ganglia, spinal cord, or higher centers, so that excitation results from the activity of vagal preganglionic fibers, and inhibition from sympathetic activity.
FIGURE 16-2 The enteric plexuses in the intestinal layers. The chief neural
plexuses are in the submucosal and intermuscular layers.
FIGURE 16-3 Interaction between extrinsic neural control, sensory pathways,
and enteric plexuses. Vagal command fibers synapse with preprogrammed circuits having “hard-wired” functions that drive motor and secretory processes. The vagus is composed of preganglionic cholinergic fibers that synapse with preprogrammed circuits in the ganglionated enteric plexuses. These enteric neurons include myenteric cholinergic neurons that, in turn, excite smooth muscle cells to contract, or surface epithelial cells to absorb or secrete fluids and electrolytes. Since there is a great disparity between the limited number of extrinsic nerve fibers and the millions of enteric plexus neurons, it is currently believed that motor or secretory programmed circuits are controlled by command vagal preganglionic or sympathetic postganglionic fibers. Thus, there are approximately 40,000 preganglionic vagal fibers (many of which are afferent, not efferent) at the level of the diaphragm; in contrast, 100 million neurons populate the enteric nervous system. The sympathetic supply inactivates neural circuits that generate motor activity while allowing intrinsic inhibitory innervation by the enteric nerves. Extrinsic vagal fibers also synapse with noradrenergic inhibitory intramural neurons in the gut, which produce transmitters such as nitric oxide, vasoactive intestinal peptide, and somatostatin. Loss of the sympathetic inhibitory supply (“the brake”) results in excessive or uncoordinated phasic pressure activity in the gut that may manifest with gut motor overactivity, including diarrhea. The extrinsic innervation of the gut consists of the parasympathetic vagal and sacral (S2, S3, and S4) nerves and the sympathetic outflow from the intermediolateral column of the spinal cord between the fifth thoracic and upper lumbar levels. The sympathetic nerves synapse in the prevertebral celiac, superior mesenteric, and inferior mesenteric ganglia; sympathetic fibers follow the respective arterial trunks.
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Extrinsic nerves are intimately involved in the control of the striated muscle portions of the esophagus and the external anal sphincter. Although the smooth muscle portion of the gut can function fairly normally without the extrinsic nerves, the latter modulate the intrinsic neural circuits, integrate activity in widely separated regions of the gastrointestinal tract, and appear to influence greater control in certain regions (e.g., the stomach and distal portion of the colon) than in others (e.g., the small bowel). COMMON GASTROINTESTINAL SYMPTOMS IN NEUROLOGICAL DISORDERS
Dysphagia Dysphagia is the sensation of difficult swallowing. Oropharyngeal, or transfer, dysphagia is 1 the inability to initiate a swallow or propel food from the mouth to the esophagus. The hold-up occurs in the cervical area and is generally caused by a lesion affecting any level of the swallowing pathway rather than by a process affecting the oropharyngeal mucosa. However, even patients with distal esophageal obstruction may experience a sensation of hold-up of food in the pharynx or at the level of the neck. Stroke and Parkinson's disease are the neurological disorders most commonly associated with dysphagia. Pharyngeal weakness may also occur in brainstem disease (e.g., bulbar polio, Arnold–Chiari malformations, tumors) or muscle diseases, such as dystrophies and mitochondrial cytopathy. In contrast to oropharyngeal dysphagia, esophageal dysphagia is caused by abnormal esophageal peristalsis. In esophageal smooth muscle disorders (e.g., progressive systemic sclerosis), abnormal peristalsis may be due to incoordination during early stages, accompanied by reduced amplitude of contractions during later stages of the disease. Idiopathic achalasia is a primary esophageal motor disorder characterized by aperistalsis of the esophageal body and impaired lower esophageal sphincter relaxation during swallowing. While degeneration of ganglion cells within the myenteric plexus is the primary disturbance and seems to be responsible for abnormal esophageal function, the injury can extend to the vagal nerve endings within the esophagus and neuronal bodies within the dorsal motor nucleus of the vagus. Dysphagia that is restricted to solids suggests a mechanical cause or narrowed lumen that blocks the bolus passage through the esophagus. Dysphagia restricted primarily to liquids is suggestive of oropharyngeal disease or achalasia. Neuromuscular dysphagia typically results in dysphagia to both liquids and solids, and aspiration into the upper airways. Physical examination shows evidence of the co-existing neurological disease, such as abnormal palatal or pharyngeal movements or a brisk jaw jerk, suggesting pseudo-bulbar palsy. Barium videofluoroscopy or a fiberoptic endoscopic evaluation of swallowing (FEES) is essential, can identify the motor disturbance, and can provide the basis for interventions to lessen the problem. However, these tests only indirectly assess the sensory component. Airway protective reflexes may not be properly initiated in patients with sensory deficits of the larynx or pharynx, leading to dysphagia and aspiration. Thus, sensory testing (ST), accomplished by FEES-ST 2 may help stratify the risk of aspiration in patients with pharyngeal weakness. Pharyngoesophageal motility studies, preferably using solid-state pressure transducers, also complement the diagnosis. Re-education of the swallowing process is feasible in many patients, often in a program that incorporates speech therapy. Nutritional support and prevention of bronchial aspiration are predominant considerations in planning therapy for those with more severe dysphagia not responding to these conservative measures. This may require placement of a gastrostomy feeding tube, either permanently or temporarily, while swallowing is rehabilitated. Since swallowing may improve considerably in the first 2 weeks after a stroke, long-term decisions should be delayed for that period.
Gastroparesis Gastric motor dysfunction resulting in delayed gastric emptying is a common gastrointestinal 3,4 manifestation of autonomic neuropathies such as that associated with diabetes mellitus. Symptoms range from vague postprandial abdominal discomfort to recurrent postprandial emesis, resulting in weight loss and malnutrition. Iatrogenic gastroparesis is induced by surgical vagotomy, including laparoscopic fundoplication, and by numerous medications, most commonly narcotic analgesics and tricyclic antidepressants. There may be a succussion splash on physical examination. It is essential to exclude gastric outlet obstruction by a barium or gastroscopic study. Scintigraphic gastric emptying tests confirm the impaired emptying of solids5 from the stomach; the tests may be extended over time to assess small bowel transit too. Gastric stasis may result from obstruction or from abnormal motility of the
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stomach or small bowel, and studies of pressure profiles by manometry or solid-state pressure transducers placed in the distal stomach and small bowel can help identify abnormality of motor function (Fig. 16-4A), differentiate neuropathic from myopathic 7 processes (Fig. 16-4B), and exclude mechanical8 obstruction that may have been missed on previous radiographic studies of the small bowel.
FIGURE 16-4 A, Tracing showing normal upper gastrointestinal motility in the fasting and fed states. The fasting tracing shows phase III of the interdigestive migrating motor complex. B, Manometric tracings showing the myopathic pattern of intestinal pseudo-obstruction due to systemic sclerosis (left panel). Note the low amplitude of phasic pressure activity compared with control (middle panel). A manometric example of neuropathic intestinal pseudo-obstruction in diabetes mellitus shows the absence of antral contractions and persistence of cyclical fasting-type motility in the postprandial period (right panel). (A from Malagelada J-R, Camilleri M, Stanghellini V: Manometric Diagnosis of Gastrointestinal Motility Disorders. Thieme, New York, 1986, by permission of Mayo Foundation. B from Camilleri M: Medical treatment of chronic intestinal pseudo-obstruction. Pract Gastroenterol 15:10, 1991, with permission.)
Prokinetic agents and use of a more easily digestible diet (low in fat with insoluble, large-particle [>5 mm] fibers) may be beneficial in the treatment of gastroparesis. Since cisapride has been withdrawn from the market, metoclopramide and erythromycin are the only available prokinetic agents. Because it can cause occasionally irreversible, extrapyramidal side effects, metoclopramide must be used judiciously. Erythromycin increases gastric motility by stimulating motilin receptors. A feeding gastrostomy or jejunostomy with a percutaneously placed tube, often possible via upper gastrointestinal endoscopy, may be required. Gastric electrical stimulation may also improve symptoms but not gastric emptying in gastroparesis. A total gastrectomy with esophago–Roux-en-Y jejunostomy is the last resort for patients with gastroparesis who have had previous gastric surgery.
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Chronic Intestinal Pseudo-obstruction Chronic intestinal pseudo-obstruction is a syndrome characterized by nausea, vomiting, early satiety, abdominal discomfort, weight loss, and altered bowel movements suggestive of intestinal obstruction in the absence of a mechanical cause. These symptoms are the consequence of abnormal intestinal motility rather than of mechanical obstruction. The syndrome may result from a number of neurological diseases extrinsic to the gut (e.g., disorders at any level of the neural axis), from dysfunction of neurons in the myenteric 3 plexus, or from degeneration of gut smooth muscle in familial or sporadic hollow visceral myopathy (Table 16-1). The pathophysiology of these diseases can be broadly subdivided into myopathic (e.g., infiltrative amyloidosis, hollow visceral myopathy, metabolic myopathies, muscular dystrophies) and neuropathic processes (Table 16-1). Click here to view this table.... The patient's accompanying clinical features may suggest an underlying disease process: these features include postural dizziness, difficulties in visual accommodation in bright lights, and sweating abnormalities suggestive of an autonomic neuropathy; alternatively, the occurrence of urinary symptoms such as recurrent urinary infections and problems with bladder voiding suggest genitourinary involvement by a generalized visceral neuromyopathic disorder, and accompanying peripheral sensory or motor symptoms suggest an associated peripheral neuropathy. The combination of external ophthalmoplegia, high dysphagia, peripheral neuromyopathy (e.g., increased serum creatine kinase) and acidosis (e.g., increased lactate, pyruvate) suggests mitochondrial myopathy, a rare disorder associated 9 with small bowel pseudo-obstruction and diverticulosis. Patients should be questioned about the use of narcotics, phenothiazines, antihypertensive agents such as clonidine, tricyclic antidepressants having anticholinergic effects, and calcium-channel blockers. The physical examination should pay particular attention to evaluation of pupillary reflexes to light and accommodation, measurement of the blood pressure and pulse with the patient lying and standing, and a search for abdominal distention or a succussion splash. Plain radiographs and barium studies are often nonspecific; dilatation of the small intestine was found in about 60 percent of one series of patients with chronic idiopathic intestinal 10 pseudo-obstruction, but it is probably more frequent in later stages of myopathic than neuropathic disorders. Contrast studies of the small bowel are important in ruling out mechanical obstruction but rarely lead to an etiologic diagnosis. Motility studies (Fig. 16-4) help differentiate myopathic and neuropathic processes and may also suggest the presence 8 of mechanical obstruction, even in the presence of an underlying neuromuscular disorder. When the motility tracing is suggestive of a neuropathic process, assessment of autonomic function and radiological and serological tests should be performed to identify the cause of the autonomic neuropathy or cerebrospinal disease (see later). The goals of treatment of chronic intestinal pseudo-obstruction include the restoration of hydration and nutrition, stimulation of normal intestinal propulsion, and suppression of bacterial overgrowth. Specific medications are discussed later.
Constipation Constipation is a common complaint and may be perceived by the patient as infrequent bowel movements, excessively hard stools, the need to strain excessively during defecation, or a sense of incomplete evacuation after defecation. Broadly, constipation in neurological disorders may be caused by potentially reversible factors (e.g., inadequate dietary fiber intake, lack of exercise, medications), slow colonic transit or pelvic floor dysfunction (i.e., a defecatory disorder)11that may be related to the neurological disorder, or another disease (e.g., colon cancer). When stool enters the rectum, rectal distention induces rectal contractions, the desire to defecate, and involuntary relaxation of the internal anal sphincter. Thereafter, defecation is accomplished by increased intra-abdominal pressure coordinated with relaxation of the anal sphincters and pelvic floor muscles (Fig. 16-5). Many neurological diseases (e.g., Parkinson's disease, multiple sclerosis, spinal cord injury, and autonomic neuropathies) can affect colonic transit and pelvic floor functions. In multiple sclerosis and Parkinson's disease, pelvic floor dysfunction may result from disordered coordination, owing to which patients cannot relax or paradoxically contract the anal sphincter or pelvic floor muscles (or both) during defecation. Because the desire to defecate is necessary to initiate the process, diminished rectal sensation (e.g., due to a neuropathy or spinal cord injury) can also affect defecation.
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FIGURE 16-5 Schema showing normal alternations of pelvic floor, rectoanal angle, and
sphincters during defecation. (Adapted from Camilleri M, Thompson WG, Fleshman JW, et al: Clinical management of intractable constipation. Ann Intern Med 121:520, 1994, with permission.) Patients use the term constipation to describe a variety of disturbances: a careful history can contribute significantly to understanding the cause. For example, the need for enemas or finger evacuation to expel the stool from the lower rectum suggests a disturbance of the pelvic floor or anorectum. The coexistence of incontinence and lack of rectal sensation suggests a pudendal neuropathy and is common among patients with diabetic neuropathy. The presence of blood in the stool with constipation necessitates further tests to exclude colonic mucosal lesions, such as polyps, or perianal conditions, such as hemorrhoids. Even when the clinical features suggest that constipation is due to an underlying neurological disorder, anatomical abnormalities (i.e., tumors, megacolon, and megarectum) that may require surgery should be excluded by colonoscopy or imaging (i.e., barium enema or computed tomography colonography). Potentially reversible factors (e.g., physical inactivity, inadequate dietary caloric or fiber intake, and neglect of the urge to defecate) should be addressed. Most constipated patients respond well to fiber, bulking agents, and stool softeners. Slow colonic transit occurs frequently in wheelchair- or bed-bound patients and may not respond to fiber supplementation, therefore requiring the addition of stimulant cathartics or prokinetic medications. Patients with spinal cord injuries usually respond to a combination of bulk laxatives and scheduled enemas daily or on alternate days. In patients with paraplegia, computer-assisted sacral anterior root stimulation has been used to evoke a coordinated sequence of sigmoid and rectal contractions and sphincter relaxation, thereby 12 simulating the dynamic events occurring during defecation. This has been shown to reduce the interval between defecations and the time taken to defecate. A dorsal rhizotomy must be performed to avoid general stimulation of autonomic responses. However, few centers have experience with this approach. When constipation does not respond to dietary fiber supplementation or osmotic laxatives, consideration should be given to assessing colonic transit and anorectal functions. Colonic 13 14 transit can be measured by radiopaque markers or by radioscintigraphy. Because pelvic floor dysfunction may result in outlet obstruction and thereby delay colonic transit, slow colonic transit does not necessarily indicate colonic motor dysfunction. The anorectal functions contributing to defecation can be tested by measuring resting anal pressure, by assessing for the rectoanal inhibitory reflex during rectal distention, and by measuring the 11,15 If clinically indicated, anorectal recto-anal pressure gradient during simulated evacuation. imaging during rectal evacuation of barium (i.e., defecation proctography) or ultrasound gel (i.e., MR proctography) should 16,17 be performed to identify occult mucosal prolapse, rectoceles, Pelvic floor retraining by biofeedback therapy, using or excessive perineal descent. surface electromyography (EMG) sensors or manometry, can improve recto-anal coordination during defecation in patients with an “idiopathic” functional defecatory disorder 18 (i.e., not due to neurological disease). Although biofeedback therapy can improve rectal sensation, partially preserved rectal sensation is necessary to participate in biofeedback therapy. Therefore, it is unclear whether patients with neurological disorders (e.g., multiple sclerosis), who often have reduced rectal sensation and impaired volitional control of the
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pelvic floor muscles, can benefit from pelvic floor retraining by biofeedback therapy. Surgery is reserved for patients with intractable symptoms. A colostomy or subtotal colectomy with ileorectostomy may be necessary for colonic inertia. Other surgical procedures may be necessary to correct a rectal prolapse or a rectocele.
Diarrhea Diarrhea is loosely defined as passage of abnormally liquid or unformed stools at an increased frequency. For adults on a typical Western diet, a stool weight exceeding 200 g/day probably reflects diarrhea. The duration of diarrhea guides the differential diagnosis. Diarrhea may be further defined as acute if less than 2 weeks, persistent if 2 to 4 weeks, and chronic if more than 4 weeks in duration. Acute diarrhea is most frequently caused by infectious agents or is secondary to20medications. The differential diagnosis of chronic diarrhea is discussed in detail elsewhere. In autonomic neuropathies (e.g., diabetes), chronic diarrhea may be caused by rapid intestinal transit due to sympathetic denervation or by bacterial overgrowth secondary to gut dysmotility. Osmotic agents (e.g., artificial sweeteners) may also cause or aggravate diarrhea. Dysautonomic diarrhea, as in patients with diabetic neuropathy, is often multifactorial and may be associated with secretion, malabsorption secondary to rapid transit, or bacterial overgrowth and high-amplitude propulsive contractions in the colon that result in 20–22 urgency and sometimes incontinence of stool. A careful history and physical examination are extremely important to guide diagnostic tests. Secretory diarrhea persists with fasting, whereas osmotic diarrhea does not. Features of fat malabsorption (e.g., greasy, difficult-to-flush stools, weight loss) should prompt a 24- to 48-hour stool collection with quantitation of stool fat. The coexistence of diarrhea and neurological manifestations may be explained by autonomic dysfunction (e.g., in diabetic neuropathy), the neurological consequences of malabsorption (e.g., myopathy or neuropathy in celiac disease), and rare diseases with neurological manifestations (e.g., Whipple's disease). After excluding a structural cause (e.g., inflammatory bowel disease) and malabsorption, most patients with diarrhea due to disordered motility can be treated effectively with loperamide, beginning with 2 mg taken 30 minutes before meals, and titrated to control symptoms up to a maximum of 16 mg daily. Patients should be tested and treated for bacterial overgrowth. The α2-adrenergic agonist clonidine also reduces diarrhea by improving intestinal absorption and inhibiting intestinal and colonic motility.
Fecal Incontinence Common neurological disorders associated with fecal incontinence include multiple sclerosis, Parkinson's disease, multiple system atrophy, Alzheimer's disease, strokes, diabetic neuropathy, and spinal cord lesions. In addition to generalized neuropathies (e.g., diabetes), obstetrical trauma and stretch-induced pudendal nerve injury related to excessive straining in 23 constipated patients are other causes of a pudendal neuropathy. Thus, a subset of patients with chronic constipation develop excessive perineal descent, a stretch-induced pudendal neuropathy, and ultimately anal sphincter weakness, culminating in fecal incontinence. An alteration in bowel habits (i.e., diarrhea) frequently precedes the transition from asymptomatic pelvic floor injury to fecal incontinence. Symptoms may provide clues to the etiology of fecal incontinence. Incontinence occurring only at night suggests internal anal sphincter dysfunction (e.g., progressive systemic sclerosis); stress incontinence during coughing, sneezing, or laughing suggests loss of external sphincter control, typically from the pudendal nerve or S2, S3, and S4 root lesions. Leakage of formed stool suggests more severe sphincter weakness than leakage of liquid stool alone. Examination of the incontinent patient should include inspection of the anus with and without straining to detect rectal prolapse; a digital rectal examination to exclude impaction or mucosal disease; and proctoscopy and barium enema or colonoscopy to exclude mucosal lesions. Anal examination may disclose normal (e.g., multiple sclerosis) or reduced (e.g., diabetes mellitus, scleroderma) anal resting tone. The external sphincter and puborectalis contractile response during squeeze is often reduced. Perineal weakness is often manifested by excessive perineal descent (>4 cm) on straining. The perianal wink reflex is absent in lesions of the sacral reflex arc. In evaluating such patients, it is important first to exclude overflow incontinence due to fecal impaction. Similarly, overuse of laxatives or other medications, such as magnesium-containing antacids, may result in reversible incontinence. If these fail to identify the cause of incontinence, further tests may be necessary: anorectal manometry,
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assessment of rectal sensation, and the ability to expel a balloon from the rectum. Anal sphincter defects and atrophy can be visualized by endoanal ultrasound or magnetic resonance imaging (MRI). Rectal evacuation and anatomical abnormalities (e.g., rectocele, rectal intussusception) can be assessed by a barium defecating proctogram or by dynamic MRI. In contrast to defecating proctography, dynamic MRI can visualize global pelvic floor motion (anterior, middle, and posterior compartments) in real-time without radiation exposure. EMG provides a sensitive measure of denervation (fibrillation potentials) and can usually identify myopathic damage (small polyphasic motor unit potentials), neurogenic damage (large polyphasic motor unit potentials), or mixed injury. Anal EMG should be considered in patients with clinically suspected neurogenic sphincter weakness, particularly if there are 24 features suggestive of proximal (i.e., sacral root) involvement. Neurogenic changes isolated to the external anal sphincter may be caused by injury at any level along the lower motor neuron, that is, from motor neurons in the sacral spinal cord to the nerve fascicles entering the anal sphincter (e.g., caused by local or obstetrical trauma). Therefore, a pudendal neuropathy can be diagnosed with certainty only when neurogenic changes diffusely affect the anal sphincter (i.e., anterior and posterior quadrants) or when the changes affect the anal sphincter and ischiocavernosus muscle. 25
It is important to maintain perianal hygiene and integrity by perianal protective devices. Medical management is focused on restoring regular bowel habits. In contrast, biofeedback therapy has little impact on anal resting tone or on squeeze responses in patients with weakness of the pelvic floor muscles. In patients with reduced rectal sensation (e.g., due to diabetes), biofeedback retraining can restore rectal sensation and improve fecal continence. A colostomy may be necessary in patients with medically refractory fecal incontinence. It is important to exclude mucosal prolapse in association with incontinence; surgical correction of the prolapse may at least temporarily improve continence by permitting better function of the 26 external sphincter. Though more complex surgical procedures (i.e., artificial anal sphincter, dynamic graciloplasty) may improve fecal continence, these procedures are associated with considerable morbidity and are not routinely performed in the United States. Uncontrolled studies suggest that sacral nerve stimulation can improve symptoms,27anal pressures, and rectal sensation even in patients with neurogenic fecal incontinence. EXTRINSIC NEUROLOGICAL DISORDERS CAUSING GUT DYSMOTILITY It is possible to distinguish disorders that affect the gut muscle (“myopathic disorders”), those involving the myenteric plexus, and diseases of the extrinsic path-ways that supply the gut. 28 Certain diseases affect both intrinsic and extrinsic neural control. This review concentrates on diseases of extrinsic neural control and smooth muscle. Diseases affecting the enteric 29 nervous system are reviewed elsewhere.
Brain Diseases Stroke Dysphagia may result from cranial nerve involvement and may cause malnutrition or aspiration pneumonia. Videofluoroscopy of the pharynx and upper esophagus typically shows 30 transfer dysphagia or tracheal aspiration. Colonic pseudo-obstruction occurs rarely. Percutaneous endoscopic gastrostomy is usually the most effective method to provide nutrition without interfering with rehabilitation; feedings can be given in the form of boluses or by infusion at night. Swallowing improves in a majority of survivors over time. Over 50 percent of affected individuals improve significantly within 1 week, and most improve within 3 months. 31 The severity of the initial neurological deficit is the strongest predictor of eventual recovery. The gastrostomy tube can be removed when oral intake is shown to be sufficient to maintain caloric requirements. Parkinsonism Patients with Parkinson's disease or progressive supranuclear palsy may have oropharyngeal 32 dysfunction with impaired swallowing. Shy–Drager syndrome, or multiple system atrophy, is considered later. Patients may have mild to moderate malnutrition; moderate dysphagia may be diagnosed by videofluoroscopy. In the absence of severe malnutrition or significant aspiration, conservative treatment with attention to the consistency of food (thickened liquids) and to adequate caloric content of meals will suffice. Feeding through a percutaneous gastrostomy is an appropriate alternative for severe dysphagia. 32
Constipation is common in patients with parkinsonism 34and may be the result of slow colonic 33 transit or of pelvic floor or anal sphincter dysfunction. Gastrointestinal hypomotility,
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generalized hypokinesia, associated autonomic dysfunction, and the effects of various anticholinergic and dopamine agonist medications may all play a role. The bioavailability of other medications can be altered considerably by the effects of parkinsonism on gut transit and delivery of medications to the small bowel for absorption. Head Injury Immediately following moderate to severe head injury, most patients develop transient delays in gastric emptying. The underlying mechanism is unknown, although a correlation exists between the severity of injury, increased intracranial pressure, and severity of the gastric stasis. These patients are frequently intolerant of enteral feeding and require parenteral nutrition to meet their increased metabolic demands. In practice, enteral nutrition can often 35 be reintroduced within 2 to 3 weeks as the gastric stasis resolves. Autonomic Epilepsy and Migraine Autonomic epilepsy and migraine are infrequent causes of upper abdominal symptoms, such as nausea and vomiting. Treatment is of the underlying neurological disorder. Amyotrophic Lateral Sclerosis Patients with amyotrophic lateral sclerosis (ALS) and progressive bulbar palsy have 36 predominant weakness of the muscles supplied by the glossopharyngeal and vagus nerves. Dysphagia is a frequent complaint, and patients may have respiratory difficulty while eating as a result of aspiration or respiratory muscle fatigue. Rarely, patients 37 with vagal dysfunction will show features of a chronic intestinal pseudo-obstruction syndrome. Physical examination reveals the cranial nerve palsies and muscle fasciculations. An exaggerated jaw jerk may be present in ALS. Videofluoroscopic barium swallow of liquids and solids is employed to evaluate swallowing, determine whether aspiration occurs, and guide decisions about the route to use for nutritional support (oral feeding or a percutaneous gastrostomy). Cervical esophagostomy or cricopharyngeal myotomy has been performed in selected cases for significant cricopharyngeal muscle dysfunction. Postpolio Dysphagia Patients with postpolio syndrome frequently have dysphagia and aspiration, especially if there was bulbar involvement during the initial attack. Videofluoroscopy is useful for screening and monitoring progression of disease. Attention to the position of the patient's head during swallowing and alteration of food consistency to a semisolid state can decrease the 38 prevalence of choking and aspiration. Brainstem Tumors Brainstem lesions can present with isolated gastrointestinal motor dysfunction. In the absence of increased intracranial pressure, such symptoms are probably the result of a direct mass effect in the brainstem, with distortion of the vomiting center on the floor of the fourth ventricle. Motor dysfunction is typically evident on manometric or radionuclide studies of the 39 the most common symptom, colonic or stomach and small bowel. Although vomiting is 40 anorectal dysfunction has also been described. The presence of more widespread autonomic dysfunction, particularly if preganglionic sympathetic nerves are involved, necessitates a search for a structural lesion in the central nervous system (CNS).
Autonomic System Degenerations Pandysautonomias or Selective Dysautonomias Pandysautonomias are characterized by preganglionic or postganglionic lesions affecting both the sympathetic and parasympathetic nervous systems. Vomiting, paralytic ileus, constipation, and a chronic pseudo-obstruction syndrome have been reported in acute, 41 subacute, and congenital pandysautonomia. Motor disturbances have been substantiated in the esophagus, stomach, and small bowel. Selective cholinergic dysautonomia may also impair upper and lower gastrointestinal motor activity. This picture usually follows a viral 42 infection such as infectious mononucleosis.
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Idiopathic Orthostatic Hypotension Idiopathic orthostatic hypotension is sometimes associated with motor dysfunction of the gut, such as esophageal dysmotility, gastric stasis, alteration in bowel movements, and fecal 43,44 Cardiovascular and sudomotor abnormalities usually precede gut incontinence. involvement. The precise site of the lesion causing the gut dysmotility is unknown. Postural Orthostatic Tachycardia Syndrome About one third of patients with postural orthostatic tachycardia syndrome (POTS) have 45 gastrointestinal manifestations including pseudo-obstruction syndrome. It is important to exclude dehydration, deconditioning, and functional disorders that produce similar clinical features. A collaborative approach by experienced neurologists and gastroenterologists and cautious interpretation of objective measurements are essential. Shy–Drager Syndrome In the original description by Shy and Drager, constipation and fecal incontinence were 46 included among the classic features of the disorder named after them. Other reports have documented substantial reduction in fasting and postprandial antral and small bowel motility. Abnormal esophageal motility was demonstrated by videofluoroscopy and by the occurrence 43 of frequent, simultaneous, low-amplitude peristaltic waves during esophageal manometry.
Spinal Cord Lesions Spinal Cord Injury Dysphagia after47acute cervical spinal cord injury generally improves during the initial hospitalization. Compression of the brainstem and lower cranial nerves can cause potentially life-threatening neurogenic dysphagia in patients with Chiari malformations. Early recognition of dysphagia, which often precedes other brainstem symptoms, is important to avoid irreversible brainstem injury, to preserve48nutrition and pulmonary functions, and to maximize restoration of function after surgery. Ileus is a frequent finding soon after spinal cord injury, but it is rarely prolonged. In the chronic phase after injury, disorders of upper gastrointestinal motility are uncommon, whereas colonic and anorectal dysfunction are common. The latter probably result from interruption of supraspinal49,50 control of the sacral parasympathetic supply to the colon, pelvic floor, and anal There is a decrease in colonic compliance and an absence of postprandial sphincters. 51 colonic motor and myoelectric activity in patients with thoracic spinal cord injury. The loss of voluntary control of defecation may be the most significant disturbance in patients who rely on reflex rectal stimulation for stool evacuation. Loss of control of the external anal sphincter commonly results in fecal incontinence in patients with spinal cord injury. The usual management for irregular bowel function is a combination of bulking agents and scheduled enemas. Computerized stimulation of the sacral anterior roots has been 12 proposed as a method to restore normal function to the pelvic colon and anorectal sphincters ; however, relatively few patients have been treated by this means on a long-term basis. Multiple Sclerosis Severe constipation frequently accompanies urinary bladder dysfunction in patients with 52 advanced multiple sclerosis. In one study, colonic transit of radiopaque markers was prolonged in 14 of 16 patients with multiple sclerosis and urinary bladder involvement; 10 patients also had evidence of fecal incontinence, and 5 had spontaneous rectal contractions. The studies performed to date have not been sufficiently detailed to assess the extent to which such symptoms relate to sympathetic and parasympathetic denervation. Pelvic colonic dysfunction is probably due to impaired function of the supraspinal or descending pathways that control the sacral parasympathetic outflow. Further studies are needed to address the mechanism of impaired gut transit in multiple sclerosis, which, as with spinal cord53injury, results in motility disturbances more frequently in the lower than in the upper gut.
Peripheral Neuropathy
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Acute Peripheral Neuropathy Autonomic dysfunction associated with certain acute viral infections may result in nausea, vomiting, abdominal cramps, constipation, or a clinical picture of pseudo-obstruction. In the Guillain–Barré syndrome, visceral involvement may include gastric distention or adynamic ileus. Persistent gastrointestinal motor disturbances may also occur in association with herpes zoster, Epstein–Barr virus infection, or botulism B. The site of the neurological lesion is uncertain. Cytomegalovirus has been identified in myenteric plexus in some patients with 54 chronic intestinal pseudo-obstruction. Selective cholinergic dysautonomia (with associated gastrointestinal dysfunction) has been reported to develop within a week of the onset of 42 infectious mononucleosis. Diarrhea induced by human immunodeficiency virus (HIV) may be another manifestation of autonomic dysfunction (see later), but the data require confirmation. Chronic Peripheral Neuropathy Chronic peripheral neuropathy is the most commonly encountered extrinsic neurological disorder that results in gastrointestinal motor dysfunction. Diabetes Mellitus
Diabetic autonomic neuropathy of the gut has been studied extensively and has been 55 reviewed elsewhere. In patients with type I diabetes seen at university56medical centers, gastrointestinal symptoms, particularly constipation, are quite common. However, a questionnaire-based Finnish study in a randomly selected population suggests that the occurrence and spectrum of gastrointestinal symptoms in middle-aged subjects with insulin(IDDM) and57non–insulin-dependent diabetes mellitus do not differ from those of the general population. A similar U.S.-based study in the community showed that constipation with or without the use of laxatives was the only gut symptom more frequent in IDDM patients than in age- and gender-matched controls. Patients with constipation tended 58,59 to be taking some medications that cause the symptoms, or to have bladder symptoms. Gastric emptying of digestible or nondigestible solids is abnormal in patients with diabetes mellitus and gastrointestinal symptoms (“gastroparesis”). Studies in humans have demonstrated a paucity of distal antral contractions during fasting and postprandially; small 6 with an “autovagotomy,” bowel motility may also be abnormal. These features are consistent 60 a concept originally proposed in studies of gastric secretion, or loss of the interstitial cells of Cajal, the pacemaker cells of the gastrointestinal tract. Constipation is a frequent, although often unreported, symptom in patients with diabetes. 61 Colonic motor dysfunction is associated with constipation. Streptozotocin-treated rats develop abnormal colonic compliance and selective deficiencies of certain neurotransmitters (e.g., calcitonin gene-related peptide) in the myenteric plexus. However, in a small study of patients with diabetes and constipation selected randomly from among community diabetics, 62 the pathophysiology included equally slow transit, normal transit, or pelvic floor dysfunction. Diarrhea or fecal21incontinence (or both) may result from several mechanisms (reviewed in detail elsewhere ): dysfunction of the anorectal sphincter or abnormal rectal sensation, osmotic diarrhea from bacterial overgrowth due to small bowel stasis, and rapid transit from uncoordinated small bowel motor activity. Rarely, an associated gluten-sensitive enteropathy or pancreatic exocrine insufficiency is present. These associated conditions should be sought, since they are potentially reversible. Histopathological studies of the vagus nerve have revealed a reduction in the number of unmyelinated axons; surviving axons are usually of small caliber. In patients with diabetic diarrhea, there are giant sympathetic neurons and dendritic swelling of the postganglionic neurons in prevertebral and paravertebral sympathetic ganglia as well as reduced fiber 63,64 density in the splanchnic nerves. Peripheral cholinergic agonists (such as metoclopramide, bethanechol, and cisapride) and α2-adrenergic agonists (such as clonidine) have been used, respectively, to treat gastric 65 stasis and diarrhea secondary to diabetic gut neuropathy. Available therapeutic options have resulted in only transient relief. Erythromycin (administered intravenously) stimulates motilin receptors on cholinergic neurons and gastric muscle cells and is useful during the 66 is acute phase, but few patients tolerate it beyond 2 weeks. Pancreas transplantation 67 reported to restore normal gastric emptying in patients with diabetic gastroparesis. Long-term results are not available, however, and we have certainly observed persistent gastric stasis in patients with an autonomic neuropathy that preceded the pancreas
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transplant. Paraneoplastic Neuropathy
Autonomic neuropathy and gastrointestinal symptoms have been reported in association with 68 small cell carcinoma of the lung or pulmonary carcinoid. In the largest published series, all seven patients suffered constipation, six had gastroparesis, four had esophageal dysmotility suggestive of spasm or achalasia, and two had other evidence of autonomic neuropathy that 68 IgG affected bladder and blood pressure control. Investigators detected a circulating 69 antibody (called ANNA-1 or anti-Hu) directed against enteric neuronal nuclei, suggesting that the enteric plexus is the major target of this paraneoplastic phenomenon. However, 68,70 suggesting a several patients have also had evidence of extrinsic visceral neuropathies. more extensive neuropathological process. The chest x-ray is frequently normal in these patients; a chest computed tomography (CT) scan is therefore indicated when the syndrome is suspected, typically in middle-aged smokers with recent onset of nausea, vomiting, or feeding intolerance. Ganglionic receptor-binding antibodies have also been found in a subset of patients with idiopathic, paraneoplastic, or diabetic autonomic neuropathy and idiopathic gastrointestinal dysmotility; the antibody titer correlated with more severe autonomic 71 autoimmune model of gastrointestinal dysmotility has been replicated in dysfunction. This 72 an animal model. Amyloid Neuropathy 73
Amyloid neuropathy may lead to constipation, diarrhea, and steatorrhea. Patients have 42 to uncoordinated nonpropagated contractions in the small bowel. These features are similar 74 the intestinal myoelectric disturbances observed in animals subjected to ganglionectomy. Familial amyloidosis may also affect the gut. Manometric studies and monitoring of the acute effects of cholinomimetic agents can distinguish between neuropathic (uncoordinated but normal-amplitude pressure 73 activity) and myopathic (low-amplitude pressure activity) types of amyloid gastroenteropathy. These strategies may identify patients (i.e., those with the neuropathic variant) who are more likely to respond to prokinetic agents. Chronic Sensory and Autonomic Neuropathy of Unknown Cause
This is a rare, nonfamilial form of slowly progressive neuropathy that affects a number of 75 autonomic functions. Patients may exhibit only a chronic autonomic disturbance (e.g., abnormal sudomotor, vasomotor, or gastrointestinal function) for many years before peripheral sensory symptoms develop. Autonomic dysfunction is probably responsible for functional gastrointestinal motor disorders when these develop prior to the onset of more obvious features of dysautonomia. This28may account for a subset of patients with symptoms suggestive of irritable bowel syndrome. Some investigators have reported familial cases of intestinal pseudo-obstruction with degeneration of the myenteric plexus 29 and evidence of sensory or motor neuropathies affecting peripheral or cranial nerves. Porphyria
Acute intermittent porphyria and hereditary coproporphyria frequently present with abdominal 76,77 Porphyric polyneuropathy may lead to dilatation pain, nausea, vomiting, and constipation. and impaired motor function in any part of the intestinal tract, presumably because of autonomic dysfunction. Effects of porphyria on the enteric nervous system have not been described. Human Immunodeficiency Virus Infection
It is well known that neurological disease may manifest at any phase of HIV infection. Chronic 78 or damage diarrhea may result from increased extrinsic parasympathetic activity to the gut 79 to adrenergic fibers within the enteric plexuses. Further studies are needed to characterize these abnormalities; it is, of course, important to exclude gut infections and infestations in patients with HIV seropositivity and diarrhea. GENERAL MUSCLE DISEASES CAUSING GUT DYSMOTILITY
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At an advanced stage, progressive systemic sclerosis and amyloidosis result in an infiltrative replacement of smooth muscle cells in the digestive tract. Rarely, Duchenne or Becker 80,81 82,83 and polymyositis or dermatomyositis have been associated with muscular dystrophy gastroparesis. There are a number of case or family reports of chronic intestinal pseudo-obstruction, sometimes in association with an external ophthalmoplegia, secondary 9,84–86 87 Patients with myotonic dystrophy may have megacolon ; to a mitochondrial myopathy. anal sphincter dysfunction also occurs and is88consistent with an expression of myopathy, muscular atrophy, and neural abnormalities. The myopathic nature of these disorders is reflected by the low-amplitude contractions that occur at affected levels of the gut, as studied 89–91 Myopathic disorders may be complicated by bacterial especially in systemic sclerosis. overgrowth and small bowel diverticula; pneumatosis cystoides intestinalis and spontaneous pneumoperitoneum sometimes occur in progressive systemic sclerosis. However, it is worth noting that the latter disorder affects the gut from the distal two thirds of the esophagus to the anorectum; thus, it may present with dysphagia (which may also be due to reflux esophagitis and stricture), gastric stasis, chronic intestinal pseudo-obstruction, steatorrhea due to bacterial overgrowth, constipation, incontinence 26 (particularly at night, owing to involvement of the internal anal sphincter), and rectal prolapse. Skeletal muscle EMG or biopsy may be needed to 83–85 establish the nature of the generalized neuromuscular disorder, as in mitochondrial myopathy. Treatment includes restoration of nutrition (which may necessitate total parenteral nutrition), suppression of bacterial overgrowth, and treatment of complications such as gastroesophageal reflux (with an H2-receptor antagonist or proton pump inhibitor) or esophageal strictures (by endoscopic dilatation). Colonic dilatation and intractable constipation may necessitate subtotal colectomy with ileorectostomy. Prokinetics are rarely 92 improves effective but should at least be tried. The somatostatin analogue octreotide 93 However, octreotide symptoms in the short term and may suppress bacterial overgrowth. 94 retards postprandial small bowel transit, and we use it only once per day, at least 3 hours after the last meal, to induce migrating motor activity and clear residue from the stomach and small bowel. IDENTIFICATION OF EXTRINSIC NEUROLOGICAL DISEASE IN PATIENTS WITH GASTROINTESTINAL SYMPTOMS OF A MOTILITY DISORDER Patients with lesions at virtually any level of the nervous system may have symptoms of gastrointestinal motor dysfunction. Therefore, a strategy is necessary in the diagnostic evaluation of disordered gastrointestinal function (Fig. 16-6). Here there is convergence of the paths of the neurologist and gastroenterologist. Patients should undergo further testing, particularly if they have clinical features suggestive of autonomic or peripheral nerve dysfunction or a known underlying neuromuscular disorder. It is essential to record the use of all medications that influence gut motility.
FIGURE 16-6 Algorithm for the investigation of suspected gastrointestinal (GI)
dysmotility. ANA, antinuclear antibodies; ANNA, antineuronal enteric antibodies; CK, creatine kinase; CXR, chest radiograph; Ig, immunoglobulin; TSH, thyroid-stimulating hormone. (From Camilleri M: Study of human gastroduodenojejunal motility: applied physiology in clinical practice. Dig Dis Sci 38:785, 1993, with permission.) Gastrointestinal motility and transit measurements help the clinician to objectively confirm the
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disturbance in the motor function of the gut and distinguish between neuropathic and myopathic disorders. Tests of autonomic function (see Chapter 8) are useful for identifying the extent of involvement and localizing the anatomical level of the disturbance in extrinsic neural control. There is generally good agreement between abnormalities of abdominal vagal function, including the plasma pancreatic polypeptide response to95modified sham feeding (Fig. 16-7) and cardiovagal dysfunction in patients with diabetes. When a defect of the sympathetic nervous system has been identified by conventional tests, the effect of intravenous administration of edrophonium on plasma norepinephrine levels may provide further assessment of the96,97 integrity of postganglionic sympathetic nerves, many of which supply the digestive tract.
FIGURE 16-7 Assessment of abdominal vagal function by the plasma
pancreatic polypeptide (PP) response to modified sham feeding by chewing and spitting a bacon-and-cheese toasted sandwich. Once visceral autonomic neuropathy is identified, further tests are needed to identify any occult causes of the neuropathy; examples include lung tumors (CT of the chest), porphyria (uroporphyrinogen-1-synthase and coproporphyrinogen oxidase in erythrocytes), and amyloidosis (special protein studies in blood and urine, fat, or a rectal biopsy specimen). Imaging of the brain and spinal cord is needed when autonomic tests indicate a central lesion, as when a thermoregulatory sweat test is abnormal but tests of postganglionic nerves (e.g., the quantitative sudomotor axon reflex test, or plasma norepinephrine response to 70 edrophonium) are normal. MANAGEMENT OF GASTROINTESTINAL MOTILITY DISORDERS The principles of management of any gastrointestinal motility disorder are restoration of hydration and nutrition by the oral, enteral, or parenteral route; suppression of bacterial overgrowth (e.g., with oral tetracycline); use of prokinetic agents or stimulant laxatives; and resection of localized disease. In patients with a neurological cause of constipation, it is important to ensure adequate hydration. Osmotic laxatives (e.g., milk of magnesia tablets, 2 tablets three times daily, or lactulose, 10 to 20 ml up to four times per day) may be helpful, as may increasing bulk (as with a high-fiber diet, ispaghula, or psyllium) and a stimulant laxative. If such a regime does not work, scheduled enemas every 1 to 2 days are necessary. In a recent trial, transanal irrigation with a specialized system was more effective than conservative management for alleviating symptoms in patients with spinal cord injury and constipation or fecal 98 incontinence. Sacral anterior root stimulation is worthy of further research and trials in patients with disturbances in the neural control of defecation. Future therapies may include 99 100 neurotrophins such as recombinant brain-derived neurotrophic factor or neurotrophin-3. The prokinetic effects of metoclopramide (a peripheral cholinergic agonist and dopamine D2 antagonist) are limited to the esophagus and stomach. Its clinical efficacy is restricted by the relatively high frequency of side effects, and especially of changes in affect, extrapyramidal disorders, and hyperprolactinemia (which may result in altered menstrual function and galactorrhea). Bethanechol (10 to 25 mg, 4 times daily) is a cholinergic agonist that is not specific for the
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gastrointestinal tract. It is helpful only in mild cases of gastroparesis and is now seldom used; it is sometimes prescribed in combination with metoclopramide. Tegaserod (Zelnorm) is a partial 5-HT4 receptor agonist that was previously approved for short-term treatment of women with constipation-predominant irritable bowel syndrome and for men and women with chronic constipation. Tegaserod accelerates small bowel transit and tends to accelerate colonic transit in patients with constipation-predominant irritable bowel 101 syndrome. A trend toward increased satisfaction with bowel habits and improved abdominal discomfort was also observed in a small controlled study of 15 patients with 102 constipation and Parkinson's disease. The drug is generally well tolerated; headache and diarrhea are the main side effects. A numerical imbalance in the number of cardiovascular events in patients on tegaserod compared to placebo, however, has led to recent withdrawal of the drug. Lubiprostone was recently approved by the U.S. Food and Drug Administration (FDA) for treating constipation. This drug belongs to a new class of bicyclic fatty acid compounds called prostones that are derived from a metabolite of prostaglandin E1. It activates type 2 chloride 103 channels (ClC-2), increases intestinal secretion, and thereby increases intestinal motility. At the recommended dose of 24 μg twice daily, 31.1 percent of patients receiving lubiprostone reported nausea, and 8.7 percent discontinued treatment due to nausea; 13.2 percent reported diarrhea; and 3.4 percent reported severe diarrhea. The incidence of nausea may be reduced by taking lubipro-stone with food or by reducing the dose to 24 μg once daily. Erythromycin, a macrolide antibiotic, stimulates smooth muscle motilin receptors in the gastrointestinal tract. It has a role in relieving acute gastric stasis but, because of 66 tachyphylaxis, is of little benefit beyond 2 weeks of treatment. Perhaps it is preferable to administer erythromycin as a suspension rather than tablets in patients with delayed gastric emptying. Because it is metabolized by the cytochrome P450 3A4 system, there is a potential for drug interactions, the long Q-T syndrome, and rarely torsades de pointes. 83
Octreotide's efficacy has been tested predominantly in patients with systemic sclerosis. It does not usually induce normally propagated activity in the small bowel, but it may help clear residue by virtue of the intensity of contractions and increased duration of the migrating 104 complex that it induces in the small bowel. The role of surgery for motility disorders due to neurological disease is restricted to those patients with intractable colonic or rectal symptoms, particularly incontinence. There is no good rationale for vagotomy or for partial or total gastrectomy in patients with chronic neuropathies causing gastric stasis. In patients with severe colonic inertia, subtotal colectomy with ileorectostomy is usually successful, but this treatment has been used only rarely in patients with neurological or muscle disease. Surgery for local complications of severe constipation may be necessary, as in patients with rectal intussusception or prolapse. CONCLUDING COMMENT Gastrointestinal motor abnormalities result when extrinsic nerves are disturbed and are unable to modulate the motor functions of the digestive tract, which depend on the enteric nervous system and the automaticity of the smooth muscles. Disorders at all anatomical levels of the extrinsic neural control system and degenerations of gut smooth muscle have been reported in association with gut motor dysfunction and illustrate the important role of the nervous system in the etiology of gastrointestinal symptoms. Although much emphasis in the literature is laid on dysphagia and constipation in neurological disorders, more recent studies have highlighted incontinence, vomiting, and abdominal distention in the symptomatology of such patients. Strategies that evaluate the physiological functions of the digestive tract and the function of the extrinsic neural control are available and aid in the selection of rational therapies for patients, including physical and biofeedback training (e.g., for dysphagia or incontinence), prokinetic agents (for neuropathic forms of gastroparesis, intestinal pseudo-obstruction, or slow-transit colonic disorders), and nutritional support using the enteral or parenteral route. Electrical or magnetic stimulation of lumbar sacral roots may alleviate certain symptoms, such as constipation in paraplegics. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 17 Nutritional Disorders of the Nervous System ELLIOTT L. MANCALL •
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RETINOL (VITAMIN A, β-CAROTENE) B COMPLEX OF VITAMINS THIAMINE (VITAMIN B1) Nutritional Polyneuropathy Wernicke–Korsakoff Syndrome Wernicke's Encephalopathy Korsakoff's Syndrome Cortical Cerebellar Degeneration Nutritional Amblyopia Subacute Necrotizing Encephalomyelopathy NIACIN (NICOTINIC ACID) PYRIDOXINE (VITAMIN B6) COBALAMIN (VITAMIN B12) CALCIFEROL (VITAMIN D) TOCOPHEROL (VITAMIN E) FOLIC ACID OTHER DISORDERS WITH A POSSIBLE NUTRITIONAL BASIS Marchiafava–Bignami Disease Central Pontine Myelinolysis Jamaican Neuropathy HYPERALIMENTATION
Nutritional disorders of the nervous system, although changing to some extent in character and distribution over the years, remain remarkably common. Affecting people from birth—or before—to old age, such disorders are of universal concern. Widely recognized 1in the urban United States, particularly in the nutritionally depleted adult alcoholic population, nervous system diseases due to dietary deprivation appear under circumstances as diverse as famine; extreme poverty; incarceration in prisoner-of-war camps; intestinal malabsorption due to disorders such as sprue or to major gastrointestinal surgery including gastric plication; administration of metabolic antagonists such as isonicotinic acid hydrazide (INH); anorexia nervosa; and food fads, perhaps especially among adolescents. As a general rule, affections of the nervous system due to nutritional depletion present in a
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symmetric distribution, both clinically and pathologically, and in a stereotyped and thus readily identified fashion. These features are common to many metabolic disorders of the nervous system. The precise factors underlying development of such neurological disease have been well established in only some instances, such as the Wernicke–Korsakoff syndrome. Often the exact nutrient lacking cannot be defined with certainty, and it is not unlikely that a combination of dietary defects may be necessary for a given disease to develop. The complex inter-relationship between total caloric intake, relative balance of carbohydrate/protein/fat in the diet, and lack of one or more specific nutrients appears important under some circumstances; extreme caloric deprivation alone may not be a sufficient explanation for these disorders. At times, totally unanticipated factors—for example, autoimmune mechanisms, as documented for pernicious anemia, or inherent genetic defects, as have been suggested in the Wernicke–Korsakoff syndrome—may be of fundamental pathogenetic significance. Difficulties encountered in establishing a clear-cut dietary history and practical problems in the documentation of deficiencies of, for example, isolated vitamins in the clinical laboratory, add yet more complications to the assessment of nutritional disorders as a whole. Finally, our understanding of these disorders is impeded by the fact that data derived from animal investigations cannot always be translated successfully to naturally occurring disease in the human. In view of the lack of precision related to establishing the pathogenesis of many of these disorders, no classification can be entirely satisfactory. Because most clearly defined nutritional diseases reflect depletion of a vitamin or vitamins (most commonly the group B vitamins), the presentation of these disorders that follows adheres to an outline based on specific vitamins whenever possible. The ambiguities and uncertainties of such an approach cannot, however, be ignored. Perhaps not surprisingly, many of these disorders occur in combination with one another, rendering any classification still more arbitrary and incomplete. 2
The therapeutic use of vitamins is itself not without hazard ; potentially toxic complications of hypervitaminosis are most prominent with vitamins A and B6, as discussed later in this chapter. RETINOL (VITAMIN A, β-CAROTENE) A deficiency of vitamin A is remarkably common in parts of the world, such as Southeast Asia, Africa, and the Middle East, where extreme poverty and nutritional depletion are 3 endemic. Hypovitaminosis A leads most importantly to a variety of ophthalmic disorders, 4 loosely grouped under the rubric xerophthalmia. An early manifestation of such depletion is night blindness, reflecting the importance of retinol in the production of rhodopsin (visual purple). After light absorption in the rods, retinol is released from rhodopsin and is available for recycling, with continuous regeneration of rhodopsin. The rods, which are present in the more peripheral portions of the retina but not in the macula and which subserve vision in conditions of low illumination, use rhodopsin as their primary chemical photoreceptor. A defect in vitamin A leads directly to deficient rod performance and thus to night blindness. The potential additive or potentiating role of protein malnutrition (e.g., kwashiorkor) remains insufficiently explored. A continuing severe deficiency of vitamin A results in progressive changes in both the conjunctiva and cornea. Corneal ulceration and keratomalacia lead ultimately to irreversible corneal damage and blindness. Hypovitaminosis A has also been implicated, albeit rarely, in 4 the development of pseudotumor cerebri during infancy (discussed later). Recommended daily allowances of vitamin A are 4,000 USP units in female subjects and 5,000 in male subjects; both parenteral and oral preparations of retinol are available for management of documented hypovitaminosis A, but great care must be used to avoid toxicity when administering this agent chronically. An excess of vitamin A results from a diversity of factors, including ingestion of carotene-rich polar bear liver or excessive amounts of vitamin A itself, ingested either as a food fad or as treatment for a host of dermatological conditions. A daily intake of as little as 7.5 mg retinol over time may produce toxic manifestations; acute hypervitaminosis A may follow the ingestion of 500 mg retinol in the adult, and less in infants and children. Such an excess is among the identified causes of the syndrome of pseudotumor cerebri (benign intracranial hypertension), a disorder characterized by generalized brain swelling associated with clinical features of increased intracranial pressure. Patients experience headache and at times slowed intellectual function; examination reveals papilledema, enlargement of the physiological blind spot, and occasionally nonspecific sixth nerve palsies. The cerebrospinal fluid (CSF) pressure is elevated, but the spinal fluid itself is otherwise normal. Computed tomography (CT) scanning or magnetic resonance imaging (MRI) demonstrates diffuse brain
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swelling with symmetrically placed ventricles, which may be small, normal, or (uncommonly) mildly enlarged. This condition represents a major threat, particularly to vision, because consecutive (“secondary”) optic atrophy may lead to progressive visual loss. Every effort must be made to prevent this complication by reducing the intracranial pressure. Therapeutic measures include the use of diuretics, corticosteroid preparations such as dexamethasone, repeated lumbar puncture, and a surgically established subarachnoid-extracranial shunt or optic nerve fenestration. Surgical cranial decompression should be avoided, if possible, and rarely requires serious consideration. B COMPLEX OF VITAMINS A number of factors in the B group of vitamins are of clinical importance with regard to neurological disease. These vitamins include thiamine (vitamin B1), niacin (nicotinic acid), pyridoxine (vitamin B6), and cobalamin (vitamin B12). Although each is considered separately here, in many instances deficiencies of these and other vitamins occur in combination and may lead to complex clinical disturbances. THIAMINE (VITAMIN B1) Thiamine pyrophosphate, or cocarboxylase, functions as a cofactor in intermediary carbohydrate metabolism. It serves as a coenzyme in the decarboxylation of α-keto acids, that is, α-ketoglutaric acid and pyruvate dehydrogenase; it also acts as a cofactor to the enzyme transketolase in the hexose monophosphate shunt. Deficiency of thiamine in animals results in accumulation of lactic acid and reduction in oxygen uptake, especially in the 5,6 brainstem, and depression of transketolase activity, again most strikingly in the brainstem. Such observations are intriguing in light of the known predilection of the lesions of Wernicke's encephalopathy for brainstem structures. In developed countries, thiamine deficiency in humans has been studied particularly in 7,8 chronic alcoholics. In this context, alcohol plays a secondary role, essentially serving to displace food in the diet. For the most part, observations in alcoholics appear readily transposed to those in nutritionally depleted nonalcoholics. Such discrepancies as do exist may well be explained on the basis of multiple vitamin deficiencies and varying ethnic and regional dietary habits and susceptibilities. Two disorders that appear most clearly related to thiamine deficiency are nutritional polyneuropathy and the Wernicke–Korsakoff syndrome. Two others, cortical cerebellar degeneration (“alcoholic cerebellar degeneration”) and nutritional amblyopia, are probably not related to thiamine deficiency alone but nevertheless seem intimately related to thiamine lack and are considered here as well. It is of interest that an epidemic deficiency of thiamine, and of other B vitamins, including B12 and folate, on a background of excessive intake of alcohol, heavy cigarette smoking, and chronic and severe food shortages, appeared in Cuba in the early 1990s, involving more than 50,000 individuals. Clinical manifestations included retrobulbar optic neuropathy, myelopathy with spastic paraparesis, spastic bladder, deafness, and sensory neuropathy with autonomic involvement. These features are reminiscent of those of so-called Jamaican neuropathy or Strahan's syndrome, discussed later. Following recognition of the nutritional basis of this disorder, multivitamins and folate were distributed by the government to the entire population 9–11 of the island; the epidemic thereafter subsided.
Nutritional Polyneuropathy Nutritional polyneuropathy (neuritic or dry beriberi, alcoholic neuropathy) is the most common of all nutritional disorders of the nervous system. Whether it relates to isolated deficiency of thiamine or more accurately reflects deficiencies of multiple vitamins in the B group, including pyridoxine and pantothenic acid, remains unsettled. It is clear, however, that thiamine deficiency plays a dominant role in the pathogenesis of polyneuropathy in both the alcoholic and nonalcoholic population. Clinically, nutritional polyneuropathy presents as a largely symmetric, mixed sensorimotor neuropathy. The onset of symptoms is usually insidious and progression is slow, but evolution is occasionally rapid. The lower extremities tend to be involved earlier and more severely than the upper extremities, and in many cases the arms appear to be spared. The distal portions of the limbs are characteristically affected more than the proximal segments. Complaints include numbness or tingling paresthesias distally in the limbs, frequently accompanied by pain. Although it is usually dull and aching in quality, the pain is sometimes sharp and lancinating, reminiscent of the pain of tabes dorsalis. (At times it is sufficiently
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severe to warrant the appellation pseudotabes.) Cramps in the feet and calves are common. Patients may complain of severe burning pain in the feet (“burning feet syndrome”) or of restless legs, and they often experience prominent and at times disabling dysesthetic sensations that are so uncomfortable that simple weight-bearing may become impossible. Examination demonstrates variable weakness, at times amounting to virtual paralysis of the legs. Footdrop with a resultant steppage gait is frequent, and the distal muscles atrophy. The muscles may be tender to palpation, especially in acute cases. The tendon reflexes are reduced or lost. Sensory examination demonstrates reduction or loss of vibratory sense, particularly at the ankles. Proprioception may be impaired, at times profoundly. Reduction of cutaneous sensation usually takes the form of a distal impairment of pain and light-touch appreciation in a glove-and-stocking distribution; thermal sensibility is reduced in a corresponding manner. The hypalgesic areas are not crisply defined, the border between normal and abnormal portions of the limbs tending to be indistinct (in contrast to the sharply delineated glove-and-stocking sensory loss found in the patient with a conversion reaction). Not all sensory modalities are involved to an equal degree, the severity and extent of loss exhibiting considerable variability from patient to patient. Signs and symptoms of dysfunction of the autonomic nervous system are sometimes encountered as well, including vocal cord paralysis with hoarseness, dysphagia, pupillary abnormalities, and hypotension. Hyperhidrosis of the hands and feet is common. Examination of the CSF usually demonstrates at most only a mild increase in protein content. Electrophysiological studies demonstrate findings suggestive of an axonal polyneuropathy, but there may also be features of superimposed compressive mononeuropathies. Pathologically, the primary change is segmental demyelination associated with axonal degeneration, affecting particularly the distal portion of the peripheral nerves. Changes in the sympathetic nervous system may also occur. In long-standing cases, retrograde changes may be found in the spinal cord, including chromatolytic changes in the anterior horn cells and secondary (ascending) degeneration in the posterior columns. Restoration of a well-balanced diet with supplemental vitamins of the B group, especially thiamine, is the keystone of therapy. The parenteral use of vitamin preparations is advisable in the early stages of treatment. Although the minimum daily requirement of thiamine in the adult is only approximately 1 mg, injections of 50 to 100 mg daily may be used early in therapy, with 50 to 100 mg subsequently taken by mouth several times daily. Symptomatic management includes the use of analgesics, amitriptyline (25 to 50 mg or more at bedtime), or carbamazepine (up to 800 mg or more per day as required) for relief of pain. The therapeutic benefit of either gabapentin or pregabalin in patients with nutritional painful neuropathy has not been adequately documented. Sympathetic block may be necessary in instances of severe and intractable burning. Unfortunately, recovery tends to be slow and incomplete; residual and at times severe sensory and motor alterations are common, even in individuals who maintain a normal dietary intake with vitamin supplementation.
Wernicke–Korsakoff Syndrome Although Wernicke's encephalopathy and Korsakoff's syndrome are traditionally viewed as two distinct entities, they are best regarded as representing simply two aspects of the same disease, separable chronologically into acute (Wernicke's encephalopathy) and chronic 12 (Korsakoff's syndrome) phases. Considerable evidence has accumulated to support the notion that these two disorders are indeed intimately linked. Thus, the typical mental changes of Korsakoff's syndrome may be present from the earliest stages of acute Wernicke's encephalopathy or may emerge during the treatment of that disorder as other clinical manifestations recede. Furthermore, examination of patients with classic Korsakoff's psychosis often reveals residual features of previous, perhaps unrecognized, Wernicke's encephalopathy, such as nystagmus and truncal ataxia. Finally, both the nature and the distribution of the pathological changes appear identical in the two conditions, such differences as do exist being accounted for by differences in the chronology of the lesions rather than reflecting a fundamental difference in kind. There can be little doubt as to the central role of acquired thiamine deficiency in the pathogenesis of this disorder. Such deficiency is found most commonly, although certainly not invariably, on a background of long-standing dietary insufficiency conditioned by the excessive use of alcohol, at least in Western society. Thiamine deficiency associated with 13 as well as in Wernicke–Korsakoff syndrome has also been recorded in patients on dialysis 14 and carcinoma those with acquired immunodeficiency syndrome, hyperemesis gravidarum, 15 treated with the chemotherapeutic agent fluoropyrimidine dexifluridine, and after 16,17 The possibility of an inherent gastroplasty performed for management of obesity.
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predisposition to Wernicke's encephalopathy, reflecting a genetically determined error in transketolase, has been suggested as of significance in at least some instances of the 18–20 disease. Wernicke's Encephalopathy Wernicke's disease, or encephalopathy, is an acute or subacutely evolving disorder. Appearing on a background of chronic and severe undernutrition, it is frequently preceded by some additional metabolic stress related, for example, to serious trauma or infection. A carbohydrate load is the immediate precipitating factor in some patients. Characteristic clinical features of this disorder include the following. 1. Abnormal mental status. Some patients appear apathetic and listless, with a short attention span, little spontaneity of speech, mental confusion, and excessive drowsiness. Coma is rare. Other patients have perceptual distortions, hallucinations, agitation, confusion, and other clinical features reminiscent of delirium tremens. Still others exhibit features of an amnestic dementia (i.e., of the typical mental alteration of Korsakoff's syndrome) with an otherwise clear sensorium. 2. Ophthalmoplegia. Ocular palsies are a hallmark of Wernicke's encephalopathy. Bilateral sixth nerve palsies are most common, but virtually any pattern of restricted ocular motility may be found, including conjugate gaze palsies and internuclear ophthalmoplegia. Diplopia is characteristically experienced and, in fact, often represents the first subjective manifestation of the disease. Involvement of the pupils is rare. 3. Nystagmus. Nystagmus is typically encountered in both the horizontal and vertical planes. In the presence of severe abducens palsies, however, nystagmus may be lacking in the abducting eye, becoming apparent only in the course of treatment as the ophthalmoplegia itself subsides. 4. Ataxia. Patients with Wernicke's encephalopathy typically evidence ataxia of trunk and gait, at times associated with severe truncal titubation. Only modest ataxia is observed with the heel-to-knee test, and the arms tend to be involved little if at all. In some patients ataxia is minimal, being evident only with attempts at tandem walking. Autonomic changes such as postural hypotension and altered cardiac function may also be encountered in Wernicke's encephalopathy, although not with sufficient frequency to be considered characteristic of the disease. Hypothermia is well described. True beriberi heart disease is infrequent, but sudden death may occur from acute cardiovascular collapse, 21 so-called shoshin beriberi. The clinical 12 course of Wernicke's encephalopathy is dramatically altered by the administration of thiamine. Within hours of the parenteral administration of 25 to 50 mg thiamine, the ophthalmoplegia im- proves, and ocular palsies generally disappear entirely within several days. Nystagmus similarly improves but less dramatically, and most patients are left with permanent horizontal nystagmus of modest amplitude. The truncal ataxia also improves, but again rather slowly and often incompletely; one half of the patients continue to exhibit at least mild residual ataxia. In contrast, improvement in the mental status is less predictable. Patients with a quiet confusional state or delirium tend to improve over a period of weeks; all too often, however, memory impairment, the hallmark of Korsakoff's syndrome, appears in the course of recovery and may persist thereafter. After initial management with parenteral thiamine in doses of 50 to 100 mg, patients are maintained on an oral dosage at 50 to 100 mg three or four times daily. The pathological alterations of Wernicke's encephalopathy are found in a remarkably stereotyped distribution, predominantly involving brainstem and hypothalamus. The characteristic lesion is one of subtotal tissue necrosis involving neurons, axons, and myelin to variable degrees. Lesions are typically found centrally disposed in the mammillary bodies, along the walls of the third ventricle, in the medial dorsal nucleus of the thalamus, in the periaqueductal gray matter of the mesencephalon, in the floor of the fourth ventricle, and in the superior cerebellar vermis. Within the lesions there is a glial response that is chronologically appropriate to the age of the destructive lesions. Inflammatory changes are lacking. In some cases fresh hemorrhages are found (responsible at least in part for the name Wernicke himself gave to this disease, i.e., polioencephalitis hemorrhagica superioris). It is probable that these hemorrhagic changes are secondary rather than primary events. Vascular proliferation is occasionally encountered. In terms of clinicopathological correlation, it is likely that the ophthalmoplegias are caused by lesions in the periaqueductal gray matter
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and pontine tegmentum, nystagmus by lesions typically involving the vestibular complex at the pontomedullary junction, and truncal ataxia by lesions in the superior cerebellar vermis. The alterations in attention, cognition, and memory are probably caused by lesions in the mammillary bodies and medial and posterior thalamus. Korsakoff's Syndrome Korsakoff's syndrome, or psychosis, the chronic form of the Wernicke–Korsakoff syndrome, is characterized primarily by an amnestic dementia, that is, a profound disorder of memory with relative preservation of cognitive abilities per se. The core of the defect appears to be an impairment of the ability to acquire new information (i.e., to establish new memories); thus, anterograde amnesia results. Patients with Korsakoff's psychosis also typically have some degree of retrograde amnesia, extending backward over a variable period of time before onset of the disease. Memories of events in the more remote past are often retained, but commonly in chronological disarray. The most striking impairment is without doubt the inability to learn newly presented information. Confabulation, probably representing, in large part, suggestibility on the part of the patient, is frequently encountered in Korsakoff's syndrome, but not invariably so. Because confabulation also occurs in other states of mental incapacity, it cannot be looked on as specific or in any way pathognomonic of Korsakoff's syndrome. The degree to which conscious mechanisms enter into confabulation under any circumstances remains unclear. Although the primary defect in Korsakoff's syndrome centers about memory, other cognitive impairment may be found, although usually of lesser severity. Thus, defects may be evident in visual and verbal abstracting ability, shifting mental sets, and concept formation, which are functions in which memory does not play a major role. In addition, the behavior of many patients with Korsakoff's syndrome is abnormal, being characterized by apathy, lack of interest, and listlessness, but without a clear defect in attention or vigilance. On careful examination, most patients with Korsakoff's syndrome show other clinical features of the Wernicke–Korsakoff syndrome, including horizontal nystagmus and variable gait ataxia. Not unexpectedly, many also demonstrate features of an associated nutritional polyneuropathy. The outlook for patients with established Korsakoff's syndrome is discouraging. Only a relatively small proportion of these patients recover memory function to any significant degree, although many evidence at least modest return, permitting them to function to a limited extent in society. One would anticipate that if vigorous therapy with thiamine were to be instituted during the acute phase of the disease (i.e., early in the course of Wernicke's encephalopathy), there would be a greater chance of either avoiding or appreciably lessening the ultimate memory defect; unfortunately, this has not been well documented. It is clear, however, that with continuing administration of thiamine in an oral dosage of 50 to 100 mg three or four times daily over many months, some patients who originally show little or no improvement may demonstrate gradual and at times remarkably complete functional recovery. The neuropathological changes in Korsakoff's syndrome are essentially identical in distribution and histological character to those of Wernicke's encephalopathy. The only noteworthy difference is that of a more chronic (i.e., astrocytic) form of glial reaction, in keeping with the more protracted clinical course. In terms of the anatomical substrate for the memory defect, the lesions in the mammillary bodies and thalamus appear to be of particular importance. The studies of Victor and associates have clearly demonstrated that the lesions in the medial dorsal and perhaps posterior nuclei of the thalamus are central to the memory 12 defect. In a large series of pathologically documented cases, they were able to demonstrate lesions invariably in the thalamus in patients with Korsakoff's syndrome, whereas lesions in the mammillary bodies were not consistently observed. Although cortical atrophy is a commonplace observation in the brains of chronic alcoholics, it is doubtful that a cortical pathological process plays a significant role in producing the mental changes of classic Korsakoff's syndrome.
Cortical Cerebellar Degeneration Cortical cerebellar degeneration, or “alcoholic cerebellar degeneration,” appears intimately linked to Wernicke's encephalopathy. Although a primary role for thiamine deficiency has not been convincingly established, this disorder is clearly of nutritional origin, and its close association with Wernicke's disease warrants its inclusion here.
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Cortical cerebellar degeneration is a relatively frequent complication of chronic alcoholism 22,23 Usually beginning in and is the most common of the acquired cerebellar degenerations. midlife and almost always on a background of long-standing and excessive ethanol abuse and chronic nutritional depletion, the onset of the disease is commonly marked by complaints of disordered gait or truncal stability. The gait disability worsens in subacute fashion for a period of several weeks or months or even longer, but it ultimately stabilizes, usually when patients become abstinent and improve their nutritional status. At times the disorder evolves episodically, seemingly in relation to severe systemic illness. Examination demonstrates that the primary defect is referable to the gait and stance. Truncal instability is common, and a wide-based ataxia of gait with ataxia of individual leg movements is characteristic. The patient is unable to make rapid postural adjustments and walks in tandem fashion only with difficulty. At times the ataxia is so severe that the patient cannot stand unaided, even on a wide base; most patients require at least some support for either standing or walking. In contrast to the severe affection of the lower extremities, the arms are affected little if at all. There may be ocular dysmetria, but other features suggestive of cerebellar dysfunction are either minimal or entirely lacking: dysarthria, when present, tends to be mild, and nystagmus is uncommon. Features of other neurological disorders, particularly those of Wernicke's encephalopathy and nutritional polyneuropathy, are often present. After stabilization, patients may show modest improvement as their nutrition improves, especially if supplemental vitamins are taken. However, a significant cerebellar deficit invariably remains and persists for years thereafter. Pathological changes predominate in, and may be confined to, the anterior and superior portions of the cerebellar vermis and hemispheres. Occasional lesions are also found elsewhere in the cerebellar cortex. In almost all cases the lingula, central lobule, and culmen and adjacent declive are affected in the vermis, whereas in the hemispheres it is the more anterior portion of the anterior lobes that is most commonly affected. Within these areas, all neurocellular elements are destroyed, although to variable degrees; the Purkinje cells appear to be especially vulnerable. Secondary changes may be found in the cerebellar white matter, deep cerebellar nuclei, and related brainstem nuclei, such as the olivary complex. The typical histological features of Wernicke's encephalopathy are conjoined in many cases. Well-documented cases of a similar form of cerebellar degeneration occurring in conditions 24 of severe nutritional depletion unrelated to the abuse of alcohol have been reported, suggesting that “alcoholic” cerebellar degeneration is in fact of nutritional origin. The appearance of similar clinical and pathological features in the course of Wernicke's encephalopathy, and the occurrence of characteristic features of Wernicke's encephalopathy in otherwise straightforward instances of cerebellar degeneration, suggest that the two disorders are closely linked. It is therefore tempting to ascribe the cerebellar disease also to thiamine deficiency, but this cannot be stated with certainty at this time. The significance of the reportedly low CSF levels of thiamine in certain inherited ataxias, and specifically in 25 olivopontocerebellar atrophy and Friedreich's ataxia, remains unclear in this respect. The transient cerebellar syndrome encountered as an evanescent ataxia of gait in acute alcoholic intoxication (or rarely in withdrawal states) is not associated with any fixed cerebellar lesions. The cerebellar dysfunction that occurs in these circumstances presumably reflects a reversible biochemical lesion that conceivably also relates to thiamine deficiency, although this relationship remains to be established.
Nutritional Amblyopia Nutritional amblyopia (deficiency amblyopia, nutritional retrobulbar neuritis, tobacco-alcohol amblyopia) appears most frequently in the chronically malnourished alcoholic and appears 26 firmly established as a deficiency disorder of the B group of vitamins. As its name implies, it is characterized primarily by defective vision. Its onset is insidious and its course progressive. Initial impairment of the ability to read small print or to distinguish colors leads eventually to serious impairment of visual acuity, but with few (if any) other subjective ocular complaints. Examination typically demonstrates a bilateral and fairly symmetric loss of visual acuity, with bilateral central, cecocentral, or paracentral scotomas. Peripheral fields are unaffected. Funduscopic examination is usually unrevealing, although in advanced stages there may be mild optic atrophy. Signs of other disorders of nutritional origin (e.g., polyneuropathy or the Wernicke–Korsakoff syndrome) may be found. The salient pathological changes are found in the optic nerves, chiasm, and tracts in a position that corresponds to the location of the papillomacular bundles. Trans-synaptic degeneration is sometimes seen in the nerve cells of the lateral geniculate body, and in severe cases there may be loss of ganglion cells in the
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macular region of the retina. The primary site of involvement, however, is the conducting pathways themselves, in contrast to the amblyopia of methyl alcohol toxicity, which is due to primary degeneration of the retinal nerve cells. This disorder is encountered worldwide among undernourished alcoholics, in conditions of naturally occurring famine, and among incarcerated groups of people such as prisoners of war. Although there is widespread agreement that deficiency of group B vitamins is important 27 in the pathogenesis of nutritional amblyopia, it does not necessarily imply a central role for thiamine alone; a similar syndrome may appear in patients with deficiency of vitamin B12 and perhaps of riboflavin. Despite the term tobacco-alcohol amblyopia traditionally applied to this condition, it is unlikely that either tobacco or ethyl alcohol plays a significant role as a directly toxic agent. Dramatic improvement in vision, with complete return to normal acuity and fields, follows the timely introduction of treatment with group B vitamins, even if the patient continues to smoke and consume ethanol as before. If the disease is not recognized early and treated promptly, the visual changes become irreversible, with permanent blindness and optic atrophy.
Subacute Necrotizing Encephalomyelopathy The relationship of subacute necrotizing encephalopathy of childhood (Leigh's disease) to Wernicke's disease itself remains unclear. Inherited as an autosomal-recessive or X-linked trait or exhibiting a pattern of maternal inheritance, Leigh's disease typically develops within 28 the first 2 years of life. An adult form has been described. It is characterized by weakness, hypotonia, intellectual deterioration, seizures, deafness, optic atrophy and blindness, irregular respirations, ataxia, ophthalmoplegia, vomiting, and nystagmus. The disease is usually fatal within several months, but occasional patients have pursued a much more chronic course. Clinically, it thus bears no obvious relation to Wernicke's encephalopathy. However, lesions reminiscent of Wernicke's disease are found in the thalamus and brainstem; necrotic lesions may also be found in the optic nerves and posterior columns of the spinal cord. The mammillary bodies and hypothalamus are involved only infrequently. In view of this at least superficial pathological resemblance to Wernicke's encephalopathy, 29,30 the possibility that Leigh's disease relates to thiamine deficiency has been raised, 31 particularly in light of the observation of elevated blood pyruvate and lactate levels and of 32 lactic acidosis, suggesting a defect in pyruvate decarboxylation in at least some cases. Pincus and colleagues observed an absence of thiamine triphosphate in the brain of a patient dying of this disorder and noted the presence in blood, urine, and CSF of a factor inhibiting the conversion of thiamine pyrophosphate to thiamine triphosphate (and therefore inhibiting 33 the action of thiamine pyrophosphate–adenosine triphosphate phosphotransferase). Reduction in thiamine triphosphate content has been documented in other cases as well, and temporary benefit has been noted after the administration of thiamine in large amounts in at least some instances. It has become clear, however, that the fundamental defect in Leigh's disease is in fact impairment of cerebral oxidative metabolism; cytochrome c oxidase deficiency may be the most important of the numerous biochemical/enzymatic alternatives 34,35 Although thiamine may play some role in pathogenesis, a that have been described. simple dietary lack of thiamine does not appear to be of significance. NIACIN (NICOTINIC ACID) A deficiency of nicotinic acid or of its metabolic amino acid precursor tryptophan is widely accepted as the cause of pellagra. Relatively uncommon today, pellagra is occasionally encountered as a neuropathological curiosity in chronic alcoholics. It is not rare, however, in institutionalized mentally retarded or demented patients. In its fully developed clinical form, pellagra comprises a host of symptoms referable to the gastrointestinal tract (anorexia, nausea, vomiting, diarrhea), skin, and nervous system. Both central and peripheral nervous systems may be affected. Evidence of involvement of the central nervous system (CNS) includes irritability, insomnia, depression, mania, confusion, intellectual deterioration, and memory impairment. Extrapyramidal or cerebellar deficits may develop, and the optic nerves may be involved. The appearance of a polyneuropathy, usually of mild to moderate degree, indicates peripheral involvement. The clinical features are typical of most metabolic polyneuropathies and include tenderness of nerve trunks and muscles, cramps, distal weakness of the limbs, depressed tendon reflexes, and distal impairment of cutaneous sensibility. Loss of proprioception and vibratory sense may reflect either the neuropathy or an associated myelopathy whose presence is suggested by the occasional appearance of extensor plantar responses. The corneal reflexes may be decreased and the pupillary light reflexes impaired. Pathological changes in pellagra are found in the cerebrum, spinal cord, and peripheral
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nerves and roots. Chromatolytic changes in neurons (the “central neuritis” of Adolph Meyer) are encountered, involving most prominently the large Betz cells of the motor cortex; a similar neuronal change may be found ubiquitously throughout the central gray matter. Degenerative changes are found symmetrically in the posterior and lateral columns of the spinal cord. The peripheral nerves show a patchy loss of myelin and axons. Although it is widely held that all the clinical manifestations of pellagra are due to niacin deficiency, the neurological changes are remarkably resistant to treatment with niacin alone, even when 25 mg is administered intravenously twice daily. Deficiency of other vitamins such as thiamine may be important, particularly in the pathogenesis of the polyneuropathy. Furthermore, Victor and Adams have demonstrated the appearance of the typical neuronal 36 changes of pellagra in experimental pyridoxine deficiency. It is therefore possible that the full clinical syndrome of pellagra reflects deficiency of several vitamins in the B group. A reversible syndrome of niacin deficiency termed nicotinic acid deficiency encephalopathy also occurs, predominantly although not exclusively in the literature of the 1940s. This poorly understood syndrome appears to involve particularly the elderly. It is characterized by mental confusion, stupor, cogwheel rigidity, and the appearance of primitive reflexes (e.g., forced grasping). The exact nature of this disorder has never been clarified, and there are reservations as to its relationship to nicotinic acid deficiency as such because most affected patients appear to have experienced much broader nutritional defects. Finally, a relationship of nicotinic acid deficiency to Hartnup's disease is suggested by the similarity of the clinical picture of this infantile, recessively inherited familial disorder to pellagra. A genetically determined defect in intestinal transport of the nicotinic acid precursor tryptophan (and other amino acids) and reported benefit from the administration of nicotinic acid are features of Hartnup's disease that support the notion of such a relationship. PYRIDOXINE (VITAMIN B6) Neurological disorders reflecting both pyridoxine deficiency and pyridoxine excess have been recognized. Pyridoxine is a water-soluble vitamin that is converted by the enzymes pyridoxal kinase and pyridoxine phosphate oxidase to its active form, pyridoxal phosphate, a coenzyme involved in a number of decarboxylation and transamination reactions. Excessive intake of pyridoxine may saturate either of these enzyme systems, with a resultant accumulation of (inactive) pyridoxine, which occupies binding sites on the appropriate apoenzymes and thus acts as a competitive inhibitor for pyridoxal phosphate. In essence, an excess or overdose of pyridoxine leads to a deficiency of pyridoxal phosphate. Deficiency of dietary pyridoxine causes a mixed distal symmetric polyneuropathy. The lack of pyridoxal phosphate functioning as a coenzyme for serine palmityltransferase (as required for the synthesis of sphingomyelin) or amino acid decarboxylase, or both, may be responsible for the polyneuropathy. Polyneuropathy due to pyridoxine deficiency is found in patients treated 37 for tuberculosis with INH, an agent that inhibits pyridoxine phosphorylation. Patients treated with INH commonly describe numbness and tingling in the limbs, particularly involving the lower extremities, together with tenderness in the calves and pain (often burning) distally in the limbs. Examination demonstrates reflex loss, impairment of superficial sensation, and weakness in the lower extremities, with little, if any, affection of the arms. At times, INH neuropathy is extraordinarily severe, especially in seriously malnourished tubercular patients and particularly in those who are also chronic alcoholics. This finding suggests the likelihood of multiple nutritional deficiencies acting synergistically to produce a devastating neuropathy. Of additional interest in this connection is the observation that the typical central features of pellagra may appear in patients receiving INH, along with the classic dermatological and 38 intestinal manifestations of the naturally occurring disease. Neuropathy caused by INH may be prevented by the concomitant administration of pyridoxine. Although the minimum daily requirement of pyridoxine is only approximately 2 mg in adults, 50 mg/d or more may be required for successful therapy in the deficiency states. A predominantly sensory neuropathy or neuronopathy has also been recognized as a result 39,40 Female subjects are affected almost exclusively, perhaps reflecting of pyridoxine abuse. the widespread use of pyridoxine in the management of premenstrual symptoms. All exhibit symmetric and distal sensory loss; vibratory and position sense may be markedly impaired, and sensory ataxia is often prominent. The legs are usually more severely involved than the arms, reflecting the fact that the disorder is primarily a distal axonopathy. Muscle weakness has been described in a few patients. The Achilles reflexes are invariably lost. Electrophysiological studies demonstrate absent or severely reduced sensory nerve action potentials, with mild slowing of sensory nerve conduction velocities. Compound muscle action
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potential amplitudes and motor nerve conduction velocities are normal. Improvement occurs after discontinuation of pyridoxine. Complete recovery may occur in patients with a mild neuropathy who had been taking only low doses of the vitamin. During infancy, pyridoxine deficiency results in seizures, excessive irritability, tremulousness, and poor psychomotor development. This disorder appears due to an inherited metabolic defect transmitted in an autosomal-recessive manner. The seizures presumably result from depletion of γ-aminobutyric acid, the normal conversion of glutamic acid being thwarted by the absence of the coenzyme pyridoxal phosphate, acting in concert with the apoenzyme glutamic acid decarboxylase. The administration of pyridoxine arrests seizures and may also foster normal development. Finally, some patients with childhood homocystinuria, inherited as an autosomal-recessive 41 characteristic and reflecting a deficiency of cystathionine synthase, are pyridoxine responders, and may be treated effectively with fairly large doses of vitamin B6. COBALAMIN (VITAMIN B12) As is well known, pernicious anemia, which is characterized by malabsorption of vitamin B12, reflects a lack of intrinsic factor associated with gastric atrophy and gastric achlorhydria. It may have an autoimmune basis, as suggested by the fact that many patients with pernicious anemia have antibodies against gastric parietal cells as well as antithyroid antibodies; immunoglobulin G antibodies against intrinsic factor itself may also be demonstrated. Further supporting the notion of autoimmune causation is the occasional association of pernicious anemia with myasthenia gravis, a disorder of known autoimmune cause. Vitamin B12 malabsorption and deficiency may also occur under a number of other circumstances, including fish tapeworm infestation, celiac disease, sprue, gastric malignancy, chronic gastritis, thyrotoxicosis, myxedema, an extreme vegetarian diet, chronic pancreatic insufficiency, and after gastrectomy or gastrojejunostomy. Whatever its cause, vitamin B12 deficiency may lead to serious disease involving both central and peripheral nervous systems, although the precise pathophysiological mechanisms remain unclear. The most widely recognized CNS disorder resulting from vitamin B12 deficiency is subacute combined degeneration of the spinal cord, often erroneously referred to as posterolateral sclerosis or combined system disease. Clinically it presents with tingling paresthesias involving the feet, subsequently associated with weakness and stiffness of the legs and a spastic gait. As the disease progresses, the upper extremities are involved. Loss of vibratory sense, particularly in the feet, and impairment of proprioception with a resultant sensory ataxia are characteristic features. Hyperreflexia and extensor plantar responses may give way to areflexia as an associated polyneuropathy appears. Signs of a hypertonic bladder are frequent. On occasion, segmental impairment of cutaneous sensibility is observed over the torso. In addition to such features of myelopathy, many patients with subacute combined degeneration develop impairment of vision, reflecting involvement of the optic nerves; altered visual evoked potentials are common. Primary optic atrophy may appear. Central or cecocentral scotomas may be documented with visual field examination. A variety of mental changes may also be seen, ranging from depression to paranoid states, and, most important, progressive dementia with impairment of both memory and cognitive function. On MRI, an increased T2-weighted signal, decreased T1-weighted signal, and contrast enhancement of the posterior and lateral columns of the spinal cord may be found, mainly in 42 the cervical and upper thoracic regions. Pathologically, the earliest changes in the spinal cord are in the posterior columns of the thoracic cord; these changes are characterized by patchy, eventually confluent areas of myelin swelling and degeneration, ultimately with loss of axons. As the disease progresses, patchy demyelination appears in the lateral columns and sometimes spreads to involve the white matter of the cord in its entirety. The process extends to the cervical cord as the disease evolves. Demyelination may be encountered in the cerebral white matter—presumably accounting for the psychological changes found in the disease—and in the optic nerves. 43,44
Disease of the peripheral nervous system is observed in vitamin B12 deficiency as well, but the frequency of polyneuropathy is not clear. Clinical criteria alone may be insufficient to establish a diagnosis in that complaints of numbness or paresthesias, which are typical symptoms of a sensory neuropathy, are also encountered in patients with disease of the posterior columns. In addition to loss of posterior column sensibility attributable to myelopathy, however, some patients exhibit distal impairment of cutaneous sensibility in a glove-and-stocking distribution. This sensory change, coupled with loss of tendon reflexes in
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the legs, may be taken as evidence of polyneuropathy appearing either independently of or superimposed on the myelopathy. There is also45abundant electrophysiological evidence of polyneuropathy occurring in pernicious anemia. A decrease in distal sensory nerve conduction velocity is characteristic and in keeping with the observation of a reduction in the number and diameters of myelinated axons in the distal portion of peripheral nerves in patients with subacute combined degeneration. In general, the electrophysiological features in these patients are suggestive of a mixed demyelinating and axonal neuropathy; reversal of such abnormalities occurs to a variable extent with vitamin B12 treatment. Electrophysiological evidence of subclinical polyneuropathy may also be found in patients with vitamin B12 deficiency. Vitamin B12 deficiency, marginal or overt, has been implicated as a possible cofactor in the pathogenesis of cognitive alterations in patients with human immunodeficiency virus 46,47 48 although the evidence for such a relationship is not compelling. Vitamin B12 infection, deficiency has also been noted in some cases of multiple sclerosis and documented by depressed levels in both blood and CSF and elevation of plasma homocysteine and R-binder 49,50 There is anecdotal evidence of clinical improvement in some patients with capacity. multiple sclerosis treated with vitamin B12 supplements. Features of both central and peripheral nervous system disease similar to those encountered in classic subacute combined degeneration51with associated polyneuropathy may occur as a reflection of deficiency in R-binder protein, one of the two carriers responsible for extracellular transport of vitamin B12 in plasma. Attention has been drawn to the appearance of subacute combined degeneration in a patient with an abnormal plasma B12-binding 52 protein, with high serum vitamin B12 levels. In patients with neurological dysfunction secondary to deficiency of vitamin B12, therapy must be prompt and aggressive. At the outset, 1,000 μg cyanocobalamin should be administered intramuscularly daily. This dose should be continued on a daily basis, or at least several times weekly, for several months, while the patient's neurological progress is monitored. Subsequently, 1,000 μg cyanocobalamin should be given intramuscularly every 2 weeks indefinitely to patients with pernicious anemia. CALCIFEROL (VITAMIN D) The exact role of vitamin D in neuromuscular function is unclear. This nutrient appears to be involved in muscle metabolism and contractility by virtue of action either on the 2+ Ca -dependent myosin ATPase system or directly on the phospholipid component of the sarcolemmal membrane. A deficiency in vitamin D has been held responsible at least in part for the weakness, fatigability, and muscular atrophy encountered in patients with hyperparathyroidism and renal tubular acidosis. Intestinal malabsorption or dietary insufficiency may lead to vitamin D deficiency, with resultant hypocalcemia, osteomalacia, muscle weakness, and tetany; minor myopathic features may be noted histologically. 53
Hearing loss has also been reported as a reflection of hypovitaminosis D. Of particular interest is the often unappreciated development54–56 of hypovitaminosis D with hypocalcemia in including phenytoin, phenobarbital, and the course of prolonged use of anticonvulsants, carbamazepine. A depression of vitamin D levels is not invariable, however, even in the 57,58 presence of significant hypocalcemia. TOCOPHEROL (VITAMIN E) There has been growing awareness of the role of acquired vitamin59–61 E deficiency in the The exact role of production of neurological dysfunction in both children and adults. vitamin E in the nervous system is not known, although it appears important in maintaining the integrity of biological membranes and has antioxidant properties. On a background of chronic fat malabsorption—as occurs, for example, in cholestatic liver disease, cystic fibrosis, or celiac disease—a deficiency of vitamin E results in a remarkable constellation of neurological abnormalities referable to both central and peripheral nervous 62–70 Features of both spinocerebellar degeneration and polyneuropathy have been systems. recognized clinically, including progressive gait ataxia, incoordination of the limbs, ophthalmoplegia, dysarthria, extensor plantar responses, loss of reflexes in the legs, limb weakness, and marked impairment of vibratory and position sense. The occurrence of 71 seizures has been recorded, and there may be involvement of the autonomic nervous system. Vitamin E deficiency has also been documented in several instances of infantile 72 motor neuron disease (Werdnig–Hoffman disease) although without demonstrable intestinal malabsorption. When the typical clinical features of vitamin E deficiency are associated with
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retinitis pigmentosa, acanthocytosis, and abetalipoproteinemia, the rubric Bassen–Kornzweig syndrome is used. A lack of73tocopherol has been demonstrated in peripheral nerves in vitamin E–deficient patients. Electrophysiological studies demonstrate reduced sensory action potentials and at least mild abnormalities of peripheral sensory conduction velocity, reverting to normal after 74 treatment with vitamin E. Somatosensory evoked potentials exhibit a central delay in conduction, in keeping with pathological changes in the posterior columns, and there may be a prolonged P100 latency in visual evoked potentials. Pathological studies demonstrate loss of large-caliber myelinated axons in the peripheral nerves; accumulation of lipid pigment in nerve cells bodies in the dorsal root ganglia, anterior horns, and brainstem motor nuclei; degenerative changes in the cerebellar cortex; and, most strikingly, degeneration of the posterior columns and, to a lesser extent, the spinocerebellar tracts. There is remarkable plate- or disc-like swelling of axons in the posterior columns, in Clarke's column, and in the cuneate nuclei of the brainstem. Such axonal swelling, referred to as neuroaxonal dystrophy, is also found in experimental vitamin E deficiency. Similar disc-like swellings of axons are found in Hallervorden–Spatz disease, but no definite alteration of vitamin E absorption has been documented in that disorder; furthermore, the vitamin E deficiency disorders fail to demonstrate deposition of iron in the basal ganglia, which is the hallmark of Hallervorden–Spatz disease. Variable improvement in the clinical and electrophysiological manifestations of vitamin E deficiency has been observed after the administration of tocopherol either orally or, perhaps preferably, parenterally. Intramuscular injection of 50 to 100 mg of vitamin E, given every 3 to 7 days for up to 44 months, may arrest the evolution of the neurological disease but not 75 necessarily reverse the clinical symptomatology. Chronic oxygen neurotoxicity, perhaps in association with a loss of calcium homeostasis, may be a pathogenetic factor of possible significance in degenerative diseases of the nervous system such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's76disease. The demonstration of a genetically determined deficiency of superoxide dismutase, an enzyme that detoxifies oxygen free radicals, in familial instances of amyotrophic lateral sclerosis underscores the potential importance of this concept. As a corollary, the antioxidant properties of α-tocopherol and of ascorbic acid and β-carotene as free radical scavengers have prompted their consideration as therapeutic agents in such degenerative disorders. However, in preliminary studies, any benefit from the use of these antioxidants appears conjectural at best. FOLIC ACID Reduced serum folate levels have long been recognized in patients with subacute combined degeneration of the spinal cord and vitamin B12 deficiency, and the association of maternal dietary folate deficiency in pregnancy with fetal neural tube defects is well established. Reversible depression and cognitive decline have frequently been reported in individuals with 77,78 A folate deficiency, especially the elderly, and perhaps related to homocysteine levels. link to Alzheimer's disease has been suggested, though never adequately demonstrated. A single case of Kearns–Sayre syndrome associated with reduced plasma and cerebrospinal 79 fluid folate has been reported. An infantile sporadic cerebral folate deficiency syndrome has been defined, recently 80 suggested as being due to the presence of autoantibodies to folate receptors. The disorder develops ordinarily within 4 to 6 months postpartum and is characterized clinically by psychomotor retardation, ataxia, signs of upper motor neuron dysfunction, and a variety of abnormal movements. Some patients have seizures, and a small number with mental retardation appear autistic. Visual failure with optic atrophy may be manifested late in the course. At least some clinical abnormalities appear to respond to the administration of folinic acid. OTHER DISORDERS WITH A POSSIBLE NUTRITIONAL BASIS
Marchiafava–Bignami Disease Marchiafava–Bignami disease, or primary degeneration of the corpus callosum, is a rare disorder encountered largely, although not exclusively, in nutritionally depleted chronic 23,81 Originally it was thought to appear particularly in middle-aged or elderly men of alcoholics. Italian descent addicted to drinking crude red wine, but now it is clear that the most important factor underlying its appearance is actually chronic and severe nutritional depletion.
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Characteristic changes of the disease have been noted in association with disorders of clearly recognized nutritional origin such as Wernicke's encephalopathy and pellagra; in several well-documented, pathologically verified instances, there has been no history of 82 alcohol ingestion. It is unfortunately not possible to define more precisely the specific nutritional defect in this disease, although it has been suggested that thiamine deficiency is of primary importance. The clinical features of Marchiafava–Bignami disease, which are nonspecific, include a variety of psychiatric symptoms, dementia, aphasia, seizures, heightened muscle tone, tremor, paralysis, stupor, and coma. The course of the disease may be measured in terms of months, occasionally years. Although progressive in an overall sense, patients have occasionally exhibited clinical plateaus or even frank remissions in their clinical course. The fundamental pathological change is a symmetric degeneration of the myelin sheaths in the mid-zone of the corpus callosum, with relatively good preservation of axons and without appreciable inflammatory changes. Such degenerative changes are not confined to the corpus callosum; similar changes may be found in the anterior commissure, symmetrically disposed in the cerebral white matter, the optic chiasm, or the middle cerebellar peduncles. Although Marchiafava–Bignami disease was once looked on as a neuropathological curiosity not diagnosable during life, the lesions may be readily identified with CT scanning or MRI.
Central Pontine Myelinolysis 83
First described in 1959 but reported in large numbers since, central pontine myelinolysis is characterized clinically by a rapidly evolving flaccid quadriplegia with bulbar paralysis; pathologically it is identified by demyelination confined for the most part to the basal portion of the middle and upper pons and symmetrically distributed about the midline. Extrapontine myelinolysis has been observed in a number of instances. Consciousness is preserved, and patients may be able to communicate by moving the eyelids, the only motor activity remaining in extreme cases; the term locked-in syndrome is appropriately applied to cases of this sort. The course of the disease is rapid, and patients usually84die within 3 weeks of the onset. Clinical recovery has been observed in rare instances. Although originally looked on as nutritional in origin, it has become apparent that many if not most cases of 85 central pontine myelinolysis are in fact due to overly vigorous correction of the 86,87 or hyponatremia, as frequently encountered in the neglected, malnourished alcoholic, under other circumstances, as discussed in detail in Chapters 19 and 37 and ranging from 88 ornithine carbamoyl transferase deficiency in childhood to orthotopic liver transplantation 89,90 It has been suggested that in most cases an with concomitant use of cyclosporine. osmotic shift may be more important in producing demyelination than the serum level of 91 sodium per se. It is unclear whether chronic nutritional depletion plays a specific role in the pathogenesis.
Jamaican Neuropathy In 1897, Strachan described a group of patients in Jamaica who presented with numbness and burning in the limbs, girdle pains, impaired vision and hearing, muscle weakness and wasting, hyporeflexia, and sensory92ataxia in association with a mucocutaneous lesion such cases were subsequently reported in a as angular stomatitis and glossitis. Virtually identical 93 variety of circumstances of nutritional depletion. The clinical features are predominantly those of a sensory neuropathy. Pathological alterations have been described in the peripheral nerves, posterior columns, spinocerebellar tracts, and optic nerves. Similar clinical features 94 and occurring in association with spasticity were later described by Denny-Brown 95 Cruickshank. In the spastic form of the disease, severe degeneration of both the pyramidal tracts and posterior columns of the spinal cord has been documented, with involvement of the spinocerebellar and spinothalamic pathways in some cases. It is unclear whether the neuropathic disorder of Strachan and the myelopathic variety of Cruickshank represent different entities or simply different manifestations of the same process. The designation Jamaican neuropathy is often applied indiscriminately to all such instances. Those disorders characterized by myelopathic features (i.e., spasticity) are, however, sometimes referred to titers to human T-lymphotrophic as tropical spastic paraparesis; in the latter group, antibody 96–98 retrovirus type I have been documented repeatedly, and it is presumed on this basis that viral infection plays a major role in pathogenesis, as discussed in Chapter 47. Whether nutritional depletion plays any role in either form of the disease remains unclear. The use of clioquinol has been implicated in the development of subacute myelo-opticoneuropathy, a similar disorder occurring most commonly in Japan. HYPERALIMENTATION
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Parenteral hyperalimentation using a central venous catheter, usually placed in a jugular vein, is widely used in the management of chronic nutritional depletion at all ages. A number of 99 neurological disorders appear in such patients, reflecting either mechanical or metabolic problems. Complications attributed to mechanical factors, with or without sepsis, include 100 101 cortical vein thrombosis, infected subdural collections, cerebral air embolization, 102 103–105 pseudotumor cerebri, and, in infants, communicating hydrocephalus. Metabolic alterations are usually held responsible for a variety of encephalopathic, neuropathic, or myopathic manifestations, virtually all of which are reversible when the underlying metabolic defect is identified and treated appropriately. Encephalopathy is attributed most commonly to 106,107 108 or hyperammonemia ; hyperosmolarity has also been implicated hypophosphatemia and appears to be of particular 109 importance in experimental models of the disorder. Biotin deficiency has been described. Patients receiving prolonged parenteral nutrition without thiamine supplementation are at110 risk for development of an acute and fatal encephalopathy resembling Wernicke's disease. Severe hypophosphatemia has also been blamed for the appearance of a peripheral neuropathy characterized by weakness, areflexia, and paresthesias and sensory 111 impairment. Ataxia, cranial nerve palsies, ophthalmoplegia, blurred vision, and respiratory failure have all been described. At times, the clinical evolution of this disorder is sufficiently 112,113 114 Chromium and linolenic acute to suggest a diagnosis of Guillain–Barré syndrome. 115 acid deficiency have been documented in individual cases. Selenium deficiency has been 116–118 associated with a reversible myopathy, evidenced by proximal muscle weakness and tenderness and an elevated serum creatine kinase level. Selenium deficiency may relate to parenteral or enteral nutrition, or malabsorption; insufficient selenium intake in low soil-selenium areas; and chronic conditions associated with oxidative stress, such as chronic 118 alcohol abuse and human immunodeficiency virus (HIV) infection. Selenium supplementation usually reverses myopathic symptoms when the cause is parenteral or enteral nutrition, or malabsorption; when deficiency occurs in low soil-selenium areas, other factors may also be important, as selenium supplementation and placebo have similar effects 118 on muscle symptoms. Patients with copper deficiency may present with gait disturbances from a sensory ataxia related to posterior column dysfunction. Lower-limb spasticity is common and a polyneuropathy is generally present, so that the clinical picture resembles that of vitamin B12 deficiency. The syndrome has followed prolonged total parenteral hyperalimentation, copper deficiency in enteral feeding, gastric surgery, malabsorption, and excessive zinc 119–121 but a cause cannot always be identified. Serum zinc level may be elevated absorption, and the diagnosis is suggested by low ceruloplasmin and copper levels in the absence of evidence for Wilson's disease. Anemia (macrocytic, normocytic, or microcytic), leukopenia, and thrombocytopenia may occur; the hematological findings may resemble a sideroblastic anemia or myelodysplastic syndrome. Abnormalities of somatosensory evoked potentials and of MRI, when present, help to demonstrate involvement of the posterior columns of the spinal cord. Copper supplementation may arrest the course of the disorder, which should therefore be excluded in patients with an ataxic spastic paraparesis or neuromyelopathy of uncertain cause. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 18 Neurological Dysfunction and Kidney Disease MICHAEL J. AMINOFF •
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UREMIC ENCEPHALOPATHY Pathophysiology Clinical Features Investigations Treatment of Uremic Convulsions UREMIC NEUROPATHY Polyneuropathy Pathophysiology Clinical Features Treatment Autonomic Neuropathy OPTIC NEUROPATHY NEUROLOGICAL COMPLICATIONS OF DIALYSIS Entrapment Mononeuropathies Carpal Tunnel Syndrome Ulnar Nerve Lesions Ischemic Neuropathy Dialysis Dysequilibrium Syndrome Wernicke's Encephalopathy Dialysis Dementia Clinical Aspects Pathogenesis Treatment COMPLICATIONS OF TRANSPLANTATION Femoral and Related Neuropathy Tumors Brain Tumors Central Nervous System Infections HEREDITARY DISORDERS OF THE NERVOUS SYSYEM AND KIDNEYS Fabry's Disease von Hippel–Lindau Disease Polycystic Kidney Disease
The neurological aspects of renal disease and the neurological complications of dialysis and
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renal transplantation are discussed in this chapter. The neurological complications of renal carcinoma are not considered, but paraneoplastic complications of malignancy are considered in Chapter 27, and the neurological consequences of radiation and chemotherapy in Chapter 28. The subject itself is complicated because many of the causes of renal failure lead to neurological complications that also occur in uremia. Thus, collagen vascular diseases are commonly associated with encephalopathy or seizures, and diabetes with neuropathy or encephalopathy. Attention here is directed primarily to complications that are a direct consequence of the renal failure and its treatment rather than to the underlying cause of the kidney disease. In addition, however, certain hereditary disorders that affect both the nervous system and the kidneys are considered. UREMIC ENCEPHALOPATHY The neurological consequences of uremia resemble other metabolic and toxic disorders of the central nervous system (CNS). Thus, the clinical features of the encephalopathy that occurs in uremic patients include an impairment of external awareness that ranges from a mild confusional state, with diminished attention and concentration, to coma. The presence of coma may indicate severe uremia or reflect a complication 1–3 such as hypertensive encephalopathy, posterior reversible leukoencephalopathy, fluid and electrolyte disturbances, seizures, or sepsis. Other causes of an encephalopathy in uremic patients include dialysis, thiamine deficiency, drug toxicity, and transplant rejection. Finally, the encephalopathy and renal impairment may both relate independently to the same underlying systemic illness, such as diabetes or connective tissue diseases. All these factors complicate clinical assessment. In addition to an alteration in external awareness, patients with uremic encephalopathy may have seizures, dysarthria, gait ataxia, asterixis, tremor, and multifocal myoclonus. As with all metabolic encephalopathies, symptoms and signs typically fluctuate in severity over short periods of time, such as over the course of a day or from day to day.
Pathophysiology In early studies, various pathological changes were described in the brain of uremic patients, but these probably did not relate directly to the uremia. Thus, neuronal degeneration and necrosis of the granular cell layer of the cerebellar cortex probably related to preterminal hypoxia, and focal demyelination 4and necrosis to coexisting hypertensive cerebrovascular disease that led to small infarcts. Glycolysis and energy utilization are reduced in the brain, probably as a consequence of a disturbance of synaptic transmission that leads to decreased 4 neuronal interaction and thus to reduced cerebral oxygen consumption. Uremic encephalopathy almost certainly relates to a variety of metabolic abnormalities, with the accumulation of numerous metabolites, imbalance in excitatory and inhibitory neurotransmitters, and hormonal disturbances leading to cerebral dysfunction. The European Uremic Toxin Work Group has listed 90 compounds considered to be uremic toxins; 68 have a molecular weight less than 5,6 500 Da, 12 exceed 12,000 Da, and 10 have a molecular weight between 500 and 12,000 Da. A few merit brief discussion here. Retention of urea occurs; urea clearance, even in well-dialyzed patients, amounts to only one sixth of physiological 6 clearance. Accumulation of guanidinosuccinic acid, methylguanidine, guanidine, and creatinine, all of which are guanidine compounds, in the serum and cerebrospinal fluid (CSF) 7–9 of uremic patients, may play a role in causing uremic seizures and cognitive dysfunction. Activation of N-methyl-d-aspartate (NMDA) receptors and inhibition of γ-aminobutyric acid-A 7 (GABAA) transmission may be involved, on the basis of studies in animals. Guanidinosuccinic acid may inhibit transketolase, a thiamine-dependent enzyme involved in 8,9 the pentose phosphate pathway and in the maintenance of myelin. It remains unclear whether 10 low-level aluminum overload in renal failure causes gradual deterioration in cerebral + + triphosphatase function. Abnormalities of the membrane pumps for both Na ,K –adenosine 11,12 and may be of and calcium ions have been described in experimental studies in animals clinical relevance. Hormonal changes may also be important in the pathogenesis of uremic encephalopathy. Serum concentrations of parathyroid hormone, growth hormone,13prolactin, luteinizing hormone, insulin, and glucagon are elevated in uremic patients. Parathyroid hormone levels increase with the severity of the encephalopathy, and alterations in brain calcium could influence neurotransmitter release, the sodium-potassium pump, intracellular enzyme activity, and intracellular metabolic processes, and thereby may affect cerebral function. Experimental studies show that the calcium content of the cerebral cortex is greatly increased in uremia, and this is unrelated to alterations in calcium concentration in the plasma16or cerebrospinal 14,15 Both clinical and electroencephalographic (EEG) abnormalities, and changes in fluid.
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cerebral calcium concentration,
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are improved by parathyroidectomy.
In contrast to the process in subjects with normal kidneys, the removal of uremic toxins in dialysis is achieved by a one-step, membrane-based process and is intermittent. The resulting stepwise variation in plasma concentrations of uremic toxins contrasts with the 6 continuous function of normal kidneys.
Clinical Features The clinical features of uremic encephalopathy do not show a good correlation with any single laboratory15abnormality but can sometimes be related to the rate at which renal failure develops. Thus, stupor and coma are relatively common in acute renal failure, whereas symptoms may be less conspicuous and progression more insidious despite more marked laboratory abnormalities in chronic renal failure. Dialysis relieves or prevents some of the more severe features of this encephalopathy. The most reliable early indicators of uremic encephalopathy are a waxing and waning 2 reduction in alertness and impaired external awareness. The ability to concentrate is impaired, so that patients seem preoccupied and apathetic, with a poor attention span; they become increasingly disorientated with regard to place and time and may exhibit emotional lability and sleep inversion. An impairment of higher cognitive abilities, such as of executive function, becomes evident, and patients become increasingly forgetful and apathetic. With progression, patients become more obtunded so that it may then be necessary to shout or gently shake them to engage their attention and elicit any responses, which are likely to be of variable accuracy and relevance. Delusions, illusions, and hallucinations (typically visual) often develop, and patients may become agitated and excited, with an acute delirium that eventually is replaced by stupor and a preterminal coma. Tremulousness may be conspicuous and usually occurs before asterixis is found. A coarse postural tremor is seen in the fingers of the outstretched hands, and a kinetic tremor is also common. Asterixis is a nonspecific sign of metabolic cerebral dysfunction. An intermittent loss of postural tone produces the so-called flapping tremor of asterixis after several seconds when the upper limbs are held outstretched with the elbows and wrists hyperextended and fingers spread apart; irregular flexion-extension occurs at the wrist and of the fingers at the metacarpophalangeal joints, with flexion being the more rapid phase. There is complete electrical silence in the wrist flexors and extensors during the downward (flexor) movements, followed by electrical activity in the extensors as they restore the limb's posture. The axial structures, including the trunk or neck, may also be affected. Asterixis can also be demonstrated in the lower limbs, and flapping may even be elicited in the face by forceful eyelid closure, strong retraction of the corners of the mouth, pursing of the lips,4 or protrusion of the tongue, provided that some degree of voluntary muscle control persists. In obtunded or comatose patients, or others in whom voluntary effort is limited, asterixis can still be 7 elicited, but at the hip joints. With the patient lying supine, the examiner grasps both ankles of the supine patient and moves the feet upward toward the patient's body, flexing and abducting the thighs: irregular abduction–adduction movements at the hips indicate asterixis. Spontaneous and stimulus-sensitive myoclonus is common in uremia and in other metabolic encephalopathies and reflects increased cerebral excitability. The myoclonus is typically multifocal, irregular, and asymmetric; it may be precipitated by voluntary movement (action myoclonus). The myoclonic jerks may be especially conspicuous in the facial and proximal limb muscles. Uremic myoclonus in humans resembles the reticular reflex form of postanoxic 17 action myoclonus. It is usually not associated with EEG spike discharges, although such discharges have sometimes been encountered with the myoclonus. The myoclonus may respond to clonazepam. Multifocal myoclonus is sometimes so intense that muscles appear 4 to be fasciculating (uremic twitching). Tetany may occur. Seizures are common. They are usually generalized convulsions, may be multiple, and are often multifactorial in etiology. In acute renal failure, convulsions commonly occur several days after onset, during the anuric or oliguric phase. In chronic renal failure, they tend to occur with advanced disease, often developing preterminally; they may relate to the uremia itself or to electrolyte disturbances, medications (such as penicillin, aminophylline, or isoniazid), or an associated reversible posterior leukoencephalopathy syndrome (characterized by vasogenic white-matter edema predominantly localized to the posterior cerebral hemispheres on imaging studies, as shown in Figure 18-1). Their incidence has declined, perhaps because of more effective treatment of renal failure and its complications. Seizures also occur in patients undergoing hemodialysis in the dialysis dysequilibrium syndrome (discussed on p. 335). Focal seizures sometimes occur. Occasional patients develop nonconvulsive status epilepticus that may not be recognized unless an EEG is
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18,19
obtained.
FIGURE 18-1 Imaging findings of a patient with seizures who was diagnosed
with posterior reversible leukoencephalopathy. A, Axial computed tomography (CT) scan demonstrates bilateral low-density involvement of the occipital lobes. B, Axial T2-weighted magnetic resonance imaging (MRI) shows high signal intensity lesions without mass effect involving white matter bilaterally in the occipital lobes. (Courtesy of William P. Dillon, MD, University of California, San Francisco.)
FIGURE 18-2 Electroencephalogram (EEG) showing a diffusely slowed
background with triphasic waves in a patient with uremic encephalopathy. During the early stages of uremia, patients may be clumsy or have an unsteady gait. Paratonia (gegenhalten) a variable, velocity-dependent resistance to passive movement, especially rapid movement, is common, and grasp and palmomental reflexes may be present, presumably as a result of a depression of frontal lobe function. As uremia advances, extensor muscle tone increases and may be asymmetric; opisthotonos or decorticate posturing of the limbs may eventually occur. Motor deficits may include transient or alternating hemiparesis that shifts sides during the course of the illness, flaccid quadriparesis related to hyperkalemia, or distal weakness from uremic neuropathy. The tendon reflexes are generally brisk unless a significant peripheral neuropathy is present and may be asymmetric; Babinski signs are often present. Encephalopathy may occur in uremic patients for reasons other than uremia, such as in relation to dialysis, thiamine deficiency, electrolyte imbalance, medication-related toxicity, and graft rejection. These disorders are considered in later sections of this chapter.
Investigations Laboratory studies provide evidence of impaired renal function but are of limited utility in monitoring the course of the encephalopathy. Furthermore, abnormal renal function tests do not exclude other causes of encephalopathy. An underlying structural lesion must be excluded in uremic patients who have had seizures, especially when focal or multiple
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seizures have occurred. The CSF is commonly abnormal, with a pleocytosis that is unrelated to the degree of azotemia and an increased protein4 content that sometimes exceeds 100 mg/dl. In the older literature, summarized by Raskin, up to 30 percent of uremic patients were found to have neck stiffness and Kernig's sign, and in this context the finding of abnormal CSF may lead to the erroneous conclusion that the patient has a meningitic or encephalitic illness. The EEG is diffusely slowed, with an excess of intermittent or continuous theta and delta waves that may show a frontal emphasis, perhaps reflecting a decreased cerebral metabolic rate. Triphasic waves are often present, with an anterior predominance (Fig. 18-2). Bilateral spike-wave complexes may be present either in the resting EEG or with photic stimulation, as in 14 percent of the patients on a chronic hemodialysis program reported by Hughes, none of 20 whom had experienced a seizure. The EEG becomes increasingly slowed with progression of the encephalopathy, so that delta activity becomes more continuous; the findings correlate best with the level of retained nitrogenous compounds, although no clear relationship exists between the EEG and a specific laboratory abnormality. Similarly, there are delays of visual, 21 reveal auditory, and somatosensory evoked cerebral potentials. Event-related potentials 13 abnormalities even in asymptomatic patients, with an increase in P3 latency. In a study involving transcranial magnetic stimulation, 36 patients with end-stage renal disease were 21 evaluated at different stages of the disease and under different treatment. Patients on conservative treatment showed a significant reduction of short-interval intracortical inhibition that could be reversed by hemodialysis, peritoneal dialysis, or renal transplantation. After hemodialysis, intracortical facilitation increased, and this was inversely correlated with the decline in plasma osmolarity induced by the dialytic procedure. In other words, patients showed alterations in cortical excitability that were reversed by treatment of the renal disease. Cerebral imaging studies are of limited help except in excluding other, structural causes for the encephalopathy. They may reveal a reversible, predominantly posterior 2,3 leukoencephalopathy, with subcortical edema without infarction. There may be multiple areas of symmetric edema in the basal ganglia,1brainstem, or cerebellum, with—in severe cases—focal infarcts, sometimes hemorrhagic.
Treatment of Uremic Convulsions Treatment involves correction of renal failure and related metabolic abnormalities. In patients who have had seizures, anticonvulsant medication may be required, especially when the convulsions are of uncertain cause. If status epilepticus occurs, it is managed as in other circumstances. Various considerations make anticonvulsant therapy difficult to manage in uremia. As 22 discussed in Chapter 58 and also reviewed elsewhere, plasma protein binding and renal excretion are reduced, and dialysis may remove drugs from the circulation. Phenytoin is often used in this context: reduced protein binding leads to a greater volume of distribution and lower serum concentrations, but the proportion of unbound (active) phenytoin increases and maintains the benefit of a given dose. Free phenytoin rather than total plasma levels are used to monitor treatment; the optimal therapeutic range is 1 to 2 μg/ml. The total daily dose generally need not be changed, but it is probably best taken divided rather than in a single 23 24 dose. Dialysis does not remove phenytoin from the circulation to any significant extent. Valproic 23 acid is helpful for treating myoclonic seizures and generalized convulsions in uremic 24 patients. Protein binding decreases, but the free fraction remains constant. Dialysis does not necessitate additional doses. Plasma phenobarbital levels are unaffected by renal insufficiency. Lower doses of phenobarbital are used for long-term maintenance therapy, however, because the drug may 23,24 24 ; additional doses may be required after dialysis. Primidone and its accumulate 23 metabolites may also accumulate, causing toxicity in uremic patients. Serum 24 carbamazepine levels are unchanged, and dosing does not need alteration. Impaired renal function leads to decreased clearance of felbamate, gabapentin, topiramate, levetiracetam, vigabatrin, pregabalin, and oxcarbazepine. Gabapentin, pregabalin, and topiramate are 25–27 and the daily dose will need to be reduced in uremic excreted mainly by the kidneys, 28 Hemodialysis necessitates patients; dosing of zonisamide may also need reduction. 29 additional doses of levetiracetam (typically 250 to 500 mg) and gabapentin (200 to 300 mg); 27 26 supplemental doses of topiramate and pregabalin after hemodialysis may also be required. Extra doses of zonisamide may not be necessary if this drug is given in a single 30 show little daily dose after dialysis sessions. Tiagabine and lamotrigine pharmacokinetics31,32 change even in severe uremia, and dosage adjustment is usually unnecessary.
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UREMIC NEUROPATHY
Polyneuropathy Peripheral nerve function becomes impaired at glomerular filtration rates of less than 12 13 ml/min, with clinical deficits developing at rates of about 6 ml/min. More than 50 percent of patients with end-stage renal disease have clinical (neuropathic symptoms or signs) or electrophysiological abnormalities, the exact number depending on the series and diagnostic criteria utilized. Pathophysiology Because uremic neuropathy improves with dialysis, uremic neuropathy has been attributed to the accumulation of dialyzable metabolites. Hemodialysis regimes sufficient to control urea or creatinine may neverthe-less fail to prevent the development of neuropathy, and this observation led to the “middle molecule” hypothesis. In particular, the lower prevalence of neuropathy in patients on peritoneal dialysis than on hemodialysis suggested that the responsible substance was better dialyzed by the peritoneum, and it was proposed that these substances might be in the middle-molecule range (500 to 12,000 Da), which is poorly cleared by hemodialysis membranes. The adoption of dialysis strategies4,33 to improve the Babb and clearance of middle molecules reduced the rates of severe neuropathy. colleagues have reviewed the data both supporting and conflicting with the middle molecule hypothesis; the preponderance of evidence supports the hypothesis, although convincing 34 studies are lacking. The identity of the responsible neurotoxin has remained elusive. Some evidence exists for the neurotoxicity of parathyroid hormone, as was discussed earlier. Parathyroid hormone prolongs motor conduction velocities in dogs perhaps through accumulation of calcium in peripheral nerves; parathyroidectomy of three dogs with chronic renal failure was associated with reversal of the motor conduction abnormalities and calcium content of nerve despite an 35 of parathyroid additional period of renal failure. Studies in uremic patients of the effect 36 and conflicting hormone on peripheral nerves, however, have yielded both supporting 37 results. On the basis of the published literature, Bostock and colleagues have emphasized that for a substance to be accepted as a uremic neurotoxin, it must satisfy certain criteria, namely, (1) it must be an identifiable chemical; (2) its concentration in the blood should be increased in patients with uremia; (3) a direct relationship should exist between its blood level and neurological dysfunction; (4) it should be neurotoxic in animals at appropriate blood levels; (5) its removal from the blood should abolish neurological dysfunction; and (6) dialysis should 38 remove the substance from the body, but more slowly than it removes urea. If these criteria are accepted, the middle molecule hypothesis cannot be accepted at this time because no identifiable chemical with established neurotoxicity has been demonstrated, with a clear relationship between its blood level and neurological dysfunction, except for parathyroid hormone, which is not dialyzable. These authors proposed instead that mild hyperkalemia was responsible. It is known that hyperkalemia typically recurs within a few hours of a dialysis session as a result of re-equilibration between intracellular and extracellular fluid 39 Prolonged hyperkalemia may disrupt 33,38 normal ionic gradients and activate compartments. ++ Ca -mediated processes that are damaging to axons. 40
41
Motor and sensory nerve excitability has been studied in relation to changes in serum levels of potential neurotoxins, including calcium and potassium ions, urea, uric acid, and certain middle molecules. Predialysis measures of nerve excitability were abnormal, consistent with axonal depolarization, and correlated strongly with serum potassium levels, suggesting that hyperkalemic depolarization may underlie the development of uremic neuropathy. The severity of symptoms also correlated with excitability abnormalities. Most 40,41 The findings support the nerve excitability parameters were normalized by hemodialysis. belief that hyperkalemia is primarily responsible for uremic depolarization and probably + + contributes to the development of neuropathy. There is no evidence of significant Na /K 42 pump dysfunction, despite earlier suggestions to the contrary. If hyperkalemia does indeed have a role in mediating these abnormalities, measures of dialysis adequacy based solely on blood urea or creatinine concentrations may be inadequate for determining whether dialysis will prevent neurotoxicity. Monitoring the serum potassium level and ensuring that it is maintained within normal limits between periods of dialysis may be more relevant in this regard.
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Clinical Features Uremic neuropathy is more common in men than women and in adults than children. It is characterized by a length-dependent, symmetric, mixed sensorimotor polyneuropathy of axonal type that resembles other axonal metabolic-toxic neuropathies. Its clinical manifestations, severity, and rate of progression are variable. As with uremic encephalopathy, its severity correlates poorly with biochemical abnormalities in the blood, but neuropathy is more likely to develop in chronic or severe renal failure. Initial symptoms commonly consist of dysesthesias distally in the legs; muscle cramps may also be troublesome. The restless legs syndrome often develops before or with the clinical onset of neuropathy, and its occurrence may therefore indicate incipient peripheral nerve involvement. As with many other neuropathies, the earliest clinical signs are of impaired vibration appreciation and depressed or absent tendon reflexes distally in the legs, indicating involvement of large-diameter myelinated fibers. Progression is typically insidious over many 43,44 Thus, a more months but occasionally is rapid, leading early to severe disability. progressive, predominantly motor subacute neuropathy may occur in uremic patients with diabetes and lead to severe weakness over a few weeks or months; nerve conduction studies 44 but may show demyelination typically demonstrate features of an axonal neuropathy 43 43 to transplantation or to a switch from features, and the neuropathy may respond 44 conventional to high-flux hemodialysis. The course may be arrested at any time despite continuing or worsening renal failure. It is hard to predict the likely clinical course in individual patients. Most patients are left with distal motor and sensory deficits, but some become severely disabled with a flaccid quadriparesis or paraparesis. Severe neuropathy has become less prevalent with the introduction of dialysis and transplantation techniques but remains common. Histopathological examination of nerve biopsy specimens confirms that the neuropathy is a length-dependent axonal degeneration accompanied by secondary demyelination, although in 45 some cases the demyelination seems the predominant finding ; damaged endoneural blood capillaries may also be found and support an ischemic theory as one mechanism in the 46 pathogenesis of uremic neuropathy. Nerve conduction studies also support an axonal process, with reduced conduction velocities and response amplitudes; abnormalities are common even in clinically unaffected nerves. The amplitude of the sensory nerve action potential is affected particularly, especially that of the sural nerve. Large fibers are affected 47 more often than small fibers, but in occasional patients a predominantly small-fiber neuropathy has been reported. Thus, impaired thermal discrimination was the first sign of neuropathy in 15 percent of one series of 64 nondiabetic uremic patients, indicating that a 48 small-fiber uremic neuropathy may exist as a separate entity. The findings on nerve 49 conduction studies may 50 improve after effective treatment51of the underlying renal failure, sometimes very rapidly, but this is not always the case ; sensory nerve conduction velocities in the median, ulnar, and sural nerves may be the most sensitive 52 electrophysiological indices of the beneficial effect of hemodialysis. Needle electromyography (EMG) may reveal evidence of denervation, particularly in the distal muscles of the legs. Abnormalities of late responses (F waves and H reflexes) are frequent and may be helpful early in the53,54 course of renal failure, when standard nerve conduction study results are sometimes normal. Laaksonen and colleagues examined the clinical severity of uremic neuropathy in 21 patients, using a modified version of the neuropathy symptom score combined with results of 55 electrophysiological studies. They found that 81 percent of uremic patients were diagnosed with neuropathy: the neuropathy was asymptomatic in 19 percent, associated with nondisabling symptoms in 48 percent, and accompanied by disabling symptoms in 14 percent. Patients with the restless legs syndrome develop an irresistible urge to move the legs that is worse at night and during periods of inactivity. They complain of curious sensations—often described as creeping, crawling, prickling, or itchy feelings—in the lower limbs, and these tend to be worse in the evening or when the limbs are not in motion. Such sensations are experienced most commonly in the legs but occasionally occur in the thighs or feet; the upper limbs are also sometimes involved. Low hemoglobin levels, high serum phosphorus levels, high anxiety levels, and a great degree of emotion-oriented coping seem to be related to the 56 presence of restless legs syndrome in uremic patients undergoing hemodialysis. Treatment of restless legs syndrome is with clonazepam,57dopamine agonists, levodopa, or opioids (propoxyphene or codeine) taken at bedtime. In addition, coexisting anemia and hyperphosphatemia should be corrected.58,59 Successful renal transplantation may ameliorate or eliminate symptoms within a few weeks.
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Treatment Uremic polyneuropathy may stabilize or even show some improvement with dialysis, but mild 51,60,61 Renal progression is not uncommon and recovery of severe neuropathy is unlikely. 62 transplantation improves uremic neuropathy, sometimes very rapidly and with a negative correlation between electrophysiological change and serum creatinine and myoinositol50 concentrations, suggesting that metabolic factors may underlie the rapid improvement ; in other instances, improvement is more gradual over a number of months, is characterized electrophysiologically by improvement in motor and sensory conduction velocities, and is often incomplete, perhaps because the main reason for improvement is segmental 49 remyelination, with some fibers remaining degenerate in severe neuropathies.
Autonomic Neuropathy Uremic patients may develop postural hypotension, impaired sweating, impotence, gastrointestinal disturbances, and other dysautonomic symptoms, which progress in some 63 with patients—but not all —despite continuing hemodialysis. The dysautonomia correlates 64 the presence or severity of peripheral neuropathy in many but not all patients and may be corrected by renal transplantation. The mechanism underlying the development of uremic 65 autonomic neuropathy is unknown. In patients with diabetic renal failure, dysautonomia may relate also to the diabetes. Studies of both cardiovagal and sympathetic function (discussed 63,64,66–70 that may be in Chapter 8) have revealed objective evidence of dysautonomia sub-clinical. Intradialytic hypotension is a frequent67,69 complication of hemodialysis and has been shown to regardless of whether a peripheral neuropathy is relate to67impaired autonomic function present ; however, there is no agreement on this point, and some investigators have found that hypotension-prone patients are not distinguished by impaired predialytic or intradialytic 71 Midodrine may have a role in the therapy of patients with control of the blood pressure. 72 intradialytic hypotension. 73,74
Dialysis may not benefit autonomic neuropathy. However, Vita and colleagues found that when patients were switched from acetate to bicarbonate dialysis, all the patients in a small 75 After renal transplantation, series eventually showed a reversal of autonomic damage. 65,73 but at a variable rate. autonomic function may improve or normalize OPTIC NEUROPATHY A progressive optic neuropathy may occur over several days; visual loss is accompanied by reduced pupillary response to light and by papillitis. Prompt hemodialysis and corticosteroid 76 therapy may restore vision in some patients. The optic neuropathy may be neurotoxic, ischemic, related to side effects of medication or intracranial hypertension, or inflammatory in 77 nature. In ischemic optic neuropathy, coexisting hypotension and anemia may be important risk factors, and treatment may require78intravenous saline or blood transfusions in addition to the other measures mentioned earlier. Calcific uremic arteriolopathy may also have an 79 etiological role. NEUROLOGICAL COMPLICATIONS OF DIALYSIS Dialysis has been associated with subtle cognitive alterations, possibly reflecting an early 80 manifestation of dialysis dementia at a reversible stage. More commonly, psychological studies have shown significant improvement in short-term memory both after onset of maintenance dialysis and when comparisons are made between the day before and after an individual dialysis treatment session; attentional functions also seem to improve after dialysis 81 as well. Subdural hematoma (Fig. 18-3) may occur in patients on maintenance 82 hemodialysis and its symptoms attributed to dysequilibrium syndrome or dialysis dementia. Its occurrence may relate to anticoagulation used to maintain the patency of the conduit for hemodialysis; platelet function may be impaired in uremia but, in itself, is unlikely to be responsible. A rare case of manganese-induced parkinsonism has been described in a patient on maintenance hemodialysis and was attributed to long-term ingestion of a health supplement; the clinical, laboratory, and magnetic resonance imaging (MRI) findings were 83 abnormal, but the patient improved on edetic acidinfusion therapy. These complications will receive no further discussion here.
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FIGURE 18-3 Axial noncontrast CT scan shows a mixed-density left subdural
hematoma producing marked mass effect on the left hemisphere and midline shift. The low density within the subdural hematoma is a feature of active hemorrhage. (Courtesy of William P. Dillon, MD, University of California, San Francisco.) Muscle cramps are common, tending to occur toward the end of a dialysis session: their etiology is uncertain, but plasma volume contraction and hyponatremia are among the factors that have been incriminated. Headache, nausea, and vomiting may also occur during dialysis, sometimes as the initial manifestations of the dysequilibrium syndrome (discussed later). The risk of cerebrovascular disease is increased in patients undergoing dialysis and seems related to accelerated cerebrovascular disease and the high incidence of malnutrition, 84,85 Presentation may be hypertension, diabetes, and hyperlipidemia among these patients. with hypertensive encephalopathy, transient ischemic attacks, or occlusive or hemorrhagic 86 stroke. Infarcts may show a predilection for the vertebrobasilar arterial territory. The osmotic demyelination syndrome may occur after hemodialysis, leading clinically to convulsions, an alteration in the level of consciousness, and quadriparesis with hyperactive tendon reflexes and bilateral Babinski87responses. MRI shows findings of demyelination in pontine and often extrapontine regions. The effects of dialysis on uremic encephalopathy and neuropathy have already been discussed, but dialysis may cause other neurological disturbances that merit comment.
Entrapment Mononeuropathies Carpal Tunnel Syndrome It was originally believed that carpal tunnel syndrome occurred because of increased venous pressure in the distal limb when an arteriovenous shunt had been placed for hemodialysis, the increased extravascular volume within the carpal tunnel or steal being held responsible for the median nerve compression. Recent studies support an etiological role for arteriovenous fistulas. Thus, in one study, carpal tunnel syndrome was diagnosed significantly less frequently in the contralateral wrist than that ipsilateral to the arterio-venous fistula, and a positive correlation was found between the duration of the fistula and development of carpal tunnel syndrome; in contrast to such clinical assessment, however,
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electrodiagnostic studies indicate no significant association between the frequency of carpal 88 tunnel syndrome and arteriovenous fistula or its duration. The occurrence of β2-microglobulin amyloidosis is probably more important etiologically in 89–91 Amyloid fibrils have been this context, particularly in patients on long-term hemodialysis. isolated from amyloid-laden tissues inside the carpal tunnel and the protein identified as 90 β2-microglobulin. Circulating β2-microglobulin presumably cannot be removed by conventional hemo dialysis and accumulates in tissues; the consequent formation of amyloid fibrils appears to have a 90 relatively high affinity for the region of the carpal tunnel, leading to carpal tunnel syndrome. A significant increase in carpal tunnel width and thickness in the palmoradiocarpal ligament, correlating with duration of long-term hemodialysis, has been 92 reported based on ultrasound examination of the wrists of hemodialysis patients. The prevalence of carpal tunnel syndrome and the severity of symptoms have been improved by 93 maneuvers to reduce the levels of β2-microglobulin. Uremic tumoral calcinosis may also be 94,95 responsible in some instances. Treatment is as in other patients, with decompressive surgery if symptoms fail to respond to conservative measures. Ulnar Nerve Lesions A high prevalence (between 41% and 60%) of ulnar neuropathy in patients has recently been 96 reported in patients receiving hemodialysis for end-stage renal disease. This may relate to arm positioning during hemodialysis, underlying polyneuropathy, upper-extremity vascular 96,97 access, and uremic tumoral calcinosis.
Ischemic Neuropathy A shunt for access during chronic hemodialysis and inserted between the radial artery and cephalic vein in the upper arm was reported by Bolton and colleagues to have caused a distal, ischemic neuropathy in two patients; electrophysiological evidence was present of axonal degeneration of sensory fibers with mild ischemia, and of both motor and sensory 98 nerve fibers with more severe ischemia. This has been attributed to shunting of arterial blood away from the limb distally, with the nerves being selectively affected because of their greater vulnerability to ischemia. Other cases of this so-called ischemic monomelic 99 neuropathy have since been reported, and the disorder is particularly 100 likely in diabetics with renal failure and preexisting peripheral vascular disease or neuropathy. Multiple upper-limb mononeuropathies98–101 develop, leading to burning pain and to sensory and motor deficits in the Motor conduction block may be detected electrophysiologically forearm and hand. shortly after the onset of symptoms, preferentially involving the median nerve, with clinical 102 and electrophysiological improvement following ligation or revision of the shunt. In some instances, more widespread signs of upper-extremity ischemia may be found distal to the 103 fistula, such as established or impending tissue loss or nonhealing wounds.
Dialysis Dysequilibrium Syndrome Several neurological disturbances may arise during or after hemodialysis or peritoneal dialysis, including headache, nausea, anorexia, muscle cramps, irritability, restlessness, agitation, confusion, coma, and seizures; increased intracranial pressure may lead to papilledema. Such symptoms tend to occur at the beginning of a dialysis program and were particularly conspicuous in the past when patients with advanced uremia were dialyzed aggressively; patients now enter dialysis programs at an earlier stage of renal failure and have shortened dialysis times, and this may account for the reduced incidence of the disorder, which seems more common in children and the elderly than in other age groups. Marked104 metabolic acidosis and the presence of other CNS disease may also be predisposing factors. Symptoms typically appear toward the end of a dialysis session, sometimes 8 to 24 hours later, and subside over several hours. When an agitated confusional state develops, it may persist for several days. Many patients manifest exophthalmos and increased intraocular pressure at the height of the syndrome, which may be helpful clinically for diagnostic 4 purposes. Headache is the most common symptom reported by patients undergoing dialysis, and migrainous episodes may be precipitated during or after hemodialysis in patients with preexisting migraine. Headache is otherwise usually diffuse and throbbing in quality. Subdural hematoma sometimes mimics the dysequilibrium syndrome and requires 82 exclusion.
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Movement of water into the brain leads to cerebral edema. According to the hypothesis known as the reverse urea effect, a rapid reduction in blood urea level lowers the plasma osmolality, thereby producing an osmotic gradient between blood and brain. Although urea is able to permeate cell membranes, this may take several hours to reach completion; accordingly, there is not enough time for urea equilibration when the blood urea level is reduced rapidly by hemodialysis. There is thus an influx of water into the cells. This results in increased intracranial pressure and cerebral edema. Alternatively or additionally, the osmotic gradient between brain and blood may not reflect simply the movement of urea; unidentified osmotically active substances (“idiogenic osmoles”) are present in the brain of 105 dialyzed uremic animals (but not dialyzed nonuremic animals) and may be responsible. It has been suggested that a decrease in cerebral intracellular pH, reflecting an 104 increased production of organic acids that are osmotically active, is important in this regard. A number of other disorders, such as uremic encephalopathy, intracranial infection or hemorrhage, cerebral infarction, hyponatremia, hypoglycemia, and medication-related encephalopathy must be excluded before the diagnosis is made with confidence. Prophylactic measures involve the gradual reduction in blood urea level by attention to the hemodialysis technique. In patients with established dialysis dysequilibrium syndrome, mild symptoms usually clear spontaneously over several hours, and symptomatic and supportive measures are all that are required; however, it may be necessary to slow or discontinue the dialysis session. Dialysis is stopped in patients with seizures or an altered level of conscious-ness and, if necessary, the plasma osmolality can be raised with either hypertonic saline or mannitol. Management is otherwise supportive, and improvement can be expected over the following day.
Wernicke's Encephalopathy Thiamine is a water-soluble vitamin that passes through dialysis membranes. However, 106,107 and no dialysis does not remove more thiamine than is normally excreted in the urine, consistent change occurs after hemodialysis in plasma levels of the B vitamins. Wernicke's encephalopathy has occurred in patients on chronic dialysis but is relatively infrequent. It has been related to anorexia, vomiting, a diet low in thiamine-containing foods, and intravenous alimentation without thiamine supplementation; other potential causes in uremia are infections that may stress thiamine reserves and the use of repeated infusions of glucose, 107 insulin, and bicarbonate to lower the serum potassium level. Among five patients undergoing dialysis in whom Wernicke's encephalopathy developed in the absence of alcoholism or other precipitating factors and was diagnosed at autopsy, 107 triad of ophthalmoplegia was evident in only one instance, but in other instances the full108 ophthalmoplegia, ataxia, 109 and an altered level of consciousness were encountered. Hypothermia is common. Intravenous administration of thiamine reverses the clinical deficit. Given the reversible nature of the disorder, it is important to consider it in all patients on hemodialysis who exhibit at least one of its classic features; dialysis dysequilibrium syndrome, dialysis dementia, and uremic encephalopathy have each been diagnosed 108 erroneously in patients who were subsequently found to have Wernicke's encephalopathy. Indeed, in one series of 30 consecutive patients on regular hemodialysis or peritoneal dialysis who were admitted with an alteration in mental status, 10 had an unexplained encephalopathy after initial evaluation and were eventually 110 found to have thiamine deficiency; nine responded to thiamine supplementation and one died.
Dialysis Dementia Clinical Aspects There has been a decline in the incidence of this progressive encephalopathy, which may occur in patients undergoing long-term dialysis. The first symptom is often a stammering hesitancy of speech that eventually progresses to speech arrest, dysarthria, and expressive aphasia. The speech disorder is intensified during and immediately after dialysis and initially may occur only at these times. Other manifestations such as tremor, myoclonus, asterixis, seizures, and dementia become apparent as the disorder advances, and hallucinations and delusional thinking round out the clinical picture. Focal neurological abnormalities are found occasionally. Symptoms initially occur immediately after dialysis and then clear, but eventually they fail to resolve and the patient becomes increasingly demented.111The EEG shows abnormal bursts of high-voltage slow activity and spikes anteriorly. The CSF is normal. The differential diagnosis includes other causes of dementia, but metabolic encephalopathy and 82 structural lesions such as subdural hematoma, normal-pressure hydrocephalus, hypertensive encephalopathy, multi-infarct dementia, and stroke require exclusion.
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Pathogenesis A clustering of cases in areas with aluminum-contaminated water was noted originally, and water-purification measures have led to a substantial reduction in the incidence of the disorder. The disorder results from accumulation of aluminum in the brain and is now rarely 112 encountered because 113 of elimination of aluminum in the dialysate. Phosphate retention occurs in renal failure, leading eventually to hyperparathyroidism, and reduction of the serum phosphate concentration with phosphate binders is therefore important. The substitution of phosphate binders such as calcium carbonate and calcium acetate, and of nonmineral-containing phosphate binders, for oral aluminum-containing114phosphate binders has also been important in reducing the aluminum content in the brain. Although parathyroid hormone increases aluminum absorption from the gut, parathyroidectomy has not 4 affected the course of dialysis dementia. The toxicity of aluminum may involve disruption of the inositol phosphate system and115 calcium regulation, facilitation of oxidative injury, and disruption of basic cell processes. Postmortem immunochemical analysis of frontal cortex of 15 dialysis patients treated with aluminum showed changes in tau protein processing in the brain resembling those seen in Alzheimer's disease, although none had signs of dialysis 116 dementia. Treatment Diazepam is initially helpful in treating the myoclonus and seizures and in improving speech, but it is less effective later. Increased dialysis time and renal transplantation have not altered 4 the natural history. In untreated patients, death usually occurs within a year of the onset of symptoms. The chelator deferoxamine can remove excess aluminum and thereby reverse acute encephalopathy, as well as the osteomalacia and anemia that may also be associated with aluminum overload. However, its introduction was associated with visual and auditory toxicity and with increased neurological and other side effects from acute aluminum toxicity (presumably because of the rapid mobilization of stored aluminum) in occasional patients; some patients developed a rapidly progressive and fatal systemic or rhinocerebral 117 mucormycosis. Experimental studies in animals suggest that deferoxamine enhances the pathogenicity 118,119 of the responsible organism and reduces the effectiveness of treatment with Nevertheless it is the mainstay of treatment for established dialysis amphotericin. dementia. Several protocols for the administration of deferoxamine have been proposed, and the 120 National Kidney Foundation has published guidelines. A baseline serum aluminum level is determined: normal levels are 6 ± 3 μg/L, but excess aluminum deposition is unlikely when values are less than 20 μg/L. If baseline levels are increased, a low-dose deferoxamine test is performed by administering 5 mg/kg 1 hour before the end of dialysis if aluminum overload (serum aluminum levels of 60 to 200 μg/L) is present or toxicity is suspected clinically. Deferoxamine can be given to symptomatic patients in a single dose of 1 to 6 g (30 to 40 mg/kg) once weekly in the last hour of a dialysis session; however, to avoid the risk of deferoxamine neurotoxicity, it is not given to patients with very high plasma aluminum levels (exceeding 120 μg/L) until the level is first lowered by withdrawal of aluminum exposure. When serum aluminum levels exceed 200 μg/L, daily hemodialysis using high-flux membranes and a low dialysate aluminum concentration, and withdrawal of all aluminum-containing oral agents, is necessary; a low-dose deferoxamine test (5 mg/kg) is given after 4 to 6 weeks of such treatment to determine the timing of further treatment. 120 The length of treatment required is uncertain, but it Further details are given elsewhere. 4 Many cases of dialysis dementia have been stabilized or may need to be for many months. 121,122 The need for treatment is unclear in patients with an improved by deferoxamine. asymptomatic increase in aluminum levels. COMPLICATIONS OF TRANSPLANTATION Various neurological complications are caused by the neurotoxicity of immunosuppressive agents, as discussed in Chapter 46. When acute rejection encephalopathy occurs, patients experience headache, confusion, and seizures, sometimes accompanied by papilledema, increased CSF pressure, and computed tomography (CT) evidence of diffuse cerebral edema. The EEG is diffusely slowed and may show focal features. Treatment of the rejection episode leads to improvement.
Femoral and Related Neuropathy Femoral neuropathy is a common complication of renal transplantation in the iliac fossa, 123 occurring ipsilateral to the transplant surgery with an incidence on the order of 2 percent.
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Nerve compression typically occurs intraoperatively, for example, with prolonged use of retractors. When compression leads to neurapraxia, recovery is likely to be rapid and complete, as in most patients; severe compression or nerve ischemia leads to axonal loss, 124 delayed recovery, and residual deficits. In patients undergoing renal transplantation involving either the internal or external iliac artery, sensory disturbances may be the sole manifestation and are not necessarily confined to the territory of the femoral nerve: in one series of 20 patients in which the internal iliac artery was used, for example, sensory 125 complaints were in the anterior thigh in 15, lateral thigh in 3, and anterolateral thigh in 2, suggestive of involvement of the lateral femoral cutaneous nerve.
Tumors The rates of malignancies among 35,765 first-time recipients of deceased or living donor kidney transplantations between 1995 and 2001 was examined by Kasiske and associates 126 using Medicare billing claims. For common tumors, such as of the colon, lung, prostate, stomach, esophagus, pancreas, ovary, and breast, cancer rates were approximately twice as high after kidney transplantation than in the general population. Melanoma, leukemia, hepatobiliary tumors, cervical, and vulvovaginal tumors were each increased about 5-fold; testicular and bladder cancers about 3-fold; kidney cancer (typically of the native kidney) 15-fold; and Kaposi's sarcoma, non-Hodgkin's lymphomas, and nonmelanoma skin cancers more than 20-fold. Thus, cancer screening and attention to prophylactic measures are important after kidney transplantation. The development of such neoplasms may involve the nervous system directly by metastatic spread, may lead to a paraneoplastic syndrome, or may produce secondary neurological abnormalities as a consequence of treatment (Chapters 27 and 28).
Brain Tumors Non-Hodgkin's lymphoma constitutes more than 90 percent of lymphomas in transplant 127 recipients. Most of these lymphomas are of the B-cell type and follow B-cell proliferation related to infection with Epstein–Barr virus in patients who are chronically immunosuppressed. Extranodal involvement after organ transplantation occurs commonly 128 and—in almost one quarter of patients —involves the CNS (Fig. 18-4). Involvement of the transplanted kidney may also occur, causing renal failure. The degree of 129 immunosuppression, age (greater in those younger than 25 years), time since transplant (greater in the first year), race (greater in Caucasians than in African Americans), and130 serological status regarding Epstein–Barr virus infection influence the risk of disease. The development of mental status changes or new neurological abnormalities should raise concern about the possibility of CNS involvement. Imaging studies (CT or MRI) of the head, CSF analysis for Epstein–Barr virus and cytological examination for malignant cells, and brain biopsy generally lead to the diagnosis. In one autopsy study of 10 patients, all had tumor infiltration in CNS regions that were normal on imaging studies, indicating that MRI may 131 underestimate the extent of the tumor. Bulky disease is seen as a contrast-enhancing lesion because of disruption of the blood–brain barrier, but microscopic tumor infiltration may 131 cause T2 hyperintensity or show no imaging abnormality.
FIGURE 18-4 A, Axial post-contrast T1-weighted MRI demonstrates an
enhancing mass located in the right lateral recess of the fourth ventricle. B, Coronal post-contrast T1-weighted image shows an enhancing subependymal
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mass involving the left lateral ventricle. The findings are most consistent with CSF spread of lymphoma. (Courtesy of William P. Dillon, MD, University of California, San Francisco.) The use of corticosteroids, which alter the imaging and histopathological findings, may confound interpretation. Since the advent of modern chemotherapeutic regimens, the natural history seems to have changed in that systemic metastases outside the CNS are uncommon, 127 and some patients may survive for much longer than in the past. 132
The incidence of primary CNS lymphoma is increasing, especially among the elderly. The tumor is located supratentorially in more than two thirds of instances and typically is periventricular and involves deep subcortical structures such as the basal ganglia and corpus callosum (Fig. 18-5); subependymal spread is common. Abnormal lymphocytes may disseminate along CSF pathways and subsequently spread throughout the CNS. The eye may also be involved. As with systemic lymphoma, the high incidence of primary CNS lymphoma in transplant recipients receiving immunosuppressants indicates involvement of the immune system in its pathogenesis and, again, the Epstein–Barr virus may have a role. Presenting symptoms depend on the location of the lesion. Supratentorial lesions may cause headaches (sometimes from increased intracranial pressure or meningeal involvement), personality changes, cognitive abnormalities, blurred vision, or focal motor or other deficits. Convulsions are relatively uncommon. Cranial neuropathies, ataxic syndromes, and other signs of brainstem involvement occur with infratentorial intracranial involvement. Meningeal involvement is relatively common as the disease advances and leads to multifocal disease with cranial and spinal neuropathies, headaches, signs of meningeal irritation, and, occasionally, hydrocephalus. In rare instances of primary spinal involvement, there is weakness, sensory loss, and sphincter dysfunction, depending on the site and extent of the lesion. Spinal lesions are more often intramedullary, whereas in patients with systemic lymphoma diffuse leptomeningeal involvement or extradural nodules are more likely. Recurrence is usually within the brain, but systemic dissemination occurs occasionally and tends to involve extranodal organs, such as kidneys or skin.
FIGURE 18-5 MRI of a patient with biopsy-proven primary lymphoma of the
brain. Axial post-contrast T1-weighted MRI shows an enhancing mass involving the splenium of the corpus callosum as well as two satellite nodules
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within the white matter of the left posterior frontal lobe. (Courtesy of William P. Dillon, MD, University of California, San Francisco.) The CSF usually shows nonspecific findings, but cytology may reveal malignant cells, especially if repeated examinations are performed. The absence of such cells does not exclude the diagnosis. CT usually shows a mass much larger than that suggested by the clinical findings; there are usually isodense, hyperdense, and hypodense areas, with contrast enhancement. On T2-weighted MRI, the mass may appear isointense to hypointense, enhances homogeneously with contrast administration, may be associated with extensive133 edema, is often in contact with the subarachnoid space, and typically is without necrosis. 134 One third of these tumors are multifocal. Tumors may be missed by one imaging modality and detected by the other; both may miss meningeal disease. MRI or myelography detects spinal disease. A definitive diagnosis is made by histopathological examination after stereotactic biopsy. Extensive resection of the tumor is usually not attempted given its deep location and often multifocal nature and because of the high surgical morbidity. Treatment is by radiation therapy plus corticosteroids. The role of chemotherapy is under reexamination, and various regimens have been advocated. Meningeal lymphoma is treated by intrathecal methotrexate. Most patients die within a few weeks to months after diagnosis.
Central Nervous System Infections In renal transplant recipients, the risk of infections (and neoplasia), with135their attendant mortality and morbidity, increases with increasing immunosuppression rather than with the use of a specific immunosuppressive agent. It is important to bear this in mind when the addition of a potent immunosuppressive agent is under consideration for the treatment of acute rejection episodes. The risk of infection is also influenced by environmental exposure, by the presence of indwelling catheters that may serve as a conduit for infection, and by whether peritoneal dialysis rather than hemodialysis was utilized prior to transplantation (as the former is associated with a higher risk of infection). Other factors that bear on the issue are coexisting diseases such as diabetes that render patients more prone to infection, poor nutritional status, metabolic abnormalities such as uremia, and infection with immunomodulating viruses such as Epstein–Barr and human immunodeficiency virus. CNS infections are an important consideration in transplant recipients. When acute meningitis occurs, it is usually caused by Listeria monocytogenes, whereas subacute or chronic meningitis is commonly caused by Cryptococcus neoformans, although systemic infection with M. tuberculosis, L. monocytogenes, H. capsulatum, N. asteroides, and certain 136 other organisms may have a similar presentation. Signs of meningeal irritation may be subtle or absent in patients with meningitis as a consequence of the anti-inflammatory effects 136 of immunosuppressants. Fever, headache, and impairment of consciousness may also be due to CNS lymphoma, which must therefore be distinguished, as described earlier. The presence of unexplained fever and headache in transplant recipients mandates brain imaging by CT scan or MRI and examination of the CSF. Brain abscesses (Fig. 18-6) are well described in transplant recipients and, in most instances, the primary source of infection is the lung. CT of the chest is therefore important, especially when chest radiographs are normal or unhelpful, for diagnostic purposes in differentiating fungal brain abscess from brain tumor in transplant recipients. Aspergillus has a predilection for dissemination to the brain and accounts for most fungal brain abscesses; such fungal infections usually lead to multiple 137 brain abscesses and have a poor prognosis. Abscess may also result from L. monocytogenes, Toxoplasma gondii, or N. asteroides. With Listeria infection, abscesses are 138 also commonly multiple, with a high mortality. The clinical presentation is often with 139 neurological deficits or seizures of abrupt onset or with a worsening confusional state. The CT scan may show poorly circumscribed, low-absorption areas with minimal or no contrast 139,140 MRI shows ring-enhancing lesions with surrounding enhancement and little mass effect. edema; distinction from tumor is sometimes difficult, but diffusion-weighted imaging is helpful in this regard. The CSF may be unrevealing. Brain biopsy is sometimes the only reliable way to establish a diagnosis. Treatment is discussed in later chapters.
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FIGURE 18-6 A, Axial post-contrast T1-weighted image demonstrates a ring-enhancing mass lesion in the right frontal lobe with surrounding vasogenic edema. B, Axial T2-weighted fluid-attenuated inversion recovery (FLAIR) image demonstrates a mass surrounded by a zone of increased signal intensity consistent with vasogenic edema. The mass itself consists of several layers of abnormal signal. Within the center of the mass, a zone of lower signal is seen, surrounded by alternating zones of higher and lower signal. The capsule of the mass shows low signal and is the area that enhances with contrast material (see A). C, Axial diffusion-weighted image. The central portion of the mass shows high signal, consistent with restricted diffusion. The appearance of a ring-enhancing mass containing material with restricted diffusion is most consistent with a cerebral abscess. D, Axial diffusion-weighted image at the level of the lateral ventricles shows abnormal high-signal layering within the right lateral ventricle and in the sulci of the left hemisphere, consistent with both meningeal and intraventricular extension of abscess material. (Courtesy of William P. Dillon, MD, University of California, San Francisco.)
Progressive multifocal leukoencephalopathy (Fig. 18-7) due to JC virus infection has been described in transplant recipients and leads to cognitive changes, seizures, and focal neurological deficits. In one reported case, immunosuppression was discontinued and the patient returned to hemodialysis; his neurological symptoms and imaging abnormalities 141 gradually re-solved completely. Similar clinical deficits may relate to other viral infections, such as herpes simplex or Epstein–Barr virus, or may reflect toxicity of immunosuppressants such as cyclosporine or tacrolimus.
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FIGURE 18-7 A, An immunosuppressed patient with alteration of mental status.
Axial T2-weighted fluid-attenuated inversion recovery MRI demonstrates several discrete areas of T2 prolongation involving the right and left thalamus and the left posterior frontotemporal area. Despite the large size of the lesion, no mass effect is present. B, Axial post-contrast T1-weighted image demonstrates well-circumscribed low-intensity lesions without contrast enhancement. Subsequent brain biopsy confirmed the diagnosis of progressive multifocal leukoencephalopathy. (Courtesy of William P. Dillon, MD, University of California, San Francisco.) West Nile virus infection manifests similarly in transplant recipients as in other patients, but 142 neurological damage tends to be especially severe. HEREDITARY DISORDERS OF THE NERVOUS SYSYEM AND KIDNEYS Various uncommon inherited disorders affect both the kidneys and the nervous system, meriting brief discussion here.
Fabry's Disease Fabry's disease is an X-linked lysosomal storage disease resulting from deficiency of ceramide trihexosidase (αgalactosidase), which catalyzes the hydrolytic cleavage of the terminal galactose from143 globotriaosylceramide. It relates to mutations of the α-galactosidase A (GLA) gene at Xq22. It leads to a small-fiber neuropathy, with severe neuropathic or limb pain and dysautonomic symptoms, accompanied by evidence of other organ involvement from glycosphingolipid accumulation, including in the kidneys. Renal involvement leads to polyuria and polydipsia; progressive renal failure typically develops in adulthood. Kidney function is worse in patients with undetectable α-galactosidase activity compared to those with some residual activity. Cerebrovascular involvement is associated with transient ischemic attacks and strokes: the vertebrobasilar circulation was symptomatic in 67 percent of hemizygotes and 60 percent of the heterozygotes in one meta-analysis, and elongated, ectatic, tortuous vertebral and basilar arteries were the most common angiographic and 144 pathological findings. The MRI may show white matter lesions in affected males and in female carriers. A fatal outcome is common in middle life from uremia or cerebrovascular disease Treatment of neuropathic pain with gabapentin, carbamazepine, or amitriptyline may be helpful. Nonsteroidal anti-inflammatory agents are usually ineffective, and narcotics are best avoided. Treatment with recombinant α-Gal A may provide symptomatic benefit but is 145 not curative.
von Hippel–Lindau Disease In autosomal-dominantly inherited von Hippel–Lindau disease, the responsible gene maps to chromosome 3p25 and is a tumor suppressor gene. Renal cysts and cancers occur in patients with CNS and retinal hemangioblastomas (often bilateral), and sometimes with pancreatic cysts and pheochromocytoma. The CNS hemangioblastomas commonly involve the cerebellar hemispheres and may be asymptomatic; spine and brainstem lesions are also
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well described (Fig. 18-8). A variety of visual complications may occur, mandating the need for regular ophthalmological screening. Monitoring for the development of renal lesions by CT scan and ultrasound, and for CNS lesions by gadolinium-enhanced MRI of the entire neuraxis, also is important. Treatment is surgical or by radiation therapy.
FIGURE 18-8 Sagittal post-contrast T1-weighted image through the cervical
spinal cord and lower cerebellum demonstrating several intensely enhancing pial-based hemangioblastomas (arrows) associated with nonenhancing cysts. (Courtesy of William P. Dillon, MD, University of California, San Francisco.)
Polycystic Kidney Disease At least two different genetic loci for autosomal-dominant polycystic kidney disease have been identified. The renal manifestations of this disorder includehypertension, urinary tract infection, polyuria, hematuria, nephrolithiasis, pain in the flank, and progressive renal failure. Hypertension also may occur in relation to the kidney disease. Intracranial arterial aneurysms, sometimes multiple and unrelated to the occurrence of hypertension, are associated, and rupture may lead to subarachnoid or intracerebral hemorrhage. In a retrospective study of 77 patients from 64 families with ruptured (71 instances) or unruptured (6) aneurysms, mean age at the time of rupture was 39.5 years (range, 15 to 69 years), renal function was normal in half of the patients, and 11 percent were on renal replacement therapy. The ruptured aneurysm was usually located on the middle cerebral artery; in 31 percent of the patients, additional intact aneurysms were found. On long-term follow-up, 27 (38%) were left with severe disability. Five patients bled from another aneurysm 2 days to 14 146 years after initial rupture. Treatment of ruptured aneurysms is as for aneurysmal subarachnoid hemorrhage occurring for other reasons, involving emergency CT scanning, four-vessel angiography, and surgery or endovascular treatment. Screening by MR angiography or high-resolution CT angiography at periodic intervals for the presence of aneurysms is probably worthwhile, at least in high-risk patients, such as those with previous aneurysmal rupture or a positive family history of an intracerebral bleed, but no clear
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guidelines exist for the frequency with which this should be undertaken. The value of widespread screening for intracranial aneurysms in patients with polycystic kidneys has otherwise been questioned because most intracranial aneurysms detected by presymptomatic screening in this population are small, and follow-up studies do not suggest an increased risk for growth and rupture, compared to intracranial aneurysms in the general 147 population. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 19 Neurological Manifestations of Electrolyte Disturbances JACK E. RIGGS •
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SODIUM Hyponatremia Subarachnoid Hemorrhage and Unselected Intracranial Disease Central Pontine Myelinolysis (Osmotic Myelinolysis) Hypernatremia POTASSIUM Hypokalemia Hyperkalemia CALCIUM Hypercalcemia Hypocalcemia MAGNESIUM Hypomagnesemia Hypermagnesemia
Electrolyte disturbances are common in clinical practice and are associated with a1variety of characteristic central or peripheral (including muscle) neurological manifestations. Since electrolyte disturbances are typically secondary processes, effective management requires identification and treatment of the primary disorder in addition to correction of the electrolyte abnormality. The neurological consequences of electrolyte disorders are usually functional rather than structural. Consequently, the neurological manifestations of electrolyte disturbances are usually reversible, particularly if corrected and effectively managed at an early stage. The neurological manifestations of abnormalities of serum sodium, potassium, calcium, and magnesium are reviewed in this chapter. SODIUM Extracellular fluid volume is directly dependent on total body sodium, the principal osmotic component of that fluid compartment. Consequently, most patients with hyponatremia are hypo-osmolar, and those with hypernatremia are hyperosmolar. The symptomatic neurological manifestations of serum sodium abnormalities typically involve the central, rather than the peripheral, nervous system and reflect, respectively, hypo-osmolarity in hyponatremia and hyperosmolarity in hypernatremia. Because of the brain's ability to adapt to changes in serum osmolarity, the propensity of hyponatremia or hypernatremia to produce
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neurological symptoms generally depends on the rapidity with which the sodium disturbance 1 develops.
Hyponatremia Hyponatremia with normal osmolarity (pseudohyponatremia) occurs, although relatively infrequently, in the setting of hyperlipidemia or hyperproteinemia. Hyponatremia with hyperosmolarity usually occurs in the setting of hyperglycemia. Hyponatremia is most often associated with hypo-osmolarity and is classified into three categories, depending on whether the extracellular fluid volume is decreased, normal, or increased. Hypo-osmolar hyponatremia with hypovolemia results from excessive renal sodium loss (e.g., from diuretic usage, or in association with mineralocorticoid deficiency, salt-losing nephropathy, and osmotic diuresis) or extrarenal sodium loss (e.g., by vomiting, diarrhea, and third-space losses). Hypo-osmolar hyponatremia with normovolemia (no edema) results from conditions such as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), glucocorticoid deficiency, hypothyroidism, and stress, or in response to various drugs, including carbamazepine and many psychotropic agents. Hypo-osmolar hyponatremia with excess extracellular fluid (edema) occurs in conditions such as cirrhosis, cardiac failure, nephrotic syndrome, and acute or chronic renal failure. The separation of hypo-osmolar hyponatremia into these three categories based on the extracellular fluid volume status has therapeutic implications. In normovolemic and hypervolemic hypo-osmolar hyponatremia, the fundamental principle of therapy is water restriction, whereas in hypovolemic hypo-osmolar hyponatremia the basis of therapy is replacement of water and sodium (generally with 1–3 isotonic saline). Among hospitalized patients, the incidence of hyponatremia is about 1.0 percent and 4,5 increases the risk of death 7 to 60 times that of hospitalized patients without hyponatremia. However, the increased mortality associated with hyponatremia may reflect the seriousness 1 of underlying disorders rather than the hyponatremia per se. Neurological symptoms related to hyponatremia are seen much more frequently in patients 1–3 with acute, rather than chronic, hyponatremia. For example, a serum sodium concentration of 130 mEq/L may produce neurological symptoms if it developed rapidly, whereas a serum sodium concentration of 115 mEq/L may be asymptomatic if it developed slowly. An alteration in mental status is the most common neurological manifestation of hyponatremia and ranges from mild confusion to coma. The encephalopathy is associated with nonspecific generalized slowing on the electroencephalogram (EEG). The occurrence of convulsions in the setting of acute hyponatremia (typically with a serum sodium concentration less than 115 mEq/L) is ominous and portends a mortality rate exceeding 50 percent. The occurrence of seizures in patients with acute hyponatremia represents a medical emergency and necessitates rapid, but only partial, correction of the serum sodium concentration. Control of hyponatremic seizures can obtained by the judicious use of 3 percent saline (4 to 6 ml/kg) in an attempt to 6 raise the serum sodium concentration by small 3 to 5 mEq/L increments. Occasionally, focal neurological signs and symptoms are seen in the setting of hyponatremia and include hemiparesis, monoparesis, ataxia, nystagmus, tremor, rigidity, aphasia, and unilateral 1 corticospinal tract signs. These focal abnormalities often represent an aggravation of an underlying structural lesion and remit with resolution of the hyponatremia. Although occasional muscle twitches and fasciculations may be seen in acute hyponatremia, muscle 7 symptoms other than cramps are not common. The central nervous system (CNS) manifestations of acute hyponatremia are related to cerebral edema, but understanding is incomplete regarding the factors that mitigate hyponatremic osmotic brain swelling and 8–11 reduction in the brain's intracellular organic osmolytes. The use or restriction of fluids may have profound effects on the eventual outcome of patients with hyponatremia and acute neurological disease. Subarachnoid Hemorrhage and Unselected Intracranial Disease Hyponatremia frequently develops in patients with subarachnoid hemorrhage due to ruptured saccular aneurysms and is often attributed to SIADH. Clinicians manage SIADH by instituting some degree of fluid restriction. This measure may not be entirely unwarranted, since some patients with subarachnoid hemorrhage may do better when fluid is restricted early in the 12 course of the disorder. In a retrospective study of 134 consecutive patients from the Netherlands, 44 patients developed hyponatremia between the second and tenth days 13 following subarachnoid hemorrhage. Hyponatremia was defined as a serum sodium level below 135 mEq/L on at least two consecutive days. Of the 44 hyponatremic patients, 25 fulfilled the laboratory criteria for SIADH. Cerebral infarction, defined as a focal neurological
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deficit with or without computed tomography (CT) confirmation or deterioration in the level of consciousness with CT confirmation of ischemic changes, occurred in 46 of the 134 patients. Of the cerebral infarcts, 27 occurred in the 44 hyponatremic patients (61.4%), but only 19 occurred in the 90 normonatremic patients (21.1%). Of the 44 hyponatremic patients, 26 were fluid-restricted; of these, 21 developed infarcts (80.8%). Of the 18 hyponatremic patients who were not fluid-restricted, only 6 developed infarcts (33.3%). Of the 25 patients who fulfilled the laboratory criteria for SIADH, 17 were fluid-restricted; of these, 15 developed infarcts (88.2%). Thus, fluid restriction in hyponatremia following subarachnoid hemorrhage, particularly in those thought to have SIADH, appears to markedly increase the risk of cerebral infarction. Some insight has been gained into the basis for this risk in fluid restriction in patients with subarachnoid hemorrhage who develop hyponatremia. In a study of 12 unselected neurosurgical patients with intracranial disease who fulfilled the laboratory criteria for SIADH, 14 absence of hypovolemia 10 had significant decreases in their total blood volume. Because 15 is considered one of the criteria for making the diagnosis of SIADH, the finding of decreased blood volume in patients with hyponatremia and intracranial disease suggests that these patients did not have SIADH. In a prospective study of 21 patients with aneurysmal subarachnoid hemorrhage, plasma volume decreased by more than 10 percent in 11 of the 16 patients. Serum sodium decreased in 9 of the 21 patients. Plasma volume decreased by more than 10 percent in 6 of 9 patients with hyponatremia, and a similar decrease occurred in 5 of 12 patients with normal serum sodium. Eight of the 9 patients with hyponatremia had a negative sodium balance, whereas only 4 of the 12 patients with normal serum sodium had a negative sodium balance. Finally, 10 of the 12 patients with a negative sodium balance had a decrease in plasma volume of more than 10 percent. Hyponatremia following from 16,17 as aneurysmal subarachnoid18hemorrhage appears to be related to cerebral salt-wasting, was originally suggested, and is not due to SIADH. Fluid restriction instituted to correct hyponatremia attributed to presumed SIADH in patients with subarachnoid hemorrhage appears to exacerbate an already volume-depleted state and subjects the patient to an even greater risk of ischemic cerebral damage from vasospasm. Central Pontine Myelinolysis (Osmotic Myelinolysis) Central pontine myelinolysis was recognized as a distinct clinical entity in 1959 in four cases 19 occurring on a background of alcoholism and malnutrition. Its pathological features are symmetric noninflammatory demyelination in the base of the pons with relative sparing of neurons and axons. The classic clinical presentation includes pseudobulbar palsy and spastic quadriparesis. Following the original description, many additional cases were reported in rapid succession, suggesting that central pontine myelinolysis is not a rare disorder. Many cases of central pontine myelinolysis were not associated with alcoholism or malnutrition. It may, for example, occur in subjects with extensive burns (p. 1032). By 1964, the relatively 20 was noted, and this was validated by high frequency of small subclinical lesions (Fig. 19-1) 21,22 subsequent reports.
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FIGURE 19-1 Macrosection of the pons demonstrating central demyelination, an
incidental finding of subclinical central pontine myelinolysis in a patient with a history of electrolyte abnormalities and diuretic use (Luxol fast blue). In 1963, Aleu and Terry suggested that central pontine myelinolysis must be related to 23 recently introduced factors. Also in 1963, the initial suggestion that an24“electrolyte imbalance may be a contributing factor” in its development was made. The observation was subsequently made that acute cases of central pontine myelinolysis (i.e., acute quadriparesis) developed only in hospitalized patients who were being hydrated. From an analysis of 12 acute cases in 1980, Leslie and associates noted that there had been a recent rapid rise of 25 serum sodium in each patient. They suggested that central pontine myelinolysis “is an iatrogenic disorder that in most25cases is caused by a rapid correction of serum sodium rather than by hyponatremia per se.” The factors that led to the appearance of the disorder during the 1950s were the introduction of diuretics, the liberal use of intravenous fluids, and the 1 ability to rapidly measure serum electrolytes. Prospective magnetic resonance imaging (MRI) studies have now demonstrated the development of characteristic pontine lesions in patients treated for hyponatremia in whom the rate of correction of the hyponatremia was 26 rapid. Of undefined significance, in one retrospective study of published reports of patients with central pontine myelinolysis in whom initial values of sodium and potassium were given, 27 all patients who developed thedisorder were also hypokalemic initially. Patients who develop hyponatremia following liver transplantation may be particularly vulnerable to central 28 pontine myelinolysis if their hyponatremia is rapidly corrected. Sterns and colleagues, in a review of their experience, noted neurological complications in 29 eight patients whose serum sodium had been corrected by more than 12 mEq/L per day. Conversely, patients with hyponatremia that was corrected more slowly made uncomplicated recoveries. In a review of the literature, these authors found 80 patients with severe hyponatremia (serum sodium <106 mEq/L). Of the 80 patients, enough detail was reported in 51 to determine a maximal rate of correction of serum sodium. In 39 of 51 patients who were
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corrected rapidly (>12 mEq/L per day), 22 (58%) had some type of neurological complication. Of these 22 patients 14 (64%) were suspected of having central pontine myelinolysis. Of the 13 patients who were corrected slowly (<12 mEq/L per day), none experienced a neurological complication. Concerning the optimal rate of correction of hyponatremia, even previous advocates of rapid correction have agreed 30 that large increases in serum sodium concentration can result in cerebral demyelination. Because chronic hyponatremia is less likely to produce neurological symptoms, and rapid correction of chronic hyponatremia is more likely to produce 31 a judicious approach to the correction of chronic neurological injury in experimental models, 1,2,32 There is no justification for using hypertonic saline to treat hyponatremia is urged. asymptomatic hyponatremia, or to rapidly correct hyponatremia to levels above 120 to 125 mEq/L in significantly symptomatic hyponatremia. Animal models of central pontine myelinolysis have been developed in the dog and the 33–35 In both animals, demyelination follows rapid correction of sustained, rat. vasopressin-induced hyponatremia with hypertonic saline. The label osmotic myelinolysis has been suggested in preference to central pontine myelinolysis because of the well-recognized 36 occurrence of extrapontine myelinolysis. The myelinolysis occurs in areas of the brain characterized by an extensive admixture and apposition of gray and white matter. Although the pathogenesis of osmotic myelinolysis remains undefined, the topography of oligodendrocytes may play a role. Oligodendrocytes in these vulnerable areas are predominantly located within adjacent gray matter rather than within the white matter bundles matter, oligodendrocytes (Fig. 19-2). Because gray matter is much more vascular than white 36 in this location may be more vulnerable to serum osmotic shifts.
FIGURE 19-2 Gray and white matter bundles in normal human pons. Note that
most oligodendrocytes (small cells with dark nuclei) are within gray matter rather than within the white matter bundles (hematoxylin and eosin, 640×). The rapid re-induction of hyponatremia has been associated with a reduction in neurological 37 38 signs and symptoms suggestive of osmotic myelinolysis in both rats and humans who had experienced a rapid increase in serum sodium during the treatment of chronic hyponatremia. Corticosteroids, myoinositol, immunoglobulin, and thyrotrophin-releasing hormone have been suggested 39–41 as possible treatments of or preventive measures for the osmotic demyelination syndrome.
Hypernatremia Symptoms due to hypernatremia are usually referable1,42 to the CNS and most often are seen Hypernatremia is most frequently with serum sodium concentrations above 160 mEq/L. encountered in the very young or the very old. In infants, fluid loss due to gastroenteritis is a
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common cause. In the elderly, dehydration resulting from an inability to obtain water because of debilitation is the most frequent cause. Diabetes insipidus rarely presents with severe hypernatremia unless the patient is also denied access to water. Structural lesions (e.g., gliomas and metastatic tumors) in the hypothalamic thirst center are an uncommon cause of hypernatremia in patients with neurological disease. Alteration of mental status is a frequent manifestation of hypernatremia and ranges from 1,42,43 Pathological studies suggest that osmotic forces present during the lethargy to coma. development of hypernatremia, particularly when acute, may produce shrinkage of brain parenchyma. This may result in parenchymal hemorrhages or tearing of bridging veins, producing subdural hematomas or subarachnoid hemorrhage. An initial mortality rate of 20 percent and an incidence of permanent brain44damage of more than 33 percent have been the setting of noted in children with severe hypernatremia. Seizures frequently occur in 45 hypernatremia and paradoxically may be more frequent during rehydration. The seizures may be related to either the focal hemorrhages that occur during the development of hypernatremia or the cerebral edema that may develop during the rehydration phase of treatment. Rigidity, tremor, myoclonus, asterixis, and chorea have been associated with 46 thalamic signal changes on MRI have been associated with hypernatremia. Transient 47 of hypernatremia are much less severe hypernatremia. Neuromuscular manifestations 7,48–50 Episodic muscle weakness may occur in frequent. Rhabdomyolysis has been reported. 51 patients with essential hypernatremia. POTASSIUM In contrast to sodium, the neurological manifestations 1of potassium disturbance, whether hypokalemia or hyperkalemia, rarely involve the CNS. About 98 percent of total body potassium is located intracellularly; 60 percent of intracellular potassium is within muscle. This distribution may, in part, account for the predominance of muscle symptoms associated with either hypokalemia or hyperkalemia.
Hypokalemia Hypokalemia is the most frequent electrolyte disorder encountered in clinical practice and is produced by a variety of mechanisms, including inadequate potassium intake or excessive renal or gastrointestinal potassium loss. Symptoms of hypokalemia are typically 1,52,53 Serum potassium concentrations of 3.0 to 3.5 mEq/L may be associated with muscular. mild muscle weakness, myalgia, and ease of fatigue. Serum potassium concentrations of 2.5 to 3.0 mEq/L are associated with the development of clinically significant muscle weakness, particularly of the proximal limb muscles, and with muscle cramps. The cranial musculature is characteristically spared in hypokalemia-induced muscle weakness. When the serum potassium level falls below 2.5 mEq/L, and usually below 2.0 mEq/L, structural muscle 54–56 damage, including rhabdomyolysis and myoglobinuria, may occur. Tetany occurs in some patients with hypokalemia, particularly when associated with 1 alkalosis. Hypokalemia may mask the tetany of hypocalcemia. Paradoxically, tetany may occur during the treatment of hypokalemia in patients who are also hypocalcemic. 1
Cerebral symptoms in hypokalemia are distinctly unusual. Reference to symptoms such as lethargy, apathy, drowsiness, confusion, irritability, delirium, and coma in hypokalemia are 57 rare and suggest that an associated acid-base disturbance may have been responsible for these encephalopathic symptoms. Brain concussion has been associated with mild transient 58 hypokalemia.
Hyperkalemia The cardiac toxicity of hyperkalemia essentially precludes the appearance of significant 1 as neurological manifestations. Most patients develop serious cardiac abnormalities, such 59,60 ventricular fibrillation or asystole, before the appearance of neurological symptoms. Chronic potassium homeostasis is dependent on renal mechanisms. Acute potassium regulation is dependent on extrarenal hormonal mechanisms primarily involving insulin, aldosterone, and epinephrine. Clinically important etiologies of hyperkalemia include renal failure, adrenal insufficiency (Addison's disease), and acidosis with or without insulin deficiency. Cerebral symptoms due to hyperkalemia must be uncommon, since they do not 61 occur in hyperkalemic periodic paralysis. The cerebral symptoms (nervousness and lethargy) that frequently occur in Addison's disease are more likely related to the associated hyponatremia or acidosis. The most frequent neurological manifestation of hyperkalemia is 1,7 the development of muscle weakness, which occurs most often in the setting of chronic
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adrenal insufficiency. However, profound muscle weakness with hyperkalemia is rarely 62 reported. CALCIUM Plasma calcium stabilizes excitable membranes in muscle and nervous tissue. Disorders of 1 calcium would therefore be expected to produce neurological manifestations. The coordinated interactions of parathyroid hormone, cholecalciferol, and probably calcitonin regulate intestinal calcium absorption, renal calcium reabsorption, and bone resorption to 63 control closely plasma calcium concentration.
Hypercalcemia Malignant neoplasms and hyperparathyroidism account for 70 to 80 percent of cases of 64 hypercalcemia. The neoplasms most frequently associated with hypercalcemia are breast cancer, lung cancer, and multiple myeloma. Although most instances of hypercalcemia in the setting of malignancy are due to osteolytic skeletal metastases, some carcinomas, particularly of the lung, are associated with elevated levels of parathyroid hormone. Single adenomas of the parathyroid gland account for 75 percent of cases of primary hyperparathyroidism. Because patients with malignant neoplasms often have several mechanisms of neurological injury, the incidence of neurological manifestations in hyperparathyroidism (which is at least 40%) represents a reasonable incidence of 65 neurological manifestations in hypercalcemia. Alterations in mental status are common in hypercalcemia (particularly with serum calcium concentrations of more than 14 mg/dl) and generally consist of progressive lethargy, confusion, and ultimately coma. These reversible symptoms are directly related to the degree of hypercalcemia and require immediate therapy. Headache, elevated1,64,65 cerebrospinal fluid protein, and, rarely, convulsions also occur in patients Hyperparathyroidism has also rarely been associated with severe with hypercalcemia. CNS dysfunction, including ataxia, internuclear ophthalmoplegia, corticospinal tract 66 Hypercalcemia has been associated with apnea in dysfunction, dysarthria, and dysphagia. 67 68 children and with the posterior reversible encephalopathy syndrome. Hypercalcemia produces reduced neuromuscular excitability and may cause muscle weakness. Easy fatigability and muscle weakness is more common in 1,69 than in other hypercalcemic conditions. The clinical features of hyperparathyroidism hyperparathyroid myopathy include proximal, though seldom disabling, muscle weakness and wasting with preserved or even brisk reflexes and mild nonspecific myopathic features on 1,69 The pathogenesis of hyperparathyroid electromyogram (EMG) and muscle biopsy. myopathy remains undefined, although hypercalcemia, vitamin D1 deficiency, chronic phosphate deficiency, or neuropathic influences may play a role. Hyperparathyroid myopathy is similar to the vitamin D deficiency myopathy that can occur with uremia, phenytoin therapy, and osteomalacia. Carpal tunnel syndrome has occasionally been associated with 1 hyperparathyroidism.
Hypocalcemia Hypocalcemia is relatively rare except in neonates and individuals with renal failure. Severe acute hypocalcemia is most frequently encountered following thyroid or parathyroid 1,68 Hypocalcemia is also a common complication of acute pancreatitis. The surgery. neurological manifestations of hypoparathyroidism resulting from primary, secondary, or pseudohypoparathyroidism (parathyroid hormone–resistant syndromes) largely reflect hypocalcemia. The most common CNS manifestations are seizures (which may be focal or generalized) and alterations of mental function. The latter symptoms include irritability, anxiety, agitation, confusion, delirium, delusions, hallucinations, psychosis, depression, mental dullness, mental retardation, and dementia. Chorea and parkinsonism are seen with increased frequency in patients with chronic hypocalcemia. Although a causal relationship has not been established, the regularity with which calcification of the basal ganglia is seen in 70–72 seems more than coincidental. Some patients patients with chronic hypoparathyroidism with chronic hypoparathyroidism may have quite extensive brain calcification and associated 73 neurological symptoms. Less frequent CNS manifestations of hypoparathyroidism are pseudotumor cerebri and myelopathy due to vertebral lamina overgrowth. Tetany is the most frequently recognized symptom of hypocalcemia referable to the 1,64 Tetany originates in the peripheral nerve axon and is due to peripheral nervous system. spontaneous, irregular, repetitive nerve action potentials. When the ionized calcium concentration reaches a low enough level, the peripheral nerve membrane may spontaneously discharge at the normal resting membrane potential. Latent tetany may be
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unmasked clinically by hyperventilation or ischemia (Trousseau's test). The first symptom of tetany is tingling that initially occurs periorally and distally in the limbs and then spreads proximally. This is followed by a feeling of muscle spasm that has an initial distribution similar to that of the early sensory complaints and becomes increasingly severe as it spreads proximally. Finally, muscles may go into tonic spasms, commencing distally (carpopedal 74 spasm). Laryngeal stridor may ultimately develop. Opisthotonos may occur if spasms involve the trunk. Elevated serum creatine kinase levels have been reported in patients with hypoparathyroidism, although clinical and morphological evidence of myopathy has been scant. Hypoparathyroidism has been associated with the Kearns–Sayre syndrome and muscle phosphorylase deficiency (perhaps related to failure of calcium to activate phosphorylase kinase). MAGNESIUM Less than 2 percent of total body magnesium is located within the extracellular fluid compartment. Although magnesium has an intracellular-extracellular distribution similar to that of potassium, most of the intracellular magnesium is bound and not exchangeable with the extracellular fluid. In fact, intracellular free magnesium is rigidly regulated despite wide variations in extracellular magnesium concentrations. The teleological basis for this situation relates to the critical role of magnesium in intracellular metabolism. Magnesium is required for activation of a wide range of intracellular enzymes. Additionally, extracellular magnesium exerts significant effects on synaptic transmission in the central and peripheral nervous 1,75 system.
Hypomagnesemia Because magnesium is predominantly an intracellular electrolyte, the finding1,75 of Important hypomagnesemia does not always accurately reflect magnesium depletion. mechanisms of hypomagnesemia and magnesium depletion include decreased intake (as in starvation), decreased intestinal absorption (as in malabsorption syndromes such as nontropical sprue), and increased renal loss (as with diuretic usage, chronic alcoholism, diabetic acidosis, and renal tubular acidosis). The neurological manifestations of hypomagnesemia are essentially hyperirritability with agitation, confusion, convulsions, tremor, myoclonus, hyperreflexia, Chvostek's sign, and 76,77 These signs and symptoms typically occur with serum magnesium concentrations tetany. of less than 0.8 mEq/L.78Occasionally, even focal neurological signs may be seen in patients with hypomagnesemia. When convulsions occur in patients with hypomagnesemia, parenteral administration of magnesium salts is required. However, renal function should be assessed before parenteral magnesium is administered. When magnesium is given by slow intravenous bolus, calcium gluconate should be available to counteract transient hypermagnesemia, which may cause apnea as a result of respiratory muscle paralysis. The neurological manifestations of hypomagnesemia are similar to those of hypocalcemia, which 79 is not surprising, since hypocalcemia often accompanies hypomagnesemia. The hypocalcemia or hypomagnesemia is produced or exaggerated in some instances by a hypomagnesemia-induced decrease in parathyroid hormone or end-organ resistance to the 80 action of parathyroid hormone. This leads to an important therapeutic point, namely, that it is necessary to evaluate magnesium in a hypocalcemic patient who fails to respond to calcium supplementation. Conversely, in magnesium-deficient patients who are normocalcemic but have symptoms suggestive of hypocalcemia, calcium may still be responsible for the symptoms, since normocalcemic hypomagnesemic patients may have decreased serum ionized calcium concentrations. Hypomagnesemia develops frequently with cisplatin use. In that81setting, only patients who are also hypocalcemic develop tetany with carpopedal spasm. Muscle weakness develops in some patients with 1hypomagnesemia, dogs and rats, a although coexistent hypokalemia or hypophosphatemia may contribute. In 82,83 Chronic84 necrotizing myopathy has been induced by chronic magnesium depletion. hypomagnesemia has been associated with a cardioskeletal mitochondrial myopathy.
Hypermagnesemia Symptomatic hypermagnesemia is uncommon in clinical practice and is typically encountered in the setting of excessive magnesium intake in conjunction with impaired renal function.85 Unsuspected symptomatic hypermagnesemia may occur more frequently in the elderly. In contrast to hypomagnesemia, the neurological manifestations of hypermagnesemia are characterized by nervous system depression. Loss of deep tendon reflexes is an early sign of
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hypermagnesemia and occurs at serum magnesium concentrations of 5 to 6 mEq/L. At serum magnesium concentrations of 8 to 10 mEq/L, CNS depression is said 86 to occur, with lethargy and confusion being the most common neurological manifestations. However, in human subjects in whom the serum magnesium concentration was increased to 15 mEq/L, 87 no CNS depression occurred, although there was slowing of the electroencephalogram. The predominant neurological manifestation of severe hypermagnesemia is muscular 1 paralysis. Untreated, this weakness, which can involve respiratory muscles, may result in respiratory insufficiency with subsequent hypoxia, hypercapnia, coma, and ultimately death. The flaccid muscle weakness of hypermagnesemia is due to a blockade of neuromuscular 88 transmission.
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 20 Thyroid Disease and the Nervous System CHRISTINE E. BURNESS • PAMELA J. SHAW •
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NEUROLOGICAL COMPLICATIONS OF HYPOTHYROIDISM Neurological Features of Congenital Hypothyroidism Encephalopathy, Coma, and Seizures Mental Changes Disorders of Sleep Cerebellar Ataxia Cranial Nerve Disorders Hypothyroid Myopathy Clinical Features Investigations Pathology Pathophysiology Treatment and Prognosis Peripheral Neuropathy Entrapment Neuropathy Diffuse Peripheral Neuropathy Miscellaneous Associated Conditions Myasthenia Gravis Neuroleptic Malignant Syndrome Giant Cell Arteritis and Polymyalgia Rheumatica NEUROLOGICAL COMPLICATIONS OF HYPERTHYROIDISM AND GRAVES' DISEASE Hyperthyroid Myopathy Clinical Features Physiological and Biochemical Changes in Skeletal Muscle Pathology Treatment and Prognosis Periodic Paralysis Clinical Features Physiology and Pathophysiology Treatment Myasthenia Gravis Peripheral Neuropathy Corticospinal Tract Dysfunction Movement Disorders
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Chorea Tremor Other Movement Disorders Thyroid-Associated Ophthalmopathy Clinical Features Prognosis Pathogenesis Treatment Encephalopathy Seizures Mental and Psychiatric Disorders Miscellaneous Associated Conditions Headache Stroke NEUROLOGICAL COMPLICATIONS OF EUTHYROID HASHIMOTO'S THYROIDITIS Hashimoto's Encephalopathy MISCELLANEOUS ASSOCIATIONS BETWEEN NEUROLOGICAL DISORDERS AND THYROID DYSFUNCTION Endocrine Dysfunction in Long-Term Survivors of Primary Brain Tumors Multiple Sclerosis and Thyroid Disease Subclinical Hypothyroidism in Children on Anticonvulsant Therapy Recurrent Laryngeal Nerve Palsy
Disorders of the thyroid gland are common and are frequently accompanied by neurological complications. One study of unselected general medical, geriatric, and psychiatric inpatients 1 showed that 1 to 2 percent of patients had some form of thyroid disease. It is important for the neurologist to be aware of the common and also the more unusual neurological complications of thyroid disease, both because they may be the presenting feature of the thyroid disorder and because they are usually readily corrected with appropriate treatment. The neurological complications of thyroid disease may result from hormonal alterations or from immune-mediated mechanisms. Alteration in the levels of circulating thyroid hormones may produce a new neurological disorder, exacerbate a preexisting neurological problem, or increase the severity of a subclinical problem. Local compression of adjacent structures from enlargement of the thyroid gland can occasionally result in neurological complications. Other mechanisms resulting in central nervous system (CNS) complications include pituitary enlargement resulting from thyroid failure, the development of cerebral metastases from thyroid carcinoma, and the onset of benign intracranial hypertension in patients with hypothyroidism. It is apparent that the cellular and molecular mechanisms for the neurological complications of thyroid disease are still incompletely understood. NEUROLOGICAL COMPLICATIONS OF HYPOTHYROIDISM Hypothyroidism is 2a common disorder, affecting approximately 0.9 to 14.4 percent of the elderly population. It is therefore important that neurologists and general physicians be familiar with the full range of neurological complications that can occur in this condition. The commonest causes of hypothyroidism are autoimmune destruction of the thyroid, thyroidectomy, and radioiodine ablation of the gland. Fewer than 10 percent of cases of hypothyroidism are secondary to pituitary or hypothalamic disease. Neurological complications are commonly found in patients with hypothyroidism, and all levels of the nervous system may be involved. The neurological complications of hypothyroidism may be grouped into the following categories: (1) congenital hypothyroidism or cretinism; (2) encephalopathy that may result in coma or a seizure disorder; (3) psychological changes; (4) sleep disorders; (5) cerebellar ataxia; (6) cranial nerve lesions; (7) myopathy; (8) peripheral nerve disorders; and (9) miscellaneous conditions.
Neurological Features of Congenital Hypothyroidism Congenital hypothyroidism is the commonest treatable cause of mental retardation with a 3 prevalence of 1 in 3000. It occurs secondary to dysgenesis of the thyroid gland or to severe maternal deficiency of dietary iodine. A study of endemic foci of cretinism in western China and central Java revealed the following neurological complications as common features of the condition: mental 4retardation, pyramidal signs in a proximal distribution, and extrapyramidal signs. Many patients had a characteristic gait, reflecting dysfunction of both the pyramidal and the extrapyramidal motor systems, in combination with laxity and deformity of the joints. Other clinical features commonly seen in patients with cretinism included strabismus, deafness, ataxia, and primitive reflexes. Imaging of the brain showed basal
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ganglia calcification in one third of patients. The characteristic motor abnormality in adult patients with cretinism has been emphasized, with rigidity and spasticity affecting the trunk 5 and proximal limb-girdle musculature, and relative sparing of the distal extremities. Magnetic resonance imaging (MRI) of the head in three patients showed abnormalities in the globus pallidus and substantia nigra, with increased signal on T1-weighted images and hypointensity on T2-weighted images. There was only modest cerebral atrophy, and the cerebral cortical gyral pattern and thickness appeared normal. The corpus callosum and cerebral white matter were well myelinated, and there was no significant atrophy of the brainstem and cerebellum. The authors suggested that the main insult to the CNS may involve processes such as dendritic arborization and synaptogenesis, which are not evident on MRI and which occur relatively late in development. Studies have shown that, in the developing brain, thyroid 6 hormone has important effects on the regulation of neurofilament 7gene expression and on the expression of several genes encoding mitochondrial proteins. Hypothyroidism increases AMP hydrolysis in the hippocampal and cortical synaptosomes of rats and influences synaptic 8 function control throughout cortical development. Thyroid hormone also regulates the timing of appearance and regional distribution of laminin, an extracellular matrix protein that provides key guidance signals to migrating neurons within the CNS. It has been suggested that disruption in the expression of laminin may play a role in the derangement of neuronal 9 migration observed in the brain of patients with congenital hypothyroidism. Recently a novel syndrome has been described in which mutations in the monocarboxylate transporter 8 (MCT8) gene, located on the X chromosome, causes abnormal levels of three circulating iodothyronines, as well as neurological abnormalities including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotatory 10 nystagmus, and impaired gaze and hearing in affected males. Heterozygous females had a milder thyroid phenotype and no neurological abnormalities. MCT8 appears to have an important physiological role as a thyroid hormone transporter. Another group of patients has been described in which congenital hypothyroidism was poorly responsive to conventional treatment, and the endocrine problem was accompanied by choreoathetosis, muscular hypotonia, and pulmonary problems. This clinical picture matched the phenotype of mice targeted for deletion of the transcription factor gene Nkx2-1 and genetic screening identified 11 heterozygous loss of function mutations in the human NKX2-1 gene in affected individuals. The Nkx2-1 transcription factor appears to have an important role in the development and function of the thyroid, basal ganglia, and lung.
Encephalopathy, Coma, and Seizures Slowness, impairment of attention and concentration, somnolence, and lethargy are common symptoms in hypothyroidism. Occasionally, a life-threatening encephalopathy known as myxedema coma develops in patients with chronic, untreated hypothyroidism. Myxedema coma may result from a variety of precipitating factors causing decompensation of the 12 physiological adaptations to the hypothyroid state. A high index of suspicion is required to diagnose myxedema coma, particularly in the elderly population, in whom features of hypothyroidism may be difficult to distinguish from the effects of aging. In the compensated hypothyroid state, physiological adaptations include a shift of the vascular pool13away from the periphery to the central core, to sustain normal body temperature. In chronic hypothyroidism, these adaptations tend to produce a degree of diastolic hypertension, as well as a decrease in blood volume of up to 20 percent. Many other organ systems and metabolic pathways are profoundly altered by chronic deficiency of thyroid hormone. Alterations in myocardial biochemistry produce impairment of cardiac contractility, the ventilatory response to hypercapnia is abnormal, hyponatremia may result from a reduction in free water clearance, and there may be a degree of suppression of bone marrow function resulting in normochromic normocytic anemia and an impaired white blood cell response to infection. Reduction in insulin clearance and decreased gluconeogenesis may produce a tendency to hypoglycemia, and patients are predisposed to toxic effects owing to reduced plasma clearance of all drugs. The corticosteroid response to stress is likely to be 13 impaired, even when basal serum cortisol levels are normal. The majority of patients who develop myxedema coma are elderly. In more than 50 percent of cases, coma develops after the patient has been admitted to the hospital, often following a history of gradual deterioration. Common precipitating factors include infection, trauma, stroke,13hypothermia, hypoglycemia, carbon dioxide narcosis, and administration of certain drugs. Three key clinical features are universally present in myxedema coma: depression of level of consciousness, defective temperature control, and a precipitating illness or event. The body
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temperature is subnormal in the majority of cases, but relative hypothermia may also be present, in which the patient has an inappropriately normal temperature in the presence of sepsis. Most patients have clinical signs in keeping with long-standing hypothyroidism. Seizures occur in approximately 20 percent of cases. Focal neurological signs are not usually observed unless there has been a concomitant cerebrovascular event. The pathophysiology of myxedema coma is not fully understood but is likely to be multifactorial. Contributory factors may include derangement of blood gas levels, 14 hyponatremia, hypopituitarism, hypotension, sepsis, and seizure activity. The results of laboratory investigations in patients with myxedema coma are often abnormal 12 but seldom show diagnostic abnormalities. In critically ill patients, it may be difficult to distinguish between severe hypothyroidism and the euthyroid-sick syndrome, and it may be necessary to measure levels of free circulating thyroid hormone. The electrocardiogram (ECG) typically shows sinus bradycardia, with low voltage and prolongation of the QT interval. Chest radiography may reveal a pleural effusion or enlargement of the cardiac silhouette due to pericardial effusion. The patient may be mildly anemic, usually with normochromic normocytic indices. Hyponatremia may be present, and the serum cholesterol level may be elevated. The serum creatine kinase and lactate dehydrogenase levels are often raised and may be present in a pattern suggestive of myocardial damage. Arterial blood gases may be abnormal, with carbon dioxide retention or hypoxia. Lumbar puncture may reveal a high cerebrospinal fluid (CSF) opening pressure, and the CSF protein level is often raised. The electroencephalogram (EEG) is likely to be abnormal in patients with myxedema coma. Initially, there is a decrease in the frequency of the alpha rhythm, a reduction of photically evoked responses, and an overall decrease in the amplitude and slowing of the dominant rhythm, often with low-range theta activity. An EEG pattern of triphasic waves has also been described in some individuals. The key to the successful treatment of myxedema coma is the early recognition of the condition and the rapid institution of appropriate therapeutic measures, usually in an intensive care unit setting, based on an understanding of the underlying pathophysiological 12–14 Hypothyroid coma has a high mortality rate, and treatment should not be processes. delayed by waiting for the arrival of confirmatory laboratory data. Besides the use of intravenous thyroxine, broad-spectrum antibiotics to cover the possibility of an underlying infection and coverage with stress doses of hydrocortisone are indicated in the initial stages of treatment until specific laboratory results become available. It should be noted that the patient may not mount an appropriate leukocyte response or fever even in the presence of severe infection. The main principles of management of myxedema coma include correction of electrolyte and blood sugar abnormalities, passive rewarming, treatment of associated infections, control of seizures, respiratory and circulatory support, administration of stress doses of glucocorticoids, and thyroid hormone replacement. Intravenous thyroxine 14 (200 to 500 μg as the initial dose, followed by 50 to 100 μg daily) has been recommended. Some experts suggest that concomitant therapy with oral tri-iodothyronine may be useful. A study from Japan examined factors associated with mortality in 87 cases of myxedema coma 15 reported in the literature. Greater age, cardiac complications, and high-dose thyroid hormone replacement (thyroxine, ≥500 μg/day, or triiodothyronine, ≥75 μg/day) were significantly associated with a fatal outcome within 4 weeks of the development of myxedema 16 coma. Reduced conscious level on admission to hospital also predicts a poor outcome. Neuropathological studies of patients with myxedema coma have been few and have usually shown only the presence of cerebral edema with or without diffuse neuronal changes. There is a relatively high incidence of seizures in hypothyroidism. Approximately 20 percent of patients with untreated hypothyroidism will develop seizures or syncopal episodes. Drop attacks (sudden repeated falls without warning symptoms and without loss17of consciousness) also occur as a complication of hypothyroidism that resolves with therapy. Patients with 18 severe hypothyroidism may present with status epilepticus. Clinicians should be alert to the possibility of underlying hypothyroidism when the recovery time of the patient following a seizure is unusually prolonged.
Mental Changes Severe psychiatric features are relatively common in untreated hypothyroidism. In one series of 100 hypothyroid patients, 5 percent developed psychosis and 29 percent had significant 19 memory impairment. The colorful term myxedema madness has been used to describe the florid mental state changes that can occur in hypothyroid patients, including irritability, paranoia, hallucinations, delirium, and psychosis. This problem resolves rapidly following the 20 administration of thyroid hormone replacement therapy.
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Several investigators have reported an increase in the incidence of hypothyroidism in various groups of patients with major psychiatric illnesses.21An association between hypothyroidism and bipolar affective disorder has been proposed. Even higher rates of hypothyroidism have been reported22in a subgroup of manic-depressive patients who have the “rapid cycling” form of the illness. Up to 50 percent of these patients have positive antithyroid antibody titers. Clinical and subclinical hypothyroidism in 23 depression and bipolar disorder may adversely affect or delay the response to treatment. It is also noteworthy that many patients with depression, even when viewed as chemically euthyroid, have alterations in their thyroid function, including slight elevation of the serum thyroxine, blunting of the thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) stimulation,25detectable 24 titers of antithyroid antibodies, and loss of the normal nocturnal rise in TSH. These changes are generally reversed following alleviation of the depression. Hypothyroidism is an important cause of dementia, most commonly manifesting as psychomotor slowing, memory impairment, visuoperceptual problems, and reduced 26 constructional dexterity. In one study, reversible cerebral hypoperfusion, determined by single-photon emission computed tomography (SPECT) brain imaging, was reported in a27 patient with hypothyroid dementia caused by excessive treatment of a hyperthyroid state. Both the mental changes and the SPECT abnormalities reversed following return of the patient to euthyroidism. Adverse effects of hypothyroidism on cerebral phosphate metabolism 31 have28also been shown using P nuclear magnetic resonance spectroscopy of the frontal lobe. More subtle neuropsychological abnormalities have also been documented in patients with hypothyroidism. In one study, a comparison was made between 54 nondemented hypothyroid 29 patients and 30 control subjects. The hypothyroid patients showed significantly lower scores on the Mini-Mental Status Test and in 5 of 14 neuropsychological tests compared with control subjects. The aspects of cognitive function most affected in the hypothyroid patients included learning; word fluency; visuospatial abilities; and some aspects of attention, visual scanning, and motor speed. Treatment of the hypothyroidism resulted in demonstrable improvement in three of the most sensitive neuropsychological measures employed. A review of the literature suggests 30 that thyroid replacement does not always lead to complete of resolution of cognitive impairment. Lai and co-workers investigated the recovery potential 31 CNS complications of hypothyroidism by serially measuring central conduction in adult rats. Before thyroxine treatment, there was a consistent prolongation of central conduction. After thyroid hormone replacement, the central conduction usually returned to normal if the hypothyroid state was not more than 5 months in duration. However, when the hypothyroidism was present for 7 months or more, there was incomplete recovery of the central conduction disorder. The authors suggested on the basis of these findings that there may be a “therapeutic window” for reversal of the CNS effects of hypothyroidism. Evidence has recently been presented that mood and neuropsychological function may improve more satisfactorily in patients with hypothyroidism treated with a combination of thyroxine plus 32 tri-iodothyronine, rather than thyroxine alone.
Disorders of Sleep 33
Both obstructive and central sleep apnea may occur in patients with hypothyroidism. Both depression of the respiratory center and an altered bellows action of the thorax have been described. In one study of 20 patients with untreated hypothyroidism who underwent an overnight sleep study with polysomnography, there was a 25 percent incidence of obstructive 33 sleep apnea. Factors contributing to the development of obstructive sleep apnea are likely to include narrowing of the upper airway due to deposition of mucopolysaccharides and extravasation of protein into the tissues of the tongue and nasopharynx, as well as hypertrophy of the genioglossus. The decreased hypoxic ventilatory drive in hypothyroidism 34 can be corrected with thyroid hormone replacement therapy. The mechanism of central 35 apnea in hypothyroidism may involve a disturbance in serotonin (5-HT) neurotransmission. Thyroid hormone replacement therapy usually results in improvement in ventilatory drive over a rapid time period. Improvement in airway dimensions may require a longer period of 33 euthyroidism (up to 12 months), and only at this stage will nocturnal snoring decrease. In some patients, sleep apnea does not satisfactorily remit with adequate treatment of the hypothyroidism, and additional measures such as nasal continuous positive airway pressure (CPAP) may be required.
Cerebellar Ataxia
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Reference to unsteadiness of gait may be found in the earliest clinical descriptions of hypothyroidism. Several studies have indicated that approximately 5 to 10 percent of patients 36–39 A detailed assessment of 24 with hypothyroidism develop significant ataxia of gait. patients with hypothyroidism and ataxia revealed that all 24 patients complained of impairment of balance, a tendency to fall, or incoordination of the upper or lower limbs, and in 38 many cases these were the presenting clinical features. Gait ataxia, with a broad base to the gait, impaired heel-toe walking, and unsteadiness on turning were present in many cases. A total of 10 of the 24 patients had definite incoordination of the limbs, and one had a cerebellar dysarthria, but no patients had nystagmus. The cause of the hypothyroidism varied in these patients. Rapid and complete or almost complete resolution of the cerebellar features occurred following achievement of euthyroidism. The pathophysiological basis of cerebellar dysfunction in hypothyroidism remains unknown. The rapid resolution of the ataxia with thyroid replacement therapy in most patients suggests that the problem may be caused by a reversible metabolic factor. Some authors have suggested that ataxia becomes apparent when the metabolic defect of hypothyroidism is 40 superimposed on a preexisting subclinical deficit in the cerebellar system. Selim and Drachman reported six patients with Hashimoto's autoimmune thyroiditis who developed clinical ataxia while euthyroid (three were on oral replacement with l-thyroxine); all had mid-line cerebellar atrophy on MRI, and alternate causes were excluded. The authors postulated an immune-mediated mechanism of cerebellar degeneration in a subset of patients and suggested that immune suppression may be a therapeutic option for this 41 group. Pathological reports are few, and the patients described have had coexisting medical problems, including cerebrovascular disease and alcoholism. Depletion of Purkinje cells has been reported in one patient, the presence of novel “myxedema bodies” in the brain of another,42and cerebellar atrophy most markedly affecting the anterosuperior vermis in a third patient. Developmental studies in young rats have shown that hypothyroidism interferes with the development of Purkinje cell dendrites and the normal inward migration of cells from the external granular layer. However, cerebellar ataxia has not been documented as a prominent feature of cretinism or hypothyroidism of childhood.
Cranial Nerve Disorders Primary thyroid failure may be associated with pituitary enlargement resulting from hyperplasia due to lack of negative feedback from circulating thyroid hormones. In one recent study, pituitary enlargement on MRI was found in 37 of 53 (70%) patients with primary 43 hypothyroidism. Subtle visual field defects resulting from pituitary enlargement with pressure on the40optic chiasm have been reported in a majority of patients with primary hypothyroidism. Visual evoked potentials may be abnormal in hypothyroid patients, but severe visual field loss and blindness are rare. Thyroid hormone replacement therapy may 44 lead to a reduction in pituitary size and an improvement in vision. 45This sequence of events may result in the development of an empty sella in some patients. The association between pituitary gland enlargement and primary hypothyroidism should be kept in mind when pituitary hyperplasia is detected on neuroimaging, so that unnecessary invasive interventions are avoided. Some patients with hypothyroidism develop benign intracranial hypertension resulting in 46 headache and papilledema after the initiation of thyroxine replacement therapy. An atypical facial pain syndrome may also occur. Hearing impairment and tinnitus commonly occur in patients with hypothyroidism. Studies 47 using pure-tone audiometry have reported hearing loss in as many as 85 percent of cases. Brainstem auditory evoked potentials in hypothyroidism are “slow and low” compared with 47 those in normal subjects. Multiple sites of pathology can cause hearing loss in this group of patients. Abnormalities in the middle ear, and at cochlear and retrocochlear sites, have 47 been described, and the hearing loss may have conductive, neural, and central components. Hearing loss may improve when the hypothyroidism is treated. Dysphonia in patients with hypothyroidism appears to arise from local myxedematous changes in the larynx rather than from cranial nerve dysfunction.
Hypothyroid Myopathy Clinical Features
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Muscle involvement is common in clinical and subclinical hypothyroidism, with more than 60 48 percent of patients reported to have an elevated serum creatine kinase (CK) level. The level of increase correlates with the severity of hypothyroidism and corrects when thyroid function normalizes with treatment. Symptomatic muscle disease is less common. Clinical49evidence of hypothyroid myopathy occurs in 30 to 80 percent of patients with hypothyroidism. Myopathy 50 may develop within 2 to 6 weeks following the development of biochemical hypothyroidism. Kliachko and Prikhozhan studied clinical features in 81 patients 4 weeks after stopping 51 thyroxine treatment. Half of the patients developed muscle pain, 82 percent had a prolongation of the ankle reflexes, 14 percent had objective muscle weakness, 6 percent had muscle cramps, and 6 percent had myopathic features on electromyography (EMG). The major clinical features of hypothyroid myopathy include weakness, cramps, aching or painful muscles, sluggish movements and reflexes, and myoedema (ridging of the muscle on percussion), and there may be a discernible increase in muscle bulk. The degree of weakness37is usually relatively mild and tends to involve the pelvic- and shoulder-girdle muscles. The gait tends to be slow and clumsy. This slowness of movement is particularly apparent on initiation of walking and in cold temperature conditions. Occasionally, patients have been described with more severe myopathic symptoms, including the development of 52 or respiratory insufficiency requiring long-term ventilatory rhabdomyolysis and renal failure 53 several patients with hypothyroidism who support. Martinez and colleagues described 54 developed diaphragmatic dysfunction. The severity varied from mild weakness predominantly affecting exercise tolerance to very severe compromise mimicking diaphragmatic paralysis. Muscle 55 pain, particularly during and after exertion, is a prominent feature of hypothyroid myopathy, and it has been stressed that hypothyroidism should be considered in patients presenting with musculoskeletal pains of uncertain cause. Patients 19 may experience painful muscle cramps in a widespread distribution. Muscle pain, stiffness, cramps, and delayed relaxation in adult hypothyroidism is sometimes referred to as Hoffmann's syndrome. Kocher–Debré–Sémélaigne syndrome is the unusual association of muscle hypertrophy with childhood hypothyroidism. The patient may have all the clinical features of cretinism, including retarded intellectual, physical, osseous, and dental development, constipation, bradycardia, characteristic facies, large tongue, coarse hair and skin, hypotonia, and prolonged tendon reflexes, with the added feature of generalized muscular hypertrophy so that the child has an athletic, almost herculean appearance. A delay in the relaxation of muscle (pseudomyotonia) is commonly observed during assessment of the tendon reflexes in hypothyroid patients. All phases of the tendon reflex are delayed, although only slowing of the relaxation phase is clinically apparent. Pseudomyotonia differs from true myotonia in that there is reduction in the speed of both the contraction and relaxation phases, and this slowness is not increased after rest or relieved by repeated muscle contractions. EMG does not show the characteristic “dive-bomber” effect seen in true myotonia. In the pseudomyotonia of hypothyroidism, there is a continuous burst of action potentials that begin abruptly, fire at a constant rate, and then terminate abruptly. Percussion of the muscle commonly causes a slow prolonged mounding effect, called myoedema. This event, unlike myotonia, is electrically silent. It has been postulated that myoedema results from derangement of intracellular calcium homeostasis. Occasionally, hypothyroidism may precipitate56true myotonia in patients who have underlying myotonic dystrophy or myotonia congenita. The muscles in hypothyroid myopathy often have a feeling of increased volume and firmness. This muscle enlargement is most obvious in the tongue, arms, and legs. There have been occasional reports of patients with hypothyroidism developing an acute 57 58 compartment syndrome or having acute muscle edema. The differential diagnosis of hypothyroid myopathy includes 59 other causes of painful stiff muscles, such as polymyalgia rheumatica and polymyositis. Attention has been directed to the frequency of neuromuscular symptoms in patients with subclinical hypothyroidism, and the suggestion has been made that such patients should be treated early not only to prevent 60 progression to frank hypothyroidism but also to improve their neuromuscular dysfunction. Investigations The majority of patients with hypothyroidism have an elevated serum CK level, even when the myopathic features are not clinically obvious. In symptomatic patients, the serum CK level 48,61 Neurophysiological assessment may rise to more than 10 times the upper limit of normal. may show no significant abnormalities. However, in approximately 30 percent of patients with hypothyroidism, significant abnormalities are observed on EMG; these may include abnormal insertional activity or hyperirritability, an increase in polyphasic motor unit potentials, and a reduction in duration and amplitude of motor unit potentials.
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Pathology In many cases of hypothyroidism, pathological changes in muscle are subtle and rather nonspecific. Light microscopy may demonstrate a variety of changes, which are usually insufficient to account for the weakness, including atrophy, necrosis or hypertrophy of fibers, increased numbers of nuclei, glycogen accumulation, and the increase in interstitial 62 connective tissue within the muscle. There may be vacuolation in many large fibers, and crescents of material containing acid mucopolysaccharides may be found beneath the sarcolemmal sheath. Selective atrophy of type II fibers, with hypertrophy of type I fibers has been reported. The neuromuscular junction appears normal, but loss of the myelin sheath of intramuscular nerves may be observed. The following abnormalities have been observed on electron microscopy of muscle in hypothyroid myopathy: mitochondrial swelling and inclusions, fragmentation and disorganization of myofibrils, accumulation of glycogen or lipoid granules, 62 T-tubule proliferation, dilatation of the sarcoplasmic reticulum, and autophagic vacuoles. These changes resolve with thyroxine replacement therapy. Pathophysiology Thyroid hormone is intimately linked to carbohydrate metabolism and mitochondrial function and, possibly, to the function of the sarcoplasmic reticulum and intrinsic contractile properties 63 of muscle. However, the structural–functional relationships are still incompletely understood, although it is assumed that the underlying biochemical changes in hypothyroidism lead to prolongation of the contraction and relaxation phases of muscle activity. The microscopic abnormalities observed suggest that reversible excessive glycogen storage and mitochondrial dysfunction63are likely to be important factors in the pathogenesis of muscle dysfunction in hypothyroidism. Magnetic resonance spectroscopy of hypothyroid muscle shows a low intracellular pH in resting muscle and delayed glycogen breakdown in 64 exercising muscle. A reduction in activity of the glycolytic enzyme α-glucosidase (acid maltase) has been found in hypothyroid myopathy and may contribute to glycogen 65 accumulation. Mitochondrial oxidative capacity is reduced in hypothyroidism, and there is decreased responsiveness of β-adrenergic receptors to the enzymes of glycogen 66 metabolism. It has been suggested that low levels of the mitochondrial transcription factor A (h-mtTFA), a proposed target of thyroid hormone action, occurs in the muscle in hypothyroid myopathy and that abnormal h-mtTFA turnover may be implicated in mitochondrial alterations 67 in this condition. The decreased responsiveness to adrenergic stimulation and alterations in muscle carbohydrate metabolism may contribute to the impaired ischemic lactate production, weakness, exertional pain, and fatigue occurring in hypothyroidism. Hypothyroidism is associated with alterations in myosin, lactate dehydrogenase, and myofibrillar ATPase activity from a68pattern characteristic of fast-twitch fibers to one resembling the pattern of slow-twitch fibers. These changes may underlie the observed slowing of muscle contraction and relaxation. Both protein synthesis and breakdown are reduced in hypothyroidism, with a + + -K pump activity in skeletal muscle is also balance resulting in net protein catabolism. Na 69 reduced in the hypothyroid state. Treatment and Prognosis The only effective therapy for hypothyroid myopathy is to restore the patient to the euthyroid state. Most patients respond to thyroxine therapy with complete clinical and biochemical recovery. However, some patients require prolonged therapy with thyroxine before they fully recover from their muscle disorder. Khaleeli and Edwards reported that 7 of 19 patients with hypothyroid myopathy still had myopathic weakness 12 months after euthyroidism had been 70 patient with restored. One report described persistence of weakness and wasting in a 71 hypothyroid myopathy 6 years after restoration of thyroid function to normal. Serum CK levels correct rapidly with thyroxine replacement therapy, even before the TSH level has 62 returned to normal. Some patients may develop increased muscle pain and weakness after starting thyroxine replacement, and the short-term addition of corticosteroid therapy may be helpful if this problem arises.
Peripheral Neuropathy Hypothyroidism may be complicated by the development of entrapment mononeuropathies or a more diffuse peripheral neuropathy. Entrapment Neuropathy Evidence of entrapment neuropathy is found in around 35 percent of patients with
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hypothyroidism. The most common mononeuropathy is carpal tunnel syndrome. Compression of the median nerve results from deposition of acid mucopolysaccharides in the nerve and surrounding tissues. Surgical decompression for the median nerve entrapment is not usually required in patients with underlying hypothyroidism, as symptoms gradually 73 resolve once euthyroidism is achieved. Diffuse Peripheral Neuropathy The symptoms of peripheral neuropathy in patients with hypothyroidism may be masked by more intrusive symptoms. Perhaps for this reason, the reported incidence of peripheral 19,74 In a study neuropathy in hypothyroidism has varied widely, ranging from 9 to 60 percent. of 39 consecutive patients with hypothyroidism, Beghi and colleagues found subjective sensory symptoms in 64 percent of cases, objective clinical findings supporting a diagnosis of polyneuropathy in 33 percent, and neurophysiological evidence of polyneuropathy in 72 75 percent. Guieu and co-workers studied the nociceptive threshold in 12 hypothyroid patients and found values significantly higher than those of normal control subjects; values returned to 76 normal 6 weeks after starting thyroxine replacement therapy. The peripheral neuropathy of hypothyroidism is usually relatively mild and predominantly sensory. The knee and ankle reflexes are reduced, distal vibration and joint position sense 77 are mildly impaired, and the patient may describe episodes of lancinating pain. The severity of the neuropathy appears to correlate with the duration of the disease rather than the 78 severity of the biochemical disorder. 72,77
Neurophysiological abnormalities have been documented in several reports. Pollard and associates reported absent sensory action potentials and significant slowing in motor nerve conduction velocities in patients with hypothyroidism, suggesting the presence of segmental 77 demyelination. Other studies have shown decreased amplitudes of motor and sensory action potentials and mild slowing of sensory and motor conduction velocities consistent with 78 axonal pathology. The pathological changes described in hypothyroid neuropathy include segmental demyelination, axonal degeneration, and deposition of mucopolysaccharides in the endoneurial interstitium and perineurial sheath. Opinions have varied as to whether axonal degeneration or demyelination is the primary pathological process. Dyck and Lambert reported the presence of segmental demyelination and remyelination, accumulation of glycogen granules, increased numbers of mitochondria, and Schwann cell cytoplasmic79 lamellar bodies and lipid droplets in nerve biopsies from patients with hypothyroidism. They postulated that the primary pathological process is demyelination due to metabolic derangement of the Schwann cell. They also reported an increase in glycogen content and degenerative changes within axons. However, other authors have77–80 concluded that axonal In these studies, degeneration and regeneration is the major pathological process. electron microscopy demonstrated shrinkage of axons, disruption of neurotubules and neurofilaments, and active axonal breakdown. Segmental demyelination, when present, was considered likely to be secondary to primary axonal degeneration. Experimental work, demonstrating a reduction in the velocity of slow axonal transport in the sciatic nerve of 81 hypothyroid rats, tends to support the concept of primary axonal pathology. Multifocal motor neuropathy associated with elevated titers of IgM antibodies against GM1 and its response to intravenous immunoglobulin therapy have been described in association 82 with Hashimoto's thyroiditis.
Miscellaneous Associated Conditions Myasthenia Gravis An association between hypothyroidism and myasthenia gravis has been reported, although this is less common than the association with hyperthyroidism. The myasthenic symptoms can appear before, with, or after the development of hypothyroidism, and the severity of the myasthenia may or may not improve following treatment of the hypothyroidism. Neuroleptic Malignant Syndrome There have been occasional reports of neuroleptic malignant syndrome developing in patients with hypothyroidism. Moore and colleagues described two patients with primary hypothyroidism who developed neuroleptic malignant syndrome while taking a neuroleptic 83 drug. They suggested that thyroid disease predisposes to the development of neuroleptic
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malignant syndrome by altering brain dopamine metabolism. Giant Cell Arteritis and Polymyalgia Rheumatica In 1977, How and co-workers described a patient in whom both 84 giant cell arteritis and hypothyroidism were present, and suggested a common cause. Subsequently, Wiseman and associates reviewed 36 elderly85patients presenting with giant cell arteritis or polymyalgia rheumatica during a 6-year period. A total of 15 of the 36 (42%) patients had hypothyroidism before or at the time of presentation or during subsequent follow-up. The authors stressed the importance of recognizing this association to prevent the musculoskeletal symptoms of hypothyroidism being misinterpreted as an exacerbation of polymyalgia rheumatica, resulting in unnecessary escalation of the dose of corticosteroid therapy. NEUROLOGICAL COMPLICATIONS OF HYPERTHYROIDISM AND GRAVES' DISEASE There are several potential underlying causes of hyperthyroidism, including (1) Graves' disease, (2) excess release of stored hormone during subacute thyroiditis or following thyroid irradiation, (3) uncontrolled hormone formation in single or multinodular goiters (Plummer's disease), (4) ingestion of excess thyroid hormone, (5) rare TSH-secreting pituitary tumors, and (6) drug-induced disease. Graves' disease is the commonest cause of thyrotoxicosis and occurs with a female-to-male preponderance of 7:1. The neurological complications of hyperthyroidism are diverse, as noted in the following discussion.
Hyperthyroid Myopathy Clinical Features Muscle weakness and wasting in patients with thyro-toxicosis was first observed by both Graves and Von Basedow in their classic descriptions of the condition. Some degree of muscle weakness probably occurs in every patient with hyperthyroidism and is generally 86 associated with fatiguability and varying degrees of muscle wasting. Men appear to develop symptomatic myopathy during the course of hyperthyroidism more commonly than women. The muscle weakness may not always be sufficiently severe for the affected individual to be aware of it. The thyroid overactivity can be relatively mild and of long duration or may be present for only a few weeks before the onset of weakness. In a carefully assessed cohort of 54 patients86with thyrotoxicosis, Ramsay reported that 82 percent had evidence of muscle weakness. The weakness was confined to the proximal muscles in 63 percent, and it involved both proximal and distal muscles in 18.5 percent of patients. In another study of 50 consecutive patients with hyperthyroidism, 6 percent reported muscle weakness as the primary problem, and an additional 28 percent had noticed significant loss87of muscle power, whereas 80 percent had demonstrable muscle weakness on examination. There is no close correlation between the severity of the thyrotoxicosis and the degree of muscle weakness. Individuals with thyrotoxic myopathy characteristically complain of difficulty with activities involving use of the shoulder- and pelvic-girdle muscles, such as climbing stairs, rising from a low chair, or performing tasks that involve raising the arms above the head. Muscle pain and stiffness are common associated symptoms, and occasionally patients report severe muscle cramps. Symptomatic weakness of the facial, laryngeal, and lingual muscles is uncommon. Dysphagia is the most common symptom of bulbar myopathy. Difficulty in swallowing may be due to esophageal dysfunction as well as bulbar muscle weakness. In one study, 17 percent of patients with chronic thyrotoxic myopathy were reported to show evidence of bulbar 88 paresis. Voice alterations such as nasality, low volume, and dysphonia may also occur. There have been occasional reports of thyrotoxic patients presenting with disabling nonmyasthenic bulbar myopathy that may be complicated by aspiration pneumonia. Exceptionally, involvement of the respiratory muscles occurs and may necessitate ventilatory support. Compression of the recurrent laryngeal nerve may occur when the thyroid gland is enlarged, resulting in vocal cord paralysis. Muscle wasting is commonly found on examination of patients with thyrotoxicosis. Havard reported 87 obvious wasting of the pectoral- or pelvic-girdle musculature in 46 percent of patients. Atrophy most often affected the deltoid, supraspinatus, and quadriceps muscles. Some patients, especially males, show gluteal muscle wasting, and in some patients winging of the scapula is noticeable. The presence of tremor may create the appearance of muscle 89 fasciculation, but this usually disappears when the limb is completely relaxed. The tendon reflexes are normal or hyperactive, with shortening of the relaxation phase.
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Some authors have described acute and chronic forms of thyrotoxic myopathy as entities with distinctive clinical features. In chronic thyrotoxic myopathy, the patient has insidiously 89 progressive weakness and wasting of muscles in addition to weight loss. Other features of thyrotoxicosis may not be obvious or may be masked—for example, if the patient is on β-blocker therapy. These features may resemble the progressive muscular atrophy (PMA) variant of motor neuron disease. The severity of the muscle weakness may be marked, but most patients retain the ability to walk. The weakness is usually generalized, although the pelvic- and shoulder-girdle muscles are most severely affected. 90
Acute thyrotoxic myopathy was first described by Laurent in 1944. It is rare, and some authors have doubted its existence, suggesting that the described cases had myasthenia gravis superimposed on the hyperthyroid state. However, there are reports of patients with an acutely developing myopathy in whom myasthenia gravis was carefully excluded. Acute thyrotoxic myopathy presents with muscle weakness progressing rapidly over a few days. The weakness may be pro-found, bulbar muscles are often affected, and the patient may develop respiratory failure. The tendon reflexes may be reduced or absent, but sphincter function is preserved. Some patients develop an associated encephalopathic state. In contrast to hypothyroid myopathy, the serum CK level in hyperthyroid myopathy is usually 91 normal or reduced, although rhabdomyolysis and elevation of the CK level may occur. EMG 87 changes are found in 90 percent of patients with thyrotoxicosis. The main abnormalities are a reduction in the mean duration of motor unit potentials and an increase in the occurrence of polyphasic potentials. Repetitive nerve stimulation may show a decrement in the size of the compound muscle action potential and post-tetanic effects suggestive of either a postsynaptic or presynaptic neuromuscular junction abnormality. The ankle reflex has been studied physiologically using the half-relaxation time. Among 70 thyrotoxic adults, 66 showed 92 a reflex response of shortened duration. The mean value for the group was 230 msec, which was significantly shorter than the mean of 322 msec for an age-related group of normal subjects. Physiological and Biochemical Changes in Skeletal Muscle Hyperthyroidism affects both the physiological and the biochemical properties of skeletal 93 muscle with a preferential effect on the slow type 1 fiber. The muscles most commonly affected in hyperthyroidism are those used during prolonged effort. The reason that the responsiveness of slow-twitch muscle to thyroid hormone is greater than that of fast-twitch muscle may relate to the greater density of cytoplasmic thyroid94hormone receptors and the greater capillary density and blood supply in slow-twitch fibers. Reported biochemical changes include increases in marker enzymes of the mitochondrial electron transport chain and citric acid cycle and increased levels of glycogen phosphorylase, hexokinase, and mitochondrial glycerol phosphate dehydrogenase. These biochemical alterations result in an elevation of aerobic carbohydrate metabolism by muscle and an increase in the basal metabolic rate. The pattern of glycogen utilization and lactate production in muscle is altered 31 and in hyperthyroidism. Using in vivo P magnetic resonance spectroscopy, Erkintalo 95 colleagues found evidence of reduced efficiency of skeletal muscle energetics. At rest, the concentration of phosphocreatine was reduced in thyrotoxic patients compared with that in control subjects. At the onset of exercise, the magnitude of glycolysis activation was significantly larger in the thyrotoxic group, and this resulted in a marked decrease in pH. The energy cost for exercise was significantly higher in thyrotoxic patients, with greater activation of both anaerobic and aerobic pathways throughout 3 minutes of exercise. Thus, a hyperthyroid muscle requires more energy to function than an equivalent normal muscle and, as a result, is potentially more fatiguable. Increased synthesis of proteolytic enzymes also occurs, and there is increased breakdown of skeletal muscle protein, which may be an important cause of the reduction in muscle mass commonly seen in patients with hyperthyroidism. Hyperthyroidism changes the characteristics of slow muscles to those resembling fast 93 muscles. The speed of muscle contraction is enhanced and its duration is reduced, resulting in a weakening and loss of endurance of muscle action. The number of fibers with “fast-type” myosin ATPase activity is increased, and there is conversion of myosin light chains from “slow” to “fast.” The hyperthyroid state also results in changes in isometric twitch contractile properties, increases the volume of the sarcoplasmic reticulum, and increases the 96 rate of calcium flux. The excitability of muscle membranes is impaired, muscle fibers are depolarized, and the action potential threshold is increased. The basic biochemical mechanism of thyrotoxic myopathy remains unknown, but several of the changes discussed previously may be contributory pathogenetic factors.
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Pathology Microscopic examination of muscle from patients with thyrotoxicosis may show no abnormality or varying degrees of fiber atrophy, fatty infiltration, and87nerve terminal damage with clubbing of the motor end-plate and swelling of terminal axons. Electron microscopy has shown mitochondrial hypertrophy, focal loss of mitochondria from muscle fibers, focal myofibrillar degeneration beginning at the Z disc, focal dilatations of the transverse tubular system, subsarcolemmal glycogen deposits, and papillary projections of the surface of muscle fibers, probably resulting from fiber atrophy. Most patients with hyperthyroid myopathy show an increase in mitochondrial size and number in muscle fibers. Paracrystalline 97 rectangular inclusions have been reported in skeletal muscle mitochondria. Treatment and Prognosis The muscle weakness and EMG changes resolve gradually as euthyroidism is achieved, although complete resolution may take several months. Some improvement in the level of 98 muscle weakness may occur following the institution of β-blocker therapy. Norrelund and associates undertook a serial study of muscle mass assessed by computed tomography99(CT) and isometric muscle strength in patients with thyrotoxicosis before and after treatment. They concluded that in thyro toxic patients muscle mass is reduced by approximately 20 percent and muscle strength by about 40 percent and that 5 to 9 months will elapse before normal muscle mass and power are restored.
Periodic Paralysis Hypokalemic periodic paralysis as a complication of hyperthyroidism is relatively common in Asian populations, but it is rare in patients from other ethnic groups. In Asian populations the 100 reported incidence is about 1.9 percent in thyrotoxic patients. Robust figures for the incidence in non-Asian populations are not available, but experience at the Mayo Clinic 101 indicated an incidence rate of 0.15 to 0.2 percent in patients from the United States. This represents less than one tenth of the incidence seen in Asian thyrotoxic patients. However, given modern population mobility, the disorder is increasingly being seen in non-Asian countries. Clinical Features Except for concomitant features of thyrotoxicosis, the clinical picture of thyrotoxic periodic paralysis is identical to that seen in familial hypokalemic periodic paralysis. Males are affected much more commonly than females. Affected individuals develop recurrent attacks of flaccid weakness, which may be asymmetric and affect the lower limbs to a greater extent than the upper, and the proximal muscles more than the distal. The attacks may be heralded 101 by prodromal symptoms of muscle aching, stiffness, or cramps. The weakness usually develops rapidly and varies in severity from mild weakness to total paralysis. The muscles most vigorously used before an attack tend to be the ones most severely affected. Bulbar, ocular, and respiratory muscles tend to be spared, although there have been occasional reports of respiratory compromise. Usually, the tendon reflexes are depressed or absent during an attack, but in some patients they remain normal. Muscle weakness usually resolves within 24 hours, but in the wake of severe attacks weakness and muscle pain may persist for several days. Patients may be able to abort impending attacks by mild exercise. Attacks may occur with or without a triggering factor. Recognized precipitants include high carbohydrate intake, strenuous physical activity followed 102 by a period of rest, trauma, cold exposure, infection, menses, and emotional stresses. A seasonal pattern of attacks has been recognized, with episodes being more common in the summer months. There is also a characteristic diurnal pattern, with attacks frequently developing during the night when the patient is in bed. Cardiac dysrhythmias occasionally accompany the paralytic attacks, and the electrocardiogram may show conduction abnormalities or changes in keeping with 102 hypokalemia. Patients with thyrotoxic periodic paralysis have attacks only when they are in the hyperthyroid 103 state, and paralytic episodes cannot be induced in patients who have become euthyroid. Periodic paralysis may occur in association with hyperthyroidism of any cause, but is most commonly seen in patients with Graves' disease. In patients with familial hypokalemic periodic paralysis, iatrogenic induction of hyperthyroidism does not appear to precipitate attacks of weakness. The cardinal biochemical abnormality during an attack of thyrotoxic periodic paralysis is
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hypokalemia resulting from an intracellular shift in potassium. Although the serum potassium decreases during the attack, it may not always decline below the normal range. The neuromuscular symptoms resolve over a period of hours as potassium moves back to the extracellular space. The most consistent ultrastructural finding in muscles from patients with thyrotoxic periodic paralysis is a proliferation and focal dilatation of the sarcoplasmic reticulum and transverse tubular system, resulting in the appearance of vacuoles. The vacuoles are characteristically seen in paralyzed muscles and are less apparent between attacks. Physiology and Pathophysiology The attacks of weakness in thyrotoxic periodic paralysis are associated with a disorder of muscle membrane excitability, as shown by reduced evoked action potential amplitude and failure of the muscles to respond to direct electrical stimulation. Hypokalemia and muscle paralysis result from a sudden intracellular shift of intracellular potassium. Increased + + activity and an enhanced insulin response are postulated to contribute Na ,K -ATPase pump 104 to the hypokalemia. Any hypothesis for the pathophysiology of thyrotoxic periodic paralysis must explain the striking male predilection, the absolute requirement for hyperthyroidism for the expression of the disorder, and the fact that attacks cannot be induced in nonsusceptible subjects even in the presence of severe thyrotoxicosis. It has been suggested that an underlying genetic defect is unmasked by the development of hyperthyroidism. The genetic changes involved in familial hypokalemic periodic105 paralysis have generally not been found in patients with thyrotoxic periodic paralysis. In familial hypokalemic periodic paralysis, mutations or polymorphisms in several ion channel subunits have been uncovered including KCNE3 and KCNE4,106 KCNE1 and KCNE2, KCNE1L, KCNJ2, KCNJ8, KCNJ11, CACNA1S, and been uncovered. Potential SCN4A. The precise cellular basis of the disorder has+ not + 107 contributory factors may include increased activity of Na ,K -ATPase, an important regulator of potassium homeostasis, although corresponding genetic abnormalities were not 108 ; found in a recent study of 99 male Chinese patients with thyrotoxic periodic paralysis 109 increased tissue responsiveness to110 β-adrenergic stimulation ; an increased insulin response to carbohydrate ingestion ; and alteration in intracellular calcium homeostasis in muscle. An association of polymorphisms of the calcium-channel α1-subunit with thyrotoxic 111 periodic paralysis has been reported. Treatment The mainstay of treatment is to render the patient euthyroid, when attacks of periodic paralysis will cease. While normalization of thyroid function is being achieved, the patient should avoid recognized precipitating factors. Recurrent attacks are not consistently prevented by prophylactic potassium administration. Propranolol may be useful in reducing 102 the frequency and severity of paralytic attacks. Acetazolamide is not of benefit in prevention and has been reported to actually increase the severity of attacks in some 112 patients. Once an attack has started, standard therapy is to administer potassium, although there have been no controlled studies to demonstrate the efficacy of this measure. Oral therapy is usually recommended, to avoid the rebound hyperkalemia resulting from intravenous potassium administration. One empirical protocol that has been recommended is the oral administration of 27 mEq of potassium every 2 hours until muscle power starts to 113 improve, and thereafter every 4 hours until strength is fully recovered.
Myasthenia Gravis A long-recognized association exists between thyroid disease and myasthenia gravis. There is no evidence that thyroid dysfunction causes myasthenia gravis, or vice versa, and the coexistence of the two conditions is likely due to an underlying genetic predisposition to autoimmune disease. Myasthenia gravis may be associated with both hyperthyroidism and hypothyroidism. Hyperthyroidism occurs in 2 to 17.5 percent of patients with myasthenia 114 gravis. In one study of 104 patients with myasthenia gravis, 6 percent had thyrotoxicosis, 10 percent had subclinical hyperthyroidism, 2 percent had hypothyroidism, 3.4 percent had subclinical hypothyroidism, and 11.5 percent had autoantibodies directed against thyroid 115 antigens. The incidence of myasthenia gravis in patients with hyperthyroidism is less than 1 percent. In general, there are few unusual characteristics of either condition in terms of clinical features or management when the two appear in the same patient. However, Marino and colleagues, in a study of 129 patients with myasthenia gravis, of whom 56 had
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autoimmune thyroid disease (25 with autoimmune thyroiditis and 3 with Graves' disease), concluded that myasthenia associated with autoimmune thyroid disease has a mild clinical expression, with preferential ocular involvement, a lower frequency of thymic disease, and 116 control of less likelihood of detectable acetylcholine receptor antibodies in serum. The 117 myasthenia gravis may deteriorate with departure from the euthyroid state. However, treatment of the thyroid disorder does not have a predictable effect on the myasthenia. Dramatic increases in the severity of myasthenia have been reported following treatment of the thyroid disease, but this is uncommon. In some patients, an improvement in myasthenic weakness occurs after treatment of hyperthyroidism. There have been reports of thyrotoxic myasthenic patients in whom repetitive nerve stimulation suggested the presence of either a disorder such as the Lambert–Eaton myasthenic syndrome118or both presynaptic and postsynaptic disturbances of neuromuscular transmission. Differentiating between ophthalmoplegia due to myasthenia gravis and dysthyroid eye 119 disease may be difficult, and the two may coexist. Signs of orbital congestion or abnormal forced ductions suggest the presence of ophthalmopathy. Ptosis, exotropia, or weakness of the orbicularis oculi should alert the physician to the possibility of myasthenia gravis.
Peripheral Neuropathy Peripheral neuropathy is rarely associated with hyperthyroidism, in contrast to its relatively common association with hypothyroidism. Severe paraparesis in hyperthyroidism was first described by Charcot. The term Basedow's paraplegia was coined for the flaccid paraplegia that occurs in hyperthyroidism. The paraplegia is usually accompanied by areflexia, without sphincter dysfunction but occasionally with some sensory deficit. There may be evidence of neurogenic changes in the distal lower-limb musculature. Several case reports have documented the clinical features and neurophysiological findings of peripheral neuropathy (including Guillain–Barré syndrome) in patients with hyperthyroidism. The pathophysiological basis of peripheral nerve dysfunction in hyperthyroidism is unclear. Slowing of nerve conduction velocity has been found in some patients and an axonal neuropathy in others. One report described a severe subacute motor axonal neuropathy 120 induced by T3 hyperthyroidism and reversible on control of the hyperthyroid state. Mononeuropathies associated with hyperthyroidism are relatively rare. Occasionally, patients 121 122 common peroneal neuropathy, and meralgia with carpal tunnel syndrome, 122 paresthetica have been reported. It has been suggested that infiltration of tendon sheaths by mucopolysaccharides is the cause of carpal tunnel syndrome associated with hyperthyroidism. A prospective study of 60 patients with untreated hyperthyroidism showed that 5 percent had clinical and neurophysiological features of carpal tunnel syndrome and an 121 additional 8 percent had subclinical neurophysiological abnormalities. The symptoms of median nerve compression resolve with control of the thyroid disease, and surgery is not usually necessary.
Corticospinal Tract Dysfunction Signs of corticospinal tract dysfunction may be associated with thyrotoxicosis. In many early reports, any causal relationship was indefinite. However, more recently, a number of cases of 123–126 corticospinal tract dysfunction associated with hyperthyroidism have been documented. Clinical features emphasized in these reports include spasticity and weakness, particularly affecting the lower limbs, as well as hyperreflexia, clonus at the ankles and knees, and extensor plantar responses. Occasionally, patients with upper motor neuron signs in the limbs also have had sensory abnormalities, including impaired vibration sensation and proprioception, upper motor 123,125 neuron bladder disturbance and urinary incontinence, and Some patients had lower as well as upper motor neuron alteration in conscious level. signs, a combination resulting in a clinical picture similar to that of amyotrophic lateral 124,126 Several authors have reported a clinical picture similar to that of motor neuron sclerosis. 127 disease in patients with untreated hyperthyroidism. Treatment of the hyperthyroid state usually results in complete or nearly complete recovery of the upper motor neuron signs. Ozata and co-workers studied central motor conduction following transcranial magnetic 128 stimulation of the motor cortex in 19 patients with hyperthyroidism. The mean central motor conduction time (CMCT) was significantly prolonged in the hyperthyroid group compared with a control group. Two of the 19 patients (10.5%) had abnormal CMCT values that exceeded the mean ±2.5 SD of the normal control subjects. The underlying cause of pyramidal tract dysfunction in hyperthyroidism has not been elucidated. No histopathological studies have been reported. Thyroid hormones can have
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important effects on CNS neurotransmitter systems and may also affect the activity of certain brain enzymes. Further histopathological and neurochemical studies in animal models are required to define the pathophysiological basis of corticospinal tract dysfunction in thyrotoxicosis.
Movement Disorders Chorea Chorea is an unusual complication of hyperthyroidism that may relate to a preexisting subclinical abnormality of basal ganglia function. The association of chorea with hyperthyroidism has not been universally accepted as a definite clinical entity, and some authors have suggested that it is probably simply an exaggeration of the hyperkinesis or fidgetiness seen in most thyrotoxic patients. Shapiro reported a case of chorea associated 129 with hyperthyroidism and reviewed 11 previously published cases. The problem is more common in women. In all cases, the choreiform movements involve the limbs; the face, neck, or tongue are affected in some patients. 130 Paroxysmal choreoathetosis has also been the described in patients with thyrotoxicosis. The chorea usually resolves with control of131 hyperthyroidism but occasionally has continued after euthyroidism has been achieved. The pathophysiological basis of hyperthyroid chorea is unknown. It has been suggested that chorea may be mediated by the sympathetic nervous system, because some reports have indicated that β-blocker therapy may improve the involuntary movements. Another hypothesis is that thyrotoxicosis induces increased responsiveness of striatal dopamine receptors, resulting in reduced dopamine turnover within the brain and decreased homovanillic acid levels in CSF. Dopamine receptor antagonists, such as haloperidol and sulpiride, have been effective in the treatment of hyperthyroid chorea. Tremor Tremor is almost universally present in patients with untreated hyperthyroidism. The outstretched hands and protruded tongue are especially likely to be affected, but the lips and facial muscles may also be involved. The tremor has the characteristics of an exaggerated physiological tremor. It is rapid (8 to 12 Hz), is present on maintaining a posture, and persists during movement, but it is not present in the resting position. The tremor probably132 results from increased β-adrenergic activity because it is alleviated by β-blocker therapy. Rare cases of coexisting parkinsonism and thyrotoxicosis have been described. These probably represent the coincidental occurrence of two common conditions. Other Movement Disorders Isolated case reports have described several other movement133 disorders in patients with 134 bilateral chorea-ballism, hyperthyroidism including paroxysmal kinesigenic dyskinesia, 135 136 spasmodic truncal flexion, and platysmal myoclonus.
Thyroid-Associated Ophthalmopathy Thyroid-associated ophthalmopathy is a potentially disfiguring and sight-threatening complication of Graves' disease. It is clinically apparent in 25 to 50 percent of patients with Graves' hyperthyroidism, and in nearly 70 percent of these patients if either CT scan137,138 appearances or intraocular pressure on upgaze are used to establish the diagnosis. However, fewer than 5 percent of patients with Graves' disease have severe ophthalmopathy requiring aggressive therapeutic intervention. Ophthalmopathy may also occur occasionally in patients with Hashimoto's thyroiditis and in those with euthyroid Graves' disease. Clinical Features 1. Eyelid changes are among the most frequent ocular findings in Graves' disease. Retraction of the upper eyelid may result from one of several mechanisms, including increased sympathetic stimulation of Müller's muscle; fibrosis or adhesions of the upper eyelid retractors; and increased tone and overactivity of the levator superior 137,138 Ptosis is rectus muscle complex resulting from fibrosis of the inferior rectus. rarely found in dysthyroid eye disease but may occasionally occur as a result of 138 disinsertion of the levator palpebrae superioris as a result of severe proptosis. 2. Inflammation of the orbital soft tissues may cause complaints of epiphora,
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photophobia, a gritty sensation over the cornea, and retro-orbital pain. The clinical signs include hyperemia and edema of the lids and conjunctiva, incomplete lid closure, palpable swelling of the lacrimal glands, extrusion of fat through the orbital septum, 139 and inflammatory changes at the insertions of the horizontal rectus muscles. 3. Proptosis is defined as measured exophthalmos greater than 2 mm above the upper normal limit. It is found in approximately 20 to 30 percent of patients with Graves' 140 disease and results from increased volume of the orbital contents. 4. Extraocular muscle pathology leading to ophthalmoparesis is clinically apparent in 10 to 15 percent of patients with Graves' hyperthyroidism (Fig. 20-1). If neuro-imaging methods are employed, enlargement of the extraocular muscles will be found in 60 to 138 98 percent of these patients (Fig. 20-2). The factors that cause impairment of extraocular muscle function include progressive enlargement due to lymphocytic infiltration, perimysial fibroblast proliferation, and edema, followed eventually by a restrictive fibrosis that results in a tethering effect. Patients may complain ofblurred vision with binocular gaze, diplopia that may be continuous or intermittent, or a pulling sensation on attempted upgaze. Upward gaze is the most restricted eye movement, followed by abduction and then adduction, with downward gaze being least commonly affected.
FIGURE 20-1 Dysthyroid eye disease showing impaired upgaze and lid
retraction affecting the patient's left eye.
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FIGURE 20-2 Transverse (A) and coronal (B) orbital computed tomography (CT)
scans showing enlargement of the extraocular muscles, particularly inferior rectus and medial rectus, in dysthyroid eye disease. (From Shaw PJ: Neurological abnormalities associated with eye disease. p. 81. In Goetz CG, Aminoff MJ (eds): Handbook of Clinical Neurology, Vol 70. Elsevier Science Publishers, Amsterdam, 1998, with permission.) 5. Corneal alterations in Graves' ophthalmopathy are the result of exposure keratopathy and defective tear film maintenance. Minor corneal changes such as stippling occur in the majority of patients with dysthyroid eye disease, but more serious corneal 140 problems such as ulceration or perforation are fortunately rare. 6. Optic nerve compression occurs in fewer than 5 percent of patients with Graves' 141 disease. Optic nerve dysfunction in Graves' ophthalmopathy occurs as a result of apical compression from enlargement of the extraocular muscles and the orbital connective tissue. Early recognition of the problem is important; as many as 21 141 percent of untreated patients may develop a permanent loss of vision. Patients may have rapid or gradual loss of visual acuity, impairment of color perception, or a visual field defect. Funduscopy may be normal, but swelling of the optic disc is seen in 25 to 33 percent of patients and optic disc pallor is seen in 10 to 20 percent; in occasional 141 patients, choroidal folds are observed. A recent review has highlighted the findings that patients with dysthyroid optic neuropathy may not have severe proptosis and orbital inflammation and that the most useful clinical criteria for diagnosing the problem include optic disc swelling, impaired color vision, and radiological evidence of optic 142 nerve compression. 7. Other symptoms may occur. Episodic spasms of the extraocular muscles and ocular neuromyotonia have been described in several patients with thyroid-associated 143 reports of patients complaining of photopsia ophthalmopathy. There have also been 144 in the superior visual field on upgaze. The latter symptom is probably due to phosphenes resulting from compression of the globe by a tight inferior rectus or traction on the insertion of the inferior rectus. It is important to be aware that Graves' ophthalmopathy may cause only unilateral eye involvement in a significant proportion of patients (5% to 14%). Graves' disease appears to be the 140 most common cause of unilateral proptosis, accounting for 15 to 30 percent of such cases. The primary importance of unilateral eye involvement, particularly in patients who are euthyroid, is the need for rapid exclusion of other causes of unilateral proptosis. Euthyroid Graves' disease, defined as the presence of Graves' ophthalmopathy in a patient with normal circulating thyroid hormone levels and no prior history of treatment of hyperthyroidism, 145 accounts for approximately 10 percent of cases of Graves' ophthalmopathy. Advances have occurred in investigative techniques. STIR (short tau inversion recovery) MRI gives an indication of muscle water content, and a high signal is seen in patients with active 146 ophthalmopathy. Cine-MRI undertaken in the burned-out phase of the disease is useful in demonstrating reduced elasticity of the extraocular muscles, with failure of the normal 146 stretching on eye movement. The value of amplitude reduction on pattern electroretinography as a sensitive measure for demonstrating early impairment of optic nerve 147 visual evoked potentials is also useful in the function has been reported. Measurement of 147 detection of subclinical optic nerve involvement. Prognosis
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Thyroid-associated ophthalmopathy tends to follow a fairly rapidly progressive course, reaching a peak after 6 to 24 months, followed by a prolonged plateau phase, and then by gradual but often incomplete regression of the eye changes. Lid retraction is the feature most likely to remit, and orbital soft tissue changes resolve over 1 to 5 years in most patients. Ophthalmoparesis is less likely to resolve rapidly, but one third of patients show some improvement without specific therapy. Proptosis is the feature least likely to improve or resolve. Bartley and colleagues undertook a long-term follow-up study of Graves' ophthalmopathy in an incidence148 cohort of 120 patients, more than 80 percent of whom were followed for more than 5 years. Persistent visual loss from optic neuropathy occurred in only two eyes, and only two patients had persistent diplopia, which was readily corrected with prism spectacles. One third of patients had some persistent ocular discomfort, usually dryness of the eyes. Sixty percent of patients reported that the appearance of their eyes had not returned to normal, and one third of patients were dissatisfied with the appearance of their eyes. The authors concluded that few patients have significant long-term functional impairment from Graves' ophthalmopathy but that there are important psychological, esthetic, and social sequelae for a significant number of patients. Pathogenesis There have been several excellent reviews of the current state of knowledge concerning the 149–151 Environmental and immunogenetic factors pathogenesis of Graves' ophthalmopathy. probably play a part in its development. An association exists between cigarette smoking and 152 the development of ophthalmopathy. The therapy chosen to treat the thyrotoxicosis in Graves' disease may affect the development or progression of the eye disease; in particular, concern exists that the administration of radioactive iodine therapy may exacerbate the 153 dysthyroid eye disease. Restoring the patient to euthyroidism has a beneficial effect on the ophthalmopathy. The following scheme for the pathogenesis of Graves' ophthalmopathy has been proposed. Circulating T cells in patients with Graves' disease, directed against an antigen on thyroid follicular cells, recognize this antigen on orbital fibroblasts or perhaps on extraocular muscle cells. The T cells then infiltrate the orbit and an interaction between activated CD4 T cells and local fibroblasts results in the release of cytokines (particularly interferon-γ, interleukin-1α, and tumor necrosis factor-β) into the surrounding tissue. These stimulate the expression of immunomodulatory proteins that perpetuate the autoimmune response in the orbital connective tissue. In addition, particular cytokines stimulate glycosaminoglycan production by fibroblasts and proliferation of fibroblasts, leading to accumulation of glycosaminoglycans and edema in orbital connective tissue. The increase in connective tissue volume and the fibrotic restriction of extraocular muscle movement lead to the clinical features of the ophthalmopathy. Thyrotropin-receptor RNA has been demonstrated in orbital fibroblasts and in extraocular, but not nonocular, skeletal muscle, raising the possibility that this antigen is the link between the thyroid and the eye 149,154 Antibodies against several other orbital antigens manifestations of Graves' disease. have been demonstrated. These include the flavoprotein subunit of succinate 155 dehydrogenase, the G2s protein, the calcium-binding protein calsequestrin, and sarcalumenin, a glycoprotein localized at the lumen of the longitudinal sarcoplasmic reticulum 156,157 It has been suggested that some of these antibodies against of skeletal muscle. epitopes on intracellular proteins may be secondary markers of the orbital immune-mediated reaction rather than being primarily involved in the pathogenesis of the ophthalmopathy. Treatment Management of Graves' ophthalmopathy does not usually fall to neurologists, and a 137,158 detailed No discussion of therapy is outside the scope of this chapter but is reviewed elsewhere. preventive therapy is available, and the condition is usually only treated actively when symptoms are severe or vision is threatened. The administration of corticosteroid therapy for 3 months may prevent the appearance or worsening of the ophthalmopathy seen in some 159 patients following radioactive iodine therapy. Botulinum toxin may be used in the treatment of dysthyroid strabismus, primarily as a temporary measure during the active phase of the 160 disease. Corticosteroids and orbital radiotherapy are most effective for the inflammatory features of Graves' ophthalmopathy. These therapies may inhibit the production of cytokines by activated mononuclear cells and orbital fibroblasts. Transantral orbital decompression, followed if necessary by surgical recession of the extraocular muscles, is appropriate for severe exophthalmos or when vision is at risk from optic neuropathy. This procedure decompresses the orbit by allowing some movement of orbital tissue into the maxillary sinus. The role of endoscopic orbital decompression for Graves' ophthalmopathy has recently been 161,162 highlighted.
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Encephalopathy Florid thyrotoxic encephalopathy, sometimes referred to as “thyroid storm,” is fortunately now uncommon, but it may occasionally be seen in a patient with untreated or partially treated hyperthyroidism. Radioactive iodine therapy, surgical procedures, or intercurrent illness are recognized precipitating factors. The patient usually shows overt systemic clinical features of thyrotoxicosis and, in addition, may have fever, cardiac dysrhythmias, heart failure, vomiting, diarrhea, derangement of plasma electrolytes, or jaundice. Affected individuals are commonly confused or agitated. The patient's conscious level may further deteriorate with the development of stupor or158coma sometimes associated with seizures, bulbar weakness, or of bilateral basal ganglia infarction during corticospinal tract signs. The development 163 thyroid storm has been described. 164,165
The mortality of thyroid storm is between 20 and 50 percent. Successful treatment depends on early recognition and aggressive intervention. Recommended therapeutic measures include cooling and rehydrating the patient, administration of antithyroid medication or iodine to reduce circulating thyroid hormone levels, β-blockers to inhibit peripheral effects, 165–167 dexamethasone, and treatment of125 the precipitating factor. Plasmapheresis has been employed for occasional patients. The pathogenesis of thyroid storm has not been established, and at postmortem examination few changes are found in organs other than the thyroid gland.
Seizures Seizures are a relatively frequent complication of metabolic encephalopathies in general, but they are not commonly seen as a complication of thyrotoxicosis. Hyperthyroidism may 168 Seizures have been reported both in patients exacerbate a preexisting seizure disorder. 169 170 with Graves' disease and in patients with hypothyroidism overtreated with thyroxine. β-Blockers have also been implicated as a potential contributory factor in the development of seizures in thyrotoxicosis. The etiology of thyrotoxic seizures remains unknown. Early studies of cerebral metabolic rate and oxygen consumption in hyperthyroid patients have shown no major differences from control subjects. EEG abnormalities are commonly observed in patients with hyperthyroidism. In one series of 20 patients with hyperthyroidism, 17 had mild to moderate abnormalities before treatment; after treatment for 4 weeks, all patients were clinically euthyroid but 12 continued to have 171 some milder degree of EEG changes. The commonest changes are generalized slow activity, but focal slowing and excess fast activity171 have been documented in some patients; definite epileptiform activity is sometimes found. In patients with florid thyrotoxic 172 encephalopathy or thyroid storm, EEG may show the presence of triphasic delta waves. EEG changes usually improve when the thyrotoxic state is controlled.
Mental and Psychiatric Disorders Minor mental disturbances are almost uniformly found in patients presenting with untreated hyperthyroidism. Complaints of insomnia and impairment of concentration and attention span are common. The patient's relatives frequently describe irritability, emotional lability, and capricious behavior. Several types of more serious neuropsychological disturbances have 173 been described, which usually resolve with successful treatment 173 of the hyperthyroidism. Agitated delirium, with confusion, restlessness, and hyperkinesia and an apathetic state with lethargy and depression may occur in thyrotoxic patients. Both psychosis and affective 174 disorders have been described. Among 32 hyperthyroid patients and 30 euthyroid controls, Demet and co-workers175 found a significant overlap between symptoms of hyperthyroidism and of depression-anxiety. It is therefore important to be alert to the possible psychiatric manifestations of thyroid dysfunction and to reassess patients once they become euthyroid. It should be noted, however, that Engum and associates assessed the thyroid status and self-rating of depression and anxiety of 589 adults and found no significant association 176 between thyroid dysfunction and the presence of depression or anxiety disorder. Studies of the incidence of subclinical thyroid disorders in patients with psychiatric diseases also have produced conflicting results, with some showing no clear association and others 177,178 No systematic study has been showing surprisingly high rates of thyroid disorder. undertaken of the effect of correcting the thyroid problem on the course or prognosis of the psychiatric disorder.
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Miscellaneous Associated Conditions Headache 179
Chronic headache has been described as a complication of hyperthyroidism, 180 although a recent observational study found no cases attributable to thyroid dysfunction. It has also been suggested that intracranial pressure may be reversibly increased in patients with 181,182 but this possibility has not been investigated systematically. thyrotoxicosis, Stroke 183
Atrial fibrillation develops in 10 to 15 percent of patients with hyperthyroidism. It has been suggested that 10 to 40 percent of patients184with thyrotoxic atrial fibrillation have embolic events, the majority of which are cerebral. It is uncertain whether thyrotoxic patients have an embolic risk greater than that for patients with chronic atrial fibrillation from other causes. A link between Moyamoya or giant cell arteritis and hyperthyroidism has been suggested but not demonstrated reliably. Hypothyroidism is associated with a worse cardiovascular risk 185 factor profile and leads to progression of atherosclerosis. NEUROLOGICAL COMPLICATIONS OF EUTHYROID HASHIMOTO'S THYROIDITIS Several thyroid-related autoantibodies may be present in Hashimoto's thyroiditis, reacting against thyroglob ulin, an antigen present in the microsomal fraction of the cell, a second 186 colloid-related cell surface antigen, TSH receptor, and thyroxine and tri-iodothyronine. Affected individuals may also develop cell-mediated immunity directed against thyroid 186 antigens. Patients who develop Hashimoto's thyroiditis may have widespread systemic manifestations of autoimmune disease. In a review of 153 patients with Hashimoto's thyroiditis seen over a 34-year period at the Mayo Clinic, 36 (23.5%) had associated illnesses, including pernicious anemia, rheumatoid arthritis, myasthenia gravis, Addison's 187 disease, systemic lupus erythematosus, and ulcerative colitis. Patients with autoimmune thyroiditis have also been reported to develop glomerulonephritis mediated by 188 immunocomplexes containing thyroglobulin antigen and its antibody.
Hashimoto's Encephalopathy The possibility of an association between Hashimoto's thyroiditis and the development of an 189 and was autoimmune encephalopathy was first suggested by Brain and colleagues in 1966 190–193 Alteration in the thyroid metabolic status subsequently confirmed by other authors. clearly did not explain the encephalopathy in these patients. The majority of reported patients are euthyroid at the time of the neurological presentation; 35 percent have subclinical 194 hypothyroidism at the time of onset of the encephalopathy. The encephalopathy usually presents with an abrupt or subacute onset of a confusional state or alteration of level of consciousness and is frequently accompanied by the193 development of accounting for focal or generalized seizures. There is a preponderance of female patients, 194 81 percent in a recent series of 85 patients. A relapsing course, association with myoclonus or tremulousness, and superimposed episodes of “stroke-like” deterioration are notable features 192 that should alert the physician to the diagnostic possibility of Hashimoto's 195 function, encephalopathy. Some patients experience an insidious decline in cognitive 196 which in children may manifest as a deterioration in school performance. Patients have 197 also been described with recurrent status epilepticus. Recently patients have been 198 described with evidence of a more focal CNS abnormality such as a cerebellar syndrome 199 or selective involvement of the nucleus accumbens. The encephalopathy usually responds well to corticosteroid therapy, although additional immunosup-pressive agents are sometimes required, and the long-term prognosis generally appears to be favorable.200,201 Patients who are unresponsive to corticosteroids may derive benefit from plasma exchange. The characteristic findings on investigation of patients with Hashimoto's encephalopathy include high titers of antithyroid antibodies in blood and a high CSF protein level without an 194 or focal slow-wave activity, and in accompanying pleocytosis. EEG may show generalized 194,202 Antithyroid antibodies may be some patients triphasic waves or periodic sharp waves. 192,194 Brain imaging with CT and cerebral detectable in the CSF in some patients. angiography usually are normal. Isotope brain scans show diffuse patchy uptake in some patients. Cerebral white matter abnormalities have been described on MRI in up to 49
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194,203
percent of patients. One patient was described in whom diffuse subcortical MRI signal abnormalities were seen during a subacute exacerbation of Hashimoto's encephalopathy and 204 resolved after the institution of corticosteroid therapy. SPECT scanning in another patient with a rapidly progressive dementia demonstrated global hypoperfusion with normalization on 205 clinical recovery. Few detailed histological studies of this condition have been reported. Several cases206,207 have been described in which an inflammatory infiltrate has been One of these showed a lymphocytic infiltrate within leptomeningeal but not documented. parenchymal vessels. The infiltrate consisted almost exclusively of T cells and was present 207 predominantly in the brainstem. An autopsy report from a patient who developed fatal status epilepticus due to Hashimoto's encephalopathy demonstrated mild perivascular lymphocytic infiltration throughout the brain and leptomeninges plus diffuse gliosis of gray matter in the cortex, basal 208 ganglia, thalamus, and hippocampus, and to a lesser extent in the parenchymal white matter. Several hypotheses have been put forward to explain the encephalopathy associated with euthyroid Hashimoto's disease. Brain and colleagues considered that localized cerebral 189 edema might explain the cerebral dysfunction. Autoimmune cerebral vasculitis, perhaps developing as a result of immunocomplex deposition, has also been postulated as a potential 202,207 The fact that Hashimoto's thyroiditis is pathogenic mechanism by several authors. occasionally associated with the development of vasculitic peripheral209 neuropathy and immunocomplex glomerulonephritis lends support to this hypothesis. Other suggested pathophysiological mechanisms include the existence of an unidentified antigen expressed in both the brain and the thyroid gland, or an excess of TRH within the CNS. Henderson and co-workers postulated that the relapsing encephalopathy is due to recurrent acute 203 disseminated encephalomyelitis. The potential roles of an antineuronal antibody reacting 210 with a 36-kDa protein present in a soluble fraction obtained 211,212 from human cerebral cortex and autoantibodies against the amino terminal of α-enolase have been described. A high index of suspicion is necessary for establishing the diagnosis of Hashimoto's encephalopathy. Since the clinical and other findings in this condition are not specific, other causes of encephalopathy, including infectious, metabolic, toxic, vascular, neoplastic, and paraneoplastic, should be excluded. Future progress in elucidating the pathogenesis of Hashimoto's encephalopathy will require the availability of brain tissue for detailed histopathological and immunological evaluations. MISCELLANEOUS ASSOCIATIONS BETWEEN NEUROLOGICAL DISORDERS AND THYROID DYSFUNCTION
Endocrine Dysfunction in Long-Term Survivors of Primary Brain Tumors Endocrine dysfunction, including hypothyroidism, has been highlighted as a frequent and frequently overlooked long-term complication of radiotherapy for primary brain tumors, with a 213 significant impact on the well-being of the patient. In one series of 31 patients examined 1.5 to 11 years after radiotherapy, 26 percent showed evidence of hypothalamic 213 hypothyroidism. Hypothalamic hypogonadism in males, and hyperprolactinemia and oligomenorrhea in female patients, were also found frequently. It was suggested that endocrine function should be evaluated periodically in long-term survivors of primary brain tumors treated with radiotherapy.
Multiple Sclerosis and Thyroid Disease Karni and Abramsky undertook a controlled prospective study to evaluate the prevalence of thyroid disease in patients with multiple sclerosis and found that thyroid disorders were at least three times more common in women with multiple sclerosis than in female control 214 subjects. This was predominantly due to an increase in the prevalence of hypothyroidism. The authors suggested that this association may support the concept of an autoimmune pathogenesis for multiple sclerosis. An interesting report recently documented thyroid-related complications in a group of 27 patients with multiple sclerosis treated with pulsed monoclonal antibody therapy (humanized anti-CD52 monoclonal antibody Campath-1H) to deplete 215 circulating lymphocytes. Although radiological and clinical markers of disease activity related to multiple sclerosis were significantly decreased for at least 18 months following therapy, one third of treated patients developed antibodies against the thyrotropin receptor and autoimmune hyperthyroidism. The authors concluded that treatment with Campath-1H caused the immune response to change from the Th1 phenotype, suppressing disease activity in multiple sclerosis but permitting the generation of antibody-mediated thyroid disease.
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Subclinical Hypothyroidism in Children on Anticonvulsant Therapy The problem of subclinical hypothyroidism in children with epilepsy treated with valproate or 216 carbamazepine therapy has been highlighted. Elevation of the TSH level was found in 8.2 percent of children on carbamazepine therapy and 26 percent of those on valproate therapy, compared with only 3.6 percent of healthy control children. It was suggested that thyroid function should be monitored at intervals in children on long-term therapy with these anti-epileptic agents.
Recurrent Laryngeal Nerve Palsy 217,218
219
Both malignant disease of the thyroid gland and thyroidectomy may be associated with hoarseness and other bulbar symptoms due to damage to the recurrent laryngeal nerve. Invasion of the recurrent laryngeal nerve by thyroid carcinoma can be accurately predicted by 217 the finding of effaced fatty tissue on MR imaging. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 21 Diabetes and the Nervous System RODICA POP-BUSUI • KELLI A. SULLIVAN • EVA L. FELDMAN •
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PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF DIABETES Prevalence Pathogenesis of Diabetic Neuropathy Increased Aldose Reductase Activity, Osmotic Stress, NAD(P)-Redox Imbalances, Signal Transduction, and Nerve Blood-Flow Auto-oxidation of Glucose, AGE Formation, and PKC Activation Oxidative Damage Classification of Diabetic Neuropathy Evaluation of Diabetic Neuropathy Motor and Sensory Function Autonomic Function Electrophysiological Testing Patterns of Diabetic Neuropathy Distal Symmetric Sensorimotor Polyneuropathy Autonomic Neuropathy Acute Painful Neuropathy With Weight Loss Focal and Multifocal Weakness Diabetic Radiculopathy and Polyradiculopathy Plexopathy Cranial Neuropathy Compression Neuropathies Treatment of Diabetic Neuropathy Control of Blood Glucose Level Experimental Therapies Symptomatic Treatment Physical Approaches Pharmacological Approaches CENTRAL NERVOUS SYSTEM COMPLICATIONS OF DIABETES Metabolic Derangements Diabetic Ketoacidosis Hyperosmolar Hyperglycemic State Hypoglycemia Cerebrovascular Disease Hypertension and Arteriolosclerosis
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Atherosclerosis Stroke in Diabetics Other Central Abnormalities
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of1susceptible organs, especially the eyes, kidneys, peripheral nerves, heart, and blood vessels. Deficient insulin action within target tissues results from inadequate insulin secretion or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action. This results in the abnormalities of carbohydrate, fat, and protein metabolism characteristic of diabetes. Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient, and it1 is often unclear which abnormality, if either alone, is the primary cause of the hyperglycemia. The current classification and diagnosis of diabetes used in the United States was developed 2 by the National Diabetes Data Group (NDDG) in 1979 and endorsed by both the World Health Organization (WHO) Expert Committee on Diabetes and the WHO Study Group on Diabetes Mellitus. The NDDG/WHO classification, highlighting the heterogeneity of the diabetic syndromes, divided diabetes mellitus into five distinct types: insulin-dependent diabetes mellitus (IDDM), non–insulin-dependent diabetes mellitus (NIDDM), gestational diabetes mellitus (GDM), malnutrition-related diabetes, and other types. However, based on emerging research, the American Diabetes Association (ADA) recommended3 modification of the NDDG classification and diagnosis criteria first in 1997 and later in 2003. Consistent with ADA recommendations, three ways to diagnose diabetes are possible, based on either (1) fasting plasma glucose ≥126 mg/dl (7.0 mmol/L), (2) an oral glucose tolerance test with the 2-hour post-load value ≥200 mg/dl (11.1 mmol/L), or (3) symptoms with a casual plasma glucose ≥200 mg/dl (11.1 mmol/L). Each measure, in the absence of unequivocal hyperglycemia, must be confirmed, on a subsequent day, by any one of the three methods 1,3 given. Although measurement of hemoglobin A1c (HbA1c) levels is not currently recommended for 1 diagnosis of diabetes, some studies have shown that the frequency distributions for HbA1c have characteristics similar to those of the fasting plasma glucose and the 2-hour oral 4,5 glucose tolerance test. Moreover, these studies have defined an HbA1c level above which the likelihood of having or developing macro- or microvascular disease rises sharply and provide a useful screening tool for the diagnosis of diabetes. Furthermore, HbA1c and fasting plasma glucose (in type 2 diabetes) have become the measurements of choice in monitoring treatment, and decisions on when and how to implement therapy are often made on the basis of HbA1c. The vast majority of cases of diabetes fall into two broad categories: type 1 diabetes, caused by an absolute deficiency of insulin secretion, and type 2 diabetes, caused by a combination1 of resistance to insulin action and an inadequate compensatory insulin secretory response. Type 1 diabetes accounts for only 5 to 10 percent of those with diabetes and results from a cellular-mediated autoimmune destruction of the β-cells of the pancreas with subsequent loss of insulin secretion and absolute insulin deficiency. Type 2 diabetes accounts for about 90 to 95 percent of those with diabetes and is due to a combination of genetic and nongenetic factors that1 lead to insulin resistance and usually relative (rather than absolute) insulin deficiency. Type 2 diabetes is commonly associated with obesity or central adiposity (or both), a sedentary lifestyle, increasing age, and high caloric intake. The most common neurological complication of both types of diabetes is diabetic 6 neuropathy. Diabetic neuropathy is a syndrome comprising a series of separate clinical disorders that affect distinct components of the peripheral nervous system (Table 21-1).The focus of this chapter is on the 6most common type of diabetic neuropathy, distal symmetric sensorimotor polyneuropathy. The other peripheral neurological diabetic syndromes are discussed, although in less detail. Finally, consideration is also given to the central nervous system (CNS) complications. Click here to view this table.... PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF DIABETES
Prevalence The reported prevalence of diabetic polyneuropathy in diabetics depends on the diagnostic criteria used to confirm the diagnosis. A generally accepted overall prevalence rate is 50
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percent, although estimates vary from 10 to 100 percent. Probably the most frequently cited prospective study on diabetic polyneuropathy was completed in an outpatient clinic over a 25-year period by Pirart. He examined 4,400 patients, 10 percent of whom had neuropathy at 7 the time of diagnosis. After 25 years of diabetes, half (50%) of the patients had neuropathy. A similar prevalence was reported in the Rochester Diabetic Study, in which 59 percent of 8,9 type 2 and 66 percent of type 1 diabetics had neuropathy. Prior to entering the Diabetes Control and Complication Trial (DCCT), 39 percent of 278 otherwise healthy type 1 diabetic 10 patients met the clinical criteria for diabetic polyneuropathy. Among type 1 patients older than 30 years followed in11the Pittsburgh Epidemiology of Diabetes Study, 58 percent had diabetic polyneuropathy. The prevalence of diabetic polyneuropathy has been the subject of several large European multicenter studies. In Italy, 32.3 percent of 8,757 patients with diabetes had neuropathy diagnosed and staged with the Michigan Diabetic Neuropathy Score, a composite12score derived from a simple neurological examination and routine nerve conduction studies. In the United Kingdom, a focused neurological examination and assessment of symptoms found that 44 percent of 6,487 diabetic patients between 70 and 79 13 years of age had polyneuropathy. In both of these large, prospective studies, the prevalence of polyneuropathy increased with duration of disease.
Pathogenesis of Diabetic Neuropathy The mechanisms underlying the development of diabetic neuropathy are a source of continued active investigation. Animal and in vitro experiments implicate a number of enzymatic and nonenzymatic pathways of glucose metabolism in its initiation and progression. These include (1) increased aldose reductase pathway activity, leading to sorbitol and fructose accumulation; NAD(P)-redox imbalances and changes in signal transduction; (2) auto-oxidation of glucose; (3) nonenzymatic glycation of proteins, yielding “advanced glycation end-products” (AGEs); and (4) activation of protein kinase C (PKC), initiating a cascade of stress responses. Increased reactive oxygen species and oxidative stress may occupy a central position, linking this network of metabolic perturbations into a synergistic “feed-forward” system of progressive metabolic derangements (Fig. 21-1). This self-reinforcing network of metabolic perturbations is thought to cause, and to be accelerated 14 by, abnormal microvascular function in complication-prone tissue. This conclusion is based on the observations that antioxidant therapy 15,16 improves nerve blood-flow in diabetes and that In nerve, this pattern of metabolic and ischemic hypoxia promotes oxidative stress. vascular disturbance impairs mitochondrial function and neurotrophic support and mediates apoptosis of neurons and Schwann cells, culminating in progressive damage and loss of 15–18 peripheral nerve fibers and impaired sensory function.
FIGURE 21-1 Oxidative stress in diabetic neuropathy. Increased glucose initiates a
cascade of cytotoxic events through glycation, formation of advanced glycation end-products (AGEs), and increased sorbitol formation through the aldose reductase (AR) pathway. AGEs promote the generation of reactive oxygen species and increase oxidative stress. Activity through the AR pathway depletes the necessary cofactors required for antioxidative defense and further promotes oxidative stress. Both AGE
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accumulation and AR pathway activity also damage mitochondria, and this too further impairs oxidative defense mechanisms. Nerve growth factor (NGF) activity is altered and impaired in the setting of oxidative stress and mitochondrial dysfunction. Collectively, these events lead to increased ischemia with resultant programmed cell death (PCD). The final result is the presence of both peripheral and autonomic neuropathy. Potential treatments with aldose reductase inhibitors (ARIs), growth factors, and antioxidants may block this pathway at one or more steps and provide a means of interrupting oxidative stress and thus the evolution of diabetic neuropathy. GLUT1, glucose transporter 1. Increased Aldose Reductase Activity, Osmotic Stress, NAD(P)-Redox Imbalances, Signal Transduction, and Nerve Blood-Flow Cells compensate for extracellular hypertonic stress by elevating intracellular osmolality without raising ionic strength by accumulating nonperturbing organic osmolytes that include sorbitol, myo-inositol, and taurine. Hypertonic stress raises intracellular sorbitol by inducing aldose reductase expression, and it raises intracellular myo-inositol and taurine by increasing + the activity and expression of their respective Na -cotransporters. In the diabetic state, isotonic hyperglycemic stress selectively induces sorbitol accumulation by providing additional substrate (glucose) for aldose reductase. By raising intracellular osmolarity, sorbitol accumulation produces a reciprocal decrease in myo-inositol and taurine from their low basal levels to the point that their depletion interferes with cell metabolism. Myo-inositol depletion interferes with intracellular phosphoinositide signaling, and depletion of 14 taurine, a chelator and PKC inhibitor, diminishes antioxidative defense and activates PKC. Enzymatic reduction of glucose to sorbitol by aldose reductase is linked to the oxidation of NADPH to + 14 NADP , compromising antioxidative defense by the glutathione reductase reaction. + Oxidation of sorbitol to fructose by sorbitol dehydrogenase is linked to reduction of NAD to NADH, potentially creating cytoplasmic “reductive stress” (especially if mitochondrial oxidative metabolism is impaired), and fructose is more prone to undergo glycation and glycoxidation 14 flux through the aldose reductase and sorbitol than is glucose. Thus, in diabetes, glucose + dehydrogenase pathways oxidizes NADP /NADPH, depletes taurine and reduced glutathione, and produces fructose. These changes augment production of, and impair detoxification of, reactive oxygen species, including the reactive 14,17 superoxide anion and the hydroxyl radical, which in turn mediate oxidative tissue damage. Auto-oxidation of Glucose, AGE Formation, and PKC Activation Oxidative stress is further promoted by auto-oxidation of glucose, catalyzed by trace amounts of free transition metals such as iron and copper, leading to formation of reactive oxygen 14,17 Transition metal handling is impaired in experimental diabetes, and species. metal-chelating agents preserve nerve conduction velocities and nerve blood-flow in diabetic 14,17 Levels of AGE correlate with many vascular complications of diabetes mellitus, rats. including diabetic neuropathy. Reactive oxygen species may also interconnect auto-oxidation and AGE formation. Reactive oxygen species accelerate AGE formation, and AGEs, in turn, 19 supply reactive oxygen species, a process known as auto-oxidative glycosylation. Binding of AGEs to their cell surface receptor (RAGE) is associated with activation and nuclear translocation of the transcription factor NFκB, possibly contributing20to cytokine activation, endothelial dysfunction, impaired nerve blood-flow, and ischemia. AGEs may also lead to the thickening of21basement membrane, cytokine production, and generation of reactive oxygen species. Activation of PKC is reported in some, but not all, tissues prone to diabetic complications, and PKC inhibitors specific for the β-isoform improve microvascular function in experimental 14,17 diabetes. The role of PKC activation in diabetic nerve is complex. Total PKC activity in rat sciatic nerve is reduced or normal,14,17 rather than increased, by diabetes, although specific Increased aldose reductase pathway activity promotes isoforms of PKC may be elevated. de novo diacylglycerol (DAG) synthesis and PKC activation by stimulating the pentose phosphate shunt and diverting dihydroxyacetone phosphate toward formation of 14,17 α-glycerophosphate, a DAG precursor. Osmotic stimulation of stress-activated protein kinases can stimulate PKC. PKC is also activated by the reciprocal accumulation of sorbitol 14,17 and depletion of taurine and glutathione, both of which possess PKC-inhibitory capacity. PKC activation may inhibit myo-inositol uptake, promoting myo-inositol depletion, which may 14,17 diminish neuronal PKC activity. Activation of PKC may thus have a bifunctional effect on diabetic neuropathy in the rat, improving nerve blood-flow and nerve conduction at low levels, but impairing nerve function possibly by interfering with neurochemical regulation at higher
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14,17
levels.
Oxidative Damage As summarized previously, oxidative stress in diabetes is attributed to a combination of increased flux of glucose through aldose reductase into sorbitol, with depletion of NADPH, glutathione, and taurine, coupled with glucose auto-oxidation and/or glycoxidation and decreased activity of superoxide dismutase and glutathione peroxidase. Superoxide dismutase detoxifies superoxide to hydrogen peroxide (H2O2), which is converted 14 to water by cytosolic catalase and by cytosolic and mitochondrial glutathione peroxidase. Mitochondria would be particularly vulnerable because they lack catalase and are therefore dependent on glutathione peroxidase to quench reactive oxygen species. Mitochondrial function would be further perturbed by ischemic hypoxia in diabetic nerve and retina, further disturbing antioxidative defense by diminishing ATP for the de novo synthesis of glutathione. Accumulation of conjugated dienes and reductions in superoxide dismutase, glutathione 16,17 are regarded as evidence of increased peroxidase, and taurine in peripheral nerve damage by reactive oxygen species and reduced oxidative defense in experimental diabetic neuropathy. Oxidative stress impairs endothelial function by quenching nitric oxide, impairing nitric oxide synthase (in part by NADPH depletion), and altering prostanoid metabolism or 16,17 Ischemic hypoxia also further exacerbates production of reactive oxygen PKC regulation. species. If left unchecked, this process would produce lipid, DNA, and protein peroxidation 16,17 and cellular apoptosis, which are well documented in experimental and clinical diabetes. Pro-oxidants administered to normal rats produce effects that mimic aspects of experimental diabetic neuropathy, including reductions in nerve blood-flow, endoneurial oxygen tension, and conduction velocities. Treatment of streptozotocin-diabetic rats with antioxidants such as butylated hydroxytoluene, probucol, or lipoic acid restores normal nerve blood-flow and 22 selectively corrects nerve conduction slowing. Glutathione supplementation has similar beneficial effects and is particularly effective in preventing the onset, rather than the 23 progression, of diabetic neuropathy. Collectively, these data suggest that the various glucose-mediated changes all act additively or synergistically to promote damage by reactive oxygen species, supporting an important role of oxidative stress in the pathogenesis of 23–27 diabetic neuropathy.
Classification of Diabetic Neuropathy Classification of all types of diabetic neuropathy provides a framework for differential diagnosis. When the clinician approaches a diabetic patient with neuropathy, it is useful to know whether the type of neuropathy is compatible with a diabetic etiology. The less a particular pattern is associated with diabetes, the more vigorously an alternative explanation should be sought. The other value of classification is that it may aid in offering a prognosis to the individual patient. Indolently progressive, distal symmetric neuropathy rarely remits. The subacute, asymmetric proximal neuropathies, by contrast, usually reach a plateau of maximal deficit and then improve spontaneously.
Evaluation of Diabetic Neuropathy Motor and Sensory Function Accurate evaluation is important for diagnostic purposes, for serial assessment of patients, and for use in research protocols. This should involve both qualitative and quantitative approaches to the assessment of the symptoms and deficit. Some form of structured inquiry about symptoms is essential for following the diabetic patient. Symptom inquiry will be the major source of serial evaluation for most patients. It is therefore necessary to ask about the presence of specific symptoms that may not be volunteered in the setting of a busy diabetic clinic. Specific inquiry should be made about motor, sensory, and autonomic symptoms. At the least, the symptoms summarized in Table 21-2 should be sought. This type of structured history has been formalized into questionnaires for research 28,29 In the diabetic clinic, a less structured checklist following the guidelines set out purposes. to evaluate and record signs and symptoms quickly, and several in Table 21-2 can be used28,30 Particular attention should be paid to signs and symptoms that simple tools are available. are not usually volunteered either because of embarrassment or because the patient believes that they are trivial. Click here to view this table....
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Sensory loss must be defined in terms of extent, distribution, and modality involved. In the clinical examination, there is always a compromise between completeness and the time allowed for the examination. The patient's cooperation and alertness are essential,and the experienced examiner knows that a reliable sensory examination must be performed quickly, before the patient becomes bored and inattentive. For this reason, if a focal deficit is suspected, that should be defined first. If a generalized distal abnormality is suspected or a screening examination is undertaken, the examiner should use defined points on all four 31 extremities. The dorsum of the digit just proximal to the nail provides an area of skin that is not usually subjected to trauma and is therefore less prone to callus formation. A survey of sensory function might include assessment of threshold for vibration, light touch, joint position, and pinprick sensation. Evaluation of threshold is probably more reproducible than subjective assessment by the patient of the strength of stimulus. The examiner can vary the intensity of vibration and assess whether the threshold at which the patient perceives vibration is normal. For focal sensory loss, mapping is best done with pin, touch, and temperature sensation. 32
Quantitation of sensory deficit using automated or computer-assisted techniques has the most value in studying populations of patients for the purpose of defining either the natural history of disease or the response to treatment in a clinical trial. True weakness occurs in severe cases of diabetic neuropathy and is common in diabetic 33 plexopathies and radiculopathies. Weakness is evaluated with the use of the Medical Research Council (MRC) scale. Reflexes are usually depressed or absent and are graded as 2 (normal), 1 (depressed), or 0 (absent). Autonomic Function A detailed discussion of autonomic function testing is beyond the scope of this section. Increasingly sophisticated methods are becoming available for assessing all modalities of 34 autonomic function. Certain bedside and office tests of autonomic function are simple and reproducible, as discussed in Chapter 8. Orthostatic hypotension can be evaluated by measuring blood pressure with the patient in the supine, sitting, and standing positions. The blood pressure should be recorded after the subject has been in the standing position for 1 minute. A decline in systolic pressure of more than 20 percent is considered by us to be abnormal. Others consider a fall in the absolute value of the systolic pressure by 20 to 30 mmHg or of the diastolic pressure by 10 mmHg on standing to be abnormal. If a decline in blood pressure is associated with assuming the erect position, heart rate should also be recorded. If the sympathetic input to the heart is intact, a reflex tachycardia should accompany the decline in the blood pressure. A fall in blood pressure accompanied by an increase in heart rate might be due to volume depletion secondary to hyperglycemia, dehydration, or diuretic use. If the pulse rate does not increase, sympathetic denervation should be suspected. A fixed tachycardia that does not slow in response to the Valsalva maneuver may indicate loss of parasympathetic vagal innervation to the heart. Abnormalities of sweating cannot be quantitated in the office, although dry skin may be one indicator of loss of sudomotor function. The thermoregulatory sweat test measures distribution of sweating in response to heating the body core temperature by 1°C. If combined with sudomotor axon reflex testing, this test can determine whether sweating loss is due to central or peripheral autonomic failure. Electrophysiological Testing Nerve conduction studies and electromyography (needle electrode examination of muscle) may aid in the clinical evaluation or study of diabetic patients in several ways: confirmation of the clinical diagnosis of neuropathy, identification of a pattern of electrophysiological changes characteristic of diabetes, monitoring of progression or remission of disease, and detection of 35,36 asymptomatic cases. In general, electrophysiological studies are not required to make a diagnosis of peripheral neuropathy. Such a diagnosis can be made on a clinical basis in most cases. In some patients, however, the diagnosis may not be completely clear clinically. In the patient with purely autonomic symptoms and signs, electrophysiological evidence of generalized neuropathy may help by demonstrating that the peripheral nervous system is involved in a neuropathic process. In the patient with pain alone, particularly localized pain from truncal radiculopathy or lancinating distal limb pain, the electrophysiological studies again may add
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information by showing generalized nerve involvement. It should be noted that distal burning pain and hyperalgesia may be produced by relatively pure small-fiber (unmyelinated and slowly conducting myelinated C fibers) involvement that would be undetected by standard electrophysiological testing. Such selective small-fiber loss is uncommon in diabetes even when the clinical picture is suggestive. This is different from hereditary neuropathies, in which a single class of fibers may be affected almost exclusively. Electrophysiological studies cannot specifically diagnose diabetic neuropathy. There is no pattern of change that is pathognomonic of the condition. However, there are patterns that are suggestive of diabetic neuropathy. These may be summarized briefly. In very mild or asymptomatic cases, the only change may be distal slowing of conduction. This is usually not uniform, some nerves being more affected than others, with focal areas of slowing, particularly at common compression sites. In cases of clinically overt neuropathy, there is virtually always a mixture of changes, suggesting both demyelination and axonal degeneration. As the neuropathy progressively worsens, the findings of axonal degeneration predominate: decreased amplitude of compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs), relative preservation of proximal conduction velocities, and evidence of fibrillation potentials and motor unit remodeling on needle examination. Careful examination of multiple nerves usually shows a multifocal pattern of 37 involvement rather than a completely diffuse symmetric pattern. In clinically focal cases of neuropathy, there are electrophysiological signs of more widespread involvement. For example, in patients with a monoradiculopathy, particularly of the truncal (thoracic or upper lumbar) type, the needle examination shows diffuse change in paraspinal muscles characteristic of polyradiculopathy. In patients with signs of single entrapment neuropathy, there are often more diffuse changes, with slowing of conduction across multiple entrapment points. Electrophysiological abnormalities are frequently present in completely asymptomatic diabetics. These observations are of interest in population studies and in clinical trials and also in investigating the pathogenesis of diabetic neuropathy. However, it is unknown whether minor degrees of conduction slowing constitute a sign of impending clinical neuropathy. If they do and if effective treatment becomes available, screening for these early changes may become very important in clinical management. When neuropathy is established, there is a general relationship between degree of structural change and abnormalities in nerve conduction, as is true for any form of peripheral neuropathy. However, early in the course of human diabetes as well as in animal models, reversible changes in conduction velocity occur. It is not clear whether these represent acute metabolic changes and are unrelated to the later development of structural neuropathy, whether they are the forerunners of later structural changes, or whether they represent markers of early but readily reversible structural change. There is some evidence in favor of each viewpoint. Reversibility can be accomplished in humans by the establishment of 38–41 and prevented from developing in animals by administration of insulin, glycemic control dietary supplementation with myo-inositol, or the use of aldose reductase inhibitors that 42 43 prevent sorbitol increase in nerve or antioxidants. The conduction changes may be mimicked acutely by glucose infusion into rats, and the degree of change correlates with change in44nerve fiber geometry (shrinkage), presumably produced by acute osmotic changes.
Patterns of Diabetic Neuropathy Distal Symmetric Sensorimotor Polyneuropathy 6
This is the most common form of diabetic neuropathy. Symptoms usually begin insidiously and may be positive or negative. Negative symptoms in the feet may be described in a variety of ways (Table 21-2). If nociceptive fibers are involved, loss of feeling may not be noticed and the patient may present with painless injury. An object may become lodged in the shoe and erode through the skin with normal walking and weight bearing. Painless ulcers may develop over pressure points, most commonly under the metatarsal heads. However, any areas of skin subjected to constant friction may ulcerate. Another presentation for painless neuropathy is with the Charcot joint. The patient complains of progressive ankle and foot deformity with relatively little pain. Radiographs show disorganization and collapse of the ankle joint. This presentation may occur when the signs of neuropathy are otherwise minimal. In the patient with involvement of large sensory fibers, the negative symptoms may include loss of balance, especially at night or with the eyes closed.
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Positive symptoms also vary according to the class of sensory fibers involved. Small-fiber involvement produces burning and stinging sensations that are almost constant. Involvement of larger fibers tends to produce a tight, band-like feeling around the extremity or an electrical tingling sensation. These symptoms are often similar to those described by patients with lesions in the posterior columns of the spinal cord. The first step in evaluating these symptoms in a diabetic patient is to confirm the presence of neuropathy by clinical examination. In most cases, distal symmetric sensory loss is apparent. Among patients who complain only of distal burning, the loss of distal pain sensation may be subtle. In severe cases, if distal symmetric neuropathy progresses, motor involvement becomes clinically apparent. It begins distally with weakness of toe dorsiflexion and intrinsic hand muscles. This weakness may gradually progress to involve the leg muscles, but it is rare for weakness to occur proximal to the knee or elbow. Diminution of deep tendon reflexes tends to parallel the sensory loss. Investigations for other causes of neuropathy yield normal results. The cerebrospinal fluid (CSF) protein concentration may be normal or modestly elevated (to <80 mg/dl). In the established diabetic, there is rarely any confusion about the diagnosis of this type of neuropathy. The factors summarized in Table 21-3 suggest other causes for neuropathy in patients with diabetes. Click here to view this table.... Autonomic Neuropathy In most patients with diabetes and peripheral neuropathy, some degree of autonomic 6 neuropathy can be detected with the use of special testing methods. In some cases, the autonomic abnormalities may be asymptomatic. However, if carefully questioned, many patients with diabetes and distal symmetric neuropathy report some of the symptoms described here. When severe autonomic neuropathy is present, it has an adverse effect on 6 survival. Pupil Abnormalities 34
Pupil abnormalities are seen commonly but are usually asymptomatic. Although some patients may complain of accommodation difficulty, this usually relates to changes in lens and ocular hydration rather than to autonomic neuropathy. The variation in hydration depends acutely on changes in blood sugar. When autonomic neuropathy is present, pupil size usually decreases and the response to light or accommodation is lost. In extreme cases, this may mimic the Argyll Robertson pupil of tabes. Sudomotor Function 34
Sudomotor function is almost universally affected in diabetics with neuropathy. This loss of sweating capacity is usually asymptomatic. In severe cases, loss of thermoregulation may occur. Occasionally, compensatory hyperhidrosis or gustatory sweating in areas of retained sudomotor function is reported. It is possible that loss of sweat secretion contributes to skin ulceration, but this has not been studied. Cardiovascular Abnormalities
Cardiovascular abnormalities may produce symptoms of orthostatic hypotension. In older patients, these symptoms may be vague and potentiated by diuretics. In other patients, the symptoms of orthostatic hypotension may be confused with those of hypoglycemia. The recording of lying and standing blood pressures and pulse rates should be a routine part of the neurological examination of diabetics. More extensive testing methods are available, but 34 usually they are not necessary for clinical purposes. If the patient's blood pressure falls upon standing, no compensatory rise occurs in pulse rate, and the patient is not on medications that affect heart rate, an autonomic neuropathy is likely. If the blood pressure fall is accompanied by an increased heart rate, volume depletion should be suspected. Gastrointestinal Function
Gastrointestinal function may be affected in a variety of ways; the most common are gastroparesis and diarrhea. Any 34 part of the gastrointestinal tract can exhibit reduced motility, but this is usually asymptomatic. Gastroparesis may be asymptomatic, but it may also
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present acutely with nausea and vomiting or with chronic vomiting. The vomiting is characterized by the presence of food eaten more than 12 hours previously. Diabetic diarrhea probably results from disordered motility of the small intestine. Significant abnormalities of intestinal motility occur in diabetic subjects. Disordered motility alone is not the only cause of the diarrhea; other factors—such as metabolic alteration, vascular changes, altered hormonal control, and increased susceptibility to infection—also play a role. Decreased motility with secondary bacterial overgrowth produces diarrhea that responds to treatment with tetracycline. The clinical features of the diarrhea are characteristic. It is usually explosive and frequently occurs at night, which may lead to nocturnal incontinence. It is usually painless, watery, and very rarely bloody. Periods of diarrhea are interspersed with periods of resistant constipation. An obstructive bowel lesion must be excluded with contrast-enhanced imaging studies and proctoscopy before the diagnosis of diabetic complications can be made with confidence. During the contrast studies, the radiologist can also estimate the transit time through the stomach and intestines and observe gastric dilatation if present. Diabetic Bladder Disease
Diabetic bladder disease is usually asymptomatic until recurrent urinary tract infections occur. These may precipitate or potentiate renal failure. Loss of afferent information from nerves in 34 the detrusor muscle leads to progressive bladder enlargement. Impairment of Sexual Function
Impairment of sexual function has been studied primarily in men. This bias, although in part cultural, is also due to the relative ease with which penile erectile dysfunction is recognized by the patient and studied by the investigator. Mechanisms for studying disorders of the physiology of female sexual responses have not generally been applied to diabetics. There is some evidence that diabetic women with autonomic neuropathy are less prone to sexual dysfunction than men. In diabetic men with autonomic involvement, erectile dysfunction or ejaculatory failure is common. Evaluation of this problem is complex and involves psychological considerations, but techniques are now available for studying the physiology of erection. Further comment is provided in Chapter 34. Insensitivity to Hypoglycemia
Insensitivity to hypoglycemia may occur. The physiological response to hypoglycemia involves epinephrine release and increased sympathetic activity, which produce the characteristic symptoms of hypoglycemia. Since epinephrine release is mediated by the splanchnic nerves, this response may be lost in patients with autonomic neuropathy. This leads to attenuation of both the symptoms of and the physiological compensation for hypoglycemia. Acute Painful Neuropathy With Weight Loss 45
This syndrome was first described by Ellenberg and then more clearly delineated in 46 neurological terms by Archer and colleagues. All cases described by these workers were in males, whereas we have observed the syndrome in patients of both sexes. The cardinal features are weight loss and severe pain, often accompanied by depression and impotence. There appear to be two circumstances in which this syndrome occurs. The first involves a profound weight loss over a fairly short period of time. This loss may exceed 50 percent of original body weight and may occur spontaneously, owing to uncontrolled diabetes, or intentionally, as part of the management of diabetes. Once the pain begins, the patient becomes anorexic and depressed, which accelerates the weight loss. In the second circumstance, the patient has had uncontrolled hyperglycemia for a prolonged period, either because the diabetes was undiagnosed or the disease was recognized but poorly controlled. Within 1 to 2 weeks of instituting tight control, the painful neuropathic symptoms begin. We have seen examples of this occurring in patients who have started treatment with continuous insulin infusion pumps. In either circumstance, there is rapid onset of severe, superficial pain, which is usually described as burning, stinging, or electrical shock–like. This pain may begin distally in the limbs and spread proximally or, in some cases, begin proximally in the anterior thighs. The pain is worse with weight bearing, and the patient cannot bear to have the skin touched by clothes or bed coverings. In our experience and in the patients described by Archer and
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46
co-workers, sensory loss on examination was minimal and weakness did not occur. 45 Ellenberg described weakness in his cases, but it is not clear whether this was neuropathic weakness or generalized weakness secondary to cachexia and pain. Improvement begins after the patient starts to regain weight, which is often helped by the use of antidepressants. In individuals in whom the pain began after institution of good control, some relief can be obtained by relaxing the glycemic control and then gradually reinstituting normoglycemia. Complete resolution of symptoms is the rule, but it usually occurs over 6 to 24 months, suggesting that axonal regeneration is a factor. Focal and Multifocal Weakness Two types of focal neuropathy are seen in diabetic patients: those occurring spontaneously and those occurring as a result of nerves crossing common pressure points. The spontaneously occurring neuropathies characteristically occur at the level of the root, plexus, or individual nerve. The underlying pathology in these cases is probably vascular. Diabetic Radiculopathy and Polyradiculopathy Radiculopathy may be the presenting feature of diabetes, but more commonly it occurs in the context of long-standing disease. It is very uncommon in patients younger than 40 years. Monoradiculopathies may occur at any spinal level and therefore may be confused with a compressive root lesion. Clinical features help differentiate between compressive and diabetic root lesions. Location of the symptoms and the character of the pain are the most useful items. Pain is the prominent symptom and begins acutely or subacutely. It occurs most frequently on the trunk and is unilateral. Burning and supersensitivity of the skin are the most common features of the pain, but it may be of a deep aching character. Although pain is severe, sensory loss is minimal or absent on examination and weakness is not usually apparent in the trunk muscles. Characteristically, thoracic and upper lumbar roots are involved. If L3 and L4 are affected, the pain begins in the anterior thigh and is followed quite rapidly by weakness of quadriceps and other muscles. Some cases cannot be resolved on a clinical basis, and the electrophysiological features may then be helpful. In diabetics, the symptoms and signs may be entirely at one root level, but the electrophysiological changes are more diffuse. Typically, fibrillation potentials are found at multiple levels in the paraspinal 36 muscles. The electrophysiological changes of polyneuropathy may not be present. If there is diagnostic uncertainty, imaging may be required to exclude a mass lesion. Because of the common occurrence of this problem in the thoracic or lumbar region, the differential diagnosis may include a visceral cause of the pain. In the chest, cardiac or pleural disease may be suspected. Significant weight loss occurs in more than 50 percent of 33,47 and a search for malignancy may be initiated. cases, The prognosis for recovery from these symptoms is excellent. The pain usually reaches a maximum within weeks of onset, persists for several months, and then gradually resolves completely. A small number of patients develop recurrent diabetic radiculopathy at different spinal levels. Episodes may be separated by months or years. Multiple levels may be involved coincidentally in the form of a polyradiculopathy. Symptoms may begin in one limb, with focal pain that spreads to involve different dermatomes; it is then followed over days or weeks by weakness in corresponding myotomes. The symptoms at one root level may be stable or even improving as another root becomes involved. This sequence may then spread from one leg to the other and, rarely, to the cervical levels, producing arm pain and weakness. Progression may occur over many months, with one limb improving as another becomes involved. The ultimate prognosis for some degree of recovery is good, but improvement may be slow. The differential diagnosis, once a structural lesion has been excluded, includes chronic inflammatory demyelinating polyradiculoneuropathy, Lyme disease, malignant infiltration (especially by lymphoma), acquired immunodeficiency syndrome (AIDS), and sarcoidosis. Electrophysiological features may help separate diabetic polyradiculopathy from chronic inflammatory demyelinating polyradiculoneuropathy. Examination of the CSF may be helpful and is important in distinguishing between the diagnostic possibilities. The protein concentration is modestly elevated (50 to 125 mg/dl) in the diabetic patients. In chronic inflammatory demyelinating polyradiculoneuropathy, it may be much higher (100 to 4,000 mg/dl). Pleocytosis is usually not present in either case. The presence of cells in the CSF raises the question of lymphoma, sarcoidosis, AIDS, or Lyme
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disease. In the latter three circumstances, the cells are usually polyclonal. The last two can be readily distinguished by serology. Infiltration of roots by lymphoma should be suspected if surface markers suggest a monoclonal cell line in the CSF. Infiltration of roots by other malignant cells may be confirmed by cytological identification in the CSF. Plexopathy Plexopathy overlaps in clinical presentation with diabetic radiculopathy and polyradiculopathy. The terms diabetic amyotrophy, diabetic myelopathy, diabetic femoral neuropathy, and more recently proximal motor neuropathy all have been used to describe this syndrome. The preferred term is polyradiculoneuropathy or radiculoplexopathy. The characteristic syndrome of diabetic plexopathy begins rapidly over days to a few weeks, typically in older patients. The initial symptom is pain in the anterior thigh followed by buckling of the knee due to quadriceps weakness. Maximal deficit is usually reached in a few weeks; the deficit is then stable for weeks to months and improves over months to years. Some degree of improvement is universal, and usually functional recovery is good. Neurological examination shows weakness and often severe atrophy of the quadriceps muscle. Also present may be accompanying weakness of any of the muscles innervated by the lumbar or sacral plexus. The most commonly affected muscles are those supplied by the L3 and L4 roots. Sensory loss is minimal; typically, small patchy areas of hyperesthesia or hyperpathia over the anterior thigh are noted. The knee reflex is reduced or absent. Extensive investigations are not usually necessary. The differential diagnosis during the progressive phase may include malignant infiltration of the plexus, especially in the older patient who has accompanying weight loss. Computed tomography (CT) scanning through the plexus and a period of clinical observation resolve this question. If the CSF is examined, it is usually normal. Electromyography shows involvement of muscles beyond those that are 33 clinically weak. Evidence of distal peripheral neuropathy may or may not be present. It has been suggested that patients with accompanying distal neuropathy tend to have more severe 33 diabetes and a more indolent clinical course of the proximal motor neuropathy. Cranial Neuropathy The occurrence of isolated third and sixth nerve palsies is well recognized as a complication of diabetes, as is facial palsy. Trigeminal neuropathy and trigeminal neuralgia do not appear to be more common in diabetics than in the general population. Oculomotor palsy is characterized by rapid onset over hours to days, accompanied by pain in the forehead. Examination shows typical third-nerve palsy with ptosis but sparing of the pupillary reflex. The differential diagnosis includes compressive lesions, especially aneurysms and meningiomas that usually produce early loss of the pupillary reflex. Intrinsic brainstem lesions in the region of the third-nerve nucleus and medial longitudinal fasciculus may produce oculomotor paralysis with pupil sparing. Complete recovery is the rule. The underlying pathology is a vascular lesion in the third nerve that spares the more circumferentially placed pupillomotor fibers. Compression Neuropathies The incidence of compression neuropathies (carpal tunnel syndrome, ulnar neuropathy at the elbow, and peroneal neuropathy at the fibular head) is higher in diabetics than in the 48 population at large. Management of compression neuropathy in diabetics is similar to that in nondiabetics except that surgical decompression should be contemplated only when the nerve entrapment is clearly producing a significant deficit. Transposition of the ulnar nerve is virtually never indicated in the diabetic patient.
Treatment of Diabetic Neuropathy Treatment can be broadly divided into therapies aimed at correcting the underlying pathogenetic mechanism and those that help relieve symptoms. Both are important. Most cases of diabetic neuropathy are treatable to some extent; a nihilistic approach to therapy is not appropriate. Control of Blood Glucose Level Two major studies have proved that normalization of blood glucose levels has a major effect
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in preventing microvascular complications, including neuropathy. Both studies involved randomization of patients 39,49 with type 1 diabetes to either conventional insulin therapy39and a or continuous subcutaneous insulin infusion pumps. In both multiple-injection regimen studies, there was an unequivocal benefit of the near-normoglycemic state. The physician must therefore provide diabetic patients with access to the best methods of obtaining glycemic control. Two recent reviews out-line the pivotal role of glycemic control and 49,50 prevention of neuropathic complications in diabetes. Experimental Therapies An improved understanding of the pathogenesis of diabetic neuropathy affords multiple opportunities for intervention. Phase 2 or 3 clinical trials are ongoing to treat patients with diabetic symmetric polyneuropathy. Therapies being tested include the potent antioxidant 43 42 lipoic acid, two aldose reductase inhibitors, and a growth factor analogue. These putative therapies are based on interrupting the probable pathways that contribute to the development of diabetic neuropathy, as outlined at the beginning of this chapter.
Symptomatic Treatment Physical Approaches In patients with diabetic polyneuropathy, pain and anesthesia are the most troubling features. Anesthesia predisposes the limb to ulceration and infection. Proper footwear is essential, and the diabetic with an anesthetic foot must be instructed in foot care. The insides of the shoes should be inspected three times daily to ensure that no stones or other sharp objects are present or producing perforation. Any suggestion of blistering due to pressure from shoes must be corrected immediately. Any signs of local infection should be treated aggressively by medical and surgical means. We have reviewed elsewhere our approach to the diabetic foot 51 ulcer. In patients with compression neuropathy, education in the avoidance of repeated trauma is important. Crossing of the legs and leaning on the elbows may be the cause of symptoms and should be avoided. Nocturnal splinting may help the patient with carpal tunnel syndrome. Attention to the avoidance of intraoperative pressure or traction trauma to nerves is particularly important in the diabetic. Patients with focal neuropathies should receive aggressive physical therapy. The prognosis for recovery from radiculopathies and plexopathies is excellent. The weakness may be profound and recovery slow, so that avoidance of pressure injury to skin or joint contractures requires the help of the skilled physiotherapist. Pharmacological Approaches The major symptom requiring treatment in the patient with neuropathy is pain. There is some evidence that the major generator of pain in peripheral neuropathy is the distal end of the 52,53 but it is not clear whether distal degeneration or regenerative sprouting is damaged fiber, the most important component. Ectopic impulses may be generated by unstable distal membranes or possibly by ephaptic transmission from demyelinated adjacent fibers. A stepwise treatment protocol for our patients with painful diabetic polyneuropathy has the 6 greatest success rate. In all patients, the same management guidelines for glycemic control and foot care are recommended, regardless of the extent of pain. As a general rule, patients with acute painful diabetic polyneuropathy (defined as pain of less than 6 months' duration) fare better than those with chronic painful diabetic polyneuropathy (symptoms of more than 6 6 months' duration). A list of the drugs that we use in our clinics for the treatment of painful diabetic polyneuropathy is provided in Table 21-4. We restrict our use to therapies that have been shown to be effective in double-blind placebo-controlled trials. We also attempt to target therapy to the type of pain. Click here to view this table.... Joint pain is commonly confused with foot pain, particularly in elderly type 2 diabetic patients with moderate to severe sensory impairment. In these patients, nonsteroidal anti-inflammatory drugs provide relief, and both ibuprofen, 600 mg four times daily, and 54 sulindac, 200 mg twice daily, effectively decrease symptoms. These therapies must, however, be used with caution and are not indicated in patients with renal impairment. Recently, two new compounds were approved by the U.S. Food and Drug Administration (FDA) for initial treatment of painful diabetic polyneuropathy. There are no clinical trials
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comparing the efficacy of these two compounds with each other or with other established therapies. It is difficult to make a direct comparison, based on the published literature. This is because study designs vary considerably among the different trials with respect to the primary endpoints and patient selection. The two new FDA drugs are duloxetine, a dual uptake inhibitor (serotonin and 55 a drug from the antiepileptic family which acts in the spinal norepinephrine), and pregabalin, 56 cord to decrease glutamate levels. Different pain scales were employed in the respective phase 3 double-blind placebo-controlled trials for duloxetine and pregabalin, but the published data generally suggest that the two therapies are equally efficacious at reducing 55,56 Duloxetine is taken with a meal and begun at a dose of either 20 or 30 mg daily. pain. The drug can then be slowly titrated to 60 mg per day, taken in one dose. Patients frequently experience nausea with onset of therapy. A slow titration of drug can usually prevent this common side effect. The most common side effects of duloxetine, besides nausea, are sedation and generalized sleepiness. It is essential that the physician instruct the patient55that duloxetine should not be taken with other serotonin or norepinephrine uptake inhibitors. Pregabalin is begun at 50 to 100 mg daily and can be increased up to 150 mg twice daily. Its side effects are similar to those of duloxetine, although patients do not frequently experience nausea. Pregabalin is a schedule V drug, and unlike its predecessor, gabapentin, there is a possibility it can be habit forming. It is consequently recommended that the drug be slowly 56 discontinued if a decision is made to stop therapy. Unlike duloxetine, pregabalin can be given with serotonin or norepinephrine uptake inhibitors, or indeed with duloxetine. The tricyclic antidepressants remain the most commonly used class of drugs for the treatment of painful diabetic polyneuropathy, especially if the pain has produced a depressed 57 affect or has reduced the patient's ability to sleep. These drugs block norepinephrine and serotonin uptake in the brainstem and spinal cord, which facilitates norepinephrine inhibition of pain pathways. Amitriptyline, nortriptyline, and imipramine are each effective in the treatment of painful diabetic polyneuropathy. A patient with no history of cardiac disease or prostatism can begin with 10 mg of amitriptyline per night. The dose is increased by 10 mg every 3 days until the patient is symptom free, the dose reaches 100 mg, or the patient develops intolerance to sedation and dry mouth, two common side effects. Patients remain on 100 mg per night for 1 month. The same regimen is used if symptoms persist, to reach a dose of 150 mg. There is no observed increase in efficacy with doses greater than 300 mg, 58 and there are reports of worsening neuropathy with amitriptyline abuse. If a patient cannot tolerate amitriptyline, the physician can prescribe nortriptyline, using the same dosing schedule as for amitriptyline. Nortriptyline is less sedating, and there are fewer reports of drug-induced urinary retention and orthostasis than with amitriptyline. Doxepin is the tricyclic antidepressant of choice for treating painful neuropathy in a diabetic patient with a significant cardiac history; the same dosing paradigm for doxepin is employed as for amitriptyline. Another class of antidepressant medications has been used, although less commonly, in the treatment of diabetic polyneuropathy. Trazodone and paroxetine are effective but should not be combined with a57tricyclic antidepressant. Paroxetine, at doses of 40 mg, can provide good relief of symptoms. Two anticonvulsant drugs are efficacious in the treatment of painful diabetic polyneuropathy: 59,60 Accordingly, if a patient continues to experience gabapentin and carbamazepine. disabling pain despite antidepressant therapy, an anticonvulsant is added to the therapeutic regimen. The antidepressant is continued unless the patient is intolerant of side effects. Gabapentin is begun at 300 mg three times daily, and the dose is doubled at weekly intervals until it reaches 900 to 1,200 mg three times daily. Side effects that may require discontinuation of gabapentin include unsteadiness, somnolence or confusion (especially in the elderly), headache, nausea, and diarrhea. Carbamazepine carries a similar side-effect 60 profile, 61although individual patients may tolerate one anticonvulsant regimen better than another. Therapy is begun at 100 mg twice daily, increased by 100 mg each week until the patient is taking 200 mg three times daily. The risk of carbamazepine-associated leukopenia and pancytopenia mandates that patients have total blood counts determined after the first month of therapy and monthly for 3 months. 61 Phenytoin is not a useful anticonvulsant in the treatment of painful diabetic polyneuropathy. If a patient continues to experience pain on therapeutic doses of two medications, capsaicin cream (0.075%), a topical therapy, is applied four times daily. Capsaicin inhibits substance P uptake at sensory endings, and some patients experience increased pain within the first 3 62 days of therapy prior to reporting the onset of pain relief. If these therapeutic strategies fail, we assess the patient's overall health and take one of two approaches. We stop the anticonvulsant and, after the patient has received medical
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clearance from a cardiologist, institute the cardiac antiarrhythmic drug mexiletine. 63 Mexiletine is effective in a subgroup of refractory patients. Therapy is begun at 150 mg daily, with the goal of reaching a final daily dose of 600 to 800 mg in three to four divided doses. Common side effects include nausea and rash in patients who otherwise were 63,64 We do not use intravenous lidocaine, although this antiarrhythmic refractory to treatment. 65,66 drug provides symptom relief and can predict in part a patient's response to mexiletine. Several other oral agents have been used in the treatment of painful diabetic polyneuropathy. Phenothiazines provide symptomatic relief of pain, but the long-term side-effect profile, including particularly the facial and oral dyskinesias, makes this class of drugs unacceptable. Tramadol binds to low-affinity micro-opioid receptors and is effective in the treatment of diabetic polyneuropathy, particularly breakthrough pain. Tramadol is begun at 50 mg daily and can be increased up to 400 mg per day, administered in divided doses every 4 to 6 hours. Side effects include fatigue, somnolence, and confusion. Local nerve blocks, a TENS unit, acupuncture, and biofeedback all are used in patients refractory to the therapeutic approach outlined earlier. Unfortunately, the prognosis for this group of patients is poor, and they frequently require long-term care in a pain clinic. CENTRAL NERVOUS SYSTEM COMPLICATIONS OF DIABETES In addition to the well-recognized peripheral nervous system complications of diabetes mellitus, some derangements of CNS function are commonly encountered in diabetics. Most of these result from the severe metabolic abnormalities that develop during the course of the disease and attempts at its control (e.g., diabetic ketoacidosis or hypoglycemia) or from the cerebrovascular disease known to afflict diabetics with greater frequency.
Metabolic Derangements Diabetic Ketoacidosis Diabetic ketoacidosis and hyperosmolar hyperglycemic state are two of the most serious acute complications of diabetes. These hyperglycemic emergencies continue to be important causes of morbidity and mortality among diabetic patients in spite of major advances in the understanding of their pathogenesis and more uniform agreement concerning their diagnosis and treatment. Once the most common cause of diabetic death (74% of deaths due to diabetes prior to insulin therapy), diabetic ketoacidosis is still a major cause of morbidity (up to 14% 67 of diabetic hospitalizations) and mortality (9% to 10% of deaths due to diabetes in 4 to 9 percent of all hospital discharge summaries among yearly). Currently, it appears 68 for diabetic ketoacidosis patients with diabetes. Mortality rates, which are below 5 percent 68–70 increase substantially with and around 15 percent for hyperosmolar hyperglycemic state, age and the presence of concomitant life-threatening illness. A recent analysis of national mortality data reported that among Americans with diabetes, death rates for hyperglycemic crisis declined substantially between 1985 and 2002, and the downward trend was seen in all 71 age groups and sex-race groups examined. Diabetic ketoacidosis consists of a biochemical triad of hyperglycemia, ketonemia (presence of ketone bodies, acetoacetate and β-hydroxybutyrate in blood and urine), and acidemia. The degree of hyperglycemia is variable and may not be a determinant of the severity of the ketoacidosis. Up to 20 percent of patients may visit the emergency room with either diabetic71 ketoacidosis or hyperosmolar hyperglycemic state without a previous diagnosis of diabetes. Diabetic ketoacidosis develops acutely or subacutely over a period of days as a result of an absolute or relative lack of insulin. It has been repeatedly shown that infection (typically pneumonia and urinary tract infection) is the most common precipitating event in diabetic 68 ketoacidosis and hyperosmolar hyperglycemic state, especially in Caucasian populations. Recent studies suggest that omission of insulin or undertreatment with insulin may be the most important precipitating factor in urban African American populations. In addition, acute medical illnesses such as alcohol abuse, trauma, pulmonary embolism, and myocardial infarction, which occur in both type 1 and 2 diabetes, as well as various drugs that alter carbohydrate metabolism (corticosteroids, sympathomimetic agents, α- and β-adrenergic blockers, excessive use of diuretics) may also precipitate diabetic ketoacidosis. Diabetic ketoacidosis is increasingly noted in newly diagnosed obese type 2 diabetic patients, 71–73 Therefore, the concept that the presence especially in the African American population. of diabetic ketoacidosis in type 2 diabetes is a rare occurrence is incorrect. Although the pathogenesis of diabetic ketoacidosis is better understood than that of hyperosmolar hyperglycemic state, the basic underlying mechanism for both disorders is a reduction in the net effective concentration of circulating insulin, coupled with a concomitant
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elevation of counter-regulatory stress hormones (glucagon, catecholamines, cortisol, and growth hormone). Thus, they are extreme manifestations of impaired carbohydrate regulation that occur in diabetes. In patients with ketoacidosis, the deficiency in insulin may be absolute, or it may be insufficient relative to an excess of counter-regulatory hormones. This lack of insulin, coupled with the effect of counter-regulatory hormones, especially glucagon, causes impaired entry of glucose into target tissues and augmented glucose production via glycogenolysis and gluconeogenesis, leading to hyperglycemia. From a quantitative standpoint, increased glucose production by the liver and kidney represents the major pathogenic disturbance responsible for hyperglycemia in these patients, and gluconeogenesis plays a greater metabolic role than glycogenolysis. In addition, hepatic fatty acid catabolism is increased, leading to ketosis. These metabolic derangements produce the typical clinical syndrome of dehydration due to osmotic diuresis, with thirst, polyuria, anorexia, and fatigue. Only about 10 percent of patients with diabetic ketoacidosis progress to frank coma, but most show some alteration of 74 consciousness. Focal neurological findings and seizures are not common. The pathophysiological mechanisms leading to stupor and coma are not adequately understood and appear to be complex and multifactorial. Serum osmolality has been shown to correlate significantly with mental status in both diabetic ketoacidosis and 69,71 hyperosmolar Most authors hyperglycemic state and is the most important determinant of mental status. agree that serum hyperosmolality is a major contributing factor. Other possible mechanisms include acidosis, alterations in cerebral blood-flow, disseminated intravascular coagulation, lysolecithin and free fatty acid toxicity, hypoxia, and a defect in brain carbohydrate metabolism. Serum hyperosmolality provides a driving force for water efflux from brain cells. The resultant shrinkage of cells is counteracted, in part, by slow inward diffusion of osmotically active agents (e.g., sodium or glucose) into brain tissue and by production of “idiogenic osmoles.” These include unidentified osmotically active molecules that contribute to the osmotic pressure of brain cells but are not measurable as part of the usual osmotically active 75 agents. They are believed to arise at least in part from production of free amino acids, such as glutamine, glutamate, and aspartate, and from dissociation of free intracellular cations, especially potassium. Clearly, such changes in intracellular constituents would have significant effects on cellular excitability in addition to providing osmotic stabilization, which could play a role in the development of encephalopathy in diabetic ketoacidosis. It is also possible that hyperosmolality disrupts the blood–brain barrier, thereby altering the 76 brain's internal environment and contributing to the encephalopathy. Although hyperosmolality itself may produce brain dysfunction, its successful treatment may trigger an even more profound disorder—cerebral edema. Cerebral edema constituted a significant cause of mortality before the use of low-dose insulin regimens, and it continues to be seen in children, with resultant coma and death. Focal neurological signs are extremely uncommon in diabetic ketoacidosis, but hemorrhagic 77 brain infarction or multifocal hemorrhage may complicate the condition. Conversely, stroke in a diabetic patient can trigger diabetic ketoacidosis. Acidosis alone is usually not a cause of encephalopathy in most cases of diabetic ketoacidosis because the respiratory compensation induced by the metabolic acidosis reduces CSF as well as serum CO2, and the blood–brain barrier protects the brain from acid metabolites. Thus, the pH of the CSF is maintained at nearly normal in the setting of significant systemic acidosis. There is no correlation between the state of consciousness and the serum pH. In severe and protracted cases of diabetic ketoacidosis, the pH of the CSF may fall and stupor or coma may result. Furthermore, during treatment of systemic acidosis with bicarbonate, a transient acidification of CSF may occur because increased CO2 in the blood is transported into the CSF more rapidly than is the bicarbonate. This produces a mild, transient depression in the level of consciousness. There is poor correlation between the level of consciousness and the level of ketone bodies in blood or CSF in diabetic ketoacidosis. Although experimental infusion of acetoacetate into animals may cause coma, β-hydroxybutyrate, the78major abnormal anion in diabetic ketoacidosis, does not produce encephalopathy. Despite reduced arterial partial pressure of carbon dioxide (Pco2), dehydration, and sometimes hypotension, cerebral blood-flow has been shown to be normal or even greater than normal in comatose ketoacidotic patients. Thus, there may be impaired regulation of cerebral blood-flow, but clearly hypoperfusion cannot be the cause of the alteration in
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consciousness in diabetic ketoacidosis. Pathological evidence of disseminated intravascular coagulation (DIC) has been found in several cases of fatal diabetic ketoacidosis, with antemortem documentation of disturbance 79–81 It has been suggested that of fibrinolytic and coagulation mechanisms in some instances. DIC may be a major factor contributing to the encephalopathy of diabetic coma, but clinical evidence of this entity seldom develops during diabetic ketoacidosis, and other autopsy studies have failed to find pathological support for this concept. There is one reported case of nonketotic diabetic coma with clinical and laboratory evidence of DIC that responded to anticoagulant therapy. Another possible contribution to CNS dysfunction in diabetic ketoacidosis may come from the toxic effects of elevated levels of lysolecithins and nonesterified fatty acids, analogous to their 82 putative toxic effects in Reye's syndrome and acute pancreatitis. It is possible that in the setting of grossly deranged carbohydrate and lipid metabolism in diabetic ketoacidosis, a primary defect in cerebral carbohydrate metabolism underlies the encephalopathy. Complications of Therapy for Diabetic Ketoacidosis
Various other complicating factors may serve to contribute to the degree of CNS dysfunction, either initially or during the course of therapy, including electrolyte disorders, thrombotic phenomena, and infection. Hypokalemia and hypophosphatemia frequently develop with insulin and fluid replacement, and although the theoretical CNS sequelae of hypophosphatemia have not been clearly 83,84 it is prudent to replace deficits. demonstrated to occur in diabetic ketoacidosis, Hyponatremia may develop with overly rapid correction of hyperosmolality, especially in 85 cases of inappropriate antidiuretic hormone (ADH) secretion. Thromboembolic disorders can complicate the course of diabetic ketoacidosis, contributing to the degree of stupor or coma. They are precipitated by increased blood viscosity due to dehydration and by the increased platelet adhesiveness and decreased fibrinolytic activity 86 that occur in these patients. Complications such as myocardial,86cerebral, or mesenteric infarction are important causes of death in ketoacidotic patients. Infection may be difficult to recognize because some degree of hypothermia is common in diabetic ketoacidosis and may mask a fever, and because leukocytosis is commonly seen even in the absence of infection. Signs of meningitis, however, would not be masked. Hypoxemia may be a contributing factor to CNS depression in certain circumstances, such as severe diabetic ketoacidosis with respiratory depression, and during vigorous fluid replacement with crystalloids, when some degree of pulmonary edema or adult respiratory 87 distress syndrome may develop. In addition, there may be a shift to the left of the hemoglobin–oxygen dissociation curve owing to depressed levels of 2,3-diphosphoglycerate 88 in red blood cells. Cerebral edema may develop during otherwise successful treatment of diabetic ketoacidosis—an occurrence more common in young patients and almost uniformly fatal 85 once clinically apparent. The typical setting is that of an apparently good response to insulin and fluid therapy, with correction of the acidosis and improvement in hyperglycemia. Sudden neurological deterioration may be heralded by headache and confusion. It rapidly progresses to markedly increased intracranial pressure with herniation. Pathological examination reveals massive cerebral edema. Rapid, aggressive therapy with mannitol has salvaged a few 89 patients, but these have had severe neurological sequelae. When there is any sign of increased intracranial pressure associated with rapid neurological deterioration, intracranial pressure monitoring should be considered. 90–92
93
and CT scans have shown that some degree of Serial measurements of CSF pressure elevated intracranial pressure or brain swelling is common during the course of therapy for diabetic ketoacidosis in both children and adults. In one series, there was a correlation 90–92 In between the degree of increased pressure and transient93depression in consciousness. other cases, the swelling appeared to be asymptomatic. The pathogenesis of this cerebral edema is not clearly understood. Osmotic dysequilibrium is thought to develop between brain and blood as a result of rapid correction or overcorrection 94 75 of “idiogenic osmoles,” by of serum osmolality. It may be exacerbated by production 95 activation of the sodium-hydrogen ion transport system, or by serum hyponatremia. 96 Alterations in the cerebral capillary blood–brain barrier may play a role in edema formation. 97 In some cases, arterial thrombosis may precipitate the event. Although the devastating and
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severe cerebral edema following initial chemical improvement is uncommon, subclinical and asymptomatic brain edema may occur even before treatment, suggesting a role for as yet unidentified factors. Fatal edema during treatment may be a progression of an already 98 initiated physiological process. 71
No single factor has been identified to predict the development of cerebral edema. Lowering blood glucose in patients with diabetic ketoacidosis or hyperosmolar hyperglycemic state at a rate of 50–70 mg/dl per hour with “low-dose” regimens (10 U/h) and adding 5 percent dextrose to the hydrating solution when blood glucose is approximately 300 mg/dl are 91,92 pru- dent until more information on the mechanism of cerebral edema is obtained. Although cerebral edema has occurred even when fluids and insulin were administered 99 it appears that the risk is greater if fluids are replaced at a rate greater than 4 cautiously, 2 85 L/m daily and if hyponatremia develops. Hyperosmolar Hyperglycemic State The term hyperosmolar hyperglycemic state has replaced the former terms hyperglycemic hyperosmolar nonketotic coma and hyperglycemic hyperosmolar nonketotic state to reflect the facts that (1) alterations of sensation may often be present without coma, and (2) the hyperosmolar hyperglycemic state may consist of moderate to variable degrees of clinical ketosis as determined by the nitroprusside method. The incidence of hyperosmolar hyperglycemic state is difficult to determine owing to a lack of population-based studies and the multiple illnesses often found in these patients. In general, it is estimated that the rate of hospital admissions due to hyperosmolar hyperglycemic state is lower than the rate due to diabetic ketoacidosis and accounts for less than 1 percent of all primary diabetic admissions. Common precipitating factors include infection, extensive burns, acute pancreatitis, hyperalimentation, stroke, myocardial infarction, corticosteroid therapy, use of certain drugs (e.g., furosemide, dopamine, phenytoin), peritoneal dialysis, and, especially, major surgeries. Although it is most commonly encountered in elderly diabetics, it is also seen in young type 1 diabetics, and the same patient may develop diabetic keto-acidosis or nonketotic hyperosmolar coma on different occasions. In hyperosmolar hyperglycemic state, there is a residual amount of insulin secretion that minimizes ketosis by preventing hepatic activation of ketogenesis but is insufficient to control hyperglycemia. Hyperglycemia leads to osmotic diuresis in both diabetic ketoacidosis and hyperosmolar hyperglycemic state. The extent of dehydration, however, is typically greater in the latter. At first, this seems paradoxical, since patients with diabetic ketoacidosis experience a dual osmotic load of ketones and glucose. The more severe dehydration in hyperosmolar hyperglycemic state, despite the lack of severe ketonuria, may be attributable to the more gradual onset and longer duration of metabolic decompensation and partially to the fact that patients typically have impaired fluid intake. Other factors that may contribute to excessive volume losses include diuretic use, fever, diarrhea, and nausea and vomiting. Severe dehydration, together with the older average age of patients with hyperosmolar hyperglycemic state and the presence of other comorbidities, almost certainly accounts for the higher mortality of this disorder. The metabolic derangement progresses gradually over several days to weeks, with hyperglycemia, osmotic diuresis, and dehydration, eventually leading to extremely high serum glucose levels (often greater than 800 mg/dl) and serum osmolality (>350 mOsm/kg). Virtually all patients with hyperosmolar hyperglycemic state show some degree of renal 94 dysfunction, which potentiates the development of hyperglycemia. There is no significant associated ketoacidosis. The small amount of insulin activity present100 in these patients is believed to be sufficient to prevent hepatic activation of ketogenesis. 101
Many patients show some degree of metabolic acidosis due to either lactic acidosis or an unidentified anion. Some have small amounts of keto acids present; indeed, rather than being two pathophysiologically distinct entities, diabetic ketoacidosis and hyperosmolar hyperglycemic state probably represent extremes of a continuum, the metabolic result of decreased or absent insulin effect and increased glucagon effect. A large proportion of patients in a hyperosmolar hyperglycemic state have accompanying serious medical conditions, which in some cases may have triggered the metabolic changes. These include gram-negative pneumonia, myocardial infarction, stroke, gastrointestinal 101,102 hemorrhage, gram-negative sepsis, pulmonary embolism, uremia, and pancreatitis. These illnesses may contribute to the inadequate hydration and lack of recognition of symptoms during progression of the syndrome and are the major reason for the high 67,101 mortality rate. Hyperosmolar hyperglycemic state has also been reported in association with corticosteroid
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therapy, thiazide diuretics, renal dialysis, and severe burns, precipitating or associated factors.
or without clear
Progressive lethargy leading to unresponsiveness is the most common reason for seeking 101 medical attention, but a number of other neurological symptoms and signs may be the presenting feature. Seizures and focal neurological deficits are quite common, unlike in 74 106 94 diabetic ketoacidosis. Focal and generalized seizures may occur, and stroke-like 102 syndromes are common, sometimes with radiological evidence107,108 of cerebral infarction. A hallucinations, and flapping tremor of the upper extremities, hemichoreoathetosis, hemianopia have also been reported. A patient who died in a hyperosmolar hyperglycemic state developed lateral pontine and extrapontine myelinolysis, presumably owing to the rapid 109 increase in serum osmolality. Alterations in the patient's level of consciousness are more prevalent in hyperosmolar hyperglycemic state than diabetic ketoacidosis. In one series, 30 of 34 patients had a 102 decreased level of consciousness, reflecting both the higher serum osmolality (due to glucose and sodium) and the compounding effects of associated medical illness on the encephalopathy. Despite the very high serum osmolalities reached, with serum glucose sometimes surpassing 2,000 mg/dl and osmolality greater than 450 mOsm/kg, treatment with insulin and fluids has only rarely resulted in cerebral edema, such as that encountered in diabetic ketoacidosis. 94 Arieff described five cases, all of which involved rapid lowering of plasma glucose to below 300 mg/dl in the first 24 hours of therapy. This situation, he believed, produces an 75,94 accumulation of “idiogenic osmoles” within the brain, thereby producing cerebral edema. Little or no insulin appears to be required to correct the hyperglycemia of the hyperosmolar 110 hyperglycemic state once fluid replacement is undertaken. Lactic acidosis is more common in diabetics than in the general population, but accurate 67 study, 50 percent of the reported cases of figures on its incidence are not available. In one 111 idiopathic lactic acidosis occurred in diabetics. The reason for this association is not clear, but vascular disease and congestive heart failure predisposing to tissue ischemia may be responsible. In past years, administration of the biguanide oral hypoglycemic agent phenformin was associated with an increased incidence of lactic acidosis. This agent has not been available for a number of years. Treatment should be directed at reversing the underlying cause of lactic acid accumulation whenever possible and to correcting severe acidemia, which sometimes requires large 112 that bicarbonate treatment may amounts of sodium bicarbonate. It has been suggested 113 worsen lactate levels by increasing lactate production. Hypoglycemia Hypoglycemia may occur in a large number of different conditions, but excessive doses of insulin for the treatment of diabetes are the most common cause of severe hypoglycemic coma. In addition, patients with early diabetes114 and diabetics with renal insufficiency may show spontaneous mild postprandial hypoglycemia, and both insulin and oral hypoglycemic agents may produce hypoglycemia of variable severity with a corresponding range of neurological symptoms and signs. Newer, rapidly acting insulin analogues have not had a 115 significant effect on the rate of hypoglycemic episodes in diabetics. Not only are diabetics more prone to developing hypoglycemia, but they also may be particularly sensitive to it. There is evidence that chronically high blood glucose produces a reduction in the number and activity of glucose transporters in the brain, so that glucose 111 transport is lower at a given low plasma glucose level. Clinically, this correlates with the “hypoglycemic” symptoms that occur despite blood glucose levels in the normal range in diabetics after rapid reduction from hyperglycemia. Intensively treated diabetics with tight control seem to be at greater risk of both severe and symptomatic hypoglycemia. One study has shown that the epinephrine and other counter-regulatory responses were delayed and diminished in these patients, and electroencephalographic changes compatible with hypoglycemia were more commonly seen than in poorly controlled or nondiabetic patients with similar blood glucose levels. The metabolic alterations underlying the brain dysfunction and pathological changes that occur in hypoglycemia are not completely understood. Many comparisons have been drawn 116,117 Notable differences include the profound between anoxic and hypoglycemic damage. functional changes in brain activity early in hypoglycemia, with alterations in consciousness despite relative maintenance of cerebral blood-flow, oxygen utilization, and high-energy
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phosphate stores, as well as the remarkable capacity for recovery even after prolonged hypoglycemic coma. It appears that energy failure is not the cause of the alteration in consciousness in hypoglycemic patients. It is probable that some other aspect of glucose metabolism is rapidly impaired despite high energy stores. The ongoing oxidative metabolism suggests that other substrates are being utilized, such as endogenous glycogen, and this may contribute to the patient's capacity for recovery. Striking similarities have been noted among the pathological changes in anoxia, status 116 epilepticus, and hypoglycemia with respect to the nature and distribution of cell changes. All exhibit “selective neuronal vulnerability,” with damage predominating in certain layers of 117 the cerebral cortex, areas of the hippocampus, parts of the striatum, and the cerebellum. Some differences exist on the subcellular level and in topographical distribution between hypoglycemia and anoxia or status epilepticus, but the similarities are so great as to suggest a common pathophysiological mechanism in all three instances. A great deal of evidence has been gathered implicating increased intracellular calcium and excitatory neurotransmitters as possible mediators of this selective cellular injury. Intracellular acidosis and toxic free radical 17 formation may also be involved. If strict control is attempted, an occasional “insulin reaction” is unavoidable. Diabetics are familiar with the typical symptoms of the “sympathetic” phase of hypoglycemia, which usually occurs at plasma glucose levels of less than 40 to 50 mg/dl. This phase includes dizziness, 118 Such warning signs may weakness, tremor, and palpitations due to epinephrine release. 118 be absent in diabetics with autonomic dysfunction or may be neglected because of intervening “neuroglycopenic” symptoms affecting behavior and judgment. One study showed nocturnal hypoglycemia in 22 of 39 poorly controlled diabetics; it lasted more than 3 hours in 119 17 patients. Although family members reported daytime behavioral abnormalities, only 6 patients were aware of hypoglycemia. Recurrent nocturnal hypoglycemia has produced the 119 clinical picture of dementia, which was reversed with appropriate treatment. In other patients, repeated or prolonged hypoglycemic attacks may produce dementia and irreversible 120 pathological changes. The neurological effects of hypoglycemia have been described as progressing in a reverse 121 phylogenetic order, with the cerebral hemispheres affected first and most commonly, and patients subsequently progressing to diencephalic, mesencephalic, and finally medullary phases of dysfunction. This ordered topographical progression is not always borne out in clinical experience; instead, different areas of the brain appear to be most affected in different attacks. Four forms of acute metabolic encephalopathy have been described in hypoglycemia: (1) delirium, either quiet or manic; (2) multifocal brainstem dysfunction with neurogenic hyperventilation and decerebrate spasms, but with preserved oculocephalic and oculovestibular responses; (3) stroke-like events with or without coma, with focal deficits that may shift from one side to the other, tend to resolve, and may occur without evidence of 122,123 ; and (4) seizures, single or multiple, which may underlying vascular or other pathology be the only manifestation of124 hypoglycemia. Hypothermia is common and may be a clue to the presence of hypoglycemia. Although there is not a tight correlation between plasma glucose levels and neurological 120 symptoms, confusion and behavioral changes generally appear at levels below 30 to 40 mg/dl, with stupor and seizures occurring as the level declines further, and profound coma 125 with levels below 10 mg/dl. In milder cases, hypoglycemic symptoms are quickly reversed by oral or intravenous glucose. In some cases, however, coma may persist despite restitution of normoglycemia, for reasons that are not clear. In general, complete recovery is the rule, even after an hour or more of 120 and repeated coma. There may be some residual focal neurological signs after recovery, 120,125 severe attacks are known to produce cognitive decline. In addition to the behavioral changes, alterations in consciousness, and focal hemispheric and brainstem signs described earlier, 126 hypoglycemia has also been reported to cause recurrent or persistent choreoathetosis (presumably reflecting susceptibility of the basal ganglia to hypoglycemia) and recurrent focal neurological deficits in the distribution of a 127 stenosed atherosclerotic vessel (probably reflecting disruption of borderline perfusion and substrate delivery in the normoglycemic state).
Cerebrovascular Disease Stroke is two to six times more common in diabetics than in nondiabetics and is involved in 128 about 25 percent of diabetic deaths. Although much of129this increase in incidence of stroke is attributable to an increase in cerebral atherosclerosis, other factors also are probably
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important. Hypertension is common in diabetics and, in addition to contributing to atherosclerosis, also promotes both intracranial small-vessel disease and heart disease, 130 which can lead to lacunar and embolic infarction, respectively. Atherosclerotic heart 131 disease and congestive heart failure are more common in diabetics than in nondiabetics. Metabolic and hematological abnormalities occurring in diabetes may aggravate the damage resulting from any of these ischemic insults. Hemorrhagic stroke is not increased in incidence 132,133 in diabetes and may actually be less frequent. It was believed until recently that cerebrovascular disease and stroke were not more common in diabetics than in the general population. Large autopsy studies, however, have shown an increase in encephalomalacia (cerebral infarcts) in diabetics, with 1.5 to 2.0 times the 134 incidence of infarcts, particularly in small, deep, and infratentorial areas, suggesting small-vessel disease. The increase over nondiabetics was more apparent in subjects younger than 60 years. Hypertension did not account for all the increased incidence of encephalomalacia in diabetics. Furthermore, in all of these studies, hemorrhagic stroke was found to be less frequent in diabetics than in nondiabetics, which would not be expected if hypertension were the only pathogenetic influence. Diabetes is an important risk factor for 135 African Americans, stroke in blacks. Both diabetes and hypertension are more common in 135 resulting in stroke being the third leading cause of death in U.S. blacks. A recent meta-analysis of all available randomized trials suggests that improved diabetes control 136 reduces the risk of stroke in both type 1 and 2 diabetic patients. Hypertension and Arteriolosclerosis Hypertension is known to be a major risk factor for cerebral infarction. It contributes to the pathogenesis of lacunar and atherothrombotic infarction and also to that of cardioembolic brain infarcts as a result of related heart disease and atrial fibrillation. Hypertension is 1.5 to 3 times more common in diabetics than in the general population. One half of129,137 diabetics have a medical history of hypertension, and it is controlled in only 30 to 50 percent. Arteriolosclerosis is associated with hypertension. It is characterized by thickening of the arteriolar wall (“hyaline degeneration”) and in some cases permeation of plasma into the wall, 138,139 This process appears to be rendering it an amorphous mass (“fibrinoid necrosis”). physiologically related to aging but is accelerated by hypertension and is also increased in 138,139 In brain, it diabetic tissue, where it may be seen even in the absence of hypertension. has been 140 found to be increased in proportion to the increased frequency of hypertension in diabetics. The clinical correlate of arteriosclerosis is infarction, particularly of deep structures supplied by end-arterioles (so-called lacunar infarction). Intraparenchymal hemorrhage, another common consequence of hypertensive small-vessel disease, is actually reduced in incidence in diabetics, as noted earlier. One study found arteriolar necrosis, which may lead to hypertensive hemorrhages, to be significantly less common in diabetics than in nondiabetics of equivalent hypertensive status. It has been suggested that some specific diabetic changes protect the arterioles from hypertensive damage. Large-vessel atherosclerosis is also promoted by hypertension. Atherosclerosis Atherosclerosis is known to be more common in diabetics, to be more severe at an earlier 128,129,141 The vessels of the lower age, and to involve smaller vessels than in nondiabetics. extremities, heart, and brain all are affected. Comparison of atherosclerosis in the circle of Willis as a function of sex, age, and diabetic status showed striking increases in the frequency and severity of atherosclerosis in diabetes, especially in women, who, by the fourth 138 decade, surpassed diabetic men in this regard. These data were not corrected for the presence of hypertension, which is more common in diabetics and certainly contributes to the increase in atherosclerosis. The epidemiology of vascular disease in diabetics has been thoroughly reviewed 142 elsewhere. In those with onset of diabetes before 40 years of age, the influence of the duration of diabetes on the severity of vascular disease is striking, with very few patients free from significant disease after 20 years of diabetes. Autopsy studies have provided many data but are not necessarily representative of the population as a whole. Population studies have 132,133,138,140,143,144 and have shown confirmed the excess risk of atherosclerosis in diabetes that the usual measurable associated risk factors cannot account for the total increase in symptomatic arteriosclerotic disease in diabetics.
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Stroke in Diabetics In an individual patient, determining whether a stroke has occurred (and, if so, its pathogenesis) is difficult. This leads to methodological problems in epidemiological studies of stroke and diabetes. Although CT scans are a major help in distinguishing hemorrhagic events, they usually are negative in acute ischemic stroke. The best criterion for determining that a stroke has occurred is a neurologist's clinical evaluation at the time of the acute events. An attempt should be made to determine the subtype of ischemic stroke: large-vessel occlusive disease due to atherothrombosis, lacunar infarction due to arteriolar disease, or embolic stroke due to cardiac disease. Diabetes and related conditions may contribute to each of these. The increased incidence of stroke in diabetics has been well documented in epidemiological 132,133,143 145 It is now accepted as an independent risk factor. Although one study studies. 146 showed no increased risk of stroke in normotensive diabetics, this same study did find an increased risk of stroke in hypertensive diabetics compared with hypertensive nondiabetics. Furthermore, a number of large prospective studies, including the Honolulu Heart Program, the Gothenburg Cohort Study, and the Framingham Study, have found diabetes to provide a 132,133,143 separate risk of stroke, independent of associated risk factors. 132,143
The relative risk of stroke due to diabetes itself is about twice normal. Even high-normal serum glucose levels in 132 those not carrying a diagnosis of diabetes are associated with an increased risk of143 stroke. Including all risk factors, the relative risk of stroke in diabetics is higher in133women and may be as high as 13 times the normal risk in the younger age groups. In addition to increased frequency of stroke in diabetes, the resulting impairment tends to be greater and survival poorer in diabetic than in nondiabetic stroke patients. In a study of patients with peripheral vascular disease, the incidence of stroke with permanent neurological deficit was twice as high in diabetics as in nondiabetics with equivalent atherosclerotic 146 cerebrovascular disease, as determined by noninvasive tests. Nondiabetics, however, had more transient ischemic attacks (TIAs), and the total numbers of ischemic events in the two groups were equivalent. This suggests that diabetics are more prone to irreversible destruction of ischemic brain tissue. In another study, diabetic patients followed for 5 years after their first stroke or TIA showed only a 20 percent 5-year survival, compared with 40 147 percent in matched or random nondiabetic stroke patients. Thus, diabetes provides an independent risk of ischemic stroke, separate from other risk factors. In addition, it appears to increase the morbidity and mortality following stroke. This may be mediated in part by an increase in the severity of atherosclerosis in diabetics. It is possible that some risk factors serve to increase atherosclerosis in diabetics even beyond the increase that would be expected on the basis of known associated risk factors, such as hypertension, hyperlipidemia, and obesity. The possibilities include an atherogenic effect of hyperglycemia itself or of insulin, alterations in blood coagulability and viscosity, possible effects of microvascular disease on arterial walls, and a genetic predisposition to enhanced 128,129,140 atherogenesis in diabetics. It is the clinical impact of cerebrovascular disease, rather than the severity of atherosclerosis, that is measured in epidemiological studies. Although the rate of stroke may reflect an actual increase in vascular disease per se, it may also reflect an increased tendency to stroke on the basis of blood or tissue factors. Certain features common in diabetes may serve to enhance the rate of atherogenesis, promote thrombosis, or reduce the ability of brain tissue to tolerate an ischemic insult. Hyperglycemia, for example, has been associated with an increased morbidity after stroke, and in animals it enhances the extent and degree of brain damage from controlled degrees of 148 cerebral ischemia. This has been shown to result from intracellular lactic acidosis in tissue receiving a trickle of flow rich in glucose. Because hyperglycemia is common following stroke 149 even in patients not previously diagnosed as diabetic, it clearly may aggravate the morbidity due to stroke; furthermore, stroke and TIA occur more frequently in patients with 150 may act in another manner to promote stroke, in poorly controlled diabetes. Hyperglycemia 151,152 Alterations in platelet adhesiveness, coagulation that it may promote atherogenesis. 153 factors, and fibrinolytic activity have been documented in diabetics. Through their relation to endothelial cell function, these factors may be involved in the pathogenesis of 154 97 atherosclerosis. Clearly, they may also lead to the thrombotic complications of diabetes. A prospective study showed a significantly increased risk of arterial occlusion in diabetic men, with increased spontaneous platelet aggregation or abnormalities in fibrinogen or von 155 Willebrand's factor.
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Thus, diabetes, with its associated metabolic and vascular abnormalities, greatly increases the risk of ischemic stroke. Some of the abnormalities may not be modifiable, but a significant part of this increased risk may be amenable to treatment, with good control of hyperglycemia 136,142 and hypertension.
Other Central Abnormalities The most common CNS abnormalities in diabetics result from cerebrovascular disease and metabolic derangement, as described earlier. Whether there are, in addition, primary abnormalities of the CNS inherent to diabetes is less clear. 156
A number of autopsy studies have documented spinal cord lesions in diabetics. Many show degeneration of the posterior columns, which probably is secondary to disease of the dorsal 157 Corticospinal tract degeneration has been related to root ganglia or the peripheral nerves. 158,159 Some authors believe that diabetic myelopathy lesions higher in the nervous system. 160 exists as a distinct entity. The existence of a primary diabetic encephalopathy is similarly unclear. Several reports document 161–164 slowing of conduction velocity in brainstem auditory or somatosensory evoked but it is possible that this is due to ischemic microvascular damage. Overall, potentials, there is no convincing clinical or pathological evidence to suggest brain dysfunction or lesions 120,138,139 that could not be explained on the basis of previous metabolic or vascular insults. Some of the peripheral complications of diabetes can lead indirectly to alterations in brain function. Autonomic neuropathy may produce syncope from orthostatic hypotension. Generalized cerebral hypoperfusion and decreased levels of consciousness may occur with a 165 painless myocardial infarction. Uremic encephalopathy should be considered in a diabetic with nephropathy. Other CNS changes reported in diabetes include abnormal hypothalamic regulation of166growth hormone in poorly controlled diabetes, focal seizures with isolated hypomagnesemia, 167 and pituitary insufficiency. The prevalence of migraine is reported to be lower in diabetics, and it has been167 suggested that the diminished vasodilatory capacity in diabetic brain may be Diabetics may be at increased risk of developing neuroleptic-induced tardive protective. 168–170 dyskinesia. Certain other neurological entities are associated with secondary diabetes, including Friedreich's ataxia and myotonic dystrophy. An increased prevalence of diabetes has also 171 been shown in Huntington's disease. A large proportion of patients with stiff-person syndrome are diabetic, with anti–islet cell antibodies and antibodies172 directed against glutamic acid decarboxylase that are strongly associated with this condition. Although it has commonly been held that diabetics are more prone to infection, presumably on the basis of impaired neutrophil function, epidemiological data do not confirm a significant 173,174 Certain unusual infections, increase in infection in diabetics other than bacteriuria. 173 however, are seen essentially only in diabetics. Rhinocerebral mucormycosis is the only one affecting the CNS. This fungal infection of the nose and orbit may invade the brain, with 131 It is neurological sequelae, or it may invade locally to produce peripheral facial weakness. 131 more common in acidotic patients but may occur in any diabetic. Although the greatest impact of diabetes is on the peripheral nervous system, there are significant effects on central neurological function, mediated by vascular disease and metabolic derangements. Neurological disease in a diabetic should be viewed with this in mind. ACKNOWLEDGMENTS The secretarial assistance of Judith C. Boldt is greatly appreciated. The work of the authors is supported by the National Institutes of Health (NS36778 and NS38849), UPDATE, the Juvenile Diabetes Research Foundation (JDRF) Center for the Study of Complications in Diabetes, a grant from the American Diabetes Association, and the Program for Neurological Research and Discovery. Previous
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Table of Contents This Chapter by Chapters
Keyword Index
Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 22 Sex Hormones and the Nervous System HYMAN M. SCHIPPER •
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SEX STEROID–NEURAL INTERACTIONS Organizational Effects Activational Effects HUMAN MENSTRUAL CYCLE AND HORMONAL CONTRACEPTIVES MIGRAINE STROKE EPILEPSY MOVEMENT DISORDERS Chorea Parkinsonism Wilson's Disease Other Movement Disorders NERVOUS SYSTEM NEOPLASMS Meningiomas Gliomas Other Tumors MULTIPLE SCLEROSIS ALZHEIMER'S DISEASE NEUROPSYCHIATRIC DISORDERS The Porphyrias Premenstrual Syndrome Depression and Psychosis SLEEP DISORDERS INTRACRANIAL HYPERTENSION NEUROMUSCULAR DISEASES Catamenial Sciatica Other Neuromuscular Disorders CONCLUDING COMMENTS
The effects of sex steroids on neurological function in health and disease constitute a rich and rapidly expanding area of basic and clinical neuroscience. Several factors account for the burgeoning of this field over the past several decades. First, the development of radioimmunoassay, autoradiography, immunocytochemistry, and in situ hybridization has permitted meticulous determinations of circulating hormone profiles and mapping of steroid
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hormone binding sites within the nervous system. Second, ample evidence has accumulated attesting to the potent modulatory effects of sex hormones on monoaminergic, cholinergic, and peptidergic neurotransmission and the role of such interactions in diverse normal and pathophysiological states. Finally, there is the recognition by clinicians that many neurological conditions are influenced by hormonal fluctuations associated with the menstrual cycle, pregnancy, the menopause, and use of oral contraceptives. A growing appreciation of these relationships is currently being rewarded by the development of specific hormonal and antihormonal therapies for neurological disorders as disparate as catamenial epilepsy and acute intermittent porphyria. SEX STEROID–NEURAL INTERACTIONS In mammals of both sexes, estrogens, progestins, and androgens represent the three major classes of endogenous sex steroids (Fig. 22-1). Prototypical hormones in each class include 17β-estradiol, progesterone, and testosterone. Plasma sex hormones are secreted directly from ovaries, testes, and adrenal glands but may also be derived from enzyme-mediated conversions from prohormones in extraglandular tissues (Fig. 22-2). Important examples of 4 the latter include the aromatization of the androgens Δ -androstenedione and testosterone to estrone and 17β-estradiol, respectively, in brain and adipose tissue. Approximately 98 percent of the circulating sex hormone pool is protein bound and functionally inert. The remaining “free” fraction is highly lipophilic and readily penetrates the blood–brain barrier and neuronal cell membranes. Within the cytoplasm or nucleus of the target cells, sex hormones form complexes with specific receptor proteins. Subsequent binding of these complexes to steroid response elements within the promoter regions of various genes induces or suppresses the transcription of these genes. In neurons, sex steroids modulate the biosynthesis of enzymes and structural proteins concerned with cell membrane function, energy metabolism, hormonal sensitivity, and neurotransmission. In addition, steroid hormones are capable of far more rapid1,2 modulation of neuronal firing by direct (nongenomic) interactions with nerve cell membranes.
FIGURE 22-1 Sex steroids, nonsteroidal estrogens, and steroid antagonists.
(Courtesy of Dr. E. E. Baulieu, Faculté de Médecine de Bicêtre, France, with modifications. From Schipper HM: Neurology of sex steroids and oral contraceptives. Neurol Clin 4:721, 1986.)
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4
FIGURE 22-2 The brain-pituitary-ovarian axis. Δ A, delta-4-androstenedione;
ACh, acetylcholine; DA, dopamine; E1, estrone; E2, estradiol; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; 5-HT, 5-hydroxytryptamine (serotonin); LH, luteinizing hormone; NE, norepinephrine; P, progesterone; T, testosterone. In rodents and primates of both sexes, estrogen-binding neurons are located in the preoptic area, medial basal hypothalamus, medial amygdala, and circumventricular organs. Estrogen-binding neurons also reside, albeit to a lesser extent, in the basal forebrain, hippocampus, several thalamic nuclei, sensory regions of the brainstem and spinal cord, and 3,4 target neurons the neonatal neocortex. The topographies of the progestin and androgen 3 exhibit considerable overlap with the estrogen-concentrating populations.4,5In addition to and undergo neurons, some periventricular astrocytes also contain estrogen receptors 6 morphological and histochemical changes after sex hormone exposure. These latter observations may be important insofar as some human glial tumors appear to be responsive to sex hormones.
Organizational Effects Organizational effects refer to the irreversible dif-ferentiation of neural circuitry resulting from exposure to sex steroids during critical periods of brain development. This is perhaps best exemplified by the role sex steroids play in the gender-specific organization of the 7 hypothalamic-pituitary-gonadal axis in neonatal rodents (Fig. 22-3). Sexually dimorphic regions have been defined in the human brain, including the sexually dimorphic nucleus of the preoptic area, subregions of the hypothalamic suprachiasmatic nucleus, the bed nucleus 8 of the stria terminalis, and certain white matter tracts. Clinical and experimental evidence
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suggests that abnormal exposure to circulating sex hormones in utero or during infancy, as might occur after maternal exposure to diethylstilbestrol (Fig. 22-1) or in children with congenital adrenal hyperplasia, may result in altered development of one8or more sexually dimorphic brain regions and expression of gender-associated behaviors. Whereas during the neonatal and peripubertal periods estrogens and aromatizable androgens induce trophic (synaptogenic) changes in the rodent hypothalamus, in later life estrogens accelerate aging-related changes in the endocrine hypothalamus that may contribute to the onset of reproductive senescence.
FIGURE 22-3 The classic organizational hypothesis. Female (left panel): During
the first week of life (neonatal critical period) in female rodents, ovary-derived estradiol (E2) is bound to circulating α-fetoprotein (αFP) and does not readily cross into the brain. The hypothalamic circuitry subserving pituitary gonadotropin regulation is intrinsically “female” in organization and releases gonadotropin-releasing hormone (GnRH) in a pulsatile (phasic) fashion. The latter is necessary for stimulating the luteinizing hormone (LH) surge that sustains ovulation. αFP levels progressively decline after birth, permitting ovarian estrogen to modulate the brain-pituitary axis after puberty. Testosterone administered to female rodents during the critical period does not bind to αFP and thus gains access to the developing hypothalamus, where it is converted to E2 by the enzyme aromatase. This E2 (ironically) “masculinizes” the gonadotropin-regulating hypothalamic pathways, resulting in permanent nonpulsatile (tonic) release of GnRH and LH. At puberty, in the absence of LH surges, the animal develops irreversible anovulatory sterility and multicystic ovaries. Male (right panel): Testosterone secreted from neonatal testes during the critical period does not bind αFP, undergoes aromatization to E2 within the hypothalamus, and reorganizes the intrinsically “female” circuitry to express “male” (tonic) patterns of GnRH and LH secretion. This nonpulsatile pattern of LH release suffices to maintain normal levels of testicular androgen production at puberty. In genetic males, “female” (pulsatile) patterns of GnRH-LH secretion occur at puberty if the animals are castrated at birth or treated with antiestrogens or aromatase inhibitors during the critical period.
Activational Effects The activational effects of sex steroids encompass a myriad of largely reversible neurophysiological influences exerted by gonadal hormones on the mature nervous system. Such interactions are essential for regulation of the brain-pituitary-gonadal axis and the establishment of normal patterns of sexual, aggressive, cognitive, and autonomic behaviors. Furthermore, by impacting the metabolism and release of various central neurotransmitters and neuromodulators, hormonal fluctuations associated with (1) specific phases of the menstrual cycle, (2) pregnancy, (3) the meno-pause, and (4) exposure to exogenous sex hormones may induce or modify a host of neurological and neuropsychiatric disorders.
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HUMAN MENSTRUAL CYCLE AND HORMONAL CONTRACEPTIVES Sex steroid fluctuations in the course of a typical menstrual cycle are depicted in Figure 22-4A. Plasma estradiol levels increase during the late follicular phase of the cycle and peak just before ovulation. A smaller but more sustained elevation in circulating 17β-estradiol occurs during the luteal phase. Progesterone levels are negligible during the follicular phase and rise markedly during the luteal phase in synchrony with the second 17β-estradiol surge. In the late luteal phase, a decline in sex hormone levels triggers the menstrual flow. High concentrations of circulating sex steroids resulting from ingestion of oral contraceptives inhibit ovulation through a negative feedback action on the hypothalamic-pituitary unit (Fig. 22-2). In the most widely used combined oral contraceptives, fixed doses of estrogen and progestin are administered for 21 days, followed by a 7-day placebo period during which time menstruation occurs. The estrogenic component of “the pill” consists of either ethinyl estradiol or mestranol (which is metabolized to ethinyl estradiol). Commonly used progestogens include ethynodiol diacetate, norethindrone, norethynodrel, norgestrel, norgestimate, gestodene, and desogestrel. The synthetic steroids are readily absorbed from the gut, freely traverse the blood–brain barrier, and are metabolized by the microsomal enzyme system in the liver. Common minor adverse effects of “the pill” include nonvascular headaches, dysphoria, and decreased libido. The remainder of this chapter is concerned with major neurological complications of endogenous sex steroids and oral contraceptives. Wherever possible, a distinction is made between “high-dose” (≥50 μg) and the more recently introduced “low-dose” (20 to 35 μg) estrogen preparations because there appear to be significantly fewer neurological and non-neurological complications with use of the latter. MIGRAINE Although no gender difference in the prevalence of migraine is apparent before puberty, the 9 condition is three times as common in adult women (18%) as in men (6%). Approximately 60 percent of women with migraine experience perimenstrual exacerbations of their headaches (catamenial migraine). The late luteal phase decline in plasma estradiol (but not 10 progesterone) appears to play an important role in the precipitation of catamenial migraine (Fig. 22-4). The frequency or severity (or both) of migraine attacks often diminishes with 11 gestation, particularly in patients whose headaches are linked to the menstrual cycle. The absence of rhythmic estrogen “withdrawal” characteristic of the pregnant state is believed to be responsible for the reduction in migraine activity. Indeed, many women whose headaches are attenuated by pregnancy experience relapses at the time of parturition, when sex 12 In some patients, migraine arises de novo or appears to hormone levels fall precipitously. 13 14 worsen during gestation or the perimenopausal period. A first approach to the management of gestational migraine should be nonpharmacological (e.g., relaxation training, biofeedback), especially during the first trimester when risks of teratogenicity and embryotoxicity are greatest. For severe attacks, acetaminophen with codeine or nonsteroidal anti-inflammatory drugs (NSAIDs) can be used. Further discussion is provided in Chapter 35. For status migrainosus in pregnancy, chlorpromazine, meperidine, morphine, or prednisone 15 may need to be administered. Perimenopausal migraine often responds to standard estrogen replacement therapy, but this must be weighed against the risk of developing breast 14 cancer in individual patients.
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FIGURE 22-4 A, Daily plasma concentrations of estradiol and progesterone throughout a normal menstrual cycle in a woman with premenstrual migraine (vertical arrow indicates onset of headache). B, Plasma estradiol concentrations during a normal and estradiol-treated cycle in a woman with premenstrual migraine. (From Somerville B: The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 22:355, 1972, with permission.)
An association between migraine and “the pill” is frequently encountered in general and neurological practices. Women often exhibit new-onset or exacerbation of migraine while taking oral contraceptives. Attacks tend to manifest during the first few cycles (particularly on placebo days in accord with the estrogen withdrawal hypothesis) and usually, but not invariably, resolve on discontinuation of the medication. A qualitative change in the pattern of migraine is noted in some patients. For example, a migraineur may develop a focal prodrome for the first time while taking oral contraceptives. Women in this category may be at high risk of infarction in regions reflecting the distribution of their auras. Amelioration of migraine after exposure to oral contraceptives is observed in a few women. Psychological factors, such as the diminished fear of accidental pregnancy, may in part contribute to the improvement. The pathophysiology of estrogen-related migraine is incompletely understood. Estrogens may act directly on vascular smooth muscle as well as modulate the activity of vasoactive substances at the neurovascular junction. 16 In addition, by altering central prostaglandin, serotonin, opioid, or prolactin metabolism, premenstrual changes in circulating estrogens may activate vasoregulatory elements in the brainstem or hypothalamus, which, in turn, may 17 trigger symptomatic alterations in cerebrovascular tone. First-line therapy for menstrual migraine should include the standard pharmacological, dietary, and psychological modalities employed in the general migraine population.
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Sumatriptan and related serotonin 5-HT1D (presynaptic autoinhibitory) receptor agonists are 18 equally effective for noncatamenial and menstrual migraine. Refractory cases of severe catamenial migraine may benefit from late luteal phase therapy with19prostaglandin inhibitors (e.g., naproxen, 250 to 500 mg orally twice daily) and mild diuretics. Various hormonal interventions in catamenial migraine have been largely unsuccessful and often complicated by unpleasant side effects. Oral contraceptives usually exacerbate migraine and probably should not be used in20the treatment of this disorder. The use of estrogen implants has yielded contradictory results. The risk-benefit ratio accruing to long-term estrogen therapy must be carefully assessed before such treatment can be advocated for this relatively benign 22 21 condition. The antiestrogen tamoxifen (Fig. 22-1) may either alleviate or precipitate catamenial migraine. The beneficial effect of tamoxifen21may be due to inhibition of calcium 23,24 danazol (200 uptake or prostaglandin E synthesis in these subjects. In several reports, mg twice daily for 25 days), a testosterone derivative used in the management of endometriosis, aborted or ameliorated premenstrual migraine for the duration of treatment. Catamenial headaches resumed on discontinuation of this medication. Continuous bromocriptine therapy (2.5 mg three times daily) resulted in a 72 percent decline in headache 25 frequency in a study involving 24 women with menstrual migraine. STROKE “The pill” has been implicated as a significant risk factor in thromboembolic cerebral 26 infarction, subarachnoid hemorrhage, and cerebral venous thrombosis. In 1969, American 27 and British case-control studies revealed, respectively, a 19- and 6-fold increased risk of ischemic stroke in young women related to the use of oral contraceptives. Hypertension, migraine, and age older than 35 years were associated, 28 but independent, risk factors for cerebral infarction in patients taking oral contraceptives. Cigarette smoking by women on “the pill” was found to increase further the likelihood of hemorrhagic but not thromboembolic stroke. Ingestion of lower dose (30 μg) estrogen preparations appears to be responsible for a 29 decline in rates of thromboembolic disease among users of oral contraceptives. In a population-based case-control study, the odds ratio of ischemic stroke in current users of low-dose estrogen contraceptives (20 to 35 μg) was only 1.18 in comparison with former 30 users or women who were never exposed to oral contraceptives. However, the risk of stroke remains unacceptably high in low-dose oral contraceptive users if they smoke and are 31 older than the age of 35. Although less often implicated than estrogens, progestins may contribute to the danger of cerebral infarction by promoting hypertension, hypercoagulability, 32,33 and adverse serum lipoprotein levels. Ischemic strokes in users of oral contraceptives have been localized to the carotid (usually the middle cerebral artery or its deep penetrating branches) and vertebrobasilar distributions. There is usually no radiological or pathological evidence of disseminated vascular disease in 34 young women with oral contraceptive–related stroke. Cerebral thromboembolism resulting from estrogen-induced hypercoagulability is a likely etiology for such strokes. Estrogen increases plasma levels of fibrinogen and clotting factors VII, VIII, IX, X, and XII. The steroid also enhances platelet aggregation and suppresses antithrombin III activity and the fibrinolytic system. A host of estrogen-regulated genes that may 35 impact the risk of ischemic stroke, either positively or negatively, are listed in Table 22-1. Elam and associates have reported an increased prevalence of mitral valve prolapse among users of oral contraceptives with 36 ischemic stroke. The combination of a fixed valvular anomaly and an estrogen-related hypercoagulable state may render patients particularly vulnerable to thromboembolic complications. Sex hormone–induced hypercoagulability is thought to play an important role in the pathogenesis of cerebral venous thrombosis complicating pregnancy, the puerperium, 37 and use of hormonal contraceptives. Click here to view this table.... Data concerning the impact of hormone replacement therapy (HRT) on stroke incidence and severity are conflicting, with reports of neutral, increased, and decreased stroke risk accruing from this intervention. In some observational studies, HRT-related stroke risk was significantly 38 modified by the presence or absence of associated factors such as hypertension or smoking. Importantly, several large randomized controlled studies indicated that HRT with conjugated equine estrogen or 17β-estradiol, alone or combined with medroxyprogesterone acetate, does not protect against stroke (or coronary artery disease) in women with39,40 established vascular disease and may actually worsen outcomes in this high-risk In healthy women without prior cerebrovascular history enrolled in the population. Women's Health Initiative (WHI) study, an increased risk of ischemic but not fatal or 41 hemorrhagic stroke was again attributed to 17β-estradiol replacement therapy. Interestingly, men with the common ESR1 c.454-397CC variant of the estrogen receptor-alpha (ESRa) gene may be more prone to ischemic stroke than men bearing other ESRa genotypes after
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adjusting for age, hypertension, diabetes, blood lipid levels, and smoking status.
42
In a study by the Royal College of General Practitioners, the relative risks for subarachnoid hemorrhage in former users, current users, or subjects who had ever used moderate- to 43 high-dose oral contraceptives were 4.5, 3.2, and 4.0, respectively. The odds ratio for hemorrhagic stroke in current users of low-dose estrogen contraceptives (20 to 35 μg) in comparison with former users or nonusers is negligible (1.14). As in the case of ischemic stroke, cigarette smoking and age older than 35 years substantially increase the risk of 30,43 Female sex hormones may subarachnoid hemorrhage in users of oral contraceptives. predispose to bleeding from both aneurysms and arteriovenous malformations, although the 34 pathophysiological mechanisms underlying these phenomena remain controversial. By analogy to their effects on endometrial spiral arteries, fluctuating sex hormone levels may compromise the integrity of cerebral arterial walls, rendering them more susceptible to 44 rupture. During pregnancy, hemodynamic changes may facilitate engorgement and bleeding from cerebral arteriovenous malformations. In addition, sex hormones may exert direct trophic influences on these malformations analogous to their effects on other highly 45 46 vascularized lesions such as spider angiomas, gingival epulis, and meningiomas (discussed later). Rarely, subarachnoid hemorrhage is secondary to cyclic bleeding from 47 hormone-sensitive ectopic endometriomas of the spinal canal. EPILEPSY 48
Normal reproductive processes may be disrupted by seizure disorders49and their therapies. Abnormal limbic discharges may be responsible for the hyposexuality and increased 48,50 noted in prevalence of hypogonadotropic hypogonadism and polycystic ovary syndrome patients with temporal lobe epilepsy. Pregnant epileptic women experience higher rates of maternal and fetal complications, including vaginal hemorrhage, prematurity, low birth weight, 51 and perinatal mortality. As discussed in Chapter 35, anticonvulsant therapy in women of childbearing age may result 52 expected oral in failure of oral contraceptives and in teratogenicity. On the basis of the 53 Coulam and contraceptive failure rates reported for the general population by Tietze, 54 Annegers calculated a 25-fold increased risk of oral contraceptive failure in patients concomitantly exposed to anticonvulsants. Phenytoin, phenobarbital, primidone, 55,56 ethosuximide, and carbamazepine have been implicated in oral contraceptive failure. These anticonvulsants induce the hepatic cytochrome P450 microsomal enzyme system, which, in turn, accelerates catabolism of endogenous and exogenous sex hormones. In addition, the anticonvulsants augment the synthesis of sex hormone–binding globulins, 57 resulting in reduced levels of circulating free (active) hormone. Anticonvulsants may also promote the clearance of sex hormones by influencing sulfate conjugation and 55 glucuronidation of the latter in the gut wall and liver. Oral contraceptive failure does not occur with valproic acid, which may actually inhibit cytochrome P450 enzymes, causing elevations in plasma steroid concentrations. Valproic acid, however, may cause 48,58 Of the newer antiepileptic medications, hyperandrogenism and polycystic ovaries. lamotrigine, gabapentin, vigabatrin, and clobazam do not induce the hepatic P450 microsomal enzyme system, and56,59 oral contraceptive failure has not been reported with Topiramate and felbamate have modest effects on sex concomitant use of these drugs. 60 hormone pharmacokinetics and may affect contraceptive efficacy. Although breakthrough bleeding has been reported with tiagabine, the impact of this drug on ovarian hormone 61 metabolism is believed to be minimal. The course of epilepsy and its management may be greatly influenced by specific phases of the reproductive cycle and exposure to steroid contraceptives. A variety of seizure disorders have been documented to worsen around the time of ovulation or premenstrually (catamenial 62,63 64 65,66 Data amassed from human and animal studies epilepsy) and during pregnancy. indicate that58estrogens and progestins have epileptogenic and anticonvulsant properties, respectively (Table 22-2). Estrogen augments glutamatergic and suppresses GABAergic neurotransmission, favoring epileptogenesis, whereas progesterone has the opposite 58 effects. Conceivably, a rising estrogen:progesterone ratio during the late luteal phase triggers catamenial seizure activity. Furthermore, the markedly elevated estrogen:progesterone ratio characteristic of the polycystic ovary syndrome may, in part, contribute to the relatively frequent association of this reproductive disorder with temporal 50 lobe epilepsy. Exposure to oral contraceptives consisting of estrogen-progestin 56 combinations does not appear to worsen seizure control significantly. Management strategies for catamenial epilepsy include (1) premenstrual or periovulatory supplemen-tation of anticonvulsant doses or addition of an adjunctive antiepileptic drug such as clobazam; (2) cyclic administration of acetazolamide, a mild diuretic with weak antiepileptic activity; and (3) 67,68 progesterone supplementation by mouth or suppository.
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Click here to view this table.... With respect to gestational epilepsy, factors such as maternal sleep deprivation, stress, and inadequate anticonvulsant levels are probably more important than direct hormonal epileptogenesis. During pregnancy, serum levels of phenytoin, phenobarbital, and valproic acid may decrease by 30 to 40 percent of pregestational levels, with a lesser decline in carbamazepine. Primidone levels are reportedly stable during69pregnancy, but the concentration of primidone-derived phenobarbital is reduced. Decreased drug compliance, bioavailability, and protein binding, as well as an increased volume of distribution and metabolic clearance, are factors contributing to the fall in anticonvulsant levels during 67 preparations on pregnancy. The influences of the menstrual cycle and of oral contraceptive 70 anticonvulsant disposition appear to be of minor clinical significance. MOVEMENT DISORDERS
Chorea Pregnancy and steroid contraceptive therapy have infrequently been complicated by the acute or subacute development of choreiform movements of the face and extremities associated with limb hypotonia and pendular reflexes. Fever, dysarthria, and neuropsychiatric symptoms may complete the clinical picture. Gestational and oral contraceptive–related 34 chorea have a close association with previous rheumatic fever. Contraceptive-related chorea has also been reported in71,72 patients with a history of congenital cyanotic heart disease Pharmacological, epidemiological, and pathological and Henoch–Schönlein purpura. evidence suggests that altered hormonal patterns characteristic of pregnancy and ingestion of oral contraceptives may unmask latent chorea by augmenting dopaminergic neurotransmission in basal ganglia previously damaged by rheumatic or hypoxic 17 encephalopathy. Estrogens may facilitate dopaminergic neurotransmission by upregulation of postsynaptic dopamine receptors, by inhibition of central monoamine oxidase activity, and possibly through conversion to catechol-estrogens (Fig. 22-1). The latter may compete for the catecholamine degrading enzyme, catechol O-methyltransferase, resulting in the excessive 73 accumulation of dopamine and other neurotransmitters within the affected brain regions. In most cases, chorea gravidarum and oral contraceptive–related dyskinesias resolve completely by the end of pregnancy or after discontinuation of the medication, respectively. As many as 20 percent of women experience recurrences of chorea with subsequent 74 at increased risk of later developing oral pregnancies. Patients with chorea75gravidarum are 76 contraceptive–related dyskinesias, and vice versa. In patients with suspected chorea gravidarum, appropriate clinical and laboratory investigations may be required to exclude other causes of chorea, such as acute rheumatic fever, systemic lupus erythematosus, hyperthyroidism, and Wilson's disease. Chorea gravidarum is usually self-limited, and abortion or premature delivery is rarely indicated. Judicious use of neuroleptics or other medications may afford symp-tomatic relief in severe cases. Women with a history of gestational or oral contraceptive–induced chorea should probably minimize further exposure to any estrogen-containing medications.
Parkinsonism There are anecdotal reports in the early clinical literature of motor deterioration in idiopathic and neuroleptic-induced parkinsonism after exposure to exogenous estrogen. Furthermore, premenopausal women were reportedly more susceptible to drug-induced parkinsonism than 77 men of similar age. These observations argued for a potentially antidopaminergic role of estrogen in this condition. Yet, in two studies of premenopausal women with idiopathic Parkinson's disease, motor symptoms were noted to worsen premenstrually when estrogen 78,79 Data titers were falling, favoring a stimulatory influence of estrogen on striatal dopamine. from several investigations suggest 80,81 that postmenopausal estrogen replacement is beneficial In other studies, postmenopausal estrogen therapy in women with Parkinson's disease. 82 or was associated with worsening motor either had no significant dopaminergic effect 83 (natural or surgical) scores. Recent epidemiological studies suggest that early menopause 84,85 and that the latter may may be a risk factor for the development of Parkinson's disease 86 be offset by post-menopausal estrogen replacement. In a Swedish population, polymorphisms of the estrogen receptor–beta gene (an important mediator of estrogenic effects on the nigrostriatal pathway), although not associated with an overall risk of contracting Parkinson's disease, may have an impact on the age of symptom onset in this 87 condition.
Wilson's Disease
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Wilson's disease is an inborn error of copper metabolism that is characterized by hepatic cirrhosis and degenerative changes in the basal ganglia. Patients with this rare condition exhibit decreased serum ceruloplasmin levels, increased plasma levels of nonceruloplasmin copper, and reduced biliary excretion of the heavy metal. Movement disorders, seizures, and 88 psychosis result from the toxic effects of excessive copper deposition in neural tissues.89 In normal individuals, serum ceruloplasmin and copper levels increase during pregnancy and 17 after administration of estrogen or estrogen-progestogen contraceptives. The rise in ceruloplasmin resulting from exposure to oral contraceptives is responsible for the green-tinged serum occasionally noted in these women. In patients with Wilson's disease, increased serum ceruloplasmin levels occur during pregnancy and after treatment with exogenous estrogens. Effects on serum copper, however, are inconsistent. Normalization of serum ceruloplasmin levels by estrogen administration has no therapeutic benefit, and such exposure may lead to neurological deterioration in some individuals. Exposure to hormonal contraceptives may yield “falsely normal” 17 ceruloplasmin levels in patients with Wilson's disease, resulting in a delay in diagnosis.
Other Movement Disorders A broad spectrum of movement disturbances appear to be influenced by changes in the sex steroid milieu. Included are cases of posthypoxic and hereditary myoclonus, dominantly inherited myoclonic dystonia, tardive dyskinesia, a pyramidal-extrapyramidal syndrome, hemiballismus, ill-defined tremors and drop attacks, familial episodic ataxia, Gilles de la 17,90,91 Tourette's syndrome, and the neuroleptic malignant syndrome. NERVOUS SYSTEM NEOPLASMS
Meningiomas Sex steroids may play an important role in the biology of meningiomas. These tumors occur 92 before puberty or during more frequently in women than in men and are rarely diagnosed 93 the senium, corresponding94to the time of maximal gonadal activity. Meningiomas are more 95 common in obese women and in patients with hormone-dependent breast carcinoma. The greater prevalence of these tumors in obese individuals may be related to higher circulating96 estrogen levels derived from the aromatization of androstenedione to estrone in adipocytes (Fig. 22-2). Meningiomas have been documented clinically and radiologically to undergo relatively rapid expansion during pregnancy, followed by spontaneous regression 17,97 Some women suffer exacerbations of symptoms in the luteal phase of the postpartum. menstrual cycle. These fluctuations in tumor size have been attributed to steroid-induced fluid retention by the lesion, increased vascular engorgement of the tumor, and direct trophic 98,99 effects of gonadal hormones on meningioma cells. Numerous investigators have demonstrated the presence of progestin- and, to a lesser extent, estrogen- and androgen-binding proteins in a significant number of human 17 meningioma specimens. These observations suggest that progestins and possibly other gonadal steroids may directly modify the growth and differentiation of these tumors. The presence of progestin receptors may indicate a more favorable prognosis because progesterone receptor–negative meningiomas have been associated with a greater tendency 100 and shorter disease-free for brain invasiveness, higher mitotic indices and necrosis, 101 intervals. In an early study, the antiestrogen tamoxifen (Fig. 22-1) did not102appreciably affect tumor size or neurological status in patients with inoperable meningiomas. By contrast, the antiprogestin RU486 (Fig. 22-1) has been reported to induce stabilization or regression of meningiomas in a cohort of patients,103 suggesting that antiprogesterone therapy may be useful the effects of progestins and RU486 on in the management of these tumors. However, 104–106 and patients chronically treated with 107 meningioma growth in vitro are contradictory, RU486 may require glucocorticoid replacement to counteract its antiglucocorticoid effects.
Gliomas There are anecdotal reports of astrocytomas enlarging during pregnancy, only to shrink 108 spontaneously in the puerperium. As in the case of meningiomas, certain human gliomas may selectively bind estrogens, progestins, and androgens. Some of these tumors may also contain enzymes 109,110 (e.g., 17β-oxidoreductase and aromatase) that catalyze steroid hormone interconversions. The origin of putative steroid receptors in glial cell tumors is obscure, although significant numbers of normal astrocytes in certain brain regions possess estrogen 4,5 receptors. Astroglial tumors predominantly express estrogen receptor–beta, and 111 expression levels reportedly decline with increasing histological grade of malignancy. High-dose tamoxifen therapy (Fig. 22-1) may result in clinical and radiological stabilization of
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http://www.merckmedicus.com/pp/us/hcp/printpage.jsp 112–114
astrocytomas and glioblastoma multiforme in some patients. These benefits are more 112,113 or its role as a likely due to the115inhibitory effects of tamoxifen on protein kinase C radiosensitizer than to any accruing antiestrogenic activity. Human oligodendrogliomas have also been reported 116 to contain sex steroid receptors and could theoretically be subject to hormonal manipulations.
Other Tumors 117
Responsiveness to 118 sex hormones has been reported in cases of acoustic neuromas, 119 pituitary adenomas, and breast cancer metastases to the nervous system. Sex steroid receptors have also been reported in hemangioblastomas, anaplastic ependymomas, malignant lymphomas, and primitive neuroectodermal tumors, suggesting that the natural 120,121 history of these neoplasms may be influenced by sex hormones and their antagonists. MULTIPLE SCLEROSIS Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS) that often afflicts men and women during their reproductive years. An ESR1 gene polymorphisms and MS has been reported in some association between specific 122,123 124 studies but not others and may be population dependent. Physicians are often asked by young women with MS whether their condition will be worsened by preg- nancy. Contrary to medical dogma promulgated before World War II, initial epidemiological studies have indicated that the overall effect of one or more 125,126 As discussed in Chapter 35, subsequent pregnancies on MS-related morbidity is nil. studies involving larger patient cohorts have amply demonstrated a tendency for MS exacerbation during the first 3 postpartum months that is counterbalanced by significant 127,128 Indeed, the approximately 70 suppression of disease activity in the third trimester. percent reduction in the relapse rate of MS in the third trimester is more robust than that 129 accruing from interferon-beta, glatiramer acetate, or intravenous immunoglobulin therapy. Immunomodulation that is necessary to prevent rejection of the semiallogenic fetus is probably responsible for the dampening of third trimester disease activity in MS and other immune-mediated conditions. Factors that have been implicated in gestational immunosuppression include estradiol, progesterone, human chorionic gonadotropin, human placental lactogen, cortisol, 1,25-dihydroxyvitamin D3, α-fetoprotein, pregnancy-associated 129,130 glycoprotein, “blocking antibodies,” immunocomplexes, and interleukin-10. In animals, pregnancy significantly delays the onset of experimental allergic encephalomyelitis (a model 131,132 If for MS) after inoculation with spinal cord homogenate or myelin basic protein. necessary, intravenous steroids can be used for MS attacks in pregnancy. Interferon-beta should be discontinued 3 months before planned conception and should not be used during 129 pregnancy or while breast-feeding. In one study, none of 14 pregnant women with relapsing-remitting MS who received prophylactic intravenous immunoglobulins immediately 133 postpartum exhibited disease relapse in the first 6 months after delivery. ALZHEIMER'S DISEASE Alzheimer's disease is a common dementing illness characterized by progressive neuronal degeneration, gliosis, marked depletion of acetylcholine and other neurotransmitter disturbances, and the accumulation of senile (amyloid) plaques and neurofibrillary tangles in 134 discrete regions of the basal forebrain, hippocampus, and association cortex. At the time of publication of the third edition of this book (2001), there were promising reports suggesting that estrogens play an important role in normal human cognition, have a salutary effect on the manifestations of Alzheimer's disease, 135 and may even protect against the development of this estrogens neurodegenerative disorder in women. Fundamental research indicated that 136 exert trophic influences on cholinergic neurons of the rodent basal forebrain, induce dendritic spines (synapses) and functional N-methyl-d-aspartate receptors (important for 137 memory) in adult rat hippocampus, and induce massive neuritic growth in rodent 138 hypothalamic explants. In addition, estrogens were shown to manifest antioxidant properties, reduce the deposition of fibrillar β-amyloid, modulate apolipoprotein E expression, 139–141 suppress inflammatory responses implicated in neuritic plaque formation, and increase cerebral blood-flow and glucose utilization (which are deficient in subjects with Alzheimer's 139,140 The 1990s brought to light evidence that estrogens improve cognitive disease). behaviors in rats and monkeys, psychometric performance in women is influenced by menstrual cycle phase, cross-gender hormone therapy affects cognition in transsexual men and women, and estrogen replacement therapy augments verbal memory scores in normal 139,142–144 Moreover, early clinical studies suggested that estrogen menopausal women. replacement therapy may improve cognitive performance, especially language function, 139,142,144,145 verbal memory, and attention, in menopausal women with Alzheimer's disease,
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and enhance the146,147 likelihood of a beneficial response to acetylcholinesterase inhibitors in 148–150 In several case-controlled studies, in153 initial prospective affected151,152 women. and in a meta-analysis of 12 observational studies, postmenopausal studies, estrogen replacement therapy appeared to be associated with a significantly decreased risk of developing Alzheimer's disease. There was also some indication that postmenopausal estrogen replacement therapy protected against the development of dementia in women with 154 Parkinson's disease and that androgen (testosterone) treatment conferred cognitive 155,156 benefits in elderly men with Alzheimer's disease and mild cognitive impairment. The results of recent, large, randomized, placebo-controlled prospective trials evaluating the potential benefits of sex hormone replacement therapy in preventing the dementia of Alzheimer's disease have been disappointing. In a substudy of the Heart and Estrogen/Progestin Replacement Study (HERS), age-adjusted cognitive function scores were no different in women with coronary artery disease who received estrogen and progestin (n = 157 517) than in placebo-treated controls. Surprisingly, in the Women's Health Initiative Memory Study (WHIMS) involving over 6,000 participants, the hazard ratios for development of dementia were 1.49 for women randomized to receive 0.625 mg conjugated equine estrogen and 2.05 for those receiving 0.625158 mg estrogen plus 2.5 mg medroxyprogesterone acetate relative to placebo-treated controls. On the basis of current knowledge, and despite initial optimism to the contrary, the third Canadian Consensus Conference for the Diagnosis and Treatment of Dementia (2006) recommended against the use of estrogen/progestin replacement therapy for reducing the risk of dementia in postmenopausal women. It was also concluded that there is insufficient evidence for or against prescription of androgen replacement for cognitive dysfunction in elderly men. NEUROPSYCHIATRIC DISORDERS
The Porphyrias The porphyrias are characterized by the excessive production of porphyrins and porphyrin precursors resulting from specific enzymatic defects in the heme biosynthetic pathway. Neurological manifestations, when present, include seizures, neuropsychiatric symptoms, and sensorimotor and autonomic neuropathies. Estradiol and other steroids with a 5β configuration induce the enzyme δ-aminolevulinic acid synthase and may thereby precipitate porphyric crises. Oral contraceptives increase urinary excretion of this enzyme in normal individuals, and it has been suggested that asymptomatic relatives of patients with porphyria should avoid “the pill.” In many women with acute intermittent porphyria, cyclic attacks of variable severity may occur during the late luteal phase or, less commonly, at ovulation. Paradoxically, some patients exhibit prolonged remissions after suppression of ovarian 17 cyclicity with oral contraceptives. Although acute treatment with GnRH agonists, such as d-His or leuprolide, stimulates the pituitary-ovarian axis (Fig. 22-2), chronic administration of these agents downregulates gonadotrope GnRH receptors, resulting in long-term 159 suppression of pituitary-ovarian function. In the first reported case, d-His administration (5 μg subcutaneously daily) yielded complete remission of severe premenstrual acute intermittent porphyria for the duration (8 months) of therapy (Fig. 22-5). Similar benefits were 160 and hereditary observed in subsequent cases of catamenial acute intermittent porphyria 161 GnRH coproporphyria in response to GnRH analogue therapy. Side effects of long-term 159,161 GnRH treatment include hot flashes, diminished breast size, and bone demineralization. analogs, unlike sex159 steroids, do not appear to induce porphyrin accumulation in chick embryo hepatic cell culture and provide a rational approach to the management of catamenial porphyria.
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FIGURE 22-5 Course of symptoms, menses, and plasma hormone levels in a patient
with acute intermittent porphyria during 8 months of treatment with an agonist (d-His) of luteinizing hormone–releasing hormone. (From Anderson KE, Spitz IM, Sassa S, et al: Prevention of cyclical attacks of acute intermittent porphyria with a long-acting agonist of luteinizing hormone–releasing hormone. N Engl J Med 311:643, 1984, with permission.)
Premenstrual Syndrome The premenstrual syndrome occurs in approximately 30 percent of women during their reproductive years. Common neuropsychiatric symptoms of this disorder include headache, fatigue, depression, irritability, increased thirst or appetite, and craving for sweet or salty 162 foods. Symptoms typically begin toward the end of the luteal phase of the cycle and usually, but not invariably, resolve with the onset of flow. The pathophysiology of this disorder remains obscure. An increased luteal phase estrogen:progesterone ratio, hyperprolactinemia, disturbances of the renin-angiotensin-aldosterone axis, hypothyroidism, and abnormal 162 secretion of opioid peptides are among the causes considered for this enigmatic condition. Numerous hormonal and nonhormonal therapies—including natural progesterone, oral contraceptives, bromocriptine, GnRH agonists, diuretics, prostaglandin inhibitors, vitamin B6, and lithium—are prescribed for the management of premenstrual syndrome. However, with the possible exception of the GnRH agonists,163none has proved to be unequivocally 162 effective. In a double-blind crossover trial, induction of “artificial menopause” with a GnRH agonist (d-Trp-Pro-NEt-Gn-RH, 50 μg per day subcutaneously) relieved both physical and neuropsychiatric symptoms in eight women with rigorously defined premenstrual syndrome. Although the authors reported no side effects (except for hot flashes in one patient), prolonged hypoestrogenemia resulting from the long-term use of these agents may predispose to osteoporosis. Such therapy should probably be reserved for patients with incapacitating symptoms, and low-dose estrogen replacement may have to be considered when the duration of treatment exceeds several months.
Depression and Psychosis Depression and other major affective disorders may surface in relation to the menstrual cycle, the puerperium, and menopause. In patients with postmenopausal depression, mood 1 elevation and anxiolysis often occur promptly in response to estrogen replacement. 164 Paradoxically, oral contraceptives may precipitate depression in susceptible individuals. Estrogen has also been implicated in the pathogenesis of anorexia nervosa in view of the high preponderance of this condition in women and the potent anorexic effects of estrogen in 165 animals. Psychotic disorders characterized by extreme agitation, hallucinations, paranoid delusions, 166 incoherent speech, and mood lability may arise during the postpartum period or may recur consistently during the late luteal phase of the cycle. Such disorders may be refractory to
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conventional therapies (neuroleptics, lithium, electroconvulsive treatment) but may respond 167 well to specific hormonal interventions, including the use of oral contraceptives, 168 169 intramuscular progesterone, and danazol. “Menopause” induced by GnRH analogs may also be of considerable benefit in the management of cyclical psychosis. SLEEP DISORDERS Estrogen and progestin replacement may shorten mean sleep latencies, extend the duration of rapid-eye-movement sleep periods, and diminish nocturnal movement arousals, thereby 170–172 The GABA-active metabolites improving sleep in hypogonadal women. allopregnanolone and pregnanolone may mediate the reduction in vigilance during 173 wakefulness observed after the administration of progesterone to healthy men. Progestins may also provide stimulatory drive to brainstem respiratory centers in subjects with central 174 sleep apnea and thereby improve hypoventilation. The hypocapnic apnea threshold is lower in women than in men, and testosterone administration increases this threshold in 175 in a nonobese premenopausal women. In one case, obstructive sleep apnea resolved 176 woman after removal of a benign testosterone-producing ovarian tumor. INTRACRANIAL HYPERTENSION Progesterone has been shown to suppress post-traumatic cerebral edema and intracranial hypertension in rodents. This progestational effect has been attributed to reduction in blood–brain barrier permeability and inhibition of cerebrospinal fluid production by the choroid 177–179 Estrogens, by contrast, appear to180,181 enhance cerebral endothelial cell permeability plexus. Estrogenic attenuation of the and post-traumatic brain edema in female rats. blood–brain barrier may also play a role in the pathogenesis of pseudotumor cerebri (benign intracranial hypertension) in humans and explain the robust female predilection for this 180 disorder. NEUROMUSCULAR DISEASES
Catamenial Sciatica Ectopic endometrial tissue (endometriosis) is hormone sensitive and undergoes epithelial sloughing and hemorrhaging at the time of menses. Ectopic endometrial tissue may destroy lumbar vertebrae, producing back pain; invade the lumbosacral plexus in the retro-peritoneal 17,182 The latter causes radicular pain space; and implant within the sheath of the sciatic nerve. in the distribution of the nerve that usually begins 2 to 3 days before the onset of menses and may continue for a variable duration after cessation of flow (catamenial sciatica). In addition to pain, there is often numbness, weakness, and loss of ankle reflexes. In contrast to far more common discogenic radiculopathy, endometriotic sciatica is less likely to respond to bed rest and the imaging findings are usually unimpressive. There may or may not be evidence of endometriosis elsewhere, and surgical exploration of the sciatic nerve may be required for diagnosis. In positive cases, the nerve appears blue and a dark, hemorrhagic fluid is expressed after incision of the sheath. Biopsy specimens reveal characteristic 182 glandular elements. Symptoms of catamenial sciatica may show dramatic improvement with standard therapy for endometriosis, including danazol, progestins, and in refractory 47,182 cases, bilateral oophorectomy.
Other Neuromuscular Disorders Endogenous and administered sex hormones (mainly estrogens) may influence the natural 41 history of Bell's palsy, recurrent brachial plexopathy, and the carpal tunnel syndrome. Abnormally high estrogen levels have been reported in male patients with amyotrophic lateral sclerosis, Kugelberg–Welander disease, bulbo-spinal muscular atrophy (Kennedy's syndrome), Duchenne muscular dystrophy, and the Crow–Fukase syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein,17,183 and skin changes [POEMS It is unclear whether syndrome], usually associated with plasma cell dyscrasias). hyperestrogenemia plays any significant role in the pathogenesis of these neuromuscular disorders. In an anecdotal report, high-dose testosterone therapy yielded considerable 184 symptomatic improvement in a patient with bulbospinal muscular atrophy. The authors conjectured that the testosterone therapy may have ameliorated some toxic gain of function ascribed to the mutated androgen receptor in this condition. Finally, Mastrogiacomo and co-workers have hypothesized that dysfunction of testicular peritubular myoid cells and corpus cavernosum smooth muscle may be contributing to the hypergonadotropic 185 hypogonadism and impotence that complicate myotonic dystrophy in men. CONCLUDING COMMENTS
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Sex hormones influence a broad spectrum of normal and abnormal neurological functions. Relationships between endogenous and exogenous sex hormones and many neurological conditions, such as migraine, stroke, and chorea, are well established. In other diseases, including such diverse entities as primary CNS neoplasms and various movement disorders, this relationship has not been confirmed but appears likely in the light of rapidly accumulating clinical, epidemiological, and biochemical data. Fluctuating sex hormone levels also influence the expression of certain neuropsychiatric states and neuroendocrine disorders. The ubiquitous nature of these interactions warrants routine inquiry into potential symptom modifications associated with the menstrual cycle, pregnancy, menopause, and hormonal contraceptive exposure in women with neurological and psychiatric illness. A more thorough understanding of the mechanisms mediating sex hormone–related neural function and dysfunction should facilitate the refinement of rational hormonal and antihormonal therapies for many of the conditions discussed in this chapter. ACKNOWLEDGMENT The author thanks Adrienne Liberman for assistance in preparation of this manuscript. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 23 Other Endocrinopathies and the Nervous System CHERYL A. JAY • GARY M. ABRAMS •
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PITUITARY GLAND Sellar and Parasellar Lesions Anterior Pituitary Prolactin Growth Hormone Adrenocorticotropic Hormone and Cushing's Disease Thyroid-Stimulating Hormone Clinically Nonfunctioning Pituitary Adenomas Pituitary Apoplexy Posterior Pituitary Diabetes Insipidus Syndrome of Inappropriate Antidiuretic Hormone Secretion Cerebral Salt Wasting Hypopituitarism PARATHYROID GLANDS Primary Hyperparathyroidism Hypoparathyroidism ADRENAL GLANDS Cortex Hyperaldosteronism Cushing's Syndrome Adrenal Insufficiency Medulla Pheochromocytoma and Related Disorders
The endocrine and nervous systems interact in intricate ways, and hence it is not surprising that disorders in one system may cause clinically evident dysfunction of the other. For example, anterior pituitary tumors produce symptoms principally as the result of hormonal hyperfunction when small and of either hypersecretion or hyposecretion and dysfunction of 1 adjacent cranial nerves or hemispheric structures when large. The protean clinical features of hormonal2,3 excess and deficiency states include both central and peripheral nervous system dysfunction. Conversely, various cerebral disorders may cause posterior pituitary dysfunction, such as diabetes insipidus and the syndrome of inappropriate secretion of antidiuretic hormone.
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In general clinical practice, the most common endocrine disorders causing neurological disease are likely diabetes mellitus and thyroid disease, topics addressed in Chapters 20 and 21. Specific central or peripheral nervous system complications may develop on a background of known diabetes mellitus or thyroid disease, or the neurological syndrome may suggest a diagnosis of these endocrine disorders. The same is true for the neurological manifestations of parathyroid and adrenal disorders, whose numerous systemic and neurological manifestations can make diagnosis of these less common, yet treatable, disorders quite challenging. Finally, hormonal therapy or its cessation influences the course of various neurological disorders and may lead to specific central and peripheral nervous system complications. The neurological aspects of sex hormones are reviewed in Chapter 22. Prescribed for diverse systemic and neurological indications, corticosteroid administration or withdrawal is a common cause of hyperadrenalism or hypoadrenalism. In this chapter, disorders of the pituitary, parathyroid, and adrenal glands are reviewed, with particular focus on features relevant to neurological practice. PITUITARY GLAND The complex anatomy of the sellar region influences the clinical features of pituitary 4 disorders. The pituitary gland, or hypophysis, sits in the sella turcica, a bony depression in the posterior sphenoid bone. The tuberculum sellae and anterior clinoid processes form the anterior boundary of the sella turcica, and the dorsum sellae forms its posterior margin. Dural reflections border the pituitary superiorly and laterally. The diaphragma sellae, which contains a central opening that allows passage of the pituitary stalk into the pituitary fossa, forms the roof of the sella turcica. Adjacent to the pituitary bilaterally are the cavernous sinuses, which drain the ophthalmic and middle and inferior cerebral veins, and the sphenopalatine sinus. In addition, the carotid artery and cranial nerves III, IV, V1, V2, and VI pass through the cavernous sinus. The anterior pituitary, or adenohypophysis, derives embryologically from Rathke's pouch, an evagination of the oropharyngeal membrane, which originates from ectoderm. The adenohypophysis is composed of three parts: pars distalis, constituting most of the anterior pituitary; pars tuberalis, a small extension of pars distalis adherent to the infundibulum; and pars intermedia, vestigial in adults and thought to have little functional significance in 4 humans. Hormones secreted by the anterior pituitary include prolactin, growth hormone (GH), adrenocorticotropic hormone (ACTH), thyrotropin (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The hypothalamus controls anterior pituitary hormone secretions through various hypophysiotropic substances, most of which are peptides (Table 5 23-1). The superior hypophysial artery, a branch of the internal carotid, supplies a hypothalamic capillary bed linked to the anterior pituitary capillary bed by portal veins that may be capable of bidirectional flow. Adenohypophysial capillaries also drain into the posterior pituitary and cavernous sinus. The unique vascular anatomy of the hypophysial-portal system provides the basis for feedback loops that regulate the 6 hypothalamic-pituitary axis. Click here to view this table.... The posterior pituitary, known also as the neurohypophysis or pars nervosa, derives from a neuroectodermal extension of diencephalon that fuses with Rathke's pouch. Also of neuroectodermal origin is the infundibulum, which directly links the pituitary to the hypothalamus at the median eminence, which also forms the floor of the third ventricle. The optic chiasm liessuperior to the pituitary and anterior to the pituitary stalk. Neurohypophysial hormones include oxytocin and antidiuretic hormone (ADH), or vasopressin. The inferior hypophysial artery, a branch of the cavernous carotid, supplies the neurohypophysis. The juxtaposition of the pituitary gland to hypothalamus, third ventricle, cavernous carotid arteries, and cranial nerves related to vision, extraocular movements, and mid- and upper facial sensation accounts for many of the neurological manifestations of lesions in and around the sella. Endocrine disturbances arising from excess or insufficient secretion of one or more pituitary hormones may also cause neurological as well as systemic symptoms, signs, and laboratory abnormalities. Improved neuroimaging techniques have greatly 4,7 facilitated assessment of sellar and parasellar lesions. A detailed discussion of the increasingly complex array of stimulation and inhibition studies used to assess the integrity of 5 specific elements of the hypothalamic-pituitary axis is beyond the scope of this chapter. However, a basic understanding of pituitary hormone physiology is essential to evaluating patients with mass lesions in and around the gland and is reviewed here after a discussion of the neurological symptoms and signs resulting from these lesions.
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Sellar and Parasellar Lesions Pituitary adenomas are the most common sellar region mass and account for 10 to 15 4,5 percent of intracranial neoplasms. Classification based on histological staining properties, which designated these anterior pituitary tumors as acidophilic, basophilic, or chromophobic, has given way to categorization by the hormone or hormones secreted and more recently by 1,8,9 Pituitary adenomas are also classified by size. Microadenomas (Fig. cytodifferentiation. 23-1A), lesions that are 10 mm or smaller, typically spare adjacent neural or vascular structures and generally come to medical attention during evaluation for symptoms and signs of hormone oversecretion. Lesions larger than 10 mm are called macroadenomas (Fig. 23-1B). In addition to causing manifestations of hormone excess, these larger tumors may impair normal glandular function, resulting in hypopituitarism, or compress adjacent neural or 1,8 vascular structures, causing neurological dysfunction. Common clinical symptoms include visual loss, ophthalmoparesis, facial sensory symptoms, and headache. Macroadenomas extending superiorly compress the optic chiasm, nerves, or tracts. Bitemporal hemianopia is10 the classic syndrome, although monocular visual loss or junctional scotoma also may occur. Because adenomas grow slowly, visual deficits may not be appreciated by the patient until they are quite advanced. Third ventricular extension occasionally causes acute or chronic hy drocephalus. Lateral extension, with subsequent cavernous sinus involvement, disturbs extraocular motility and sensation in the upper and middle face. Head pain may be quite5 nondescript, mimicking tension-type headache, and does not correlate with lesion size. Very large lesions involving inferior frontal or medial temporal lobes may cause cognitive impairment, behavioral changes, and seizures. A few pituitary tumors extend inferiorly, causing epistaxis or cerebrospinal fluid (CSF) rhinorrhea.
FIGURE 23-1 A, Microadenoma. Gadolinium-enhanced T1-weighted magnetic
resonance imaging (MRI) shows a small focus of decreased enhancement compatible with microadenoma in a young woman with galactorrhea-amenorrhea. B, Macroadenoma. Large sellar lesion, subsequently shown to be a nonsecretory adenoma, in a gadolinium-enhanced T1-weighted MRI obtained in a middle-aged man with progressive visual loss. The extensive differential diagnosis of sellar region masses includes other pituitary tumors, nonpituitary neoplasms, metastases, infectious and inflammatory disorders, vascular lesions, and cysts (Table 23-2). Most of these lesions are quite rare. Click here to view this table.... Craniopharyngiomas account for nearly 3 percent of intracranial tumors and arise from 4 epithelial cell rests of Rathke's pouch. Among malignant lesions, pituitary carcinomas are quite rare; metastases to the pituitary are recognized more frequently at autopsy than during 11 life. Among more common disorders, the empty sella syndrome is often associated with an incompetent diaphragma sellae, which allows arachnoid and CSF to herniate into the sella. Typically an incidental finding on neuroimaging studies, the empty sella syndrome is not 4,7 usually associated with endocrinopathy. Other non-neoplastic sellar lesions include granulomatous processes, such as tuberculosis or sarcoidosis, and vascular lesions, 1,5 particularly cavernous carotid aneurysms or cavernous sinus thrombosis. Magnetic resonance imaging (MRI) before and after gadolinium enhancement, with high-resolution thin sections in the sagittal and coronal planes, allows visualization of the pituitary stalk and surrounding neural and vascular structures, and is the test of choice for
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pituitary-region imaging. On T1-weighted images, high signal intensity in the posterior pituitary 4,7 is referred to as the bright spot and is believed to represent ADH in neurosecretory vessels. Pituitary adenomas typically enhance less intensely than normal glandular tissue (Fig. 23-1A). Dynamic imaging, which acquires images rapidly in a time-scale synchronous with the microcirculation, may improve detection of microadenomas. In patients who cannot undergo MRI, precontrast and postcontrast computed tomography (CT) images through the area can be obtained. A consequence of modern neuroimaging is detection of the 12 asymptomatic pituitary mass, the so-called pituitary “incidentaloma.”
Anterior Pituitary Prolactin Prolactin acts on mammary tissue to promote lactation, in addition5to inhibiting cyclic gonadotropin secretion and directly suppressing gonadal function. Hypothalamic control of basal prolactin secretion occurs primarily by inhibition, with the major inhibitory factor being dopamine. An important clinical consequence is that pituitary stalk disruption from lesions other than prolactinomas may elevate serum prolactin levels, although rarely above 200 5 mild ng/ml (normal <20 ng/ml). Neuroleptics and other dopamine antagonists can also cause 13 hyperprolactinemia; some newer atypical antipsychotics may not raise serum prolactin. Dopaminergic drugs are used therapeutically to lower prolactin levels. Prolactin-releasing factors are less well understood, although thyrotropin-releasing factor (TRH) plays a role. Consequently, in primary hypothyroidism, when TRH is elevated, the prolactin level may be elevated as well. The pituitary may be enlarged in primaryhypothyroidism, and hence 1 diagnostic confusion with prolactinoma may occur. The differential diagnosis of hyperprolactinemia (Table 23-3) also includes pregnancy and lactation and chest wall 1,5 stimulation. Serum prolactin may be modestly increased in the first hour after a generalized tonic-clonic or complex partial seizure and, when measured at 10 to 20 minutes after a suspected event, is sometimes a useful adjunct for the differentiation of generalized 14 tonic-clonic or complex partial seizure from psychogenic nonepileptic seizure. Click here to view this table.... Amenorrhea-galactorrhea in women and impotence and decreased libido in men should 15 prompt consideration of hyperprolactinemia. For most of the secondary causes just discussed, serum prolactin levels rarely exceed 150 ng/ml. History and examination, with particular attention to medication use, along with blood biochemical screening tests and 13 thyroid function and pregnancy tests will exclude most secondary causes. The most common cause of an elevated prolactin level is a prolactinoma, and these lesions are the most common type of pituitary adenoma, accounting for up to 60 percent of hormonally active 16 tumors. In a patient who is not pregnant, serum prolactin levels greater than 200 ng/ml and CT or MRI features compatible with pituitary adenoma are diagnostic of prolactinoma. Levels lower than this may be seen with any type of macroadenoma due to stalk compression. It can also be seen with macroprolactinomas owing to the “hook effect,” whereby the radioimmunoassay used to determine serum prolactin returns a falsely low value in severe 8,15,16 Performing the assay with diluted serum samples reveals the true, hyperprolactinemia. markedly elevated prolactin level and should be requested when prolactin levels are not 1 markedly elevated in a patient with a macroadenoma. Prolactin levels usually are not as high with microprolactinomas. Prolactin levels between 20 and 100 ng/ml can be difficult to 15 interpret; MRI and serial prolactin measurements may be helpful. Amenorrhea-galactorrhea and infertility bring women to early medical attention, and microadenomas predominate. Macroadenomas are more common in men, classically presenting with headache or visual impairment on a background of impotence, loss of libido, 15 or infertility. Treatment of prolactinomas restores fertility and also lowers the risk of osteoporosis associated with persistent hypogonadism. Ergot derivatives, such as the 17 tumor dopamine agonists bromocriptine or cabergoline, normalize prolactin or decrease 10 mass in up to 75 percent of macroadenomas and 90 percent of microadenomas. Surgery is typically reserved for patients with acute visual impairment or who do not improve or tolerate therapy with dopaminergic agents. As is the case for medical therapy, surgical outcomes are better for patients with microadenomas than macroadenomas. Trans-sphenoidal approaches 16 are favored, although large, invasive tumors may require bifrontal craniotomy. Regardless of whether the treatment plans include medication, surgery, or both, patients require monitoring with serial clinical assessment, prolactin levels, visual field testing, and neuroimaging. Radiation therapy has a limited effect on prolactinomas and is used primarily for patients who have undergone surgery, do not tolerate dopamine agonists, and have 12,15 Radiosurgery with the gamma knife is actively being persistent hyperprolactinemia.
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evaluated and may provide an effective and safer alternative to conventional radiotherapy for 16,18 many types of pituitary adenomas. Growth Hormone A 191-amino-acid polypeptide, GH stimulates skeletal growth and exerts a variety of 5 metabolic effects, including glucose intolerance. Insulin-like growth factor I (IGF-I)19mediates most of the growth-promoting effects of GH and exerts negative feedback control. Both stimulatory (GH-releasing hormone) and inhibitory (somatostatin) hypothalamic factors influence GH secretion. Secretory dynamics are complex; among the factors that influence 5 pulsatile GH secretion are age, nutritional state, and sleep. Excessive circulating GH before epiphysial fusion in children leads to gigantism. In adults, sustained GH excess causes acromegaly, which results from pituitary hypersecretion in 12,19 Coarsened facial features and enlargement of hands and feet may only nearly all cases. be recognized in retrospect and are a presenting complaint only infrequently. The diverse clinical manifestations include hyperhidrosis, reproductive dysfunction, skin tags, colonic 8,12,19 polyps, arthropathy, hypertension, hyperlipidemia, diabetes, and sleep apnea. Neurological symptoms include proximal weakness, carpal tunnel syndrome, and less commonly, compressive myelopathy from vertebral bony and extradural soft tissue 2 overgrowth. Because clinical manifestations develop insidiously, delayed diagnosis is common. Macroadenomas are identified in most cases, and symptoms of an expanding 1,19 In addition to neuroimaging studies sellar mass may bring the patient to clinical attention. and visual field testing, helpful initial diagnostic tests include oral glucose tolerance test for 19 GH suppression and random IGF-I measurement. Cosmetic disfigurement and chronic pain impair quality of life, and elevated cardiovascular 8,12 Fortunately, treatment appears to risk increases overall mortality twofold to threefold. decrease mortality; with normalization of GH and IGF-1, which is the overall goal of therapy, 19,20 Trans-sphenoidal resection is the primary treatment of life expectancy returns to normal. 1,8,12,20 Adjunctive medical choice for somatotroph microadenomas and macroadenomas. therapy with the somatostatin analogue octreotide can help control persistent GH hypersecretion after surgery, and newer longer-acting somatostatin analogues such as lanreotide and the GH receptor antagonist pegvisomant are expanding the role of medical 19–22 Medical therapy is also used in selected cases to shrink large treatment in acromegaly. 20 tumors before planned surgery, or when surgery is not possible. Bromocriptine, at doses higher than those required for prolactinomas (20 mg per day or higher), suppresses secretion 19,20 23 Irradiation or of GH, although the effect is less marked than for somatostatin analogues. repeat surgery may be necessary if GH levels remain elevated. Excess GH secretion has been described in association with24the diencephalic syndrome of infancy and represents an example of partial GH resistance. Manifestations include emaciation despite normal caloric intake, alert appearance, euphoria, and pallor. Mass lesions, usually gliomas, in the region of the optic chiasm and hypothalamus are usually diagnosed in association with this rare clinical syndrome. Adrenocorticotropic Hormone and Cushing's Disease ACTH is a 39-amino-acid peptide derived from pro-opiomelanocortin, a larger precursor 5 molecule that also gives rise to β-endorphin and β-lipotropin. ACTH regulates secretion of adrenocortical hormones, particularly cortisol. Corticotropin-releasing factor, secreted by the hypothalamus, and ADH stimulate ACTH release. Cortisol levels exhibit diurnal variation, with highest levels in the morning and lowest levels in late evening. Psychological or physiological stress also activates the pituitary-adrenal axis. Cushing's disease is due to ACTH hypersecretion from a pituitary adenoma and is a common 1 cause of endogenous hypercortisolism. Signs and symptoms include central obesity, hypertension, bruising, purple abdominal striae, facial plethora, hyperpigmentation, acne, 25,26 hirsutism, osteoporosis, menstrual disorders, impotence, and decreased libido. Laboratory findings include hypokalemic alkalosis, hyperglycemia, and leukocytosis. Neurological manifestations include myopathic weakness, headache, neuropsychiatric disturbances, particularly mood disorders and cognitive impairment, and less commonly 2,25–28 Diagnosis depends on epidural lipomatosis with radiculopathy or myelopathy. demonstrating endogenous hypercortisolism and then localizing the source of excess ACTH secretion to the pituitary. Commonly used screening tests include measurement of 24-hour 8,25,26 The urinary excretion of free cortisol and the low-dose dexamethasone suppression test. combined corticotropin-releasing hormone dexamethasone test may help exclude pseudo-Cushing's syndrome, such as occurs in alcoholism, depression, and chronic
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anxiety. Plasma ACTH determination and additional stimulation and suppression tests help establish ACTH dependence or independence. It can be difficult to distinguish pituitary from ectopic ACTH secretion definitively, and inferior petrosal sinus sampling aids diagnosis in centers experienced in its use. Brainstem infarction or hemorrhage are rare but serious 29 complications of 1this procedure. In Cushing's disease, most of the tumors are microadenomas. These small lesions may not be apparent by neuroimaging in 40 percent of cases; thus, a normal CT scan or MRI does not exclude the diagnosis of Cushing's 25,26 disease. Trans-sphenoidal surgery is the treatment of choice, with initial remission rates of 60 to 80 25 percent for microadenomas but less than 15 percent for macroadenomas. Transient or permanent adrenal insufficiency frequently develops postoperatively. Among options available for patients with persistent hypercortisolism after surgery are radiotherapy and 25,30 Steroidogenic inhibitors include mitotane, ketoconazole, cortisol-decreasing medications. metyrapone, and aminoglutethimide. Bromocriptine and cyproheptadine exert modest 30 suppressive effects on ACTH. Bilateral total adrenalectomy can be performed laparoscopically and is another treatment option; however, it obligates permanent adrenal replacement therapy and carries the risk of Nelson's syndrome, in which an ACTH-secreting 25 pituitary adenoma enlarges rapidly, presumably owing to loss of corticosteroid inhibition. Thyroid-Stimulating Hormone Pituitary adenomas secreting TSH cause hyperthyroidism and are rare, accounting for about 1,31 Clinical manifestations are those of hyperthyroidism 1 percent of pituitary neoplasms. (Chapter 20), with goiter in most cases, as well as features referable to an enlarging pituitary mass, because most are macroadenomas. Concomitant prolactin or GH hypersecretion occurs in some patients and hence galactorrhea-amenorrhea or features of acromegaly may 31 coexist. TSH is inappropriately high for the peripheral thyroid hormone levels. It is critical to distinguish TSH-secreting pituitary adenomas from primary hypothyroidism, another condition characterized by TSH elevation and an enlarged pituitary. Unlike patients with thyrotropin-secreting pituitary adenomas, individuals with thyroid hormone resistance are clinically hypothyroid. Additionally, in the latter disorder, medical management with thyroid replacement normalizes TSH and leads to regression of pituitary enlargement. For TSH-secreting pituitary tumors, surgery to resect or debulk the tumor is the preferred primary 31 therapy. If thyroid hormones remain elevated postoperatively, radiation or somatostatin analogues may be used as adjunctive therapy. Bromocriptine is ineffective, and antithyroid drugs such as methimazole or propylthiouracil risk increasing tumor growth by interfering with 8,31 feedback inhibition. Clinically Nonfunctioning Pituitary Adenomas About one third 5of all pituitary tumors are unaccompanied by clinical evidence of hormonal hypersecretion. Most are gonadotroph cell adenomas, which inefficiently secrete gonadotropins or discordantly secrete their α, FSH-β, or LH-β subunits. With the paucity of endocrine symptoms, most are macroadenomas, or they may be detected as incidental findings on neuroimaging obtained for other indications. Presenting features are thus those of a large pituitary mass: headache, visual32dysfunction, and hypopituitarism due to compression of normal pituitary or the portal system. Serum prolactin and assessment of anterior pituitary function should accompany neuroimaging studies and visual field testing. Surgery is the primary therapy of choice and improves visual function in many patients with visual field deficits. Radiation therapy may be beneficial to manage recurrence or for32significant residual tumor. For most patients, bromocriptine or octreotide is of limited benefit. The clinical and therapeutic features of pituitary adenomas are summarized in Table 23-4. Click here to view this table.... Pituitary Apoplexy Headache and visual loss, variably accompanied by oculomotor dysfunction, nausea and vomiting, altered mentation, and meningismus, constitute the cardinal clinical features of 33 pituitary apoplexy, caused by pituitary hemorrhage or infarction. The presenting syndrome may be fulminant, resembling subarachnoid hemorrhage,34but subacute or even asymptomatic forms have increasingly been recognized. Headache and visual loss (frequently decreased acuity or bitemporal hemianopia) are common presenting features. Ocular palsies, meningeal signs, and altered mentation also occur. Fever and hemiparesis are less common. Among endocrine disturbances, hypogonadism is nearly universal, and GH
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deficiency and hyperprolactinemia are also common. Acute adrenal insufficiency develops in two thirds of patients and can be fatal; hence, empirical corticosteroid replacement should be given to all patients with pituitary apoplexy. Hypothyroidism may also occur. Diabetes insipidus is rare. The differential diagnosis of pituitary apoplexy includes subarachnoid hemorrhage, bacterial meningitis, cavernous sinus thrombosis, and upper brainstem infarction or hemorrhage. Sellar CT and MRI are the diagnostic studies of choice; with its superior sensitivity for fresh hemorrhage, CT has its advantages in the acute setting. CSF shows nonspecific abnormalities. Empirical corticosteroid replacement and neurosurgical decompression form 33,34 Visual impairment usually responds well to surgery, which may the mainstays of therapy. also improve endocrine function. Depressed level of consciousness portends a poor outcome. Once the acute illness has resolved, patients should be monitored for hypogonadism and hypothyroidism, with hormone replacement instituted as needed. Pituitary apoplexy often occurs in adenomas, which may not have been recognized before hemorrhage or infarction. Although most cases develop without obvious cause, varied precipitants have been described, including anticoagulation, thrombocytopenia, and trauma, in addition to diagnostic tests or therapies for pituitary adenoma, such as dynamic hormone testing, bromocriptine, and pituitary radiation. Sheehan's syndrome refers to ischemic 35 pituitary necrosis after postpartum hemorrhage and hypotension.
Posterior Pituitary Magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei secrete precursor polypeptides, which ultimately are cleaved to form oxytocin and ADH, posterior 6 pituitary hormones that differ by two of their nine amino acids. Oxytocin mediates the “let-down” reflex of milk expulsion in response to suckling. ADH facilitates tubular water resorption, thus controlling renal free water clearance. In concert with hypothalamic thirst mechanisms, the renin-angiotensin systems, and cardiac and brain natriuretic factors, ADH plays an important role in salt and water balance. Deficiency or inappropriate ADH secretion may complicate cerebral disorders or their treatment and are themselves associated with neurological disturbances resulting from associated electrolyte disturbances. Diabetes Insipidus Diabetes insipidus is characterized by excessive renal water loss due to ADH deficiency, and 36 symptoms in awake patients include thirst, polydipsia, and polyuria. ADH hyposecretion leads to central diabetes insipidus and deficient renal response to adequate circulating ADH 37 levels causes nephrogenic diabetes insipidus. Both disorders have congenital and acquired forms (Table 23-5) and must be distinguished from compulsive water drinking, in which polyuria is appropriate to excessive water intake. In diabetes insipidus, patients unable to maintain adequate water intake to balance polyuria develop hypernatremia and volume contraction, which can progress to metabolic encephalopathy, coma, and death. Awake patients often increase their fluid intake sufficiently to compensate for urinary losses. Click here to view this table.... Common acquired causes of central diabetes insipidus include trauma, cerebral hypoxia-ischemia, and neoplastic, granulomatous, and inflammatory disorders of the sellar 36 region, but a specific cause cannot always be identified. Transient diabetes insipidus is not uncommon after head trauma or neurosurgery. Most acquired nephrogenic causes are 37 metabolic or toxic, including hypokalemia, hypercalcemia, and lithium. Diagnosis depends on demonstrating an inability to concentrate urine and is usually suggested by passage of large amounts of dilute urine. However, polyuria alone is not sufficient to make the diagnosis. In critically ill patients with increased intracranial pressure, for example, polyuria may reflect osmotic diuresis from mannitol therapy, rather than diabetes insipidus. Measurement of serum and urine osmolality can be helpful. Low urine osmolality in the presence of polyuria 36 and hypertonicity indicates inability to concentrate urine and, hence, diabetes insipidus. Water deprivation tests, monitoring urine and serum osmolality in the presence of dehydration, are sometimes necessary, particularly to distinguish central and nephrogenic 7 36,37 In many instances, the pituitary bright spot will not be seen on MRI. diabetes insipidus. The response, after water deprivation, to exogenously administered desmopressin, an ADH 36,37 analogue, indicates whether the diabetes insipidus is central or nephrogenic. For both the central and nephrogenic disorders, correcting the water deficit is an important therapeuticgoal. Desmopressin can be given parenterally, intranasally, or orally and is the
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treatment of choice for central diabetes insipidus. In the nephrogenic disorder, therapy includes eliminating the underlying cause combined with sodium restriction and thiazide 36 diuretics, which enhance sodium excretion. Syndrome of Inappropriate Antidiuretic Hormone Secretion Diagnosis of the syndrome of inappropriate ADH secretion (SIADH) depends on criteria set forth in the original description of the syndrome: low serum sodium and osmolality; elevated urinary sodium excretion; urine osmolarity exceeding plasma38,39 osmolarity; euvolemia; and Neurological manifestations normal cardiac, renal, hepatic, adrenal, and thyroid function. of SIADH are those of hyponatremia, specifically, encephalopathy and seizures; milder degrees of hyponatremia impair performance on tests of attention and may predispose 40 patients to falls. Neurological causes of SIADH include head trauma, neurosurgery, brain tumor, central nervous system (CNS) infection, stroke, hydrocephalus, delirium tremens, acute intermittent porphyria, and Guillain–Barré syndrome. Ectopic ADH production may occur, either from systemic malignancies or in association with pulmonary disease. Among the many drugs associated with SIADH are carbamazepine, antidepressants, neuroleptics, antineoplastic agents, and thiazide diuretics. The causes of SIADH are summarized in Table 23-6. Osmotic myelinolysis, a rare but often devastating cerebral disorder associated with rapid correction of hyponatremia of any cause, has helped fuel an ongoing controversy as to the optimal management of SIADH and other hyponatremic states, including mild 41 hyponatremia. Fluid restriction and management of the underlying cause are mainstays of treatment as discussed in Chapter 19, but patient adherence with the former is usually poor. Hypertonic saline and diuretics such as furosemide may be necessary for patients with 38,39 For patients with chronic, severe, refractory seizures or otherwise severely symptomatic. SIADH anddifficulty adhering to fluid restriction, demeclocycline, which induces nephrogenic 39 diabetes insipidus, can be administered. Click here to view this table.... Cerebral Salt Wasting Not all hyponatremia in patients with intracranial disease results from the impaired free water excretion that characterizes SIADH. In cerebral salt wasting, hyponatremia results from renal 42 sodium loss, which also causes hypovolemia, in contrast to the euvolemia of SIADH. The disorder has been reported after head trauma and neurosurgery, and in patients with primary brain tumors, carcinomatous meningitis, and subarachnoid hemorrhage. Diagnosis depends on recognizing the hypovolemia that accompanies the hyponatremia of cerebral salt wasting. Unlike SIADH, cerebral salt wasting is managed with water and salt supplementation and can be worsened by fluid restriction. The cause of cerebral salt wasting is incompletely understood. Atrial natriuretic peptide or other natriuretic hormones and altered sympathetic input to the kidney have been proposed as possible causes.
Hypopituitarism Hypothalamic and intrinsic pituitary disorders may lead to impaired secretion of anterior or 43 posterior pituitary hormones (Table 23-7). Hypersecretion of an anterior pituitary hormone accompanied by deficiency of others may occur in patients with large secretory adenomas. Because prolactin, unlike other anterior pituitary hormones, is primarily regulated by inhibition, large mass lesions or other processes that disrupt the pituitary stalk can elevate prolactin levels. Prolactin levels in the resulting “stalk syndrome” will be elevated, but not to levels seen with prolactinomas. In general, pituitary adenomas, even when large, tend to spare posterior pituitary dysfunction. Thus, the triad of diabetes insipidus, hyperprolactinemia, and deficiency of one or more anterior pituitary hormones suggests hypothalamic dysfunction or disruption of the hypothalamic-pituitary stalk. Click here to view this table.... As discussed previously, acute hypopituitarism may occur with pituitary apoplexy, causing death from acute adrenal failure. Chronic pituitary failure often develops insidiously. Early symptoms include fatigue, decreased sexual interest and function, loss of body hair, and cold intolerance. Symptoms reflect the extensiveness of trophic hormone deficiencies. Prolactin deficiency is rarely symptomatic. GH deficiency during childhood causes growth failure and there is growing evidence that GH deficiency in adults may be associated with increased 44 cardiovascular disease. Hypoadrenalism due to ACTH deficiency is usually less severe than in intrinsic adrenal disease, owing to preserved mineralocorticoid secretion. Thyroid dysfunction resulting from TSH deficiency is generally less severe than primary
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hypothyroidism. Gonadotropin deficiency causes loss of libido and impotence. A striking feature of more advanced hypopituitarism is neuropsychological dysfunction, including 6 apathy, depression, impaired memory, mental slowing, and, occasionally, delirium or coma. Multiendocrine deficiency, particularly hypocortisolism, is believed to cause cerebral dysfunction, which typically reverses, although sometimes incompletely, with hormone replacement. PARATHYROID GLANDS Derived embryologically from the third and fourth branchial pouches, the parathyroids are two paired glands situated behind the thyroid gland. Chief cells,45the principal parenchymal cell of the parathyroid gland, secrete parathyroid hormone (PTH). PTH is the prototype polypeptide hormone and increases calcium concentration in extracellular fluid through direct effects on kidney and bone and indirect effects on gastrointestinal absorption. Its secretion, in turn, is regulated by ionized calcium concentration in extracellular fluid. Parafollicular cells of the thyroid secrete calcitonin, which inhibits bone resorption, thus opposing PTH activity and lowering serum calcium levels. Vitamin D and its metabolites also influence absorption of calcium and other minerals and are sometimes used to treat parathyroid disorders.
Primary Hyperparathyroidism Primary hyperparathyroidism most commonly results from PTH oversecretion by the 45 parathyroid. In most cases, the cause is a solitary parathyroid adenoma, occurring as a sporadic disorder; less commonly, multiple adenomas may occur as inherited syndromes 46 such as multiple endocrine neoplasia type 1. Routine assessment of serum calcium concentration, made possible with widespread use of multichannel serum analyzers, has significantly altered the epidemiology of primary hyperparathyroidism. With the ease of detecting hypercalcemia, it has become clear that the disorder is not rare, and the diagnosis 47 is frequently made in patients with few or no symptoms. The classic triad of nephrolithiasis, osteitis, and peptic ulcer disease (“stones, bones, and abdominal groans”), characteristic of advanced primary hyperparathyroidism, is rarely seen today. Common symptoms include fatigue and subjective weakness, although diverse central and 2,3,46,48 Neuropsychiatric peripheral nervous system syndromes have been reported. syndromes include impaired memory, personality changes, affective disorders, delirium, and 49 psychosis. Elderly patients may be50particularly vulnerable. Parkinsonism and a syndrome resembling motor neuron disease, reversing with parathyroid surgery, have also been described. The degree of hypercalcemia does not always correlate with clinical severity, although neurological manifestations typically resolve with treatment of the endocrine disorder. Myelopathy has been reported, from compression by “brown tumors” seen in osteitis fibrosa or on a presumed metabolic basis with normal spine MRI. Neuromuscular symptoms include proximal weakness, muscle pain and stiffness, and paresthesias. Both myopathic and neurogenic syndromes have been described and typically respond to parathyroidectomy. Neuromuscular symptoms are relatively uncommon in mild 51 hyperparathyroidism. Hypercalcemia, usually with concomitant hypo-phosphatemia, and elevated levels of immunoreactive PTH suggest the diagnosis. Distinguishing malignancy-associated hypercalcemia, with or without ectopic PTH secretion, from primary hyperparathyroidism can be challenging. Parathyroidectomy46,47 relieves symptoms and normalizes serum calcium levels In patients with mild disease or who are not surgical in mild as well as severe disease. candidates, treatment options include maintaining mobility and hydration, moderating calcium 52,53 Calcimimetic drugs such as cinacalcet, which intake, and taking potent bi phosphonates. 53 decrease PTH secretion, have shown promise in clinical trials.
Hypoparathyroidism Hypoparathyroidism46results from decreased PTH secretion and leads to hypocalcemia and hypophosphatemia. The hormonal deficiency occurs most commonly after thyroidectomy and can also develop after parathyroidectomy. Hypoparathyroidism may also develop as a feature of autoimmune endocrinopathies and inherited disorders such as Kearns–Sayre syndrome and DiGeorge's syndrome. Other causes include glandular destruction from infiltrative processes or radiation. Severe magnesium depletion impairs both PTH secretion and its peripheral action. PTH resistance may develop as a consequence of circulating antagonists, abnormal receptors, or defects in receptor-linked enzyme activity and is referred to as pseudohypoparathyroidism. Diverse central and peripheral nervous system disorders may occur, primarily owing to
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2,3,46,48,54–56
hypocalcemia. Dementia and psychosis have been described, with varying degrees of improvement after correction of serum calcium concentration. Seizures, usually 56 generalized, are a well-recognized feature of hypoparathyroidism. Antiepileptic drugs usually are not effective, and attention should be directed toward correcting the serum calcium concentration. Intracranial calcification, most commonly in the basal ganglia in addition to cortex, brainstem, and cerebellum, develops in many hypoparathyroid patients, most of whom are asymptomatic. Diverse extrapyramidal syndromes, with or without associated intracranial calcification, have been described, including parkinsonism, choreoathetosis, hemiballismus, and torticollis. Tetany is the classic peripheral nervous system manifestation of hypocalcemia and may be difficult to distinguish from seizures. Findings on examination include Trousseau's and Chvostek's signs and carpopedal spasm. Clinically significant autonomic dysfunction is rare; the electrocardiogram may demonstrate a prolonged QT interval. Less common neurological syndromes include myopathy,55peripheral neuropathy, sensorineural hearing loss, and idiopathic intracranial hypertension. ADRENAL GLANDS The paired adrenal glands are situated atop the kidneys and consist of the medulla, derived from neuroectoderm, enveloped by cortex, derived from mesoderm. Their distinct embryological origins parallel their different endocrine functions. Adrenal medullary chromaffin cells secrete catecholamines, principally epinephrine, regulated primarily by cholinergic preganglionic sympathetic neurons. Adrenal cortical cells are arranged in layers. Zona reticularis, the deepest layer, is adjacent to the medulla and secretes sex hormones. Zona fasciculata, the middle layer, synthesizes and secretes corticosteroids, and the 57 outermost zona glomerulosa secretes mineralocorticoids. In contrast to the primarily neural control of adrenal medullary secretion, the hormones ACTH and angiotensin II regulate cortical function. Although traditional views have conceptualized the adrenal medulla and cortex as distinct endocrine organs, it has become clear that adrenocortical regulation is considerably more integrated and complex. This complex integration of neural, metabolic, and endocrine information allows the adrenal gland to fulfill its critical role in coordinating energy homeostasis and stress responses.
Cortex Hyperaldosteronism Aldosterone is the major mineralocorticoid in humans, promotes sodium retention and potassium excretion, and is primarily controlled by the renin-angiotensin system. In primary hyperaldosteronism, the adrenal gland itself stimulates excess hormone production, most commonly from an aldosterone-secreting adenoma. Presenting features include hypertension, due to volume expansion, as well as neurological manifestations of 57 hypokalemia and alkalosis, such as muscle weakness, paresthesias, tetany, or paralysis. Secondary hyperaldosteronism develops when renin-angiotensin system activation stimulates 58 the zona glomerulosa. Causes of increased renin include renal hypoperfusion and edema-forming states. Cushing's Syndrome As discussed previously, Cushing's disease refers specifically to excess circulating corticosteroids induced by an ACTH-secreting pituitary adenoma. Cushing's syndrome is a more general term for hypercortisolism and its associated clinical features and includes ectopic ACTH production, autonomous adrenocortical secretion, and exogenous 25,26 Systemic and neurological clinical manifestations corticosteroid administration as causes. are the same as Cushing's disease (p. 431). Similarly, diagnosis is directed toward demonstrating hypercortisolism and defining the source of corticosteroid excess. Screening tests include 24-hour urinary free cortisol and the low-dose dexamethasone test, followed by plasma ACTH determination and additional stimulation and suppression testing 8,12,25,26 Hypercortisolism may also as reviewed earlier in the discussion of Cushing's disease. occur without clinical Cushing's syndrome in association with physical stress (including hospitalization), malnutrition, psychiatric illness, particularly major depression and alcoholism, glucocorticoid resistance, and conditions associated with elevated cortisol-binding globulin, such as pregnancy, estrogen therapy, and hyperthyroidism. Non-Cushing's hypercortisolemia is referred to as pseudo-Cushing's syndrome. The differential diagnosis of hypercortisolism is outlined in Table 23-8. Click here to view this table....
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Probably the most common cause of Cushing's syndrome is corticosteroid therapy, which occasionally develops with topical or inhaled agents, as well as with oral or parenteral corticosteroids. Endogenous Cushing's syndrome is typically divided into ACTH-dependent and ACTH-independent causes. The former is more common and includes Cushing's disease, as well as ectopic ACTH production from lung or other tumors. ACTH-independent causes account for 15 to 20 percent of 25 patients with Cushing's syndrome and include adrenal adenoma, hyperplasia, and carcinoma. Treatment depends on the specific underlying cause and may include steroidogenic inhibitors, as discussed previously. Adrenal Insufficiency In general practice, a common cause of adrenal insufficiency is rapid withdrawal of corticosteroid therapy prescribed for a wide variety of conditions, such as autoimmune disorders, asthma, inflammatory bowel disease, and sarcoidosis. Acute adrenal failure can be lethal and should be considered in patients with otherwise unexplained hypotension. When adrenal insufficiency develops more gradually, systemic manifestations include fatigue, weight loss, hyperpigmentation, hypotension, hyponatremia, hyperkalemia, and 59 gastrointestinal symptoms. Cerebral symptoms include apathy, depression, confusion, and, occasionally, paranoia and psychosis. Myopathic weakness, cramping, and hyperkalemic 2,3,60,61 periodic paralysis may develop. Primary adrenal insufficiency, or Addison's disease, results from glandular dysfunction or destruction, acutely or chronically, by hemorrhage, infection, autoimmune attack, surgery, 59,60 Inherited causes include metastases, or heredofamilial disorders. adrenomyeloneuropathy and adrenoleukodystrophy, which are X-linked disorders 60,62 Adrenal disease may characterized by accumulation of very long chain fatty acids. antedate neurological symptoms or occur in isolation, and the diagnosis should be considered in young men with Addison's disease. Secondary adrenal insufficiency results from ACTH deficiency, due to hypothalamic or pituitary lesions or surgery, or suppression of the hypothalamic-pituitary-adrenal axis by exogenous steroid administration. The differential diagnosis of adrenal insufficiency is outlined in Table 23-9. Click here to view this table.... The synthetic corticotropin stimulation test usually constitutes the initial step in evaluating 59 suspected adrenal insufficiency. Steroid replacement is lifesaving in acute adrenal failure and relieves symptoms in chronic states.
Medulla Pheochromocytoma and Related Disorders Pheochromocytomas are rare catecholamine-secreting tumors that arise from chromaffin cells. Although most derive from adrenal medulla, about 15 percent develop from 63 sympathetic ganglia and are referred to as catecholamine-secreting paragangliomas. Most are sporadic, but pheochromocytomas may occur as a part of inherited endocrine or neurological disorders, including neurofibromatosis, von Hippel–Lindau disease, tuberous sclerosis, and Sturge–Weber syndrome. Sustained or paroxysmal hypertension and episodic headache, palpitations, and diaphoresis are common symptoms, although the clinical manifestations are quite diverse. Included in the extensive differential diagnosis are anxiety disorders, panic attacks, migraine, hyperthyroidism, menopausal symptoms, effects of sympathomimetic drugs, and dysautonomia. Screening tests include 24-hour urinary excretion of catecholamines, metanephrines, and vanillylmandelic acid. Measurements of plasma-free metanephrines or urinary-fractionated metanephrines (normetanephrine and metanephrine separately) appear to be the most sensitive tests for diagnosis and the most suitable for reliable exclusion of pheochromocytoma. CT scanning is most often used to localize tumors, but 63 T2-weighted MRI may be the better test. Surgical resection is the treatment of choice. Pheochromocytomas are neuroendocrine tumors arising from APUD (amine precursor 64 uptake and decarboxylation) cells. The term APUDoma has given way to neuroendocrine neoplasm, grouped as epithelial (group I) or neural (group II) tumors. Group I neoplasms include carcinoid tumors, gastrinoma, pancreatic islet cell carcinoma, medullary thyroid carcinoma, and small-cell carcinoma of the lung. In addition to pheochromocytoma and paraganglioneuroma, group II tumors include classic and olfactory neuroblastoma and primitive neuroectodermal tumors, such as medulloblastoma, retinoblastoma, pineoblastoma, and peripheral neuroepithelioma. With many of these neoplasms, secretion of biogenic
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Table of Contents This Chapter by Chapters
Keyword Index
Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 24 Neurological Disorders Associated With Bone and Joint Disease ANN NOELLE PONCELET • ANDREW P. ROSE-INNES •
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DEGENERATIVE DISEASE OF THE SPINE Cervical Spondylosis and Disc Disease Lumbar Disc Disease LUMBAR SPINAL STENOSIS AND NEUROGENIC CLAUDICATION OSTEOPOROSIS OSTEOMALACIA OSTEOPETROSIS PAGET'S DISEASE OF BONE VERTEBRAL OSTEOMYELITIS POTT'S DISEASE ANKYLOSING SPONDYLITIS RELAPSING POLYCHONDRITIS
The brain, spinal cord, cranial nerves, and spinal roots share an intimate anatomical relationship to the spine and skull. As a result, disorders of the skeletal system may result in neurological compromise. This broad group of conditions includes congenital malformations and degenerative, metabolic, traumatic, neoplastic, infectious, and inflammatory disorders of the bones and joints. The craniosynostoses (premature closure of the cranial sutures) are 1 covered in major texts of pediatric neurology and are not addressed here. The neurological complications of skeletal trauma and neoplastic involvement of bone are also covered 2,3 elsewhere. The neurological complications of rheumatoid arthritis are discussed in Chapter 29. Neurological complications of a number of other bone and joint diseases are described here. DEGENERATIVE DISEASE OF THE SPINE Degenerative disease of the spine is a broadly inclusive pathological category that includes degenerative change of both the intervertebral discs and the vertebrae (“spondylosis”). In general, these changes become more evident with age: the lifelong mechanical stress sustained by the highly mobile cervical spine and the mobile, weight-bearing lumbar spine accounts for the preponderance of degeneration in these two regions. Spinal degeneration may be entirely asymptomatic or may cause back or neck pain, referred pain, radiculopathy, or myelopathy. Degenerative spinal disease is common on computed tomography (CT) and 4,5 magnetic resonance imaging (MRI) of asymptomatic older adults. In the individual patient,
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therefore, a neurological deficit cannot simply be causally attributed to radiologically demonstrated disease of the spine. The pathophysiology of disc and bone degeneration is incompletely understood. Even less is known about etiology and the reason that neurological symptoms develop in one individual and not another with similar spinal changes. The components of the spine may be conceptualized as forming motion segments (i.e., functional units)—two adjacent vertebrae joined by paired facet joints and an intervening intervertebral disc. A layer of hyaline cartilage is interposed between each disc and the adjacent vertebral bodies. The spinal cord and the pairs of exiting spinal nerve roots lie in close anatomical proximity to the spine and are thus vulnerable to encroachment by bone or disc. The disc itself is formed from two histologically distinct parts: the tough collagenous outer annulus fibrosus and the gel-like, proteoglycan-rich nucleus pulposus. There is nerve and blood supply to the outer annulus only. The interior of the annulus and the nucleus pulposus require diffusion exchange of nutrients and metabolic products from the blood vessels of the adjacent vertebral bodies. The intervertebral discs change in composition and 6 structure with age. Different individuals may have very different patterns of disc degeneration. Beginning in the second decade, disc growth outstrips vasculature, the water content of the nucleus is reduced, and collagen content increases. In middle age, the nucleus tends to harden and the annulus may develop fissures. In the elderly, the disc is a thinned plate of fibrocartilage, representing the last stage of this degenerative process. These age-related changes alter the mechanical properties of the vertebral column and predispose to disc herniation. From the second decade onward, disc degeneration and its consequent clinical manifestations become steadily more frequent. Concomitant degeneration of the bony elements of the spine also occurs: “lipping” of the superior and inferior margins of the vertebral bodies, the formation of osteophytes, osteoarthritic changes of the facet joints (subluxation, osteophytosis and cartilaginous changes), narrowing of the intervertebral disc space, hypertrophy of the ligamentum flavum, instability of adjacent vertebrae with variable spondylolisthesis (anteroposterior slippage of one vertebra on an adjacent one), and narrowing of the lateral recess and intervertebral foramina. Encroachment on the spinal canal 7 leads to spinal stenosis. Neurological symptoms and signs develop when the spinal roots or spinal cord become compromised by encroachment of bone or disc. A body of recent work has emphasized that inflammatory mechanisms (resulting from exposure of the normally immunologically sequestrated nucleus pulposus) 8–10 in addition to simple mechanical compression contribute to The spinal cord terminates at approximately the L1–L2 the occurrence of radiculopathy. interspace and is thus vulnerable to compression by spinal disease above this level, often in association with radiculopathy. Below this level, the lumbosacral roots forming the cauda equina are exposed to injury, which may involve multiple roots bilaterally. The clinical features, differential diagnosis, and management of degenerative disease in the cervical and lumbar regions are discussed in detail later. Although plain radiography of the spine may occasionally identify a vertebral fracture or other focal bony pathological process, it 11 is not an adequate screening investigation and may be omitted if MRI or CT is requested. Degenerative disease of the spine is well demonstrated by either of these imaging modalities, and a focal disc protrusion at the appropriate site is compelling evidence that segmental symptoms and signs are indeed due to compression at that level. Spinal MRI is particularly valuable for demonstrating disc and other soft tissue anatomy, clearly indicates compression of root and cord, does not expose the patient to ionizing radiation, and is increasingly the imaging method of choice. Spinal CT provides detailed views of the bony components but 12,13 provides considerably less soft tissue resolution. Electromyography (EMG) provides additional, complementary information: a neurological deficit may be accurately localized to a particular nerve root, and evidence of axonal or 14 demyelinating injury (the latter indicating a more favorable prognosis) may be apparent. EMG is particularly helpful in excluding other peripheral nerve conditions that may be difficult to distinguish clinically.
Cervical Spondylosis and Disc Disease Degenerative disease of the cervical spine is a frequent cause of neck pain and neurological 15 deficit in adults. In addition to disc degeneration and vertebral spondylosis, the contribution of a congenitally narrow vertebral canal, buckling of the ligamentum flavum with neck extension, the formation of compressive spondylotic “bars,” and ischemic factors have been proposed as mechanisms leading to neural injury (Fig. 24-1 and Fig. 24-2).
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FIGURE 24-1 Cervical spondylosis. Sagittal T2-weighted MRI of the cervical
spine. Multilevel spondylotic disease with spinal stenosis and signal changes in the spinal cord are indicative of myelopathic injury.
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FIGURE 24-2 Cervical disc disease. Sagittal T2-weighted MRI of the cervical
spine. A herniated cervical disc is seen to compress the thecal sac at the C6–C7 level. Several aspects of the anatomy of this region are important to appreciate: eight pairs of cervical nerve roots are arranged such that a root exits above its respective vertebra after leaving its segmental origin in the spinal cord. The C2 root exits between the C1 and C2 vertebrae, and the C8 root exits between the C7 and T1 vertebrae. A lateral disc herniation at the C5–C6 level will tend to compromise the C6 root. This is the most common level of cervical radicular involvement, followed in order by a herniation at C6–C7 (C7 root), and then at C4–C5 (C5 root). There is relatively little space between the cervical cord and the walls of the vertebral canal in the cervical region. Spondylotic narrowing of the canal may compress the spinal cord and produce features of myelopathy. Relatively small degrees of stenosis may produce cord compression in the setting of a congenitally narrow spinal canal. A canal diameter of 11 to 13 mm is frequently narrow enough to produce features of myelopathy. The clinical manifestations of cervical spondylosis are neck pain, often associated with a limited range of movement of the neck, referred pain to the arm (often worse with coughing, straining, or particular positions of the head), and radiculomyelopathy. Men are affected two to three times more often than women. An acute root injury may occasionally result from rapid movement of the neck with disc herniation or manifest with a less abrupt onset more often consequent on foraminal stenosis secondary to spondylosis. Pain tends to be a prominent early symptom: it is often sharp and classically radiates into the upper arm within a dermatomal distribution. It is associated with numbness and paresthesias in the hand and with weakness when motor roots are involved. Appropriate motor, sensory, and reflex changes are found on examination. Single-level disease is seen in 15 to 40 percent and 16 multilevel disease occurs in 60 to 80 percent of cases. Cervical myelopathy tends to be a chronic, progressive process, but it may occasionally be
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abrupt in onset and catastrophic in its severity. There are few data to indicate how often cervical spondylotic radiculopathy is eventually associated with myelopathy. Compression of the spinal cord is often heralded by difficulty in walking and may be followed by sensory loss in the lower limbs and the development of urinary dysfunction (frequency and nocturia). Lhermitte's sign may be a feature of spinal cord involvement and is experienced as a shooting “electrical” sensation down the spine with flexion of the neck. “Numb, clumsy17hands” is an unusual symptom complex resulting from compression of the upper spinal cord. Examination shows a spastic paraparesis and an (ascending) sensory level that may involve the hands. Depression of segmental reflexes at the level of compression is characteristic. The differential diagnosis of pain and sensorimotor deficit in an upper limb together with spasticity in the lower limbs is wide. Radiculopathy alone may be confused with peripheral mononeuropathy such as carpal tunnel syndrome or acute brachial neuritis (brachial 16 plexopathy or amyotrophy). Pain in the neck due to degenerative disease must be distinguished from more sinister causes of neck pain (e.g., tumor, infection, and fracture). Myelopathy can be due to other compressive lesions of the spinal cord and a variety of intrinsic spinal cord pathologies (e.g., multiple sclerosis, motor neuron disease, and vitamin 18 B12 deficiency). The natural history of cervical radiculomyelopathy is poorly documented. Good recovery of function frequently follows root injury, especially with a demyelinative radiculopathy, from which full recovery within weeks may be expected. Even after partial axonal injury, considerable reinnervation occurs in time. The course of untreated cervical myelopathy tends toward slow progressive worsening, but a range of outcomes is seen, and precise prognostication is not possible in individual patients. The myelopathy may remain static for years, improve with conservative measures, or progress rapidly. Treatment of radiculopathy varies considerably, and there is no universally agreed upon 19 despite a lack standard of care. Surgery is frequently performed for a variety of indications,20–22 In view of of large-scale controlled trials comparing surgical and nonsurgical outcomes. the generally favorable prognosis for recovery of radiculopathy, it is reasonable to embark on a trial of conservative treatment (limited rest, soft collar, analgesics, anti-inflammatory drugs, muscle relaxants, limited course of opiates for severe pain) in all cases except documented 16,23 The role of local corticosteroid axonal radiculopathy with progressive muscle weakness. injection is not clearly established: temporary symptomatic relief is often achieved, but it probably has little influence on the ultimate outcome. Established myelopathy is usually 24 regarded as a firm indication for decompressive laminectomy, with halting of progression or clinical improvement in most25,26 patients. Some 15 to 20 percent, however, will continue to deteriorate despite surgery.
Lumbar Disc Disease The epidemiology of lumbar disc disease is poorly defined. Some 80 percent of the adult population will have a functionally significant episode of low back pain over a lifetime; a 27 subset of this group will have discogenic disease. Middle-aged men are most frequently affected. Disc herniation is seen less often in the elderly, probably as a consequence of a less mobile lifestyle and the gradual replacement of the disc material with fibrocartilage. Lumbar disc disease often coexists with bony changes of the vertebrae. Lumbar spine disease (Fig. 24-3) is frequently an asymptomatic radiological finding, but it may produce a range of symptoms. Patients may present with low backache, locally referred pain, radiating radicular pain (“sciatica”), a radicular neurological deficit, or some combination of these symptoms. The clinical onset may be spontaneous or associated with mechanical stress to the spine. A flexed posture or a transient increase in the pressure gradient across the dura (e.g., by coughing or sneezing) may exacerbate symptoms.
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FIGURE 24-3 Degenerative disease of the lumbar spine with spinal stenosis.
Sagittal and axial T2-weighted MRI of the lumbar spine. Multilevel discogenic disease is apparent in the lumbar spine on the sagittal view. Disc material is seen compressing the anterior aspect of the thecal sac on the axial image. The site of disc pathology may be marked by local tenderness to palpation or percussion over the spinous processes. The patient may adopt a fixed posture, often tilted away from the affected side, and resist movement. Lumbosacral root or sciatic nerve involvement is suggested when passive hip flexion with the leg extended at the knee reproduces the patient's usual back or leg pain. When radiculopathy is present, the pattern of neurological deficit will allow identification of the affected root. Most lumbar disc pathology involves the L4–L5 and L5–S1 interspaces. Disc abnormalities at L1–L2, L2–L3, and L3–L4 are rare, accounting for less than 5 percent of the total. Lumbar disc protrusions are most often posterolateral and affect either descending or exiting nerve roots; they cannot result in myelopathy because the spinal cord ends above the L1–L2 interspace. An asymptomatic disc protrusion may either miss nerve roots completely or, despite anatomical distortion of a root, fail to cause neurological symptoms. Two features allow a degree of correlation with the site of pathology when clinical manifestations are present. The roots are posterolaterally placed at the intervertebral foramen and pass through this aperture in a superior position. A disc protruding at the same level will tend to pass underneath the root exiting at the same interspace, but it often compresses the root of the segment immediately below, as it travels to its exit foramen. An L4–L5 disc will usually compromise the L5 root and leave the L4 root unaffected; similarly, an L5–S1 disc will usually compromise the S1 root. There are exceptions to this rule—clinical assessment should always allow that a nerve root can be compromised at any point in its intraspinal course. A large central disc may produce bilateral radicular signs or occasionally result in acute cauda equina syndrome with flaccid paralysis, lower-limb areflexia, or urinary and fecal incontinence. Acute cauda equina syndrome is a surgical emergency and, even when 28 promptly managed, carries a poor prognosis for neurological recovery. Chronic lumbar canal stenosis may lead to neurogenic claudication (see later). The features of low backache, referred pain to the legs or buttocks, and radicular deficit seen in lumbar disc disease are common to many other conditions. The large differential diagnosis encompasses diverse pathological processes involving the nerve roots, meninges, spine, paraspinal muscles, and viscera. For patients with acute low back pain (duration of less than 3 months), the emphasis of the initial assessment is on exclusion of serious underlying pathology. Neoplastic, infective, and traumatic causes are particularly important to identify and require specific treatment. Otherwise, conservative measures (limited bed rest, analgesic and anti-inflammatory treatment, physical therapy, and the use of local corticosteroid injections in selected patients) without further investigation represent the most appropriate 29–31 When there is no improvement, further investigation is indicated. initial management. The natural history of uncomplicated lumbar disc disease is usually one of eventual disc resorption with improvement of symptoms. Despite this generally good prognosis, lumbar disc surgery represents the most common elective surgical procedure involving the nervous 28 system. Surgical intervention is mandatory and urgent in acute cauda equina syndrome. Surgery is indicated when a motor deficit (by clinical examination or EMG) is worsening despite conservative management. There is much debate regarding the efficacy of surgery for patients outside these circumscribed categories, and few prospective data are available to 32,33 Incapacitating pain alone help predict which patients are likely to be successfully treated.
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in the setting of disc disease is commonly regarded as an indication for surgery, although the evidence to support this is incomplete. LUMBAR SPINAL STENOSIS AND NEUROGENIC CLAUDICATION Stenosis of the lumbar spinal canal is a radiological diagnosis and is frequently asymptomatic. Boden and colleagues found that 21 percent of (asymptomatic) adults older 4 than 60 years had lumbar spinal stenosis on MRI. Such narrowing may, however, be associated with low back pain, cause focal nerve root deficits, or give rise to neurogenic 34 claudication. Neurogenic claudication of the cauda equina is classically described as discomfort and aching pain in the lower back, buttocks, and legs that is precipitated by walking and relieved by sitting. Patients may experience numbness, paresthesias, or a sense of weakness in the legs, usually bilaterally and asymmetrically. Pain and other sensory symptoms may occur in a radicular distribution. Up to 11 percent of patients present with bladder and sexual dysfunction. Sitting will usually relieve symptoms sufficiently to allow further walking. Relief of symptoms with flexion of the spine explains why it is often easier to walk up an incline rather than on a level surface. Neurogenic claudication is usually of gradual onset and, once established, results in symptoms that may become disabling but tend to be unassociated with progressive neurological deficit. Neurological examination35at rest is usually normal unless radiculopathy due to degenerative spine disease coexists. The pathogenesis of intermittent neurogenic claudication resulting from lumbar spinal 36 stenosis is incompletely understood. Venous pooling with exercise in the stenotic canal may lead to intermittent ischemic neurapraxia of the cauda equina with transient conduction failure 37 and clinical and electrophysiological changes after exercise. Animal models have shown vasodilation in chronically compressed cauda equina with lumbar sympathectomy and 38 prostaglandin E receptor agonists. The anatomical substrate is most commonly that of progressive, chronic, degenerative lumbar spine disease on a background of a congenitally narrow lumbar spinal canal. Extension of the spine increases, and flexion decreases, the caliber of the spinal canal. Congenital lumbar stenosis is not clearly defined radiologically, but such patients tend to have claudication at a younger age with fewer degenerative changes 39 and stenosis at multiple levels. Central canal stenosis, lateral recess stenosis, and foraminal stenosis may coexist and contribute to any deficits. Many patients with radiological evidence of stenosis are not symptomatic and never develop neurogenic claudication. Diagnosis requires recognition of the highly characteristic history together with radiological evidence of lumbar spinal stenosis. Electrodiagnostic studies may show prolongation of minimum F-wave and soleus H-reflex latencies, but they are mainly useful to document 40,41 Degenerative lumbar spine disease in the absence of spinal associated radiculopathy. stenosis can cause intrinsic low back or leg pain that is sometimes exacerbated by activity but does not demonstrate a stereotyped relationship to walking or improve with sitting. Vascular claudication may be confused with neurogenic claudication but typically causes burning pain in the calves when walking, and there is usually evidence of circulatory insufficiency in the legs; other neurological symptoms and a radicular distribution of pain do not occur. Unlike vascular claudication, neurogenic claudication is less symptomatic when walking uphill owing to the flexed position of the spine. A variety of other neurological conditions may occasionally produce pseudoclaudication: these include multiple sclerosis and 42 spinal cord arteriovenous malformation. The literature documents a variety of measures of spinal canal and thecal sac anteroposterior diameter or cross-sectional area used to establish the diagnosis of lumbar spinal stenosis. In practice, there is little relationship between the degree of stenosis and the presence or severity of symptoms. Clinical judgment is required in each case to decide on the probable contribution of the stenosis to the patient's symptoms. Many patients with lumbar spinal stenosis find that they can remain mobile within the specific constraints of their symptoms. Surgery undoubtedly benefits many patients, but the literature 33,43 provides few controlled data comparing surgery with conservative treatment. Laminectomy with discectomy or simple foraminotomy may be sufficient to relieve symptoms where there is discrete, focal (unisegmental) narrowing of the spinal canal. Surgery is warranted if neurogenic claudication is progressive, significantly limits activities of daily living, or becomes intolerable to the patient. Interspinous decompression with placement of a device (X STOP) between the spinous processes, preventing narrowing of the canal with extension, 44 is a recent technique that has shown promise. Medical treatment of lumbar spinal stenosis may include limited bed rest, anti-inflammatory and analgesic medication, and physical therapy. Murakami and co-workers found that lipoprostaglandin E1 increased cauda equina blood-flow and relieved symptoms of neurogenic claudication in a small series of patients 45 with lumbar spinal stenosis.
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OSTEOPOROSIS Osteoporosis is “a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in 46 include aging, genetic factors, sex hormones in fracture risk.” Risk factors for bone loss 46 the United States, osteoporosis affects more than women, calcium intake, and inactivity. In 47 10 million people over the age of 50 years. More than 1.5 million Americans suffer from osteoporotic fractures annually. In 2002, the direct-care cost of osteoporotic fractures was 47 $12 to 18 billion. Risk factors for osteoporotic fractures include age, premature menopause, amenorrhea associated with low estrogen, Asian or white ethnic origin, history of fracture, low bone mineral density, glucocorticoid use, high bone turnover, family history of fracture, poor visual acuity, low body weight, neuromuscular disorders, cigarette smoking, excessive alcohol consumption, long-term immobilization, low dietary calcium intake, and vitamin D 46,47 deficiency. The spine is the most frequent fracture site, accounting for approximately 650,000 clinically detected fractures per year. The prevalence of osteoporotic fractures increases with age. In the United States, 25 percent of women older than 70 years and 5048percent of women older than 80 years are reported to have evidence of vertebral fractures. The incidence of vertebral fracture based on a large European population-based radiographic study is 10.7 per 49 1,000 person-years in women and 5.7 per 1,000 in men. The incidence increases markedly with age and is 29.3 per 1,000 person-years in women and 13.6 per 1,000 in men aged from 75 to 79 years. Vertebral fractures are most common in the low thoracic and high lumbar regions, and 50,51 Patients with any type of osteoporotic fracture are at multiple fractures are common. increased risk for another fracture. There is a 10-fold increased risk of a subsequent vertebral fracture in patients with an existing vertebral fracture. Fractures result from reduced bone strength, which is determined by the bone macroarchitecture, matrix and mineral composition, degree of mineralization, microdamage accumulation, and rate of bone 46 turnover. About one quarter of vertebral fractures occur from falls, but the majority are triggered by trivial activity such as bending, lifting a light object, or getting out of bed. Most vertebral fractures are painless, only around 30 46 percent come to a specialist's attention, and less than 10 percent result in hospital admission. Symptomatic patients usually have acute low back pain. Pain is often localized to the site of the fracture, but it can be diffuse and non-localizing. Radiating pain into the lower extremities is uncommon and usually does not 51 correspond to a lumbar root pattern. Straining and local percussion increase the pain. The patient may not be able to bear weight initially; often symptoms improve when lying down. 51 There are usually no neurological symptoms or signs. Plain radiographs of the spine are the study of choice to document the presence of vertebral fracture. The most widely accepted radiological definition of vertebral compression-fracture is a decrease of 15 to 25 percent in the anterior, central, or posterior height of a vertebral body 48 compared with adjacent normal vertebrae or a population reference. The diagnosis can be confirmed by bone scan or CT when radiographs are equivocal. Complete blood cell count, serum chemistry screen, urinalysis, thyroid function tests, and serum protein electrophoresis are recommended to exclude secondary causes of osteoporosis, which are present in up to 48 20 percent of women. Vertebral bone mineral density can be used to determine future fracture risk. Markers of bone turnover also predict fracture risk including serum bone-specific alkaline phosphatase, amino-terminal propeptide of type 1 procollagen, and 46 urine or serum telopeptides of collagen crosslinks. The optimal treatment of acute osteoporotic vertebral fractures is uncertain. Prolonged bed rest may accelerate the underlying osteoporosis, so analgesics, local heat/cold application, 48,51 Corsets and and mobilization with physical therapy and hydrotherapy are recommended. braces are rarely helpful. Narcotics are occasionally required for pain, and calcitonin may provide relief in the acute phase. With 48 persistent pain, an intercostal nerve block or epidural corticosteroid injection may be helpful. Vertebroplasty is a promising technique involving the injection of polymethylmethacrylate into a fractured vertebral body. Early uncontrolled studies 52 suggest it may have a role in pain relief and early mobilization. Preventative treatments for osteoporosis play an increasing role in reducing the number of vertebral fractures in postmenopausal women and the elderly. The American Association of Clinical Endocrinologists recommends that all women aged 65 years or more, women older than 40 years with a history of fracture not caused by severe trauma, and younger peri- and postmenopausal women who have clinical risk factors for fracture be evaluated for 47 osteoporosis. Treatment is recommended for postmenopausal women with total hip or bone
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mineral density scores less than −2.5 and for all postmenopausal women with osteoporotic vertebral fractures. Women should also be treated if they have risk factors for fracture and 47 bone mineral density scores of −2.0. Treatments include exercise, nutrition, calcium and vitamin D supplementation, hormone replacement in postmenopausal women, bisphos-phonates, selective estrogen-receptor modulators, calcitonin, and anabolic agents 46 such as teriparatide. Randomized trials have shown that estrogen replacement therapy reduces the rate of bone loss. Treatment is most beneficial if started during or soon after menopause, and the benefits appear to wane rapidly after its discontinuation. It may not be appropriate in women with a personal or family history of breast cancer, hypertension, thromboembolic disorders, 46 or gallbladder disease. It is not recommended in women with cardiovascular risk factors. The bisphosphonates (alendronate, risedronate, and ibandronate) in randomized, placebo-controlled trials show reduction in the risk of vertebral 46,47 Once-weekly or once-monthly regimens are available for fractures by 40 to 50 percent. 47 improving adherence. Raloxifene, a selective estrogen-receptor modulator showed a reduced vertebral fracture rate of 50 percent in women without prior fractures and 34 percent 46 nonvertebral fractures. in women with previous vertebral fractures. There was no effect on 47 Raloxifene also reduces serum lipids and the risk of breast cancer. Side effects include increased risk of venous thrombosis. Teriparatide, a 34-amino-acid peptide of parathyroid hormone, showed a 65 percent reduction in the risk of new vertebral fracture and 53 percent reduction in nonvertebral fracture. The46effects on bone mineral density were not sustained unless followed by a bisphosphonate. Finally, strontium ranelate reduced vertebral fractures by 41 percent after 3 years. It has only a modest effect on nonvertebral fractures. The association between vertebral fractures and chronic back pain is unclear. In patients with osteoporosis and vertebral fractures, the presence and severity of back pain correlates with 53 the number of collapsed vertebrae (thoracic only) and degree of kyphosis. Neurological complications are uncommon. They include myelopathy, cauda equina syndrome, and lumbosacral radiculopathy. The prevalence is unknown. One series from Hong Kong found that 2 percent of patients admitted for painful acute vertebral fracture had 48 neurological signs (lower-extremity weakness and sphincter disturbances). Lower-extremity symptoms may develop from 10 days to 1.5 years after onset of acute spine pain, owing to 54–57 The etiology is thought to be late collapse of the vertebral extension of vertebral fracture. 57 may body due to disruption of the microcirculation and aseptic necrosis. Severe kyphosis 54 be a risk factor for progression of vertebral fracture and neurological compromise. Neurological symptoms are insidious and may be missed. Patients eventually become unable to walk owing to back pain and lower-extremity weakness. Spinal CT or MRI reveals violation of the posterior cortex of the vertebral bodies (burst fracture) with retropulsion of bone into 54,55 The most common location is the thoracolumbar junction. the spinal canal. The best operative approach in these patients is not known. Goals include improvement of the neurological deficit, correction of the deformity, and stabilization of the spine. Clinical 54–57 results are mixed, ranging from marked improvement to worsening of function. 56 Significant rates of instrument failure and postoperative mortality occurred in one series. Another series compared anteroposterior surgery with posterior closing wedge for 57 osteoporotic fracture with neurological compromise. Although there was no significant difference in neurological recovery, there was a significantly shorter operative time with less bleeding in the group undergoing posterior closing wedge56osteotomy. Postoperative bracing potentially can reduce the rate of instrumentation failure. 55A small group of patients treated conservatively also had significant recovery over months. Occasionally, patients with vertebral fracture have radicular symptoms, with pain radiating into the lower extremity that worsens with change in position or on standing. There may be dermatomal sensory loss and weakness in a myotomal distribution. A study of seven patients with radiculopathy following osteoporotic vertebral fracture and who were not operative candidates showed substantial or complete resolution of symptoms following 52 vertebroplasty. Advantages include minimal invasiveness without the need for general anesthesia. Risks include leakage of the cement into the intervertebral foramen. OSTEOMALACIA Osteomalacia is a metabolic bone disorder characterized by defective mineralization, which results in the accumulation of unmineralized matrix or osteoid in the skeleton. Normal bone mineralization requires adequate circulating 58 levels of vitamin D metabolites, a normal supply The most common cause of osteomalacia is of minerals, and optimal osteoblast function. 58 58 vitamin D deficiency. Other causes of osteomalacia are listed in Table 24-1. Reduced cutaneous production of vitamin D is a concern in the elderly who are institutionalized or housebound, in Asian immigrants to northern countries, in women who adopt strict dress
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codes that prohibit exposure of uncovered skin, and in postmenopausal women. Dark-skinned people require 4 to 5 times more sun exposure than those who are light skinned. The prevalence of low 25(OH)D levels (<20 ng/ml) is 36 percent in healthy young adults aged 18 to 29 years, 42 percent in black women aged 15 to 49 years, 41 percent in outpatients aged 49 to 83 years, up to 57 percent in general medicine inpatients in the United States, 58 and even higher in Europe (28% to 100% of healthy and 70% to 100% of hospitalized adults). A study of nonelderly, ambulatory, primary-care outpatients with persistent, nonspecific musculoskeletal pain59refractory to standard pharmaceutical agents demonstrated hypovitaminosis D in 93 percent. Up to 40 percent of patients with femoral fracture have evidence of osteomalacia. Malabsorption is also an important cause and results from decreased absorption of vitamin D, increased catabolism of vitamin D metabolites, and malabsorption of calcium or phosphate. Click here to view this table.... The classic clinical features include musculoskeletal pain, skeletal deformity, muscle 58 weakness, and symptomatic hypocalcemia. The early symptoms are vague, and without a high index of suspicion the diagnosis is easily missed. Bone pain is invariably present and is especially prominent in the spine, ribs, pelvis, and lower extremities. The pain is worse with muscle strain, weight bearing, or pressure, but persists with rest. The pain can be elicited on physical examination by applying minimal pressure with the thumb or forefinger on the sternum or anterior tibia. Although the exact reason for it is unknown, it is postulated that collagen-rich osteoid deposited on the periosteal surface of the skeleton becomes swollen, similar to the hydration of gelatin-based food products. This swelling could put outward 58 pressure on the periosteal covering that is innervated with nociceptors. These patients are most often misdiagnosed as having fibromyalgia, chronic fatigue syndrome, or myositis and treated inappropriately with nonsteroidal anti-inflammatory drugs (NSAIDs). 60,61
A proximal myopathy is common, and weakness can be the presenting complaint. 62 The incidence of myopathy in osteomalacia is estimated from 73 percent to 97 percent. Weakness is the presenting symptom in 30 percent of cases. The limb-girdle63muscles are the most affected and result in a waddling gait, Gower's sign, or inability to walk. The proximal upper extremities and neck flexors are occasionally involved; distal weakness is rare. Bulbar and sphincter muscles are spared. Weakness is accompanied by myalgias and muscle 64 of weakness, atrophy, and atrophy. Tendon reflexes are often brisk, and the combination62,65 Vitamin D deficiency may hyperreflexia can be mistaken for amyotrophic lateral sclerosis. contribute to age-related muscle weakness and falls. A meta-analysis of randomized controlled trials of vitamin D supplementation for elderly ambulatory and institutionalized 66 people showed a greater than 20 percent reduced risk of falls in treated patients. Other studies exploring vitamin D levels and fall risk also support the role of 58 osteomalacia-associated myopathy in elderly patients. Hypocalcemia is associated with osteomalacia, and hypomagnesemia (from malabsorption) also occurs, sometimes leading to additional clinical disturbances as discussed in Chapter 19. Some epidemiological studies suggest that the risk of developing multiple sclerosis is reduced in populations with higher 58 vitamin D intake. Bone deformities occur late in the disease and are the result of softening of the bones. They include kyphosis, scoliosis, shortening of the spine, and deformity of the rib cage, pelvis, and 63 Fracture risk is only minimally increased due to increased elasticity of the long bones. 63 bones. Osteomalacia in childhood results in rickets with short stature, bowing of the legs, and widening of the metaphyses, which in the ribs leads to a “rickety rosary” appearance. Premature closure of the sagittal cranial sutures may result in craniotabes, and 63 hydrocephalus may occur in severe cases. The classic radiological features include translucent bands of demineralized bone (Looser's zones) in the proximal femur, humeral neck, pubic rami, ribs, metatarsals, and outer border 63 of the scapula. The softened vertebrae become deformed with a uniformly biconcave codfish appearance. There may uncommonly be deformities of the rib cage, pelvis, and long bones. Radiological features of secondary hyperparathyroidism may also be present. The biochemical abnormalities may be minimal and vary with the cause of osteomalacia. In vitamin D deficiency, the earliest finding may be hypophosphatemia (as a result of secondary hyperparathyroidism due to calcium deficiency). Serum 25-hydroxyvitamin D is the major circulating metabolite of vitamin D and reflects vitamin D input from cutaneous synthesis and dietary intake. The standard clinical measure of vitamin D status is the serum 25-hydroxyvitamin D level. A minimum level of 20 ng/ml is necessary to minimally satisfy the body's vitamin D requirement, though a level of 30 to 50 ng/ml is preferred. An increased 67 serum alkaline phosphatase level is present in 57 to 72 percent of cases. There may be
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mild hypocalcemia. Low serum albumin and iron-deficiency anemia can reflect malabsorption. Despite clinical evidence of myopathy, the serum creatine kinase is 60–62 Parathyroid hormone levels may be elevated. Levels of vitamin D or its normal. metabolites are inconsistently reduced. Hypocalcemia is usually present in osteomalacia associated with renal failure, but the serum phosphate is normal or high because of reduced urinary excretion of phosphate. The plasma 1,25-dihydroxycholecalciferol level is low. The diagnosis of difficult cases depends on histological study of undecalcified bone. There is an increase in the thickness of the osteoid and increased osteoid surface. Reduced mineralization 65,67 activity can be demonstrated using tetracycline labeling of the calcification front EMG may be normal in patients with weakness but in 66 to 83.3 percent before biopsy. shows small, short-duration, and polyphasic motor unit action potentials in proximal muscles, 61,62,64,65,68 The findings on muscle biopsy are without abnormal spontaneous activity. 61,62,65 Treatment of vitamin D deficiency nonspecific and most often are of type II atrophy. osteomalacia includes ultraviolet irradiation UV-B (wavelength of 290 to 315 nm) and vitamin 58 D replacement. Holick recommends treating vitamin D deficiency with an oral dose of 50,000 IU/week of vitamin D2 for 8 weeks, with monitoring of 25-hydroxyvitamin D levels. In some cases, a second once-weekly 8-week course of 50,000 IU of vitamin D2 may be necessary to boost 25-hydroxyvitamin D levels into the desired range of more than 30 to 50 ng/ml (75 to 125 nmol/L). For patients prone to developing vitamin D deficiency, after the deficiency is corrected, 50,000 IU every 2 weeks will maintain a vitamin D–sufficient state. Another option is 1,000 IU of vitamin D3 intake. Cutaneous exposure to sunlight or artificial UV-B such as a tanning bed is also helpful, especially in patients prone to vitamin D 58 deficiency. Calcium and magnesium supplements are recommended. Malabsorption and renal failure can be treated with vitamin D metabolites (calcitriol, 1 to 4 μg). Treatment of the underlying disorder should be attempted in malabsorption. The hypophosphatemia and hypocalcemia resolve in weeks,58and the serum alkaline phosphate level may increase initially and then improve over months. The bone pain, symptoms of hypocalcemia, and proximal weakness often resolve completely over weeks to months. Deformities persist despite remodeling of the bone. X-linked hypophosphatemic osteomalacia is different from other causes of osteomalacia in regard to the neurological complications. This is an X-linked dominant syndrome with hypophosphatemia, osteomalacia, short stature, and the eventual development of new bone 58,63 The proximal myopathy seen with other forms of osteomalacia does at various body sites. 69,70 The not occur. Rarely, myelopathy develops as a result of intraspinal new bone formation. mid- and low thoracic spine is the predominant site of involvement, but the cervical spine can also be affected. Symptoms can be intermittent and involve multiple levels of the spinal cord, 69,70 The onset is acute or insidious with paresis, sensory loss, mimicking multiple sclerosis. and less frequently, bladder symptoms. CT of the spine shows enlargement of the facet joints, thickening69of the laminae, and ossification within the spinal canal, resulting in severe central stenosis. Surgery is difficult owing to thickening of the bone and adherence69of the dura to the ligamentum flavum but can result in improvement or resolution of deficit. Treatment includes an oral neutral phosphate with 1,25-dihydroxyvitamin D (calcitriol). Excess vitamin D replacement can cause hypercalcemia, leading to soft-tissue calcification. To avoid complications such as nephrocalcinosis, serum calcium levels should be measured monthly. Diuretics such as amiloride and hydrochlorothiazide enhance calcium reabsorption and can reduce the risk of nephrocalcinosis. OSTEOPETROSIS Osteopetrosis is a rare group of sclerosing bone disorders characterized by a generalized 71,72 Its increase of skeletal bone mass due to a defect in osteoclastic bone resorption. The disease is caused by a classification by mode of inheritance is shown in Table 24-2. + defect in a proton pump (the α3 subunit of vacuolar-type H -ATPase, encoded by the gene variously termed ATP6i or TCIRG1) or the ClC-7 chloride channel (CLCN7 gene). These ion channels are responsible for acidifying the bone surface adjacent to osteoclasts, which affects bone resorption. The development of the marrow cavity is delayed or absent. Impaired bone modeling during longitudinal growth results in a broad cylindrical shape at the ends of the long bones. These bones are brittle with an increased susceptibility to fracture. The most serious complications of the osteopetroses affect the nervous system. Cranial nerves, blood vessels and the71spinal cord are compressed by either gradual occlusion or lack of growth of skull foramina. The symptoms vary depending on age of onset and severity of disease. Click here to view this table.... Malignant osteopetrosis presents during infancy and is the most common form of childhood osteopetrosis. The course is severe, with most children receiving the diagnosis within the first 71 year of life and only 30 percent surviving to the age of 6 years. Its incidence is
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approximately 1 in 300,000 births, but it is almost 10 times as high in Costa Rica. Neurological involvement occurs frequently and includes optic atrophy with blindness, nystagmus, strabismus, trigeminal neuropathies, facial paralysis, deafness, dysarthria, 71 hydrocephalus, intracranial hemorrhage, mental retardation, and convulsions. Hydrocephalus is due to obstruction of the venous outflow at the cranial foramina and to inadequate intracranial space for circulation of cerebrospinal fluid as a consequence of 73 thickening of the bones of the skull. Cranial nerve involvement relates to bony encroachment, and successful results have followed decompression of the optic, facial, and 74 acoustic nerves. CT scan is recommended for evaluating the optic canal. Retinal 73 degeneration has been described in some patients and is another cause of visual loss. The most frequent sign of early damage is a change in flash-elicited visual evoked potential (VEP) latency. Systemically, the constricted bone marrow cavity cannot support adequate hematopoiesis, resulting in hepatosplenomegaly, thrombocytopenia, anemia, and infectious complications. Clinical symptoms respond to calcitriol, which enhances bone resorption; prednisone, which improves hematological indices; and interferon-γ1b, which reduces the 75 number of infections. Allogenic hematopoietic cell transplantation is currently the only therapy capable of producing long-term benefit in children; early treatment by this means 76 limits neurosensory defects and impaired bone growth. It also results in reconstitution of normal hematopoiesis and neutrophil function. Significant risks include a high frequency of graft rejection, veno-occlusive disease, and severe pulmonary hypertension. Patients with intermediate autosomal-recessive osteopetrosis have a less severe course than those with malignant osteopetrosis. The clinical presentation includes recurrent fractures, osteomyelitis, dental abnormalities, and short stature. Mild-to-moderate anemia, extramedullary hematopoiesis, mandibular prognathism, proptosis, and deafness are also present. The radiological features are typical, with a generalized increase in bone density and thickening and sclerosis of the skull. The outcome and life expectancy are better than with malignant osteopetrosis. Autosomal-dominant osteopetrosis includes three types. Type I benign osteopetrosis has 75 uniformly denser bones, and the cranial vault in particular shows sclerosis and thickening. Its frequency is estimated at 1:100,000 to 1:500,000, but an epidemiological study carried out 75 in Denmark revealed a frequency of >1:20,000. In type II, there is variable density that leads to characteristic “endobones” in the spine, iliac wings (“bone in bone” appearance), and skull 75 base. Both77types present in adulthood and are often found incidentally on routine radiographs. About 50 percent of patients are asymptomatic, and another 40 percent have fractures or osteomyelitis. Bone marrow failure does not occur. Neurological involvement occurs in 16 percent of cases; cranial nerve palsies occur as the result of bony 78 The second, seventh, and eighth cranial nerves are the most commonly encroachment. 74 affected. Type III, or “centrifugal osteopetrosis,” is characterized by sclerosis of the distal 75 appendicular skeleton and the skull with only minor involvement of the axial skeleton. Carbonic anhydrase II deficiency (also known as Guibaud–Vainsel syndrome or marble brain disease) is an autosomal-recessive disorder resulting in osteopetrosis, renal tubular acidosis, 75 and cerebral calcification. It presents in late infancy or early childhood with developmental delay, short stature, failure to thrive, dysmorphic features, weakness, cranial nerve compression, and a history of multiple fractures. Motor retardation occurs during the first year of life. Patients may have apathy, global hypotonia, or muscle weakness that may be explained by acidosis and diminished blood levels of potassium from their renal tubular acidosis. Rarely, hypokalemic weakness or paralysis occurs episodically. More than one half of all patients develop cranial nerve deficits, particularly optic atrophy, facial palsy, and 79 deafness. Plain radiographs show increased density in the long bones, vertebral bodies, pelvis, and skull. Cranial CT shows diffuse calcifications of the brain, particularly the basal 71 can be made by erythrocyte assay or by molecular probes for ganglia. The diagnosis 80 been found in the carbonic anhydrase carbonic anhydrase II. Five different mutations have 81 II gene on the long arm of chromosome 8 (8q22). Prenatal diagnosis must be made at the DNA level, because carbonic anhydrase II is not expressed in fetal erythrocytes. There is no established treatment for this condition, and bicarbonate treatment does not clearly reverse the growth retardation. Infantile neuroaxonal dystrophy is a rare autosomal-recessive disorder with widespread accumulation of neuroaxonal spheroids in cortex, basal ganglia, mesencephalon, brainstem, 75 and spinal cord, which has been reported in association with osteopetrosis. It presents during the first year of life with weakness, hypotonia, rigidity, pyramidal signs, diminished pain sensation, optic atrophy, and mental impairment. This is accompanied by hypocalcemia, hypomagnesemia, severe anemia, thrombocytopenia, hepatosplenomegaly, jaundice, and metabolic acidosis. Cranial CT shows agenesis of the corpus callosum and ventriculomegaly. This form of osteopetrosis is fatal within the first year of life.
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Transient infantile osteopetrosis that spontaneously resolved by the age of 28 months has been reported in a child. Unlike malignant osteopetrosis, the child was asymptomatic without abnormal physical findings or hematopoietic impairment. The osteoclasts appeared normal on bone biopsy, and the spontaneous resolution of radiographic abnormalities soon after birth 75 differentiated this transient osteopetrosis from the malignant form. PAGET'S DISEASE OF BONE Paget's disease is a focal disorder of bone turnover. There is excessive bone resorption coupled with abnormal new bone formation resulting in architecturally disorganized and 82 mechanically weak bone. It has a predilection for the axial skeleton and involves the cervical spine in 14 percent,82thoracic spine in 45 percent, lumbar spine in 58 percent, and studies skull in 42 percent of cases. The prevalence based upon autopsy and radiographic 83 is 3 to 3.7 percent, and it is found primarily in populations of Anglo-Saxon origin. Its 84 prevalence increases with age. There is a family history in 14 to 40 percent of patients. The etiology is poorly understood and may relate to a combination of 82 genetic susceptibility, environmental factors, and a viral agent such as paramyxovirus. Three genes are identified in familial Paget's disease and related disorders. They encode RANK, a receptor that regulates osteoclast activity; osteoprotegerin, a decoy receptor for RANK; and sequestosome 84 1, a scaffold protein in the NF-κB signaling pathway. Histologically, increased bone resorption is followed by a mixed osteolytic-osteoblastic phase, with deposition of poorly 82 organized bone with ineffective mineralization. The bones are thickened, with replacement of the marrow by highly vascularized fibrous tissue. Later, there is primarily abnormal bone deposition. 82
Most patients with Paget's disease are asymptomatic. The most common presentation in symptomatic patients is local bone pain with overlying skin warmth due to increased bone microvasculature. The pain is continuous and worse at rest. There may be obvious deformity of the bones. Skeletal complications include osteoarthritis, fractures, and sarcomatous 82 change. 82
Plain radiographs may show lytic lesions early in the disease. Later, there is a chaotic crisscross pattern with thickened cortical and trabecular bone, sometimes accompanied by pseudofractures. Bone scintiscanning may reveal lesions not seen by plain films. Markers of bone turnover are often elevated, including serum alkaline phosphatase and urine hydroxyproline. 82,85
Asymptomatic patients Treatment depends on the location and activity of the disease. often do not require treatment. Calcitonin inhibits osteoclast activity and can be effective in the acute setting. Relapses are common. Bisphosphonates produce a marked and prolonged inhibition of osteoclast function, and newer agents such as alendronate and risedronate are used for chronic treatment. The bisphosphonates are currently first-line therapy for active Paget's disease. A recent study showed alendronate had equivalent efficacy to intravenous 86 pamidronate in previously untreated patients (91% versus 86%). Alendronate resulted in biochemical remission in 86 percent of patients who did not respond to pamidronate. Adherence to oral bisphosphonates is impacted by the need to fast before and after treatment and to remain upright for at least 30 minutes after ingestion to reduce the risk of upper gastrointestinal side effects. A study comparing a single infusion of zoledronate to a 2-month course of daily risedronate therapy showed a therapeutic response in 96 percent 87 of patients receiving zoledronate compared to 74.3 percent of patients receiving risedronate. The relapse rate in the zoledronate group was significantly lower than in the risedronate group (0.9% versus 25.6%). Calcium supplementation is recommended to prevent symptomatic hypocalcemia. Surgical treatment is sometimes required to treat fracture, osteoarthritis, and bone deformity. Conventional bone scan is recommended prior to medical therapy and at 6 months and 12 months after medical therapy to monitor disease activity. Bone markers should be monitored every 3 to 6 months. Neurological involvement occurs as a result of the close anatomical relationship of bone with 82,88 Compression from the brain, spinal cord, cauda equina, spinal roots, and cranial nerves. expanding bone or fracture is the most common cause of neurological dysfunction. Less common causes include ossification of extradural structures, osteosarcoma, and epidural hematoma. Ischemia of the nervous system can occur owing to compression of vascular structures or a vascular steal phenomenon. Measurement of skeletal blood-flow by 18 F-clearance demonstrates that affected bone receives up to 18 percent of the cardiac 89 output compared with 5 percent in normal bone. Calcitonin reduces the abnormal skeletal blood-flow to normal. The incidence of neurological involvement from cranial disease is unknown. Irreversible
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82
hearing loss occurs in 13 percent of patients, but other neurological complications of cranial disease, such as headache, epilepsy, dementia, brainstem and cerebellar dysfunction, and 90 cranial neuropathies, are rare. Headache is severe, frequently occipital, and worsened by coughing, sneezing, or straining. Dementia occurs from direct compression of the cerebral 91–93 In its94extreme, dementia is accompanied by hemispheres or as a result of hydrocephalus. a paucity of motor activity resembling akinetic mutism. Epilepsy occurs as a result of 91 compression of the cerebral hemispheres. In advanced cranial disease, there is softening of the skull base that can result in an anatomical lowering of the skull onto the upper cervical vertebrae (basilar invagination). This leads to obstructive hydrocephalus and compression of the cerebellum, lower cranial nerves, corticospinal tract, and upper cervical nerves. The severity ranges from asymptomatic to acute tonsillar herniation and death. The typical presentation is that of slowly progressive ataxia, vertigo, tinnitus, dysphagia, dysarthria, and occipital headache. Basilar invagination can result in vertebrobasilar insufficiency as well as obstructed venous return. An unusual picture resembling amyotrophic lateral sclerosis has been reported in association with 90 cervical cord involvement. Any of the cranial nerves may be affected, but the olfactory and auditory nerves are95the most 90 commonly involved. Hearing loss is common, occurring in 37 percent of patients. It may be neuronal, conductive, or of mixed type. The cochlea is the most common site of involvement. The optic nerve may be affected at the optic foramen by compression or from compromise of the vasa nervorum. Clinically, there is diminished vision or 91 blindness, retinal hemorrhages, choroiditis, optic atrophy, papilledema, and angioid streaks. The oculomotor nerves (III, IV, and VI) are vulnerable as they pass through the superior orbital fissure, with resulting diplopia and pupillary abnormalities. Exophthalmos from direct impingement of the extraocular muscles rarely occurs. Trigeminal nerve involvement leads to facial numbness and trigeminal neuralgia. Involvement of the facial nerve (VII) may result in hemifacial spasm 95 or facial paresis with a frequency of 8.3 percent. 96
Osteosarcoma of the skull occurs in less than 1 percent of patients with Paget's disease. It usually presents as a partially fluctuant and locally painful skull mass with rapid neurological deterioration after long-standing “benign” bone disease. The prognosis is poor despite radiation therapy and 83 surgery. The occurrence of an associated sarcoma is linked to a gene on chromosome 18q. Epidural hematomas may cause acute compression of the spinal cord or brain and relate to the increased blood flow to bone and increased risk for 97–100 The prognosis in these cases is also poor, owing to excessive pathological fractures. bleeding during surgery. The spine is the second most common site of involvement in Paget's disease and may result 83 in symptoms of spinal stenosis. Mechanisms of neurological compromise include (1) direct compression of the spinal cord, cauda equina, or nerve roots by enlarged vertebrae or expansion of the facet joint; (2) pathological fractures or subluxation; (3) ossification of extradural structures; (4) diversion of the local blood supply to the highly vascular bone; and 88 (5) pressure on vessels as they pass through the intervertebral foramina. Compression of neural structures by the expanding pagetic vertebrae is the most common cause of 101,102 The onset of neurological dysfunction. Sarcomas or epidural hematomas are rare. continuous severe spinal pain and rapid neurological deterioration in association with an 93,103 affected vertebra should raise concern of osteosarcoma. 83
Back pain occurs in 11 to 43 percent of patients with involvement of the spine. Osteoarthritis is prevalent in this elderly population and can be hard to distinguish from 83,103 Other changes in the spine include Paget's disease as the cause of back pain. thickening of the pedicles and laminae, flattening of the vertebral bodies, and encroachment of the spinal canal by osteophytes. Involved vertebrae are increased in width and reduced in height. The most commonly involved levels are the upper and lower cervical, low thoracic, 103 and mid-lumbar vertebrae. Of the patients with involvement of the spine by plain radiographs, two thirds will have evidence of spinal stenosis by CT and104 half of those patients will have clinical evidence of myelopathy or a cauda equina syndrome. There is no association between number of vertebrae involved and presence of symptomatic spinal 83 stenosis. Low back pain may respond to treatment with bisphosphonates. Pain that does not respond to antipagetic therapy after 3 months should be treated with nonsteroidal anti-inflammatory agents. Spinal stenosis should first be treated with antipagetic therapy. Improvement or reversal of symptoms is 83 demonstrated with calcitonin, mithramycin, etidronate, pamidronate, and clodronate. Prompt surgical decompression is appropriate for patients who do not respond to pharmacological treatment. Preoperative assessment of bone vascularity by radionuclide bone blood-flow can help direct perioperative medical therapy and prevent massive bleeding.
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Extradural ossification of the ligamentum flavum and epidural fat can105–107 result in compression of Myelopathy and the spinal cord or nerve roots and requires surgical decompression. cauda equina syndrome can occur without evidence of compression on neuroimaging, however, and respond dramatically to medical therapy, suggesting that ischemia due to a 108–110 vascular steal phenomenon is responsible. Serum alkaline phosphatase concentrations and urine hydroxyproline are usually increased in patients with neurological complications, 111 but alkaline phosphatase levels are normal in almost one third of patients with spinal stenosis. Plain radiographs and radionuclide scans should be obtained to localize disease activity and identify pathological fractures. Cranial CT or MRI, and CT myelography or MRI of the spine are necessary to demonstrate compression of neural structures and to exclude other causes for symptoms (Fig. 24-4). Sarcomatous transformation is best assessed withMRI. The use of MRI perfusion scans to assess vascular steal may be of clinical value in the future. Patients with neurological complications should have serum alkaline phosphatase and urinary hydroxyproline level determinations every 6 months. Clinical monitoring of neurological function in symptomatic patients and repeat radiographs of the skull and weight-bearing long bones are recommended every 6 to 12 82 months in patients with osteolytic lesions.
FIGURE 24-4 Paget's disease of bone. Axial-view CT scan of the head with
bone windows. The white arrow shows thickened osteosclerotic bone anteriorly. The black arrow shows thickened hypodense osteolytic bone posteriorly. The type of treatment required for the neurological complications of Paget's disease depends on their location, basis, and clinical course. Asymptomatic disease affecting the skull or spine 82,85 Patients with neurological compromise may should be treated with bisphosphonates. 82,85,89,108,110,112–117 The respond to calcitonin, etidronate, and/or intravenous palmidronate. newer oral bisphosphonates, such as alendronate or risedronate, are recommended for patients with slowly progressive symptoms. Intravenous bisphosphonates are sometimes
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effective in cases where calcitonin or oral bisphosphonates fail ; decompressive surgery may otherwise be necessary. Rapidly progressive neurological deterioration should be treated with calcitonin or intravenous bisphosphonates before surgery to minimize bone hemorrhage intraoperatively. Obstructive hydrocephalus does not respond to medical therapy and requires the placement of a ventricular shunt. Hydrocephalic dementia with memory loss, gait disturbance, and 118,119 urinary incontinence may improve with shunting and bisphosphonate85therapy. Bisphosphonate treatment results in the stabilization of hearing loss. Memory loss and optic 114 neuritis may respond to a combination of etidronate and91calcitonin. Trigeminal neuralgia and hemifacial spasm are treated with carbamazepine. Hemifacial spasm may also 95 Facial nerve paresis sometimes responds to surgical respond to calcitonin or alendronate. 91 decompression, and there are older reports of benefit with suboccipital93craniectomy and upper cervical laminectomy for patients with lower cranial neuropathies. Botulinum toxin injection is an option for hemifacial spasm that is refractory to medical treatment. Surgical treatment of spinal disease is difficult because involvement is often at multiple levels, vascular bone leads to problematic bleeding, and patients are generally in an older age group. A review of 65 111 surgical cases showed some degree of benefit in 85 percent but an 11 percent mortality rate. Reoperation was required in 9 percent. Medical treatment (calcitonin or bisphosphonates) for symptomatic spinal stenosis has been reported to result in marked or complete110,113,117 reversal of myelopathy or cauda equina syndrome in more than 80 percent of Relapses may occur after calcitonin, bisphosphonates, or surgical patients. 108,111–113,115,116 and benefit may then follow repeating or changing therapy. treatment, VERTEBRAL OSTEOMYELITIS Infection of bone may be due to a wide variety of pathogenic microorganisms, including pyogenic bacteria, mycobacteria, and fungi. Although osteomyelitis of the long bones may occasionally involve injury to peripheral nerves, and infection of the facial and skull bones may lead to extradural abscess formation, meningeal infection, and venous sinus thrombosis, it is infection of the vertebrae that is most often associated with neurological complications. 120 Recent observations suggest an increasing incidence. Bacteria may reach the spine by hematogenous spread from a distant source of sepsis, may spread from a local focus of 121 contiguous infection, or may be introduced by direct penetrating trauma or surgery. The lumbar spine is most commonly affected, followed by the cervical spine. With hematogenous spread, septic emboli lodge in the metaphyseal subchondral area of the vertebra, often causing bone infarction. Ischemic necrosis may result in the formation of islands of devascularized bone (sequestra). Infection within the vertebral body tends to spread sequentially to involve the adjacent intervertebral disc and then the next adjacent vertebra (spondylodiscitis). This propensity to traverse the disc space distinguishes osteomyelitis from neoplasia, which tends to remain confined. Abscesses may form within the disc or in adjoining tissues when infection extends beyond the cortex of the vertebra. An epidural abscess may cause radicular injury or, more ominously, spinal cord compression. Extraspinal abscesses may track to a variety of sites (paraspinal, retroperitoneal, psoas). Chronic osteomyelitis is characterized by necrosis of bone, a predominantly mononuclear infiltrate, fibrosis, and few organisms. A sinus tract may develop between bone and skin. Osteomyelitis resulting from blood-borne bacterial seeding is almost always the result of infection by a single organism. Diabetes and chronic alcoholism are risk factors. More than half of infections are due to Staphylococcus aureus (in recent series, methicillin-susceptible staphylococci accounted for the majority) and are often associated with vascular catheters 122 and invasive medical procedures. Other organisms commonly involved include Escherichia coli and other gram-negative bacteria, Brucella, and fungi (Candida). Pseudomonas and staphylococcal infections are associated with intravenous drug use. Streptococci and 123,124 Tuberculous infection of the enterococci are frequently associated with endocarditis. spine is discussed separately. Trauma and spread of contiguous infection often produce polymicrobial (“mixed”) cultures. S. aureus is again commonly implicated, but gram-negative and anaerobic bacteria are also frequently involved. Back pain, often with local tenderness, is the most frequent presenting feature of spinal 125,126 The clinician should be alerted by pain that is not relieved by rest and that osteomyelitis. persists at night. The spine may be held rigidly, with paraspinal muscle spasm. In many patients, back pain is preceded by a subacute prodrome of constitutional symptoms—fever, fatigue, lethargy, anorexia—that may last for several weeks. By the time of initial presentation, however, the patient may be afebrile with few other signs of systemic ill health. Neurological deficit occurs in only approximately half the patients. Encroachment on sensory
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and motor roots gives rise to pain and segmental sensorimotor loss. A cauda equina syndrome may result from compression of multiple lumbosacral roots. Epidural abscess formation with compression of the spinal cord may develop acutely or subacutely over several weeks and requires immediate surgical decompression. Because of the frequency of back pain due to other etiologies and the nonspecific character of the clinical presentation, a high index of clinical suspicion is required for the prompt diagnosis of osteomyelitis; this is crucial, because effective antibiotic therapy may prevent necrosis of bone with permanent skeletal abnormality, but diagnosis is unfortunately often delayed. Plain radiography is frequently normal in the first 2 to 4 weeks, since lytic lesions are not apparent until significant bone loss has already occurred. Erosions may be seen at the endplates, and the disc space is narrowed. Spinal CT may provide additional details of bony anatomy, but MRI is necessary to define the anatomy of neural structures within the spinal canal and the surrounding soft tissues (Fig. 24-5). In early disease, vertebral body edema may be the sole imaging abnormality; other findings include spondylodiscitis, erosion of bone, and intra- and extra-vertebral collections. Radionuclide bone scanning is highly sensitive but not specific; it is particularly useful where MRI may be contraindicated because of spinal instrumentation. Scintigraphy also reflects the activity of a focus of infection, allowing a 127 measure of the response to therapy.
FIGURE 24-5 Osteomyelitis. Sagittal T1-weighted MRI of the lower thoracic
spine, with contrast. A septic focus is seen to involve the intervertebral disc and the two adjacent vertebral bodies. An epidural abscess compresses the thecal sac. Specimens for microbiological culture and anti-biotic sensitivity should always be obtained before the institution of antibiotic therapy. Blood culture may be positive in one third of cases. Material from the focus of infection may be obtained by needle aspiration or bone biopsy. Antibiotics are introduced in high dose and administered intravenously. Empirical treatment (usually a penicillinase-resistant penicillin plus a third-generation cephalosporin) may be necessary before the microbiology results are available. Further therapy is then guided by these results. Antibiotics are generally initiated intravenously and may be continued for an extended period of weeks to months before switching to an oral preparation once a favorable response has been achieved. Imaging abnormalities tend to persist despite clinical128and laboratory measures of improvement, and are not necessary for routine follow-up. Bed rest with external immobilization is generally enforced until back pain has receded. With appropriate antibiotic therapy, recovery is the rule; surgery is required in 10 to 20 percent of
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cases, in general for drainage of large abscesses, decompression in cases of progressive neurological deficit, fixation for spinal instability, and débridement in severe, unresponsive 129,130 Residual disability is seen in approximately one third of patients, particularly infection. 131 those with structural damage to the spine. Osteomyelitis resulting from trauma or contiguous infection is often polymicrobial and requires broad-spectrum antibiotic therapy and, frequently, surgical débridement. The management of chronic osteomyelitis is difficult and controversial, usually requiring complete surgical removal of the nidus of infection, together with long-term antibiotic therapy. There is no consensus regarding timing of surgery, operative approach, or the use of 132 instrumentation. POTT'S DISEASE Tuberculous spondylitis with kyphotic deformity of the spine was first reported in detail by Sir Percivall Pott in the late eighteenth century, although the condition had been133 recognized in antiquity, and Pott was not aware of the tuberculous etiology of the disease. The features of Pott's disease have been demonstrated in preserved human remains dating from Egyptian times. In early clinical series, tuberculous involvement of bone and joint tissues was seen in 8 to 9 percent of cases of extrapulmonary tuberculosis, with the spine as the most common site. The incidence of tuberculosis in the Western world has declined in recent times with the introduction of specific chemotherapy and the success of public health measures. In contrast to the patients first described by Pott, who were all infants and young children, Pott's disease in developed societies is largely a disease of adults. Tuberculosis has become increasingly prevalent in the immunosuppressed population, particularly those infected with the human 134 immunodeficiency virus. It is a treatable condition, with a significant likelihood of permanent disability if the diagnosis is delayed. Tuberculous infection of the spine, although occasionally a presenting manifestation of the underlying infection, is most often a late feature, representing reactivation of a focus of latent infection with hematogenous or lymphatic spread to the spine, often years after the initial pulmonary infection. Typically, the vertebral body is affected, most commonly in the thoracic and upper lumbar spine. This is followed by spread to adjacent vertebrae, often with involvement of the intervening disc, and loss of disc space height. Destruction of cancellous bone renders the involved vertebral body liable to compression fractures and vertebral body collapse. A wedge fracture in the anteroposterior plane may produce kyphosis. In advanced cases, both kyphosis and scoliosis produce a striking gibbous deformity. 135,136 Compression of the Such spinal cord is an unusual but devastating consequence of Pott's disease. compression may be seen in association with spinal deformity, but it may occur in its absence with the formation of an epidural abscess within the spinal canal. Extension of infection outside the spine may result in the formation of paravertebral collections at various sites including within the psoas muscle. Back pain, often with local tenderness, is the most common clinical manifestation of Pott's disease. A predilection for the thoracolumbar junction distinguishes it from degenerative disc disease, which is most commonly seen in the cervical or lumbosacral regions. Constitutional symptoms (lethargy, night sweats, weight loss) and systemic signs (anemia, low-grade fever) are frequent but may not be prominent. Neurological features are present in fewer than half of patients. Radicular symptoms and signs reflect involvement of the sensory and motor roots at the level of the lesion; myelopathic features may herald the development of spinal cord compression and represent a medical emergency. Paraplegia occurs in up to 10 percent of patients. The possibility of tuberculous infection of the spine may be a clear consideration in patients with recognized pulmonary tuberculosis, particularly when treatment was incomplete, or in immunosuppressed patients, but137only a minority of patients have a history of previous tuberculosis or tuberculous contacts. In other instances, a high index of clinical suspicion and appropriate (radiological) investigations are needed for recognition. In many series, diagnosis was delayed for 12 to 18 months after presentation. Differential diagnosis includes neoplastic disease of the spine, pyogenic and fungal osteomyelitis, inflammatory conditions, and sarcoid arthritis. There may be few clues to the diagnosis on routine tests: erythrocyte sedimentation rate and C-reactive protein are likely to be elevated, and the peripheral white count may be normal or slightly elevated.138Chest radiography is often completely normal, and sputum negative for acid-fast bacilli. Plain radiographs of the spine are often unremarkable but may show involvement of adjacent vertebral bodies, with reduction in the intervening disc space height representing disc involvement. CT scan and particularly MRI of the spine provide the greatest
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detail ; characteristic findings include involvement, often with heterogeneous enhancement, of several contiguous vertebral bodies, with either sparing or involvement of the intervening discs, and the presence of epidural and subdural collections. In contrast, pyogenic infections typically involve the disc (“spondylodiscitis”) and tend to enhance 138 homogeneously. Late-stage disease with kyphosis is the result of pathological fractures of the vertebral bodies and destruction of all elements of the motion segment. MRI is particularly helpful in demonstrating encroachment onto the spinal cord and roots. Radiological changes tend to persist, suggesting that imaging need not be repeated in patients with clinical and 128,141–144 laboratory measures of improvement. Confirmation of the tuberculous nature of such a radiographically identified lesion is usually straightforward (and is necessary in the absence of pulmonary manifestations for a definitive diagnosis). Biopsy (needle aspiration or open biopsy) demonstrates the characteristic caseating granulomatous histology with Langhans giant cells and acid-fast bacilli, and culture is frequently positive. In most cases, a purified protein derivative (PPD) skin test is positive. Treatment is with prolonged antituberculous chemotherapy. There is often a rapid response to treatment as judged by clinical and laboratory measures. Surgery is sometimes required in addition to drug therapy, particularly for those patients with spinal instability or severe 145,146 Spinal cord compression is a medical disease, but should not be routinely performed. emergency necessitating immediate surgical decompression. “Cold abscesses” at other sites may also require drainage. ANKYLOSING SPONDYLITIS Ankylosing spondylitis is an HLA-B27–associated chronic inflammatory disease affecting the 147 sacroiliac joints, spine, and peripheral joints. Pathologically, there is synovitis and inflammatory lesions of ligamentous attachments (enthesopathy) with local erosion of bone. This is followed by calcification and ankylosis of axial joints and supporting structures, 148 including ligaments and tendons. There may be accompanying osteoporosis. Extra-articular manifestations include acute anterior uveitis, aortic insufficiency, cardiac 147 conduction disturbances, inflammatory bowel disease, and renal amyloidosis. The prevalence of ankylosing spondylitis in the general population is 0.1 to 0.2 percent, and 1 to 2 percent of HLA-B27–positive individuals will have the disorder. HLA-B27 is present in 90 148 percent of Caucasian patients with ankylosing spondylitis. Serum IgA levels are elevated in 50 to 60 percent of patients, correlating with disease activity and the presence of peripheral 147 arthritis and inflammatory bowel disease. Intestinal pathogens such as Klebsiella pneumoniae may play a role in peripheral arthritis and inflammatory bowel disease. Clinical manifestations typically begin in late adolescence or early adulthood. Presentation 147,149 after 50 years of age is rare. There is a male predominance of 2 to 3:1. Women usually are less symptomatic, have less severe disease, and have more involvement of the cervical 148 symptoms are low back pain and stiffness, which occur in 90 to spine. The most common 148 95 percent of patients. The initial pain is felt deep in the gluteal region. It can be severe and is often referred along the iliac crest to the greater trochanteric region or down the dorsal thigh. It may be accentuated by cough, sneeze, or a twisting motion of the back. Five features help differentiate it from mechanical low back pain: onset of back discomfort before the age of 40 years, insidious onset, persistence for at least 3 months, associated morning stiffness, 149 and improvement with exercise. Within a few months, it becomes persistent and bilateral. Enthesopathy of the costosternal and manubriosternal joints results in chest pain with reduced mobility that may seem pleuritic. Ankylosing spondylitis is a chronic disease with periods of remission, and patients have excessive mortality compared with the general population. Severe fractures are infrequent. The clinical examination and radiographs of the sacroiliac joints are used to make the diagnosis of ankylosing spondylitis (Fig. 24-6). Physical examination findings include flattening of lumbar spine and loss of lumbar lordosis. There is limited motion of the axial skeleton, especially with hyperextension and lateral bending. Percussion over the sacroiliac joints elicits pain. Human leukocyte antigen testing is positive in 90 percent of patients but is not specific. The erythrocyte sedimentation rate (ESR) is increased in 80 percent of patients 148 with active disease. Antinuclear antibody and rheumatoid factor are usually absent. The characteristic radiological changes may not be apparent early in the disease. Erosion of the joints occurs, followed by widening of the joint. Late stages of sacroiliitis include complete ankylosis with total obliteration of the joint space. Calcification ofthe annulus fibrosus and anterior and posterior longitudinal ligaments can be seen.
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FIGURE 24-6 Ankylosing spondylitis. Plain radiograph of lumbosacral spine.
The characteristic “bamboo spine” with fusion of the intervertebral ligaments is evident. The arrows show fusion of the sacroiliac joint. No treatment has been shown to alter the course of the illness, particularly the loss of spinal 148,150 Therapies that have evidence-based beneficial effects for ankylosing mobility. spondylitis include physical therapy, nonsteroidal anti-inflammatory drugs, and 151 disease-modifying drugs including tumor necrosis factor alpha (TNF-α) inhibitors. Intensive 152 physical therapy and exercise are important to maintain mobility. Braces, splints, and corsets should be avoided. Nonsteroidal anti-inflammatory drugs are effective in suppressing inflammation and ameliorating pain and are recommended as a first-line drug. Continuous use may slow the progression of spine ankylosis. Sulfasalazine has a role for peripheral arthritis but no impact on spinal mobility. The TNF-α inhibitors include etanercept and infliximab. In one study, at 4 months, 75 percent of the etanercept group had improvement in 148 morning stiffness, pain, and function compared with 30 percent of the placebo 148,153 group. Similar improvement was seen in studies of infliximab compared with placebo. Patients who are positive for C-reactive protein are more likely to respond. Relapse is common after termination of either therapy. Potential complications include reactivation of tuberculosis, hematological disorders including malignancy, central and peripheral demyelinating disorders, congestive heart failure, elevated153 serum levels of liver enzymes, and is hypersensitivity and autoimmune reactions. Treatment with TNF-α inhibitors 151,153 recommended for patients with refractory, severe, and active disease. Surgical 148,150,151 There is a treatment plays a limited role when nonsurgical treatment has failed. significant risk of operative and perioperative complications. Neurological complications are uncommon and occur in 2.1 percent of patients with 154 ankylosing spondylitis. They include radiculopathy from foraminal stenosis or inflammation.
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Myelopathy can result from fracture-dislocation, atlantoaxial subluxation, pseudoarthritis, ossified intraspinal ligaments, or granulation tissue. Cauda equina syndrome is a late complication attributed to arachnoiditis. Sciatic nerve compression due to contraction of the piriformis muscle can occur secondary to inflammation of the attachment of the piriformis148 muscle to the sacroiliac joint, mimicking sciatica from root compression (pseudosciatica). There is an increased incidence of vertebral compression fractures in ankylosing spondylitis. The spine is brittle and prone to fracture. The fracture often goes entirely through the vertebral body and ossified ligaments, resulting in increased instability and neurological 148 damage. The most common location of fracture is the cervical spine (C6–C7). In one series, the risk for traumatic spinal cord injury in patients with ankylosing spondylitis was 11.4 155 times greater than expected for the population at large. Cervical myelopathy occurred in 84 percent of patients with ankylosing spondylitis who had traumatic spine injury compared with 48 percent of all patients with traumatic spine injury. Neurological dysfunction may not develop until several weeks following the initial spine trauma. Surgical intervention is 148 indicated in these patients, but as many as 85.7 percent will have a residual deficit. Patients with148,150 complete paraparesis for more than 2 hours do not respond to surgical intervention. Spinal stenosis with cord compression is rare. Patients may develop “radicular” pain without neurological symptoms or signs, and this usually resolves spontaneously. The cervical spine may be involved, resulting in atlantoaxial subluxation. The incidence of this complication 156,157 Ramos-Remus and co-workers found ranges from 2 to 21 percent in different series. atlantoaxial subluxation in 22 of 103 consecutive patients with ankylosing spondylitis 156 (21%). One third of these patients had clinical evidence of myelopathy, and two patients had surgical fusion because of severe myelopathy. Atlanto-occipital subluxation with vertebral occlusion, brainstem transient ischemic attack (TIA), and infarction are also described in 156–158 Aortic root disease and valve disease are more patients with ankylosing spondylitis. common in patients with ankylosing spondylitis than in age-matched controls (82% compared 159 with 27% in one study ). TIA or stroke occurred in 2 of 44 patients without a clear etiology. Studies of the natural history of ankylosing spondylitis have demonstrated that cerebrovascular disease is a common cause of mortality in patients younger than 60 years. Prophylactic antiplatelet therapy may be indicated. 160–163
Patients have an Cauda equina syndrome occurs in rare patients late in the disease. average of 32 years before the onset of cauda equina syndrome, and most patients are 154 male. The typical presentation includes insidious onset and progression of bowel and bladder symptoms, sensory loss (often asymmetric) in an L5–S4 distribution, pain radiating into a limb or the rectal area, and minimal weakness in muscles innervated by the L5–S2 segments. Bladder symptoms include decreased awareness of bladder sensation, decreased ability to empty the bladder, hesitancy, decreased force of urinary stream, urgency, and frequency. Radiography of the lumbar spine may show erosions of the lamina. Spinal MRI shows dorsal dural diverticula associated with a widened thecal sac and scalloped erosions 160,163 Nerve roots appear to deviate toward the of the laminae and spinous processes. diverticula. They may be displaced posteriorly and appear adherent to the arachnoid membrane and to each other, suggesting arachnoiditis. There is no enhancement with gadolinium. Spinal CT typically demonstrates asymmetric, multilevel erosions that selectively 164 involve the pedicles, laminae, and spinous processes of the lumbosacral spine. Infrequently, erosion of the posterior portion of the vertebral body is found, or involvement is unilateral or confined to one level. Myelography is technically difficult and possibly dangerous in patients with ankylosing spondylitis. Cerebrospinal fluid is normal or shows a slightly elevated protein concentration. The pathological findings depend on the timing of surgery or autopsy relative to the onset of 162 neurological symptoms. Early pathological findings include inflammation of the spinal ligaments, dura, and arachnoid. Over time, there is fibrosis and chronic arachnoiditis embedding atrophic nerve roots, with small sacral roots splayed and adherent to the dura. Compression of the nerve roots by diverticula has been described. Some roots appear normal, but others are fibrosed in the later stages. The cauda equina syndrome has been attributed to arachnoiditis. Arachnoid adhesions may lead to blind pouches into which cerebrospinal fluid is forced by the pumping action of arterial pulsation, with consequent enlarging arachnoid cysts and pressure erosion of the adjacent bone. A resorption defect of the cerebrospinal fluid has been documented and may contribute 165 to to thecal sac enlargement and other structural changes. Nerve root injury may relate 162 arachnoiditis with subsequent neuritis, vasculitis, adhesion formation, or tethering. The role of surgery and decompression of the cysts is unclear, but a meta-analysis of 86 patients reported in the literature showed worsening of all patients who received no treatment or
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corticosteroids. Nonsteroidal anti-inflammatory drugs result in improvement of back pain without improvement of neurological deficits. Patients may have improvement of neurological function or halting of progression with either lumboperitoneal shunting or laminectomy. 148 Neurological deficits may persist despite surgical intervention in 85.7 percent of patients. The clinical course is slowly progressive, although patients rarely lose the ability to walk. In the cohort described in the meta-analysis, weakness occurred in 62 percent, sensory loss in 154 96 percent, and loss of reflexes in 93 percent. Bowel dysfunction was seen in 80 percent and bladder dysfunction in 95 percent of patients. It was recommended that any patient with longstanding ankylosing spondylitis who develops sphincter dysfunction receive a careful neurological assessment. The response to lumboperitoneal shunting may suggest that the dural ectasia is in part a cause of the neurological deficits in these patients. Case reports suggest an association between ankylosing spondylitis and multiple 158,166 The incidence of multiple sclerosis in patients with ankylosing spondylitis sclerosis. followed at a referral center is approximately 1,000 per 100,000, which is significantly greater 167,168 In contrast, 2,000 members of the than that of the general population (50 per 100,000). National Ankylosing Spondylitis Society were reviewed without169 a clear association being evident between multiple sclerosis and ankylosing spondylitis. A definitive population study has not been done. RELAPSING POLYCHONDRITIS Relapsing polychondritis is an uncommon, multisystem disorder characterized by recurrent episodes of inflammation and eventual destruction of cartilaginous tissues, which may have delay an autoimmune basis. It is diagnosed on clinical grounds (Table 24-3), and the average 170 171 to diagnosis from symptom onset is 2.9 years. The prevalence is 3.5 per million. The reported age range is from 16 to 84 years, with a peak onset in the fifth decade. Most authors 172 report an equal prevalence in males and females, and it is described in all races. It can affect all types of cartilage including the ears and nose (most commonly), peripheral joints, fibrocartilage at axial sites, and the tracheobronchial tree (which can be life threatening). The eye, heart, blood vessels, and inner ear are rich in proteoglycans and can also be affected. There is evidence of HLA-DR4 linkage and frequent concurrence of other autoimmune diseases. More than 30 percent of patients with relapsing polychondritis have an associated rheumatological or hematological disorder. Antibodies to type II collagen are present during acute attacks, and immunocomplex deposition is found in cartilage. Experimental models suggest the binding of these antibodies to cartilage leads to complement-mediated inflammation and the release of inflammatory cytokines, including TNF-α. Monocyte chemoattractant protein 1, macrophage inflammatory 173 protein 1 beta, and interleukin-8 are also elevated in patients with relapsing polychondritis. Click here to view this table.... The clinical presentation is with the abrupt onset of ear pain, tenderness and swelling of the external auditory meatus, erythema, and a clear serous discharge from the ear. Ear involvement is the initial presenting symptom in 39 percent and ultimately occurs in 85 to 95 172 percent of patients. The noncartilaginous lobule is spared. Repeated bouts of inflammation result in afloppy ear (Fig. 24-7). Nasal pain, hoarseness, and difficulty in talking are also common. Repeated inflammation of the nasal cartilage results in a saddle-nose deformity. Systemic symptoms include fever, lethargy, and weight loss. The course is relapsing; over the course of the illness, progressive significant disability occurs in most patients. Inflammation of the trachea and larynx occurs in 50 percent of patients and may be fatal. Cardiovascular involvement includes myocarditis, pericarditis, silent myocardial infarction, 170 paroxysmal atrial tachycardias, and first-degree and complete heart block. The arthropathy is episodic, nonerosive, migratory, and asymmetric, lasting from weeks to months.
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FIGURE 24-7 Relapsing polychondritis. Example of a “floppy ear” from repeated
inflammation and destruction of the cartilaginous portion of the ear. Vertigo and conductive or sensorineural hearing loss are common and are present in 5 170 percent at the onset of the disease and in 13 to 50 percent over the course of the illness. The conductive hearing loss is due to closure of the eustachian tube from inflammation in the cartilaginous wall, auricular cartilage collapse, or edema in the canal with subsequent serous otitis media. The sensorineural hearing loss is attributed to vasculitis of the vestibular or cochlear branch of the internal auditory artery. The abrupt onset of hearing loss, sometimes accompanied by vertigo, nausea, vomiting, and imbalance, can mimic a posterior circulation stroke. Ocular involvement occurs in 65 percent of patients. Recurrent conjunctivitis, episcleritis, scleritis, iritis, and keratoconjunctivitis sicca are common. Chorioretinitis, retinal vasculitis, exophthalmos due to orbital pseudotumor, extraocular muscle palsies, and optic neuritis may occur but are rarer. Extraocular palsies occur either from direct extension of pseudotumor-like inflammation in the orbit or from vasculitic ischemia to the third, fourth, or 172 sixth cranial nerves. Vasculitis occurs in 11 to 56 percent of patients with relapsing polychondritis and affects the 174 skin, internal organs, or central nervous system (CNS). It can affect the large arteries, resembling Takayasu's arteritis (<15175 percent of cases), and in several reported cases it affected the internal carotid arteries. Aortic dissection and rupture have been described, and aortic regurgitation occurs owing to involvement of the ascending portion of the aorta. Systemic vasculitis affecting small- to medium-sized vessels occurs in 10 percent of 174 cases. The prognosis in patients with systemic vasculitis is poor, with a 5-year survival rate of 45 percent. Neurological involvement 176 occurs in 3 percent of patients with relapsing polychondritis but may 170,177,178 It may be manifested by cranial neuropathies, cerebral be the presenting feature. 170,177,178 174 174 mononeuritis multiplex, sensorimotor distal symmetric neuropathy, vasculitis, 179,180 181,182 aseptic meningitis, meningoencephalitis with limbic encephalopathy, acute cord infarction due to aortic disease, and170thromboembolic strokes secondary to vasculitis or an associated anticardiolipin antibody. Two cases of cerebral aneurysm have been
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183,184
reported.
Cranial nerve abnormalities are the most frequent, with involvement of II, VI, VII,170and VIII 170 being most common. Involvement of III, IV, and XII has also been described. Vasculitic infarction is the presumed etiology. CNS involvement may be due to vasculitis or a meningoencephalitis. Patients have an acute headache with encephalopathy, personality change, hallucination, seizures, and focal or multifocal deficits such as hemiparesis or 170,177,178 Presentation is sometimes with an acute limbic encephalitis. Papilledema or ataxia. meningeal signs may occur. Aseptic meningitis presents with headache, meningeal signs, and fever. With CNS vasculitis, the erythrocyte sedimentation rate is elevated (>100 mm in 1 hour), and mild leukocytosis may be present. The cerebrospinal fluid is normal or shows pleocytosis. The electroencephalogram may be normal or slow or show focal epileptiform activity. Cranial CT often demonstrates cerebral and cerebellar atrophy but may be normal. There may be 178 focal areas of hypodensity. The MRI is suggestive of cerebral vasculitis, with increased signal in the periventricular white matter and185centrum semiovale, focal lesions in the gray of limbic encephalitis, the MRI shows matter, and wedge-shaped cortical infarcts. In cases181 increased signal in one or both medial temporal lobes. Brain biopsy in these cases revealed marked gliosis, perivascular cuffing, and destruction of the vascular wall. The diagnosis of relapsing polychondritis is made on clinical criteria. Biopsy of the ear cartilage may be diagnostically helpful and shows loss of basophilic staining of the matrix, perichondrial inflammation, and eventually destruction of cartilage with replacement by 186 fibrous tissue. Nonspecific laboratory findings include anemia, peripheral leukocytosis, or throm-bocytosis. Serum creatinine and urinalysis should be checked to assess renal involvement. Evaluation for associated rheumatological disorders should include a screen for rheumatoid factor, antinuclear antibodies, antineutrophil cytoplasmic antibodies (ANCA), and complement levels. The airway should be evaluated by radiography, pulmonary function tests, and high-resolution CT scans. The differential diagnosis includes Wegener's granulomatosis; distinguishing clinical features include involvement of the mucosa and lung parenchyma and a positive ANCA, which are not seen in uncomplicated relapsing polychondritis. Aseptic meningitis results in neutrophil-predominant pleocytosis in the cerebrospinal fluid, with elevated total protein and normal glucose levels. Mild inflammation of joints, ear, or nose can be managed with nonsteroidal anti-inflammatory drugs, dapsone, or colchicine. Treatment of the CNS vasculitis, meningoencephalitis, and aseptic meningitis includes high-dose corticosteroids, often with additional “corticosteroid sparing” agents during the course of the illness. These adjunctive therapies include azathioprine, cyclophosphamide, cyclosporine, penicillamine, plasma exchange, dapsone, and methotrexate. Relapses are common, with cumulative persistent deficits. Refractory relapsing polychondritis may respond to agents that interfere with TNF-α (etanercept or 187–189 infliximab). Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 25 Otoneurological Manifestations of Otological and Systemic Disease JOSEPH M. FURMAN • MICHELE B. ST. MARTIN •
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NEUROLOGICAL MANIFESTATIONS OF OTOLOGICAL DISEASE Complications of Middle Ear Pathology Labyrinthine Disorders Eighth Nerve Lesions Cerebellopontine Angle Disorders Central Vestibular Disorders Central Auditory Processing Disorder OTONEUROLOGICAL MANIFESTATIONS OF SYSTEMIC DISEASE Infection Immune-Mediated/Connective Tissue Disease Neurocutaneous Syndromes Metabolic and Endocrine Disorders Diseases of Bone Drug-Induced Disorders Environmental Disorders Nutritional Disease Neoplastic Disease NEURO-OTOLOGICAL MANIFESTATIONS OF AGING Dysequilibrium of Aging Presbycusis
NEUROLOGICAL MANIFESTATIONS OF OTOLOGICAL DISEASE
Complications of Middle Ear Pathology 1,2
Intracranial complications occur in 0.25 to 0.5 percent of all cases of otitis media. The mortality rate of intracranial complications has decreased dramatically over the last century, 3–5 However, from approximately 90 percent in the pre-antibiotic era to 10 percent at present. 6 significant morbidity still exists despite the improvement in survival. Diagnosis of an intracranial complication of otitis media relies heavily on an accurate history. Important elements include determining whether the patient has acute or chronic otitis media, a prior history of otologic disease or surgery, a history of head trauma or temporal bone fracture, previous antibiotic treatment, and symptoms suggesting intracranial involvement such as
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headache, lethargy, visual changes, fever, and nausea or vomiting.
The differential diagnosis for a patient with otitis media and symptoms and signs of intracranial involvement is long, as potential complications are numerous. The list includes extradural abscesses or granulation tissue, dural venous sinus thrombophlebitis, petrous subdural apicitis (Gradenigo's syndrome; Fig. 25-1), intraparenchymal brain abscesses, 3,7,9 Otitic abscesses, and meningitis, with purulent meningitis being the most common. hydrocephalus may also occur; intracranial pressure is increased secondary to venous sinus thrombosis and may manifest with bilateral papilledema. Despite its name, the ventricles are not enlarged in otitic hydrocephalus. The triad of headache, high fever, and focal neurological deficits should lead the clinician to suspect a brain abscess. Focal signs depend on the 7 location of the abscess; visual field defects are often an early finding. Temporal lobe lesions can lead to an expressive aphasia when located in the dominant hemisphere. Other neurological signs include homonymous hemianopia, limb paralysis, or extraocular palsies from involvement of cranial nerves III, IV, or VI. Nystagmus, papilledema, and ipsilateral pupillary dilatation may also be seen. Signs of a cerebellar abscess include nystagmus and 9,10 ataxia of the ipsilateral limbs.
FIGURE 25-1 Computed tomography (CT) scan showing right petrous apicitis.
Upper scan: Soft tissue algorithm demonstrating enhancement at the tip of the petrous apex affecting Dorello's canal (arrow head). Lower scan: Bone algorithm demonstrating a lytic cell in the petrous apex with loss of septation (arrow). (Courtesy of Hugh D. Curtin, MD, Massachusetts Eye and Ear Infirmary, Boston.) The microbiology of the intracranial complications of otitis media varies with the duration of otitis as well as the type of complication. Complications of acute otitis media usually are secondary3,6,7 to Streptococcus pneumoniae or Haemophilus influenzae, as would be expected. Chronic otitis media frequently leads to complications with gram-negative 6,7 bacteria, such as Pseudomonas or anaerobes. Otitic meningitis is most commonly caused
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by S. pneumoniae, H. influenzae, Proteus, Pseudomonas, and Staphylococcus aureus. Brain 10 abscesses are typically polymicrobial. If an intracranial complication is suspected on the basis of history or physical findings, further evaluation should include computerized tomography (CT) of the temporal bones to evaluate for bony erosion, congenital malformation, or fracture; magnetic resonance imaging (MRI) to evaluate for enhancement of the meninges or brain abscess; and a lumbar puncture if no 1,7,10 The cerebrospinal fluid (CSF) will show increased mass effect is visualized on imaging. protein and decreased glucose concentrations, and organisms on Gram's stain in meningitis; in otitic hydrocephalus, the opening pressure will be increased, but the other studies will be 7 normal. A positive blood culture can indicate the presence of sigmoid sinus thrombophlebitis. Figure 25-2 shows the appearance of sigmoid sinus thrombosis on temporal bone CT.
FIGURE 25-2 Sigmoid sinus thrombosis. CT venography performed after
retromastoid craniectomy reveals a filling defect in the right transverse (dashed arrow) and sigmoid (solid arrow) sinuses, representing subocclusive thrombus. (Courtesy of Barton F. Branstetter, MD, University of Pittsburgh.) Treatment of intracranial complications of otitis media includes inpatient admission and medical stabilization. Broad-spectrum intravenous antibiotics should be initiated empirically. Complications due toacute otitis media may be treated with a second- or third-generation cephalosporin to target the usual three pathogens: H. influenzae, Moraxella catarrhalis, and S. pneumoniae. Gram-negative and anaerobic coverage should be added for complications of chronic otitis media. Corticosteroids such as dexamethasone (Decadron), when administered concurrently with intravenous antibiotics,7can reduce the chance of sensorineural hearing loss due to otogenic meningitis.
Labyrinthine Disorders Meniere's disease and benign paroxysmal positional vertigo are two of the most common labyrinthine disorders that cause vertigo and dysequilibrium. The pathophysiology of Meniere's disease is thought to be endolymphatic hydrops, which is usually idiopathic but can 11 occur following inner ear trauma or infection. Patients with Meniere's disease typically experience episodes of unilateral tinnitus, unilateral hearing loss, unilateral ear fullness, and vertigo lasting for minutes to hours. They do not experience neurological symptoms that cannot be attributable directly to the inner ear. However, some patients experience visual changes, especially blurred vision, during attacks of Meniere's disease, and headaches may
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occur during attacks. Other patients become anxious during attacks and may experience numbness and paresthesias. The first attack of Meniere's disease often prompts an evaluation in an emergency department that leads to brain imaging to exclude cerebellar hemorrhage or infarction. Treatment of Meniere's disease consists of sodium restriction and a diuretic, typically a combination of hydrochlorothiazide and triamterene. Benign paroxysmal positional vertigo (BPPV) is caused by free-floating otolithic debris in the 11 posterior semicircular canal. As with Meniere's disease, benign paroxysmal positional vertigo may follow inner ear trauma or infections but usually is idiopathic. Patients typically have positionally induced vertigo when rolling over in bed or looking up. Vertigo typically lasts for less than 1 minute but more generalized symptoms of dizziness and dysequilibrium may persist for several hours. Neurological symptoms other than vertigo and transitory visual difficulties are generally absent. On physical examination, the findings on Dix–Hallpike 12 maneuvers, illustrated in Figure 25-3, are diagnostic. Treatment (Fig. 25-4) consists of a particle repositioning maneuver, which is highly successful. Despite the “benign” nature of benign paroxysmal positional vertigo, the initial episode often leads to emergency medical care. Since several nonbenign conditions, such as posterior fossa tumors, may present with positional dizziness, a thorough neurological evaluation of all patients with positional vertigo is warranted.
FIGURE 25-3 Dix–Hallpike maneuver. The Dix–Hallpike test of a patient with
benign paroxysmal positional vertigo (BPPV) affecting the right ear. A, The examiner stands at the patient's right side and rotates the patient's head 45 degrees to the right to align the right posterior semicircular canal with the sagittal plane of the body. B, The examiner moves the patient, whose eyes are open, from the seated to the supine right-ear-down position and then extends the patient's neck slightly so that the chin is pointed slightly upward. The latency, duration, and direction of nystagmus, if present, and the latency and duration of vertigo, if present, should be noted. The arrows in the inset depict the direction of nystagmus in patients with typical BPPV. The presumed location in the labyrinth of the free-floating debris thought to cause the
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disorders is also shown. (With permission from Furman JM, Cass SPC: Benign paroxysmal positional vertigo. N Engl J Med 341:1590, 1999.)
FIGURE 25-4 Particle repositioning maneuver for the bedside treatment of a
patient with benign paroxysmal positional vertigo affecting the right ear. The presumed position of the debris within the labyrinth during the maneuver is shown in each panel. The maneuver is a three-step procedure. First, a Dix–Hallpike test is performed with the patient's head rotated 45 degrees toward the right ear and the neck slightly extended with the chin pointed slightly upward. This position results in the patient's head hanging to the right (A). Once the vertigo and nystagmus provoked by the Dix–Hallpike test cease, the patient's head is rotated about the rostral-caudal body axis until the left ear is down (B). Then the head and body are further rotated until the head is face down (C). The vertex of the head is kept tilted downward throughout the rotation. The maneuver usually provokes brief vertigo. The patient should be kept in the final, face-down position for about 10 to 15 seconds. With the head kept turned toward the left shoulder, the patient is brought into the seated position (D). Once the patient is upright, the head is tilted so that the chin is pointed slightly downward. (With permission from Furman JM, Cass SPC: Benign paroxysmal positional vertigo. N Engl J Med 341:1590, 1999.)
Eighth Nerve Lesions Eighth nerve lesions leading to neurological manifestations include auditory neuropathy and vestibular neuronitis. Auditory neuropathy is a recently defined entity in which the function of
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the cochlea's outer hair cells appears intact, but dysfunction or disturbed synchrony of the inner hair cells13,14 or cochlear nerve leads to hearing loss and impaired speech Risk factors for auditory neuropathy include prematurity, discrimination. 15 hyperbilirubinemia, and exposure to ototoxic medications. Genetics also13play a role. This type of hearing loss can be associated with other neurological diseases and may be seen in 16 up to 11 percent of children with sensorineural hearing loss. Vestibular neuronitis is an idiopathic inflammation of the vestibular portion of the eighth cranial nerve leading to acute symptoms of vertigo, nystagmus, nausea, and vomiting. Acute symptoms persist for several days and are often preceded by viral illness. Unilateral reduction in vestibular response is seen on caloric testing. Possible etiologies include viral infection, 17 immunological causes, or vascular occlusion. The superior or inferior vestibular nerve, or both, may be involved. If the auditory portion of the eighth cranial nerve is involved, which is uncommon, hearing loss will be present.
Cerebellopontine Angle Disorders Cerebellopontine angle masses can cause hearing loss, tinnitus, and vertigo. The most common type of mass found in this location is a vestibular schwannoma, commonly referred to as an acoustic neuroma. Symptoms arise from compression of the nerve and surrounding vessels as the tumor enlarges. Symptoms are typically of insidious onset, but sudden hearing loss or vertigo may occur. Additionally, facial weakness or numbness may be seen with large tumors due to compression of the facial or trigeminal nerves, respectively. Without treatment, lower cranial nerve involvement and brainstem compression may eventually occur (Fig. 25-5). The underlying lesion is detected by MRI. Acoustic neuromas are treated with surgical excision or stereotactic radiation; small tumors may be observed for evidence of growth. Other masses occurring in the cerebellopontine angle include meningiomas, epidermoid tumors, and metastases, which may cause similar symptoms due to compression.
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FIGURE 25-5 Magnetic resonance imaging (MRI) of a large acoustic neuroma
with brainstem compression. Axial contrast-enhanced T1-weighted MRI reveals a large, lobulated, enhancing mass (arrows) filling the left cerebellopontine angle, with compression of the pons and thinning of the brachium pontis. The patient was known to have neurofibromatosis type 2, and this lesion is most likely a schwannoma of the eighth cranial nerve. (Courtesy of Barton F. Branstetter, MD, University of Pittsburgh.)
Central Vestibular Disorders The most common central vestibular disorders include migraine-related dizziness, vascular disease affecting brainstem and cerebellar vestibular pathways, cerebellar degeneration, and Chiari malformations. Migraine-related dizziness, which can be considered a migraine variant, affects women more often than men, particularly women in their childbearing years. As with migraine headache, it is a diagnosis of exclusion, since there are no pathognomonic tests for this condition. Diagnostic criteria consist of a combination of the International Headache Society criteria for migraine headache and recently conceived criteria specifically 18 for migraine-related dizziness. Establishing a diagnosis of migraine-related dizziness requires a temporal association between dizziness and either migraine headache or typical migrainous symptoms and the absence of another diagnosis that can account for dizziness. The pathophysiology is uncertain but is likely to be related to serotonin effects on central vestibular structures. Treatment is similar to the treatment for migraine headache and includes both decreasing triggers for migraine and use of pharmacotherapy. For patients with frequent episodes of migraine-related dizziness, prophylactic medications are indicated and include antidepressants, beta-blockers, anticonvulsants, and calcium-channel blockers. Some patients may benefit from triptans. Central vestibular structures in the brainstem and cerebellum are supplied by the posterior inferior cerebellar artery (PICA) and the anterior inferior cerebellar artery (AICA). Infarction in the territory of the PICA leads to Wallenberg's syndrome, wherein one of two vestibular nuclear complexes is damaged, leading to central vestibular imbalance. Accompanying symptoms are caused by involvement of the ascending spinothalamic tract and descending sympathetic tracts. Patients with Wallenberg's syndrome may experience lateropulsion (i.e., a sense of being pushed or pulled to one side). Over time, symptoms largely resolve. Infarction in the territory of the AICA leads to a syndrome that can be quite similar to and sometimes indistinguishable from Wallenberg's syndrome except for the presence of unilateral hearing loss resulting from cochlear ischemia (the internal auditory artery arises from the AICA). Another condition to be considered in patients with acute vertigo and accompanying neurological disturbances referable to the brainstem and cerebellum is that of cerebellar hemorrhage or infarction with concomitant brainstem compression. This condition represents a neurosurgical emergency. The ability to ambulate, even with some difficulty, usually excludes a life-threatening cerebellar vascular event. However, brain imaging provides definitive diagnostic information. Vertebrobasilar insufficiency may present with various neurological symptoms including vertigo and changes in hearing as well as with neurological symptoms referable to parenchymal posterior fossa structures such as changes in vision, sensation, strength, or level of consciousness. Symptoms typically last for minutes. Isolated vertigo is rarely a result 19,20 Repeated episodes of vertigo in the absence of of vertebrobasilar insufficiency. accompanying neurological symptoms are never caused by vertebrobasilar insufficiency. Diagnostic imaging such as magnetic resonance angiography can be helpful in establishing a diagnosis of vertebrobasilar insufficiency. Treatment with antiplatelet agents and management of risk factors for cardiovascular disease are warranted. Cerebellar degeneration can be associated with dizziness and dysequilibrium. Some types of cerebellar degeneration (particularly SCA6) can also be associated with episodic features including episodic vertigo and dysequilibrium. In association with such symptoms, patients with cerebellar degeneration often manifest limb ataxia and sometimes long-tract signs. Chiari malformations sometimes present with “dizziness” and dysequilibrium. Physical examination may disclose down-beating nystagmus (i.e., vertical nystagmus with a downward fast component), which may reflect a central vestibular imbalance. Additionally, patients with Chiari malformations often have nonvestibular symptoms such as dysphagia and long-tract signs. A diagnosis of a Chiari malformation can be confirmed by sagittal MRI (Fig. 25-6). Treatment is surgical with suboccipital craniectomy.
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FIGURE 25-6 Chiari malformation. Sagittal T2-weighted MRI through the
cranio-cervical junction shows the cerebellar tonsils (solid arrow) extending far below the foramen magnum (dashed line). The medulla is compressed. (Courtesy of Barton F. Branstetter, MD, University of Pittsburgh.)
Central Auditory Processing Disorder Central auditory processing disorder, as its name implies, is characterized by defects in higher level processing of auditory information in the setting of normal hearing as measured by conventional audiometry (www.nidcd.nih.gov/health/voice/auditory.asp). This disorder leads to difficulty in understanding oral communication, particularly when there is background noise, and can be associated with attention deficit–hyperactivity disorder, learning disabilities, 21–23 Psycho-acoustic testing often identifies head trauma, and other neurological disorders. 24 specific deficits that correlate with patients' symptoms. Treatment consists of improving the signal-to-noise ratio with amplification or reduction of background noise, as well as auditory 23 training. OTONEUROLOGICAL MANIFESTATIONS OF SYSTEMIC DISEASE
Infection Many infections can cause otoneurological symptoms and signs. Viral infection, in particular 25,26 herpes simplexdvirus (HSV), is thought to be responsible for many cases of Bell's palsy. Figure 25-7 shows HSV-1 particles seen by electron microscopy in the geniculate ganglion of mice with experimentally induced Bell's palsy.27Viral infection is also thought to play a role in 28 idiopathic sudden sensorineural hearing loss and vestibular neuronitis. Corticosteroids with or without antiviral medication are used for treatment. Mumps, measles, and congenital 29 rubella infection may cause significant hearing loss.
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FIGURE 25-7 Herpes simplex virus (HSV) in a mouse model of Bell's palsy. A,
The intratemporal portion of the facial nerve from the paralyzed side showing a neuron in the geniculate ganglion. Replicating HSV-1 viruses in the rough endoplasmic reticulum of a neuron in the geniculate ganglion are indicated by the arrows. B, The geniculate portion of the facial motor nerve. Arrows indicate vacuolar changes in the cytoplasm of a Schwann cell. These resulted in demyelination. Scale bars: A, 1 μm; B, 5 μm. (Reproduced with permission from Takahashi H, Hitsumoto Y, Honda N, et al: Mouse model of Bell's palsy induced by reactivation of herpes simplex virus type 1. J Neuropathol Exp Neurol 60:621, 2001.) Another member of the herpesvirus family, varicella-zoster virus (VZV), causes herpes zoster oticus, often referred to as Ramsay Hunt syndrome. Ramsay Hunt syndrome, from reactivation of VZV in the geniculate ganglion, causes facial weakness, sensorineural hearing 30 The symptoms loss, vertigo, and vesicular lesions in the external auditory canal and auricle. 30 that the are typically preceded by otalgia. Recently, investigators have postulated 31 reactivation of VZV may occur in the vestibular and spiral ganglia as well. Ramsay Hunt syndrome may involve other cranial nerves; polymerase chain reaction has localized viral material to the CSF in some cases. MRI typically reveals enhancement of the geniculate ganglion on the affected side. Treatment is with antiviral agents and corticosteroids. The facial palsy associated with Ramsay Hunt syndrome has a poorer prognosis than that of 32 Bell's palsy. 33
Otosyphilis was first described in 1887 by Politzer. Following the introduction of penicillin, it became rare. However, with the emergence of human immunodeficiency virus (HIV) infection, syphilis has experienced a resurgence in the United States and Western Europe, as 34,35 Otoneurological manifestations may occur in secondary, discussed in Chapter 41. tertiary, or congenital syphilis. Sensorineural hearing loss and hydropic symptoms of episodic tinnitus and vertigo may occur. Treatment is with penicillin G and corticosteroids. 36
Lyme disease (Chapter 41) may cause sudden sensorineural hearing loss or facial palsy. 37 Vertigo is uncommon but has been reported. The mainstay of treatment is intravenous ceftriaxone; corticosteroids may be added for treatment of otoneurological manifestations.
Tuberculosis may affect the ear. As with syphilis, tuberculosis has become increasingly 38 38 common in patients with HIV infection. Fortunately, tuberculous otitis media remains rare. The classic description of mycobacterial39otitis media is of chronic otorrhea and multiple perforations of the tympanic membrane. Polyps and granulation tissue38may also be seen. Treatment is primarily medical, with surgery reserved for complications. Finally, HIV infection and immunodeficiency may cause otological symptoms. Otitis externa however, opportunistic may be caused by common pathogens such as Pseudomonas; 40 infections such as Pneumocystis may also be responsible. There are also reports of malignant otitis externa (i.e., skull base osteomyelitis secondary to otitis externa) in 41 of malignant individuals with HIV infection, although some authors note that the incidence 42 otitis externa is not increased in the HIV-infected population as a whole. Children with HIV
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infection often suffer from chronic otitis media. Serous otitis media may result from eustachian tube obstruction secondary to adenoid hypertrophy. Sensorineural hearing loss 43 occurs in 21 to 49 percent of HIV-positive patients and is thought to be multifactorial. Possible causes include secondary infection, central nervous system (CNS) involvement, and 40 44 ototoxicity. Finally, facial palsy is more common in HIV-positive patients.
Immune-Mediated/Connective Tissue Disease There are a number of autoimmune and connective tissue disorders (Chapter 29) that cause otoneurological symptoms, ranging from otitis media to hearing loss or vertigo. Wegener's granulomatosis is characterized by vasculitis of medium and small vessels, as well as by necrotizing granulomas of the upper and lower respiratory tract. Up to 70 percent 45–47 The most common of patients with this disorder experience otological symptoms. otoneurological manifestation of Wegener's granulomatosis 48 is serous otitis media, resulting from inflammatory changes of the nasopharyngeal mucosa. This may cause conductive hearing loss and require treatment with pressure-equalization tubes. The middle ear space can be affected by granulomas, leading to a clinical picture resembling chronic suppurative vasculitis or direct otitis media (Fig. 25-8). Facial palsy can also result, either from45,47,48 Sensorineural hearing involvement of the facial nerve by the granulomatous process. 46 loss occurs in 8 percent of patients and can be rapidly progressive. Vertigo is uncommon. Inflammation of the auricle mimicking relapsing polychondritis may be seen, although this is 46 rare. Wegener's granulomatosis is diagnosed by the presence of c-ANCA antibodies and by the combination of necrotizing granulomas and vasculitis seen on histopathology. Treatment iswith high-dose corticosteroids and immunosuppressive agents such as 45,46 cyclophosphamide.
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FIGURE 25-8 Chronic otitis media in Wegener's granulomatosis.
Granulomatous swelling of the posterior part of the left eardrum viewed through an otomicroscope (arrow). The large white area inferior and to the left of the eardrum is the anterior wall of the external ear canal. (Reproduced with permission from Rasmussen N: Management of the ear, nose, and throat manifestations of Wegener granulomatosis: an otorhinolaryngologist's perspective. Curr Opin Rheumatol 13:3, 2001.) Sarcoidosis is an immune-mediated disease of unknown etiology characterized by hilar adenopathy, pulmonary infiltrates, peripheral lymphadenopathy, and cutaneous and splenic involvement that can affect the CNS (Chapter 51). The characteristic histopathological finding is of noncaseating granulomas. The most common otoneurological manifestation of sarcoidosis is facial palsy, which may be uni- or bilateral and can be associated with parotiditis, fever, and uveitis (uveoparotid fever or Heerfordt's disease). Multiple cranial nerve palsies are common in neurosarcoidosis, which typically involves the meninges of the skull 49,50 Hearing loss base, and occurs in approximately 5 percent of patients with sarcoidosis. and vertigo due to involvement of the eighth cranial nerve are less common. The presentation 49,51 of hearing loss is variable, ranging from mild to severe, and may be unilateral or bilateral. 51 Vestibular testing may be abnormal. Auditory and vestibular symptoms are thought to reflect involvement of the eighth cranial nerve by neurosarcoidosis rather than a direct effect 51 on the inner ear end organs. MRI may show enhancement of the basal leptomeninges 50 following administration of gadolinium; intracranial mass lesions can also be seen. Systemic lupus erythematosus (SLE) may cause sensorineural hearing loss that is uni- or 52–54 The hearing loss bilateral in 8 to 31 percent of patients and can be rapidly progressive. appears to be associated with elevated anticardiolipin antibodies but not with ANA titer and 53,54 54 Vestibular symptoms are less common. frequently improves with treatment. Hearing 52,55 loss is also commonly seen in rheumatoid arthritis, manifesting in 29 to 48 percent of It may be sensorineural, conductive, or mixed in type, and its severity is patients. 55 correlated with disease activity. Conductive hearing loss is thought to be secondary to involvement of the ossicular chain by rheumatoid arthritis, whereas sensorineural hearing loss may be due to immunocomplex deposition, antibodies against inner ear antigens, or 55 of patients with cell-mediated immune processes. Investigations into the vestibular function 56 rheumatoid arthritis have revealed no significant differences from controls. Other immune-mediated diseases causing otologi-cal symptoms include polyarteritis nodosa, Cogan's syndrome, Behçet's syndrome, relapsing polychondritis, Sjögren's syndrome, and Churg–Strauss syndrome. Polyarteritis nodosa, a small-vessel vasculitis, can cause sudden 52 sensorineural hearing loss. Cogan's syndrome is characterized by sudden or rapidly progressive sensorineural hearing loss, vestibular dysfunction, and interstitial keratitis, and it can mimic syphilis or Meniere's disease. Symptoms often respond to treatment with52 52 corti-costeroids. Behçet's syndrome may cause hearing loss, tinnitus, and vertigo. Relapsing polychondritis typically involves the cartilage of the external ear and nose; 52 however, as the disease progresses, hearing loss and vertigo sometimes develop. High-frequency hearing loss may also be seen in 25 percent of patients with Sjögren's 52,57 53 Churg–Strauss syndrome causes hearing loss in rare instances. syndrome. Autoimmune hearing loss also may occur in the absence of systemic illness. It is characterized by fluctuating or rapidly progressive bilateral sensorineural hearing loss that is 52 Antibodies to inner-ear antigens have been responsive to immunosuppressive therapy. 53 detected in some of these patients.
Neurocutaneous Syndromes The most common neurocutaneous syndrome causing otoneurological symptoms is neurofibromatosis type 2 (NF2). This disease is characterized by bilateral vestibular schwannomas, eventually causing bilateral deafness and vestibular dysfunction. Three subtypes have been described. The Wishart type is characterized by onset in the second or third decade and the occurrence of multiple tumors besides vestibular schwannomas. The Gardner type is milder and presents later in life. There is also a subtype called segmental 58 NF2 thought to be caused by somatic mosaicism. Otological manifestations consist of progressive hearing loss that may be unilateral or bilateral, tinnitus, vestibular dysfunction, and facial weakness. Genetic testing is available to detect mutations in the NF2 tumor suppressor gene, although routine screening for children of affected parents is not universally 58 recommended because of its high false-negative rate. Auditory rehabilitation of affected patients is complex owing to the presence of bilateral acoustic neuroma; auditory brainstem
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Metabolic and Endocrine Disorders Certain metabolic or endocrine disorders60,61 are known to contribute to hearing loss. Diabetes perhaps secondary to microangiopathy or mellitus has62,63 been linked to hearing loss, A small subset of diabetic patients has been found to have a mitochondrial neuropathy. mutation causing 64 both hearing loss and diabetes, termed maternally inherited diabetes and deafness (MIDD). Diabetic patients frequently suffer from dizziness and imbalance as well. Peripheral 65 neuropathy, autonomic dysfunction, and peripheral vestibular deficits all play a role in etiology. 66
Renal failure in the absence of diabetes is also associated with high-frequency hearing loss. Additionally, Alport's syndrome is associated with congenital hearing loss and renal failure. 29 Neonatal jaundice can cause downward-sloping sensorineural hearing loss. Hyperlipidemia 29 has also been associated with fluctuating hearing loss and vestibular dysfunction.
An association between thyroid disease and otological symptoms also exists. Vertigo and 67 hearing loss have been described in the setting of hypothyroidism. Pendred's syndrome is characterized by congenital hearing loss, reduced vestibular responses, and goiter. In a study of 42 kindreds, resistance68to thyroid hormone was found to be associated with hearing loss in 21 percent of individuals. Certain mucopolysaccharidoses (MPS) are associated with hearing loss, and many forms predispose to otitis media. The Hurler/Scheie and Hunter forms (MPS I and II) cause sensorineural hearing loss. The mechanism of loss is unclear and may involve deposition of 69 glycosaminoglycans in the cochlea.
Diseases of Bone Several disorders of bone lead to otoneurological manifestations, most notably hearing loss. These include osteogenesis imperfecta, Paget's disease, fibrous dysplasia, and osteopetrosis. Osteogenesis imperfecta is an autosomal-dominant disease caused by mutations in the COL1A1 or COL1A2 genes, which code for type 1 collagen. The disorder is characterized by fragility of bones, hearing loss, and blue sclera. Five major types are currently described; hearing loss is most common in types IA and IB. Hearing loss occurs in 22.6 to 58 percent 70 of patients with osteogenesis imperfecta and typically presents in the second or third decade. It typically begins as a conductive loss and progresses to become mixed or largely sensorineural in nature; both ears are eventually affected. Hearing loss may be treated with amplification or stapedectomy, although surgical results are somewhat disappointing compared with those enjoyed by patients with otosclerosis. Tinnitus and vertigo are also common in osteogenesis imperfecta, particularly in those patients with sensorineural hearing loss. Vertigo is typically mild, triggered by head movements or position change, and brief in 71 duration. Abnormalities are frequently seen71on electronystagmography but do not necessarily correlate with subjective vertigo. Paget's disease, first described in 1877, is caused by increased bone absorption and repair, leading to an overall increase in the amount of bone. There is both a monostotic and a polyostotic form. Hearing loss is common in Paget's disease and is usually mixed conductive and sensorineural. Conductive hearing loss may be caused by ossicular fixation or obliteration of the72oval or round window. Bony changes in the cochlea may also contribute to the hearing loss. Furthermore, involvement of the petrous portion of the temporal bone may alter the shape of the internal auditory canal, potentially impairing the function of the eighth cranial nerve. Histologically, Paget's disease is characterized by disordered lamellar bone (Fig. 25-9). CT may reveal demineralization of the temporal bone. Treatment is with bisphosphonates and calcitonin, which may prevent further hearing loss.
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FIGURE 25-9 Histological examples of Paget's disease. A, Hematoxylin and eosin stain of pagetoid bone (original magnification 100×). Note the relatively continuous irregular pattern of bone with vascular channels. B, Hematoxylin and eosin stain of pagetoid bone (original magnification 500×). Note multinuclear osteoblast with lacunar lucency (below) and rimming of bone with osteoblasts (above). (Reproduced with permission from Hullar TE, Lustig LR: Paget's disease and fibrous dysplasia. Otolaryngol Clin North Am 36:707, 2003.)
Fibrous dysplasia, like Paget's disease, also has monostotic and polyostotic forms. It is nonfamilial, but caused by mutations in the GNAS1 gene, which codes for a second messenger G protein. The disease is characterized by expansile bony lesions (Fig. 25-10). Involvement of the temporal bone can cause narrowing of the external auditory canal, resulting in conductive hearing loss. A lesser percentage of 72 patients will manifest sensorineural hearing loss, labyrinthitis, or facial weakness. Treatment is with bisphosphonates or surgical resection.Irradiation increases the risk of malignant transformation and is not indicated.
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FIGURE 25-10 Histology of fibrous dysplasia. Histological examples of fibrous
dysplasia. A, Hematoxylin and eosin stain of fibrous dysplasia (original magnification 100×). Note prominent, disconnected, Chinese-character bone fragments. B, Hematoxylin and eosin stain (original magnification 500×). Note abundant osteoblastic activity surrounding bony fragments. (Reproduced with permission from Hullar TE, Lustig LR: Paget's disease and fibrous dysplasia. Otolaryngol Clin North Am 36:707, 2003.) Osteopetrosis is characterized by decreased osteoclastic activity, leading to constriction of various skull base foramina. Hearing loss, vertigo, and facial palsy or spasm may develop secondary to compression. Furthermore, eustachian tube dysfunction and middle ear 74 73 effusions may be seen. Treatment is with calcitriol, prednisone, and interferon-gamma.
Drug-Induced Disorders There are numerous medications that exert ototoxic effects on the cochlea and labyrinth. The most commonly encountered ototoxic medications are chemotherapeutic agents, antibiotics, and loop diuretics. Cochlear ototoxicity is typically heralded by tinnitus or a sense of fullness in the ear; however, high-frequency hearing loss may also occur without the patient's knowledge. Hearing loss due to certain drugs, most notably salicylate and furosemide, can be reversible, whereas toxicity secondary to cisplatin and aminoglycosides is most often permanent. Vertigo and75disequilibrium may result from vestibular toxicity; bobbing oscillopsia is a common symptom. Conditions contributing to higher risk for ototoxicity include renal insufficiency, hepatic insufficiency, elevated serum medication levels, preexisting hearing loss or vestibular dysfunction, use of multiple ototoxic medications or a previous history of ototoxic medication use, treatment for more than 14 days, prior exposure to noise, hypovolemia, 75,76 bacteremia, fever, and age over 65 years.
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Ototoxicity leads to distinct histological changes within the cochlea and labyrinth. In the cochlea, initial damage occurs in the basal turn to the outer hair cell layer 1 (OHC1). This can be seen in Figure 25-11. Later, degeneration occurs of the outer hair cell layers 2 and 3, followed by damage to inner hair cells. In the labyrinth, type 1 hair cells on the crista ampullaris are the first to degenerate, followed later by macular cells of the utricle and 75 saccule.
FIGURE 25-11 Hair cell loss due to ototoxicity. Three-day-old rat organ of Corti
explants after 72 hours in vitro. Fluorescein isothiocyanate–conjugated phalloidin-stained stereocilia bundles and cuticular plates of whole-mount organotypic cultures viewed with a Zeiss Axiophot epifluorescence microscope. A, The middle turn of a control explant demonstrating orderly rows of inner hair cells (wider arrow) and three rows of outer hair cells (thinner arrow). B, The middle turn of an explant exposed to 10 μg/ml cisplatin. The disrupted pattern of cytoarchitecture and the loss of a significant number of hair cells (arrow) are evident. C, The middle turn of an explant that was pretreated with 10 mmol/L N-acetyl-l-cysteine (L-NAC) before exposure to toxic (10 μg/ml) doses of cisplatin. The cytoarchitecture has been preserved, and hair cell survival is also significantly improved (arrows) when compared with the hair cell survival in the unprotected explants. (Reproduced with permission from Feghali JG, Liu W, Van De Water TR: L-n-acetyl-cysteine protection against cisplatin-induced auditory neuronal and hair cell toxicity. Laryngoscope 111:1147, 2001.) Aminoglycoside antibiotics have been known to be ototoxic since the parenteral use of streptomycin for tuberculosis in the early twentieth century. Symptomatic hearing loss occurs
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in 2.4 to 13.9 percent of patients treated with aminoglycosides ; however, high-frequency 78 (10 to 20 kHz) audiometry reveals the incidence of hearing loss to be as high as 62.3 percent. Certain aminoglycosides, such as streptomycin and gentamicin, cause vestibular toxicity prior to causing cochlear toxicity. It is unclear whether elevated serum levels of antibiotic correlate with increased risk of toxicity. The pathogenesis is thought to involve generation of free 79 radicals leading to apoptosis of hair cells. There is evidence that certain mitochondrial 80 mutations cause increased susceptibility to the ototoxic effects of aminoglycosides. Numerous animal studies are ongoing to evaluate potential protective 76,79 agents such as Other anti-infective antioxidants or iron chelators that may be administered concomitantly. agents reported to cause ototoxicity include vancomycin, macrolides, fluoroquinolones, tetracycline, antivirals, amphotericin, flucytosine, and antimalarials. Cisplatin is the chemotherapy81–83 agent most frequently associated with ototoxicity, with an Hearing loss initially manifests in the high frequencies and incidence of 20 to 65 percent. progressively worsens with continued administration. Tinnitus is a common presenting complaint. Ototoxicity appears related to the cumulative dose. Cisplatin damages the stria 75 vascularis, resulting in hair-cell loss. Ongoing studies are evaluating agents such as amifostine that may protect against cisplatin-induced ototoxicity. Other ototoxic chemotherapeutic agents include carboplatin, oxiliplatin, Vinca alkaloids, bexarotene, and taxane. Loop diuretics can cause hearing loss, tinnitus, and occasionally vertigo, perhaps because disturbances in the sodium and potassium concentrations in endolymph cause edema of the stria vascularis. Hearing loss is typically reversible and is usually seen with parenteral rather 75 than oral administration of the offending medication. Bumetanide may be less ototoxic than furosemide or ethacrynic acid. Salicylates can cause tinnitus and reversible hearing loss, although some cases of permanent hearing impairment have been reported following overdoses. Owing to the high incidence of ototoxicity with aminoglycosides and cisplatin, patient monitoring with high-frequency audiometry and careful attention to symptoms is recommended for early diagnosis and management.
Environmental Disorders Numerous types of environmental injury can result in otoneurological symptoms. Barotrauma may cause otologic injury through multiple mechanisms. The most common otologic injury seen with barotrauma is perforation of the tympanic membrane. Increased pressure in the middle ear may lead to facial palsy if portions of the facial nerve are dehiscent; vertigo and 84 conductive hearing loss may also result. Inner ear barotrauma can manifest as a perilymphatic fistula and can be characterized by hearing loss, vertigo, nausea, and vomiting following exposure to increased atmospheric pressure. Inner ear decompression sickness 85 causes similar symptoms, usually manifesting itself after surfacing from a dive. The prognosis for recovery is good for inner ear barotrauma, but progressive damage to the 86 cochlear and vestibular organs often occurs following inner ear decompression sickness. Lightning strikes have also been documented to have otoneurological sequelae. Lightning 87,88 Hearing loss, may produce injury either through a direct strike or over telephone lines. 89 tinnitus, tympanic membrane perforation, facial palsy, and vertigo have been reported. Hearing loss may have a mixed conductive and sensorineural pattern and appears stable 90 over time. Blast injuries to the ear are also of significance. The tympanic membrane may rupture. Sensorineural hearing loss is also common; it appears to occur via a different mechanism 91 from noise-induced hearing loss, as the audiometric pattern lacks a notch at 4000 Hz. Fortunately, hearing loss tends to recover fairly quickly following injury and any residual 91 hearing loss is often minimal. Vertigo is uncommon. Severe thermal injury to the ear may result from slag burns. Often non-healing perforations of the tympanic membrane are seen. Facial paralysis, sensorineural hearing loss, and vertigo 92 have also been reported. Noise exposure is well known to cause hearing loss, typically with a notched pattern at 4000 Hz on the patient's audiogram. Both occupational and recreational exposure can cause significant loss. Some individuals appear more likely than others to sustain noise-induced 62 loss.
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Nutritional Disease Wernicke's encephalopathy, which results from hypovitaminosis B1 (thiamine), manifests as ataxia, abnormal eye movements, and mental status change. Vestibular laboratory testing of patients with Wernicke's encephalopathy typically indicates bilaterally reduced vestibular 93 responses and abnormal central vestibular processing. Treatment is by replacement of thiamine, which usually corrects the abnormal eye movements and ataxia. Vestibular function remains abnormal.
Neoplastic Disease The temporal bone is affected by primary malignancies as well as metastatic disease. Primary tumors may origi nate in the external ear, middle ear and mastoid, or inner ear structures. Squamous cell carcinoma and basal cell carcinoma can affect the auricle and external auditory canal. Squamous cell carcinoma may either arise primarily in the ear or metastasize from local or regional disease. Pain is a common complaint, although hearing 94 loss and facial weakness may also occur. Rhabdomyosarcoma may originate in the temporal bone in the pediatric population. Endolymphatic sac tumors occur both sporadically 95 and associated with von Hippel–Lindau disease (Fig. 25-12). Symptoms arise from local 95 extension of the tumor and may include pain, hearing loss, and, less commonly, vertigo. Cancer of the breast, 94 kidney, lung, stomach, thyroid gland, and prostate all may metastasize to the temporal bone.
FIGURE 25-12 MRI of endolymphatic sac tumor. Axial contrast-enhanced
T1-weighted MRI demonstrates an irregular, enhancing mass along the posterior border of the petrous apex, at the expected location of the endolymphatic sac (dashed arrow). The mass erodes into the underlying temporal bone (solid arrow). (Courtesy of Barton F. Branstetter, MD, University of Pittsburgh.) NEURO-OTOLOGICAL MANIFESTATIONS OF AGING
Dysequilibrium of Aging Dysequilibrium of aging refers to a loss of balance in association with advanced age in individuals whohave no other known etiology for their balance disturbance. Patients with
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dysequilibrium of aging are generally in their seventies and demonstrate white matter disease on MRI including periventricular and subcortical white matter disease (Fig. 25-13) that may 96 relate to microvascular ischemic changes. Treatment consists of managing risk factors for cerebrovascular disease and balance therapy. Vestibular-suppressant medications should be discontinued.
FIGURE 25-13 MRI of a patient with microvascular disease seen in
dysequilibrium of aging. Axial fluid-attenuated inversion recovery (FLAIR) image through the bodies of the lateral ventricles shows extensive, confluent areas of abnormal signal in a periventricular and subcortical distribution, consistent with white matter microvascular disease. The ventricles are slightly enlarged from associated central volume loss. (Courtesy of Barton F. Branstetter, MD, University of Pittsburgh.)
Presbycusis Sensorineural hearing loss related to aging is termed presbycusis. Approximately one third of persons between the ages of 60 and 70, and up to half of those between 70 and 80, have 62 of presbycusis have been described, relating to different hearing loss. Four subtypes 97 audiometric patterns. The most common type is called sensory presbycusis, manifesting as a symmetric high-frequency downward-sloping sensorineural hearing loss that progressively worsens62with age (Fig. 25-14). Both genetic and environmental factors play a role in speech when there is etiology. Patients typically complain of difficulty in understanding 98 background noise, and they may also suffer from tinnitus.
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FIGURE 25-14 Audiogram of presbycusis. This audiogram shows sensorineural
hearing loss in a downsloping pattern, typical of presbycusis. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 26 Orbital and Ocular Manifestations of Neurological Disease KIMBERLY P. COCKERHAM • ANDREA OLMOS •
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ARTERIOLIZED CONJUNCTIVAL VESSELS Cavernous Sinus Fistula Epidemiology Ocular Symptoms Ocular Signs Diagnosis Management Cavernous Sinus Thrombosis Epidemiology Symptoms Ocular Signs Diagnosis Management ORBITAL OR OCULAR PAIN DUE TO INTRACRANIAL PROCESSES Trigeminal Neuralgia Epidemiology Ocular Symptoms and Signs Diagnosis Treatment Cluster Headache Epidemiology Ocular Symptoms and Signs Diagnosis Management Pituitary Apoplexy Epidemiology Symptoms and Signs Diagnosis Management Tolosa–Hunt Syndrome Epidemiology Ocular Symptoms and Signs Diagnosis Management
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CRANIAL NEUROPATHIES INVOLVING THE EYE Cranial Nerve II Papilledema Papillitis and Retrobulbar Neuritis Optic Atrophy Cranial Nerves III, IV, and VI Epidemiology Ocular Symptoms and Signs Diagnosis Management Cranial Nerve V Epidemiology Ocular Symptoms and Signs Diagnosis Management EYELID RETRACTION WITHOUT LAGOPHTHALMOS Guillain–Barré Syndrome Epidemiology Ocular Symptoms and Signs Diagnosis and Management Parinaud's Syndrome Epidemiology Ocular Symptoms and Signs Diagnosis Management
The eye and its surroundings, the orbit and periorbital tissues, are intimately related to pathological processes occurring in the superior orbital fissure, cavernous sinus, parachiasmal region, and anterior cranial fossa. These various processes are discussed with emphasis on their epidemiology and on ocular symptoms and signs, diagnosis, and management. Due to space constraints, the entire subspecialty of neuro-ophthalmology cannot be covered within the context of this chapter; instead, a number of disorders that are of particular importance to neurologists and internists have been selected. The interested reader is directed to more detailed texts providing a1,2comprehensive description of all ophthalmic manifestations of neurological disease. Specifically, disorders of the pupil, ocular motility (Table 26-1 Table 26-2 Table 26-3), and the optic nerve are discussed only briefly in this chapter, the focus being on the most common ocular and orbital manifestations of intracranial processes. Important signs include arterialized vessels (cavernous sinus fistula, thrombosis); orbital or ocular pain (trigeminal neuralgia, cluster headache, pituitary apoplexy, and Tolosa–Hunt syndrome); corneal numbness (intracranial tumors); multiple cranial neuropathies (cavernous sinus fistula or thrombosis, pituitary apoplexy, Tolosa–Hunt syndrome); lid retraction without lagophthalmos (Miller Fisher variant of Guillain–Barré syndrome [GBS] and Parinaud's syndrome); and papilledema (increased intracranial pressure [ICP], which is idiopathic or due to tumor, infection, or inflammation). Click here to view this table.... Click here to view this table.... Click here to view this table.... ARTERIOLIZED CONJUNCTIVAL VESSELS
Cavernous Sinus Fistula Epidemiology Direct or fast-flow carotid-cavernous fistulas (CCFs) type A result from a single tear in the wall of the cavernous segment of the internal carotid artery, thus creating a direct communication between the internal carotid artery and the cavernous sinus. Direct CCFs are usually caused by head trauma, which may be severe enough to require hospitalization, or seemingly trivial, requiring no treatment until symptoms and signs of the fistula develop. Patients are commonly young men. A substantial number of direct CCFs result from a preexisting aneurysm of the cavernous segment of the internal carotid artery. They may also occur after various diagnostic and therapeutic procedures or after maxillofacial surgery. Spontaneously symptomatic direct CCFs may also occur. Patients who develop a direct fistula spontaneously usually have an underlying systemic vasculopathy or connective tissue 1 disorder.
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Dural or slow-flow CCFs result from lesions in one or more meningeal branches of the internal carotid artery, the external carotid artery, or both. Type B fistulas are rare and supplied only by meningeal branches of the internal carotid artery, type C fistulas by branches of the external carotid artery, and type D fistulas by meningeal branches of the internal and 3 external carotid arteries. Dural CCFs are often spontaneous and unrelated to trauma. Pregnancy, systemic hypertension, atherosclerotic vascular disease, connective tissue disease, and minor trauma may cause a predisposition to symptomatic dural CCFs. Spontaneous dural CCFs are more common in elderly women than in men. They usually occur in middle-aged or elderly women, but can produce symptoms at any age in both 1 sexes. Ocular Symptoms Characteristic ocular symptoms include an ache that may be worse on eye movements, double vision, and, rarely, decreased vision. Patients may experience pulsatile tinnitus, and examination may reveal a bruit that is synchronous with the heartbeat and most obvious when patients are recumbent. The eyelids may become moderately or severely swollen in the early stages of a direct CCF. This swelling can lead to progressive changes in the eyelid and its vasculature. Diplopia occurs1 in 60 to 70 percent of patients with direct CCF, and glaucoma in 30 to 50 percent of patients. Fistula size and location within the cavernous4 sinus, rate of flow, and pattern of venous drainage influence symptoms of dural CCFs. With posterior drainage, dural CCFs typically do not produce ocular symptoms, but they may produce a cranial neuropathy, such as trigeminal neuropathy, facial nerve paresis, and an ocular motor nerve paresis. They may also cause brainstem neurological deficits; in rare instances, intracranial hemorrhage 1 occurs. For anteriorly draining dural CCFs, symptoms are similar to, but usually milder, than those of direct CCFs. The mildest cases result in redness of one or, rarely, both eyes due to dilation and arterialization of conjunctival and episcleral veins. More severe cases of dural CCFs 1 show symptoms identical to those of direct CCF. Ocular Signs The conjunctival vessels may become more prominent with irritation, allergies, or inflammatory conditions such as thyroid eye disease, but none of these disorders causes the vessels to become tortuous and engorged right up to the corneal edge or limbus (Fig. 26-1). This characteristic vascular pattern of arterialized conjunctival vessels is seen as a manifestation of the flow alterations created by cavernous sinus fistulas and less commonly by cavernous sinus thrombosis.
FIGURE 26-1 Carotid-cavernous fistula: the characteristic arteriolized
conjunctival vessels are demonstrated. Other characteristic ocular findings in patients with CCF include increased intraocular pressure, chemosis (Fig. 26-2), alterations in eye movement due to passive engorgement or cranial nerve impairment, proptosis, and increased resistance to retropulsion (a firmness to
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the eyeball on palpation).
FIGURE 26-2 Carotid-cavernous fistula: the severe hemorrhagic chemosis
associated with a high-flow fistula can be seen. Diagnosis The diagnosis is based on clinical and imaging findings. Orbital ultrasonography, computed tomography (CT), CT angiography, magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), and conventional angiography are all valuable tools in identifying the enlarged superior ophthalmic vein (Fig. 26-3). Such imaging may also be used to show enlargement of the extraocular muscles, enlargement of the affected cavernous sinus, and abnormal intracranial vessels. Passive enlargement of the extraocular muscles is 1 common, causing a forward movement of the globe resulting in axial proptosis.
FIGURE 26-3 Carotid-cavernous fistula: magnetic resonance imaging (MRI)
shows enlarged superior ophthalmic vein and fullness of the cavernous sinus. Note the convex wall on the involved side. Catheter angiography is still the main diagnostic test for the definitive diagnosis of both direct and dural CCFs. It is the only technique that can accurately define the location of a fistula, its arterial supply, and the venous drainage pathways. However, angiography is invasive and impractical to perform during the follow-up of CCF patients after surgical treatment or embolization. The combined application of transcranial color Doppler imaging and carotid duplex sonography may be used to monitor the flow characteristics of fistulas and obtain accurate estimates of flow velocity and the extent of a CCF and its draining system. By correlating hemodynamic changes with clinical symptoms, this approach provides a noninvasive, reproducible, reliable, and inexpensive way to determine the efficacy of 5 treatment. Carotid duplex sonography alone has also been proposed as a useful instrument for early diagnosis and long-term follow-up of patients with dural CCFs. The resistive index of the external carotid artery of a dural CCF was determined to be the best parameter for
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MRA is another noninvasive technique that can diagnose CCFs by demonstrating the draining veins. However, whereas both MRA and MRI easily7visualize high-flow CCFs, low-flow CCFs are not seen as easily with these techniques. CT angiography is a reliable diagnostic tool for evaluating CCFs in a clinical context and providing a safe, noninvasive, and accurate method for follow-up. Although this technique can distinguish certain draining veins, it rarely shows the exact site of fistulas in direct CCFs or the small feeding branches in dural CCFs. Consequently, CT angiography cannot replace 8 the use of conventional angiography in planning endovascular interventional treatment. Because dural or low-flow CCFs show less specific clinical features and may be difficult to distinguish using CT and MRI, they present diagnostic challenges. However, transcranial Doppler ultrasonography is useful in detecting both dural and direct CCFs and in following the results of treatment, by detecting changes in blood flow within the orbit. It is especially important in the diagnosis and management of dural CCFs, which may exhibit subtle 9 hemodynamic changes. Although traumatic CCFs are rarely diagnosed early, high venous oxygen saturation values that rapidly reach arterial saturation values in the jugular bulb10may reveal the presence of a CCF before the appearance of clinical symptoms and signs. Management Closure of the abnormal arteriovenous communication without obstruction of the internal carotid artery is the optimal treatment of direct CCFs. This may involve direct obliteration of the fistula by surgical repair of the damaged portion of the cavernous internal carotid artery or endovascular closure of direct CCFs by embolization through the transarterial route using platinum coils and detachable balloons. In more than 80 percent of cases, the fistula is successfully closed, and the internal carotid artery remains unobstructed. The most common complications are aggravation of ocular signs, such as proptosis, ophthalmoparesis, and pain, and development of new neurological 1deficits. Severe complications include sepsis, stroke, blindness, and aneurysm formation. When the transarterial endovascular approach fails, the next treatment option is usually transvenous embolization with detachable balloons, standard platinum coils, liquid adhesives, or silk sutures. However, this alternative is not possible when venous routes are inaccessible. Embolization via a transvenous approach through the superior ophthalmic vein or the inferior petrosal sinus may also be used to treat 1 11 CCFs. This option has been more successful in treating low-flow indirect CCFs than high-flow CCFs. Direct CCFs with small fistulous communications have been successfully treated with Guglielmi detachable coils via the transarterial approach. The placement of these coils can be well controlled, and they are easily retrieved, repositioned, and exchanged. Although they are expensive compared to the complex fibered coils typically used for embolization, they offer another approach to treat appropriate fistulas or after transarterial embolization has 12 attempts fail and symptoms persist, a direct failed. When both transarterial and transvenous 11 surgical approach is a remaining option. Treatment options for dural CCFs include conservative treatment, direct surgery, conventional radiation therapy, stereotactic radiosurgery, and intermittent self-compression of the affected internal carotid artery. However, the optimal treatment for lesions producing aggressive symptoms and signs such as visual loss, diplopia, intolerable bruit, severe proptosis, increased intraocular pressure, or cortical venous drainage is endovascular 2 embolization. In most (70% to 95%) cases, dural CCFs are successfully closed by standard particulate or glue embolization. Complications of endovascular treatment include hemorrhage at the catheter site or in the orbit, local infection, sepsis, and temporary and permanent neurological deficits. For the endovascular embolization of dural CCFs, the transvenous route is preferred to the transarterial route. Relative to the transarterial approach, transvenous embolization has a high success rate and a low probability of serious 4 complications. There are various venous routes for executing an endovascular embolization, depending of the type of venous drainage (anterior, posterior, or cortical) and the anatomy. The inferior petrosal sinus is the simplest and shortest route to the cavernous sinus, allowing successful management13in most cases. Other options include the pterygoid plexus and the superior petrosal sinus. Transvenous coil occlusion of the superior and inferior ophthalmic veins and the cavernous sinus of the affected eye is a successful, efficient, and safe 4 treatment for dural CCFs.
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Cavernous Sinus Thrombosis Epidemiology Cavernous sinus thrombosis is usually secondary to paranasal sinus infection, orbital cellulitis, or midface infection. Although most cases occur in14healthy people, this disorder often occurs in immunocompromised and diabetic patients. Pathological changes associated with cerebral venous thrombosis depend on the location and degree of propagation of the clot and on the extent of collateral venous drainage. Symptoms may develop acutely (less than 48 hours), subacutely (48 hours to 30 days), or chronically (more than 30 days). Clinical manifestations also vary, depending on the site of obstruction, the extent and rate of occlusion, the underlying etiology, and the health or fragility 1 of the patient. Three factors are necessary for thrombus to form in the cavernous sinus: damage to the 15 intima of the vessel wall, hypercoagulability of the blood, and vascular stasis. Predisposing infection is usually streptococcal, staphylococcal, or pneumococcal. Anaerobic bacteria may also be responsible. Aseptic cavernous sinus thrombosis is usually secondary to some mechanical phenomenon and is sometimes associated with mechanical obstructive 16 pathology, such as a tumor or aneurysm. The most common pathogenesis is the development of an abscess, cellulitis, or other infected source leading to phlebitis of the veins draining the central portion of the face toward the cavernous sinus. The phlebitis propagates along these veins to the cavernous sinus, resulting in thrombophlebitis of the cavernous sinus. Because of the intercommunicating sinuses, the thrombophlebitis quickly becomes bilateral. Mycotic embolism may also be responsible. In this case, an abscess or infection in the middle third of the face can cause a mycotic embolus that becomes embedded in the cavernous sinus, initiating a thrombophlebitis. A third mechanism is a phlebothrombosis that occurs primarily in the cavernous sinus or one of the veins directly associated with the sinus. Aseptic cavernous sinus thrombosis can arise in this manner after intracranial surgery or other manipulation during which a thrombus with direct continuity to the cavernous sinus is created. Relative to 16 the first two processes, the signs and symptoms are subtler. Septic cavernous sinus thrombosis is commonly preceded by infections of the mid-face or by 15 paranasal (usually sphenoid) sinusitis, otitis media, or dental abscesses. Gram-positive bacteria are typically the pathogens that enter the facial vein and pterygoid plexus in this case. When dental infection is responsible, streptococci, fusobacteria, and Bacterioides species are the most common pathogens. Untreated or incompletely treated bacterial or fungal ear infections may also result in septic cavernous sinus thrombosis, which has a 30 percent mortality rate regardless of therapy. Survivors have neurological deficits, such as diplopia, visual sensory dysfunction, neurotrophic keratrophy, facial numbness, paresthesias, and pain from trigeminal neuropathy. Symptoms Visual symptoms are similar to those in CCF and include an orbital ache and diplopia, but the process is more commonly bilateral. Patients with cavernous sinus thrombosis occurring in conjunction with neurotrophic keratopathy or optic neuropathy may also experience loss of vision. Additionally, patients with septic cavernous sinus thrombosis may experience an altered sensorium and more generalized headache with nausea and vomiting; chills and diaphoresis may also be features, and seizures sometimes occur. Laboratory abnormalities include a pronounced leukocytosis and positive blood cultures. Evidence of meningitis or 1 brain abscess may be present. Complications include blindness, focal seizures, vascular steal syndromes, hemiparesis, and hypopituitarism. Other possible complications are intracranial infection, multiple brain 16,17 abscesses or systemic abscesses, and cerebral edema. Ocular Signs Clinical manifestations depend in part on whether the condition is infectious or aseptic. Pain around the eye is common and associated with several ocular signs, such as proptosis, conjunctival vessel arterialization, chemosis, ptosis, and ophthalmoparesis (Fig. 26-4). When facial, dental, or ethmoidal infection is responsible, eyelid edema is common. Lid swelling may also occur and can conceal neurogenic ptosis. Any or all of the cranial nerves passing
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through the cavernous sinus may be affected. Because the abducens nerve passes through the center of the sinus, lateral gaze palsy may be an early sign and can precede the development of complete ophthalmoplegia (i.e., lack of movement in all gazes due to 15 dysfunction of the third, fourth, and sixth cranial nerves). Damage to the first division of the trigeminal nerve in the cavernous sinus leads to corneal anesthesia or hypesthesia. Intraocular pressure is often elevated due to diminished outflow from episceral veins. Other ocular signs include increasing dilation of retinal veins, venous stasis retinopathy (dot-blot hemorrhages throughout the retina) and low-grade optic disc swelling (Fig. 26-5).
FIGURE 26-4 Carotid-cavernous fistula: bilateral chemosis and severe
dysmotility are demonstrated.
FIGURE 26-5 Intracarotid cavernous thrombosis: dilated tortuous retinal vessels
characterize venous stasis retinopathy and dot-blot hemorrhages. Mild disc edema may be present and may mimic papilledema when bilateral. Although superior ophthalmic vein thrombosis is a well-known sign of cavernous sinus 18 thrombosis, it is not always present. Diagnosis Conventional angiography has been replaced by noninvasive neuroimaging as the primary method of diagnosis. CT scanning and MRI can provide information about localization, cause, 1 and severity of the disease. Direct signs of cavernous sinus thrombosis include changes in the density/signal intensity and in the size and contour of the cavernous sinus. Indirect signs are related to associated venous obstruction and include dilatation of the superior ophthalmic vein, exophthalmos, and increased dural enhancement along the lateral border of the 18 cavernous sinus. However, overlap between normal variations and pathological abnormalities of the cavernous sinus makes it difficult to interpret CT and MR studies when performed at an early stage for the evaluation of sus pected septic cavernous sinus thrombosis, the origin of which is being recognized increasingly within the sphenoethmoidal sinus on these studies. CT and MR examinations are also required for early detection of intracranial complications. For example, high-resolution CT and MRI are used to recognize intracavernous carotid arterial wall 18 inflammation as a source of ischemic complications. CT scanning is relatively insensitive for diagnosing cavernous sinus thrombosis, but
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nonenhanced CT scans may show diffuse cerebral swelling, single or multiple hemorrhages, areas of hemorrhagic infarction, and small ventricles. CT with intravenous contrast may show 15 occlusion of the sinus or a dilated superior ophthalmic vein. MRI is the imaging study of choice for diagnosis and follow-up, demonstrating fullness of the cavernous sinus, 15 alternations in the carotid flow void, and the stages of thrombus evolution. It can detect thrombosis in cerebral veins and sinuses, but also distinguishes abnormalities in the brain parenchyma that reflect the pathophysiology of the disease. Advances in diffusion-weighted imaging and other techniques can also provide information about such parenchymal changes. MRI supplemented by a contrast-enhanced spoiled gradient–recalled acquisition in the steady-state sequence may serve as an alternative18to diagnose cavernous sinus thrombosis as well as tributary venosinus thrombosis. Gadolinium-enhanced MRI is also effective in early diagnosis and may reveal low-density areas that probably represent blood 19 clot. The differential diagnosis includes infection, especially fungal; inflammation, such as sarcoidosis; mass lesions (e.g., meningioma); and aneurysm. Management Management depends on the cause of the disorder. Options include antithrombotics in conjunction with corticosteroids if no infection is present. Occasionally surgery is required to obtain a biopsy specimen of the mass. Surgical excision of meningiomas from the cavernous sinus is often complicated by permanent injury to the cranial nerves, and radiation is thus the preferred therapeutic modality. In septic cases, antibiotics or antifungal agents are instituted. The penetration of antibiotics may be limited by thrombus, so that treatment is usually continued for at least 3 weeks with high doses of intravenously administered antibiotics. Empiric therapy should include either nafcillin or oxacillin at maximal doses plus either ceftriaxone or cefepime; if a dental or sinus infection is likely, metronidazole is added. Anticoagulation may be necessary to prevent septic emboli, corticosteroids to reduce edema, and surgery to drain the primary infective 14 source. Delays in diagnosis can result in significant mortality and permanent sequelae. ORBITAL OR OCULAR PAIN DUE TO INTRACRANIAL PROCESSES
Trigeminal Neuralgia Epidemiology 20
Trigeminal neuralgia has an estimated prevalence of 100 to 200 cases per million people. Vascular contact of the trigeminal nerve root at its entry (or exit) zone with a branch of the superior or anterior inferior cerebellar artery results in demyelination of trigeminal sensory fibers within the nerve root or brainstem in 80 to 85 percent of cases; in another 2 percent of cases, a structural anomaly other than neurovascular compression by a normal vessel (e.g., by posterior fossa neoplasm,21cysts, arteriovenous fistulas, cavernous malformations, and arteriovenous malformations ) is responsible. Hypertension is associated with trigeminal 22 in the posterior neuralgia. Multiple sclerosis and compressive space-occupying masses 23 fossa are other causes of trigeminal neuralgia involving demyelination. Ocular Symptoms and Signs 20
The facial pain of trigeminal neuralgia is often associated with photophobia and tearing, but unlike cluster headache, there are no eyelid, conjunctival, or pupillary findings. Nevertheless, complete eye and neurological examination is essential to detect signs of corneal anesthesia (cranial nerve V), involvement of cranial nerves II to VII, or long-tract signs, which would suggest an underlying structural cause for the disorder other than anomalous microvascular compression of trigeminal nerve fibers. Diagnosis CT and angiography can24be used to exclude aneurysm, tumor, or other structural lesions as the cause of symptoms. MRI is the preferred imaging modality, but high-resolution magnetic resonance tomographic angiography (MRTA) is also useful25for visualizing the neurovascular relationships at the trigeminal nerve root entry or exit zone.26 Spoiled gradient–echo (SPGR) MRI, MRA, and three-dimensional imaging are also helpful to demonstrate abnormalities such as tumors, cerebral aneurysms, arteriovenous malformations, and vascular anomalies.
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Treatment Pharmacological treatment options include carbamazepine and phenytoin, but 25 percent of 27 patients do not respond. Surgical procedures are available for medically refractory trigeminal neuralgia. Microvascular decompression is suggested for20otherwise healthy patients with isolated pain in the first ophthalmic trigeminal division. Operative success is more likely in cases in which20,28 the symptoms and signs are typical and severe and have been Gamma knife has also been used with mixed success;27the present for less than a year. most common complications are facial numbness, facial paresthesias, and dysgeusia.
Cluster Headache Epidemiology Cluster headache is a migraine variant characterized by recurring incidents of severe, unilateral orbital or temporal pain associated with cranial autonomic features and usually occurring with circadian periodicity. The prevalence of cluster headache is an estimated 0.1 percent, with a male-to-female ratio of 3.5 to 7:1. Cluster headache can start at any age, but the most common age at onset is 30 to 40 years. Acute attacks are often29provoked by alcohol, nitroglycerin, exercise, and elevated environmental temperature. Chronic cluster 30 headache usually develops from episodic cluster headache, but may also develop de novo. People with episodic cluster headache typically experience one to two attack phases each year, with phase durations ranging from 4 to 16 weeks and remission periods of 6 months to 2 years. Patients with chronic cluster headache experience phase durations exceeding 1 1 year, with remission periods of less than 1 month. The pathophysiology of cluster headache is unknown, although evidence exists indicating that the pain and autonomic symptoms result from activation of both the trigeminal vascular and cranial parasympathetic pathways. There is also evidence that nitric oxide may play a role; it is increased in patients during and between attacks. Hypothalamic dysfunction has been claimed as a potential cause of the rhythmic nature of cluster headache, and altered 1 circadian rhythms of hypophysial hormone systems have been reported in cluster headache. Cluster headache is occasionally associated with trigeminal neuralgia (cluster-tic syndrome). Also, approximately one half to two thirds of patients develop Horner's syndrome (ptosis and miosis) during an attack and may develop a permanent Horner's syndrome after multiple cluster headache attacks. Secondary 30 cluster-like headaches are those with an underlying medical disorder or a structural lesion ; clinical examination may be useful in distinguishing these from primary cluster headaches. Ocular Symptoms and Signs Severe unilateral orbital, supraorbital, or temporal pain occurs, lasting for 15 to 180 minutes. However, any part of the head may be affected and, although the attacks are strictly 29 unilateral, the affected side may alternate. Ipsilateral accompaniments include nasal congestion, rhinorrhea, or both; forehead and facial swelling; and a29sense of restlessness Ocular signs include and agitation. Nausea, vomiting, and photophobia may also occur. 1,30 The conjunctival conjunctival injection, tearing, eyelid edema, and miosis and ptosis. injection is usually diffuse and mild without associated chemosis. The conjunctival vessels are never tortuous (arterialized) as seen with cavernous sinus fistula and thrombosis (Fig. 26-6). Tearing and photophobia are typically present; the eyelids may be erythematous or edematous. Horner's syndrome may be present. The pupil on the involved side is smaller, and this anisocoria is more obvious in the dark.
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FIGURE 26-6 Cluster headache: the diffuse conjunctival injection can be seen.
Note that the vessels are much smaller and less tortuous than those seen in patients with carotid-cavernous fistulas. Diagnosis The diagnosis can be difficult when the attributes of cluster headache are mimicked by other headaches and the patient has an unrelated conjunctival injection due to allergy, infection, or irritation. Differential diagnoses to consider are secondary causes 29 of cluster headache, other trigeminal autonomic cephalgias, migraine, and hypnic headache. MRI can be helpful in distinguishing between cluster headache mimics and primary cluster headache. All patients with a headache should have their optic nerves examined for signs of papilledema (bilateral disc edema, lack of venous pulsations that may be accompanied by venous fullness and retinal hemorrhages), malignant hypertension (discs that are typically hyperemic bilaterally and associated with retinal microinfarcts, so-called cotton wool spots), or optic nerve pallor due to ischemic damage or vasculitis (temporal arteritis). Management Treatment is acute or prophylactic. For acute treatment, inhalation of 100 percent oxygen for 15 minutes may stop an attack. The advantages of oxygen therapy are that it has no established adverse effects, it can be combined with other acute and preventive treatments, 29 and it can be repeated if29necessary. Subcutaneous sumatriptan is the medication of choice to abort a cluster attack. Most oral medications are not absorbed quickly enough to relieve the pain of a cluster headache within a reasonable time. Preventive therapy is required when cluster headache attacks are frequent, severe, and so short that abortive medications are not effective. Medication for preventive therapy is started early in the cluster period and continued until the patient is free from headache for 2 weeks, after which the dose is progressively decreased. Prednisone is the fastest-acting preventive drug; many consider verapamil, a calcium-channel blocker, the best preventive drug; lithium is also effective. Short-term prevention is an option for patients with short bouts or to control attack frequency, but the drugs used for this purpose should not be taken on a long-term 29 basis. They include corticosteroids and nocturnal ergotamine. Patients are advised not to drink alcohol during the cluster bout, warned against prolonged 29 exposure to volatile substances, and advised to avoid afternoon naps.
Pituitary Apoplexy Epidemiology Pituitary apoplexy is an acute life-threatening condition that is typically associated with acute enlargement of a pituitary adenoma resulting from hemorrhage or infarction and occurs in either gender and at31any age. It has been reported in 0.6 to 17 percent of patients with pituitary adenomas. It may be the initial presentation of the tumor (regardless of histological
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subtype ) and can be precipitated by trauma, radiation, bromocriptine or estrogen therapy, pregnancy, angiography, anticoagulation, adrenalectomy, cardiac or other recent surgery, dialysis, dynamic pituitary function or stimulation tests, and transient changes in ICP due to 1 coughing, sneezing, or spinal anesthesia. Other predisposing factors including pituitary irradiation, alterations in pressure gradients, diabetes, chronic systemic hypertension, reduction or acute increase in pituitary blood-flow, and abnormal vascularity of pituitary tumors. The clinical 31,32 presentation of pituitary apoplexy is not influenced by the presence of The disorder is probably caused by capillary compression or the associated disease. outstripping of vascular supply as the pituitary tumor expands. Symptoms and Signs The classic triad of pituitary apoplexy is pain, double vision, and bitemporal hemianopia. Pituitary apoplexy causes sudden, severe headache that may be retro-orbital, frontal, or diffuse. Other symptoms include neck pain, photophobia, nausea, vomiting, visual disturbances, autonomic dysfunction, hormonal dysfunction, and alteration of consciousness. However, pituitary apoplexy may also occur with a more gradual onset or with almost no 31,33 symptoms at all. The sudden expansion of the pituitary results in compression of the optic chiasm and ischemia of the optic nerves. Ocular signs include unilateral or bilateral visual loss that is associated with bitemporal hemianopias. The expanded pituitary may also compress cranial nerves III, IV, V, and VI as they course through the cavernous sinus. If all three of the oculomotor cranial nerves are affected, gaze may be absent in all directions. This is often 34,35 referred to as complete ophthalmoplegia or a frozen globe in the ophthalmic literature. Pituitary apoplexy may also occur in association with Horner's syndrome, thought to be the result of disruption of the sympathetic fibers as they course through the cavernous sinus in close proximity to the carotid artery and sixth cranial nerve. Additionally, pituitary apoplexy can produce subarachnoid hemorrhage without aneurysm. Other signs include pyrexia, epistaxis, or cerebrospinal fluid (CSF) rhinorrhea when the mass ruptures 36 or erodes into the sphenoid sinus, and complications of blood or necrotic debris in the CSF. This topic is discussed further in Chapter 23, where its associated endocrine disturbances are also considered. Diagnosis MRI is the main diagnostic tool, being more sensitive than CT, which is usually used in the acute setting to evaluate the sudden severe headache brought on by pituitary apoplexy. Using CT, an apoplectic pituitary tumor shows up as a heterogeneous mass with areas of 33 hyperdensity that correspond to the presence of hemorrhage. CT will sometimes permit recognition of the pituitary adenoma. MRI is superior to CT33in detecting apoplectic changes and also allows the age of a hemorrhage to be estimated. MRI provides a more accurate evaluation of the pituitary fossa contents and can identify areas of hemorrhage and34infarction that might be expected to resolve without invasive surgical intervention (Fig. 26-7).
FIGURE 26-7 Pituitary apoplexy: MRI demonstrates massive enlargement of
the pituitary gland (arrows). The hetero-geneous appearance is due to a mixture of hemorrhage and necrosis. The proximity of the pituitary to the underlying optic chiasm and cavernous sinus results in the classic triad of pain, bitemporal hemianopia, and diplopia. Management
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Management depends on the state of the patient. If the patient is alert and has mild dysmotility, conservative management may be appropriate. On the basis of clinical and tomographic findings, medical treatment with corticosteroids alone, or even no treatment, 37 may be sufficient. Other endocrinological support is sometimes required. If the patient experiences visual loss or persistent cognitive dysfunction, surgical decompression by a 1 transsphenoidal route may be necessary. Studies indicate that early surgery (within 8 days of onset) promotes significantly greater34,35 improvement in visual acuity and visual field deficits Clinical assessment and MRI can help to predict than delayed surgery (after 8 days). 34 which patients should be managed conservatively or surgically.
Tolosa–Hunt Syndrome Epidemiology Tolosa–Hunt syndrome of painful ophthalmoplegia is caused by idiopathic granulomatous inflammation, with epithelioid cells and occasional giant cells, anywhere from the orbit to the 38 superior orbital fissure and cavernous sinus. Rarely, inflammation also spreads intracranially. The syndrome affects people of all ages and either sex; it has been reported in 38 nearly every continent. Ocular Symptoms and Signs The primary symptom is pain, often described as intense, severe, boring, or stabbing. The pain is periorbital and can extend to the retro-orbital, frontal, and temporal regions to become hemicranial. Untreated, it lasts for about 8 weeks. Nausea and vomiting may also occur and 38 probably result from the intense orbital pain. The pain may occur in combination with ipsilateral palsies of the third, fourth, and sixth cranial nerves at the onset of pain or following it within about 2 weeks. The pain may also be accompanied by oculosympathetic paralysis and sensory loss in the distribution of the ophthalmic division of the trigeminal nerve. In contrast to other cavernous sinus processes such as fistula and thrombosis, there is no arterialization of the conjunctival vessels, chemosis, eyelid erythema/edema, or elevation of the intraocular pressure (Fig. 26-8).
FIGURE 26-8 Tolosa–Hunt syndrome: the patient has a complete left
third-nerve palsy. The eyelid has to be held up to examine ocular motility. The patient has been asked to look right, and there is no movement of the eye. In a complete third-nerve palsy, the superior and inferior divisions of the nerve are affected. Optic nerve dysfunction has also been reported; the optic disc can appear swollen, pale, or normal. The resulting degree of visual decline ranges from minimal to blindness. Loss of acuteness varies and can be permanent. Additional cranial nerves outside of the cavernous sinus and the superior orbital fissure may also be affected including the facial nerve and the 38 maxillary and mandibular branch of the trigeminal nerve. Diagnosis
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CT and MRI techniques are used to visualize the cavernous sinus and superior orbital fissure. Contrast-enhanced MRI with multiple views is recommended as the initial diagnostic study. The MRI technique is limited, however, by its lack of specificity. For example, certain signal characteristics used to diagnose Tolosa–Hunt syndrome may also be consistent with other conditions such as meningioma, lymphoma, and sarcoidosis. In response, some authorities suggest additional MRI studies after a systemic course of corticosteroids to support the diagnosis; resolution or reduction in size of the initial imaging abnormalities is 38 supportive, but not diagnostic, of Tolosa–Hunt syndrome. Similar clinical and radiological responses to corticosteroids have been reported in painful ophthalmoplegia caused by sarcoidosis, aneurysm, actinomycosis, lymphoma, plasma cell dyscrasia, and other solid 39 tumors. Although less sensitive than MRI, high-resolution CT may identify changes in soft tissue in the region of the cavernous sinus and superior orbital fissure. Furthermore, CT can be used in addition to MRI to detect bone changes and calcification. Abnormalities in the intracavernous carotid artery38of patients with Tolosa–Hunt syndrome have also been detected using cerebral angiography. Neurosurgical biopsy is rarely used to make the diagnosis. Its use is considered in patients who have progressive neurological deficiencies, do not respond to steroid treatment, or whose neuroimaging studies continue to demonstrate abnormalities 38 associated with Tolosa–Hunt syndrome. 38
The diagnosis of Tolosa–Hunt syndrome can only be made by exclusion, as it 39 is difficult to visualize lesions in the cavernous sinus by classic neuroradiological techniques. Other causes of painful ophthalmoplegia include parasellar syndrome; craniocerebral trauma; vascular lesions, such as intracavernous carotid aneurysm, CCF, and cavernous sinus thrombosis; neoplasm; and other specific inflammatory disorders. Painful ophthalmoplegia may also occur without involvement of the cavernous sinus or the superior orbital fissure, as in various orbital diseases, diabetic ophthalmoplegia, posterior fossa aneurysm, and giant cell 38 arteritis. Specific criteria have been suggested for diagnosing Tolosa–Hunt syndrome. These include (1) steady pain in the ophthalmic division of the trigeminal nerve, (2) dysmotility and pupillary changes due to dysfunction of cranial nerve III, IV, or VI, (3) acute or subacute symptoms that are responsive to corticosteroids, and (4) inflammation limited to the cavernous sinus. Optic nerve involvement is not characteristic and suggests involvement of the orbital apex (i.e., orbital apex syndrome) that may be due to infection, inflammation, or infiltration. Spontaneous remissions and recurring episodes at intervals of months or years have been 36 reported. Management Treatment with systemic corticosteroids usually results in improvement of signs and symptoms within 48 hours. However, spontaneous remissions may occur after days or weeks 40 and recurring attacks can also occur after months or years. If recurrence occurs after taper of the corticosteroids, the diagnosis of lymphoma and sarcoidosis should be considered. In unusual cases, biopsy may be necessary. CRANIAL NEUROPATHIES INVOLVING THE EYE
Cranial Nerve II Papilledema Epidemiology
The epidemiology of papilledema reflects the etiology of increased ICP. Increased ICP may result from brain tumor at any age and in either gender. Intracranial masses that obstruct CSF outflow may be relatively small and still result in markedly increased ICP and papilledema. Pseudotumor cerebri (also known as idiopathic or benign intracranial hypertension) characteristically presents in obese women of child-bearing age. In contrast, infection can result in meningeal infiltration and meningitis at any age and in any gender. Inflammation due to sarcoidosis is more common in African Americans and Scandinavians. Predisposing factors for papilledema include a history of carcinoma or lymphoma and recent viral, bacterial, or tuberculous infection. Risk factors for increased ICP include recent weight
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gain, use of exogenous estrogen or vitamin A, and intake of certain drugs (antibiotics, corticosteroids, isotretinoin). Ocular Symptoms and Signs
Symptoms of increased ICP include headache, transient visual obscurations, intracranial 41–44 noises (humming or ringing), decreased vision, and double vision. The most common presenting ocular symptom of papilledema is transient visual obscurations that are described as graying or blacking out of vision that lasts only for seconds and can be precipitated by moving from a lying to a sitting or standing position. Many patients notice a whooshing sound in one or both ears when lying down. Less frequently, horizontal diplopia that is most prominent at a distance is the first symptom of a sixth nerve palsy associated with the increased ICP. Retro-orbital ache is sometimes present and may be worse with eye movement. Headache is a common presenting symptom; it is typically present upon awakening and associated with nausea and emesis but may be nonspecific in character. Early enlargement of the blind spot is followed by peripheral constriction of the visual fields, especially in the nasal quadrants, which can eventually progress to central visual loss in advanced cases. Early papilledema is associated funduscopically with bilateral, although frequently asymmetric, opacification of the nerve fiber layer, lack of spontaneous venous pulsation, and obliteration of the central cup. Hemorrhages and exudates may also occur. In chronic papilledema, small telangiectatic vessels and white concretions on the disc surface may be present, and afferent function may be abnormal (central visual acuity, color, pupils, and visual 41,42,44,45 With chronic papilledema, choroidal folds (Paton lines) or optic atrophy may fields) result (Fig. 26-9). Rarely, subretinal neovascularization develops due to fracture of Bruch's membrane in the retina and the growth of new vessels through this layer with subsequent leakage of blood and fluid.
FIGURE 26-9 Chronic papilledema is characterized by subtle edema: as the
optic nerve fibers die, they no longer can swell, and become pale. Paton lines are visible adjacent to the disc. Diagnosis
Bilateral disc edema is a clinical diagnosis that is not appropriately termed papilledema until increased ICP is diagnosed. The differential diagnosis of bilateral disc swelling includes malignant hypertension, central retinal vein occlusion, anterior ischemic optic neuropathy, papillitis, or optic nerve involvement by inflammation, infection, or neoplasia (Table 26-4); none of these entities disrupt spontaneous venous pulsations. Occasionally, a patient will present with headaches and atypical-appearing optic nerves. “Pseudopapilledema” may be diagnosed due to optic nerve head drusen, anomalous optic nerves, hyperopic nerves, or tilted discs.
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Click here to view this table.... If there is doubt as to whether disc edema is truly present, several diagnostic testing techniques are available. Ultrasonography (B mode) is used to detect buried drusen. Fluorescein angiography is used to identify early vessel dilatation and leakage. In uncooperative children or adults, fundus photos are invaluable to document the features of the optic nerve heads. Management
Although afferent function may be normal in the early stages of papilledema, formal visual field testing is key to management at all stages. Neuroimaging, preferably MRI, is performed to look for an intracranial mass. In patients with persistent papilledema or who are unusual or unresponsive to medication, magnetic resonance venography should be considered as a diagnostic tool to exclude venous thrombosis. When a lumbar puncture is performed, opening pressure should be documented and the CSF should be analyzed for cells, glucose, 46,47 and protein content. Management is of the underlying disorder and is considered in standard textbooks of neurology. If a tumor is present, surgical intervention is necessary. If pseudotumor cerebri is diagnosed, weight loss should be encouraged and the patient followed very closely with visual field testing. Failure to monitor visual fields can result in permanent visual loss and even blindness. If visual field defects are present, the patient should be placed on a minimum of 1 g acetazolamide. The sustained action capsules are superior to the tablets and result in less gastric disturbance. Corticosteroids are sometimes helpful. If medical therapy fails to relieve the headache or visual loss progresses, surgical options should be discussed. Optic nerve sheath fenestration is indicated if a shunt fails to normalize the visual field or there is catastrophic visual loss with mild or absent headache. Papillitis and Retrobulbar Neuritis Epidemiology
The term papillitis is used for disc edema of uncertain etiology. As such, there are no specifics to the race, gender, or age of those affected. Papillitis may be unilateral or bilateral and, in some cases such as inflammation or neoplasia, occurs recurrently. Bilateral disc edema of uncertain etiology, even if associated with a headache, should be referred to as bilateral papillitis. Ocular Symptoms and Signs
In contrast to disc edema secondary to increased ICP, papillitis is associated with acute onset of visual loss. An afferent pupillary defect, color desaturation, and central visual field defect are present. Papilledema does not typically present with decreased vision, an afferent pupillary defect, color desaturation, or significant visual field defects. The most common visual field defect in papillitis is a central scotoma; by contrast, early papilledema produces only an enlarged blind spot (which may be missed with the new automated fields). Diagnosis
Papillitis may represent an optic neuritis, which is often associated with the development of or coexistent multiple sclerosis (MS). In contrast to the symptoms and signs of papilledema, optic neuritis is typically acute in onset and is associated with retrobulbar pain that is worse with eye movement; it is not accompanied by headache. Transient visual obscurations are not typical. Optic neuritis is commonly retrobulbar (behind the globe) and the optic nerve is entirely normal in appearance. In addition, spontaneous venous pulsations are present, the veins are of normal appearance, and hemorrhages and exudates are absent. If macular edema is present and the exudates form a macular star as it recedes, the diagnosis is more likely infectious (e.g., cat-scratch disease) rather than optic neuritis associated with multiple sclerosis. If microin-farcts (cotton wool spots) are present, the diagnosis is either malignant hypertension or vasculitis such as occurs with systemic lupus erythematosus or temporal arteritis. Papillitis may be idiopathic, infectious, due to ischemia (acute ischemic optic neuropathy or AION), or due to a tumor (optic nerve or sphenoid wing meningioma, glioma, or parasellar process).
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Compressive lesions can also cause cavitation (optic nerve cupping) or shunt vessels on the surface of the disc. Temporal arteritis should be considered in all patients older than 50 years with headaches, especially when visual symptoms are present. In that disorder, transient visual obscurations may precede visual loss; vision may be poor (less than 20/400) unlike in patients with papilledema, in whom vision is typically good unless the papilledema is long-standing. Diplopia due to cranial nerve impairment may also occur. The ocular signs may include optic nerve pallor, swelling, or cavitation. A branch or central retinal artery occlusion may also occur. Occasionally, both optic nerves become swollen in rapid succession and are inappropriately designated papilledema. Management
Management depends on the cause. Oral or intravenous corticosteroids are indicated in inflammatory papillitis, but oral corticosteroids are contraindicated as the initial treatment for optic neuritis. If temporal arteritis is suspected, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complete blood count should be obtained. Elevation of the ESR and CRP along with anemia and thrombocytosis is characteristic. An oral corticosteroid dose of at least 1 mg/kg is initiated and tapered slowly over at least 6 months. Optic Atrophy Epidemiology
Optic atrophy is the nonspecific end-product of all optic neuropathies, so there is no specific age, gender, or race predilection. End-stage glaucoma is associated with optic atrophy and pallor; conversely, cavitation of the optic nerve without pallor can be the only evidence of an intracranial tumor or temporal arteritis. Ocular Symptoms and Signs
Visual loss may be acute, subacute, chronic, or unrecognized. It is not unusual to identify optic atrophy with the associated optic nerve pallor, nerve fiber loss, and visual field defects in patients with multiple sclerosis and no specific memory of an acute event. Chronic compression from Graves' ophthalmopathy, optic nerve tumors, hyperostosis of the optic canal, or other intracranial processes is characteristically slowly progressive and with an onset that is not easily identified by the patient. Diagnosis
Optic atrophy is not a diagnosis; the cause of the pallor or cavitation (cupping) must be sought. Posterior ischemic optic neuropathy is defined as an optic neuropathy without optic disc swelling that evolves into optic nerve pallor over 3 to 4 weeks. Its causes include temporal arteritis, traumatic optic neuropathy, and optic nerve dysfunction related to coma and hypotension. Retrobulbar neuritis is most commonly due to multiple sclerosis. A complete evaluation should include neuroimaging, laboratory studies for temporal arteritis if the patient is at least 50 years old, and studies to exclude such infective processes as syphilis, tuberculosis, and Lyme disease. Rarely, hereditary conditions such as Leber's optic neuropathy, nutritional neglect, and toxic etiologies are present. Management
The management depends on the cause and is discussed in standard comprehensive neuro-ophthalmic texts.
Cranial Nerves III, IV, and VI These three cranial nerves are conveniently discussed as a single group. Disturbances of ocular motility are summarized in Table 26-1 Table 26-2 Table 26-3. Epidemiology
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A combination of cranial nerve III, IV, V, and VI dysfunction may be temporary or permanent as a result of an intracranial process at the level of the superior orbital fissure, cavernous sinus, or brainstem. If the orbital apex is involved, decreased vision due to optic nerve dysfunction is characteristic. Such disorders may affect patients of any age, gender, or race. Ocular Symptoms and Signs The differential diagnosis of involvement of these cranial nerves includes disorders of the orbit, cavernous sinus, and brainstem. Several of the entities already described may cause dysfunction of motility, including orbital infiltration, infection, hemorrhage or mass; cavernous sinus fistula, thrombosis, infection, or mass; and brainstem stroke, infiltration, or compression. Localization of the disorder is based on the associated symptoms or signs. Of note, cavernous sinus fistulas and thrombosis may result in protrusion of the globe anteriorly (prop-tosis or exophthalmos) and increased resistance when an attempt is made to push on the closed eyelid (retropulsion) to feel the firmness of the globe. In contrast, inflammation (Tolosa–Hunt syndrome) or hemorrhage and necrosis (pituitary apoplexy) do not cause proptosis or increased resistance to retropulsion. Classically, processes that infiltrate the orbital apex impair multiple cranial nerves. In these cases, dysmotility due to cranial nerve dysfunction must be distinguished from gaze limitations from muscle dysfunction. Cranial neuropathies are typically associated with slow saccades and no intraocular pressure elevation with eye movement. In contrast, restricted muscles due to infiltration, inflammation, or entrapment are associated with normal saccades, but the intraocular pressure elevates in the gaze that is limited. For example, in Graves' disease, the inferior rectus is often enlarged and can limit upgaze. Intraocular pressure measured in attempted gaze is often 5 to 8 mmHg higher than it is in primary gaze. The speed (fast, normal, or slow) and accuracy (hypometric, normal, or hypermetric) of saccades are normal. The cranial nerves are affected in the region of the superior orbital fissure in the sphenoid bone. Immediately adjacent to the superior and inferior orbital fissures is the optic canal, which transmits the optic nerve, ophthalmic artery, and sympathetic fibers to the orbit. Patients with orbital apex syndromes therefore also have impairment of optic nerve function, including an afferent pupillary defect, whether unilateral or asymmetric; color vision abnormalities; visual field defects; and optic nerve abnormalities. If there is uncertainty about whether a slight afferent pupillary defect is present, testing for red desaturation is useful. The patient is presented with a red test object or item: the better eye is examined first and the patient is then asked whether the color red appears the same on the involved side. If there is optic nerve dysfunction, the patient will describe the red color as “desaturated” to a more brown or orange color. In ophthalmic notation, the patient, for example, then subjectively quantitates the desaturation as 20 percent less red. The visual field defects characteristic of optic nerve involvement include a central or centrocecal scotoma and arcuate or altitudinal defects. The optic nerve is often swollen early in the process. Optic pallor does not develop for at least 3 weeks after injury, so the optic nerve may initially be normal. Chronic compression can result in cavitation (cupping of the optic nerve). Pathological processes in the cavernous sinus are associated with other findings of venous outflow alteration. These include conjunctival injection (discussed earlier), chemosis, elevated intraocular pressure, and proptosis. Finally, other neurological symptoms and signs, as detailed in standard neurological textbooks, accompany disorders of the brainstem such as stroke or infiltration. Diagnosis MRI with gadolinium is the preferred modality to image either the cavernous sinus or brainstem. Further details were provided earlier regarding cavernous sinus fistula, thrombosis, infiltration, and inflammation. Management The reader is referred to standard textbooks of neurology for management of cavernous sinus processes and brainstem syndromes.
Cranial Nerve V
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Epidemiology Diminished corneal sensation may be caused by herpes simplex, ocular surgery, cerebellopontine angle tumors, dysautonomia, and certain congenital disorders. Changes in corneal responsiveness also occur normally with variations in physiological and environmental factors. For example, corneal sensitivity decreases with age, and brown-eyed individuals have corneas that are usually less sensitive than blue-eyed individuals. Ocular surgery and panretinal photocoagulation may denervate parts of the cornea. A permanent reduction in corneal sensitivity occurs in about 10 percent of patients who undergo radial keratotomy for myopia and about 50 percent of patients who also receive transverse incisions 1 for astigmatism. Isolated corneal hypesthesia usually results from acquired local disease of the cornea or sclera. Unilateral corneal hypesthesia can occur with various orbital diseases, Adie's tonic pupil, lower brainstem lesions, and iatrogenic lesions of the trigeminal pathway. Ocular Symptoms and Signs Presenting symptoms include conjunctival injection, tearing, and photophobia in cases of mild corneal breakdown. The surface of the cornea (epithelium) can be disrupted unintentionally by the patient during sleep or with eye rubbing. If the corneal abrasion is not identified early, it may progress to corneal ulceration and infection. In severe cases, the infection can progress posteriorly into the globe and cause endophthalmitis. In neglected cases, loss of vision and the entire globe may occur. In contrast to cavernous sinus fistulas and thrombosis, the conjunctival injection is not tortuous, chemosis is absent, and the intraocular pressure is normal. In contrast to cluster headache, it is not cyclic, but an unrelated headache may be present. Motility is normal and the pupil is not affected. Diagnosis Sensory testing of the cornea can be done without specialized equipment. A cotton tip applicator can be used to touch or brush the inferior aspect of the cornea, and the response evaluated. Corneal sensation may also be assessed by subjective and objective responses (such as involuntary blink reflex and head withdrawal) to eyedrop instillation and quantified using anesthesiometers. Management Topical drops and ointments may be helpful in preventing corneal breakdown in transient or mild cases, but more commonly punctal closure with plugs or cautery is required. Surgical closure of the eyelids (tarsorrhaphy) is sometimes necessary. In severe cases, the conjunctiva can be mobilized as a flap to cover the cornea (Gunderson flap) or the eyelids can be closed permanently. EYELID RETRACTION WITHOUT LAGOPHTHALMOS
Guillain–Barré Syndrome Epidemiology GBS is characterized by an acute onset of a rapidly progressive peripheral demyelinating polyneuropathy. An axonal variant of GBS has also been reported. GBS and its variants are discussed in detail in Chapter 60. The Miller Fisher syndrome is a variant of GBS and is defined as a combination of ophthalmoplegia, ataxia, and areflexia. In the majority of cases, the lesion responsible for the syndrome is in the cranial and peripheral nerves. Although there is usually bilateral involvement of the oculomotor, trochlear, and abducens nerves, partial and asymmetric syndromes also exist. Facial and bulbar weakness are also commonly included as part of the 48 syndrome is much less common than GBS, with a Miller Fisher syndrome. Miller Fisher 49 reported incidence of 0.1 per 100,000. A recent study suggested that cases of isolated abducens nerve palsy associated with antecedent illness, acral paresthesias, hypo- or areflexia, and CSF albuminocytological
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dissociation can be categorized as a regional variant of GBS or as a mild form of Miller Fisher 50 syndrome. Ocular Symptoms and Signs The predominant symptom of GBS is weakness ranging from mild ataxia to total paralysis of any or all muscles supplied by motor and cranial nerves. Full details are provided in Chapter 60. Other symptoms include ophthalmoplegia, absent tendon reflexes, cranial nerve palsies, 51,52 Third-nerve palsy, for instance, was reported to dysautonomia, paresthesias, and pain. 53 occur in 17 percent of GBS cases in one case series. The conjunctival vessels are normal and there is no chemosis. The intraocular pressure is unaffected. The eyelids and globe position are normal. Although uncommon, optic neuritis1 may occur. Papilledema is a rare complication. Light-near dissociation has been reported. Patients with Miller Fisher syndrome have dysmotility due to involvement of cranial nerve III, 1,48 Approximately one third of patients develop IV, or VI, ataxia, and loss of tendon reflexes. facial weakness. Other common symptoms are proprioceptive sensory problems, and areflexia develops after 1 week. The findings on examination of the eyes may mimic an internuclear ophthalmoplegia or a skew deviation. Internuclear ophthalmoplegia is characterized by limitation of adduction (medial gaze) and horizontal gaze-evoked nystagmus on abduction (lateral gaze). Skew deviation is defined as a vertical misalignment of the two eyes associated with vertical diplopia that is usually less than 5 prism diopters, may be torsional, and is not due to a cranial nerve or extraocular muscle problem. Paralysis may be confined to the eye muscles and the face, in which case full recovery is very likely with or without treatment. Extensive paralysis indicates an acute immune axonal polyneuropathy commonly associated with Campylobacter jejuni infection, with a prognosis for recovery that 1 is less favorable. Diagnosis and Management These are discussed in Chapter 60, to which the reader is referred.
Parinaud's Syndrome Epidemiology Parinaud's midbrain syndrome is a form of ophthalmoplegia involving the internal neuromuscular mechanism of the eye, with hypertonicity and paresis of pupillary constriction and accommodation. It typically results from damaged premotor pathways for binocular upward gaze in the dorsal mesencephalon. The most common causes of Parinaud's 54 syndrome are pineal gland tumors and midbrain infarction. Neoplasms, vascular occlusions, trauma, extra-axial and intra-axial arteriovenous malformations, demyelination, giant aneurysms of the posterior fossa, infections, trauma, stereotactic surgery for pain, and 36 hydrocephalus from various causes have also been associated with Parinaud's syndrome. Ocular Symptoms and Signs Ocular signs of Parinaud's syndrome include bilateral eyelid retraction without lagophthalmos and limitation of upgaze (supraduction) (Fig. 26-10). Skew deviation, head tilt, and deviation of the subjective visual vertical have been reported. Light-near dissociation is typical (i.e., the pupils constrict more when the eyes converge than in response to a light stimulus). Vertical voluntary saccades are also affected, and vertical smooth pursuit and vestibular eye movements are sometimes affected, depending on the involvement of the interstitial nucleus of Cajal. Other associated ocular signs include pseudoabducens palsy, convergence-retraction nystagmus, spasm or paresis of convergence, and spasm or paresis 40,55 With obstruction of the aqueduct, internal hydrocephalus develops of accommodation. 36 and papilledema may be found.
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FIGURE 26-10 Parinaud's syndrome: there is the characteristic bilateral eyelid
retraction. The patient has been asked to look up and is unable to do so. Diagnosis Neuroimaging (MRI with gadolinium) is essential to look for hydrocephalus, stroke, tumor, 54 infection, and other structural lesions. Management Most patients with Parinaud's syndrome improve immediately or within a few months of treatment of the hydrocephalus. Those patients who do not show improvement within this time are assumed not to have potential for subsequent progress. A patient's improvement depends on the nature and extent of the damage in addition to the duration between onset of the condition and treatment. If dysmotility persists after treatment of the56underlying cause, surgery on the eye muscles can be performed to achieve single vision. ACKNOWLEDGMENT The authors thank Anthony Liu, BS, for help with preparation of the text and illustrations for this chapter.
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 27 Paraneoplastic Syndromes Involving the Nervous System JEROME B. POSNER •
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GENERAL CONSIDERATIONS Incidence Pathogenesis Diagnosis Treatment SPECIFIC SYNDROMES Cerebellar Degeneration Clinical Findings Laboratory Evaluation Pathology Diagnosis Treatment Subacute Sensory Neuronopathy/Encephalomyelitis Subacute Sensory Neuronopathy Limbic Encephalitis Hypothalamic Dysfunction Cerebellar Degeneration Brainstem Encephalitis Myelitis Autonomic Neuropathy Anti-Hu and Other Paraneoplastic Antibodies Opsoclonus-Myoclonus Anti-Ri Syndrome Visual Loss Retinopathy Optic Neuropathy SPINAL CORD SYNDROMES Stiff-Person Syndrome PERIPHERAL NERVE SYNDROMES NEUROMUSCULAR JUNCTION SYNDROMES NEUROMYOTONIA MUSCLE SYNDROMES
The term paraneoplastic syndrome refers to disorders of an organ or tissue that are caused
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by cancer but are not a direct effect of the primary tumor mass or of a metastasis on the involved organ. Paraneoplastic syndromes can affect many organs (Table 27-1) including the nervous system. Cancer can also indirectly affect the peripheral or central nervous system (CNS) in several ways (Table 27-2), all of which can be considered paraneoplastic 2 1 with cancer (e.g., hypercalcemia, syndromes. Thus, metabolic disorders associated 3 4 5,6 inappropriate antidiuretic hormone secretion, hypoglycemia, cerebrovascular disorders associated with hypercoagulability or hypocoagulability, and opportunistic infections [e.g., 7 progressive multifocal leukoencephalopathy ]) are all paraneoplastic. However, the neurologist usually uses the term paraneoplastic syndrome to refer to a group of neurological disorders that occur with increased frequency in patients with cancer and are not caused by infection, systemic metabolic disorders, vascular disease, or side effects of cancer therapy 8 (Table 27-2). These disorders, also termed remote effects of cancer on the nervous system, encompass a much less common and a clinically and pathologically more restricted group of disorders than other nonmetastatic effects of cancer. It is these remote effects of cancer on the nervous system that are addressed in this chapter. Click here to view this table.... Click here to view this table.... GENERAL CONSIDERATIONS
Incidence Several studies have addressed the frequency of paraneoplastic syndromes. Data from these studies depend on (1) the definition of paraneoplastic syndromes, (2) the rigor used to exclude other causes of neurological dysfunction, (3) the care with which the neurological evaluation was performed, and (4) the referral pattern to specialists. For example, the Lambert–Eaton myasthenic syndrome (LEMS) occurs in 3 percent or less of patients with 9 small-cell lung cancer, but when the symptom of paraneoplastic neuromuscular dysfunction is expanded to include any subjective or objective muscle weakness, the frequency rises to 10 with any type about 50 percent. Croft and Wilkinson found that 7 percent of 1,476 patients 11 of cancer had a neuromyopathy as assessed by physical examination, but Lipton and co-workers 12 found abnormalities of peripheral nerve function by quantitative sensory testing in colleagues found myopathic changes on muscle biopsy in 33 of 44 percent, and Gomm and 13 100 patients with lung cancer. Camerlingo and associates examined and followed 51 patients with peripheral sensory neuropathy of unknown cause; 18 patients (35%) developed 14 cancer within 6 years. With some exceptions, 15 such as myasthenia gravis, which occurs in 10 to 15 percent of 9 patients with thymoma, LEMS occurring in about 3 percent of patients with lung cancer, and paraneoplastic peripheral neuropathy in 10 percent of malignant monoclonal 16 17 gammopathies and 50 percent of patients with osteosclerotic myeloma, most paraneoplastic syndromes listed in Table 27-1 are so uncommon that exact incidence figures cannot be established, but probably occur in less than 1 percent of cancer patients.
Pathogenesis Although the etiology of most neurological paraneoplastic syndromes is unknown (Table 27-3), several potential mechanisms have been proposed. Click here to view this table.... Oppenheim, in 1888, proposed that some neurological disorders associated with cancer resulted from release by the tumor of a toxic substance. That tumors can secrete substances that interfere with the function of the CNS is now well established. Examples include the secretion by tumors of parathormone or adrenocorticotropic hormone (ACTH)–like substances; the former results in hypercalcemia, the latter in Cushing's syndrome. In 1948, Denny-Brown, in describing what were probably the first cases of anti-Hu–positive subacute sensory neuronopathy (see later), noted a similarity between the dorsal root 10 ganglionitis in his patients and that seen in swine deprived of pantothenic acid. He suggested that the malignancy and the nervous system were competing for a vital nutrient. Metastatic carcinoid tumors and large retroperitoneal sarcomas appear to cause neurological symptoms by such a mechanism. However, no evidence indicates that small and occult cancers, such as those usually encountered with paraneoplastic syndromes, are capable of depriving the nervous system of any essential substrate.
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Opportunistic viral infections involving the CNS complicate the clinical course of many patients whose immune systems are suppressed by cancer or its therapy. Progressive multifocal leukoencephalopathy, originally classified as a remote effect, is one such infection. However, most paraneoplastic syndromes affect patients who are not immunosuppressed, making opportunistic infection unlikely unless these patients suffer isolated, currently unknown disorders of immunity. The absence of other opportunistic infections, such as progressive multifocal leukoencephalopathy or herpes zoster, also indicates a lack of significant immunosuppression in most patients with paraneoplastic syndromes. Although individual paraneoplastic syndromes may have different causes and a given paraneoplastic syndrome such as paraneoplastic cerebellar degeneration (PCD) may have more than one cause, an immune mechanism is now the most attractive hypothesis as the cause of most, or perhaps all, paraneoplastic syndromes. The current concept of paraneoplastic syndrome pathogenesis is that the tumor must18–21 ectopically express an antigen (Some of these so-called that normally is expressed exclusively in the nervous system. onconeural antigens are also expressed in the normal testes, an organ that, like the brain, is 22–24 ) Onconeural antigens are present in the tumors of all an immunologically privileged site. patients with antibody-positive paraneoplastic syndromes. In some tumors, such as small-cell lung cancer, onconeural antigens are present in all tumors, even in those patients who do not develop para-neoplastic antibodies or a paraneoplastic syndrome. The onconeural antigen in the tumor cell is probably recognized by the immune system when tumor cells spontaneously undergo apoptosis and the apoptotic bodies containing the antigen are phagocytized by 25–27 Current evidence suggests that the antigens in the tumor are identical in dendritic cells. structure to the neural antigen but, nevertheless, are seen by the immune system as foreign, leading to development of antibodies (paraneoplastic antibodies are discussed in detail in the sections on individual paraneoplastic syndromes) and to an immune attack on both tumor 28 immune attack may control the growth of the tumor and, in and the nervous system. The 29,30 In patients with paraneoplastic syndromes, the tumors, rare instances, obliterate it. although identical in histological type to tumors of patients without paraneoplastic syndromes, are more likely to be heavily infiltrated with inflammatory cells including T cells, B cells, and 31 plasma cells. The immune response also attacks the nervous system either where there is no blood–brain barrier (e.g., myasthenia gravis, LEMS) or where immune cells are able to cross18the blood–brain barrier and react with neurons expressing the onconeural antigens. The T cells found in the nervous system have a limited Vß chain T-cell repertoire, suggesting they are 32 either mono- or oligoclonal and respond to a specific antigen. Both B cells and T cells can be found in the CNS of patients with CNS paraneoplastic syndromes. The B cells generally reside in the perivascular spaces and the T cells in both 33,34 perivascular spaces and in the parenchyma. Paraneoplastic antibodies (anti-Hu immunoglobulin G [IgG]) have been identified in the nervous system and within neurons of some patients who died of paraneoplastic 33,34 This finding has been met with skepticism, but others have found encephalomyelitis. antibodies, particularly to double-stranded DNA, the hallmark of systemic lupus 35,36 erythematosus, that can enter cells and bind to the nucleus, including brain cells. Further evidence of an immune reaction comes from examination of the cerebrospinal fluid (CSF) of patients with paraneoplastic CNS disorders. Early in the course of the disease, there is usually a pleocytosis with a slightly elevated protein level, increased IgG, and oligoclonal 37,38 The bands. Oligoclonal bands in CSF have been identified as paraneoplastic antibodies. relative specific activity of the antibody in spinal fluid (expressed as concentration of antibody against total IgG) is substantially higher than that in the serum indicating that the antibody 39 was synthesized within the CNS rather than simply diffusing across the blood–brain barrier. Furthermore, five plasma exchanges, although effective39in substantially lowering antibody titer in the serum, have no effect on CSF antibody titer. The exact mechanism by which the immune reaction damages neural structures is not established for most paraneoplastic syndromes. The two paraneoplastic syndromes whose immune mechanism has been clearly established to meet the Drachman criteria for an 40 antibody-mediated autoimmune disease (LEMS and myasthenia gravis, see later) are primarily B-cell (i.e., antibody) mediated, but with a T-cell component. Paraneoplastic 41 stiff-person syndrome may be caused by amphiphysin antibodies and perhaps paraneoplastic autonomic neuropathy by antibodies to ganglionic acetylcholine receptor 42 paraneoplastic antibodies. However, increasing evidence, particularly concerning 27,32,43,44 In anti-Yo PCD, CDR2 syndromes of the CNS, suggests a major T-cell component. antigen–specific CD8 T cells can be found in both tumor and brain.
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Tumors express paraneoplastic antigens relatively commonly, raising the question of why more cancer patients do not develop immune responses to their tumors. Activation of the CD8 T cells in the lymph node relies on the presence of CD4 helper cells and the absence of inhibitory factors. Imbalance in these regulatory pathways might underlie the presence or absence of paraneoplastic syndrome antigen–specific CD8 T cells in individual cancer patients.
Diagnosis Paraneoplastic syndromes are encountered in patients not known to have cancer, in patients with active cancer, or in patients in remission after cancer treatment. The first is the most common situation. When they present in pure form, the classic syndromes are not easily confused with other causes of neurological disability. Frequently, however, patients present with one or more atypical features that obscure the diagnosis. In patients with known cancer, other cancer-associated processes need to be excluded before a diagnosis of paraneoplastic syndrome is made. Depending on the part of the nervous system affected, the work-up should include magnetic resonance imaging (MRI) to exclude parenchymal, epidural, and leptomeningeal metastasis; CSF examination to exclude leptomeningeal metastasis; measurement of metabolic and endocrine substances; coagulation studies; and electrophysiological testing. In patients without known cancer, if other causes of nervous system dysfunction have been excluded, a careful evaluation for systemic cancer must be performed. As is detailed later, certain syndromes are associated with particular types of cancer; recognizing these associations helps to focus the search for an underlying neoplasm on a particular organ or organs. Although the clinical presentation varies, several clinical features assist in diagnosis: 1. Most paraneoplastic syndromes develop rapidly, progress over weeks to months, and then stabilize. Syndromes that begin insidiously or are characterized by exacerbations and remissions are less likely to be paraneoplastic. 2. Most paraneoplastic syndromes result in serious neurological disability. 3. Paraneoplastic syndromes affecting the CNS are often associated with an inflammatory CSF, including a pleocytosis, elevated levels of protein, and oligoclonal bands. Leptomeningeal metastases are 45,46 excluded by contrast medium–enhanced MRI and cytological examination of the CSF. 4. Although some patients with paraneoplastic encephalomyelitis have clinical evidence of widespread nervous system dysfunction, and some patients with restricted clinical signs have pathological evidence of diffuse involvement of the neuraxis, many patients present with a clinical and pathological syndrome that predominantly affects one specific portion of the nervous system. 5. Several of the syndromes (e.g., LEMS) are so stereotypical that the correct diagnosis can be strongly suspected even before additional diagnostic testing has excluded alternative diagnoses. In recent years, the diagnosis of at least some of the paraneoplastic syndromes has been aided by the detection of characteristic autoantibodies (discussed with specific syndromes). With the exception of the antibody found in the LEMS, the etiological significance of most of these autoantibodies is unknown. However, their presence helps to confirm the clinical diagnosis of a paraneoplastic syndrome and further focuses the search for an underlying malignancy.
Treatment 47
There have been two general approaches to treatment. The most effective appears to be 48 treatment of the underlying tumor, which often prevents progression of the disease and, in some instances, leads to substantial improvement or complete amelioration of the 49 neurological symptoms. Effective treatment of the tumor should remove the inciting antigen and thus temper the immune response causing the neurological damage. Because paraneoplastic syndromes are believed to be immune mediated, the second approach to treatment is to suppress the immune response. It is important to note that 48 suppression of the immune response does not appear to worsen the outcome of the tumor. Several different forms of immunosuppression, including corticosteroids, plasma exchange, intravenous immunoglobulins, and tacrolimus have been used to treat the paraneoplastic
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43,50–52
syndromes (Table 27-4). In other paraneoplastic syndromes, especially those affecting 48 the CNS, the outcome is less clear. However, the earlier in the course of the neurological syndrome that immunosuppressive treatment or treatment of the cancer is begun, the more 53 likely the patient is to stabilize or improve. The clinical response of each paraneoplastic syndrome is discussed in the appropriate sections that follow. Click here to view this table.... SPECIFIC SYNDROMES Paraneoplastic syndromes that affect the nervous system are classified in Table 27-5. Only some of the more common syndromes are considered in this chapter. More extensive 54–58 reviews are available elsewhere. Click here to view this table....
Cerebellar Degeneration Of the paraneoplastic disorders affecting the brain, paraneoplastic cerebellar degeneration (PCD) is per haps the most easily recognized and best characterized. PCD is characterized pathologically by loss of cerebellar Purkinje cells. It is associated with several different cancers, the disorders differing somewhat in their clinical features and prognosis. Some of the disorders can be separated on the basis of characteristic anti-bodies that react with particular onconeural antigens. Clinical Findings 59
PCD was first described in 1919, but the association between it and cancer was not 60 but the most common recognized until 1938. PCD can be associated with any malignancy, 61 62 ovarian or uterine cancer, and culprits are lung cancer, particularly small-cell lung cancer, 63,64 In most patients, neurological symptoms lymphomas, particularly Hodgkin's disease. prompt medical attention before the cancer itself has been identified. The cancer is usually found within months to a year after the neurological symptoms begin, but occasionally it may elude detection for several years and, in some instances, is found only at autopsy. Typically, the disorder begins with dizziness or vertigo, nausea and vomiting followed rapidly by gait ataxia, evolving rapidly over days to a few months to include incoordination in arms, legs, and trunk; dysarthria; and often nystagmus associated with oscillopsia. Within a few months, the illness usually reaches its peak and then stabilizes. By this time, most patients cannot walk and many cannot sit unsupported, handwriting is impossible, independent eating is difficult, and speech may be difficult to understand. Oscillopsia may prevent reading or even watching television. The neurological signs are always bilateral and usually symmetric, although at times one side may be more affected than the other. In occasional patients, the asymmetry is quite prominent. Diplopia is an early symptom in many patients, although abnormalities of ocular muscles are often not detected by the examiner. Exceptions to the previous statements do occur. The onset may occasionally be abrupt (e.g., overnight) or more gradual, and the disorder itself may be relatively mild so that the patient can walk, write, and be understood, albeit with some difficulty. The signs and symptoms are frequently limited to those of cerebellar or cerebellar pathway dysfunction, but, in as many as 50 percent of patients, other neurological abnormalities, 62,63 including sensorineural hearing loss, usually mild, may be found on careful examination, dysphagia, hyperreflexia with or without extensor plantar responses, extrapyramidal signs, peripheral neuropathy, dementia, and other mental status abnormalities. One study, however, using formal cognitive testing found that dementia was not typical when testing was controlled for impaired motor and speech production, suggesting that perceived clinical changes in 65 intellectual function may be more apparent than real. Laboratory Evaluation Early in the course of this disease, the MRI is usually normal. If patients are followed for months to a few years, diffuse cerebellar atrophy appears. Occasional patients have been reported in whom hyperintensity is found in cerebral and cerebellar white matter on T2-weighted images. Rarely, transient contrast enhancement of cerebellar folia may suggest leptomeningeal tumor and associated edema may cause hydrocephalus. In most patients who are studied early, the CSF contains an increased number of lymphocytes and slightly elevated protein and IgG concentrations. Oligoclonal bands may be
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present as well. The pleocytosis usually resolves with time. Some but not all patients with PCD have autoantibodies in serum and CSF that react with most Purkinje cells of the cerebellum and the causal tumor (Table 27-6). The antibody 66 frequently associated with pure cerebellar degeneration is called anti-Yo, using the first two letters of the last name of the index patient (Table 27-6). The anti-Yo antibody recognizes a major protein antigen termed CDR2, an approximately 62-kDa protein and a minor antigen of 34 kDa that are expressed in Purkinje cells of the cerebellum. All patients with anti-Yo PCD who have ovarian or breast cancer express the Purkinje cell antigens in the tumor cells. About 60 percent of patients with ovarian cancer who do not have PCD also express CDR2 in 67 serum, their tumors. The antibody is found at higher titer in the spinal fluid than in the 39 addition to suggesting intrathecal synthesis from B cells that have crossed into the brain. In26,43 the antibody response, cytotoxic T cells against CDR2 have also been described. Click here to view this table.... A second antibody found in patients with pure PCD is the anti-Tr antibody, named after John 68 Trotter, who, with his colleagues, reported the first such patient in 1976. Anti-Tr antibodies occur in patients with PCD related to Hodgkin's disease. This disorder often begins63,69 after the diagnosis of Hodgkin's disease and sometimes when the patients are in remission. Patients are generally less severely affected than are patients with the anti-Yo or anti-Hu antibody. The prognosis for life and successful treatment of the underlying tumor is good. 70,71
; in other patients, In some patients, cerebellar symptoms outweigh other symptoms sensory neuronopathy is prominent so that it is difficult to discern whether the ataxia is due to sensory loss or cerebellar dysfunction. As with the anti-Yo antibody, symptoms are usually sudden in onset and pathological examination reveals substantial loss of Purkinje cells. More inflammatory infiltrates are found in this disorder than in the anti-Yo syndrome, but that may be because patients only survive for a shorter period of time, although one report seems to 66 suggest otherwise. The anti-Ri antibody (discussed in the section on opsoclonus) is associated with PCD, usually as part of the opsoclonus-myoclonus syndrome. Other less common antibodies include 24 anti-Ma1, an antigen restricted to brain and testis. The paraneoplastic disorder usually is associated with encephalomyelitis, particularly brainstem and hypothalamic dysfunction. The disorder is associated with a variety of tumors including those of breast and colon. Anti-CRMP5 (anti-CV2) antibodies are directed against an antigen in some glial cells and against peripheral nerve antigens. The disorder has been associated with a number of 72 neurological problems including optic neuritis. The most common tumor is thymoma, although some patients have small-cell lung and gynecological cancers. Pathology The CNS may appear grossly normal when examined at autopsy, but usually the cerebellum is atrophic, with abnormally widened sulci and small gyri. Microscopically, the hallmark of PCD is severe, often with complete loss of the Purkinje cells 73 of the cerebellar cortex (Fig. 27-1). Degenerating Purkinje cells may have swellings, called torpedoes, along the course of their axons. Other pathological features may include thinning of the molecular and granular layers of the cerebellar cortex, often without marked cell loss, and proliferation of Bergmann astrocytes. The deep cerebellar nuclei are usually well preserved, although rarefied white matter may surround the nuclei caused by the loss of Purkinje cell axons. Basket cells and tangential fibers are usually intact. Lymphocytic infiltrates, if present in the cerebellum, are usually found in the leptomeninges and in the dentate nucleus and surrounding white matter but not in the Purkinje cell layer.
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FIGURE 27-1 Paraneoplastic cerebellar degeneration (PCD). A, Section of cerebellum from a patient with autoantibody-positive PCD. The molecular and granular cell layers are relatively normal, but Purkinje cells are absent and there is a slight increase in Bergmann's astroglia. There are some inflammatory cells in the leptomeninges. B, Serum from the same patient reacted against human cerebellum by an indirect immunoperoxidase method (anti-Yo antibody). Note the staining of the cytoplasm of Purkinje cells in a granular pattern with sparing of the nucleus. There is also some peroxidase staining of Purkinje cell dendrites. Granule cells and molecular layer cells did not react but are counterstained with hematoxylin.
In many patients, the disorder is noninflammatory, with all pathological changes restricted to the Purkinje cell layer of the cerebellum. However, pathological changes outside the cerebellum do occur and differ from patient to patient. Such abnormalities may include dorsal column and pyramidal tract degeneration in the spinal cord; degeneration of the basal ganglia, specifically the pallidum; loss of peripheral nerve fibers; and inflammatory infiltrates in brainstem, spinal cord, and cerebral cortex. The tumors associated with PCD do not differ histologically from similar tumors unassociated with paraneoplastic symptoms except that the tumors are usually infiltrated with lymphocytes 31 and plasma cells. Furthermore, in many patients, the tumor, when identified, is still localized rather than widely metastatic. Diagnosis The diagnosis depends on recognizing the characteristic clinical syndrome and excluding other cancer-associated causes of late-onset cerebellar dysfunction, such as parenchymal or leptomeningeal metastases, infections, and toxicity of therapy such as cytarabine. Causes unrelated to cancer, such as viral brainstem encephalitis or cerebellitis, demyelinating
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disease, Creutzfeldt–Jakob disease, infarction, hypothyroidism, and alcoholic and hereditary cerebellar degenerations must also be excluded. A disorder clinically identical to PCD may occur without a cancer being identified. How often subacute cerebellar 74 degeneration is nonparaneoplastic is75uncertain. Henson and Urich estimate 50 percent ; others believe the figure is higher. In patients with rapidly developing cerebellar syndromes, the physician should suspect a paraneoplastic disorder, particularly if the CSF contains a lymphocytic pleocytosis. The detection of autoantibodies will identify the neurological disorder as being paraneoplastic and suggest the likely location of the tumor. The tumors may be very small and difficult to identify. If evaluation including total-body 76 fluorodeoxyglucose positron emission tomography (PET) scanning fails to identify a tumor, repeated searches may be necessary. Exploratory laparotomy with salpingo-oophorectomy has been recommended in postmenopausal women who are anti-Yo positive and whose 77 evaluation, including pelvic scans and mammograms, is negative. We have used this approach in several patients, and in all except one instance, we found a tumor in the gynecological tract, sometimes only apparent microscopically. In the one negative patient, breast cancer was identified 4 months later. Treatment Treatment of PCD is usually unsatisfactory. This may in part be due to the fact that death of Purkinje cells is the common pathological finding. Because the disease evolves rapidly, once the Purkinje cells are dead, no amount of treatment is likely to have any effect. However, several reports indicate that treatment of the tumor and immunosuppression either stabilizes 50,66,78 Therapy aimed at reducing CNS or improves PCD associated with different antibodies. 43 T cells has been tried; its efficacy has not been established. In general, however, the anti-Hu and anti-Yo antibodies rarely improve, whereas improvement has been reported in some patients with anti-Tr or anti-CRMP5 antibodies. Symptomatic improvement in the ataxia occurs in a few patients with clonazepam in daily 79 doses varying from 0.5 to 1.5 mg. Buspirone may also give modest relief.
Subacute Sensory Neuronopathy/Encephalomyelitis Henson and co-workers introduced the term encephalomyelitis with carcinoma to describe patients with cancer associated with clinical signs of damage to several areas of the nervous system and with postmortem signs of80inflammation within the brain, brainstem, spinal cord, dorsal root ganglia, and nerve roots. Most of these patients had small-cell lung cancer and most probably had the anti-Hu antibody, although clinically and pathologically similar disorders have been described with a71,81 number of other tumors. At times, the disorder is but in many patients, both clinical and pathological restricted to the dorsal root ganglion, signs of CNS damage are present either with or without evidence of a sensory neuronopathy. Signs may include dementia (limbic encephalitis), cerebellar degeneration, brainstem dysfunction, myelopathy, and autonomic neuropathy. Some patients who suffer from this syndrome, particularly when associated 71 with small-cell cancer of the lung, harbor an antibody in their serum called anti-Hu (Fig. 27-2).
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FIGURE 27-2 Paraneoplastic sensory neuronopathy. A, Dorsal root ganglion
obtained at autopsy from a patient without neurological disease. B, Dorsal root ganglion obtained from a patient with paraneoplastic sensory neuronopathy and an anti-Hu antibody. Note that there are virtually no normal dorsal root ganglion neurons in the entire section. There are a few scattered inflammatory infiltrates. C, Frozen section of a trigeminal ganglion from a patient who died without neurological disease. The ganglion is reacted to the serum of the patient whose dorsal root ganglion is shown in B and who died of paraneoplastic sensory neuronopathy and small-cell lung cancer. The reaction is an indirect immunoperoxidase method and reveals reaction product in the nuclei of trigeminal ganglion neurons with sparing of the nucleolus and cytoplasm. Subacute Sensory Neuronopathy In contrast to axonal or demyelinating sensory neuropathies, sensory neuronopathy, where the dorsal root ganglion is the site of pathology, is a rare syndrome. Sensory neuronopathy can occur in previously healthy individuals or in those with a variety of underlying autoimmune conditions, including Sjögren's syndrome. It can also be caused by heavy metal intoxication, 82 including83the chemotherapeutic agents. The disorder is paraneoplastic in only a minority of patients. At least two thirds of patients with paraneoplastic sensory neuronopathy have small-cell lung cancer as the cause. Symptoms typically begin before the cancer is identified, with dysesthetic pain and numbness in the distal extremities or occasionally in the arms, face, or trunk. The symptoms may be asymmetric at onset, but progress over days to several weeks to involve the limbs, trunk, and sometimes the face, causing a severe sensory ataxia. All sensory modalities are affected, distinguishing this disorder from cisplatin neuropathy in which pinprick and temperature sensation are spared. Deep tendon reflexes are lost, but motor function is preserved. The CSF typically contains 20 to 40 lymphocytes per cubic millimeter, particularly when the sensory changes are associated with encephalomyelitis. Sensory nerve action potentials are diminished or absent, whereas compound muscle action potentials are normal and electromyographic (EMG) evidence of denervation is absent. Pathological changes may be limited to the dorsal root ganglia with neuronal loss and lymphocytic inflammatory infiltrates (Fig. 27-2). The inflammatory process may also advance into the dorsal roots, posterior columns, and peripheral nerves. In about 50 percent of patients, clinically inapparent pathological changes are found in other regions of the nervous system. In most patients, treatment of the underlying tumor or removal of the autoantibody by plasmapheresis or immunosuppressive therapy does not alter the course of the85neurological 84 of responses to immunotherapy. Occasional disease, although there are isolated reports 86 patients have a mild and indolent neuropathy. Limbic Encephalitis
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Limbic encephalitis is a rare complication of small-cell lung or other cancers. A similar clinical syndrome can occur without88a neoplasm but is also associated with antibodies against voltage-gated potassium channels. Typically, subacute personality and mood changes are evident, with severe impairment of recent memory and occasional agitation, confusion, hallucinations, and complex partial seizures. Limbic encephalitis may occur in isolation or in association with encephalomyelitis or sensory neuronopathy. The diagnosis depends on recognizing the clinical syndrome and excluding other causes of encephalopathy. The CSF is typically inflammatory, at least early in the disease. The MRI often shows abnormalities in the medial temporal lobe or lobes, including hyperintensity on T2-weighted images, and, more 89 rarely, contrast enhancement has been reported. A glucose PET scan may show hypermetabolism in the hippocampus. The pathological changes of paraneoplastic limbic encephalitis are usually restricted to limbic and insular cortex, although other deep gray and sometimes white matter structures may be involved. Extensive loss of neurons with reactive gliosis, perivascular lymphocytic cuffing, and microglial proliferation also typify this syndrome. No treatment has been consistently beneficial, although reports relate spontaneous remissions or improvement to treatment of 90,91 the underlying tumor. Hypothalamic Dysfunction Hypothalamic dysfunction includes manifestations such as somnolence, hyperthermia, endocrine abnormalities, and hyperhidrosis. Hypothalamic dysfunction occurs in patients with 92,93 and CRMP5 (CV2)-positive thymomas. Hypothalamic Ma2 positive testicular cancer dysfunction rarely occurs in isolation; it is usually associated with limbic encephalitis or 87 brainstem encephalitis. Cerebellar Degeneration Cerebellar signs identical to those of PCD may occur as the first or only manifestation of encephalomyelitis. The only differences between isolated PCD as described earlier and cerebellar dysfunction associated with encephalomyelitis are that the patient with encephalomyelitis is more likely to have clinical evidence of wide-spread CNS and peripheral nervous system involvement, especially of sensory neuronopathy, and the pathological changes are more likely to be inflammatory. Brainstem Encephalitis Paraneoplastic brainstem encephalitis characterized by the subacute development of bulbar, midbrain, or basal ganglia signs usually occurs as part of the more diffuse syndrome of encephalomyelitis, although it sometimes presents as the dominant or isolated clinical 94,95 Any cranial nerve can be affected. The syndrome usually affects the lower finding. brainstem, causing diplopia, vertigo, oscillopsia, dysarthria, dysphagia, hypoventilation, hearing loss, facial weakness, myokymia, and facial numbness. When the upper part is involved, movement disorders including chorea, dystonia, bradykinesia, myoclonus, 96,97 and there supranuclear eye movement disorders, and typical parkinsonism may occur, may be daytime sleepiness. Myelitis Paraneoplastic non-necrotizing myelitis occurs rarely as an isolated syndrome and more commonly as a part of diffuse encephalomyelitis. Patients present with progressive weakness, sometimes with lower motor neuron signs including fasciculations, in association with sensory loss and autonomic dysfunction (e.g., incontinence and postural hypotension). In at least one instance, the disorder was episodic and primarily involved posterior column function. Early in its evolution, the disorder may clinically resemble motor neuron disease. Often, upper-extremity findings predominate owing to cervical cord involvement, and respiratory failure and death may occur. The differential diagnosis includes compressive or intrinsic spinal cord masses, other inflammatory or infectious myelopathies, and radiation injury in previously treated patients. The CSF is typically inflammatory. Neuroimaging usually shows a normal spinal cord but, occasionally, enlargement or hyperintensity of the spinal cord can be identified on T2-weighted MRI and, rarely, contrast enhancement is present. No treatment is effective. Pathologically, an intense inflammatory reaction with neuronal loss in the anterior and posterior horns is seen, with secondary nerve root degeneration and neurogenic muscle
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atrophy. Inflammation and degeneration of white matter tracts also occur. Autonomic Neuropathy Paraneoplastic98autonomic neuropathy is a rare syndrome that occurs alone or with a sensory may occur with other neuronopathy. Usually associated with small-cell lung cancer, it 99 cancers and may present before or after the cancer is diagnosed. Patients present with the subacute onset of postural hypotension, obstipation, pupillary abnormalities, or a neurogenic bladder. The syndrome is generally progressive but may stabilize or improve with treatment of the underlying tumor. When autonomic neuropathy occurs with lung cancer, it is usually part of the anti-Hu syndrome. Autonomic neuropathy also occurs with an antibody against ganglionic acetylcholine receptor (anti-nAChR). Immunization with the protein produces an 100 autonomic neuropathy and passive transfer of antibodies also causes the neuropathy indicating a B-cell–mediated disease. Anti-Hu and Other Paraneoplastic Antibodies Paraneoplastic sensory neuronopathy/encephalomyelitis may be found in association with a number of paraneoplastic autoantibodies. The same autoantibody may be associated with either a fragment of the syndrome or the entire syndrome. Paraneoplastic encephalomyelitis with the anti-Hu antibody is usually associated with small-cell lung cancer. Other antibodies include CRMP5 (often associated with thymoma), Ma-1 (associated with a variety of tumors), and Ma-2 (associated with testicular cancer). Anti-Hu encephalomyelitis is more likely to be characterized by sensory neuronopathy and anti–Ma-2 by brainstem diencephalic involvement. CRMP5 may be associated with optic neuritis. Paraneoplastic encephalomyelitis is generally poorly responsive to treatment. Ma-2-associated encephalomyelitis is more responsive than the other types, but in all of them, particularly if caught early, improvement may occur.
Opsoclonus-Myoclonus Opsoclonus, a disorder of saccadic stability, consists of involuntary, arrhythmic, multidirectional, high-amplitude conjugate saccades. Opsoclonus is often associated with diffuse or focal myoclonus and truncal titubation, with or without other cerebellar signs. It occurs primarily in children as a self-limited illness and is probably the result of a viral infection in the brainstem. This disorder also occurs as a paraneoplastic syndrome, first 101 recognized by Solomon and Chutorian in 1968. Opsoclonus-myoclonus occurs primarily in children either as a self-limited illness, probably the result of a viral infection in the brainstem, 102 or as a complication of neuroblastoma. In about 40 percent of children, it is paraneoplastic, 103,104 but the incidence of opsoclonus-myoclonus in neuroblastoma is less than 2 percent. However, given the known tendency of neuroblastoma to differentiate and resolve spontaneously, one can question whether at least some patients with opsoclonus-myoclonus without tumor are truly paraneoplastic. The age at peak incidence is 18 months, with more girls than boys affected. Neurological signs precede identification of the tumor at least 50 percent of the time, making recognition of the neurological syndrome an important clue to the presence of neuroblastoma. Ataxia, irritability, vomiting, and dementia may accompany opsoclonus-myoclonus. When a neuroblastoma is associated, there is a higher than expected incidence of intrathoracic tumors and of tumors with a benign histology. The prognosis of the neuroblastoma is better if opsoclonus-myoclonus is present than when the neurological complication is absent. Opsoclonus may respond to treatment with ACTH, plasma exchange, or intravenous immunoglobulins and may improve after chemotherapy of 105 the tumor. Rituximab has been effective in one case. 102However, many patients develop relapses and are left with significant cognitive deficits. The disorder is less common in adults than in children; in about 20 percent of adults, the 106 disorder is paraneoplastic. Lung cancer is the most common cause, but other cancers also cause the syndrome. Neurological symptoms usually precede the diagnosis of tumor and progress over several weeks, although more rapid or slower progression is observed in some instances. Opsoclonus is often associated with truncal ataxia, dysarthria, myoclonus, vertigo, and encephalopathy; some patients appear to have PCD. Ophthalmoplegia has been 107 reported. A mild CSF pleocytosis and a slightly elevated protein level are present in most patients. The results of computed tomography (CT) and MRI are usually normal; in a few patients, an abnormality in the brainstem or cerebellum is detected by MRI. 108 Immunosuppressive agents sometimes seem to be effective, although spontaneous remissions have also been described, making it difficult to interpret results. However, the
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syndrome probably responds less well to immunotherapy unless the tumor is also treated.
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Anti-Ri Syndrome A number of autoantibodies have been described in neuroblastoma-related opsoclonus, but 104,110 Affected children have a high incidence of antibodies that react with none consistently. CNS antigens, but no particular antibody is characteristic of the syndrome. Recently, an autoantibody that binds the surface of cerebellar granule cells and is cytotoxic to neuroblastoma cell lines has been identified in pediatric patients with opsoclonus-myoclonus, 111,112 Seven of the children had other with or without neuroblastoma, but not in controls. antibodies that also reacted with cerebellar structures. These included two with the anti-Hu 104 antibody. The most commonly associated antibody in adults is the anti-Ri antibody occurring in women 34,113,114 The anti-Ri with breast cancer and gynecological tumors as well as other tumors. 115 antibody identifies a protein called Nova, an RNA-binding protein that regulates messenger RNAs encoding synaptic proteins, including the glycine and GABAA receptors, inhibitory 116–118 transmitter receptors in the brainstem.
Visual Loss Paraneoplastic syndromes can cause visual loss by affecting either the retina or the optic 72,119–121 They can affect photoreceptors, either rods, cones, or both, or can cause a nerve. retinal vasculitis. A paraneoplastic visual disorder can occur either as an isolated phenomenon or as part of a more widespread encephalomyelopathy. Retinopathy Although all paraneoplastic visual disorders are rare, paraneoplastic retinal degeneration, also called cancer-associated retinopathy, is the most common. The disorder usually occurs in association with small-cell lung cancer, melanoma, and gynecological tumors. Typically, the visual symptoms, which include episodic visual obscurations, night blindness, light-induced glare, photosensitivity, and impaired color vision, precede the diagnosis of 120 cancer. The symptoms progress to painless visual loss. They may begin unilaterally but usually become bilateral. Visual testing demonstrates peripheral and ring scotomas and loss of acuity. Funduscopic examination may reveal arteriolar narrowing and abnormal mottling of the retinal pigment epithelium. The electroretinogram is abnormal. The CSF is typically normal, although elevated immunoglobulin levels have been reported. Inflammatory cells are sometimes seen in the vitreous by slit-lamp examination. Pathologically, a loss of photoreceptors and ganglion cells with inflammatory infiltrates and macrophages is usually noted. The other parts of the optic pathway are preserved, although a loss of myelin and lymphocytic infiltration of the optic nerve may occur. Several autoantibodies have been identified in patients with cancer-associated retinopathy, the most common being recoverin. Recoverin is a 23-kDa protein that modulates dark and light adaptation through calcium-dependent regulation of rhodopsin phosphorylation in 123 photoreceptor cells. The antigen is found in lung cancer cell lines. Recoverin antibodies can cross the blood–brain barrier gaining access to photoreceptor cells within the aqueous 124 Several other autoantibodies also occur in patients with paraneoplastic visual humor. 122,125,126 loss.
122
Treatment of cancer-associated retinopathy is usually unsuccessful. Various immunosuppressive treatments have been tried. These include intravenous corticosteroids, plasma exchange, and intravenous immunoglobulins as well as treatment of the underlying 120,127 128 Success using intravenous immunoglobulins has been reported. It is not malignancy. clear whether the presence of the retinopathy or of antiretinal autoantibodies affects the prognosis of the cancer. Optic Neuropathy Paraneoplastic optic neuropathy occurring in the absence of other neurological symptoms is extremely uncommon. Cross and colleagues described 16 patients with optic neuritis (five of whom also had retinitis), all 72 of whom harbored antibodies to CRMP5, a collapsin response–mediator protein. The patients had subacute visual loss. Optic discs were swollen and visual field defects were present. All the patients had a variety of other neurological symptoms including cognitive changes, ataxia, sensory neuropathy, and
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myelopathy. Three patients resembled Devic's disease at onset of symptoms. A variety of tumors were associated with the syndrome, the most common being small-cell lung cancer; 129 one patient had thyroid130 cancer. Other reports have described this disorder in association 120 with multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, and lymphoma. SPINAL CORD SYNDROMES Paraneoplastic disorders may affect the spinal cord, either in an isolated fashion or as part of a more widespread encephalomyelitis. Subacute necrotizing myelopathy is a rare syndrome 131–133 (Fig. 27-3). Antoine and that occurs with lymphoma, leukemia, or lung or other cancers colleagues reported a patient with myasthenia gravis and a thymoma who developed 134 neuromyelitis optica (Devic's disease) 4 months after treatment of the tumor. The onset of the paraneoplastic disorder may precede or follow the diagnosis of cancer. Patients typically present with rapidly ascending flaccid paraplegia; back pain or radicular pain may precede the onset of neurological dysfunction. The disease may ascend the spinal cord, leading to respiratory failure and death. Inflammatory cells are usually present in the CSF. The MRI may be normal or show spinal cord swelling or contrast medium enhancement. The absence of an epidural mass or discrete intramedullary enhancement rules out metastatic myelopathy, which is much more common. Treatment is usually unsuccessful, although one patient is 135 reported to have responded to intrathecal dexamethasone. Pathologically, there is widespread spinal cord necrosis involving all components of the cord, but with some white matter predominance. Inflammatory infiltrates are not typical.
FIGURE 27-3 Subacute necrotic myelopathy in a patient with carcinoma of the
lung. Neurological symptoms of transverse myelopathy had evolved over several days and preceded the diagnosis of the cancer. Note the widespread necrotic changes of both gray and white matter in the cord. As in most instances, vascular changes and inflammatory infiltrates are absent. 136
Motor neuron disease may occasionally occur as a paraneoplastic syndrome. Paraneoplastic motor neuron disease can include amyotrophic lateral sclerosis with both upper and lower motor neuron dysfunction, progressive muscular atrophy, a pure lower motor neuron syndrome that is sometimes reversible and associated with lymphoproliferative disorders, or primary lateral sclerosis, a pure upper motor137 neuron syndrome associated with solid tumors as well as with lymphoproliferative disorders. The clinical and pathological characteristics differ little from nonparaneoplastic motor neuron disease except for the fact that the paraneoplastic disorders are often more rapid in onset and evolution, sometimes reverse spontaneously, and, at autopsy, may be more inflammatory than in the nonparaneoplastic disorder.
Stiff-Person Syndrome Originally called the stiff man syndrome, although it affects more women than men, the 138 syndrome is characterized by muscle stiffness and rigidity that are usually painful. The muscles involved almost always include paraspinal and abdominal muscles and usually those of the lower extremities as well. In some instances, the illness is restricted to a single
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extremity. Sustained muscle contraction results in an abnormal posture such as an exaggerated lumbar lordosis. In addition to the chronic contractions, severe muscle spasms may be precipitated by voluntary movements, unexpected environmental stimuli, and emotional upset. The arms are less commonly involved, and although stiffness of the neck and face can occur, it is rarely severe. On examination, the muscles feel hard and may be difficult to move passively. An unexpected external stimulus or a voluntary movement may precipitate an observable spasm. The EMG is characterized by sustained continuous motor unit activity that disappears during sleep and general anesthesia. The nonparaneoplastic disorder is associated with diabetes and antibodies to glutamic acid decarboxylase. The paraneoplastic disorder is associated with antibodies against 139 (Amphiphysin amphiphysin, a synaptic protein that plays a role in vesicle endocytosis. 139 with the antibodies have also been detected in patients with myelopathy. ) Some patients 140,141 with or paraneoplastic disorder harbor glutamic acid decarboxylase (GAD) antibodies without antiamphiphysin antibodies. Anti-Ri antibodies were reported in one patient with 142 stiff-person syndrome and metastatic adenocarcinoma. A single patient with antibodies to gephyrin, a postsynaptic tubulin-binding protein that binds inhibitory glycine and GABAA 143 receptors, has also been reported. The common tumors include breast cancer, small-cell 144 lung cancer, Hodgkin's disease, and colon cancer. Benzodiazepines and baclofen may relieve symptoms. Treatment of the tumor and immunosuppression with corticosteroids, intravenous immunoglobulin, and other immunosuppressive agents are also effective. PERIPHERAL NERVE SYNDROMES Virtually any of the pathological abnormalities that can affect the peripheral nervous system of 58 patients without cancer can also occur as a paraneoplastic syndrome. The most common is a subacutely developing sensorimotor neuropathy with pathological evidence of axonal damage. The exact incidence of paraneoplastic peripheral neuropathy is unknown. In one series of 422 consecutive patients with peripheral neuropathy referred to a neurological 83 referral center, 26 were believed to have a paraneoplastic peripheral neuropathy. Seven patients had onconeuronal antibodies. The overall incidence of presumed paraneoplastic peripheral neuropathy was 6 to 8 percent, varying with the type of neuropathy. For pure sensory neuronopathy, the incidence was 47 percent. The incidence was 1.7 percent for Guillain–Barré syndrome, 10.5 percent for chronic inflammatory demyelinating polyneuropathy, 10 percent for mononeuritis multiplex, and 10.3 percent for axonal polyneuropathy of otherwise undetermined cause. Subacute sensorimotor neuropathy is predominantly a distal symmetric polyneuropathy, more marked in the lower extremities with weakness, glove-and-stocking sensory impairment to all modalities, and a loss of tendon reflexes. Bulbar involvement is exceptional. Patients with mild sensory or sensorimotor neuropathy that evolves slowly over many months to years are unlikely to have carcinoma as the underlying cause. Patients with subacutely developing severe peripheral neuropathy leading to substantial paralysis and sensory loss are much more likely to be suffering from a paraneoplastic syndrome. A few patients with paraneoplastic sensorimotor neuropathy follow the remitting and relapsing course typical of chronic inflammatory demyelinating polyneuropathy. These patients may respond to corticosteroid therapy. The CSF is typically acellular, with normal or slightly elevated protein concentration. Nerve conduction studies are consistent with an axonal neuropathy, with low-amplitude or absent sensory nerve action potentials and normal or decreased motor nerve conduction velocities. A few patients have marked slowing of motor conduction velocities consistent with a demyelinating process. Pathologically, there is usually axonal degeneration; in a few patients, demyelination is prominent. Spinal root demyelination and lymphocytic infiltrates of peripheral nerves have also been reported. A relatively pure paraneoplastic sensory neuropathy (not neuronopathy) occurs with a variety of malignancies but cannot be distinguished from other causes of sensory neuropathy. In one series, when no cause of the sensory neuropathy was identified, cancer was subsequently identified as a cause in 14 approximately one third of patients. Mean time to cancer diagnosis was more than 2 years. Other neuropathies that had been reported to be paraneoplastic include subacute autonomic neuropathy. In this disorder, nicotinic acetylcholine receptor 99 antibodies may be found. Autonomic neuropathy also occurs as part of the anti-Hu syndrome. Peripheral neuropathy due to microvasculitis is rare as a paraneoplastic syndrome. The disorder is found without obvious antibody involvement in patients with a variety of cancers.
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Vasculitic neuropathy can present either as a diffuse polyneuropathy or as mononeuritis multiplex. It can involve both peripheral and cranial nerves. The importance of making a diagnosis, which may require nerve biopsy, is that the condition may respond to corticosteroid treatment. Peripheral neuropathy may be associated with multiple myeloma and Waldenström's 145–147 With the rare osteosclerotic form of myeloma, peripheral macroglobulinemia. neuropathy is present in about 50 percent of patients. Successful treatment of the myeloma often leads to amelioration of the neurological symptomatology. Amyloidosis associated with myeloma can also cause a peripheral neuropathy that responds poorly to treatment. Rituximab, an anti-CD20 (B-cell145,148 marker) antibody, is effective in treating some neuropathies associated with IgM antibodies. NEUROMUSCULAR JUNCTION SYNDROMES Paraneoplastic disorders of the neuromuscular junction include LEMS and myasthenia gravis. These disorders have a common pathogenetic mechanism (i.e., they are caused by antibodies against ion channels) and, whether paraneoplastic or not, they respond to immunological treatment. Another ion channel disorder included in the following section is neuromyotonia, a disorder not confined to the neuromuscular junction. 149
but, unlike LEMS is characterized by progressive proximal weakness and fatigability, 150,151 Respiratory myasthenia gravis, cranial nerve symptoms are usually not severe. weakness may occur. Power initially increases with effort, so that reported weakness may seem out of proportion to the examiner's findings; however, with continued effort, weakness returns. Deep tendon reflexes, especially those in the legs, are diminished or absent but may reappear after exercise. Cholinergic dysautonomia occurs in more than 50 percent of patients, causing dry mouth and impotence. Characteristic abnormalities are found on electrophysiological testing, including very small compound muscle action potentials (CMAPs) that may increase to normal after brief exercise. Repetitive stimulation causes a decrement of the CMAPs at low rates of stimulation and an increment at high rates of stimulation. About 60 percent of patients with LEMS have small-cell cancer of the lung. A few have other cancers. Some of the 40 percent who do not have cancer may have evidence of other autoimmune diseases. The disorder results from a reduced release of acetylcholine at presynaptic nerve terminals. Anti-bodies that react with the PQ-type voltage-gated calcium channel are found in patients 152 with or without paraneoplastic syndromes. The same PQ-type voltage-gated calcium channels are found in small-cell lung cancers. Interestingly, the richest source of PQ-type voltage-gated calcium channels is the cerebellum, perhaps explaining the occasional relationship of PCD and LEMS. LEMS is a classic autoimmune disease in that the binding of circulating IgG antibodies to the voltage-gated calcium channels reproduces the electrophysiological abnormalities in animals; removal of IgG antibodies from humans with the disorder improves neurological function. Accordingly, LEMS can be treated either by immunosuppression or by treatment of the 153 underlying cancer when present. Patients with small-cell lung cancer associated with LEMS have a better prognosis than patients with small-cell lung cancer who do not develop a 154 paraneoplastic disorder. Myasthenia gravis usually affects ocular, bulbar, and respiratory muscles, often sparing extremity musculature. In contradistinction to LEMS, patients grow weaker with exercise and improve with rest; repetitive stimulation decreases the CMAPs on EMG. Myasthenia gravis is usually not associated with cancer, but about 15 percent of patients suffer from thymoma, and a rare patient develops the syndrome when Hodgkin's disease directly affects the thymus. The disorder is caused by antibodies against the acetylcholine receptor at the postsynaptic myoneural junction. Patients with thymoma-associated myasthenia are more likely to have antibodies against muscle proteins such as ryanodine receptors. Myasthenia gravis usually responds to immunosuppression and thymectomy. However, thymectomy is more effective for the treatment of myasthenia gravis in patients without thymomas than for those with them. NEUROMYOTONIA Several disorders characterized by hyperexcitability of terminal arborizations of peripheral nerves occur in patients with paraneoplastic syndromes.155 These include neuromyotonia, the cramp-fasciculation syndrome, and Morvan's syndrome. Neuromyotonia occurs when single motor unit potentials fire spontaneously at 150 to 300 Hz, leading to chronic contraction of muscles that can be either focal or generalized and sometimes associated with
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pain and hyperhidrosis. The disorder is autoimmune and related to antibodies against 156 the disorder is paraneoplastic, antibodies voltage-gated potassium channels. When 139 against amphiphysin may also be found. In its mildest form it is called myokymia (repetitive and recurrent firing of a motor unit potential at 2 to 60 Hz), clinically seen as undulating muscle twitching. Patients may also demonstrate pseudomyotonia (failure of155 muscles to relax after contraction), and intestinal pseudo-obstruction has also been reported. In some patients, CNS symptoms consisting of memory loss, hallucinations, insomnia, and changes in mood (Morvan's syndrome) also appear to be related to the presence of antibodies against 156 voltage-gated potassium channels. Serum creatine kinase level is elevated in about one half of patients. The diagnosis can be made electrophysiologically when needle EMG reveals spontaneous firing of single or multiple motor units at a rate of 150 to 300 Hz. These units fire at irregular intervals and may persist during sleep, general anesthesia, and even when peripheral nerves are blocked at proximal sites. Symptoms are relieved by blocking the neuromuscular junction, indicating that the action potentials arise from terminal arborizations of the motor nerve. When these disorders are paraneoplastic, thymoma is the most common cause, but they have also been 157 158 reported with small-cell lung cancer and Hodgkin's disease. The pathophysiology of the signs and symptoms of both the CNS and peripheral nervous system involvement is unknown. The fact that symptoms are relieved by plasma exchange suggests that the disorder, or at least the major part of it, is antibody mediated. This view is supported by an experimental study in which IgG voltage-gated potassium-channel antibodies added to an NB-1 cell line reduced potassium currents independent of added complement, suggesting that cross-linking of the channel by antibody (as in LEMS) may159 be an important mechanism of symptom production. F(ab')2 fragments were also effective. Some patients respond well to anticonvulsants, such as phenytoin or carbamazepine, or to muscle relaxants such as diazepam. However, the treatment of choice is immunosuppression with plasma exchange 160 or intravenous immunoglobulins; one report suggests that plasma exchange is superior. MUSCLE SYNDROMES Polymyositis and dermatomyositis and inclusion-body myositis are common inflammatory 161 autoimmune muscle diseases. Only a minority of patients suffering from these disorders have an underlying malignancy as their cause, particularly older patients. Dermatomyositis with typical cutaneous changes is more likely than polymyositis to be paraneoplastic. Females and males are affected in approximately equal numbers. Symptoms of muscle weakness generally precede identification of the cancer. The tumor may be at any site, but breast, lung, ovarian, and gastric malignancies are the most common. Hodgkin's disease and prostate and colon cancer are also reported offenders. The clinical and laboratory findings in dermatomyositis/polymyositis associated with malignancy resemble those in the idiopathic disease, although cancer patients often have more striking abnormalities on muscle biopsy specimens. Patients characteristically present with proximal muscle weakness, elevated levels of serum creatine kinase (CK), and EMG evidence suggesting a myopathic process rather than nerve disease. A muscle biopsy specimen showing inflammatory myopathy confirms the diagnosis. Although laboratory findings do not distinguish paraneoplastic from nonparaneoplastic varieties, the presence of autoantibodies, particularly common in myositis associated with lung disease, is less common in patients with the paraneoplastic disorder. No laboratory test is absolutely diagnostic. Normal serum CK levels are occasionally found even in patients with profound muscle weakness, with or without malignancy; abnormal CK levels indicate a poor prognosis for the muscle disease. Weakness of respiratory and pharyngeal muscles may contribute to death. The prognosis is not as good for the paraneoplastic disorder as it is for the nonparaneoplastic disorder. Corticosteroids, cyclosporine, and other immunosuppressants have been used successfully. Other reports suggest that high-dose intravenous immunoglobulin is useful in patients 161 unresponsive to other forms of immunosuppression. Muscle cramps are a common complication of cancer sometimes related to electrolyte imbalance or induced by chemotherapy. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 28 Neurological Complications of Chemotherapy and Radiation Therapy SEAN A. GRIMM • LISA M. DEANGELIS •
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CHEMOTHERAPY Hormonal Agents Adrenocorticosteroids Sex Hormone Agonists and Antagonists Nonhormonal Agents Methotrexate Platinums Vincristine Nitrosoureas 5-Fluorouracil and Capecitabine Cytarabine (Cytosine Arabinoside) Ifosfamide Suramin Paclitaxel and Docetaxel Bortezomib Fludarabine OTHER AGENTS Biological Agents Retinoids RADIATION THERAPY Primary Neurological Damage Brain Spinal Cord Cranial Nerves Peripheral Nerves Secondary Neurological Involvement Radiogenic Tumors Vascular Abnormalities Endocrinopathies
Chemotherapy and radiation therapy are two of the major modalities used to treat cancer (Table 28-1). Their goal is to kill or inactivate enough cancer cells so that the body's own defenses can control the disease; this goal should be accomplished without unacceptable damage to normal tissue. Unfortunately, in most instances, the goal is not fully achieved. The
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reason is that both radiation therapy and chemotherapy are relatively nonspecific and depend on their ability to do more damage to cancer cells than to normal cells. The therapeutic/toxic ratio is often low; even in highly sensitive tumors such as acute lymphoblastic leukemia, Hodgkin's disease, testicular cancer, and choriocarcinoma, for which the cure rate is high, many patients suffer serious side effects of therapy, either immediately or months to years later. Click here to view this table.... One might expect the nervous system to be relatively insensitive to the side effects of cancer therapy. The nervous system is protected from exposure to many chemotherapeutic agents by the blood–brain, blood–cerebrospinal fluid (CSF), and blood–nerve barriers. Furthermore, most neurons do not reproduce, and glia reproduce only slowly, thus affording protection against agents that are directed against dividing cells. Nevertheless, nervous system toxicity is common, second only to myelosuppression as a reason for limiting the dose of chemotherapy and often is dose-limit-ing for radiation therapy as well. The purpose of this chapter is to describe the side effects of these therapeutic modalities on the central and peripheral nervous systems. The emphasis is on chemotherapeutic agents and radiotherapeutic approaches that are widely used in clinical practice. CHEMOTHERAPY Table 28-2 classifies the major chemotherapeutic agents that have been reported to cause central nervous system (CNS) or peripheral nervous system toxicity as well as other commonly used agents that are not neurotoxic. The neurological complications caused by neurotoxic agents1–4 are detailed in the paragraphs that follow. More extensive reviews can be found elsewhere. Click here to view this table....
Hormonal Agents Adrenocorticosteroids The chemotherapeutic agents with which neurologists are most familiar are the glucocorticoids (corticosteroids). These drugs are especially effective in treating clinical symptoms caused by brain tumors and epidural spinal cord compression. Because of their lympholytic activity, corticosteroids are also used to treat tumors of the lymphoid system, including acute lymphoblastic leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma. Common effects of corticosteroids include increased appetite and an improved5,6 sense of Other less well-being, which, in patients being treated for cancer, are considered salutary. 4,7 desirable effects are legion (Table 28-3). Only a few of neurological interest are discussed here. Click here to view this table.... Myopathy
The incidence of corticosteroid myopathy is unknown. The literature suggests that it occurs only after prolonged use of high-dose corticosteroids, particularly the fluorinated compounds, 8 such as dexamethasone. Our experience has been that most patients on conventional doses (e.g., 16 mg of dexamethasone daily) for more than 2 or 3 weeks develop at least mild myopathy. The syndrome is usually characterized by weakness of proximal muscles of the 8 hip girdle with wasting of thigh muscles. Patients complain of difficulty in arising from the toilet seat or from low chairs without using their hands.9 Patients often have trouble with climbing stairs or lifting heavy objects above the head. Bilateral psoas weakness is detected on examination even in early stages. At moderate severity, weakness of neck flexors and the shoulder girdle, particularly the deltoids, can be detected by manual muscle testing. The onset of weakness is usually gradual, but, occasionally, it is acute and painful (myalgia). Distal weakness occurs rarely. In some instances, respiratory function is compromised and is 9 manifested as dyspnea on exertion. Sensation is normal, as are deep tendon reflexes. The differential diagnosis of proximal muscle weakness in a cancer patient being treated with corticosteroids includes metabolic and nutritional myopathies associated with the cancer, leptomeningeal tumor that may occasionally cause predominantly proximal weakness, and polymyositis as a remote effect of cancer. It is particularly important to exclude polymyositis because that disorder may be effectively treated with corticosteroids. Polymyositis is characterized by muscle pain; the typical electromyographic (EMG) changes of increased
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insertional activity, elevated muscle enzyme concentrations in serum, and histological findings of muscle necrosis or inflammation indicate a paraneoplastic disorder. Clinically, the distinction between polymyositis and steroid myopathy is usually clear and rarely requires such extensive testing. The treatment of corticosteroid myopathy is to discontinue the corticosteroids, if possible, after which the myopathy usually resolves over time. Corticosteroid Psychosis
Psychotic changes associated with corticosteroids were common when adrenocorticotropic hormone (ACTH) and naturally occurring glucocorticoids were widely used. With synthetic corticosteroids, the disorder is less common, and with dexamethasone, florid psychosis is 10 rare. A double-blind prospective trial of prednisone, 80 mg daily for 5 days, given to normal volunteers revealed, however, that 11 of1112 patients developed at least a mild psychiatric reaction during treatment or withdrawal. Symptoms included irritability, anxiety, insomnia, difficulty in concentrating, euphoria, and depression. More severe psychiatric reactions are of 12,13 three general types: affective, schizophrenic-like, and delirious. 14 A reversible dementia unassociated with psychotic symptoms has also been reported. Affective disorders, either mania or, less commonly, depression (depression is more common in Cushing's syndrome than with exogenous corticosteroids), cannot be distinguished from psychiatric illness not associated with corticosteroids. Affective disorders usually begin early in the course of therapy, are more likely to affect women, and are dose related. They resolve when the corticosteroids are withdrawn. Neuroleptic drugs are effective in treating these disorders, but tricyclic antidepressant agents may worsen symptoms. The affective disorder may begin during tapering of corticosteroids but almost always resolves once the corticosteroids are entirely discontinued. A persistent bipolar disorder after withdrawal of 15 steroids has been described in one patient. Three patients on alternate-day corticosteroids have been reported to cycle, with mood elevation on the “on days” and depression on the “off 16 that prophylactic use of lithium may prevent affective days.” Several reports suggest 17 predictors to corticosteroid psychosis. However, the literature does not confirm any strong 13 identify individuals at risk, including a history of corticosteroid psychosis. The second form of corticosteroid psychosis resembles acute schizophrenia. The patient may become withdrawn or paranoid and may experience auditory or visual hallucinations. The disorder cannot be distinguished from noniatrogenic psychiatric illness and responds to the withdrawal of corticosteroids or to treatment with neuroleptics. The third form is acute delirium. The patient becomes distractible and unable to attend appropriately to environmental stimuli; confusion and visual hallucinations may also occur. Mild delirium is often not reported to the physician because the patient is neither surprised nor concerned about the hallucinations, correctly attributing them to the drug. Osteoporosis/Aseptic Necrosis
Osteoporosis is a common side effect of prolonged corticosteroid use, and patients on 18 chronic glucocorticoids should be followed with bone densitometry. Maintaining adequate intake of calcium and vitamin D, physical activity, and reducing risk factors such as tobacco smoking can help prevent osteoporosis. A randomized, controlled trial has shown that daily 19 alendronate is superior to alfacalcidol in the prevention of glucocorticoid-induced bone loss. Therefore, patients at high risk should be started on a bisphosphonate. 20
Although not a neurological disorder, aseptic necrosis of the hips (occasionally shoulders, wrist, and clavicle) may be confused with spinal cord compression or peripheral neuropathy in patients with cancer. Patients have usually been on corticosteroids for a long time, although high doses are not required. There are occasional reports of patients developing aseptic 21 necrosis after only a few weeks of treatment. The disorder is characterized by pain in the hip, often radiating down the anterior aspect of the thigh to the knee and resembling, in some respects, a femoral neuropathy or a lumbar radiculopathy. The pain causes difficulty in walking. The diagnosis can be made by reproducing the pain on rotation of the hip. Early during the course of the disorder, radiographs, radionuclide bone scans, and computed tomography (CT) scanning may be normal, but all will eventually reveal the necrosis. 22 Magnetic resonance imaging (MRI) is the most sensitive diagnostic test. Lipomatosis
Corticosteroids cause redistribution of fat, and this sometimes leads to neurological symptoms and signs. Increased fat in the orbits causes proptosis, and increased fat in the
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epidural space can cause spinal cord compression. Fat can easily be distinguished from tumor on CT scan or MRI by its density. Tapering or discontinuation of steroids does not result in sufficiently rapid redistribution of fat to relieve compression causing neurological dysfunction. In a few instances, surgical decompression of the spinal cord has been necessary to relieve neurological symptoms. Visual Changes
Corticosteroids can induce cataracts and increase intraocular pressure, leading to glaucoma, 4 and occasionally may cause exophthalmos from orbital fat deposition. They are also often responsible for changes in visual acuity, leading patients to complain of visual blurring; patients may return to their ophthalmologist several times for a new prescription for glasses, particularly during the course of a prolonged corticosteroid taper. The disorder appears to be due to changes in water content of the lens, leading to a difference in refraction, depending on the dose of the corticosteroids. It usually resolves upon discontinuation of the corticosteroid. Gastrointestinal Symptoms
Gastrointestinal bleeding and bowel perforation are well-recognized complications of 24,25 The most serious complication in neurological patients receiving corticosteroid use. 26 corticosteroids is bowel perforation ; the risk is particularly high in patients treated for spinal cord compression because they often receive high doses of dexamethasone and are prone to developing constipation, a predisposing factor for corticosteroid-induced perforation. Prevention of constipation might avert this serious complication. Many patients on corticosteroids are given a proton pump inhibitor or histamine-blocking agent in the questionable belief that they decrease the incidence of corticosteroid-induced peptic ulceration. The physician should be aware that these drugs occasionally cause encephalopathy and, rarely, coma. Corticosteroid Withdrawal Syndrome
Withdrawal of patients from corticosteroids also causes neurological disability (Table 28-4). The most striking symptom of withdrawal is “pseudorheumatism,” characterized by acute 27 myalgia and arthralgia that may be so severe as to incapacitate the patient. One of our patients was admitted to the hospital with a presumptive diagnosis of spinal cord compression because of severe pain in his legs and an inability to walk. In other patients, the disorder is milder and can be ameliorated by increasing the dose of corticosteroids and tapering more slowly. If very mild, it can be managed with simple analgesics. Click here to view this table.... Another withdrawal syndrome, first described in patients who had no neurological disability, is 28 characterized by headache, lethargy, and sometimes low-grade fever. It also occurs in patients with central nervous system (CNS) disease and may lead the physician to believe that the symptoms are due to recurrent tumor rather than corticosteroid withdrawal. Withdrawal from prolonged corticosteroid treatment has been reported to cause pseudotumor 29 cerebri. Sex Hormone Agonists and Antagonists Androgens and estrogens and their antagonists are not generally associated with neurological side effects. Tamoxifen, however,30,31 has been reported to cause reversible visual All antiestrogens increase the risk of disturbances or, more rarely, encephalopathy. 32 thromboembolic disease and stroke.
Nonhormonal Agents Table 28-2 lists some nonhormonal chemotherapeutic agents. Most do not cause significant neurotoxicity. One reason is that when experimental drugs are discovered to cause major neurotoxicity, they rarely reach the market. However, several chemotherapeutic agents can produce substantial dysfunction of the central or peripheral nervous system, and a few, such as the Vinca alkaloids, methotrexate, and cisplatin, are major offenders. The specific neurotoxicity of these and other commonly used drugs is reviewed in the following paragraphs. Others are noted in Table 28-5. Specific details can be found either in the cited
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1–4
Click here to view this table.... Methotrexate Methotrexate causes both acute and delayed neurotoxicity. The acute reactions are aseptic meningitis and33transverse myelopathy, both of which are associated with intrathecal administration primarily after administration by lumbar puncture rather than via34ventricular cannula, and a stroke-like syndrome after intravenous high-dose methotrexate. Acute Toxicity
Aseptic meningitis (Table 28-6) begins 2 to 4 hours after the drug is injected and generally lasts for 12 to 72 hours. The symptoms are headache, stiff neck, nausea, vomiting, fever, and lethargy. A CSF pleocytosis is often present and can mimic acute bacterial meningitis, except that it occurs too soon after injection to be caused by bacterial growth. The syndrome is common; in some series, more than 50 percent of patients treated with intrathecal methotrexate are affected. Curiously, a patient can have a florid reaction after one injection but may suffer no reaction after subsequent injections. The symptoms are self-limited, and 35 there is no specific treatment, although some inject hydrocortisone to prevent it. Oral corticosteroids can also reduce the inflammation and have been used prophylactically or as therapy. Rarely,36pulmonary edema (possibly neurogenic) has followed an intrathecal injection 37 of methotrexate ; sudden death has also very rarely followed intraventricular instillation. Click here to view this table.... Transverse myelopathy is a rare complication. Pain in the legs is followed by rapidly developing sensory changes, paraplegia, and neurogenic bladder dysfunction. The symptoms 4,38 after intrathecal treatment but may be delayed as usually begin 30 minutes to 48 hours long as 2 weeks. The pathological changes consist of a necrotic myelopathy without striking inflammation or vascular changes. The pathogenesis is believed to be an idiosyncratic reaction to the drug. A similar complication has been reported following intrathecal cytosine 39 arabinoside or thiotepa. A posterior reversible leukoencephalopathy syndrome has been described following intrathecal methotrexate and cytarabine in a nonhypertensive patient.40MR angiography displayed reversible arterial irregularities consistent with vasospasm. A stroke-like syndrome34affecting adults or children occasionally follows systemic high-dose methotrexate infusion. The disorder usually follows the second or third treatment by 5 or 6 days and is characterized by alternating hemiparesis associated with aphasia and sometimes encephalopathy or coma. Unequivocal seizure activity is rare. The electroencephalogram (EEG) is slow. The MRI displays well-marked T2 areas, and diffusion-weighted imaging displays well-delineated hyperintense areas affecting the deep white matter and not conforming to a vascular territory. Apparent diffusion coefficient maps demonstrate decreased signal intensity, in a corresponding distribution, suggesting restricted diffusion, 41 similar to an acute vascular event. Patients generally recover spontaneously in 48 to 72 hours with complete or partial resolution of the abnormalities on diffusion-weighted images. The T2 hyperintense lesions may persist. Surprisingly, in subsequent treatments, the syndrome usually does not recur, although rare recurrences have been described. The pathogenesis of the disorder is unknown, but Phillips and associates have shown marked changes in brain glucose metabolism following intravenous infusion of high-dose 42 methotrexate in rats. Delayed Toxicity
Leukoencephalopathy is the major and most devastating delayed complication of methotrexate treatment. The disorder generally follows repeated doses of intravenous high-dose methotrexate or intrathecal methotrexate, but it may occur after standard-dose 4,43 (Fig. 28-1). Although the syndrome can be caused by intravenous injection as well methotrexate alone, it is enhanced by brain irradiation and the combination of systemic and intrathecal drug. The sequence of modalities is probably also important. When methotrexate is administered concurrently with or follows cranial radiotherapy, the synergy is particularly toxic.
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FIGURE 28-1 Treatment-induced leukoencephalopathy. Fluid-attenuated
inversion recovery (FLAIR) magnetic resonance imaging (MRI) of the brain demonstrates diffuse periventricular white matter hyperintensity following treatment with methotrexate and whole-brain radiotherapy. Leukoencephalopathy may appear months to years following therapy, beginning insidiously or 44 abruptly with personality changes and learning disability. Children cured of leukemia who have received only intrathecal or high-dose intravenous methotrexate with cranial irradiation 44 show a decreased IQ after therapy. Seizures can occur, usually late in the course. The clinical course varies. Patients may recover slowly over weeks or months, their symptoms may stabilize with a mild to moderate dementia, or there may be relentless pro gression with spastic hemiparesis or quadriparesis, severe dementia, and coma, ending in death. The myelin basic protein concentration may be elevated in the CSF, presumably owing to 45 myelin breakdown. The MRI reveals cerebral atrophy, bilateral and diffuse periventricular white matter hyperintensity (on T2-weighted or FLAIR [fluid-attenuated inversion recovery] sequences), ventricular dilatation, and, sometimes, cortical calcifications; similar 46 findings may occasionally be seen in asymptomatic patients who have received methotrexate. Focal enhancement may be present in the early stages, but does not persist. Calcifications may be better visualized on CT scans. Although scans may be normal, even in patients with diminished intellect, neurological signs are usually preceded by radiographic white matter 47 changes on MRI. These abnormal images should be a warning to the physician that the patient is at risk of clinical leukoencephalopathy. White matter changes on MRI may be seen in patients years after prophylactic treatment with intrathecal or intravenous methotrexate, even in the absence of radiation therapy. 48,49
The most common is Several different pathological abnormalities have been reported. disseminated foci of white matter degeneration characterized by demyelination, axonal swelling, and dystrophic mineralization of axonal debris. These necrotizing changes may occasionally be accompanied by fibrinoid necrosis of small blood vessels. Histologically, leukoencephalopathy from irradiation or methotrexate cannot be distinguished easily, although the presence of axonal swelling is much more characteristic of methotrexate-induced leukoencephalopathy. An unusual toxicity, virtually restricted to children, is mineralizing microangiopathy characterized by noninflammatory fibrosis and calcification of arterial capillaries and venules, particularly in the basal ganglia. This is
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typically identified radiographically, where extensive calcifications are seen in the basal ganglia. It does not necessarily produce neurological dysfunction. The pathophysiology of methotrexate neurotoxicity is poorly understood. Depletion of reduced folates in the brain, inhibition of cerebral protein or glucose metabolism, injury to cerebral vascular endothelium resulting in increased blood–brain barrier permeability, and inhibition of catecholamine neurotransmitter synthesis have all been implicated but not proved to be involved. No effective treatment exists. Administration of intravenous or intrathecal leucovorin, an antidote to methotrexate-induced gastrointestinal or bone marrow toxicity, does not reverse or prevent neurological damage from the drug. Platinums The platinums (cisplatin, oxaliplatin, carboplatin) are drugs with a heavy-metal moiety. Thus, 50 it is not surprising that they, like other heavy metals, cause a peripheral neuropathy (Table 28-7). Click here to view this table.... Cisplatin
The peripheral neuropathy associated with cisplatin is dose dependent and usually follows 2 cumulative doses of greater than 40050mg/m . It is characterized by numbness and tingling in the extremities, occasionally painful. The first symptoms may not appear until cisplatin treatment is completed and then may progress for several months before the neuropathy stabilizes. The disorder affects predominantly the large sensory fibers; the deep tendon reflexes disappear and proprioception is lost, often resulting in ataxia. Pin and temperature sensation are spared, however, and power may be entirely normal. The disorder may be confused with paraneoplastic sensory neuronopathy but differs from that disorder in that paraneoplastic sensory neuronopathy usually affects all sensory modalities equally. Nerve conduction studies reveal decreased amplitude of sensory nerve action potentials and prolonged sensory latencies, compatible with a sensory axonopathy. With discontinuation of the drug, the neuropathy may improve and the patient's condition may even return to normal after many months; however, many patients are left with permanent disability. Because maximal injury is not observed until months after discontinuation of the drug, dose adjustment is not possible to accommodate ongoing neural damage. There is no known treatment. Pretreatment with amifostine, an organic thiophosphate, can reduce the incidence and 51,52 Focal neuropathies may follow arterial infusions in the severity of platinum neurotoxicity. extremities or neck. 53
Pathological examination of nerve roots reveals axonal loss with secondary demyelination. Axonal loss is also found in posterior but not anterior roots, with secondary degeneration of posterior columns. Dorsal root ganglion cells are probably the primary site of pathology, and the predominant pathological abnormality is in the nucleus. A correlation exists between the degree of histological change and the levels of platinum found in dorsal roots and peripheral nerves. 54
Lhermitte's sign appearing during or shortly after treatment with cisplatin suggests a transient demyelinating lesion in the posterior columns of the spinal cord. In some instances, patients may experience paresthesias down the arms when the upper limbs are abducted, suggesting that the brachial plexus may be demyelinated as well. Lhermitte's sign resolves completely and is not associated with any permanent damage. Muscle cramps not related to electrolyte imbalance (see later) are also common but, like 55 Lhermitte's sign, they usually resolve spontaneously. 56
Ototoxicity and vestibulopathy are also caused by cisplatin. Hearing loss results from hair 57 cell damage. The hearing loss is often subclinical and affects primarily the high-frequency range; that is, frequencies greater than 4,000 Hz. Tinnitus may precede hearing loss; rarely, high-dose cisplatin causes58acute deafness. Animal studies suggest that prophylactic vitamin E may reduce this toxicity. Vestibular toxicity is much less common than hearing loss. It is characterized by vertigo, oscillopsia, and ataxia. It may occur either with or without other symptoms of ototoxicity and may be exacerbated by previous use of aminoglycoside antibiotics. Ocular toxicity, which includes retinopathy (usually after intracarotid infusion),
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and retrobulbar neuritis, is rare. Color perception may be disturbed, probably as the result of retinal cone dysfunction. Cortical visual loss (homonymous hemianopia, cortical blindness) may be part of the encephalopathy sometimes caused by cisplatin. 60
Encephalopathy is rare following intravenous infusion but is more common following intra-arterial infusion. It is characterized by seizures and focal brain dysfunction, particularly cortical blindness, but the symptoms are usually reversible. Encephalopathy due to the drug must be differentiated from the electrolyte disorders that result from its administration. Vigorous hydration precedes cisplatin use and can lead to water intoxication and cerebral 61 herniation. A nephropathy is common following cisplatin, resulting in hypocalcemia and hypomagnesemia, which may rarely cause tetany, encephalopathy, or seizures. Hypozincemia has been reported. Inappropriate antidiuretic hormone secretion (SIADH) with hyponatremia and seizures may also occur. Cisplatin has been implicated in late vascular toxicity, such as Raynaud's phenomenon, cardiac infarction, and cerebral infarction that sometimes follows multiagent chemotherapy. Vascular toxicity can also be subacute and occur within days to weeks of cisplatin administration. Some believe that the toxicity is caused by the cisplatin and is probably related to hypomagnesemia; others believe that bleomycin is the major culprit. However, it has been observed in patients who have received cisplatin as a single agent. Other rare complications of cisplatin include irreversible myelopathy, taste disturbances, and a myasthenic syndrome. Oxaliplatin 62
Oxaliplatin produces two types of peripheral neuropathy. The first occurs during or shortly after infusion and consists of paresthesias and dysesthesias of the hands, feet, and perioral region with jaw tightness. These symptoms are usually transient, may be triggered by cold, and may increase in both duration and severity with repeated drug administration. A pharyngolaryngeal dysesthesia syndrome accompanied by a sensation of shortness of breath without any objective evidence of respiratory distress has been described. Oxaliplatin can also induce a distal peripheral sensory neuropathy similar to that seen with cisplatin. This 2 neurotoxicity generally follows a cumulative dose greater than 540 mg/m and is characterized by sensory ataxia, jaw pain, eye pain, ptosis, leg cramps, visual changes, and voice changes. Although reversible, these clinical findings may persist for several months and require discontinuation of treatment. Less common neurological complications include 63 Lhermitte's phenomenon and urinary retention. Carboplatin
Carboplatin is less neurotoxic than cisplatin or oxaliplatin. Rare cases of peripheral neuropathy have been reported after high doses of carboplatin in patients treated with 64 combinations of other cytotoxic agents. Vincristine Vincristine affects primarily the peripheral nerves but can also be toxic to the CNS, cranial nerves, and autonomic nervous system (Table 28-8). Vinorelbine and vinblastine are much 2 less neurotoxic. A dose-limiting sensorimotor neuropathy appears in virtually all patients. The earliest complaint is tingling and paresthesias of the fingertips and later of the toes. Fine 65 movements of the fingers and toes are often impaired. Loss of the Achilles reflexes is the earliest sign. With continued drug administration, other reflexes disappear as well. Muscle 66 cramps, usually diurnal, affect arms and legs and may be the first symptom of neurotoxicity. They are particularly common in the jaw and tend to occur within 1 day to 2 weeks of drug administration. Objective sensory loss is uncommon, but weakness, especially of the extensors of the feet and hands, is frequent. Foot drop is either unilateral or bilateral. Unilateral foot drop is especially common in patients who have lost weight and habitually sit with crossed legs, thereby causing compression of the peroneal nerve at the head of the fibula. The weakness is usually tolerable, but rarely patients may become bedbound or quadriparetic, particularly if there is a preexisting neuropathy. The sensory symptoms, weakness, and lost reflexes are reversible, although they may require several months after the medication is stopped to improve. Agents used to relieve vincristine neurotoxicity, including gangliosides and glutamic acid, are not very effective. Click here to view this table.... 4
Vincristine occasionally causes focal neuropathies of peripheral or cranial nerves. The most
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common is mild oculomotor nerve involvement with ptosis. Less frequent is ophthalmoplegia with diplopia. The recurrent laryngeal nerve, facial nerve, acoustic nerve, and optic nerve are also affected occasionally. These various neuropathies may be bilateral or unilateral. Night blindness due to retinal damage has also been reported. Autonomic neuropathy, characterized by colicky abdominal pain and constipation, occurs in as many as one third of patients. Rarely, paralytic ileus develops in children and may be fatal. 67 Amelioration of vincristine-induced ileus with metoclopramide has been reported, but prevention of constipation is essential; all patients receiving vincristine should receive a prophylactic bowel regimen of stool softeners and laxatives. Other manifestations of autonomic dysfunction that have been reported include bladder atony, impotence, and postural hypotension. 68
69
CNS toxicity may result from hyponatremia due to SIADH. Encephalopathy and focal or generalized seizures not associated with SIADH have also been reported. Cortical blindness and other focal cerebral signs, including athetosis, ataxia, and parkinsonian-like symptoms, usually reverse after treatment is discontinued. The diagnosis of vincristine neurotoxicity is usually not difficult even when, as is common, the weakness develops a few weeks following therapy and progresses for several additional weeks. Neurophysiological studies are usually unnecessary but, when done, show the typical 4 features of an axonal neuropathy. These findings have been confirmed by nerve biopsy. Nitrosoureas The nitrosoureas rarely cause neurological toxicity when given in conventional doses. However, in patients with brain tumors who have received radiation and are treated with intracarotid or high-dose intravenous carmustine (BCNU), both ocular toxicity and 70 encephalopathy have been reported. After intracarotid treatment, the disorder is sometimes heralded by seizures and followed by slowly progressive neurological dysfunction, the exact signs depending on the region infused. White matter abnormalities are often apparent on CT scan or MRI, sometimes at a site distant from the tumor; with time, the area of white matter signal abnormality may develop calcification. The pathology is that of a necrotizing encephalopathy, giving an appearance similar to that of radiation damage, but strictly confined to the vascular territories perfused by the drug. 5-Fluorouracil and Capecitabine Neurotoxicity is rarely seen with conventional doses of the drug except in patients with a 71 deficiency of the enzyme dihydropyrimidine dehydrogenase. In these patients or others given high doses, a cerebellar syndrome, clinically indistinguishable from paraneoplastic or cytarabine-induced cerebellar disorders, occurs, consisting of truncal and limb ataxia, 71 dysmetria, nystagmus, and slurred speech. The mechanism of this disorder or other neurotoxicity is unknown. The signs usually reverse within a week after the drug is discontinued but may recur with its reintroduction. In animals, the agent damages Purkinje cells, granule cells, and neurons of the inferior olive and vestibular nuclei. Extraocular muscle abnormalities (particularly vergence disturbances), optic neuropathy, and extrapyramidal syndromes have been reported rarely with the administration of 5-fluorouracil. Encephalopathy, with diffuse slowing of the EEG but without cerebellar symptoms, has also been reported. Ocular toxicity includes blepharitis, conjunctivitis, lacrimal duct stenosis, and excessive lacrimation. Cerebral infarcts have been reported to complicate continuous infusion of the drug. Palmar-plantar erythrodysesthesia, a rare complication, may be confused with a peripheral neuropathy because of painful hands and feet. Acute cerebellar ataxia, somnolence, and upper motor neuron signs have been reported following intracarotid arterial infusions. When levamisole is combined with 5-fluorouracil, a few patients developed an inflammatory 72 multifocal leukoencephalopathy. The disorder usually presents with confusion and focal signs, including ataxia or hemiparesis associated with multiple contrast-enhancing lesions on MRI that may be confused with metastases. Capecitabine is an oral prodrug that is converted to 5-fluorouracil. A reversible leukoencephalopathy characterized by nausea, confusion, short-term memory loss, headaches, vertigo, ataxia,73dysarthria, and body shaking or stiffening has been described following treatment with it. Associated MRI abnormalities included nonenhancing diffusion-weighted and T2 hyperintense lesions in the corpus callosum, brachium pontis, and deep periventricular white matter. The symptoms and neuroimaging findings usually resolve
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with discontinuation of the drug. Cytarabine (Cytosine Arabinoside) Aseptic meningitis and rarely myelopathy, both clinically similar to those induced by 74 methotrexate, sometimes follow intrathecal cytosine arabinoside (ara-C). Meningeal irritation causing headache, stiff neck, and pleocytosis has been encountered in approximately 30 percent of patients given the drug, but no direct relationship between this syndrome and the individual or cumulative dose has been established. Aseptic meningitis occurs in virtually all patients who receive intrathecal liposomal ara-C, and oral corticosteroids are recommended for a few days before and after each dose to reduce the inflammation. The myelopathy begins with back pain or radicular leg pain. Weakness, sensory alterations, and bowel or bladder dysfunction occur at any time from a few days to months following treatment. The clinical picture usually evolves rapidly; some patients may recover incompletely, but others may be rendered paraplegic. Examination of the CSF usually reveals an elevated protein concentration and a modest pleocytosis; an elevated myelin basic protein has also been reported. Pathologically, portions of the spinal cord reveal demyelination with associated white matter vacuolization, histologically indistinguishable from methotrexate-induced myelopathy. One patient developed a “locked-in syndrome” (preserved consciousness but inability to move or communicate except by eye movement) 48 hours after a single dose of 100 mg of intrathecal ara-C in conjunction with intravenous ara-C, cisplatin, and doxorubicin. At autopsy, there was extensive brainstem necrosis. Rarely, intrathecal administration of75ara-C has been associated with seizures or an acute or subacute encephalopathy. 2
Intravenous high-dose 76 ara-C (3 g/m per 12 hours for 8 to 12 doses) may cause several neurological disorders. Cerebellar dysfunction occurs most frequently in older patients and 2 in those with preexisting renal dysfunction, usually at a cumulative dose of at least 36 g/m . 2 However, it has been reported after a single dose of 3 g/m . Patients develop dysarthria, nystagmus, and appendicular and gait ataxia. Confusion, lethargy, and somnolence may also be seen. With cessation of the drug, complete resolution of signs and symptoms generally occurs within 2 weeks. Neuropathological changes in patients who succumb to their underlying illness include widespread Purkinje cell loss, most pronounced in the deeper portion of the primary and secondary cerebellar sulci. The rest of the CNS appears largely to be unaffected, although white matter demyelination and filamentous degeneration of neurons in brainstem and spinal cord have been reported. 77
Peripheral neuropathy, axonal or demyelinating or both, is a rare complication of ara-C; in most patients, high-dose ara-C was given along with other potentially neurotoxic agents, including fludarabine. Other reported toxicities include seizures; reversible ocular toxicity, including blurred vision, photophobia, burning eye pain, and blindness; bulbar and pseudobulbar palsy; Horner's syndrome; the “painful legs, moving toes” syndrome; brachial plexopathy; reversible bilateral lateral rectus palsies; and acute aseptic meningitis (after intravenous injection). One patient who received a cumulative dose of 72 g developed a parkinsonian syndrome that resolved within 12 weeks. The mechanism of ara-C toxicity is unknown. Some investigators believe that ara-C kills 78 neurons by interfering with cytidine-dependent neurotrophic signal transduction. There is no treatment for any of the neurotoxic effects of ara-C but, as indicated earlier, many patients recover spontaneously. Ifosfamide High-dose ifosfamide has been associated with 79 a reversible encephalopathy of varying severity, which is a dose-limiting adverse effect. The most common manifestations include confusion, stupor, and mutism, rarely evolving into coma. Other less common features include seizures, hallucinations, personality changes, blurred vision, extrapyramidal symptoms, cerebellar symptoms, and urinary incontinence. EEG abnormalities are found in 80 65 percent of patients, and cases of nonconvulsive status epilepticus have been reported. Although death can occur, the encephalopathy is usually reversible and can be treated with methylene blue. Seizures can be treated with anticonvulsants. Suramin Suramin causes a peripheral neuropathy in 40 percent of patients whose blood levels exceed 350 μg/L. This condition presents like the Guillain–Barré syndrome, with rapid onset81,82 of a predominantly motor neuropathy leading to weakness or paralysis of the extremities and
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sometimes of bulbar and respiratory muscles. Paresthesias in the face and limbs are common before the weakness. The weakness often begins proximally. The disorder probably results from demyelination causing conduction block in peripheral nerves. It reverses after the drug is discontinued and can be prevented by monitoring blood levels carefully. Paclitaxel and Docetaxel 2
Approximately 60 percent of patients receiving paclitaxel (Taxol) at 250 mg/m or less per dose develop paresthesias of the hands and 83 feet that, in most patients, do not progress and may even resolve despite continued therapy. The neuropathy is predominantly sensory and, unlike cisplatin neuropathy, affects all sensory modalities. Examination reveals loss of pain and temperature sensation as well as vibration and position sense. Paclitaxel causes axonal damage, with secondary demyelination, probably reflecting damage to the cell body. A few patients also develop proximal muscle weakness that resolves; it is usually associated with 84 peripheral neuropathy. Acute arthralgia and myalgia of the legs that curtail activity (and are sometimes mistaken for peripheral neuropathy) may occur 2 to 3 days after a course of paclitaxel and can last for 2 to 4 days. Docetaxel causes the same type of sensory neuropathy as paclitaxel but is less neurotoxic. Paclitaxel or docetaxel neuropathy is enhanced by preexisting or subsequent neurotoxic chemotherapy, particularly cisplatin or even vinorelbine. Bortezomib Bortezomib is a novel chemotherapeutic agent that acts as a proteosome inhibitor. It is primarily effective against multiple myeloma. Bortezomib causes a cumulative 85 dose-dependent peripheral neuropathy that is predominantly sensory. Symptoms usually improve, even without stopping treatment, but some patients are left with fixed deficits. Fludarabine Fludarabine (2-fluoroadenosine arabinoside) is an antimetabolite with activity against a variety of lymphoproliferative neoplasms. It is highly immunosuppressive and has been associated with the development of progressive multifocal leukoencephalopathy in some 86 cause delayed neurotoxicity leading to encephalopathy patients. In addition, fludarabine can 87,88 Older patients and those receiving higher doses of and occasionally cortical blindness. the drug are at greater risk. OTHER AGENTS
Biological Agents Several biological approaches may be used either to manipulate the immune system to destroy neoplastic cells (e.g., antibodies, cytokines, vaccines, and lymphocytes), to combat the myelotoxic effects of chemotherapy (e.g., colony-stimulating factors and bone marrow 89 A few of these agents cause transplantation), or to inhibit angiogenesis in growing tumors. 90,91 (Table 28-9). notable nervous system toxicity Click here to view this table.... Bevacizumab is a monoclonal antibody that binds to and inhibits soluble vascular endothelial 89 growth factor (VEGF), a mediator of tumor angiogenesis. An increased incidence of systemic hemorrhages has occurred in patients with colorectal or lung cancer treated with bevacizumab. The risk of CNS hemorrhage in patients with brain metastasis has not been 92 fully assessed because they were excluded from clinical trials. Bevacizumab's most common side effect is hypertension, which may have contributed to a posterior reversible 93 encephalopathy syndrome in several patients. 94
Interleukin-2 causes capillaries, including those in the brain, to leak, leading to increases in 95 brain water content on MRI and to a severe96encephalopathy. Interferons can also cause encephalopathy, which can be irreversible. Nightmares, headache, myalgias, bilateral 97 brachial plexopathy, and oculomotor palsies are also side effects of interferons.
Retinoids The retinoids are a group of compounds consisting of vitamin A and related derivatives. They have been found to exhibit antitumor effects in patients with acute promyelocytic leukemia as
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98
well as other malignancies. Although there is no formal epidemiological evidence from either treatment cohort studies or large population studies, several case reports suggest an 99 increased risk of suicide and depression in patients treated with 13-cis retinoic acid. RADIATION THERAPY Therapeutic ionizing irradiation may affect the nervous system in one of two settings: First, damage to neural structures may occur when structures are included in the radiation portal. This damage can occur whether the cancer undergoing radiation therapy is within or outside the nervous system. Second, nervous system dysfunction can also occur secondarily when therapeutic irradiation damages blood vessels supplying the brain or endocrine organs necessary for appropriate nervous system function (usually the thyroid gland) or when the irradiation causes tumors that compress or destroy nervous system structures. Nervous system dysfunction caused by radiation therapy can occur acutely or may be delayed by weeks, months, or even years following the successful completion of treatment. The likelihood that radiation therapy will damage the nervous system depends on many factors, including the total dose delivered to the nervous system, the dose delivered with each treatment or the dose per fraction, the total volume of nervous system irradiated, the time after completion of radiation therapy, the presence of other systemic diseases that enhance the side effects of irradiation (e.g., diabetes, hypertension), and other unidentifiable host factors. The side effects 4,100 of radiation therapy are detailed here, and more extensive reviews can be found elsewhere.
Primary Neurological Damage Brain Encephalopathy caused by radiation therapy occurs in three forms: acute, early delayed (2 weeks to 4 months), and late delayed (4 months to 24 years) (Table 28-10). Click here to view this table.... Acute Encephalopathy
Acute encephalopathy usually follows large radiation therapy fractions given to patients with increased intracranial pressure from4 primary or metastatic brain tumor, particularly in the absence of corticosteroid coverage. Immediately following treatment, susceptible patients develop headache, nausea, vomiting, somnolence, fever, and worsening of neurological symptoms, rarely severe enough to culminate in cerebral herniation and death. Acute encephalopathy usually follows the first radiation fraction and becomes progressively less severe with each ensuing fraction. Usually, the disorder is mild, with the patient developing headache and nausea in the evening following irradiation. The pathogenesis of the disorder is not certain. Some observers believe it is secondary to a rise in intracranial pressure, with cerebral edema following breakdown of the blood–brain barrier by ionizing irradiation. Experimental evidence indicates that a single dose of 300 cGy delivered experimentally to an animal causes substantial breakdown of the blood–brain barrier, which is still evident 2 hours after radiation; after 24 hours, the barrier has reconstituted itself. Corticosteroids substantially prevent this breakdown of the blood–brain 101 barrier. A few observers4 have noted an increase in intracranial pressure following a single such an increase either in dose of radiation therapy, but others have failed to document 102 humans or in animals even if clinical symptoms develop. For the clinician, there are two implications. First, patients harboring large brain tumors, particularly with signs of increased intracranial pressure, should probably not be treated with large doses per fraction. Doses of 200 cGy per fraction or less appear to be acceptable in such patients. Second, all patients undergoing brain irradiation should be protected with corticosteroids (8 to 16 mg of dexamethasone daily or more if increased intracranial pressure is symptomatic), preferably for at least 24 hours before the start of radiation therapy. Both clinical and experimental evidence indicates that corticosteroids ameliorate the acute complications of irradiation. Early Delayed Encephalopathy
Early delayed encephalopathy usually begins in the second or third month after irradiation but can begin anywhere from 2 weeks to 4 months after treatment. If the patient has a brain 4 tumor, the symptoms of early delayed encephalopathy often simulate tumor progression. For
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example, the patient may develop recurrence of headache, lethargy, and worsening of lateralizing signs. Changes on CT scan or MRI may include an increase in the size of the lesion and sometimes the occurrence of contrast enhancement not present previously. These changes resolve spontaneously if the disorder is due to radiation encephalopathy rather than tumor recurrence, and the resolution can be hastened by the use of corticosteroids. The patient and the scan remain improved after corticosteroids are discontinued, indicating that the disorder was early delayed encephalopathy rather than tumor recurrence. Early delayed encephalopathy also occurs in patients without brain tumors. Early delayed encephalopathy after prophylactic irradiation 103 of the brain of children with leukemia has been called the “radiation somnolence syndrome.” This disorder is characterized by somnolence often associated with headache, nausea, vomiting, and, sometimes, fever. The EEG may be slow, but there are no focal neurological signs. The syndrome is ameliorated by corticosteroids but will also resolve spontaneously. The disorder is sometimes seen in adults following prophylactic radiation therapy for small-cell lung cancer or total body irradiation in preparation for bone marrow transplantation. A rare and serious neurological syndrome is brainstem encephalopathy following irradiation of posterior fossa tumors or when the brainstem has been included in the irradiated field for 104 head and neck cancer. The most frequent symptoms are ataxia, diplopia, dysarthria, and nystagmus. Most patients recover spontaneously within 6 to 8 weeks. Rarely, the symptoms progress to stupor, coma, and death. The pathogenesis of early delayed encephalopathy is believed to be demyelination, resulting from damage to oligodendroglia and subsequent breakdown of myelin sheaths. The best evidence supporting that hypothesis consists of pathological studies in patients with early delayed brainstem encephalopathy in which confluent areas of104 demyelination with varying degrees of axonal loss are found in areas that were irradiated. There is an associated loss of oligodendrocytes and abnormal and often multinucleated giant astrocytes. Furthermore, the latency in the onset and timing of resolution correspond to the cycle of myelin turnover. Late Delayed Radiation Necrosis
Late delayed radiation necrosis usually begins a year or two after the completion of radiation therapy. The symptoms depend on the nature of the primary disease. In patients who are treated for primary or metastatic brain tumors, symptoms generally recapitulate those of the brain tumor, leading the physician to suspect tumor recurrence. In addition, the MRI or CT scan mimics recurrence, with105,106 the appearance of a contrast-enhancing lesion that is (Fig. 28-2). Occasionally, a lesion suggesting a tumor indistinguishable from tumor appears at a distant site. Fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) can help distinguish radiation necrosis from 107–109 recurrent tumor. 110 Methionine PET, using an amino acid ligand, may prove superior in this differentiation.
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FIGURE 28-2 Radiation necrosis. T1-weighted, post-contrast MRI 9 months
after stereotactic radiosurgery for a left parietal, dural-based metastasis. The lesion was hypointense on pre-contrast T1-weighted sequences. A second clinical picture has occurred when the patient's brain was included in the radiation portal, but there was no underlying brain tumor. Examples include irradiation of head and 4,107 Because neck tumors, including pituitary tumors, and prophylactic irradiation of the brain. only a portion of the brain has usually been irradiated and there was no previous brain damage, new focal neurological signs are the rule. For example, bilateral medial temporal destruction sometimes follows irradiation for nasopharyngeal or pituitary tumors, and frontal or temporal lobe destruction follows treatment for ocular or maxillary sinus tumors. The clinical features are similar to those of a brain tumor, with signs of increased intracranial pressure and focal signs, depending on the site of brain damage. The MRI usually reveals a mass, occasionally with contrast enhancement. An arteriogram may show vascular beading 4 that suggests a vasculopathy. A definitive diagnosis can only be made pathologically. Histologically, the typical lesion is an area of co-agulative necrosis in the white matter, with relative sparing of the overlying cortex. Microscopically, the most striking abnormalities are found in blood vessels, with hyalinized thickening and fibrinoid necrosis of the walls, often associated with vascular thrombosis, vascular hemorrhages, and accumulation of perivascular fibrinoid material. 107
Radiation necrosis is often treated best with resection. Most patients respond only transiently to corticosteroids, although there111 are occasional reports of prolonged responses after corticosteroid therapy without surgery. Other suggested treatments, such as vitamin E, pentoxifylline, hyperbaric oxygen and anticoagulation, are based on the rationale that the disorder is primarily vascular, but they have not proved useful in all patients. There are three hypotheses concerning the pathogenesis of this disorder. The first is that the vascular changes lead to infarction and necrosis. The second is that radiation therapy directly damages glial cells, both astrocytes and oligodendrocytes, leading to destruction of tissue. The third is that the radiation causes release of brain antigens with subsequent antibody formation and immune destruction of the brain. None of these potential mechanisms are mutually exclusive and all may contribute to the damage. Cerebral Atrophy
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Cerebral atrophy often follows whole-brain irradiation. The atrophy may occur in patients irradiated prophylactically or in those harboring a brain tumor that was eradicated by radiotherapy. It usually begins 6 to 12 months after radiation therapy. The patient may be asymptomatic but, more commonly, suffers memory loss and, in some instances, severe 112 gait abnormalities and urgency incontinence, cognitive dysfunction. Some patients have113 suggesting normal-pressure hydrocephalus. MRI of virtually all patients receiving whole-brain irradiation in excess of 3,000 cGy shows cerebral atrophy with enlarged sulci and ventricles; there may also be symmetric periventricular white matter hyperintense signals on T2-weighted or FLAIR images. Symptomatic patients appear to have greater degrees of cerebral atrophy and ventricular dilatation than asymptomatic patients. In some instances, the ventricular dilatation is out of proportion to the sulcal atrophy; when such patients are symptomatic with dementia, gait apraxia, and incontinence, they may respond to ventriculoperitoneal shunt. Cerebral atrophy also occurs in children receiving prophylactic 114 brain irradiation for acute leukemia. The atrophy is associated with a learning disability. The pathogenesis of the cerebral atrophy is not clear. In some instances, true communicating hydrocephalus, perhaps from radiation-induced arachnoiditis or obliteration of pacchionian granulations, appears to be causal. In other instances, there is simply loss of cerebral substance. Pathology reveals spongiosis of the white matter, but no vascular changes such as those seen with radiation necrosis. Except in patients who respond to shunting, there is no treatment for the cerebral atrophy. Spinal Cord There are no acute effects of radiation on the spinal cord. In the past, it was believed that, as with the brain, high doses of radiation delivered to the spinal cord for the treatment of epidural spinal cord compression might worsen neurological symptoms. Both clinical and 115,116 Therefore, clinical deterioration of experimental evidence have refuted this belief. patients with metastatic spinal cord compression during radiotherapy is usually due to tumor progression. Early Delayed Radiation Myelopathy
Early delayed radiation myelopathy is common after irradiation of the neck (Table 28-10). Several weeks after irradiation, the patient develops Lhermitte's sign that persists for weeks 117 Some investigators have reported delayed or months and then spontaneously disappears. 118 119 sensory evoked potentials, but others have not. Symptoms are believed to result from demyelination of the posterior columns of the spinal cord. Their presence does not predict the development of late delayed radiation spinal cord injury. Late Delayed Radiation Myelopathy
Late delayed radiation myelopathy appears in two forms. The first and most common is characterized by progressive myelopathy, often beginning as a Brown-Séquard116,120 syndrome Usually and progressing over weeks or months to cause paraparesis or quadriparesis. the symptoms progress subacutely, but in some instances they progress over several years and, at times, may stabilize, leaving the patient with only mild or moderate paraparesis. The disorder probably never resolves spontaneously. MRI is usually nonspecific but helps to exclude metastatic spinal cord compression or intramedullary metastasis. Hyperintense changes of the irradiated vertebral bodies due to fat replacing bone marrow may outline the 121 radiation field even if the details of the radiotherapy port are unknown (Fig. 28-3). In the acute stages, spinal cord swelling may be identified, and the area of damage may enhance 122 with contrast material. Spinal cord atrophy develops at a later stage. Pathologically, the lesions are characterized by confluent areas of necrosis with a predilection for the white matter, particularly the deeper parts of the posterior columns and superficial areas of the posterolateral tracts. Vascular changes are similar to those of radiation necrosis in the brain 123 but are usually less striking. There is no good treatment, although corticosteroids sometimes delay progression of the lesion. Other potential therapies include hyperbaric 124,125 oxygen and anticoagulation.
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FIGURE 28-3 Chronic radiation myelopathy. T1-weighted, post-contrast MRI 30
months after 3,750 cGy radiotherapy to the T8 to T12 vertebral levels for bone metastasis. Note the T8 to T12 vertebral hyperintensity and edema/expansion of the spinal cord. A few patients have been described with hemorrhage in the spinal cord developing many 126 years after irradiation. Characteristically, 8 to 30 years after radiation therapy to the spinal cord, a patient without prior neurological symptoms suddenly develops back pain and leg weakness. MRI suggests acute or subacute hemorrhage in the spinal cord. The cord may be slightly atrophic, but no other lesions are found. After several days, the patient typically begins to improve, and the neurological symptoms may resolve entirely. A few patients have had recurrent episodes of spinal cord hemorrhage. The pathogenesis is probably related to telangiectatic vascular changes caused by the radiation therapy. A biopsy sample of the 126 spinal cord from one patient was said to show an arteriovenous malformation. A second form of late delayed radiation myelopathy is a motor127,128 neuron syndrome that but has occurred after characteristically follows pelvic irradiation for testicular tumors 129 or after craniospinal irradiation for lumbosacral irradiation for other tumors 4 medulloblastoma. This disorder occurs 3 months to 23 years following irradiation and is characterized by the subacute onset of flaccid leg weakness affecting both distal and proximal muscles accompanied by atrophy, fasciculations, and areflexia. It is usually bilateral 129 and symmetric but may either begin in or remain restricted to one leg. Sensory changes are absent. Sphincter and sexual functions are normal. The CSF may contain an increased protein concentration. The myelogram is normal. Although electromyography reveals varying degrees of denervation, sensory and motor nerve conduction velocities are normal. The deficit usually stabilizes after several months to a few years; often patients are still able to walk, but some may become paraplegic. The disorder is impossible to differentiate from a pure motor polyneuropathy or isolated motor
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neuron loss. It also resembles the paraneoplastic syndrome of subacute motor neuronopathy. A single report describes a motor neuron syndrome confined to the arms that developed 3 years following cervical irradiation and was associated with a cystic hypodense cavity 130 affecting the spinal cord from C4 to C6. The pathological report of one patient with a motor neuron syndrome in the lower extremities describes randomly distributed demyelination and axonal loss in both sensory and motor roots, with areas of complete demyelination. The roots involved were primarily those of the cauda equina, with some anterior horn cells (motor neurons) in the lumbar cord exhibiting 131 chromatolysis suggestive of secondary damage. Cranial Nerves The clinical features of radiation injury to the cranial and peripheral132nerves and the special senses are shown in Table 28-11. Anosmia may follow irradiation. Taste is affected in almost every patient who undergoes cranial radiotherapy. Visual loss may follow irradiation of the eye or brain. It may be caused by radiation-induced “dry eye syndrome,” glaucoma, or 133,134 The optic cataract; more commonly, it may result from retinopathy or optic neuropathy. neuropathy following irradiation begins 7 to 26 months after the irradiation and is characterized by painless monocular or bilateral blindness. Papilledema and retinal hemorrhages may be present. The likelihood of visual loss is probably increased by the use of concomitant chemotherapy, and visual loss can generally be prevented by shielding the eyes at the time of irradiation. Hearing loss also follows radiation therapy to the brain or 135 ear. Radiation-induced otitis media causes a conductive hearing loss that may require 136 myringotomy for relief. This disorder usually appears during or shortly following radiation therapy. It is different from the sensorineural hearing loss that is a late delayed effect of radiation therapy and has been attributed to an endarteritis producing vascular damage of the 4 nerve, are cochlear or acoustic nerve. The lower cranial nerves, particularly the hypoglossal 137 often involved as a late delayed effect of radiation therapy delivered to the neck. The pathogenesis appears to be radiation fibrosis. Recurrent laryngeal, vagal, and sympathetic fibers (Horner's syndrome) may be involved as well. Click here to view this table.... Peripheral Nerves There are no acute changes in peripheral nerve function following radiation therapy, although Haymaker 138 and Lindgren mentioned that paresthesias may occur when patients are “under the beam.” Early delayed brachial plexus dysfunction is characterized by paresthesias in the hand and forearm, sometimes4,139,140 associated with pain and accompanied by weakness and Nerve conduction studies reveal segmental slowing, atrophy in a C6 to T1 distribution. and the course is characterized by recovery over a few weeks or months. This disorder is particularly common in patients with breast cancer because the brachial plexus is frequently included in the radiotherapy port of the primary cancer. Late delayed radiation plexopathy has 4,141 142,143 been reported after irradiation of either the brachial or lumbosacral plexus, although the former is much more common. The disorder usually occurs a year or more after radiation therapy with doses of 6,000 cGy or greater. Brachial plexopathy is characterized by paresthesias and weakness of the hand or arm. There may be sensory loss, particularly in the fingers and hand, but the numbness and weakness often progress to a pan-plexopathy, rendering the entire arm useless. This disorder is frequently accompanied by lymphedema and by palpable induration in the supraclavicular fossa. Myokymia on electrodiagnostic testing in the territory of 144,145 affected nerves helps to differentiate radiation damage from tumor The radiation-induced disorder is usually painless, which infiltration of the plexus. distinguishes it from tumor plexopathy, which is typically painful. A CT scan or MRI usually reveals a diffuse loss of tissue planes without a mass. Occasionally, radiation damage can produce a marked fibrotic reaction causing a mass of fibrosis that cannot be distinguished 146 from tumor recurrence. In such cases, surgical exploration of the plexus may be necessary to establish the correct diagnosis. There is no treatment for radiation plexopathy, although painful paresthesias may be relieved by amitriptyline or gabapentin. Lumbosacral plexopathy causes weakness of one or both legs. As with143,147 radiation brachial plexopathy, pain is usually absent and, when present, is generally mild. The disorder often affects the foot, and sensory disturbances as well as weakness are present in most cases. EMG frequently reveals myokymic discharges, which help to differentiate the process from tumor recurrence. At times, exploration is necessary to make the diagnosis. Radiation-induced lumbosacral plexopathy is often slowly progressive over many years. The pathogenesis of radiation plexopathy and peripheral nerve disease is believed to be related to
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fibrosis causing damage to Schwann cells, rather than stemming from direct damage to the nerves themselves.
Secondary Neurological Involvement Radiogenic Tumors The manner in which the nervous system may be affected secondarily after radiation therapy is summarized in Table 28-12. Click here to view this table.... 148
Radiation-induced tumors, including meningiomas, sarcomas, and, less frequently, 149 150 gliomas and malignant schwannomas, may appear years to decades after irradiation of nervous system tissue; secondary tumors may develop even after low doses of radiation therapy. An epidemiological study following a group of children who received low-dose scalp irradiation for tinea capitis demonstrated a 9.5-fold increase in the incidence of meningiomas 151 compared with a control group. Malignant or atypical nerve sheath tumors may follow irradiation of the brachial, cervical, or lumbar plexuses. Signs and symptoms of radiogenic tumors are no different from tumors that arise without prior radiation therapy, and their surgical treatment is similar. Some patients may be able to tolerate additional radiation therapy or chemotherapy if the tumor is malignant and cannot be excised totally. Vascular Abnormalities Lesions of large intracranial or extracranial blood vessels may follow radiation therapy by 152 months to years. Patients may develop transient ischemic attacks or cerebral infarcts. Arteriography reveals stenosis or occlusion of the artery within the radiation portal. A particularly vulnerable area is the supraclinoid portion of the internal carotid artery in children who have received brain irradiation. This occlusion is sometimes associated with moyamoya disease. The pathology of radiation-induced vascular occlusion is similar to severe 153 atherosclerosis, although there may be marked periarterial fibrosis as well. This condition can be distinguished from other forms of atherosclerosis by its restriction to the segment of vessel within the radiation field without evidence of widespread atherosclerosis elsewhere, by the younger age of the patients affected, and by the atypical location of153,154 the stenotic carotid If appropriate, segments, which are often situated distal or proximal to the bifurcation. endarterectomy or carotid stenting can be performed successfully on patients with extracranial vascular disease. Endocrinopathies Primary hypothyroidism may appear many years after irradiation for Hodgkin's disease or 155,156 head and neck tumors or, less frequently, after craniospinal irradiation. The patient may not have the typical stigmata of hypothyroidism but instead presents either with central or peripheral nervous system dysfunction, including encephalopathy, ataxia, and peripheral neuropathy. If the CSF protein concentration is elevated, as it often is in hypothyroidism, the patient may undergo an extensive work-up prior to recognition that the neurological disorder is caused by hypothyroidism. Thyroid function should be studied in any patient with neurological symptoms who has undergone prior irradiation to the neck or head. 157
Hypercalcemic hyperparathyroidism has been reported to follow radiation therapy. Hypothalamic-pituitary dysfunction is a frequent delayed complication of irradiation for head and neck or brain tumors, especially in children. In children, the most frequent endocrinopathy is growth hormone deficiency, which is more often symptomatic in patients irradiated for primary brain tumor than after prophylactic irradiation for acute leukemia 158 because of the higher doses used to treat most brain tumors. Growth should be carefully monitored in children irradiated for brain tumor, and treatment given if deficiency is detected. Growth hormone deficiency should be differentiated from growth failure resulting from spinal irradiation. Gonadotropin deficiency and secondary or tertiary hypothyroidism are less frequent endocrinopathies. In adults, hypothalamic pituitary dysfunction is a common sequela of irradiation for head and 155 neck tumors. In a large study, it was found that 5 to 9 years after irradiation, 48 percent of patients had decreased growth hormone, 13 percent had decreased cortisol (two thirds of them requiring cortisol replacement), 40 percent had increased prolactin, and 8 percent had decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Most studies suggest that the hypothalamus is more likely to be damaged by radiation compared with the
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pituitary gland itself. In adults, radiation-induced hypothalamic pituitary dysfunction also occurs in about one third of long-term survivors of primary brain tumors. The most frequent abnormalities are hypothalamic hypogonadism associated with hyperprolactinemia and hypothyroidism. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 29 Connective Tissue Diseases, Vasculitis, and the Nervous System RICHARD B. ROSENBAUM •
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CONNECTIVE TISSUE DISEASES Systemic Lupus Erythematosus Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Treatment Sjögren's Syndrome Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Treatment Systemic Sclerosis Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Treatment Mixed Connective Tissue Disease Rheumatoid Arthritis Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Myopathies in Connective Tissue Disease VASCULITIS Primary Vasculitis of the Nervous System Primary Angiitis of the Central Nervous System Nonsystemic Vasculitic Neuropathy Systemic Necrotizing Vasculitis Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Treatment Polymyalgia Rheumatica and Temporal Arteritis Systemic Disease Central Nervous System Disease
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Peripheral Nervous System Disease Treatment Takayasu's Arteritis Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Treatment Behçet's Syndrome Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Treatment DIFFERENTIAL DIAGNOSIS Central Nervous System Syndromes Meningitis Cerebrovascular Disease Relapsing-Remitting Multifocal Disease Headache Movement Disorders Myelopathy Seizures Acute Confusional State Cognitive Dysfunction Affective or Psychotic Disorders Peripheral Nervous System Syndromes Cranial Neuropathy Acute Inflammatory Demyelinating Neuropathy Dysautonomia Mononeuropathy Multiplex Myasthenia Gravis Polyneuropathy THERAPEUTIC CHOICES
The diseases discussed in this chapter are linked by their inflammatory mechanisms and the diversity of their effects on the nervous system. They often present diagnostic challenges. After reviewing each disease, the differential diagnosis of some specific neurological syndromes is explored. CONNECTIVE TISSUE DISEASES
Systemic Lupus Erythematosus Systemic Disease Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease characterized by the presence of a broad spectrum of autoantibodies, including antinuclear antibodies (ANAs). It is protean in its neurological and systemic manifestations. Its severity varies from relatively mild skin problems and arthralgias to life-threatening multiorgan failure. The American College of Rheumatology (ACR) classification criteria are helpful for assessing the possibility of SLE and for understanding its diversity (Table 29-1). However, the criteria must be used cautiously for diagnosis. Since any 4 of the 11 criteria would be sufficient to make the diagnosis, there are 330 distinct initial presentations. Many of the criteria are nonspecific and can be seen in normal individuals or in other diseases. Furthermore, the criteria are insensitive, and some patients have SLE even though they meet fewer than 4 criteria. The prevalence of SLE is 100 per million population; 90 percent of patients are women, and the disease is more prevalent in blacks than in whites. Peak age at onset is 15 to 25 years old. Click here to view this table.... SLE usually causes systemic symptoms such as fatigue and malaise. Some patients are febrile. Perhaps 80 percent of patients have skin manifestations, such as sun sensitivity or the classic malar rash, and arthralgias or nondeforming arthritis. Other systemic manifestations include pericarditis, pleuritis, renal disease (ranging from asymptomatic proteinuria or hematuria to severe glomerulonephritis), anemia (classically autoimmune hemolytic anemia), thrombocytopenia, leukopenia, or lymphopenia. Inflammation can affect nearly any part of the body, including the lungs, gastrointestinal tract, and eyes. Autoantibodies are present universally in patients with SLE. ANAs are present in nearly all
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lupus patients. ANAs also occur in about 10 percent of normal people, usually at a low titer, and in many other inflammatory diseases including rheumatoid arthritis (RA), Sjögren's syndrome, systemic sclerosis, polymyositis, and multiple sclerosis (MS). Patients with SLE often have other antibodies against specific nuclear antigens, such as extractable nuclear antigen (anti-ENA), anti-Ro (SSA), anti-La (SSB), anti-Sm (anti-Smith, not to be confused with anti-SM, which is anti–smooth muscle), and antiribonucleoprotein (anti-RNP). Anti-Ro is often positive in the rare lupus patient who lacks ANA. Anti-Sm is specific but insensitive for SLE. Anti-dsDNA (double-stranded DNA) is also strongly suggestive of SLE. Antibodies to histones are associated with drug-induced lupus. Depressed levels of complement components C3 and C4 are common in patients with lupus, particularly those with immune complex deposition, such as that seen in glomerulonephritis. 1
Many patients with SLE have serum antiphospholipid antibodies ; the most commonly assayed antibody is directed against a phospholipid, cardiolipin. In routine in vitro testing, these antibodies may prolong the partial thromboplastin time. Because of this laboratory property, antibodies to cardiolipin are sometimes called lupus anticoagulants. However, antiphospholipid antibodies rarely cause bleeding; paradoxically, they are frequently associated with thrombosis. Antiphospholipid antibodies may be responsible for false-positive serological test results for syphilis (VDRL and rapid plasma reagin [RPR], but not fluorescent treponemal antibody absorbed [FTA-ABS] test). Antiphospholipid antibodies are associated with thrombosis, especially deep venous thrombosis, pulmonary embolism, nonbacterial thrombotic endocarditis, and stroke. These antibodies may accompany failures of pregnancy, including miscarriage, fetal death, premature birth due to placental insufficiency, preeclampsia, or eclampsia. However, most people with antiphospholipid antibodies do not have lupus or other autoimmune disease. Antiphospholipid antibodies may be present transiently, especially after acute viral infections, and may occur in many other systemic illnesses (Table 29-2). Click here to view this table.... The antiphospholipid antibody syndrome is defined as the persistence of moderate to high titers of antiphospholipid antibodies combined with a clinical episode of thrombosis or of 2,3 pregnancy morbidity. Other phenomena that occur in antiphospholipid antibody syndrome include livedo reticularis, arthralgias, cardiac valve abnormalities, hemolytic anemia, thrombocytopenia, pulmonary hypertension, and Raynaud's phenomenon. The antiphospholipid antibody syndrome may occur in patients with SLE or in isolation, in which case it is called primary antiphospholipid antibody syndrome. Patients with SLE who have 4 antiphospholipid antibodies are more likely to develop neurological manifestations. This applies not only to stroke but also to nonischemic syndromes including headache and less 5,6 common inflammatory syndromes, such as chorea or myelitis. Patients with primary antiphospholipid antibody syndrome may have many of the same neurological problems that 7 occur in patients with SLE. A variety of autoantibodies, including antibodies against endothelium, neurofilament, glial fibrillary acidic protein, neurons, microtubule-associated protein 2, lymphocytes, ribosomal P8 protein, and gangliosides, occur in certain patients with neurological manifestations of lupus. None of these have proven pathogenic action or diagnostic value. Antibodies to ribosomal P protein, probably the most studied of these, occur in about one third of patients with lupus and neurological disease but also occur in other lupus patients and are not useful as a 9 diagnostic test. Central Nervous System Disease The central nervous system (CNS) manifestations of SLE vary tremendously in their symptoms, severity, mechanisms, and treatment. Although at times they are referred to collectively as neuropsychiatric lupus, they are best analyzed as a number of separate syndromes (Table 29-3). Depending on diagnostic criteria used, between 37 and 95 percent of patients with SLE have10–14 one of these during the course of their illness, and many patients Neurological events in patients with lupus may be due to will have more than one. numerous factors (e.g., hypertension, uremia, other metabolic derangements, drug toxicity, opportunistic infections, coincident illnesses) rather than to direct effects of inflammatory disease; in one series, more than two fifths of neurological syndromes in patients with lupus 12 were not directly due to lupus affecting the nervous system. Click here to view this table.... Cognitive dysfunction affects up to 80 percent of patients with SLE at some time during the
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illness. The cognitive difficulties can be relatively mild and transient; irreversible deficits or frank dementia are much less common. More than one tenth of16,17 patients with SLE experience a seizure at some time during the These can be one-time events, particularly if related to metabolic course of their illness. derangements, drug toxicity, infections, or other reversible factors. However, SLE may also cause recurrent focal or generalized seizures, particularly in patients who have antiphospholipid or anti-Sm antibodies, strokes, other evidence of focal brain lesions, or psychosis. Patients with SLE are at increased risk of ischemic and hemorrhagic stroke via a variety of mechanisms. Strokes can be caused by cardiogenic emboli (especially in patients with myocardial infarction, atrial fibrillation, or nonbacterial endocarditis), arterial atherosclerosis, arteriolar disease (especially in patients with hypertension), thrombosis associated with antiphospholipid antibodies, and very rarely by vasculitis. Patients with lupus are more than 18 twice as likely as matched controls to develop carotid plaque. All lupus patients need aggressive primary stroke prevention with attention to well-known risk factors such as smoking, hypertension, hyperlipidemia, and diabetes. When a patient does have a stroke, brain imaging is usually supplemented with a thorough evaluation of cardiac sources of emboli, arterial circulation, and antiphospholipid antibodies to clarify the etiology of the stroke and plan secondary stroke prevention. Chorea occurs in perhaps 1 percent of patients with lupus. The movement disorder can be unilateral or bilateral, evolve slowly, and remit spontaneously; it may be the first clinical sign 6 of lupus or appear later in the disease. The chorea is often sensitive to variations in female steroid hormones. Patients with chorea often have increased levels of antiphospholipid antibodies but rarely have evidence of focal cerebral ischemia. Other movement disorders, 19 such as reversible parkinsonism, are rare neurological manifestations of lupus. 20
Acute or subacute transverse myelopathy occurs in 1 to 2 percent of patients with SLE. Patients present with sensory changes, often with a thoracic sensory level, paraparesis, or sphincter dysfunction. Neurological findings in the arms are less frequent. The myelopathy may be the initial clinical manifestation of lupus. Many patients have antiphospholipid antibodies or false-positive VDRL results. Some patients also have a history of optic neuritis, so might be classified as having Devic's syndrome. Magnetic resonance imaging (MRI) of the thoracic spine often shows T2-bright intramedullary signal extending over many spinal segments. Spinal fluid commonly shows a mild pleocytosis and elevated protein concentration and occasionally contains oligoclonal bands. Uncontrolled series suggest that patients treated with corticosteroids, often combined with cyclophosphamide, can make a 20 complete or partial recovery. Acute episodes of aseptic meningitis sometimes occur in patients with SLE; the lifetime prevalence is on the order of 1 percent. The presentation is typical of other forms of meningitis with symptoms such as fever, stiff neck, and headache. In patients with meningitis, spinal fluid studies are necessary to exclude an infectious cause, particularly in immunosuppressed patients who are at risk of opportunistic infections. In patients with aseptic meningitis, spinal fluid usually shows a mononuclear pleocytosis, normal glucose, variable protein levels, and no evidence of a causative organism by culture, polymerase chain reaction (PCR), or serology. Drug-induced meningitis is an important consideration in the 21 differential diagnosis of these patients. The aseptic meningitis of lupus can be self-limited or corticosteroid responsive but is sometimes recurrent. Patients with lupus commonly experience depression, anxiety, and other affective disorders. Perhaps one fifth of patients will experience a major depression during their lives, and many more will have difficulty with mood or anxiety. These disorders do not correlate with brain inflammation and are treated with routine psychiatric drugs, such as selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines, rather than with immunosuppressive therapy. Patients with lupus are at risk of psychosis, delirium, or acute confusional states. When these occur, the differential diagnosis includes a wide variety of causes of encephalopathy, such as CNS inflammation directly from lupus, hypertensive encephalopathy, uremia, other metabolic derangements, drug toxicity, or seizures. Patients with hypertension or those22taking drugs such as cyclosporine can develop posterior reversible leukoencephalopathy. In psychotic patients 23 on steroids, differentiating lupus psychosis from steroid psychosis is key to planning therapy. The focal neurological syndromes of SLE may mimic many clinical features of MS. The ACR classification (Table 29-3) refers to these as demyelinating syndromes, but a more general
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description is multifocal white matter lesions. Like the lesions of MS, these lesions are often associated with relapsing-remitting focal syndromes involving areas such as the optic nerve, brainstem, and spinal cord. In patients with lupus, MRI of the brain often shows T2-bright signals in the cerebral white matter, including periventricular lesions. Occasionally patients with lupus have cerebrospinal fluid (CSF) oligoclonal bands or increased intrathecal immunoglobulin G (IgG) synthesis. Some patients with MS have systemic autoantibodies such as ANAs or antiphospholipid antibodies. Peripheral Nervous System Disease The peripheral nervous system is also affected in diverse ways in SLE (Table 29-4). Carpal tunnel syndrome is 24 probably the most common manifestation, occurring in up to 30 percent of patients with lupus. Patients occasionally have other compression neuropathies. Perhaps one fifth of patients have distal symmetric axonal sensory or sensorimotor peripheral 25 neuropathy, which is usually relatively mild. Patients with mild neuropathy rarely need nerve biopsy or aggressive immunosuppression, even though the nerve, if biopsied, might show some epineurial vasculitis. Findings of autonomic neuropathy, such as abnormal pupillary responses, impaired sweating, loss of cardiovascular reflexes, and impaired gastrointestinal mobility also26,27 occur in many lupus patients, regardless of whether they have sensory neuropathy. Click here to view this table.... Acute demyelinating polyneuropathy, clinical and electrodiagnostically similar to Guillain–Barré syndrome, affects perhaps 1 percent of patients with lupus, a higher incidence than that in the general population. The differential diagnosis of acute motor neuropathy in patients with lupus includes vasculitic neuropathy, particularly if the presentation is in the asymmetric pattern of mononeuritis multiplex; however, this is uncommon. Patients with lupus can also develop other inflammatory neuromuscular syndromes such as chronic inflammatory demyelinating polyneuropathy (CIPD), myasthenia gravis, or neuralgic amyotrophy. Less than 1 percent of patients with lupus develop cranial mononeuropathies, most often of 28 the facial nerve. Treatment Treatment of SLE, with or without neurological involvement, must be individualized based on the organ systems involved and the severity of involvement. Thus, mild arthralgias might be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), whereas severe renal disease often justifies treatment with cyclophosphamide. Many of the neurological manifestations of SLE can be treated symptomatically. Examples include recurrent headache, mood and anxiety disorders, carpal tunnel syndrome, and length-dependent peripheral neuropathy. Cognitive dysfunction usually29requires no specific therapy; behavioral approaches to cognitive therapy deserve exploration. All patients with SLE should attend to factors for primary stroke prevention. Those who have had a stroke associated with a cardiac source of emboli are often treated with warfarin. The appropriate anticoagulation for patients with stroke and antiphospholipid antibodies is 2,30,31 A retrospective study found that patients with antiphospholipid antibodies and debated. an episode of venous or arterial thrombosis were less likely to have recurrent thromboses if treated with warfarin, keeping the international normalized ratio (INR) to 3.0 or more, when 32 compared to patients treated with aspirin or with less aggressive warfarin doses ; however, a study of stroke patients, most of whom did not have lupus, found that in patients with stroke who had antiphospholipid antibodies, either low-dose aspirin or warfarin with a target INR of 33 1.4 to 2.8 was equally effective in preventing recurrent stroke. Patients with lupus psychosis can be managed with antipsychotic drugs, and, once corticosteroid-induced psychosis has been excluded, with steroids. Patients with Guillain–Barré syndrome or myasthenia can be treated with intravenous immunoglobulin (IVIg) or plasmapheresis; however, some patients do not respond to these but appear responsive to corticosteroids combined with cyclophosphamide. Patients with focal CNS inflammatory syndromes such as myelopathy, optic neuritis, or focal cerebral white matter lesions are sometimes treated with corticosteroids alone, but prognosis is better if this is 34 combined with immunosuppressives such as cyclophosphamide.
Sjögren's Syndrome
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Systemic Disease Sjögren's syndrome is a chronic autoimmune disorder that causes inflammation in many organs but particularly in the exocrine glands, primarily salivary and lacrimal glands causing dry mouth (xerostomia) and dry eyes (xerophthalmia), which can be severe enough to 35 damage conjunctiva or cornea (keratoconjunctivitis sicca). The salivary glands may be enlarged. In most cases, Sjögren's syndrome is associated with other rheumatic diseases such as rheumatoid arthritis, SLE, or systemic sclerosis. Sjögren's syndrome occurring without another connective tissue disease is known as primary Sjögren's syndrome, which is the focus in the following discussion of neurological manifestations. Most (90%) patients with Sjögren's syndrome are women, usually middle-aged. The prevalence in the United States exceeds 1,000 cases per million population, so an estimated 500,000 to 2 million Americans have Sjögren's syndrome. Varied diagnostic criteria have been proposed. The European classification criteria (Table 29-5) are valid and reliable. Click here to view this table.... In addition to dry eyes and dry mouth, Sjögren's syndrome can cause dysfunction of other exocrine glands, resulting in dry skin, vagina, or upper respiratory tract. Patients commonly have systemic symptoms such as arthralgias, myalgias, or fatigue, and less often weight loss or fever. Patients can have palpable purpura due to small-vessel vasculitis, but inflammation of larger arteries is uncommon. Sjögren's syndrome can also cause renal (interstitial nephritis, renal tubular acidosis), thyroid (thyroiditis or hypothyroidism), gastrointestinal (atrophic gastritis, dysphagia), pulmonary (interstitial pneumonitis), and liver (biliary cirrhosis or sclerosing cholangitis) disease. Liver, spleen, or lymph nodes may be enlarged. Patients with Sjögren's syndrome have an increased risk of developing lymphoma. Dry eyes or dry mouth are common symptoms and have ubiquitous causes including drugs, aging, or the local effects of contact lenses. In patients with sicca, parotid enlargement, systemic symptoms, and neurological findings, sarcoidosis is often prominent in the differential diagnosis. The pathogenesis of Sjögren's syndrome is unknown. The pathological changes in exocrine glands are lymphocytic infiltrates. Patients with Sjögren's syndrome commonly have serological evidence of autoimmunity including ANAs (present in perhaps three fourths of patients). The anti-Ro (SSA) and anti-La (SSB) antibodies are more specific to Sjögren's syndrome but are also sometimes present in patients with SLE and other autoimmune disease and have limited sensitivity, occurring in between one fourth and three fourths of patients. Blood studies can also show rheumatoid factor, anemia, lymphopenia, and hypergammaglobulinemia; monoclonal gammopathy occurs less frequently. Central Nervous System Disease The prevalence of CNS disease in patients with Sjögren's syndrome is debated; estimates 36 range from 0 to 100 percent. Part of this discrepancy is because the most common CNS problem is subtle cognitive change, particularly of memory or frontal lobe function, which can 37 be hard to detect without detailed psychometric testing. Sjögren's syndrome may cause focal brain lesions, which present abruptly, as for a stroke, or more gradually. Either cerebral hemisphere or the brainstem can be affected; white matter syndromes are more common than gray matter syndromes. These clinical presentations correlate with the neuropathology of the focal brain lesions, which shows38mononuclear infiltrates of veins, venules, and less commonly small arteries or arterioles. The lesions favor the periventricular or subcortical white matter and less commonly affect the gray matter. The surrounding brain tissue can show focal infarcts, which are usually microscopic. Meningeal vessels are often involved. Syndromes clinically associated with gray matter disease, such as seizures, can occur. Even though the CNS pathology in patients with Sjögren's syndrome often includes the meninges, clinical meningitis is not common; however, instances of aseptic meningitis do occur and at times become chronic or recurrent. The CSF typically shows mild mononuclear pleocytosis, occasional elevation of protein level, and, less frequently, oligoclonal bands or 39 evidence of increase intrathecal IgG synthesis. Similar CSF findings can accompany the focal neurological syndromes, such as myelopathy. The CNS lesions of Sjögren's syndrome can evolve with a relapsing-remitting course that approximates that of MS. When Sjögren's syndrome causes optic neuritis, focal paresthesias, brainstem syndromes such as internuclear ophthalmoplegia, or myelopathy, the distinction from MS is important. Surveys from MS clinics suggest that Sjögren's 40–42 syndrome is rarely misdiagnosed as MS.
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Lesions localized to the spinal cord are one of the most common focal CNS findings in Sjögren's syndrome. The myelopathy can evolve slowly or rapidly, be generalized or localized, with presentations as varied as transverse myelopathy or Brown-Séquard 43 syndrome. Some patients also have episodes of optic neuritis, so can be classified as having Devic's syndrome. In most cases, spinal MRI shows T2-bright intramedullary lesions spanning multiple spinal segments. Sometimes the cord appears swollen, and some lesions enhance with gadolinium. Peripheral Nervous System Disease In patients with Sjögren's syndrome, peripheral nervous disease is more common than CNS disease. The peripheral neuropathy is often the presenting manifestation of the Sjögren's 44 syndrome. The peripheral manifestations of Sjögren's syndrome can be separated into a number of clinical syndromes, but many patients have features overlapping more than one of these (Table 29-6). Click here to view this table.... Distal sensory or sensorimotor neuropathy is the most common peripheral neuropathy in patients with Sjögren's syndrome. Clinical examination shows this pattern in up to one fifth of patients with Sjögren's syndrome, and other patients will have asymptomatic neuropathy detectable by nerve conduction studies. The typical presentation is a chronic distal axonal neuropathy including small and sometimes larger sensory fibers. Distal motor involvement is less common. Nerve biopsy specimen usually shows nonspecific axonal loss rather than vasculitis. Some patients with otherwise idiopathic axonal neuropathy will meet diagnostic 45 criteria for Sjögren's syndrome. However, if neuropathy patients have dry eyes or dry mouth but no other objective supportive findings, they are unlikely later to develop systemic 46 manifestations of Sjögren's syndrome. Sensory neuronopathy presents acutely or indolently as asymmetric dysfunction of large and small sensory fibers. Patients often have impaired distal or proximal cutaneous touch, pain, temperature, and joint position senses.44,47 They may have pseudoathetosis and sensory ataxia. Many patients also have elements of trigeminal or They have depressed tendon reflexes. autonomic neuropathy. On electrodiagnostic studies, most patients have some low-amplitude or unobtainable sensory nerve action potentials and somatosensory evoked responses. 44,48 Sural nerve biopsy Spinal cord MRI often shows T2-bright signal in the posterior columns. shows axonal loss of large and small myelinated fibers and of unmyelinated fibers, but few biopsy specimens show vasculitic changes or lymphocytic infiltrates. Pathology of the dorsal root ganglia can include neuronal destruction and lymphocytic infiltration. In addition to dry eyes and dry mouth, these patients often fully meet diagnostic criteria for Sjögren's syndrome, including objective evidence of xerophthalmia and xerostomia and abnormal lip biopsy samples; however, they usually do not have other systemic manifestations of Sjögren's syndrome. Trigeminal neuropathy impairs sensation, usually in the mandibular or maxillary divisions, but not motor trigeminal function, unilaterally or bilaterally, with acute or subacute evolution. Electrodiagnostic studies suggest abnormality of the gasserian ganglion with impaired blink 49 reflexes but normal masseteric reflexes. Mild autonomic neuropathy, with manifestations such as Adie's pupil, orthostatic hypotension, impaired sweating, constipation or diarrhea, and abnormal cardiac reflexes, often accompanies the other neuropathies of Sjögren's syndrome. In an occasional patient, more 44 severe autonomic dysfunction is the predominant neurological problem. Mononeuritis multiplex or multiple cranial neuropathies may occur in patients with Sjögren's syndrome. In contrast to trigeminal sensory neuropathy, the multiple cranial neuropathies also affect motor function and can include nerves III, V, VI, VII,44IX, X, and XII. Biopsy of an involved peripheral nerve is likely to show epineurial vasculitis. Other neuropathic presentations occasionally found in patients with Sjögren's syndrome include painful asymmetric sensory neuropathy, proximal radiculoneuropathy, Guillain–Barré 50 syndrome, and lower motor neuronopathy. Predominantly motor neuropathy is less common in patients with Sjögren's syndrome; motor neuron disease is linked to Sjögren's 50 syndrome 51–53 by case reports. Carpal tunnel syndrome occurs in some patients with Sjögren's syndrome. Treatment
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Treatment of Sjögren's syndrome varies greatly depending on the organs involved and the severity of disease. Dry eyes may be treated with artificial tears or topical approaches; arthralgias may be controlled35with nonsteroidal anti-inflammatory drugs or with antimalarials such as hydroxychloroquine. There is no specific cure for some neurological syndromes, 54 such as mild cognitive impairment, trigeminal neuropathy, or distal sensory neuropathy. Myelopathy or symptomatic focal brain lesions are often treated with corticosteroids, sometimes in conjunction with cyclophosphamide; in one series, more than5490 percent of patients with myelopathy improved after treatment with cyclophosphamide. Mononeuritis multiplex or multiple cranial neuropathies also appear responsive to corticosteroids, sometimes with cyclophosphamide added. A minority of patients with sensory neuronopathy 44,54,55 improve after treatment with corticosteroids, IVIg, or other immunosuppressants.
Systemic Sclerosis Systemic sclerosis causes a relatively noninflammatory vasculopathy and fibrosis in multiple organs. The pathogenesis is unknown, but the combination of microvascular ischemia and fibrosis causes the bulk of clinical manifestations of systemic sclerosis. Strictly speaking, scleroderma refers to the typical skin thickening of systemic sclerosis; patients may have cutaneous scleroderma alone without having systemic sclerosis, and localized cutaneous scleroderma is not associated with the neurological complications discussed later. Estimated prevalence in the United States is between 100 and 300 cases per million population, with an annual incidence about one tenth of the prevalence; the disease affects women more than 56 men and blacks more than whites. Systemic Disease In addition to scleroderma, patients with systemic sclerosis typically have CREST: subcutaneous calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly (tight digital skin), and telangiectasia. The esophageal disease often causes dysphagia. Some patients have only CREST and no other systemic disease; however, systemic sclerosis can also cause pulmonary fibrosis or hypertension, renal or cardiac involvement, especially with hypertension, hypothyroidism, sicca syndrome, arthralgias, and tenosynovitis. Almost all patients with systemic sclerosis have some serological evidence of ANAs. These can include antibodies against antigens such as centromeres, topoisomerase, U1-RNP, RNA polymerase 57 III, U3-RNP, and Th/To. These antibodies have some prognostic value: for example, patients with anticentromere antibodies usually have the CREST syndrome, are at risk of pulmonary hypertension, but usually do not develop more diffuse systemic disease. Perhaps 58 those with anti-U1-RNP or anti-Scl-70 are more prone to neurological complications. Central Nervous System Disease CNS disease is not particularly common in patients with systemic sclerosis, so whether reported cases represent true pathogenic associations is often problematic. For example, nearly one third of patients with systemic sclerosis have migraine, but a pathological 59,60 A number of case reports link systemic sclerosis to association has not been proven. intracerebral vasculopathy, presenting with transient ischemic attacks (TIAs), ischemic strokes, or intracranial hemorrhages. Although systemic sclerosis can lead to hypertensive 61–66 In a few emergencies, cerebral vasculopathies can also occur in normotensive patients. 67 link systemic instances, patients have both MS and systemic sclerosis. Other case reports 68,69 sclerosis and optic neuropathy, memory impairment, or affective disorders. About one third of patients with systemic sclerosis, compared to less then one tenth of control 70 patients, have basal ganglia calcification visible by computed tomography (CT) scan. 71 Patients with SLE may also have an increased prevalence of basal ganglia calcification. Peripheral Nervous System Disease Carpal tunnel syndrome occurs in about one fourth of those with systemic sclerosis; one series found a higher incidence (43%) among those with anti-Pol3 antibodies, which are also associated with more diffuse disease and renal crisis. Trigeminal sensory neuropathy, clinically resembling that described in Sjögren's syndrome, affects 1 percent or more of 72,73 Distal symmetric axonal neuropathy, plexopathies, and patients with systemic sclerosis. 72–74 mononeuritis multiplex occur infrequently in patients with systemic sclerosis. Many forms of autonomic dysfunction affect patients with systemic sclerosis, including abnormal sympathetic skin responses, even in nonsclerodermatous skin, abnormal
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cardiovascular reflexes, impaired urodynamics, impotence, and abnormal pupillary responses 75 to sympathetic or parasympathetic stimuli. With the exception of impotence, these autonomic changes are usually asymptomatic. Treatment Data on the treatment of neurological disease in patients with systemic sclerosis are scant. Trigeminal neuropathy or mild distal neuropathy is usually not specifically treated. Case reports suggest possible benefit of cyclosporine in patients with systemic sclerosis and 61 cerebral vasculopathy.
Mixed Connective Tissue Disease Mixed connective tissue disease (MCTD) is one example of the many overlap syndromes in which a patient has features of more than one inflammatory disease. Patients with MCTD typically have some features of SLE and some features of systemic sclerosis, particularly 76 Raynaud's phenomenon and digital sclerotic skin changes. The serological hallmark of MCTD is high titers of autoantibodies to ribonucleoprotein (RNP or more specifically U1-RNP) and absence of anti-Sm and anti-DNA antibodies. These patients have a high incidence of pulmonary hypertension. Inflammatory muscle disease,77histologically resembling dermatomyositis, is another common aspect of MCTD. Perhaps 10 percent of patients with MCTD have CNS disease; their neurological complications are like those of SLE; in addition, similar to patients with systemic sclerosis, they probably are at increased risk of trigeminal 78–80 sensory neuropathy.
Rheumatoid Arthritis Rheumatoid arthritis is a chronic disease characterized by symmetric joint inflammation, particularly of the small distal joints such as the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. Rheumatoid arthritis has a prevalence between 10,000 and 20,000 cases per million population, affecting women more often than men. More than four fifths of those with rheumatoid arthritis have autoimmune serological changes, particularly the presence of rheumatoid factor, but rheumatoid factor is nonspecific, being present in many other inflammatory conditions and in a small percentage of the healthy population. Autoantibodies to cyclic citrullinated peptide (anti-CCP) are more specific than rheumatoid factor for the diagnosis of rheumatoid arthritis. Systemic Disease Patients with rheumatoid arthritis can develop systemic manifestations such as subcutaneous rheumatoid nodules, sicca syndrome, Felty's syndrome of hypersplenism, amyloidosis, scleritis or episcleritis, lung or heart involvement, anemia of chronic disease, eosinophilia, and thrombocytosis. A rare but serious complication is widespread rheumatoid vasculitis, with neurological complications such as those of other medium-vessel vasculitides (discussed later). A community-based survey of rheumatoid arthritis in Olmstead County, Minnesota, found extra-articular manifestation in nearly one half of patients over 30 years of follow-up; important neurological manifestations were cervical myelopathy in 2 percent, neuropathy in 2 81 percent, and major organ vasculitis in less than 1 percent. Central Nervous System Disease Patients with rheumatoid arthritis are probably at increased risk of headache and neck ache but rarely develop serious or focal cerebral disease. Strokes due to rheumatoid vasculitis or 82,83 Pachymeningitis caused by to compression of a vertebral artery are quite infrequent. rheumatoid nodules or pannus is a rare complication of chronic rheumatoid arthritis. The lesions are84visible by contrast-enhanced MRI, which can demonstrate focal or irregular dural thickening. Clinical manifestations can be absent, focal (e.g., optic neuropathy, spinal cord compression), or nonfocal (e.g., headache, mental status changes). Cervical myelopathy caused by atlantoaxial subluxation and by soft-tissue pannus is a feared late complication of rheumatoid arthritis. The subluxation is due to laxity of inflamed ligaments. Subluxation is usually anterior but can be in any direction. It is rare in the first years of rheumatoid arthritis but85develops in more than one fourth of those who have had the disease for more than 15 years. The subluxation is usually asymptomatic; however, the risk of cord compression increases as subluxation increases, particularly in those with smaller spinal canals. Signs of myelopathy (quadriparesis, spasticity, sensory loss, sphincter
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disturbance) can evolve slowly or worsen suddenly. Patients with high cervical instability are at particular risk of spinal cord injury during intubation or anesthesia. Vertical atlantoaxial subluxation can lead to brainstem compression; possible symptoms, in addition to those of cervical myelopathy, include bulbar palsy, trigeminal or high cervical sensory loss, ophthalmoparesis, nystagmus, drop attacks, hydrocephalus, and sleep apnea. A rare presentation is vertebral arterial stroke due to the subluxed neck. Cervical collars can decrease neck ache or headache due to atlantoaxial subluxation; however, a halo and cervical traction are needed if neck stabilization is required due to neurological deterioration. Surgical stabilization in patients with myelopathy or brainstem compression can stabilize the spine and prevent further neurological loss but often does not 86 improve existing neurological deficits. Peripheral Nervous System Disease Carpal tunnel syndrome is the most common neurological manifestation of rheumatoid arthritis. Estimates of its prevalence vary; careful questioning of patients with87rheumatoid arthritis can reveal median-distribution sensory symptoms in more than half. Patients with rheumatoid arthritis are more likely than age-matched controls to develop carpal tunnel syndrome and88,89 are more likely to develop carpal tunnel syndrome when they have hand flexor The carpal tunnel syndrome can improve with successful treatment of the tenosynovitis. arthritis or after carpal tunnel surgery, occasionally supplemented by tenosynovectomy. Ulnar nerve compression at the ulnar groove, radial or posterior interosseus nerve compression, compression of the peroneal or posterior tibial nerves by a Baker's cyst in the popliteal region, tarsal tunnel syndrome, and digital neuropathies may affect patients with rheumatoid arthritis. Mild length-dependent symmetric sensory neuropathy is a potential late effect of rheumatoid arthritis, especially in those with more severe disease. If a nerve biopsy is performed, the specimen may show vasculitic changes, but this is not indicative of systemic vasculitis and is not an indication for immunosuppressive treatment. Patients may also have autonomic neuropathy with impaired sweating or abnormal postural and cardiovascular reflexes, even in the absence of sensory neuropathy. Patients who develop rheumatoid vasculitis are at risk of mononeuritis multiplex.
Myopathies in Connective Tissue Disease The inflammatory myopathies 90 are dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). Both DM and PM cause subacute, predominantly proximal, weakness, sparing the face and eyes. Serum creatine kinase (CK) is elevated up to 50 times normal. Electromyography (EMG) shows brief, low-amplitude, easily recruited motor unit potentials, often accompanied by fibrillation potentials or positive sharp waves. Antisynthetase autoantibodies are present in up to one fourth of patients with DM or PM; anti-Jo is the most common of these. Despite these similarities, DM and PM differ in their pathology, immunopathogenesis, and relation to other connective tissue diseases. DM can affect either children or adults. It is usually accompanied by characteristic skin changes: heliotrope upper eyelid discoloration with swelling and an erythematous rash on the face, neck, anterior chest, back and shoulders, and extensor surfaces of extremity joints. On the fingers, a papular, reddish purple keratotic rash can involve the knuckles but spare the phalanges (Grottron rash). Fingernails may show dilated capillaries under the bases and distorted cuticles. In DM inflammatory changes concentrate around blood vessels and in the perifasicular connective tissue. Perifasicular atrophy of myocytes is characteristic. The + inflammatory cells are predominantly CD4 . DM affects about one eighth of patients with 77 systemic sclerosis and probably occurs in more than one half of patients with MCTD. PM rarely occurs before the age of 18 years. Weakness develops insidiously and is not associated with rash. Muscle biopsy sample shows inflammatory infiltrates, predominantly + CD8 lymphocytes, invading muscle fibers. PM occurs in 5 to 8 percent of patients with SLE and has a lower prevalence in patients with rheumatoid arthritis or Sjögren's syndrome. Given the vagaries of diagnostic definition and the multiplicity of overlaps among the connective tissue diseases, the division among diseases associated with DM or PM can hardly be absolute. For example, muscle biopsy samples of some patients with myositis and MCTD + + 91 endomysial CD8 cells. Furthermore, have a combination of perivascular CD4 cells and 92 DM and Sjögren's syndrome may occur together.
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Sporadic IBM usually begins after age 50, particularly in men, and is the most common progressive muscle disease in older adults. It causes a distinct pattern of weakness, favoring the quadriceps, gluteus maximus, and forearm flexors and extensors. Biceps and triceps weakness and foot drop are often present. A muscle biopsy specimen shows vacuoles in multiple muscle fibers, mononuclear cell inflammation,93intracellular amyloid deposits, and intracellular inclusions containing phosphorylated 94–97 tau. IBM is linked to the autoimmune connective tissue diseases by a few case reports. More details on the inflammatory myopathies are available in Chapter 60. Myositis is not the only form of muscle dysfunction seen in those with rheumatic diseases. Patients with advanced rheumatoid arthritis often have diffuse weakness. EMG and serum CK are normal. Muscle biopsy shows type II atrophy, the same pattern that can be seen with disuse. Similarly, patients with Sjögren's syndrome may have mild weakness with normal serum CK levels. Severe hypokalemia due to distal renal tubular acidosis is a rare cause of 98 weakness in patients with Sjögren's syndrome. Most patients with systemic sclerosis have some proximal weakness. These patients have normal or slightly elevated serum CK, sometimes mildly decreased duration or increased polyphasia of motor unit potentials99–101 by EMG, and nonspecific changes, such as type II atrophy, on muscle biopsy specimen. Drug toxicity is another cause of muscle disease in patients being treated for connective tissue diseases. Corticosteroid myopathy is a common 102,103 cause of proximal weakness, especially in patients on high doses or chronic therapy.104,105 Treatment with cyclosporine or Penicillamine can cause chloroquine may rarely cause myalgias and weakness. 106 myositis. VASCULITIS The vasculitides are a diverse group of illnesses characterized by inflamed blood vessels. They can be subdivided based on the size and type of blood vessels that are inflamed, details of pathology, and areas of the body involved. Most vasculitis is systemic, with involvement of multiple organ systems. However, there are two classic forms of vasculitis in which the principal manifestations are neurological: primary angiitis of the CNS and nonsystemic vasculitic neuropathy.
Primary Vasculitis of the Nervous System Primary Angiitis of the Central Nervous System Primary angiitis of the CNS (PACNS) is a clinical challenge: a rare disease that causes common syndromes such as headache, encephalopathy, or stroke, is potentially fatal but potentially treatable, and is difficult to diagnose, even with cerebral angiography and brain biopsy. Synonyms include cerebral granulomatous angiitis, giant cell granulomatous angiitis of the CNS, and isolated angiitis of the CNS. PACNS is pathologically defined by transmural, predominantly monocytic, infiltrates of small to medium (<200 μm in diameter) vessels in the 107,108 leptomeninges or cerebral cortex. The vessel walls show fibrinoid necrosis. Sometimes granulomas are present. Parenchymal brain tissue may show signs of ischemic or hemorrhagic infarction. Alternative diagnoses such as systemic vasculitis or infection must be excluded. 109
PACNS usually presents with headache and change in mental status. Patients less frequently have a stroke or multiple strokes; about one third of patients have focal neurological findings at presentation and another one sixth develop focal findings later in their 110 illness. Symptoms usually evolve gradually, and111most patients have been symptomatic for more than 1 month before the diagnosis is made. Myelitis is a less common presentation 112 of PACNS. Systemic symptoms such as fever or weight loss affect only a minority of patients. More than 80 percent of patients with PACNS have an elevated CSF protein level, usually over 100 mg/dl, and most have CSF pleocytosis; CSF glucose concentration is 110,111 Patients may have anemia, peripheral leukocytosis, or elevated usually normal. erythrocyte sedimentation rate. Brain CT scans or MRI typically113,114 show multiple ischemic infarcts or more diffuse confluent Focal brain hemorrhage may occur. However, a normal lesions in patients with PACNS. 115 MRI brain scan does not completely exclude CNS vasculitis. Cerebral angiographic findings of vasculitis are multifocal vessel narrowing, poststenotic 116 dilatations, and focal variations of blood flow, usually involving 107 multiple vessels. Unfortunately, these findings are neither sensitive nor specific. Therefore, the diagnosis of
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PACNS is definite only when confirmed pathologically. Brain biopsy should include both cortex and meninges and can be done at a site that is abnormal by MRI or at the nondominant frontal lobe or tip of the nondominant temporal lobe. In one series of patients with suspected PACNS, the biopsy specimen confirmed PACNS in 36 percent, established 117 an alternative diagnosis in 39 percent, and was not diagnostic in 25 percent. Patients with PACNS are typically treated with corticosteroids, often supplemented by other immunosuppressants. Although there are many anecdotal examples of treatment response, there are no controlled data on treatment. Among a group of patients with suspected PACNS and nondiagnostic brain biopsies, about one half had a good outcome 1 year later regardless 118 of whether they were treated with immunosuppressants. Nonsystemic Vasculitic Neuropathy Mononeuritis multiplex is the most common clinical presentation of nonsystemic vasculitic 119–121 neuropathy (NSVN), also called primary angiitis of the peripheral nervous system. Inflammation of individual nerves causes acute or subacute pain and sensory or sensorimotor deficit in the territory of the inflamed nerves. In some patients, discrete involvement of a few nerves is evident; in others, there is asymmetric neurological deficit including the territories of many nerves; least commonly, the overlap is so extensive that the deficit fits a distal symmetric pattern. The neurological deficit is usually worse distally, but many patients have some proximal weakness. Leg nerves, particularly the peroneal, are more often affected than arm nerves, and inflammation often affects the proximal nerve trunk rather than traditional sites for compression neuropathies. Infrequently, a cranial nerve, most commonly the facial nerve, is involved. Patients with NSVN may have some manifestations of systemic illness including weight loss, fever, elevated erythrocyte sedimentation rate, positive ANA or rheumatoid factor, anemia, 121 leukocytosis, or thrombocytosis. CSF protein concentration is occasionally elevated. Less common findings are a serum monoclonal gammopathy or mild CSF pleocytosis. In more than 90 percent of patients with vasculitic neuropathy, electrodiagnostic studies are consistent with an122 asymmetric axonal neuropathy; some patients show partial motor conduction block. The definitive pathological changes of vasculitic neuropathy are inflammatory cells infiltrating the walls of epineurial and perineurial arterioles, usually accompanied by fibrinoid necrosis, disruption of endothelial cells or the internal elastic lamina, or hemorrhage into the vessel 123,124 119,125 The involved arterioles are usually 75 to 200 μm in diameter. Typically, a wall. pure sensory nerve, such as the sural or superficial peroneal, is biopsied. Patients may also have vasculitis of muscle, especially in the perimesial arterioles, even though they have no clinical evidence of myopathy and no direct inflammation of myocytes. Biopsy of peroneus brevis muscle at the time of nerve biopsy increases the diagnostic sensitivity for vasculitis. About 60 percent of patients with a confirmed123diagnosis of vasculitis by clinical criteria show definite vasculitis by nerve or muscle biopsy. When vasculitis affects the nerve proximal to the biopsy site, nerve biopsy may show less specific findings, such as vessel thickening, narrowing, or thrombosis, epineurial capillary proliferation, periadventitial hemosiderin, 123 asymmetric nerve fiber loss, or wallerian-like degeneration. Traditional wisdom, based on uncontrolled clinical experience, has favored treatment of NSVN with corticosteroids, starting, for example, with prednisone 1 mg/kg, and then tapering the dose and changing to alternate-day dosing based on clinical response. More aggressive immunosuppression with agents such as cyclophosphamide or methotrexate would be added if patients did not respond to prednisone. However, a recent retrospective analysis suggests that response rate and prognosis are better if initial treatment combines corticosteroids and 121 cyclophosphamide. The nerve inflammation of NSVN leads to fascicular nerve infarction and axonal interruption; recovery of individual nerves can occur, but recovery of neurological function takes many months, consistent with the rate of axonal 121 regrowth. Many patients regain motor function and sensory perception but have chronic pain. Patients should be followed closely when 121 therapy is tapered; nearly one half of patients relapse despite initial responses to therapy. If patients with NSVN have no systemic features other than the nonfocal findings mentioned previously and121 do not have hepatitis B infection, the risk of later developing vasculitis in major vasculitis causes a pure sensory distal organs is low. Perhaps patients whose nerve 126 neuropathy have a more benign prognosis.
Systemic Necrotizing Vasculitis
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Systemic Disease Systemic necrotizing vasculitis of medium (0.2 to 2.0 mm diameter) and small blood vessels (arterioles, capillaries, postcapillary venules) is a spectrum of diseases including polyarteritis nodosa (PAN), Churg–Strauss syndrome, microscopic polyangiitis, Wegener's granulomatosis, and Kawasaki's disease. All can cause CNS disease, especially strokes, or disease of the peripheral nervous system, especially vasculitic neuropathy, to variable degrees. Differentiating among the systemic necrotizing vasculitides is challenging; patients 127,128 Most forms of systemic necrotizing vasculitis can often overlap diagnostic categories. cause systemic illness, necrotizing skin lesions, inflammation of the gastrointestinal tract, involvement of joints and muscles, and renal disease. A 2-year study at a British hospital serving 415,000 people found 56 cases of Wegener's granulomatosis, 23 cases of 129 microscopic polyangiitis, 18 cases of Churg–Strauss syndrome, and two cases of PAN. Polyarteritis nodosa is the prototypical systemic necrotizing vasculitis with inflammation of medium-sized arteries but is becoming less frequently diagnosed, with an annual incidence in 128 developed countries of nine or fewer per million. Chronic hepatitis B infection can cause PAN, so incidence is higher where hepatitis B is endemic. Patients with PAN are almost always systemically ill, with fever, weight loss, malaise, fatigue, and myalgias. Inflammation of medium-sized subcutaneous vessels can lead to livedo reticularis, subcutaneous nodules (to be distinguished from the palpable purpura of small-vessel vasculitis), skin ulcerations, and digital ischemia. One half of patients have gastrointestinal involvement, often with abdominal pain. Renal inflammation may cause renal infarcts, hypertension, proteinuria, hematuria, or elevated blood urea nitrogen and creatinine, but glomerulonephritis is not a feature of classic PAN. Abdominal angiography often shows multiple mesenteric or renal microaneurysms. Coronary arteriolar vasculitis can cause patchy areas of myocardial necrosis, congestive heart failure, and tachycardia; infarcts in the full territory of a coronary artery are less common. Vasculitis may extend to many other organs, including the brain, but classic PAN does not affect the lungs. Churg–Strauss syndrome can resemble PAN in its effects on skin, gastrointestinal tract, heart, muscle, nerve, and brain. Renal disease is less common than in PAN. However, Churg–Strauss syndrome is remarkable for its striking, almost universal, lung pathology with asthma and pulmonary infiltrates and for eosinophilia; all are rare in PAN. The ACR classification criteria for Churg–Strauss syndrome require that the patient have at least four of the following six findings: asthma, blood eosinophil count greater than 10 percent, mononeuropathy or polyneuropathy, pulmonary infiltrates, abnormal paranasal sinuses, and 130 biopsy evidence of extravascular eosinophilia. Wegener's granulomatosis is characterized by granulomatous inflammation and small- and medium-vessel vasculitis of the upper respiratory tract, lungs, and kidneys. The granulomas and vasculitis of the upper airway mucosa can cause inflammation and necrotic ulcers of the sinuses, pharynx, or ears. The same process in the lungs causes clinical findings ranging from transient infiltrates to severe pulmonary hemorrhage. The renal disease of Wegener's is typically glomerulonephritis, whether mild proliferative or necrotizing crescentic. The ACR classification criteria that distinguish Wegener's granulomatosis from other forms of vasculitis require any two of the following four features: nasal or oral inflammation, abnormal chest radiograph, microhematuria or red cell casts in the urine sediment, and pathological evidence of 131 granulomatous inflammation in or around the wall of an artery or arteriole. The disease evolves over months and can also cause inflammatory eye disease, myalgias, joint disease, skin lesions (either palpable purpura or the lesions of medium-vessel vasculitis), pericarditis, and neuropathy. Microscopic polyangiitis causes necrotizing vasculitis of medium and small vessels. Necrotizing glomerulonephritis is common, which distinguishes it from PAN. The diagnosis of microscopic angiitis is excluded if patients meet criteria for either Churg–Strauss syndrome or Wegener's granulomatosis. Kawasaki's disease occurs predominantly in children and, aside from aseptic meningitis, infrequently causes neurological syndromes. Necrotizing vasculitis can accompany a number of other systemic diseases, including elements of vasculitis in patients with SLE, Sjögren's syndrome, sarcoidosis, and rheumatoid arthritis. Patients with hepatitis C infection may have vasculitis associated with type 2 cryoglobulinemia, and vasculitis may accompany many other virus infections, such as with human immunodeficiency virus, hepatitis B virus, cytomegalovirus, and herpes zoster virus; syphilis, Lyme disease, and fungal, rickettsial, and mycobacterial infections may also be responsible. Cerebral vasculitis can complicate bacterial meningitis or amphetamine abuse or 132 be part of a paraneoplastic syndrome.
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Antineutrophil cytoplasmic antibodies (ANCAs) can be helpful in the diagnosis of systemic vasculitides, particularly in patients with renal disease, but must be interpreted with caution. There are two antibody patterns. The c-ANCA pattern on immunofluorescence is usually associated with antibodies to proteinase-3, which can be detected by an enzyme-linked immunosorbent assay (ELISA). The combination of the c-ANCA and antiproteinase 3 is sensitive for Wegener's granulomatosis but may be negative, particularly if the Wegener's granulomatosis spares the kidney. c-ANCA/antiproteinase 3 may also be present in PAN, Churg–Strauss syndrome, and microscopic polyangiitis, usually associated with renal involvement. The p-ANCA pattern is a much less specific finding and can be positive in a variety of inflammatory diseases. However, when the p-ANCA pattern is associated with antibodies to myeloperoxidase (anti-MPO on ELISA), the combination relatively strongly suggests glomerulonephritis associated with systemic necrotizing vasculitis such as microscopic polyangiitis, Churg–Strauss syndromes, localized necrotizing glomerulonephritis, or Wegener's granulomatosis. Central Nervous System Disease CNS syndromes in patients with systemic vasculitis are varied. A review of several series found that the leading CNS133complications of PAN are stroke (11%), altered mental status (10%), and seizures (4%). Similar presentations of cerebral vasculitis can occur in the other systemic necrotizing134vasculitides. Arteritis can affect arterioles and small arteries in the meninges and cerebrum. Strokes can be single or multiple, affecting small vessels at any place in the brain. TIAs are less frequent, and intracranial hemorrhages or extracranial arterial dissections are uncommon events in patients with systemic vasculitis. Patients with Wegener's granulomatosis have a similar incidence of strokes, seizures, and 135,136 In addition, 137 granulomatous disease can cause other focal cerebral syndromes. hypertrophic pachymeningitis or pituitary disease. Peripheral Nervous System Disease More than 50 percent of patients with PAN and an even higher proportion of patients with Churg–Strauss syndrome have some evidence of peripheral neuropathy. The classic form is ischemic mononeuropathy or mononeuritis multiplex, which is a common presenting manifestation of necrotizing vasculitis. Other patients have mild patches of cutaneous dysesthesias or paresthesias due to cutaneous mononeuropathies. Another clinical pattern of vasculitic neuropathy is a mild distal symmetric sensorimotor neuropathy. Similar neuropathies occur in patients with Wegener's granulomatosis or microscopic polyangiitis, but the clinical prevalence is lower, and neuropathy is less likely to be a presenting 136,138 However, if patients with Wegener's granulomatosis are studied with EMG symptom. and nerve conduction studies, nearly one third have some evidence of distal axonal 139 neuropathy. The clinical presentations and pathological findings of neuropathy in patients with systemic necrotizing vasculitis are similar to those described for NSVN. Exceptional findings are limitation of inflammation to vessels less than 40 μm in diameter in some cases of microscopic polyangiitis or the occasional appearance of epineurial granulomas in Wegener's 140,141 granulomatosis. A rare manifestation of systemic vasculitis is an acute ascending paralysis, clinically similar to Guillain–Barré syndrome, but distinguished on electrodiagnostic studies by results favoring142 axonal rather than demyelinating pathology and on nerve biopsy by evidence of vasculitis. Cranial neuropathies can occur in patients with systemic vasculitis; in one series, 15 instances (cranial nerves III, V, VI, VII, and most frequently VIII) were found among 114 143 patients with PAN. Single or multiple cranial neuropathies are even more frequent in patients with Wegener's granulomatosis where local granulomatous disease in the ear, sinuses, or orbit can lead to focal nerve inflammation or compression; patients with136,144,145 Wegener's granulomatosis are also at risk of hearing loss due to ear inflammation. Treatment Glucocorticoids and cyclophosphamide are mainstays in the treatment of systemic necrotizing vasculitis, but there are no rigid rules for their use. Some patients with mild disease improve when treated only with high-dose corticosteroids. Cyclophosphamide should be added if patients do not respond to corticosteroids or if they have major organ involvement, such as gastrointestinal bleeding, perforation, or infarction; pancreatitis; severe
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glomerulonephritis or renal failure; cardiomyopathy; or CNS disease. PAN and Churg–Strauss vasculitis may respond to corticosteroids alone; most patients with Wegener's granulomatosis and microscopic polyangiitis require cyclophosphamide therapy. The dose and duration of therapy are variable, balancing the need to control active disease and to avoid drug toxicity.
Polymyalgia Rheumatica and Temporal Arteritis Temporal arteritis (TA) is the most common vasculitis of large elastic arteries, characterized pathologically by granulomatous arterial inflammation with giant cells, usually located between the media and intima. Giant cell arteritis is often used as a synonym for TA, even though there are other forms of arteritis, such as Takayasu's arteritis, that are also characterized pathologically by giant cells in arteries. Polymyalgia rheumatica (PMR) is a 147 chronic idiopathic systemic inflammatory illness that is intimately related to TA. Systemic Disease Polymyalgia is a chronic disease that causes pain and stiffness in patients older than 50 years. It is common, affecting nearly 1 percent of those older than 50,147affecting women more than men, and reaching peak prevalence in the eighth decade of life. The pain typically affects proximal joints symmetrically, shoulders more than hips or neck, with prominent morning stiffness; it is often described as myalgic, but the cause is probably synovitis, and actual muscle weakness is not part of the syndrome. Symptoms can start abruptly or evolve slowly; ACR diagnostic criteria require that symptoms last for more than 1 month. Systemic symptoms can include fatigue, fever, malaise, anorexia, or weight loss. About 50 percent of patients with PMR have distal asymmetric synovitis that can cause arthralgias and tenderness of the knees, wrists, ankles, or dorsal surface of the feet. TA is a systemic vasculitis that shares the time course, systemic symptoms, and epidemiological characteristics of PMR. About one half of patients with TA have polymyalgia 148 and one sixth or more of patients with PMR have TA. The average annual incidence of TA in Olmstead149County, Minnesota, in those older than 50 years is 188 cases per million population. Characteristics of TA are headache, jaw claudication, and risk of sudden blindness and other neurological complications. Patients with TA usually have scalp pain, ranging from nonlocalized tenderness to enlarged, nodular, painful scalp arteries, particularly the temporal artery. Patients can have other manifestations of large-artery inflammation, such as asymmetric pulses or blood pressure, limb claudication, aortic aneurysm or dissection, aortic valve insufficiency, myocardial infarction, intestinal ischemia, or Raynaud's phenomenon. PMR and TA are usually associated with an elevated erythrocyte sedimentation rate and C-reactive protein (CRP). Other laboratory abnormalities can include anemia, mild leukocytosis or thrombocytosis, mild elevations of liver enzymes, 150 especially of alkaline phosphatase, and, occasionally, of antiphospholipid antibodies. The diagnosis of TA can be proven by temporal artery biopsy, but the arterial giant cell inflammation can be patchy. Ideally, the biopsy includes a portion of the artery that is abnormal to palpation. The biopsy should sample at least an inch of artery, and multiple sections should be reviewed. If the findings from the first biopsy specimen are negative on frozen sections, biopsy should be performed on the contralateral temporal artery; the biopsy 151 specimen can still be positive if corticosteroid therapy has already been started. Central Nervous System Disease Headache is characteristic of TA and is the presenting symptom in about one third of patients. The headache has no pathognomonic features, so TA should be considered in everyone older than 50 years who develops new or different headache. Sudden visual loss is one of the most serious manifestations of TA. The usual mechanism is occlusion of the posterior ciliary artery causing anterior ischemic optic neuropathy. Monocular blindness may be sudden or evolve over a few days. Some patients have had a preceding episode of amaurosis fugax. Examination shows a relative afferent pupillary defect. Within a day or two, the optic disc swells; some patients have cotton wool spots or flame-shaped hemorrhages. It is unusual for TA to cause central retinal artery occlusion. Stroke or TIA can occur in patients with TA, and focal cerebral ischemia may even be the initial manifestation of TA. However, stroke affects probably less than 5 percent of patients
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152–155
with TA. Strokes affect the extradural carotid or, more commonly, vertebral, arteries. 156 Intracranial arteries, which lack internal elastic lamina, are rarely affected by TA. Peripheral Nervous System Disease TA affects the peripheral nervous system more often than the CNS. Ophthalmoparesis occurs in as many as 6 percent of patients: in TA, the differential diagnosis of abnormal eye movement includes brainstem stroke, isolated cranial neuropathy, and ischemic necrosis of 157,158 Patients can develop other ischemic cranial neuropathies. extraocular muscles. Peripheral neuropathy patterns can be of distal symmetric polyneuropathy, mononeuropathy, 159 or mononeuropathy multiplex. Carpal tunnel syndrome is the most common focal 160 neurological manifestation of PMR and is often one of the presenting symptoms. Treatment Corticosteroids are the initial treatment for TA or PMR. For patients with TA, the initial147 prednisone dose is at least 40 mg daily; many clinicians start at 60 mg daily or more. Given the risks of major neurological complications, corticosteroids should be introduced without delay in patients in whom the diagnosis of TA is very likely on clinical grounds, without waiting for the results of biopsy; if the biopsy results are negative, the decision to continue corticosteroids must be made on clinical grounds. Patients with sudden visual loss must be treated with especial urgency because the contralateral eye can be affected within days. Patients with acute visual loss can be treated with intravenous methylprednisolone, 1 g daily, for the first 3 days before switching to oral therapy. Daily corticosteroids are more effective 161 than alternate-day treatment. In a randomized, double-blind, placebo-controlled trial comparing corticosteroids alone to corticosteroids plus methotrexate, the methotrexate did 162 not reduce the relapse rate or the cumulative steroid requirements. Retrospective data suggest that patients with TA are less likely to have ischemic visual loss or stroke if treated 163 with antiplatelet or anticoagulation drugs. Patients who have PMR without148 TA usually respond dramatically to lower doses of prednisone (10 to 20 mg daily). Occasionally patients with mild symptoms can be treated only with nonsteroidal anti-inflammatory drugs.
Takayasu's Arteritis Systemic Disease Takayasu's arteritis, also called pulseless disease, is an idiopathic large-vessel vasculitis that involves the aorta, its major branches, and sometimes the pulmonary artery. It affects adults, almost always before the age of 40, women more than men, and is more common in those of Asian descent. In Olmstead County, Minnesota, the incidence was 2.6 per million 164 malaise, population. Early symptoms of the disease can include headache, fever, 165 myalgias, nausea, vomiting, anorexia, weight loss, and irregular menses. Patients may have erythema nodosa, objective evidence of synovitis, an elevated erythrocyte sedimentation rate or C-reactive protein, mild anemia, or peripheral leukocytosis. These systemic inflammatory findings often precede vascular stenosis or occlusion by weeks, but some patients present with acute ischemic events. Typical manifestations of impaired flow in large vessels include arm or leg claudication, decreased peripheral pulses or an asymmetry of blood pressure between the arms, or arterial bruits. Patients may develop hypertension, often associated with renal artery stenosis. Angina, Raynaud's phenomenon, and tenderness over inflamed arteries are less common findings. Aortic valve insufficiency can develop due to inflammation of the aortic root. The initial systemic symptoms and laboratory manifestations of inflammation usually recede spontaneously, leaving residual findings due to stenosed or occluded major arteries. Arteriography is needed to define the extent of arterial disease. The subclavian artery is the most commonly involved, but the aorta, carotid, vertebral, renal, coronary, iliac, mesenteric, 166,167 Many other illnesses merit consideration in the and pulmonary arteries are at risk. differential diagnosis of disease of the aorta and major arteries (Table 29-7). Biopsy of an involved artery can confirm the diagnosis of Takayasu's arteritis by showing arterial inflammation microscopically identical to the changes of giant cell arteritis. Click here to view this table.... Central Nervous System Disease
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Takayasu's arteritis may cause ischemic stroke due to carotid or vertebral artery inflammation, stenosis, or occlusion. Patients are at increased risk of cardiogenic embolus if they have aortic valve disease or myocardial infarction. Takayasu's arteritis does not affect the intracranial arteries, but hypertension increases the risk of intracranial arteriolar ischemic or hemorrhagic stroke. In patients with Takayasu's arteritis, the reported prevalence of carotid and vertebral lesions is variable (e.g., 13% to 44% for carotid, 7% to 19% for vertebral); the prevalence of stroke (6% to 8%) is lower than the prevalence of asymptomatic arterial 168,169 In another series, in which patients with Takayasu's arteritis were followed for a lesions. 170 mean of 7.4 years, the prevalence of stroke or death was 20 percent. Peripheral Nervous System Disease Takayasu's arteritis does not usually affect the peripheral nervous system. Treatment Corticosteroids are standard initial treatment for171,172 Takayasu's arteritis, but many patients do Small series report successful not improve or relapse when these are tapered. treatment with methotrexate, azathioprine, cyclophosphamide, or anti–tumor necrosis factor 166,173–175 Stenotic arterial lesions are sometimes bypassed surgically or treated therapy. 172 endovascularly with angioplasty, perhaps with stenting.
Behçet's Syndrome Systemic Disease Behçet's syndrome is a multifocal systemic inflammatory disease. Characteristic manifestations are oral and genital ulcers and uveitis; patients may also have asymmetric oligoarticular arthritis, skin lesions (erythema nodosa, pseudofolliculitis, papulopustular lesions, or acneiform nodules), CNS disease, epididymitis, intestinal inflammation or ulcers, thrombophlebitis, and even arterial occlusions or aneurysms. A widely used diagnostic criteria set for Behçet's syndrome requires recurrent oral ulcerations plus two of the following: recurrent genital ulcerations, eye lesions (anterior uveitis or retinal vasculitis), and skin 176 lesions. These criteria must be used with care since many of the manifestations, such as oral ulcerations or acneifrom rashes, are common in the general population. The median age at disease onset is the late 20s. Males are affected more often than females. Behçet's syndrome is most common in the so-called Silk Route countries, lying in a band across Asia from Japan to Turkey. The prevalence varies from more than 3,000 patients per million population in some surveys in Turkey to fewer than 10 patients per million in parts of Europe 177 and the United States. There is no specific laboratory test for Behçet's syndrome. The erythrocyte sedimentation rate or C-reactive protein is often elevated. The skin pathergy test, performed by pricking the skin with a sterile needle and watching for development of a sterile papulopustular reaction in 24 to 48 hours, is positive in many patients with Behçet's syndrome 178,179 Behçet's syndrome is often classified as a vasculitis because but is nonspecific. pathology includes inflammation of venules, but there are no diagnostic pathological findings. Central Nervous System Disease About 5 to 15 percent of patients with Behçet's syndrome have CNS inflammatory 180,181 Headache is common; if patients with headache but no other neurological disease. findings are counted, the prevalence of neurological disease appears much higher. Among patients with Behçet's syndrome, men are at higher risk than women for neurological disease. The neurological manifestations are most likely to appear a few years after the systemic manifestations, so the median age at onset of neuro-Behçet's syndrome is the early 30s. However, neurological disease is occasionally the presenting form of Behçet's syndrome. 182,183
The There are two distinct patterns of inflammatory brain disease, which rarely coexist. more common is focal brain inflammation that typically affects the brainstem or basal 180,181,184 Other possible sites of inflammation are the cerebral hemispheres or the ganglia. spinal cord. Patients usually have signs of bilateral pyramidal dysfunction, hemiparesis, headache, or sphincter dysfunction. Many have behavioral changes such as apathy or disinhibition. Less common findings include ophthalmoplegia, bulbar signs, sensory impairment, meningismus, and fever. Focal neurological syndromes that are seen infrequently include seizures, psychiatric disturbance, hearing loss, cerebellar syndromes,
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optic neuropathy, hemianopia, aphasia, aneurysmal subarachnoid hemorrhage, and 180,181,185,186 stroke. Focal brain inflammation in patients with Behçet's syndrome is sometimes asymptomatic, discovered at autopsy or by MRI. When neurological symptoms develop, they usually evolve over a few days and sometimes remit, but they may proceed in a relapsing progressive or primary progressive pattern (Fig. 29-1).
FIGURE 29-1 Patterns of symptoms in patients with neuro-Behçet's syndrome
and cerebral focal lesions. (Data from Akman-Demir G, Serdaroglu P, Tasçi B, et al: Clinical patterns of neurological involvement in Behçet's disease: evaluation of 200 patients. Brain 122:2171, 1999.) Brain MRI in those with focal brain disease shows lesions that are bright on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images and absent or dark on T1-weighted 187 images. Acute lesions can be bright on diffusion-weighted images. The lesions sometimes enhance and may have mass effect; they are more often multiple than single, are most 183,188 The CSF in patients prevalent in the brainstem or basal ganglia, and can be reversible. with focal brain inflammation often shows an elevated protein level or a pleocytosis, which 181 can be mononuclear or neutrophilic; oligoclonal bands are infrequently present. The neuropathology of neuro-Behçet's syndrome includes chronic lymphocytic meningoencephalitis and perivenular infiltrates of lymphocytes, neutrophils, eosinophils, or 189 plasmacytes. The second distinct, less common, CNS syndrome in patients with Behçet's syndrome is increased intracranial pressure, usually associated with dural sinus thrombosis rather than focal parenchymal brain inflammation. Most patients with this presentation have headache and papilledema. Unilateral or bilateral sixth cranial nerve palsy sometimes occurs but other lateralizing neurological findings are less common. CSF examination shows increased spinal fluid pressure; pleocytosis, subarachnoid hemorrhage, and elevated protein level are unusual findings. In many patients with this presentation, parenchymal lesions are absent, but dural
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Peripheral Nervous System Disease Disease of the peripheral nervous system is unusual in patients with Behçet's syndrome; however, case reports document instances of associated peripheral neuropathy or focal or 190,191 generalized myositis. Treatment There is no class I evidence for efficacy of treatment of neuro-Behçet's syndrome. Evaluation of therapy is complicated because attacks of brain inflammation may remit spontaneously. Experienced clinicians recommends treating attacks of focal CNS inflammation with 183 prednisone or intravenous methylprednisolone. Some add other forms of immunosuppression. There is anecdotal evidence192of efficacy of anti–tumor necrosis factor drugs in patients with severe Behcet's syndrome. Many patients with venous sinus thrombosis are also treated with heparin or low-molecular-weight heparin if there is not a 182,183 contraindication such as a systemic aneurysm. DIFFERENTIAL DIAGNOSIS The neurological complications of vasculitis or connective tissue diseases are sporadic manifestations of uncommon illnesses, much less common than the conditions that a neurologist sees daily, such as atherosclerotic stroke, idiopathic seizures, migraine headache, MS, or diabetic neuropathy. However, these inflammatory diseases are often treatable and merit consideration in the differential diagnosis of many neurological presentations. Diagnosis is further complicated because the classification criteria used for identification of rheumatic diseases were developed and validated in groups of patients with known systemic inflammatory disease and are insensitive to mild or early presentations. Often a thorough systemic medical history, general physical examination, and basic systemic laboratory work, such as a complete blood count, urinalysis, erythrocyte sedimentation rate, and serum metabolic panel provide the first clues that a patient with a neurological presentation actually has a systemic illness. The ACR list of neurological syndromes in SLE (Table 29-3 and Table 29-4) provides a framework for reviewing the neurological differential diagnosis.
Central Nervous System Syndromes Meningitis Acute, recurrent, or chronic aseptic meningitis is an infrequent complication of SLE, Sjögren's syndrome, Behçet's syndrome, PACNS, and systemic necrotizing vasculitis. The CSF usually shows a mild mononuclear pleocytosis, normal or elevated protein level, and normal or slightly depressed glucose concentration. Patients with Behçet's or Sjögren's syndrome occasionally have more neutrophils in the CSF. In all patients with inflammatory diseases and meningitis, a high priority is excluding infectious causes, especially in patients vulnerable to opportunistic infections. Drug-induced meningitis is another important diagnostic 21 consideration. 193
Pachymeningitis is visible on MRI as thickened, gadolinium-enhancing dura. Patients may be asymptomatic or have headache, cranial neuropathies, focal brain dysfunction, or seizures. If the gadolinium enhancement of the dura is diffuse and smooth, pachymeningitis must be distinguished from intracranial hypotension. Pachymeningitis is a rare late 84 complication of rheumatoid arthritis. Pachymeningitis has also occurred in patients with 193,194 Wegener's granulomatosus, Behçet's syndrome, Sjögren's syndrome, MCTD, and TA. Some cases of pachymeningitis are idiopathic, but infections and neoplasia must be excluded. Cerebrovascular Disease The diseases discussed in this chapter can cause strokes through a wide range of mechanisms. Patients with SLE or with primary antiphospholipid antibody syndrome are prone to nonbacterial endocarditis. Patients with vasculitis can develop myocardial infarction leading to secondary mural thrombosis or arrhythmia. Patients with SLE are at increased risk of atherosclerotic disease of the carotid and other major arteries. TA or Takayasu's arteritis can lead to vertebral or carotid artery stroke. A very unusual cause of vertebral artery stroke
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is arterial distortion due to cervical ligamentous laxity in a patient with long-standing 83 rheumatoid arthritis. Intracranial arteriolar disease can arise from secondary hypertension, cerebral vasculopathy (e.g., in lupus), or cerebral vasculitis (e.g., in PACNS). Patients with antiphospholipid antibodies have an increased stroke risk. In patients presenting with a first stroke, the cause is unlikely to be one of the diseases discussed in this chapter. Among 891 first ischemic strokes recorded in a registry, 4 patients 195 had PACNS, 3 had lupus, 1 had systemic necrotizing vasculitis, and 1 had TA. Among 48 patients with cerebral vein thrombosis, 5 had Behçet's syndrome, 2 had SLE, and 1 had 196,197 Intracranial hemorrhage, with varied underlying Wegener's granulomatosis. mechanisms, is an unusual complication of SLE, Behçet's syndrome, PACNS, systemic necrotizing vasculitis, Sjögren's syndrome, or large-vessel vasculitis. Further discussion of this topic is provided in Chapter 61. Relapsing-Remitting Multifocal Disease SLE, primary antiphospholipid antibody syndrome, and Sjögren's syndrome can cause relapsing-remitting multifocal CNS syndromes that might be confused with MS. Neuro-Behçet's syndrome can also have episodic recurrences. Rarely, primary angiitis of the 112 CNS can follow a relapsing-remitting pattern. The potential for confusion is increased because patients with MS at times have antinuclear, antiphospholipid, anti-Ro, or anti-La antibodies. Nonetheless, surveys in MS clinics rarely find patients in whom an underlying systemic inflammatory disease has been overlooked. Clues that favor one of the systemic inflammatory diseases are non-neurological systemic findings, associated peripheral neuropathy, a spinal MRI showing lesions that span more than two spinal segments, or a brain MRI that is atypical for MS with gray matter lesions or sparing of the corpus callosum. In Behçet's syndrome, the MRI often shows large confluent lesions involving the brainstem or 188 basal ganglia. Although oligoclonal bands or increased intrathecal IgG synthesis are sometimes seen in SLE, neuro-Behçet's syndrome, or Sjögren's syndrome, they are present in 90 percent of patients with MS, so that their absence should lead to attention to the differential diagnosis. Headache Connective tissue diseases or vasculitis may cause headache in many ways (Table 29-8). When patients have chronic recurrent headache consistent with migraine or tension headache, treatment is often symptomatic and no specific evaluation or anti-inflammatory treatment may be needed. Evaluation is much more complex if a patient has a new or different headache. TA is part of the differential diagnosis of new headache patterns in those older than 50 years. Patients with systemic inflammatory disease and headache need assessment for acute causes, such as stroke or meningitis. There are reported associations of intracranial hypertension and Behçet's syndrome, SLE, or Sjögren's syndrome; in these patients, cerebral sinus thrombosis must be excluded, especially in those with Behçet's 198,199 syndrome. Click here to view this table.... Movement Disorders This topic is discussed in Chapter 59. The best known association between movement disorders and systemic inflammatory disease is the chorea that can occur in SLE or primary antiphospholipid antibody syndrome. In addition, chorea is a rare occurrence in Sjögren's 54,143,200,201 Also unusual is parkinsonism due to syndrome, Behçet's syndrome, or vasculitis. 202–204 Some19cases are responsive to dopaminergic vasculitis or connective tissue disease. therapy, yet reversible with inflammatory treatment. Myelopathy Acute or subacute myelopathy is a rare occurrence in SLE, antiphospholipid antibody syndrome, Sjögren's syndrome, Behçet's syndrome, and vasculitis. Especially in 205,206 patients with large-vessel vasculitis, anterior spinal artery infarction is sometimes responsible. However, a more common presentation is as an inflammatory transverse myelitis. In a survey of patients with acute myelitis, 6 percent were associated with SLE, 1 percent with antiphospholipid antibody syndrome, and 9 percent with Sjögren's syndrome, compared to 43 207 percent caused by MS. Patients with systemic inflammatory disease usually had a CSF pleocytosis (mean, 35; maximum, 160 white blood cells per cubic millimeter) and mild protein
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elevation; one sixth had CSF oligoclonal bands. The spinal MRI is often helpful in distinguishing the myelitis of systemic inflammatory disease from the myelitis of MS, because in the former but not the latter, intramedullary lesions causing T2 bright signal on MRI often span two of more spinal segments. Every patient with myelopathy needs spinal imaging to exclude cord compression. Patients with rheumatoid arthritis and atlantoaxial joint dissociation are especially vulnerable to compression of the high cervical spinal cord. Seizures Patients with systemic inflammatory disease or vasculitis are at increased risk of seizures, ranging from single episodes, often attributable to secondary metabolic derangements or infection, to recurrent focal or generalized seizures, especially in patients who have had strokes or other focal brain lesions. When seizures occur in this setting, management requires characterizing the seizure type and investigating metabolic and structural causes. A number of anticonvulsants, including phenytoin, carbamazepine, valproic acid, and 208 lamotrigine, can cause drug-induced lupus ; however, drug-induced lupus rarely causes 209 CNS disease. The use of these drugs is probably not contraindicated in patients with SLE. Acute Confusional State Delirium and other manifestations of encephalopathy can complicate a number of diseases featured in this chapter. Sometimes the pathogenesis is directly related to the inflammatory disease through stroke or focal brain lesions. However, a number of other mechanisms, such as electrolyte disturbance, hepatic or renal failure, hypertensive encephalopathy, seizures, hypoxia, opportunistic infections, or drug toxicity, must be considered, as each requires specific treatment. Some unusual causes of encephalopathy also require specific management. Reversible posterior leukoencephalopathy, which can cause headache, delirium, seizures, visual or motor deficits, and characteristic white matter changes on brain CT or MRI, can be precipitated by severe hypertension, renal failure, or medications such as cyclosporine, cyclophosphamide, and corticosteroids and has affected patients with SLE, systemic 22,210 Treatment includes blood pressure control sclerosis, and Wegener's granulomatosis. and discontinuing offending drugs. SLE can be complicated by TTP (thrombotic thrombocytopenic purpura), which is characterized by encephalopathy, fever, renal failure, 211 microangiopathic hemolytic anemia, and thrombocytopenia. TTP can also present in patients with systemic necrotizing vasculitis, systemic sclerosis, rheumatoid arthritis, or Sjögren's syndrome. Primary treatment of TTP is plasmapheresis and high-dose pulse 212 corticosteroids. Progressive multifocal leukoencephalopathy is likely to cause insidious rather than acute changes in mental status. In addition, patients often have visual, motor, sensory, or speech deficits. A number of cases have occurred in patients treated with corticosteroids or other 213–215 immunosuppressants for treatment of vasculitis or connective tissue disease. Cognitive Dysfunction Waxing and waning subtle cognitive dysfunction is frequent in patients with SLE or Sjögren's syndrome. More severe dementia can occur in these illness, Behçet's syndrome, or vasculitis, particularly in PACNS. Dementia is one of the protean presentations of TA and can 216 improve with corticosteroid therapy. Affective or Psychotic Disorders SLE is the prototype of a systemic inflammatory disease that can cause depression, anxiety, or psychosis. Depression is also common in patients with rheumatoid arthritis, systemic 39,217–220 Depression can be a prominent aspect of PMR. sclerosis, or Sjögren's syndrome. There is ongoing debate on the relative roles of organic brain disease and of217 reaction to serious illness as the cause of affective disorders in many of these patients.
Peripheral Nervous System Syndromes Cranial Neuropathy
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The ACR list of neurological syndromes (Table 29-4) places cranial neuropathy under syndromes of the peripheral nervous system, even though optic neuropathy and nuclear cranial neuropathies actually are CNS lesions. Optic neuritis occurs in patients with SLE, antiphospholipid antibody syndrome, Behçet's syndrome, Sjögren's syndrome, systemic sclerosis, and systemic necrotizing vasculitis, but the association is uncommon. For example, perhaps 1 percent of patients with SLE or Behçet's syndrome develop optic neuritis. Conversely, of 457 patients in the Optic Neuritis 221 Treatment Trial, only two had a connective tissue disease. Clinically, the visual findings do not distinguish systemic inflammatory cases from idiopathic or demyelinating optic neuritis. MRI shows enlargement and enhancement of segments of222 the optic nerve in some cases, but this finding can also be seen in idiopathic optic223neuritis. In some patients, vision improves after treatment with cyclophosphamide. Patients with vasculitis, particularly those with TA, risk sudden visual loss from acute ischemic optic neuropathy. Cases have also been reported associated with rheumatoid arthritis or antiphospholipid antibody syndrome. Patients with Wegener's granulomatosis can also develop optic neuropathy from granuloma compressing the nerve or within the 135,224 nerve. Ophthalmoparesis is an exceptional event in patients with systemic inflammatory diseases, but when it occurs, careful neuro-ophthalmological and imaging examinations may be necessary to identify the neuroanatomical localization and cause (Table 29-9). Click here to view this table.... Trigeminal sensory neuropathy, unilateral or bilateral, especially in the maxillary and mandibular divisions is particularly associated with Sjögren's syndrome, systemic sclerosis, and MCTD. Ischemic cranial mononeuropathies, especially of the facial nerve, are unusual complications of SLE or vasculitis. The annual incidence of Bell's palsy is far higher than the prevalence of SLE, and cranial neuropathies occur in less than 1 percent of lupus patients. Most patients with isolated cranial mononeuropathies do not need extensive evaluation for vasculitis or connective tissue disease, unless there are other clues to suggest systemic illness. Similarly, most225,226 cases of trigeminal neuropathy are not attributable to systemic However, in patients with painless, purely sensory neuropathy of inflammatory disease. 227 the lower face, connective tissue disease deserves more consideration. Acute Inflammatory Demyelinating Neuropathy Literature review suggests that patients with SLE or rheumatoid arthritis have an increased incidence of Guillain–Barré syndrome. An association is plausible because of the tendency of autoimmune diseases to overlap, but there are few data on whether this reflects a true 228 association or publication 229,230 bias. Case reports link other connective tissue diseases to Antiphospholipid antibodies can appear transiently in patients Guillain–Barré syndrome. with Guillain–Barré syndrome and are not by themselves diagnostic of antiphospholipid antibody syndrome. An alternative but uncommon explanation for acute ascending paralysis in patients with lupus or vasculitis is fulminant vasculitic neuropathy. Chronic inflammatory demyelinating polyneuropathy is also linked to systemic inflammatory diseases in case 231,232 reports. Dysautonomia Autonomic neuropathy, with or without sensory neuropathy or neuronopathy, may complicate a number of connective tissue diseases, including rheumatoid arthritis, SLE, Sjögren's 233 syndrome, and systemic sclerosis. In these illnesses autonomic deficits are more likely to be found on physiological testing than to be symptomatic. Mononeuropathy Multiplex Vasculitis is a common cause of mononeuritis multiplex. About one fourth of patients with mononeuropathy multiplex have nonsystemic vasculitis neuropathy and another one fourth 122 have some form of systemic necrotizing vasculitis. Nerve vasculitis can also be secondary to other systemic diseases, such as the vasculitis of rheumatoid arthritis, infectious vasculitis (especially in association with hepatitis B, hepatitis C, and human immunodeficiency virus 234 infection), vasculitis with132 sarcoidosis, or paraneoplastic vasculitis (especially in association with T-cell lymphomas). Diabetic amyotrophy, diabetic radiculopathy, and other manifestations of multifocal asymmetric diabetic neuropathy are often associated with
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vasculitis in the affected nerves, a pattern that is unusual in diabetics whose neuropathy is 235 limited to the more common distal symmetric pattern. Mononeuritis multiplex is unusual in patients with SLE or Sjögren's syndrome. Other causes of asymmetric multiple neuropathies include Lewis–Sumner syndrome, multifocal motor neuropathy with conduction block, neuralgic amyotrophy, compression neuropathies superimposed on more symmetric neuropathies especially in patients with hereditary liability to pressure palsies, amyloidosis, neoplastic nerve infiltration, Lyme disease, porphyria, and leprosy. Myasthenia Gravis Patients with myasthenia gravis have an increased incidence of other autoimmune diseases. The prevalence of rheumatoid arthritis in patients with myasthenia gravis may be 2 or 4 236–238 percent. 237
The prevalence of SLE is also increased in patients with myasthenia. Case reports link 239 Myasthenia can be a toxic effect of penicillamine or SLE and Lambert–Eaton syndrome. 240,241 chloroquine. Polyneuropathy Distal symmetric axonal polyneuropathy can accompany many of the illnesses discussed in this chapter. For example, perhaps one fifth of patients with SLE or Sjögren's syndrome have clinical peripheral neuropathy. Distal sensory neuropathy can be a late finding in rheumatoid arthritis. Vasculitic neuropathy in NSVN or systemic necrotizing vasculitis sometimes causes a distal relatively symmetric clinical pattern. Neuropathy occurs much less frequently in patients with systemic sclerosis, Behçet's syndrome, or TA. Some of the drugs used in treatment of inflammatory diseases, including gold, chloroquine, colchicine, and penicillamine, can cause neuropathy. In patients with multifocal CNS disease, concomitant peripheral neuropathy does not rule out MS but can alert the clinician to check carefully for SLE, Sjögren's syndrome, and vasculitis among a number of other systemic illnesses (Table 29-10). Click here to view this table.... THERAPEUTIC CHOICES There is a paucity of class I data on treatment of the neurological manifestations of connective tissue disease or vasculitis. The rarity and diversity of these syndromes make it difficult to design prospective, randomized, controlled treatment trials. Therefore, the more extensive experience in treating systemic manifestations of lupus or vasculitis is often extrapolated to treating neurological disease. Glucocorticoids and cyclophosphamide are the therapeutic mainstays. Other immunosuppressants such as azathioprine, methotrexate, or cyclosporine are used at times. Newer approaches to immunomodulation, such as anti–tumor necrosis factor (TNF) agents, are sometimes tried. The choice of neurological therapy depends more on the severity of the neurological complication than on underlying systemic diagnosis. Thus, mononeuritis multiplex, myelitis, symptomatic focal brain lesions, or optic neuritis often warrant aggressive immunosuppression. In contrast mild peripheral neuropathy, recurrent headache, or subtle cognitive problems might be treated symptomatically. Syndromes such as myasthenia gravis and Guillain–Barré syndrome, in which antibodies play a direct pathogenic role, often respond to plasmapheresis or IVIg. For conditions causing stroke, the mechanism of ischemia determines the appropriate type of treatment. These are complex therapeutic decisions that emphasize the challenges and rewards of treating patients who have the diseases discussed in this chapter. ACKNOWLEDGMENT The author thanks Stephen M. Campbell, MD, for his thoughtful critique of this chapter. Previous
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Table of Contents This Chapter by Chapters
Keyword Index
Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 30 Psychiatry and Neurology MICHAEL R. TRIMBLE •
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PSYCHIATRIC CONSEQUENCES OF NEUROLOGICAL DISEASE Generalized Cerebral Disturbances Symptoms of Regional Dysfunction Frontal Lobe Syndromes Temporal Lobe Syndromes Disorders of the Basal Ganglia Summary NEUROLOGICAL PRESENTATIONS OF PSYCHIATRIC ILLNESS Patient Response to Illness Somatoform Disorders Nonepileptic (Pseudo) Seizures Briquet's Syndrome or Somatization Disorder Abnormal Illness Behavior Somatoform Disorder Variants Affective Disorders Post-traumatic Stress Disorder PSYCHIATRY AND NEUROLOGY
Many close links exist between neurology and psychiatry. Historically, neurology grew out of psychiatry (or, rather, neuropsychiatry), which was a well-established discipline by the nineteenth century. The divergence of the two, which in part related to the success of localization theories in predicting central nervous system (CNS) lesions, took place mainly during the twentieth century and was accelerated by the rapid acceptance of psychoanalytical theories into the main body of psychiatric thinking. Although this was predominantly an early-century phenomenon, its legacy has lingered, with the relative failure of many to appreciate that psychiatry, in contrast to psychology, has rediscovered its biological and neurological underpinnings during the past few decades. The associations with neurology have become, once again, more obvious. The cornerstone of pathogenesis for psychiatry and neurology in recent years has been the discovery of several neurotransmitters that affect behavior and the elaboration of the functions of the limbic system, a series of interconnected neurons and pathways that modulate emotional function. The latter has provided a secure cornerstone for the neuroanatomical and neurochemical underpinnings of psychiatric disorders and formed the
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basis for the extension of localizationalist neuropsychology into the discipline of behavioral neurology. Thus, whereas biological psychiatry seeks an understanding of disturbances of the limbic system and related structures in association with primary psychiatric illness, behavioral neurology has become concerned not only with the behavioral consequences of cortical damage, as reflected in the aphasias and other problems, but also with the consequences of localized dysfunction of, for example, the temporal and frontal lobes of the brain and their behavioral correlates. The closely associated discipline of neuropsychiatry has become an accepted subspeciality in many countries. In this chapter, some of the relationships between neurology and psychiatry are examined, identifying two main areas. First, some psychiatric aspects of neurological disorders are presented, followed by neurological presentations of psychiatric disorders. PSYCHIATRIC CONSEQUENCES OF NEUROLOGICAL DISEASE Although the term psychiatry strictly refers to “the medical treatment of diseases of the mind,” in its broader sense, psychiatrists and neurologists deal with behavior problems. As a generalization, it may be said that in the past neurologists tended to be interested in the abnormal behavior of single elements of a person's repertoire and, on the whole, deal with negative1symptoms (i.e., loss of function in the sense given to it by John Hughlings Jackson ), whereas the psychiatrists' concern lies in alterations of function of the whole person, with a particular interest in positive symptoms: those that “answer to activities of healthy nervous arrangements…[which] attend activities of all which is left intact in a nervous 1 system maimed by dissolution.” The consequences of neurological disease for behavior may thus be broken down into two broad categories: general effects and those that are provoked by a focal lesion.
Generalized Cerebral Disturbances In contrast to the focal symptoms described later, patients with neurological insults often display symptoms that appear to coalesce into a recognizable but variegated pattern. However, no specific symptom or group of symptoms is pathognomonic, and, unless they are inquired about, such symptoms are often not noticed or recorded; in many cases, they are 2,3 trivialized. These generalized disturbances were of particular interest to authors in the past 4 and have not received such attention in recent times. Several expressions of CNS disintegration, which could be seen regardless of the involved region of the brain, were presented (Table 30-1). The pattern of symptoms depends on the premorbid personality of the patient, which tends to be exacerbated by any central neurological lesion, and also on the extent of the injury. Although patients with more severe brain damage may show such symptoms, they can also be seen to a varying degree with much less severe trauma. Some symptoms overlap with those of post-traumatic depression or post-traumatic stress disorder, particularly those observed in the postconcussional syndrome and later post-traumatic syndromes that follow minor head injury. Click here to view this table.... Typically, patients complain of “not being the same.” They note that their memory is poor, although often underlying this problem is a disturbance of attention or concentration. They find prolonged attention to, for example, a book or a television program fatiguing and complain that they do not remember everyday events. Their emotional reactions appear labile, and, particularly with more severe damage, they may also appear “flattened.” Outbursts of anxiety, recurrent depressive episodes, and irritability in interpersonal relationships are noted. Patients may become withdrawn from their usual company, preferring to spend more time alone in familiar surroundings and not looking forward to such everyday events as traveling or engaging in social activities. They complain that their mind is “empty,” and they do not know what to say to people. Disturbances of attention are common after cerebral injury. The term stimulus binding is sometimes used with reference to distractibility, in which an environmental stimulus may lead to an altered sphere of attention for the patient. An impairment of mental agility leads to concretization, in which thoughts are bound to immediate experiences and mental flexibility is lost. The patient is unable to grasp the essential of a given whole, and abstracting common properties, with planning ahead ideationally, becomes difficult. The blurring of sharp boundaries and the difficulty of extracting the details from situations lead to impaired judgment. The patient's general demeanor may be characterized by a lack of spontaneity, organic orderliness (akin to obsessionality, but usually not so severe as to present as an obsessive-compulsive disorder), personal neglect, diminished social awareness, and inappropriate behavior.
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After lesser head injury, when the post-traumatic amnesia is limited, patients may report symptoms that reflect a post-traumatic stress disorder and its interaction with the premorbid personality. Such patients also often report an increase in emotionality, disturbed affect with depressive symptoms, a tendency to withdraw from company, poor memory and concentration, increased distractibility, irritability, and poor tolerance for ordinary environmental stimuli. For example, they may complain that everyday noise has become intolerable. In patients with subtle brain damage, such symptoms tend to blend with the mental symptoms of generalized organic damage described previously, such that unraveling the organicity of the symptomatology becomes difficult. The constancy of symptomatology of a postconcussional syndrome, with irritability, memory complaints, dizziness, fatigue, and social withdrawal, suggests neurological underpinnings, but the clinical picture may, after a time, blend into a depressive disorder or a recognizable anxiety syndrome such as a panic disorder. Often the question arises as to whether these enduring reactions are occasioned by underlying cerebral damage, a view so easily enforced in a patient's mind by overemphasis on the head injury that originally sparked the syndrome. Neurological indices are usually normal, including magnetic resonance imaging (MRI), and, as time goes by, the psychological as opposed to the neurological flavor of the symptoms becomes apparent. If excessive dependency develops, a somatoform disorder may be suspected, and careful attention to the pretraumatic medical and psychiatric history will reveal the diagnosis.
Symptoms of Regional Dysfunction Frontal Lobe Syndromes 5
Although there are extensive accounts of frontal lobe syndromes, it is surprising how often frontal lobe damage goes unnoticed and frontal lobe symptoms are dismissed as unimportant. The clinical 6characteristics of three principal frontal lobe syndromes, as described by Cummings, are shown in Table 30-2, although many patients show an admixture of symptoms, and such discrete syndromes are rarely observed. Click here to view this table.... One of the specific deficits of frontal lobe damage is poor attention; these patients also show increased distractibility. They often present with poor memory, the latter sometimes being referred to as “forgetting to remember.” Another feature of the memory disorder is a failure to integrate events into a proper temporal sequence, remembering what, but not when. The thinking of patients with frontal lobe lesions tends to be concrete, and they may show perseveration and stereotypy of their responses. Perseveration, with the inability to switch lines of thought, leads to difficulties with arithmetical calculations such as serial sevens or carryover subtractions. Patients have no anomia, and repetition is intact, although they may have difficulty with spontaneous conversational and propositional speech. This syndrome is similar to that referred to as transcortical motor aphasia and has been designated dynamic aphasia. Other features of frontal lobe syndromes include reduced activity, lack of drive, and inability to plan ahead. Patients show lack of concern and often display aimless, uncoordinated behavior. Their affect is disturbed, with apathy, emotional blunting, and indifference. Clinically, this picture sometimes resembles that of a major affective disorder with psychomotor retardation. In contrast, other patients may show euphoria and disinhibition, but the euphoria is not that of a mania, having an empty emotional quality to it. The disinhibition can lead to markedly abnormal and sometimes antisocial behavior. Other clinical signs associated with frontal lobe damage include sensory inattention in the contralateral sensory field; abnormalities of visual searching; echophenomena; confabulation; hyperphagia; imitation behavior in which patients literally imitate the actions of the investigator, however inappropriate they may be; and so-called utilization behavior, an exaggerated tendency to grope for objects and “overuse” them. Some authors have distinguished between lesions of the lateral frontal and orbital cortex. The lateral frontal cortex is closely linked to the motor structures of the brain, and lesions in that area therefore lead to disturbances of movement and action, with perseveration and inertia. Lesions of the orbital areas, which are linked with the limbic and reticular systems, lead to disinhibition and changes of affective life. The features of these two syndromes and those of the medial frontal syndrome are shown in Table 30-2. The third syndrome is the medial frontal-cingulate syndrome, which leads to an apathetic, sometimes abulic (complete lack of will) picture, which, without careful consideration, may be mistaken for a major depressive
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disorder. In clinical practice, various tests are used to detect frontal lobe damage. If only traditional neurological and neuropsychological testing is performed, frontal lobe pathology may go unnoticed. This point cannot be overemphasized, namely, that the traditional basic neurological examination essentially seeks an alteration of function in the parietal and occipital cortices and in general does not reflect frontal and temporal lobe function. When the latter areas of the brain are damaged, the patient's motor and psychic activities are influenced, and the resulting behavior disturbances reflect the pathology. Some useful tests of frontal lobe function are given in Table 30-3, fuller descriptions being 5,6 given elsewhere. A number of syndromes of abnormal awareness have been related to frontal pathology, exemplified by Capgras' syndrome, in which patients acknowledge a person as looking like a relative or friend but maintain they are someone else in disguise. Another such disorder is reduplicative paramnesia, in which patients relocate their environment; they may know, for example, that they are in a hospital bed but also “know” that they are at home. Click here to view this table.... Various pathological processes lead to frontal lobe damage, including trauma, tumors, cerebrovascular accidents, infections, and some degenerative diseases. Of the dementias, Pick's disease and other frontotemporal dementias and normal-pressure hydrocephalus specifically affect this area. Characteristically, among various tumors, frontal meningiomas, especially if slowly growing, are likely to be missed and may lead to florid psychopathology. Anterior cerebral artery rupture is more likely to lead to frontal lobe damage than other cerebrovascular disorders, although the middle cerebral artery does supply the lateral parts of the orbital gyri and the inferior and middle frontal gyri. Intoxicants such as alcohol may preferentially damage frontal areas, and demyelinating conditions such as multiple sclerosis may also lead to frontal lobe problems. The evidence of frontal lobe involvement in depressive illness, obsessive-compulsive 7 disorder, and schizophrenia is increasing. Suffice it to say here that a number of the “negative” symptoms of schizophrenia (e.g., affective changes, impaired motivation, poor insight, and other “defect” syndromes) probably relate to abnormalities of the dorsolateral frontal cortex. Abnormalities of the frontal lobes in schizophrenic patients have been noted not only from neuropathological studies but also from clinical signs of frontal lobe deficits, neurophysiological studies, neuropsychological studies, and brain imaging studies. In affective disorders, the most consistent abnormalities on imaging are reported in the 8 subgenual region of the medial prefrontal cortex, changes here being identified in depressive disorders, with a change of activity correlating with treatment with a variety of methods including antidepressant therapy and psychotherapy. Of interest, abnormalities at this site are not found in investigations9of schizophrenia. This is a target area for deep brain stimulation for the affective disorders. The frontal lobes are particularly likely to be damaged during head injury. The relative lack of movement in the frontal and temporal lobes, held rigid by the bony anterior fossae of the calvarium, leads to strains in cerebral tissue, with lacerations and damage at these sites on impact. Patients often complain of a number of symptoms reminiscent of frontal lobe damage, but traditional neuropsychological investigation as well as routine neurological examination may be normal. It is in such patients that there should be a high level of alertness to the possibility of frontal lobe/limbic system damage, and symptoms should not be dismissed lightly. Tissue damage may be revealed by magnetic resonance imaging, the more so with newer high-resolution and tract-tracing methods. Temporal Lobe Syndromes Although a variety of pathological processes affecting the temporal lobes lead to psychopathology, most interesting and perhaps most controversial are the changes of behavior that are secondary to epilepsy that derives from the temporal lobes. This subject is 10 reviewed in more detail elsewhere. Of the various psychopathologies related to epilepsy, personality disorders and psychoses have been the subject of most debate. A considerable amount of confusion in the literature has been created by the failure of various authors to use precise terminology. Thus, with regard to personality disorder, there has been a confusion of two concepts. The first, a holdover from the earlier part of the twentieth century and the era of psychosomatic medicine,
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relates to the idea of disease-susceptible personalities. This concept was that patients with certain personality types and constitutions were susceptible to various diseases—hence, the epileptic personality. There are few adherents to such concepts today, but the second belief is very much alive. Essentially, this view holds that patients with chronic brain lesions, especially in their temporal lobes, may acquire personality changes as a direct manifestation of an organic brain syndrome. The precedent for this theory was set in the mid-twentieth century by the clear delineation of the frontal lobe personality profiles and the discovery of behavioral changes in animals after bilateral temporal lobectomy, as seen in the Klüver–Bucy syndrome. The latter include visual agnosia, increased sexual activity, and a decrease of anxiety and aggression. This pattern is sometimes seen in patients with bilateral temporal lobe damage, for example, after head injury, or in some dementias such as Pick's disease, in which the amygdala is affected early. The idea that there is a specific interictal syndrome or personality profile of patients with temporal lobe epilepsy has been most strongly argued from the clinical point of view by 11 Geschwind. He included hyposexuality, hyperreligiosity, and hypergraphia (the tendency toward extensive and compulsive writing) as its main12features. Several studies have been carried out on hypergraphia, as reviewed by Trimble, and these suggest that it occurs in a small number of patients with epilepsy, as an all-or-nothing phenomenon and is probably more common in right-sided temporal lobe epilepsy. The writing tends to have an obsessional stereotypic quality to it and often has religious, moral, and philosophical content. Variations on hypergraphia include the hiring of a stenographer to take down extensive notes or compulsive, repetitive painting or drawing. A different form of hypergraphia is sometimes seen in frontally damaged patients with utilization behavior, and hypergraphic schizophrenic script is commonly observed, overflowing with psychotic denotation. Hyposexuality is the predominant theme of any change in sexual behavior related to epilepsy, although there are few controlled studies. In those that have been carried out, significantly more patients with temporal lobe epilepsy reported hyposexuality compared to those with generalized forms of epilepsy, with patients often reporting a global loss of sexual interest and showing little concern about it. Thus, the link between low libido and temporal lobe dysfunction requires further evaluation, taking into account possible hormonal changes, which may be noted in patients with epilepsy. These include low free testosterone levels in male patients, which may be related to hepatic enzyme–inducing anticonvulsant drugs or consequent to a temporal lobe focus. The relationship between aggression and epilepsy is one that has caused considerable disagreement. There is no doubt that aggressive behavior is a common cause of referral of epileptic patients to psychiatrists, and several authors have tried to correlate aggressive behavior with abnormal limbic system (especially amygdala) activity. One of the difficulties has been in distinguishing the effects of diffuse brain damage from the effects of more discrete limbic system disease. Brain imaging studies have shown associations between thinning of the frontal cortex (especially left sided) 13 and amygdala size (decreased) in patients with epilepsy presenting with extreme aggression, suggesting some biological correlates, in keeping with the anatomical sites implicated in animal models of aggression. Epilepsy should never be diagnosed in people presenting with aggressive outbursts unless there is a clear history of a seizure disorder. Even then, the contribution of the seizures needs careful consideration, since ictal as opposed to postictal aggression is quite rare. 14
Another area of controversy has been that of the interictal psychoses. All neurologists have encountered acute psychotic disturbances in patients during the peri-ictal period; on occasion, and especially in complex partial status epilepticus, the phenomenology can resemble a schizophrenia-like illness in its entirety. However, the concept that patients with temporal lobe epilepsy may be more prone to the development of interictal psychotic disorders is less recognized. The literature emphasizes the absence of abnormal premorbid personality traits or a family history of psychiatric disturbance and an overrepresentation of temporal lobe abnormalities. Certain phenomenological differences between patients with schizophrenia and the schizophrenia-like illness of epilepsy have been noted, in particular the preservation of a warm affect and the lack of personality deterioration. The interictal psychoses of epilepsy are by no means rare, occurring in approximately 8 to 10 percent of patients with complicated temporal lobe epilepsy. The psychosis is not necessarily continuous but may be intermittent and may be provoked or exacerbated by a flurry of seizures. In other patients, the development of the psychosis is insidious and chronic, and in a small percentage of patients, it is related to a decrease in seizure frequency. In a subgroup of patients, subtle forms of psychosis can be difficult to detect. These patients are usually learning disabled and poorly expressive. They gradually become withdrawn and suspicious, but frank hallucinations or delusions are hard to elicit. Their speech is
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circumstantial, and their thought patterns seem disjointed. This picture may be misinterpreted as an intellectual decline secondary to a dementing syndrome or an encephalopathy. The schizophrenia-like presentations of epilepsy nearly always occur in patients with temporal lobe epilepsy who have complex partial seizures, often with secondary generalization. Further attempts to analyze the anatomical site of lesions in such patients suggest that it relates to a medial temporal and often a dominant hemisphere focus. Most authors agree that the psychosis develops a number of years after the onset of seizures, and there are few patients in whom seizures first occur after the onset of the psychosis. Of course, there are patients with schizophrenia in whom seizures develop secondary to the administration of neuroleptic drugs or electroconvulsive therapy. However, seizures otherwise are relatively uncommon in patients with schizophrenia, with the exception of those who have a catatonic schizophrenia. Manic psychoses are generally rare, and an interictal bipolar disorder is considered uncommon. Manias and hypomanias are most often seen in a postictal state, as one of the postictal psychoses; all reported cases have been with right-sided temporal lobe epilepsy. The postictal psychoses are important clinically and are reported more frequently with the development of inpatient video telemetry units. They usually occur after a cluster of seizures and are not simply a postictal delirium. Thus, they often follow a lucid interval in which the patient is calm and behaving normally, which can be from 24 hours to several days in duration. The psychosis is quite florid, with hallucinations and delusions, often with relatively clear consciousness. Religious delusions are common, and death by suicide is an ever-present possibility since such patients often experience command hallucinations and have a clear or relatively clear sensorium. In fact, the spectrum of postictal psychopathology is quite wide and includes depression, anxiety disorder, and panic disorder. The key to the diagnosis is the persistent presentation of a very similar psychopathological disorder within 15 about 24 hours of a seizure. There has been increasing utilization of temporal lobectomy as a treatment for intractable temporal lobe epilepsy. In many centers, patients are now evaluated psychiatrically before surgery, and there is increasing recognition that in a proportion of patients (20% to 40%), psychopathology develops after surgery. In many, this is a transient affective disorder or an emotional lability occurring in the first 3 months. However, severe depressive illness, manic states, suicidal ideation or acts, and occasional schizophrenia-like states that arise de novo 14 are reported. The more severe psychopathologies seem to arise in patients after right temporal resections, and preoperative predictors for the emergence of psychopathology include psychopathology itself, pseudoseizures, evidence of bilateral interictal electrophysiological changes, and poor psychosocial circumstances. There may also be a link with the resection of gangliogliomas. The necessity for psychiatric follow-up of these patients is clear. 16
Forced normalization is an important concept introduced by Landolt. He described a paradoxical relationship in patients with epilepsy between changes in the electroencephalogram (EEG) during limited periods of overt psychoses that lasted days or weeks. In particular, he reported improvement in previously abnormal EEGs during these episodes and referred to this EEG phenomenon as “forced normalization.” At the end of the psychotic episodes, the EEG again appeared abnormal. Although he was initially concerned with partial seizures, in his later writings, he accepted the idea that forced normalization occurred with generalized seizures and could be provoked by the prescription of anticonvulsant drugs. The term alternative psychosis has been used to emphasize the absence of seizures rather than normalization of the EEG during these psychoses. It implied that in some cases, the control of seizures did not mean the cure of the clinical problems or inactivity of any underlying disease process of epilepsy and that psychosis may occur as a result. These antagonisms occur in only a few patients but clinically are extremely important. Not only is the behavior disturbance in such patients often misunderstood and not interpreted in the light of seizure control, but it is now recognized that this phenomenon relates not only to psychoses but also to some other behavior disturbances. Common examples are conduct behavior disturbances in children and depressive illnesses or the sudden presentation of pseudoseizures in adults who are taking a variety of anticonvulsant drugs to bring their epileptic seizures under control. The drugs most commonly involved in the provocation of these syndromes are the barbiturates, benzodiazepines, and several of the newer antiepileptic agents such as tiagabine, topiramate, vigabatrin, and zonisamide. Disorders of the Basal Ganglia It has long been recognized that the basal ganglia have an important role in the development
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of psychiatric symptoms and that patients with basal ganglia disorders often present with psychopathology. Neuroanatomical techniques have unraveled some of the neurobiological underpinnings of this relationship. In particular, recognition of multiple parallel circuitry involving cortical structures and the basal ganglia has permitted distinction of the dorsal striatum (with its interconnections with the neocortex) from the ventral striatum (with its largely limbic, orbitofrontal, and cingulate connections). Furthermore, it is recognized that there is considerable cross-talk between the limbic system and the basal ganglia, allowing an understanding of the relationship between emotional and motor disorders. The concept of the extended amygdala has contributed much to this debate. This emphasizes the anatomical limbic-motor bridges between the amygdala and the ventral striatum, in part through the stria terminalis. The amygdala, with multisensory cortical inputs, has a wide range of efferents to cortical, limbic, and subcortical structures, investing considerable portions of the cerebral mantle with emotional valence. The ventral striatum, especially the accumbens, is a basal ganglia 17 structure that traffics motivational and emotional information. The concept that the basal ganglia are purely motor in function has long ceased to be part of neurological dogma. Huntington's disease exemplifies a neurological disorder that frequently presents with a psychiatric disturbance. As many as 50 percent of patients with Huntington's disease present with psychopathology before they manifest motor disorders. This ranges from behavioral disturbances, with psychopathic behavior and alcoholism, to more obvious manic-depressive psychoses and paranoid and schizophrenia-like states. Eventually, these cease to be the predominant clinical features as the dementia progresses. Parkinson's disease is associated with a depressive illness in as many as 60 percent of patients. This is often an atypical affective disorder with considerable associated anxiety, but it may also take the form of a classic unipolar depression. Psychotic states are increasingly recognized, particularly in patients with Parkinson's disease who have been on dopamine 18 agonists for several years. These may begin with simple hallucinations, for which the patient had full insight, or present as nocturnal ramblings associated with some confusion. They progress to complex hallucinations with florid scenes often involving many people, perhaps occupationally related, for which insight is lost. They are often threatening in nature, and a paranoid anxiety is an accompanying affect. They last for variable lengths of time. The extent to which medication and the underlying disease processes are interlinked with these phenomena is unclear. The misuse of dopamine agonists, with repeated self-overdosing, is now well recognized. This can have considerable social consequences, especially if associated with 19 hypersexuality, compulsive gambling, or other antisocial activities (Table 30-4). The psychiatric disorder may be extremely difficult to treat because drugs that control the psychoses are likely to exacerbate the movement disorder. Certain antipsychotic agents, exemplified by clozapine, quetiapine, and olanzapine, are proving useful in these conditions. Click here to view this table.... The Gilles de la Tourette syndrome, a condition of multiple motor and vocal tics that starts in childhood and waxes and wanes over time, is associated with hyperactivity syndromes such as attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, and self-mutilation. In many cases, the associated psychopathologies are the most difficult aspect of management and require a multidisciplinary approach. It is now suggested that underlying these states may be an autosomal-dominant gene that has varying phenotypes that include 20 Gilles de la Tourette syndrome, multiple motor tics, and obsessive-compulsive disorder. The clinical entity of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) is a related syndrome characterized by tics and obsessive-compulsive disorder following a group B streptococcal infection. There is a growing body of literature in psychiatry showing disturbed frontostriatal function in obsessive-compulsive disorder. A number of other disorders of the basal ganglia are associated with obsessive-compulsive behaviors, including Parkinson's disease, Fahr's 21 syndrome, neuroacanthocytosis, Wilson's disease, and Sydenham's chorea. The drugs used to treat psychoses, particularly the neuroleptics, are associated with the development of movement disorders, notably parkinsonism and tardive dystonia and tardive dyskinesia. Biological associations can therefore be postulated between such neurotransmitters as dopamine and both motor dysfunction and severe psychopathology. Summary
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Certain regional CNS disorders have been reviewed to emphasize one important aspect of the relationship between psychiatry and neurology, that is, the way in which neurological illness can precipitate or predispose to behavior disturbances. These areas need assessment by physicians who are familiar with the vagaries of behavior disorders and their prognoses and differing modes of presentation. The fact that a number of neurological conditions present with behavior disorders that phenomenologically resemble psychiatric conditions (e.g., the schizophrenia-like psychoses of epilepsy) makes them important models for understanding the neurological underpinnings of psychiatric illnesses and emphasizes the close links between psychiatry and neurology. The counterpart to this idea is the increasing evidence that many patients with psychiatric disorders have impaired neurological function or structural changes in the brain, as detected by the newer investigative techniques. In essence, this argument is merely continuing the progress made from previous centuries, in that behavior disorders have increasingly come to be associated with recognized neuropathology. Obvious examples from the nineteenth century include Parkinson's disease, multiple sclerosis, and general paralysis of the insane (earlier “neuroses”), whereas in the twentieth century the neurological underpinnings of dementia have became clearer. Furthermore, the evidence is now overwhelming that schizophrenia represents the outcome of neuropathological processes as yet to be clearly defined. Most investigators view it as a neurodevelopmental disorder, with subtle neuropathological changes in the hippocampus and related anatomical areas leading to the later onset of the psychotic state. An interesting analogy is with temporal lobe epilepsy. In that condition, a specific pathological process (mesial temporal sclerosis) may be the seed for the later onset of seizures (and, in some patients with temporal lobe epilepsy, a psychosis). Disturbances of the limbic system in particular are most likely to present with behavior disorders. Nevertheless, there are other neurological disorders that have obvious behavioral counterparts such as some aphasias and, in particular, cortical nondominant (right) hemispheric lesions. The confusion of a fluent aphasia punctuated with neologisms occasionally can be mistaken for a schizophasia, but close evaluation will reveal the associated neurological impairments or the underlying nature of the paranoid delusions in schizophrenia. Aprosodias, in which the melodic and intonational aspects of speech are lost, occur following nondominant hemisphere lesions in areas equivalent to those associated with language in the left hemisphere. Gesture is usually reduced in patients with dysprosody, and patients often have considerable difficulty in communicating their feelings, leading to an underestimation of their distress. The angular gyrus syndrome, which occurs following lesions of the left angular gyrus, produces a Gerstmann's syndrome (agraphia, acalculia, right-left disorientation, and finger agnosia) with, in addition, constructional disturbances, apraxia, alexia, and memory problems. The clinical picture can be so confusing that it is easily mistaken for Alzheimer's disease or for a non-neurologically based cognitive pseudodementia. Neuropsychiatric syndromes following right hemisphere dysfunction are often unrecognized. If a patient has a left hemisphere stroke, the resulting aphasia typically leads to instant referral to a neurologist. However, nondominant hemisphere lesions often present with psychopathology and the neurological underpinnings of their symptoms are missed. Secondary manias occur following lesions of the orbitofrontal cortex–basal ganglia circuitry. Depression is most frequently associated with right posterior cortical lesions, whereas delusions may arise with lesions of the right temporal lobe or temporoparietal junction. Misidentification syndromes, such as Capgras' syndrome, are more common with right-sided lesions. The psychiatric syndromes, particularly psychoses and depressions, following right hemisphere insults are difficult to treat and have a poor prognosis. Some of the neuropsychiatric syndromes reported in patients with right-sided brain lesions are shown in Table 30-5. Indeed, the22considerable importance of the right hemisphere for psychiatry is only just becoming realized. Click here to view this table.... NEUROLOGICAL PRESENTATIONS OF PSYCHIATRIC ILLNESS Requests for neuropsychiatric consultations often reflect on diagnostic difficulties, for example, on evaluating the meaning of neurological signs and symptoms that cannot be equated with an understanding of the underlying neuropathology. Other requests follow a breakdown of patient-physician relationships or discord among staff members resulting from different views about patient management. Thus, in certain settings, it is not the severity of the patient's psychopathology that leads to the referral but anxiety within the group of people looking after the patient that leads to conflicts between them. The latter can be exploited by patients, leading to unacceptable behavior. However, aggressive behavior, for example, can
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easily arise in patients with neurological illnesses because of their cerebral impairment, and a further reason for requested consultations is often to help manage such disturbances. Infrequently but importantly, patients are admitted to hospital and then confess to having suicidal ideation. One of the key functions of psychiatric assessments in such settings is to evaluate the potential risk. In practice, liaison psychiatry consultation requires assessment of the patient's mental state and evaluation of the patient's behavioral problems in relation to their medical history and their psychosocial status. Especially relevant is trying to glean knowledge of social settings in which the patient is embedded that may reveal inescapable conflicts, financial embarrassments, or bereavements. These may lead, understandably, to stress and psychiatric disorders such as anxiety or depression; such features must be placed in the context of the presentations, symptoms, and signs of neurological disease. Figures vary, but it is estimated that as many as 50 percent, at least, of patients admitted to neurological units have a recognizable psychiatric disorder, and an additional number are admitted who have more straightforward cognitive impairments rather than definitive psychiatric problems. It is also acknowledged that in more than half of these admissions, the neurocognitive and neuropsychiatric abnormalities remain undiagnosed at patient discharge, although the diagnoses may well be very relevant in terms of symptom resolution and in helping the general practitioner to the next stage of patient referral. Estimates of the primary psychiatric disorders in such populations reveal that the majority of disorders are neuroses or personality disorders, about 20 percent of patients have affective disorders (depression or bipolar disorder), and a much smaller percentage (2% to 3%) will be psychotic.23,24 In a neurological setting, incidentally, pain is a frequently reported psychiatric Headache, dizziness, body pain, and difficulties with attention and symptom. concentration are common psychiatric symptoms that occur in a neurological setting and can easily be mistaken for symptoms of a neurological disorder. It is because of such somatic symptoms that many patients with minor psychopathology are seen in neurological outpatient clinics, and it is of relevance that many neurologists choose psychotropic drugs in the management of their patients in both inpatient and outpatient settings. In a neurological setting, depression is the most common treatable diagnosis; it often presents with cognitive or somatic symptoms, but may also coexist with neurological disease, either because of the patient's own tragedy and worry at having developed some disorder that he or she does not understand and fears or because the function of the brain itself is altered, leading directly to the symptoms. Thus, many neurological diseases, being chronic and disabling, lead patients to have secondary depression, which not only can complicate and magnify the reporting of neurological symptoms but may also lead, when unrecognized, to multiple unwarranted investigations, increasing stress and worry and increasing the patient's symptoms still further. In a subsection of patients, differentiating between acute organic brain syndromes (e.g., delirium) or a cerebral signature syndrome such as apraxia or aphasia and primary psychiatric disorders such as schizophrenia or, for example, unraveling the causes of catatonia, is the diagnostic issue that may extend to the evaluation of patients in the intensive care unit with pseudocomas or nonepileptic seizures. Schiffer applied criteria of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) to 241 inpatients and outpatients on a neurology service and noted that 42 25 percent had sufficient symptomatology to justify a DSM-III diagnosis. Ten of 57 inpatients and 32 of 184 outpatients were evaluated with a chief complaint that could be classified as primarily psychiatric. In this group, the most common diagnoses were conversion disorders, anxiety disorders, and somatoform disorders. Pain, especially headache, is a frequently reported psychiatric symptom and, unrelated to overt somatic disease, may be found as a presenting symptom in 45 to 60 percent of psychiatric patients. Psychiatric illness itself is a major factor in determining the onset of pain. In one survey, 46 percent of patients who presented with the cardinal symptom of headache 26 were found to have an endogenous depression. In addition, pain presenting as a symptom in medical clinics is often associated with psychiatric illness and thus may be equally indicative of psychiatric or somatic illness. Contrary to the commonly held view, patients with chronic pain syndrome often have some form of hypochondriacal illness with somatic preoccupation or some underlying personality disorder rather than a depressive illness.
Patient Response to Illness
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In clinical practice, there are many patients who have symptoms of somatic disease without any obvious somatic underpinnings. Furthermore, a patient's psychological reaction to a known illness may itself lead to alteration of the symptoms of that illness and bring with it secondary symptoms that need evaluation in their own right. The patient's premorbid personality is an important variable that influences the response to disease. Hence, assessment of a patient's personality and individual coping style has relevance for understanding symptoms as they present. For the patient, any disease represents injury or threat of injury and often a threat of loss of some ideal-body function, body image, psychosocial role, or occupation. In this respect, neurological illness is particularly stressful and may lead to psychiatric symptoms, the latter manifesting as depression or an anxiety state, and to lesser degrees of behavior change as shown by frustration, anger, withdrawal, denial, regression, or dependence. A patient's response to disease may be related to the meaning and importance for the patient of the affected part of the body or of the actual lesion and its relation to the body image. In neurological patients, the idea of damage to the highest integrative function of the self (i.e., the brain) is particularly threatening. Additional variables include beliefs about the cause of the disease, which depend in part on cultural and educational factors, the state of the patient's current interpersonal relationships and social support systems, the extent of any mutilation and loss of ability and consequent socioeconomic disability, previous experience of disease, the patient's state of awareness and cognitive functioning, and the degree of acceptance by the patient of his or her “sick role.” The fact that, in some instances, illness paradoxically provides gain or relief for the patient must not be overlooked, and this assumption is implicit to understanding the presentation of certain varieties of what used to be referred to as “hysteria,” but now are referred to as the somatoform disorders, the more severe and enduring form being somatization disorder.
Somatoform Disorders Although it is one of the oldest words in medicine, hysteria is difficult to define and has been replaced in the DSM-III and beyond by such terms as somatoform disorder. Generally, it is 27 assumed that a diagnosis of hysteria implied a medically unexplainable condition manufactured from the metaphysical context of the patient's interpersonal relationships. In reality, it is a diagnosis most frequently made by nonpsychiatrists, often being the outcome of either a failure of the doctor–patient relationship or a frustration of the regular diagnostic process because clinical and laboratory evaluations reveal no abnormality. Hence, the diagnosis is made on purely negative grounds. A number of advances have been made in 27 understanding this area and are briefly reviewed here. A fuller account is given elsewhere. 28
An important step forward was made by Chodoff and Lyons. They highlighted the problem that historically two independent aspects had been confused, that is, a personality style (referred to as hysterical) and certain symptoms (referred to as conversion or dissociative). In other words, simply because a patient displayed a flamboyant personality style referred to as “hysterical” did not mean that the symptoms were necessarily those of hysteria. The hysterical personality includes a dramatic and emotional style of presentation, with excessive gestures and exaggerated, imprecise verbal responses. It is precisely these latter qualities that make history taking difficult, and patients with elusive neurological symptoms provide the unwary physician with a poorly defined account of their problems. Their affect appears shallow and labile but without the emptiness associated with a pseudobulbar palsy, and patients can be seductive and demanding in their interpersonal relationships. Terms such as conversion or dissociative, when applied to symptoms, are best used in a metaphorical sense without any underlying concept with regard to pathogenesis, from either a physiological or a psychological point of view. In other words, the term conversion is applied to the symptom pattern with no underlying need to explain what precisely is “converted” to what. There is some relationship between the hysterical personality and conversion symptoms, but it is not strong. Results from several studies have suggested that approximately one fifth of patients presenting with conversion phenomena show the hysterical personality style. Thus, conversion symptoms may occur in patients of different personalities, including obsessional personalities. An important association of conversion symptoms is with organic, especially neurological, disease, although this is not as strong as is often supposed. The high frequency of later development of organic disease found in the follow-up study of Slater was the reason for his 29 suggestion that hysteria is a “myth.” Of his original 85 patients, nearly 60 percent had an
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associated recognizable organic disease at the time of diagnosis of hysteria or acquired one during the follow-up interval. Slater was led to conclude that “the diagnosis of hysteria is a disguise for ignorance and a fertile source of clinical error.” Although other series have not found such a clear link, all reported a percentage of patients who later were shown to have underlying neurological illness. Thus, a diagnosis of hysteria can be made in the presence of associated neurological disease. Such a diagnosis, however, should not automatically lead to instant discharge from the clinic and failure of follow-up. Patients with these syndromes present with some interesting features in addition to the contradictory neurological features. They often reveal anesthetic patches and have other complex symptoms such as widespread pain. The sensory loss may affect several modalities, is overrepresented on the left side, and may be associated with diminished taste, smell, and hearing on that side. Further examination may reveal restricted visual fields with tubular vision, and the tendon reflexes may also be diminished on the affected side. Although there are several potential explanations for this unequal distribution of the anesthesia, including the special properties of the nondominant hemisphere for processing unconscious information, it is certainly of interest that disorders of the body image that occur after lesions to the nondominant parietal cortex, for example, anosognosia, are unilateral. Those seen after lesions of the dominant parietal cortex, such as autotopagnosia and finger agnosia, tend to be bilateral. Furthermore, anosognosia and its milder variant anosodiaphoria (denial of illness and hemiplegia) have some resemblance to the intense denial so often reported in association with hysteria, referred to as la belle indifférence. Clinically, the important point is that the anesthetic areas, which do not correspond to normal neuroanatomical boundaries, have diagnostic significance and should not be discarded by an innocent intern merely as the result of “suggestion.” They have been observed in patients who have received a diagnosis of hysteria for well over 100 years and may reflect some underlying neurophysiological change in patients who tend to somatize. Nonepileptic (Pseudo) Seizures Patients with nonepileptic seizures are being referred increasingly for evaluation. This has resulted from technical advances permitting the long-term EEG monitoring of patients with intractable seizures. Such monitoring has revealed that many patients, some of whom have carried a diagnosis of epilepsy for many years and have been treated with multiple anticonvulsant drugs, do not have epilepsy at all. Among such patients, many have only nonepileptic seizures, but a few (perhaps 20%) also have epilepsy. Evaluation of these patients can be undertaken only with the full knowledge of the psychiatric conditions that may present as seizures, including particularly panic disorder with agoraphobia, depersonalization, other anxiety states, depression, and seizures as a manifestation of dissociation. The importance of early recognition of these patients is clear because treatment is with psychotropic medications, psychotherapy, or behavioral therapy; anticonvulsant drugs should be avoided. There are certain clinical clues that should alert the physician to the diagnosis of nonepileptic seizures. These are the presentation of very frequent seizures with a normal interictal EEG; episodes of “status” with a normal interictal EEG; the presence of a history of other conversion disorders; the finding of nonanatomical anesthesias; self-harm, especially the development of carpet burns; a family history of epilepsy; and a history of sexual abuse or an eating disorder. Briquet's Syndrome or Somatization Disorder Briquet's syndrome is a polysymptomatic disorder that begins during early life. It usually affects girls and is characterized by recurrent multiple somatic complaints that are inexplicable in terms of current knowledge of pathological processes. Patients make repeated visits to physicians, are prescribed a large number of medications, and undergo frequent hospitalizations and operative procedures. In the Diagnostic and Statistical Manual of the 30 Mental Disorders, Fourth Edition (DSM-IV), it is referred to as somatization disorder, the diagnostic features of which are shown in Table 30-6. In practice, such patients are not difficult to discern, and Briquet's syndrome is reported in 1 to 2 percent of consecutive female patients attending hospitals for investigations. First-degree female relatives have a 10-fold increase in the same syndrome, whereas male relatives show a preponderance of antisocial personalities and alcoholism. Monozygotic twins have a greater concordance rate than 31 dizygous pairs. Click here to view this table....
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Briquet's syndrome assumes importance among patients presenting with neurological symptoms, with seizures, fainting, reports of loss of consciousness, visual symptoms, weakness, headaches, anesthesia, and paralysis commonly being reported by patients with the disorder. The importance of recognizing the diagnosis is that it has prognostic validity, and individual symptoms must be assessed in the full context of the overall medical and psychiatric history of such patients. Management includes avoidance of any form of invasive procedure that could lead to secondary iatrogenic damage, resistance to further surgical exploration of any symptoms, and avoidance of any addictive medications. In its more florid form this condition is so extraordinary that the diagnosis can be missed. Patients, often as young as the early twenties, may be bed bound with contractures of the hands and feet (fixed dystonias). They may be on addictive opiate drugs for pains and spasms and give a history and have treatment for such conditions as rheumatoid arthritis, asthma, irritable bowel syndrome, and celiac disease, of which there is no evidence. Catheters, stomach pegs, and even quite extensive genitourinary surgery may have been performed. Abnormal Illness Behavior The term abnormal illness behavior is popular, particularly in the setting of liaison psychiatry and is briefly discussed 32 here. Pilowsky introduced the concept based on ideas that derived from social psychology. Abnormal illness behavior is defined as “the persistence of an inappropriate mode of perceiving, evaluating, acting in relation to one's state of health, despite the fact that a doctor has offered a reasonably lucid explanation of the nature of the illness, and the appropriate course of management to be followed, based on a thorough 33 medical examination.” This broad definition covers a number of medical conditions such as hysteria, hypochondriasis, malingering, and Munchausen syndrome, in which an abnormality in the way patients evaluate and act in relation to their symptoms (illness behavior) is central. Pilowsky pointed out that these diagnoses are usually made by nonpsychiatrists on the basis of a discrepancy between detectable somatic disease and the patient's reaction; in other words, “the doctor does not believe that the sick role that the patient assumes is appropriate 33 to the objective pathology detected.” Use of the term abnormal illness behavior places understanding of these conditions in a wider sociological context. Somatoform Disorder Variants In any neurological setting there are several kinds of patient who present under the rubric of somatoform disorder (DSM-IV). There are those with obvious psychiatric disorders, the main one being a major affective disorder with somatization, in whom there is little evidence of underlying neurological illness. Anxiety states frequently present with neurological symptoms, and hyperventilation itself provokes somatic symptoms. By contrast, psychotic conditions, in particular schizophrenia, rarely present to the neurologist with conversion phenomena. There are also patients with Briquet's syndrome, the chronic, long-standing, stable form of somatoform disorder, who are best viewed as having a severe form of a personality disorder with a poor prognosis. Patients with neurological illness who present with conversion symptoms are usually of three types. First, there are those whose neuroticism threshold has been lowered in a nonspecific way by cerebral lesions and who are thus more likely to present with a neurotic illness, of which conversion disorder is one, in a setting of stress. This explanation may reflect one reason for the high association between a diagnosis of hysteria and underlying neurological disease in some earlier series and may be particularly important with such illnesses as multiple sclerosis, epilepsy (especially with anticonvulsant intoxication), head injury, and early dementia. Second, there are those patients whose conversion symptoms replicate their existing neurological illness, such as the occurrence of nonepileptic seizures in a patient with epilepsy or weakness in a patient with mild multiple sclerosis. The onset of the conversion symptoms may relate to the development of an underlying anxiety state or affective disorder or an alternative psychiatric problem. Finally, as Slater noted, there are patients who have undiagnosed neurological disease and in whom the diagnosis of hysteria is made. It is particularly because of these patients that the diagnosis of hysteria should be made on positive and not solely on negative grounds. This requires clearly demonstrating discrepancies between neurological signs and symptoms as expected and as displayed and establishing firmly, by careful dissection of the history and current mental state, some clear evidence of psychopathology and predisposition. Anesthetic patches should always be noted and not dismissed. Earlier episodes of abnormal illness behavior should be sought, and an extensive surgical history should be viewed skeptically. The finding of secondary gain, although interesting and important, is itself insufficient to make a diagnosis of a conversion disorder and in many settings is purely in the eye of the beholder. Where there is no positive evidence to make the diagnosis, it is perhaps better to wait before committing the patient to a
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diagnosis of a conversion disorder that may have unfortunate consequences. Over time, the true nature of the problem tends to reveal itself. In factitious disorder, the symptoms and signs of illness are deliberately produced in order to adopt a sick role. Although this disorder overlaps with Munchausen syndrome and malingering, it differs in that the physical signs are produced with medical knowledge, and, as a result, paramedical personnel are often overrepresented. Individuals may produce signs by, for example, coloring their urine with blood, artificially heating thermometers, or continually reinfecting skin lesions. Factitious disorders are more common in females, whereas Munchausen syndrome is more common in males. The key feature of the latter is deliberate attendance at hospitals, without medical referral, with pseudomedical complaints. Suggestions that the patient may be referred to a psychiatrist usually lead to immediate self-discharge. Malingering refers to the production of physical symptoms for some kind of personal gain, usually financial, and is not as infrequent as many would have us believe. The neurologist should be particularly alert to such a possibility in patients attending with reference to medicolegal and compensation claims. Hypochondriasis differs from the previously described conditions in being a disorder in which patients are preoccupied with their symptoms, fearing they have some dreadful ailment. They have such concern about their physical state that they are preoccupied a great deal of the waking day and fail to be reassured about their health, even if verified by physician after physician. Hypochondriasis is reported in as many as 10 percent of medical inpatient consultations and, unlike somatoform disorder, occurs with equal frequency in males and females. Unlike the rather vague documentation of the symptoms of those with conversion disorders, these patients usually keep careful documentation of their illness history, and the more obsessional develop all kinds of illness rituals. Patients are demanding, clinging, importuning and ungrateful; inevitably both patient and physician are unsatisfied with their diagnostic encounters. Eventually, if severe, the patients become isolated from their weary helpers, and their frequent appointments with doctors become their main social outlets. The question of the relative state of consciousness of patients with this spectrum of diagnoses is often raised. Traditionally, the symptoms of conversion disorder are said to be unconscious, whereas those of malingering are consciously elaborated. In reality, motivation in this spectrum of disorders varies over time, and it is usually quite impossible for the physician to make anything other than a poorly informed guess about this. Patients themselves at one time might be quite willing to admit to a deliberate exaggeration of symptoms that earlier was impervious to everyone, even themselves. In a medicolegal setting, the only way to uncover malingering is either by a self-confession from the injured claimant or by videofilm exploration or some other kind of personal inquisition that reveals the claimant to be quite unreliable with regard to the truth. A guide to the features of these disorders is given in Table 30-7. Click here to view this table.... 34
Like nonepileptic attacks, psychogenic movement disorders are now recognized as an entity that deserves special mention. The history of these disorders is revealing. It was recognized in the nineteenth century by neurologists such as Charcot that patients could develop all kinds of movement disorders, some acute and others chronic, which, for him, were a variant of hysteria. With the discovery of levodopa in the 1960s, and realization of the close link between movement and dopamine, the idea that some movement disorders could have non-neurological antecedents was firmly rejected and all abnormal movements were considered neurological. However, in the past two decades the concept of psychogenic movement disorders has been rediscovered. It is now accepted that there are a variety of presentations, from psychogenic parkinsonism through to tremor and tics to myoclonic jerks. Estimates are that from 3 to 25 percent of patients attending movement disorder clinics may have some form of psychogenic movement disorder, and 10 percent of patients diagnosed as having Parkinson's disease have normal dopamine-transporter imaging studies. Psychogenic dystonia is one interesting variant. This frequently presents as a focal dystonia such as spasmodic torticollis but often becomes more widespread and may involve the trunk, leading to bizarre posturing. The abnormal movements may come on quite suddenly and are sometimes precipitated by a minor trauma. In the upper extremity, the dystonia begins with contraction and flexion of the fingers but eventually affects the wrist and then extends more proximally. In the legs, the foot classically becomes inverted; eventually, the patient begins to walk on the lateral border of the foot. There are overlaps between psychogenic dystonia and the causalgia-dystonia syndrome and
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regional pain syndrome (reflex sympathetic dystrophy).
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In contrast to neurologically based dystonias, the psychogenic dystonias are characteristically fixed, the patient being unable to move the affected part. Any initial causalgia wanes, and the dystonia may become progressive; for example, having initially affected the lower limb on one side, it may spread to the other or even to the upper limbs. It is not unknown for amputation to follow eventually. Table 30-8 lists clues to the diagnosis of psychogenic dystonia, noting the overlap with multiple somatizations, but there is also a link to factitious disorder and malingering. Psychogenic dystonia is not improved with sleep; patients commonly show a slowness of voluntary movement and a resistance to passive movement. The curious geste antagoniste seen in many patients with neurologically based dystonia is absent. Click here to view this table....
Affective Disorders Disorders of affect, in particular depression, are frequently encountered in neurological practice, and two aspects merit consideration here: (1) the quality of the depressive symptoms reported by patients and (2) the relation of any change of affect to underlying CNS disease. In clinical practice, a common and important error is to confuse depression as an illness with depressive symptoms occurring as a reaction. The essential criterion for a depressive illness is disturbance of mood, which, moreover, must be prolonged and continuous. Episodes of more transient mood change or chronic, mild changes of mood are best referred to as dysthymic disorder. For the assessment of depressive symptoms, personality factors are often poorly taken into account, in particular premorbid neuroticism. Thus, many patients with dysphoric symptoms and complaints of depression in reality have long-standing personality disorders and tolerate life's stresses poorly. These patients should not be diagnosed as having depressive illness and are not helped by the prescription of psychotropic medications. With depressive illness, the change in mood is associated with loss of vitality, the patient ceasing to enjoy life and admitting to a loss of emotional well-being. Concentration difficulty with complaints of poor memory, increased apathy with diminution of movements, and changes in appetite, food intake, and sleep pattern are found. Sleep may be disturbed in a variety of ways, the most common being nocturnal restlessness with periodic awakening, or the more typical early morning awakening with morbid ruminations and inability to get to sleep again. Patients lose interest in their food, complain that it is tasteless, and often lose weight. Feelings of anxiety and tension are invariably present; sometimes, in contrast to the typical psychomotor retardation, agitation with indecision and excessive motor activity is seen. In an extreme form, intense, aimless pacing is noted. Patients complain of loss of energy, fatigability, and tiredness; often there is a diurnal variation, the symptoms improving as the day passes. Suicidal thoughts and preoccupations are frequent and should always be inquired about. Thoughts of worthlessness, guilt, and letting people down are typical, but crying is often not reported and should be asked about, especially in men. Increased irritability, hostility, and aggressive episodes, especially within the family setting, become troublesome. Libido is diminished. A low-dose dexamethasone test may reveal a failure of cortisol suppression. When strictly defined, the diagnosis of depressive illness among patients in neurological units is less common than is suggested by the number who are actually given that diagnosis but who in reality have more long-standing personality disturbances or understandable reactions to neurological disability. However, there are patients with a more direct association between neurological illness and depression, and this association touches on the fundamental biochemical and neurological underpinnings of affective expressions. With regard to tumors, meningiomas (especially frontal meningiomas) are notoriously liable to induce a picture typical of major depressive disorder, and diencephalic tumors have been reported to lead to an affective disorder with hypomanic swings. The association between disorders of the basal ganglia and depression is also of particular interest. Cerebrovascular accidents have also been reported as leading to a depressive illness. In a controlled study in which comparison was made with similarly disabled orthopedic patients, patients with stroke had a significantly higher incidence of depression than controls (45% versus 10%), suggesting that the mood change is not simply a reaction to disability. In a series of studies, Robinson and colleagues found that with lesions in the dominant hemisphere,36the nearer the lesion was to the frontal pole, the more severe was the depression. In the nondominant hemisphere, the farther away the lesion was from the frontal pole, the higher was the frequency of depression. There was no association with
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aphasia, although depression has been reported to be more frequent in association with 37 Broca's aphasia. These findings were related largely to depression of early onset; longer-term follow-up studies suggest that later depression associated with stroke is linked more to psychosocial factors and difficulty with rehabilitation. Patients with an affective disorder can present with a marked cognitive disturbance, with complaints of poor memory, impaired concentration, difficulty with planning and decision making, and poor abstracting abilities. The term pseudodementia has been used to specify this disorder, although it can be argued that it is better referred to as a reversible dementia and categorized as subcortical. The presentation can so resemble the dementia of Alzheimer's disease that it may be misdiagnosed and left untreated. Important clues that help distinguish this disorder from Alzheimer's disease include a history of affective disorder, a relatively acute onset with little evidence of slow cognitive decline before the development of affective symptoms, the patient's distress and complaints about cognitive function (in contrast to the lack of insight often seen in dementia), the response to questions in the mental state examination (patients often using “don't know” as an answer, whereas in dementia, the answers are more evasive), and the performance on more structured psychological tests (which do not reveal the focal deficits of early Alzheimer's disease and suggest patchy and inconsistent impairments). Although no clear pattern of cognitive change emerges, the subjective complaints of patients are often worse than is warranted by their performance on objective tests, and they in particular show difficulty with attention, speed of mental processing, attention to detail, abstraction, and memory, especially on tasks that require 38 effort, motivation, and active processing. The EEG findings can be deceptive in patients with an affective disorder. Certain waveforms that some authors have associated with affective symptoms are occasionally misinterpreted as being related to epilepsy, whereas many other authors regard them as normal variants. Rhythmic mid-temporal discharges are said to be associated39with an increased risk of psychopathology, including hypochondriasis and depression. Small sharp waves that are sometimes exclusively temporal in location and that occur during drowsy states or light sleep have also been associated with affective symptoms and a tendency toward suicide. Furthermore, 43 percent of patients with bipolar affective disorder have been reported as showing 40 small sharp waves, which may be significantly related to a family history of affective disorder. Finally, Struve and colleagues reported a highly significant positive relationship between paroxysmal EEG abnormalities and suicidal ideation and acts, as well as associated 41 destructive acts, unrelated to medications. Thus, patients with an affective disorder who present with paroxysmal episodes of poor concentration and coordination may be thought to have complex partial seizures, and their EEGs may be “abnormal.” Close attention to the total clinical picture, the family history, and the history of the patient reveals the appropriate diagnosis. In this context, it is appropriate to note that abnormal EEGs are also reported frequently in patients with personality disorders. These abnormalities are often paroxysmal in nature and temporal in location. If these patients present with pseudoseizures, any reliance on the interictal EEG leads to a misdiagnosis.
Post-traumatic Stress Disorder Patients who are involved in life-threatening accidents sometimes go on to acquire one of a number of post-traumatic syndromes. Post-traumatic stress disorder is one of the most important; its diagnostic criteria are given in Table 30-9. A number of patients with symptoms of this disorder have also had head injuries, and distinguishing between symptoms secondary to organic brain damage and those of post-traumatic stress disorder may then be difficult. Thus, one of the presenting features is alteration of memory, perhaps with hypermnesia, but also psychogenic amnesia is common, perhaps occasioned by extreme anxiety. Unraveling this from a concussional post-traumatic amnesia can be difficult. Click here to view this table.... The cardinal features of post-traumatic stress disorder relate to psychologically re-experiencing the traumatic event, increased autonomic arousal (particularly on exposure to environmental triggering stimuli or reminders of the event), and the development of avoidance phenomena, social withdrawal, and difficulty in making affective contact with relatives and friends. The disorder often comes on several weeks after the trauma and frequently is intertwined with depressive symptoms. In neurological practice, it may also be interlinked with a somatoform disorder. In such cases, the underlying constellation of symptoms of post-traumatic stress disorder may be missed unless it is sought specifically. PSYCHIATRY AND NEUROLOGY
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The intellectual and practical separations of neurology and psychiatry that characterized the first three quarters of the past century have to some extent now diminished, in some countries at least. There is a growing number of practicing neuropsychiatrists, with international and national societies and journals devoted to the subject, and there is still a requirement for neurologists to do some psychiatric training and psychiatrists to do some neurological training in many countries. Patients with emotional consequences and psychiatric disorders that arise from their neurological disorder do not benefit if these aspects are ignored, and evaluation of the personality style and mental state of all patients being assessed for neurological symptoms is quite essential, especially if there is doubt over the cause of the disorder. Many patients with easily recognizable psychiatric disorders still receive neurological labels, often setting them on a long trail of neurological investigations and sometimes years of treatments to no avail. The misdiagnosis of epilepsy is a prime example. These misdiagnoses go in the other direction as well, with meningiomas misdiagnosed as depression or a progressive dementia as depression, emphasizing the importance of the close collaboration between neurology and psychiatry, but also reinforcing the need for neuropsychiatrists: neither neurologists nor psychiatrists, but specialists with an interest in the brain and behavior and empathy for psychosocial understanding of patients' lives, conflicts, and confusions who are familiar with the causes, presentation, progress, and treatment of a broad spectrum of disturbed behaviors.
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 31 The Postconcussion Syndrome RANDOLPH W. EVANS •
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HISTORICAL ASPECTS EPIDEMIOLOGY CLINICAL MANIFESTATIONS Headaches Tension-Type Headache Occipital Neuralgia Migraine Supraorbital and Infraorbital Neuralgia Scalp Lacerations and Local Trauma Subdural Hematomas Epidural Hematomas Low Cerebrospinal Fluid Pressure Dysautonomic Cephalgia Other Types of Headache Cranial Nerve Symptoms and Signs Psychological and Somatic Complaints Rare Sequelae PATHOPHYSIOLOGY DIAGNOSTIC TESTING Electroencephalography Neuroimaging Neuropsychological Testing MANAGEMENT Headaches Cognitive Dysfunction Education Return to Play in Sports PROGNOSIS Risk Factors Symptoms Cognitive Deficits Effect of Litigation
The postconcussion syndrome refers to a large number of symptoms and signs that may
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occur alone or in combination after mild head trauma. Concussion has been defined by a subcommittee of the American Academy of Neurology as a trauma-induced alteration in 2 mental status that may or may not involve loss of consciousness. The patient's account of loss of consciousness and its duration may not be reliable. Loss of consciousness does not 3 have to occur for postconcussion syndrome to develop. 4
The syndrome develops in over 50 percent of those who have mild head injuries. The following symptoms and signs are associated with it: headaches, dizziness, vertigo, tinnitus, hearing loss, blurred vision, diplopia, convergence insufficiency, light and noise sensitivity, diminished taste and smell, irritability, anxiety, depression, personality change, fatigue, sleep disturbance, decreased libido, decreased appetite, post-traumatic stress disorder, memory dysfunction, impaired concentration and attention, slowing of reaction time, and slowing of information-processing speed. Headaches, dizziness, fatigue, irritability, anxiety, insomnia,5 loss of concentration and memory, and noise sensitivity are the most common complaints. The postconcussion syndrome may be subdivided into an early phase and a late or persistent 6 phase in which symptoms and signs persist for more than 6 months. Both the terms mild and minor head injury have been used in the literature, but “mild” is preferred as part of the continuum of mild, moderate, and severe. In addition, “minor” can denote an injury of little significance, which can be misleading. Mild head injury is typically defined by the following criteria: a duration of loss of consciousness of 30 minutes or less or occurrence of a dazed feeling without loss of consciousness, an initial Glasgow Coma Scale score of 13 to 15 without subsequent deterioration, and absence of focal neurological deficits without evidence of depressed skull fractures, intracranial hematoma, or other neurosurgical pathology. Because this definition includes a heterogeneous population, there may be merit in segregating those with Glasgow Coma Scale scores of 15 from those with scores of 13 7 and 14. In addition, because the risk of intracranial lesions is similar, the Neurotraumatology Committee of the World Federation of Neurosurgical Societies recommends reclassifying patients with a Glasgow Coma Scale score of 13 in the group with moderate head injury 8 (score of 9 to 12). Rare sequelae of seemingly mild head injury include subdural and epidural hematomas, cerebral venous thrombosis, second impact syndrome, seizures, nonepileptic post-traumatic seizures, transient global amnesia, tremor, and dystonia. HISTORICAL ASPECTS 9,10
The postconcussion syndrome has been controversial for more than 140 years. Erichsen, a London surgeon, indicated in a series of lectures in 1866 that minor injuries to the 11 head could result in severe disability due to “subacute cerebral meningitis and arachnitis.” Symptoms reported by patients with minor head injuries included headaches, memory complaints, nightmares, irritability, and light and noise sensitivity. Erichsen was defensive about these cases of cerebral concussion because many occurred after railway accidents in which litigation was involved. On the title page of his book, he quoted Montaigne, “Je raconte, je ne juge pas.” These injuries became known as “railway brain” and those of the spine as “railway spine.” He pointed out that earlier authors had described the same symptoms in the pre-railway era. He was also concerned about misdiagnosing these cases as hysteria: “Hysteria is the disease for which I have more frequently seen concussion of the spine, followed by meningomyelitis, mistaken, and it certainly has always appeared extraordinary to me that so great an error of diagnosis could so easily be made.” Railway spine and brain became topics of intense controversy. In 1879, Rigler raised the important issue of compensation neurosis when he described the increased incidence of post-traumatic invalidism after a system for financial12compensation was established for accidental injuries on the Prussian railways in 1871. In 1888, Strumpell discussed how the desire for compensation could lead to exaggeration. In 1889, Oppenheim popularized the concept of traumatic neurosis, in which a strong afferent stimulus resulted in impairment of function of the central nervous system (CNS). Charcot countered Oppenheim's work and suggested that the impairment described was actually due to hysteria and neurasthenia. covering In 1883, several articles were published in the Boston Medical and Surgical Journal 13 these different points of view. The leading article drew the following conclusions : In this iconoclastic age when we are not allowed to believe in a personal devil, or good honest ghosts, or even to coddle our own pet superstitions and hobbies without a suspicion of mental degeneration, it is natural that the medical “bugaboo” raised by Mr. Erichsen some years ago, and christened spinal concussion, should meet with little quarter at the hands of the modern scientific observer. It is possible, however, that in this, as in other things, the skeptic may have gone too far, and that although it was no ghost that has alarmed us there
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may actually have been some phosphorescent light which we do not understand, and the nature of which we cannot fully explain.…A rose, however, under any other name, will remain as fragrant to the sufferer, and whether the ailment be termed railway spine or traumatic neurasthenia, the condition is equally distressing. Postconcussion syndrome remained controversial throughout the twentieth century as well. Henry Miller, in 1961, summarized the viewpoint of those who believe that the postconcussion syndrome is really a compensation neurosis: “The most consistent clinical 14 feature is the subject's unshakable conviction of unfitness for work.…” In 1962, Charles Symonds took an equally strong opposing viewpoint when he wrote, “It is, I think, questionable whether the effects of concussion, however slight, are ever completely 15 reversible.” The earliest uses of the term postconcussion syndrome that the present author can find are 16 17 both from 1934: Grinker's textbook and an article by Strauss and Savitsky. The latter concluded: “In our opinion, the subjective posttraumatic syndrome, characterized by headache, dizziness, inordinate fatigue on effort, intolerance to intoxicants and vasomotor instability, is organic and is dependent on a disturbance in intracranial equilibrium due directly to the blow on the head. We suggest the term ‘postconcussion syndrome’ for this symptom complex.” EPIDEMIOLOGY Head trauma is a cause of significant morbidity and 18 mortality in all societies. Mild head injury accounts for 75 percent or more of all brain injuries. The annual incidence of mild head injury per 100,000 population has been estimated to be 149 for Olmsted County, 19 20 21 Minnesota, 131 for San Diego County, California, and 511 for Auckland, New Zealand. However, the incidence of mild head injury may 22 be as high as 640 persons per 100,000 population because many cases go unreported. In addition, some patients may have “hidden” traumatic brain injury in that they develop a postconcussion syndrome but do not 23 make the causal connection between the injury and its consequences. In an industrialized country such as the United States, the relative causes of head trauma are approximately as follows: motor vehicle accidents, 45 percent; falls, 30 percent; occupational 24 accidents, 10 percent; recreational accidents, 10 percent; and assaults, 5 percent. About one half of all patients with mild head injury are between the ages of 15 and 34 years. Motor vehicle 25 accidents are more common in the young, and falls are more common in the elderly. Men are more frequently injured than women, in a 2:1 ratio. Between 20 and 40 percent of people with mild head injuries in the United States do not seek treatment. CLINICAL MANIFESTATIONS
Headaches Headaches are variably estimated as occurring in 30 to 90 percent of persons symptomatic 26 are greater after mild head injury. Paradoxically, headache prevalence and lifetime duration 27 in those with mild head injury compared with those with more severe trauma. 28 Post-traumatic headaches are more common in those with a history of headache. According to the International Headache Society (second edition) 2004 criteria, the onset of the headache should be less than 7 days after the injury, although some experts suggest 29 within 3 months. Many patients have more than one type of headache or have headaches with tension and migrainous features. Neck injuries commonly accompany head trauma and can produce headaches. Although not part of the postconcussion syndrome, headaches associated with subdural and epidural hematomas are also described. Tension-Type Headache Among post-traumatic headaches, 85 percent are of the tension type. They can occur in a variety of distributions, including a generalized, nuchal-occipital, bifrontal, bitemporal, cap-like, or headband location. The headache, which may be constant or intermittent with variable duration, is usually described as a pressure, tightness, or dull aching. It may be present on a daily basis. Temporomandibular joint injury can be caused either by direct trauma or jarring associated with the head injury. Patients may complain of jaw pain and hemicranial or ipsilateral frontotemporal aching or pressure headaches. Occipital Neuralgia
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The term occipital neuralgia is in some ways a misnomer because the pain is not necessarily from the occipital nerve and does not usually have a neuralgic quality. Greater occipital neuralgia is a common type of post-traumatic headache but frequently is seen unrelated to injury. The pain may have an aching, pressure, stabbing, or throbbing quality and may be in a nuchal-occipital distribution or parietal, temporal, frontal, or periorbital or retro-orbital in location. Occasionally, a true neuralgia may be present, with paroxysmal shooting-type pain. The headache may last for minutes to hours to days and can be unilateral or bilateral. Lesser occipital neuralgia can similarly occur with pain generally referred more laterally over the head. The headache may be due to entrapment of the greater occipital nerve in the aponeurosis of the superior trapezius or semispinalis capitis muscle or may be a referred pain without nerve compression from trigger points in these or other suboccipital muscles. Digital pressure over the greater occipital nerve at the midsuperior nuchal line (halfway between the posterior mastoid and the occipital protuberance) reproduces the headache. However, pain referred 30 from the C2–3 facet joint (third occipital headache ) or other upper cervical spine pathology and posterior fossa pathology may produce a similar headache. Migraine 31
Recurring attacks of migraine with and without aura can result from mild head injury. Impact may also cause acute migrainous episodes, often in adolescents with a family history of men playing migraine. This was originally termed footballer's migraine to describe young 32 soccer who had multiple migraines with auras, triggered only by impact. Similar attacks can be triggered by mild head injury in any sport. The most famous example involved the running back of the Denver Broncos and was witnessed by hundreds of millions of people around the world during the 1998 Super Bowl. Terrell Davis, who had preexisting migraine, developed a migraine with aura after an impact on the head at the end of the first quarter. After successfully using dihydroergotamine nasal spray, he was able to return for the third quarter, scored the winning touchdown, set a Super Bowl rushing record, and was voted “most valuable player.” After minor head trauma, children, adolescents, and young adults can develop a variety of transient neurological sequelae that are not always associated with headache and are perhaps due to vasospasm. Five main clinical types are recognized: (1) hemiparesis; (2) 33 ; (4) transient blindness, often somnolence, irritability, and vomiting; (3) a confusional state 34 precipitated by occipital impacts; and (5) brainstem signs. Supraorbital and Infraorbital Neuralgia Injury of the supraorbital branch of the first trigeminal division as it passes through the supraorbital foramen just inferior to the medial eyebrow can cause supraorbital neuralgia. Similarly, infraorbital neuralgia can result from trauma to the inferior orbit. Shooting, tingling, aching, or burning pain occurs and may be associated with decreased or altered sensation and sometimes decreased sweating in the appropriate nerve distribution. The pain can be paroxysmal or fairly constant. A dull aching or throbbing pain may also occur around the area of injury. Scalp Lacerations and Local Trauma Dysesthesias over scalp lacerations occur frequently. In the presence or absence of a laceration, an aching, soreness, tingling, or shooting pain over the site of the original trauma can develop. The symptoms may persist for weeks or months but rarely for more than 1 year. Subdural Hematomas Tearing of the parasagittal bridging veins (which drain blood from the surface of the hemisphere into the dural venous sinuses) leads to hematoma formation within the subdural space. Even minor injuries without loss of consciousness, such as bumps on the head or 35 even riding a roller coaster, can result in such tearing. (Roller coaster rides can also lead to headaches due to internal carotid artery dissection, middle fossa arachnoid cyst as a risk 36 factor for bilateral subdural hygromas, posttraumatic migraine, and cerebrospinal fluid leak.) Falls and assaults are more likely than motor vehicle accidents to cause subdural hematomas. Subdural hematomas are usually located over the hemispheres, although they may be found
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in other locations, such as between the occipital lobe and tentorium cerebelli or between the temporal lobe and the base of the skull. A subdural hematoma becomes subacute between 2 and 14 days after the injury, when there is a mixture of clotted and fluid blood, and becomes chronic when the hematoma is filled with fluid more than 14 days after the injury. Rebleeding can occur in the chronic phase. Most patients with chronic subdural hematomas are late middle-aged or elderly. Subdural hematomas of all types may be present despite a normal neurological examination. The headaches associated with subdural hematomas are nonspecific, ranging from mild to 37 severe and paroxysmal to constant. Unilateral headaches are usually due to ipsilateral subdural hematomas. Headaches associated with chronic subdural hematomas have at least one of the following features present in 75 percent of cases: sudden onset; severe pain; exacerbation with coughing, straining, or exercise; and associated vomiting or nausea. Epidural Hematomas Bleeding into the epidural space from a direct blow to the head produces an epidural hematoma. The source of the bleeding is variable and can be arterial, venous, or both. In the supratentorial compartment, bleeding arises from the middle meningeal artery in 50 percent, middle meningeal veins in 33 percent, dural venous sinus in 10 percent, and other sources, including hemorrhage from a fracture line, in 7 percent. Most epidural hematomas in the posterior fossa are due to dural venous sinus bleeding. Epidural hematomas are located in the temporal region (usually under a fractured squamous temporal bone) in 70 percent of cases, frontal convexity in 15 percent, parieto-occipital region in 10 percent, and parasagittally or in the posterior fossa in 5 percent. They are unilateral in 95 percent of cases. Epidural hematomas usually occur between the ages of 10 and 40 years and much less frequently in those younger than 2 years or older than 60 years. Motor vehicle accidents or falls are the most common causes. Trivial trauma without loss of consciousness can be a cause. Among patients with an epidural hematoma, 40 percent present with a Glasgow Coma Scale score of 14 or 15. Fewer than one third of patients have the classic “lucid interval” (initial unconsciousness followed by recovery and then by unconsciousness again). 38
Up to 30 percent of epidural hematomas are of the chronic type. The patient is frequently a child or young adult who sustains an apparently trivial injury, often without loss of 39 consciousness. A persistent headache then develops, often associated with nausea, vomiting, and memory impairment that might seem consistent with a postconcussion syndrome. After the passage of days to weeks, focal findings develop. The headaches of acute and chronic epidural hematomas may be unilateral or bilateral and can be nonspecific in character. Low Cerebrospinal Fluid Pressure Trauma can cause a cerebrospinal fluid leak through a dural root sleeve tear or a cribriform plate fracture. This results in a low cerebrospinal fluid pressure headache that has the same 40 features as the headache that sometimes follows lumbar puncture. Dysautonomic Cephalgia This rare headache is due to injury of the anterior triangle of the neck or carotid sheath. Acute local pain and tenderness in the anterior triangle is followed weeks or months later by severe unilateral frontotemporal headache, ipsilateral increased sweating of the face, dilation of the ipsilateral pupil, blurred vision, ipsilateral photophobia, and nausea. The headache can occur a few times per month and last for hours or days. Other Types of Headache Hemorrhagic cortical contusions may cause headache due to subarachnoid hemorrhage. Rare types of post-traumatic headaches are cluster headaches, due to carotid and vertebral artery dissections; short-lasting unilateral neuralgiform headache attacks with conjunctival 41 injection, tearing, sweating, and rhinorrhea (SUNCT); and hemicrania continua.
Cranial Nerve Symptoms and Signs Symptoms and signs of various cranial neuropathies can occur after mild head injury. 42 Dizziness is reported by 53 percent of patients within 1 week of injury. Central and
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peripheral pathological processes, including labyrinthine concussion, perilymph fistula, and 43 Blurred vision is reported by 14 percent of benign positional vertigo, may be responsible. 44 patients, with convergence insufficiency being the most common cause. Optic nerve contusions may result in decreased visual acuity and hue discrimination. Mild head injury may also cause diplopia owing to cranial nerve III, IV, and VI palsies. Decreased smell and taste are reported by more than 5 percent of patients45after mild head injury, and light and noise sensitivity are also rather common complaints.
Psychological and Somatic Complaints Psychological and somatic complaints are common. Within 3 months of mild head injury, 46,47 The between 51 and 84 percent of patients have post-traumatic psychological symptoms. 48 prevalence of depression is at least 35 percent. In a study of patients who sustained a mild head injury in a motor vehicle accident, post-traumatic stress disorder was diagnosed in 14 49 percent within 1 month and 24 percent at 6 months after the injury. Fatigue is a common complaint 44 reported by 29 percent of patients at 4 weeks after the trauma and by 23 percent at 50 difficulty in falling asleep and arousals 6 months. Sleep disturbance is common, with 46 reported by 15 percent at 6 weeks after injury.
Rare Sequelae A variety of rare sequelae have been reported. For adults after mild injury, the incidence of 51,52 Both subdural and epidural subdural and epidural hematomas is 1 percent or less. hematomas can appear later, after an initial computed tomography (CT) scan is normal. Diffuse cerebral swelling is a rare complication of mild head injury, usually occurring in 53 children and adolescents, and resulting in death or a persistent vegetative state. When diffuse cerebral swelling occurs after a second concussion in someone still symptomatic from an earlier concussion, the term second impact syndrome is used. The second impact 54 syndrome is a rare and somewhat controversial complication. Seizures can occasionally result from mild head injury. Lee and Lui reported that approximately 2 percent of patients 55 developed seizures within 1 week, and Annegers and associates found a standardized incidence ratio of 1.5 after mild head injuries but no increase over the expected number after 56 mild rather than severe head 5 years. Nonepileptic post-traumatic seizures usually follow 57 injury and typically present during the first year after injury. Mild head injury can rarely 58 trigger transient global amnesia, which in children may actually be confusional migraine. 59 Rarely, cerebral60venous thrombosis may occur. Mild head injury sometimes produces a 61 postural tremor, and repeated injury may cause a parkinsonian syndrome. PATHOPHYSIOLOGY Mild head trauma sometimes results in cortical contusions due to coup 62 and contrecoup injuries and diffuse axonal injury from shear and tensile strain damage. Release of excitatory neurotransmitters including acetylcholine, glutamate, and aspartate may be a neurochemical substrate. Impairment in cerebrovascular autoregulation may occur. Neuroimaging studies including magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic source 63 imaging demonstrate structural and functional deficits. DIAGNOSTIC TESTING
Electroencephalography Electroencephalographic (EEG) studies have frequently been used to assess patients with mild head injury. An abnormal EEG cannot be attributed unequivocally to mild head injury in 64 the absence of a preinjury study for comparative purposes. For individual patients, EEG results have no predictive value. In one early study, an EEG taken immediately after head injury was borderline or abnormal in 43 percent of patients compared with 38 percent of 65 control subjects. An abnormal EEG study was less useful than clinical judgment in predicting time lost from work. However, for certain population groups, the EEG findings may 66,67 have some predictive value. Abnormalities in EEG power spectral analyses have been reported after mild head injury. However, the results of brain mapping may not be sensitive, specific, and reproducible68and often contain serious errors when presented as evidence in United States courtrooms. The American Academy of Neurology and the American Clinical Neurophysiology Society do not recommend the routine use of EEG brain mapping for evaluation of mild head injury and the
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postconcussion syndrome. Although auditory brainstem evoked potentials are sometimes abnormal after mild head injury, there is no correlation between abnormal results and 70 postconcussion symptoms.
Neuroimaging MRI of the brain is more sensitive than a CT scan in evaluating mild head injury. Thus, in a study comparing MRI and CT scanning in evaluating mild to moderate head injury, it was found71that MRI detected lesions in 85 percent of patients that were not detected by a CT scan. Most of the lesions were in the frontal and temporal regions. Lesions present on MRI had prognostic value for deficits of frontal lobe functioning and memory. Follow-up imaging at 1 and 3 months showed marked reduction of lesion size with improvement in cognition and memory. Subsequent MRI studies have demonstrated71–74 clinically occult contusions and white Fluid-attenuated matter changes primarily in the frontotemporal region. inversion-recovery (FLAIR) MRI is equal or superior to conventional spin-echo sequences for 75 Functional MRI may show changes following mild closed demonstrating traumatic lesions. 76 head injury. 77
In a study of 20 patients with persistent postconcussion syndrome, magnetic source imaging (a combination of MRI and magnetoencephalographic studies) detected brain dysfunction in a high percentage of patients with persistent postconcussion symptoms and in 65 percent compared with 5 percent of normal controls and 10 percent of those with a mild head injury who made a complete recovery. It was more sensitive than either EEG or MRI. Replication of this study with a larger number of subjects will be of interest. 78,79
Although SPECT scans are more sensitive than MRI and CT scans in detecting lesions, 80 the findings may not have prognostic significance and may be nonspecific. Depression and 81 multidrug abuse can produce deficits similar to those seen after mild head injury. The scientific literature does not support the routine use of SPECT for the evaluation of patients 82 with mild head injuries or postconcussion syndrome.
Neuropsychological Testing Neuropsychological testing is frequently performed to evaluate cognitive complaints. However, there are numerous problems with test sensitivity, specificity, reliability, and 83 The physician should be wary: patients are often confounding subject characteristics. 84 should be familiar with findings in misdiagnosed as brain injured. The psychologist 85 malingering and exaggerated memory deficits. MANAGEMENT
Headaches Tension- and migraine-type headaches can be treated with the usual symptomatic and prophylactic medications. In those with the migraine type, the physician should be concerned about the potential for medication overuse or rebound headaches with the frequent use of over-the-counter medications, such as acetaminophen, aspirin, and combination products containing caffeine, and prescription drugs containing narcotics, butalbital, and benzodiazepines. With such prescription medications, habituation is also a concern. Post-traumatic chronic daily headache may respond to an intravenous dihydroergotamine regimen. Occipital neuralgia may improve with local anesthetic nerve blocks, sometimes combined with an injectable corticosteroid (e.g., 3 ml of 1% lidocaine or 2.5 ml of 1% lidocaine and 3 mg 86 of betamethasone). Nonsteroidal anti-inflammatory drugs and muscle relaxants may also be beneficial. When true occipital neuralgia occurs with paroxysmal lancinating pain, trials of baclofen, carbamazepine, gabapentin, and pregabalin are warranted. Physical therapy and transcutaneous nerve stimulators help some headaches.
Cognitive Dysfunction 87
For patients with cognitive dysfunction, the efficacy of cognitive retraining is controversial. Prospective studies demonstrating efficacy are needed before routine use can be recommended. Patients with prominent psychological symptoms may benefit from supportive psychotherapy and the use of antidepressant and antianxiety medications. Tricyclic antidepressants such as amitriptyline and nortriptyline may be particularly useful in patients with post-traumatic headaches, depression, and sleep disturbance.
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Education One of the most important roles for the physician is education of the patient and family members, other physicians, and, when appropriate, employers, attorneys, and representatives of insurance companies. There is widespread ignorance88about the potential effects of mild head injury because of the “Hollywood head injury myth.” Most people's knowledge of the sequelae of mild head injuries derives largely from the cinema. Some of the funniest scenes in slapstick comedies and cartoons depict characters sustaining single or multiple head injuries, looking dazed, and then recovering immediately. In many films, head trauma is often inflicted by blows from guns and heavy objects, motor vehicle accidents, falls, fists, and kicks, all without lasting consequences. Our experience is minimal compared with the thousands of simulated head injuries seen in the movies and on television. The physician can provide education by summarizing the literature and can also use vivid examples from sports. The public is very familiar with dementia pugilistica, or the punch drunk syndrome of cumulative head injury in boxers. Many have witnessed powerful punches, resulting in dazed, disoriented boxers, or knockouts. In other sports, there is also growing awareness of the effects of cumulative concussions, for example, in professional football (quarterbacks Steve Young, Troy Aikman, and Stan Humphries) and hockey (Pat Lafontaine).
Return to Play in Sports The American Academy of Neurology2,6 has published a practice parameter on the management of concussion in sports. The report defines three grades of concussion (Table 31-1) and makes recommendations for when to return to play after removal from the contest (Table 31-2). On-site evaluation is recommended for all grades of concussion; a neurological evaluation is recommended for grades 2 and 3 but is not required for grade 1, which may be pursued depending on the clinical evaluation. Same-day return to participation is not recommended for grades 2 and 3 concussion but may occur with grade 1 concussion when there is a normal sideline assessment at rest and with exertion including a detailed mental status examination. The Academy has provided these parameters as practice options because they are based on literature review and expert opinion. It has recommended additional research, including multicenter prospective studies, to determine the physical, neurological, and neuropsychological outcomes of multiple concussions. Click here to view this table.... Click here to view this table.... PROGNOSIS
Risk Factors The persistence and severity of symptoms and neuropsychological deficits are not predicted 89 by a loss of consciousness of less than 1 hour compared with a patient just being dazed. Lesions present on MRI, usually in the frontal and temporal lobes, have prognostic value for 90 deficits of frontal lobe functioning and memory. Significant predictors for return to work by 3 months after mild head injury include older age; higher level of education, employment, and 91 socioeconomic status; and greater income. Patients with a high IQ recover faster than those with a low IQ. Age older than 4092years is a risk factor for increased duration and 4 number of postconcussion symptoms. Persistent symptoms occur more often in women. Prior head injury is a risk factor for persistence and number of postconcussion symptoms, consistent with the neuropathological concept of cumulative diffuse axonal injuries and contusions. A history of alcohol abuse may increase the amount of symptomatology. Multiple trauma can cause additional functional impairment, depression, anxiety, and stress.
Symptoms Most patients will recover within a few months. However, a significant minority have persistent problems. Because of the many variables in prognostic studies, the percentage of patients with symptoms after mild head injury varies quite markedly. Variables in prognostic studies include the definition of mild head injury, study design, and subject variables. 44
The percentage of patients with headaches at 1 month91varies from 31.3 percent to 90 95 93 94 percent ; at 3 months from 47 percent to 78 percent ; and at 1 year from 8.4 percent to
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96
35 percent. Almost 25 percent of patients have persisting headaches at 4 years. Reports 94 97 and 18 26 percent at 2 years or 4 of dizziness are made by 53 percent of patients at 1 week 98 Memory problems are reported in 18.8 percent at 1 month, 59 percent at 3 years. 91 26 96 Irritability is reported in months, 15.3 percent at 6 months,26 and 19 percent at 4 years. 95 24.7 percent of patients at 1 month and 5.3 percent at 1 year. Because the symptoms of postconcussion syndrome are so common in the general population, comparison of subjects with controls is important. Dikmen and colleagues studied 20 consecutive patients hospitalized with mild head injury and compared them with carefully 98 matched controls. They found that symptoms such as headaches, memory disturbances, dizziness, fatigue, noise or light sensitivity, difficulty in concentration, and irritability are common in control subjects but are still more frequent in patients with mild head injury.
Cognitive Deficits After mild head injury, deficits in cognitive functioning have been described, including a reduction in information-processing speed, attention, reaction time, and memory for new information. For information-processing speed, recovery is seen within 3 months in most 94,99 Memory for new information also recovers within 1 to 3 months, although 94 patients. persisting impairment in visual memory and performance of100 digit span has been noted. Reaction time abnormalities recover within about 6 months. Attention deficits show 94 persisting impairment at 3 months. Dikmen and co-workers found recovery of cognitive impairment by 1 year compared with controls, although a minority had ongoing impairment 98 preventing return to normal activities. Others have also found a101minority of patients with persistent cognitive deficits during follow-up of up to 22 months.
Effect of Litigation Patients with pending litigation are quite101 similar to those without29pending litigation with regard 101 types of headaches, cognitive test results, and to improvement of symptoms with time, 102 response to antimigraine medications. Symptoms usually do not resolve with the 103 settlement of litigation. Pending litigation may increase the level of stress for some claimants and may result in an increased frequency of symptoms after settlement. Skepticism of physicians may also accentuate the level of stress and compel some patients to exaggerate to ensure that complaints are taken seriously. 104
In a prospective study of 300 subjects sustaining mild head injuries in Lithuania (where there are minimal possibilities for economic gain, since fledgling insurance companies do not recognize postconcussion syndrome and there seems to be less expectation of persisting symptoms than in a western society), the prevalence, frequency, and visual analogue scale scores of headaches both after 3 months and after 1 year did not differ significantly between the injured and105controls. However, for a number of reasons, the study's results may not be generalizable. 85
Some patients do have persistent complaints due to secondary gain, malingering, and psychological disorders. Potential indicators of malingering after mild head injury include premorbid factors (antisocial and borderline personality traits, poor work record, and prior claims for injury); behavioral characteristics (uncooperative, evasive, or suspicious); neuropsychological test performance (missing random items, giving up easily, inconsistent test profile, or frequently stating “I don't know”); postmorbid complaints (describing events surrounding the accident in great detail or reporting an unusually large number of symptoms); and miscellaneous items (engaging in general activities not consistent with reported deficits, having significant financial stressors, resistance, and exhibiting a lack of reasonable 106 follow-through on treatments).
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 32 Neurological Aspects of Sleep BRUCE J. FISCH •
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SLEEP PHYSIOLOGY Stage I Sleep Stage II Sleep Stages III and IV Sleep REM Sleep Sleep Stage Distributions Circadian Rhythms and the Sleep-Wakefulness Cycle Functional Anatomy of Sleep DIAGNOSIS AND CLASSIFICATION OF SLEEP DISORDERS SLEEP LABORATORY TESTING Polysomnography Multiple Sleep Latency Testing Maintenance of Wakefulness Testing Actigraphy INSOMNIA Psychophysiological Insomnia Periodic Leg Movement Disorder and Restless Legs Syndrome Parkinsonism Alzheimer's Disease DISORDERS OF EXCESSIVE SLEEPINESS Sleep Apnea Narcolepsy PARASOMNIAS Confusional Arousals, Sleepwalking, and Sleep Terrors REM Sleep Behavior Disorder Nocturnal Paroxysmal Dystonia Epilepsy
Within a relatively short period of time, the centuries-old concept of sleep as a passive, monolithic, restorative process has been replaced by a view of sleep as a dynamic process in which cerebral activity at times exceeds that of waking levels and at other times decreases to levels encountered only in coma. This conceptual awakening has been led by remarkable discoveries in sleep mechanisms, such as the role of the biological clock that controls the sleep-wakefulness cycle, the suprachiasmatic nucleus of the hypothalamus, and, more
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recently, the genetic basis of inherited narcolepsy. These advances now provide a scientific basis for the neurological practice of sleep disorders medicine. Although sleep disorders medicine is an emerging field, it is already an important part of the practice of neurology. This is due partly to the striking prevalence of sleep disorders. Approximately 60 million Americans experience serious insomnia, as many as 10 million suffer from sleep apnea, 20 million have sleep-schedule disorders, and more than 125,000 have narcolepsy. Thousands of others suffer from a variety of sleep disorders, many of which complicate common neurological disorders. The International Classification of Sleep 1 Disorders currently lists 85 separate disorders of sleep, most of which are primarily disorders of the nervous system. SLEEP PHYSIOLOGY As in other areas of medicine, a knowledge of physiology forms the basis of effective diagnostic and therapeutic decision making. This information, when summarized for the patient, can also alleviate anxiety, provide reassurance, and enhance compliance. The current era of sleep physiology began in the mid-1930s with the discovery by Loomis and colleagues that sleep is separated into different electroencephalographic (EEG) 2states, now referred to as stages I, II, III, and IV of non–rapid eye movement (NREM) sleep. Following their discovery, efforts to understand sleep continued to focus on dividing it into more elemental components. Initially, this was accomplished by means of recording over extended periods of time and by using additional physiological monitors. The recording of eye movements led to3 the first description of rapid eye movement (REM) sleep by Aserinsky and (EMG) monitoring resulted in the discovery of muscle Kleitman in 1953. Electromyographic 4,5 atonia in REM sleep. The subsequent addition of respiratory, blood pressure, thermal, and cardiac monitoring further revealed the dramatic autonomic variability of REM sleep. Monitoring sleep over extended periods led to the discovery that the stages of sleep recur in cycles throughout the night. Sleep is separated into five categories: stages I, II, III, and IV, and REM sleep. This division is based on variations in three physiological functions: (1) EEG, (2) chin EMG, and (3) eye movements. According to currently accepted guidelines, the polysomnogram is scored by assigning a particular stage of sleep to each 30-second epoch of recording according to set 6 criteria provided in the guidelines. This allows for the quantitation of sleep states and for the graphical displays of sleep stages, sometimes referred to as hypnograms, as shown in Figure 7 32-1. The physiological characteristics of the various stages of sleep are summarized as follows and in Table 32-1. Click here to view this table....
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FIGURE 32-1 Hypnogram representing normal sleep at different ages. As age
increases, nocturnal arousals and awakenings increase, and stages III and IV sleep decrease. REM sleep continues to occur in approximately 90-minute cycles. (From Kales A, Kales JD: Recent findings in the diagnosis and treatment of disturbed sleep. N Engl J Med 209:487, 1974, with permission.)
Stage I Sleep Stage I sleep is referred to as light sleep or drowsiness. It is defined as a dropout of the alpha rhythm, so that alpha activity occupies less than 50 percent of the epoch being scored, often 8 associated with slow wandering lateral eye movements and a diminution of EMG activity. Not all individuals perceive themselves to be asleep during these changes and some maintain awareness of the environment. Increases in nocturnal stage I sleep occur in a variety of sleep disorders, particularly sleep apnea. The percentage of total sleep occupied by stage I sleep 9 increases with age, as illustrated by Figure 32-2.
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FIGURE 32-2 Sleep stages obtained from the second consecutive night of
polysomnography (the second night reduces problems related to adaptation to the laboratory environment). Sleep stages are shown as a percentage of the sleep period—defined as the time between sleep onset and final awakening. (From Hirshkowitz M, Moore CA, Hamilton CR, et al: Polysomnography of adults and elderly: sleep architecture, respiration, and leg movement. J Clin Neurophysiol 9:56, 1992, with permission.)
Stage II Sleep Stage II sleep is defined by the appearance of K complexes (prominent biphasic waveforms that are at least 0.5 second in duration, with an initial negative phase followed by a positive phase appearing maximally over the central head regions) or sleep spindles (complexes of 12- to 14-Hz waveforms in runs exceeding 0.5 second in duration, appearing maximally over the central head regions). Occasionally, slow lateral eye movements from stage I sleep persist into stage II sleep. Sleep spindles first appear at 1 to 3 months after birth and peak at 7 to 8 months of age, when they may be present for more than 50 percent of the time during stage II sleep. In adult sleep, they typically occur 2 to 8 times each minute, whereas K complexes occur 2 to 3 times per minute. EMG activity in stage II sleep is present but reduced from waking and stage I levels. The percentage of total sleep occupied by stage II sleep increases with age.
Stages III and IV Sleep Stages III and IV sleep, also referred to as slow-wave sleep or delta sleep, are defined by the appearance of 2-Hz or slower EEG waveforms that are at least 75 μV in amplitude when recorded from electrode derivations A1 to C4 or A2 to C3. To distinguish stage III from stage II, the delta waves must occupy at least 20 percent of the recording. When they occupy more than 50 percent of each epoch, sleep is scored as stage IV. The EMG is often active, but less so than in stage I sleep. Sleep spindles and K complexes may be present but occur less frequently as sleep deepens. Eye movements are absent.
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Slow-wave sleep is most prominent in childhood and declines with age (Fig. 32-2). Indeed, it may be absent in normal individuals over 60 years of age. This decline in slow-wave sleep roughly parallels the normal decline in amplitude of the waking EEG and may be due in part to reduced synaptic connectivity. The largest decline in slow-wave sleep occurs during the second decade of life. The arousal threshold to various stimuli is higher in slow-wave sleep than in stage I or II sleep. Children in slow-wave sleep are normally difficult to arouse and may remain confused for prolonged periods following arousal (see p. 626 under the heading of Confusional Arousals). Benzodiazepines reduce slow-wave sleep, and abrupt withdrawal may produce excessive slow-wave sleep. Growth hormone (GH) has its greatest 24-hour peak at the beginning of the night, during the initial period of slow-wave sleep. This may explain why individuals who are allowed to sleep after a period of sleep deprivation recover slow-wave sleep first. If slow-wave sleep is consistently interrupted, symptoms of fibrositis may arise. Thus, slow-wave sleep has been referred to as restorative sleep.
REM Sleep REM sleep is distinct from the other stages of sleep. Only three stages of sleep can be consistently distinguished in the neonatal period: active sleep, quiet sleep, and indeterminate or transitional sleep. Active sleep is the forerunner of REM sleep. As in adults, it is characterized by abrupt rapid eye movements, irregular respiration and heart rate, penile tumescence, muscular atonia (absent EMG activity), and a low-amplitude, irregular EEG pattern. Thermal regulation is markedly suppressed, so that neither shivering nor sweating is typically seen. In neonates, REM sleep onset is usually in active sleep, whereas in children or adults REM sleep rarely occurs during the first 60 minutes of sleep. Sleep onset with REM sleep beyond early childhood is therefore abnormal. Active sleep first appears at approximately 32 weeks of conceptional age. At term, REM (active) sleep occupies 50 percent of sleep time. After the first year of life, the majority of REM sleep occurs during the second half of the night, and REM sleep occupies 20 to 25 percent of total sleep time (Fig. 32-2). During REM sleep, brain metabolism increases dramatically to near-waking levels. The combination of atonia, active cerebral metabolism, and an EEG pattern that at times resembles alert wakefulness has led to the characterization of REM sleep as a metabolically awake brain in a paralyzed body. REM sleep is enhanced by cholinergic agonists and suppressed by tricyclic antidepressant medications, adrenergic uptake blockers, clonidine, scopolamine, propranolol, lithium, and monoamine oxidase inhibitors. Alcohol ingestion immediately before sleep suppresses REM sleep during the first half of the night but then results in excessive REM activity later in the night. Prolonged REM suppression (produced by repeatedly awakening individuals from REM sleep or by pharmacological means) is followed by a period of excessive REM sleep, often referred to as REM rebound. These observations have important implications for sleep testing. For example, the sudden withdrawal of tricyclic antidepressant medication before testing may lead to the erroneous impression of narcolepsy because of early-onset and excessive REM sleep. Similarly, the duration of the history of sleep apnea correlates with the length of REM periods (REM rebound) that appear at the time of initial treatment using continuous positive airway pressure therapy.
Sleep Stage Distributions The stages of sleep are distributed across the night in approximately four to five cycles (Fig. 32-1). Each cycle begins with NREM sleep and ends with REM sleep. After infancy, sleep begins with stage I sleep and then usually progresses from stage II to stage IV sleep, with a return to stage II sleep before the occurrence of REM sleep. As sleep continues through the night, the contribution of slow-wave sleep to each cycle decreases and REM sleep increases. REM sleep during the first cycle lasts only several minutes, whereas slow-wave sleep often lasts over 30 minutes. The duration of the first cycle is typically 70 to 110 minutes, whereas subsequent cycles last closer to 90 to 120 minutes. When viewed across the entire night, the total percentages of the stages of sleep are distributed approximately as follows: stage I, 5 percent; stage II, 45 to 55 percent; stage III, 3 10 to 8 percent; stage IV, 10 to 15 percent; and REM, 20 to 25 percent. Sleep epochs with EEG awakenings or excessive artifact caused by patient movement are scored as arousals or movement time, respectively. Increases in stage I sleep, arousals, movement time, or wakefulness after sleep onset all are common nonspecific indicators of abnormally disrupted sleep.
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As illustrated in Figure 32-2, the ability to consolidate all of one's sleep time into a single continuous major sleep period declines with age. Even though elderly individuals often appear to be excessively sleepy because of daytime napping, their total 24-hour sleep time is approximately the same as during middle age. Various strategies have been used to enhance sleep consolidation in the elderly, with limited success.
Circadian Rhythms and the Sleep-Wakefulness Cycle Circadian rhythms (circa: “around,” dia: “day”) are biological time cycles that have a period of 11 approximately 24 hours, such as the sleep-wakefulness cycle. Biological cycles that repeat more than once every 24 hours, such as the cycling of sleep stages throughout the night, are referred to as ultradian rhythms. The study of biological rhythms is referred to as chronobiology. An overview of biological functions demonstrating circadian rhythmicity is shown in Table 32-2. Click here to view this table.... One of the major advances in chronobiology has been the discovery of the biological clock that regulates the sleep-wakefulness cycle: the suprachiasmatic nucleus of the hypothalamus. In animals, bilateral ablation of12,13 this nucleus causes an immediate and total Replacement of 14 the suprachiasmatic loss of the circadian sleep-wakefulness cycle. nucleus using fetal transplant tissue restores circadian rhythmicity. Transplantation of mutant rat suprachiasmatic nucleus that has been genetically altered to produce 22-hour 15 rest-activity periods produces the same rest-activity period in the recipient rats. The nucleus, like all circadian clocks, is synchronized by an external cue or zeitgeber (“time giver”). The zeitgeber of the suprachiasmatic nucleus is light. Thus, the nucleus is set according to the day-night light cycle of the earth. Light reaches the suprachiasmatic nucleus 16 by a projection from the retina that is separate from the primary visual pathway. Following the discovery of the suprachiasmatic nucleus, the most important advance in understanding the physiological basis of sleep-wakefulness cycles has been the discovery of three genes. The clock gene controls the presence and duration of circadian rhythmicity in the mouse. Mice deprived of light exposure with homozygous clock gene mutations show no evidence of circadian rhythmicity. The clock gene is active in17the suprachiasmatic nucleus and retina as well as in the kidney and gastrointestinal tract. The per gene of the fruit fly produces mRNA that maximally expresses the PER protein 6 to 8 hours after sunset. Mutations of18the per gene can alter the period of circadian rhythmicity or abolish it completely. The tim (timeless) gene of the fruit fly responds to light exposure and facilitates 19 the entrance of the PER protein into the cell nucleus. Core body temperature appears to have a strong synchronizing effect on the sleep-wakefulness cycle. Core body temperature fluctuates over an approximately 24-hour period, with the lowest temperature occurring prior to awakening, between 4 and 5 a.m. and the highest in the late afternoon, near 5 p.m. The ability of most individuals to fall asleep is greatest at the nadir or as core body temperature declines. REM sleep, more so than the other stages of sleep, is strongly regulated by core body temperature. REM sleep is most likely to occur during the upward swing in temperature between 4 and 6 a.m. This relationship is easily demonstrated by delaying sleep onset until the end of the night, at which time REM sleep tends to predominate and may even initiate sleep onset. When individuals are placed in time isolation without zeitgebers (external time cues), the sleep-wakefulness cycle continues to parallel the temperature cycle for weeks to months. Thereafter an abrupt dissociation occurs, in which the sleep-wakefulness cycle increases to more than 24 hours even though the temperature rhythm remains stable. Thus, it appears that although circadian temperature rhythms can be entrained by the suprachiasmatic nucleus, the circadian rhythm for temperature is modulated by more than one biological clock. The clinical relevance of circadian rhythmicity to sleep becomes apparent when one tries to change a sleep-wakefulness schedule abruptly. Difficulties arise not only because the “sleep debt” is altered but also because biological rhythms that ordinarily influence the sleep-wakefulness cycle continue to cycle for varying periods of time on their own established schedules. This makes adaptations to new situations—such as time-zone changes (jet lag) or shift work—highly problematic. Elderly individuals who have difficulty in consolidating sleep and individuals with neurological disorders that disrupt the normal cycling of sleep (see p. 618 under the heading of Alzheimer's Disease) exemplify circadian rhythm disorders. One promising approach to regulating the sleep-wakefulness cycle externally is the use of strategically timed exposure to bright light. Although still experimental, it has been
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demonstrated that light exposure can lead to dramatic shifts in the circadian rhythms for body 20 temperature and cortisol secretion and can thereby speed the resetting of the sleep-wakefulness cycle.
Functional Anatomy of Sleep The nervous system structures most important for initiating and maintaining NREM sleep are the basal forebrain, anterior hypothalamus–preoptic region, midline brainstem, and dorsolateral medullary reticular formation. Severe insomnia can be induced in animals by destruction of the midbrain, pontine, and medullary tegmental serotonergic raphe nuclei or by 21 pharmacologically depleting brain serotonin. The putative role of serotonin in sleep generation in humans is also supported by reports of insomnia associated with lesions in the 22 midline mesencephalic and pontine tegmentum. In one such report, natural sleep was 23 temporarily restored by the administration of the serotonin precursor 5-hydroxytryptophan. In animals, spontaneous recovery from such lesions further suggests that serotonin is only one of several important factors in sleep generation. The presence of sleep-inducing substances in cerebrospinal fluid (CSF) has been established by experiments in which intraventricular injection of CSF taken from a sleep-deprived animal induced sleep in an alert animal. Several substances produced within the nervous system—including melanocyte-stimulating hormone, prostaglandin D2, and uridine—have been shown to have sleep-inducing effects. However, no single endogenous substance has been identified that is necessary or sufficient for the generation or 24 maintenance of sleep. Melatonin is released from the pineal gland at night and can be suppressed by sympathetic activation through light stimulation of the retinohypothalamic tract and suprachiasmatic nucleus. The role of melatonin in sleep regulation is notable because it can shift wakefulness-sleep cycles; if it is administered in the early evening, it will shift circadian rhythms and the onset of sleep to an earlier time (phase advance). This has led to the widespread use of melatonin for the rapid correction of jet lag or other altered sleep-wakefulness cycle disturbances. One of the most recent discoveries in the maintenance of wakefulness has been the 25 identification of the canarc-1 gene responsible for canine narcolepsy. This gene encodes the hypocretin (orexin) 2 neuropeptide receptor that binds hypocretin. A mouse knockout model of the orexin-2 receptor gene has been shown to produce cataplectic and REM-like sleep attacks consistent with narcolepsy. Hypocretin-secreting neurons are located in the medial and lateral hypothalamus and project widely throughout the basal forebrain and upper brainstem. It has been proposed that failure of this system occurs either as a primary genetic disorder or from diverse pathological processes (e.g., autoimmune, infectious, or traumatic processes) that injure the hypocretin-secreting neurons. Structures essential for the generation of REM sleep are located primarily within the dorsolateral pons. Animal studies and anecdotal reports of pontine lesions in humans indicate that REM initiation and maintenance (i.e., rapid eye movements and muscle atonia) can be eliminated by lesions of the dorsolateral pons ventral to the locus ceruleus. Pontine lesions smaller than those required to block REM sleep can produce REM sleep without atonia in 26 animals. Such animals may thus exhibit complex aggressive behaviors during REM sleep that appear to be the enactment of dream content and are analogous to those that occur in humans with REM sleep behavior disorder. Conversely, injections of cholinesterase inhibitors 27 into the same location within the pons may induce atonia in the absence of sleep. Using intracellular recording, such experiments have established that the atonia occurring in REM sleep is produced by the pontine activation of medullary inhibitory centers, which in turn induce postsynaptic hyperpolarization of brainstem and spinal motor neurons. Several disorders of REM sleep function in humans have been delineated that were, in part, predicted by animal experimentation. Spinal motor neuron inhibition, absent H reflexes, and suppressed or absent tendon reflexes of REM atonia occur as discrete attacks of cataplexy or sleep paralysis in narcolepsy and rarely in other neurological disorders. In narcolepsy, these attacks, together with the sudden onset of dream-like hallucinations (hypnagogic hallucinations), represent the sudden intrusion of REM sleep phenomena (atonia and dream mentation) during wakefulness. Thus, narcolepsy is actually a REM sleep disorder in which dissociated states occur. In REM sleep behavior disorder, in which sometimes violent physical activity occurs during REM sleep, the atonia of REM sleep fails and the patient becomes physically active while dreaming. The discovery of dissociated sleep states in which certain features that should be present are absent (e.g., the lack of atonia in REM sleep behavior disorder) or in which one state appears to intrude upon another (as in the atonia of
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REM sleep during wakefulness in cataplexy) underscores our current understanding of wakeful ness, NREM sleep, and REM sleep as variable associations of physiological processes rather than “all-or-none” states. DIAGNOSIS AND CLASSIFICATION OF SLEEP DISORDERS A sleep disorder is generally defined as a disturbance of sleep that is deleterious to the individual's health or psychosocial well-being. Although some sleep disorders are life-threatening owing to cardiovascular complications (e.g., sleep apnea) or the effects of sleepiness (e.g., industrial and automobile accidents), others may involve only temporary discomfort (e.g., jet lag). A patient who either complains of or is observed to have disturbed nocturnal sleep, excessive daytime sleepiness, or some other problem related to sleep is considered to have a sleep disorder. This broad definition even includes those who actually have no difficulty in sleeping but believe they do not sleep (referred to as sleep misperception disorder, pseudoinsomnia, or sleep hypochondriasis). The International Classification of Sleep Disorders groups disorders into the following eight categories: insomnias, sleep-related breathing disorders, hypersomnias of central origin, circadian rhythm sleep disorders, parasomnias, sleep-related movement disorders, isolated 1 symptoms (apparently normal variants and unresolved issues), and other sleep disorders. Table 32-3 provides an outline of the classification as well as selected examples within each category. Parasomnias are disorders intruding into the sleep process that appear to be related to difficulties with partial arousal. Sleepwalking is an example of a parasomnia. Click here to view this table.... A more practical approach to classifying sleep disorders from the clinician's point of view is according to major symptomatology. A differential listing based on clinical distinctions is provided in Table 32-4 and Table 32-5. It is beyond the scope of this review to discuss all 1the disorders listed, but summary descriptions can be found in the international classification. The clinical manifestations of disorders of primary concern to the neurologist are presented as follows, under specific headings. Click here to view this table.... Click here to view this table.... The diagnosis of sleep disorders begins and often ends with the patient's history. Patients with sleep disorders have one or more of three complaints: (1) “I cannot get enough sleep,” (2) “I'm sleepy during the day” or “I fall asleep all the time,” or (3) there is some unusual sleep behavior, often best described by a bed partner. Certain disorders may be associated with all three complaints. For example, patients with obstructive sleep apnea may complain of daytime sleepiness as well as an inability to sleep because of frequent awakenings gasping for air. As in the evaluation of a patient with epilepsy, an observer (i.e., the bed partner) should be encouraged to attend the initial interview. If possible, prior to the initial clinic visit, the patient should be sent a structured sleep questionnaire and a sleep diary to fill out. The former should contain questions concerning the patient's sleep habits; usual hours of sleep; sleep problem; current medications; other medical problems; weight gain in the last 30 years; alcohol intake; conditions under which sleep occurs; dietary stimulants (e.g., coffee, caffeinated beverages); activities other than those pertaining to sleep or sex that take place while in bed (e.g., eating and writing); occurrence or history of various abnormal sleep behaviors (e.g., enuresis and sleepwalking); and occurrence of other relevant symptoms (e.g., sleep paralysis, cataplexy, hypnagogic hallucinations, early morning headache, loud snoring, and difficulty in breathing at night). The sleep diary, which lists times of getting in and out of bed and of sleep onset and cessation, should be maintained for 1 week prior to the visit. Observing patients after they have been allowed to sit for a few minutes in a quiet waiting room often provides a rough measure of sleepiness. Patients with moderate to severe sleepiness will be asleep, and those with sleep apnea will probably be snoring loudly. Prior to performing the physical examination, the sleep questionnaire, sleep diary, psychosocial situation (occupation, current and recent life stresses, presence of drug or alcohol abuse), and medical and psychiatric history should be reviewed. As in other areas of neurology, if the diagnosis has not been limited to two or three possibilities before the physical examination is performed, it is unlikely that a correct diagnosis will be reached. The physical examination should include the patient's weight, vital signs, neurological examination, auscultation of the heart, and inspection of the nasal and oral airways. The presence of redundant tissue, tonsillar hypertrophy, micrognathia, malocclusion, and
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erythema of the soft palate and posterior pharynx (due to snoring) should be noted as risk factors for sleep apnea. In most cases, routine laboratory studies should include determination of plasma electrolytes, renal and hepatic function, and a complete blood count. In some cases, additional tests for endocrine function, rheumatological disease, or infectious disease will be suggested by the patient's medical history and physical examination. Thyroid function tests should be obtained in all patients with sleep apnea. SLEEP LABORATORY TESTING The most useful tests for diagnosing sleep disorders are the overnight polysomnogram (PSG), multiple sleep latency test (MSLT), and actigraphy. PSG is used to determine whether nocturnal sleep is disturbed and to identify any specific causes for the sleep disturbance. The MSLT is used to determine whether the patient has excessive daytime sleepiness or the likelihood that the patient has narcolepsy. The maintenance of wakefulness test (MWT) has been introduced to determine the potential impact of abnormal sleepiness on daily function. Both the MSLT and the MWT are performed during the daytime or a major wakefulness period. Actigraphy is used to establish objectively the patient's sleep-wakefulness schedule over a period of 1 or more weeks.
Polysomnography The PSG evaluation includes staging of sleep; assessment of respiratory, cardiac, and cerebral activity; and detection of movement disorders or other abnormal behaviors associated with sleep or arousal. In the past, owing to technological limitations, the range of routinely monitored functions was limited. Although this is no longer the case, some patients have difficulties in sleeping in the laboratory environment, and these will be made worse with the placement of additional monitoring devices. The likelihood of a “first-night effect” can be reduced before testing by taking time to explain to the patient what will happen in the sleep laboratory. Patients who are anxious should be encouraged to visit the sleep laboratory and talk to the technologists about testing. They should also be encouraged to bring their own sleeping clothes, pillow, or whatever else they feel might make them comfortable. There should be some provision for another adult to accompany the patient to the laboratory. In some cases, patients actually sleep far better in the laboratory than at home. This phenomenon is referred to as a “reverse first-night effect” and is most often associated with psychophysiological insomnia, an environmental sleep disorder (e.g., noise and allergies), sleep state misperception, or a psychiatric disorder. Sleep is staged using at least one channel of EEG, eye movement monitors (electrodes placed around the eyes), and submental EMG (electrodes placed under the chin). Because one channel is insufficient for assessing other cerebral activity and because the EEG changes of sleep are facilitated by additional channels of recording, PSGs typically use three or four channels of EEG recording. Respiratory functions are monitored by placing a small device (thermistor or thermocouple) between the nose and the mouth that has separate channels for detecting nasal and oral air flow. This device registers the presence of airflow by detecting temperature changes. More recently, a nasal cannula attached to a sensitive 28 pressure transducer has been shown to be more accurate for detecting changes in air flow. Because of the greater accuracy and ease of use, most sleep laboratories now use this device. Respiratory effort is monitored by placing mercury strain gauge or piezoelectrical belts around the chest and abdomen to detect changes in circumference. Intercostal EMG electrodes may be added as a backup monitor for the belts, which may become displaced during the night. Intercostal EMG may also be helpful in assessing actual effort. Oxygen saturation is monitored with a clip-on pulse oximeter, which is usually worn on the finger. Leg movements are monitored with a pair of disk electrodes placed over the pretibial surface of each leg. Finally, a video camera with low-light recording capability is used to record continuously for any behavioral changes that might occur. Video monitoring is also used by the technologist in the control room to observe the patient's activities. In selected situations, additional physiological monitors may be used. In patients with gastroesophageal reflux, a pH probe inserted nasogastrically will register sudden increases in acidity of the lower esophagus. In certain patients with subtle obstructive apnea (i.e., upper airway resistance syndrome), frequent arousals may occur with little evidence of upper airway obstruction in airflow or chest-wall or abdominal monitors. In such cases, it is helpful to place an esophageal balloon transducer that can detect slight changes in intrathoracic pressure and thereby confirm the presence of airway obstruction. 29
Although there are30–32 normative values for the distribution of sleep stages and abnormalities of the interpretation and clinical significance of the PSG usually depends breathing in sleep, on the patient's presenting complaint, current medications, medical and neurological
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evaluation, and adaptation to the laboratory environment. Thus, the PSG in isolation infrequently provides a diagnosis. The interpretation of specific PSG findings is discussed later, in the sections on specific disorders.
Multiple Sleep Latency Testing The MSLT is performed with the use of PSG monitoring during four or five daytime nap opportunities at 2-hour intervals beginning 1.5 to 3 hours after the patient arises from nocturnal sleep. For accurate interpretation, the MSLT is performed following overnight PSG. As with the PSG, the recording montage includes EEG (C3 to A2 or C4 to A1), submental EMG, and eye movement monitors for staging sleep. Additional channels of EEG recording—such as T3 to Cz, Cz to T4, and O1 to A2 or O2 to A1—are used to facilitate the recognition of sleep onset. For clinical testing, the nap is concluded if sleep does not occur after 20 minutes or 15 minutes after the first 30-second epoch of sleep. An average latency to sleep onset for each of the four or five naps (five are performed if REM sleep occurs during one of the preceding four naps) is then calculated. An average latency of less than 5 minutes is clearly abnormal, whereas an average latency of more than 10 minutes is clearly normal. Patients with excessive daytime somnolence typically have an average sleep latency of less than 8 minutes. The occurrence of REM sleep during any nap is considered abnormal. Two 1 or more naps containing REM sleep and an average sleep latency of less than 8 minutes is virtually diagnostic of narcolepsy, unless the patient suffers from another severe sleep disorder associated 33 with sleep or REM deprivation, such as sleep apnea, or a circadian rhythm disturbance.
Maintenance of Wakefulness Testing The MWT is performed with four nap studies at 2-hour intervals beginning 2 hours after awakening from nocturnal sleep. Each nap test lasts up to 20 minutes and is terminated upon sleep onset. As with the MSLT, an average of the latencies to sleep onset is calculated from all four naps. At the beginning of testing, the patient is seated and is instructed to remain awake after the room lights have been turned off. Following this protocol, approximately 95 percent of normal individuals can remain awake for an average of more than 12 minutes throughout all four nap tests and more than 50 percent of normal subjects can remain awake 34 throughout all four nap tests.
Actigraphy Actigraphy is a simple and relatively inexpensive test that allows the physician to make an objective assessment of the patient's sleep-wakefulness activity outside the laboratory. The actigraphic device is a small motion detector that is usually worn like a wristwatch. An on-board memory chip is used to store motion information. After being worn for 1 to 2 weeks, it is inserted into a computer, which generates a graphic display of motility—the actigram. Persistent quiescent periods indicate sleep, and high levels of activity correlate with wakefulness. In normal individuals, the actual correlation between wrist actigraphy and 35 with polysomnography may exceed 90 percent. This correlation is less perfect in individuals 36 abnormal sleep and during times other than active wakefulness or slow-wave sleep. Nevertheless, accuracy is sufficient to allow for a reliable objective assessment of sleep-wakefulness patterns over long periods of time. Actigraphy is most useful in the evaluation of insomnia and sleep schedule disorders. INSOMNIA Insomnia is a symptom often associated with complaints of daytime sleepiness, headache, irritability, difficulty with concentration and memory, frequent nocturnal awakenings, early morning awakening, and nonrefreshing sleep. Because insomnia is a manifestation of so many disorders, an organized approach to diagnosis is essential. The first step is to understand clearly what the patient means by insomnia and to determine the significance of the complaint. The initial history should focus on nocturnal experiences and daytime sequelae. Potential temporal relationships between stress or the introduction of medications and the onset of insomnia should be sought. The pattern of insomnia may be important. Early morning awakening is typical of depression, whereas delayed sleep onset suggests psychophysiological insomnia. Disorder-specific symptoms such as snoring, gastrointestinal discomfort, polyuria, breathing difficulties, paresthesias, itching, and involuntary movements should be sought. Because the largest proportion of patients with serious insomnia suffer from psychiatric disorders, it is important to obtain a psychiatric history. As with most disorders, duration is an important consideration in diagnosis and therapy. Transient insomnia has a duration of days and is usually related to changes in the environment,
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emotional stress, or changes in the timing of sleep (e.g., time-zone changes). Short-term insomnia has a duration of several weeks and is usually related to stress associated with acute illness, family life, or work. Chronic insomnia has a duration of more than 1 month and is often related to a primary psychiatric, neurological, or medical disorder. Most individuals who seek help at a sleep disorders center suffer from chronic insomnia. Common causes of serious insomnia (Table 32-6) are psychiatric disorders, psychophysiological factors, drug and alcohol abuse, and other sleep disorders such as 37 restless legs syndrome and sleep apnea. The diagnosis of drug and alcohol abuse may become apparent only when the patient enters the sleep laboratory or may require blood and urine toxicology screening. Table 32-7 provides a list of common medications that may interfere with sleep. Click here to view this table.... Click here to view this table....
Psychophysiological Insomnia Psychophysiological insomnia is a behaviorally conditioned sleep disorder in which sleep-preventing associations have become internalized and persist even though the initial cause of insomnia has been removed. Sleep-incompatible behavior that maintains the insomnia may be manifested by obvious poor sleep hygiene or by a subtle conditioned response to the bedroom environment. In the latter situation, patients find that they sleep better in unfamiliar environments. Psychophysiological insomnia usually develops out of periods of stress in which anxious thoughts keep the patient awake. After several nights, increased concern over an inability to sleep develops. Thereafter, a vicious cycle develops in which worry over the inability to sleep keeps the patient awake. As the insomnia develops, simple activities performed routinely before going to bed (e.g., setting the clock, brushing the teeth) become associated with an inability to sleep and eventually evoke a conditioned response. Frequent worry about the inability to sleep that overshadows other medical or social problems is a distinguishing feature of this disorder. Patients with psychophysiological insomnia rarely have significant daytime sleepiness but do experience other common symptoms of insomnia: depression and irritability, fatigue, decreased motivation, memory impairment, and poor concentration. They may also have neurasthenic symptoms, such as tension headache or cold hands and feet. Sleep occurs at times when no effort to sleep is put forth, as while reading or watching television. The PSG is characterized by an increased sleep latency (exceeding 30 minutes), increased wakefulness after sleep onset, a sleep efficiency of less than 85 percent (the ratio of total sleep time to 1,38 If a reverse first-night effect occurs, the patient time in bed), and increased stage I sleep. will be aware of it; by contrast, a patient with sleep state misperception will report poor sleep. The treatment of psychophysiological insomnia includes sleep hygiene, behavioral therapy, and occasional hypnotics. Common rules of sleep hygiene for facilitating sleep are listed in 39 Table 32-8. These rules actually apply to most patients with insomnia. Behavioral intervention consists of relaxation therapy (e.g., meditation, muscle relaxation, and breathing techniques), sleep restriction (allowing only several hours of sleep per night to improve sleep efficiency), and stimulus control therapy (patients are asked to get out of bed whenever they cannot sleep). Hypnotics may be helpful in breaking the cycle of insomnia but should be used only on one or two occasions per week. If the patient intends to attempt sleep before taking the hypnotic, then one with a rapid onset should be considered. If the patient knows that he or she will need a hypnotic ahead of time because of a potentially stressful event the next day, then the hypnotic is selected by its duration of effect. Click here to view this table.... Special care must always be taken when one uses hypnotics to treat patients with chronic insomnia. If the diagnosis is not clear, they should be avoided so as to lessen the risk of exacerbating sleep apnea or a substance abuse disorder. In either instance, sedation may be dangerous. Many patients with chronic insomnia develop paradoxical worsening of insomnia weeks or months after the introduction of benzodiazepines or barbiturates. This occurs either because tolerance has developed and the initial dosage is now too low, or because the patient tries to stop the medication only to encounter withdrawal symptoms. In either case, the best approach is to withdraw medication slowly and treat the underlying cause of insomnia. Neither physical dependence nor rebound insomnia upon discontinuation appears to occur with the newer nonbenzodiazepine hypnotics zolpidem, zopiclone, and zaleplon. Also unlike benzodiazepines, there is little change in sleep-stage architecture.
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Periodic Leg Movement Disorder and Restless Legs Syndrome Periodic leg movement disorder and restless legs syndrome are leading causes of insomnia. The former consists of repetitive, stereotyped movements that cause repeated arousals from sleep. Each periodic leg movement resembles a Babinski reflex response, with dorsiflexion of the great toe and foot often accompanied by flexion of the knee and hip. The movement may occur as a sustained contraction or as a rapid series of clonic contractions. EMG monitoring of the tibialis anterior reveals activity lasting 0.5 to 5 seconds and recurring every 4 to 90 seconds (usually every 15 to 40 seconds), mainly during stage II sleep. The contractions may affect only one leg but more often occur asynchronously in both.40Interestingly, Babinski responses can be elicited in normal individuals in NREM sleep. The resemblance to the Babinski reflex response has led to the hypothesis that the periodic leg movements are 41 caused by transient lapses in cortically mediated motor inhibition. It was originally thought that the occurrence of more than five periodic leg movements per hour was clinically significant. However, it soon became apparent that such movements occur more frequently with increasing age in otherwise normal individuals. In view of these findings, the significance of these movements now depends on whether they are associated with arousals and complaints of daytime sleepiness. Therapeutic intervention is generally warranted when 15 or more periodic leg movements associated with arousals occur per hour 42 of sleep. Patients with restless legs syndrome present with complaints of unusual and severe leg sensations, such as creeping, crawling, crushing, or searing pains. Infrequently, the pain may extend to the arms or remain unilateral. Relief is gained temporarily by walking, rubbing the legs, or applying heat. As soon as these maneuvers stop, the discomfort returns. Thus, a hallmark of this disorder is the irresistible urge to move the legs to relieve discomfort. The discomfort increases throughout the day until patients find they are unable to tolerate being stationary. Thus, not only is sleep interrupted but normal activities such as business meetings or long car rides become impossible. Restless legs syndrome is a relatively common disorder, affecting more than 5 percent of the population. Its onset may occur in childhood, but the peak onset is in middle age. The course is somewhat unpredictable, with long remissions lasting for months or years, during which symptoms are greatly diminished. A family history should be sought, as the disorder is frequently familial. Unfortunately, familial 43 cases tend to be more resistant to therapy. Almost all patients with restless legs syndrome have periodic leg movements during sleep. The restless legs syndrome is usually idiopathic but has been associated with pregnancy, uremia, rheumatoid arthritis, iron-deficiency anemia, fibromyositis, peripheral neuropathy, myelopathy, leukemia, and withdrawal from anticonvulsants, benzodiazepines, barbiturates, and other hypnotics. In the author's experience, iron-deficiency anemia is common in patients with restless legs syndrome and is quantitatively related to the severity of symptoms. Sun and colleagues reported that low serum ferritin levels (<50 μg/L) are correlated with the severity of symptoms and that ferritin levels exceeding 50 μg/L are associated with better sleep 44 efficiency and fewer periodic leg movements with arousal. Patients with a low serum ferritin level should receive iron treatment. Stimulants such as caffeine, as well as physical and emotional stress, may exacerbate the underlying condition. The restless legs syndrome and periodic leg movement disorder respond to four main 45 classes of medication: antiparkinsonian medications, anticonvulsants, benzodiazepines, and opiates. Levodopa-carbidopa, bromocriptine, and selegiline all may be effective, but treatment is usually initiated with a dopamine agonist such as ropinirole or pramipexole, beginning in the evening 1 to 2 hours before bedtime. If symptoms recur later at night or during the day, then a longer-acting preparation should be tried and if necessary taken also in the morning. The anticonvulsant gabapentin should be given to patients with mild symptoms or to those unable to tolerate dopamine agonists. Benzodiazepines have been used frequently, particularly clonazepam, but in our experience have not proved as efficacious. Moreover, sedative medications may cause daytime sleepiness or, rarely, insomnia. Opiates 46 were used successfully by Ekbom, who first described the restless legs syndrome, and remain a viable therapeutic alternative. If opiates are necessary, those with long half-lives or low addictive potential (e.g., codeine) should be tried first. In some instances, it may be necessary to combine medications.
Parkinsonism 47
As summarized by Aldrich, patients with parkinsonism are at risk for disrupted sleep owing to one or more of the following: (1) degeneration of the neural systems that regulate sleep,
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resulting in sleep fragmentation and reduced REM and slow-wave sleep; (2) bradykinesia and rigidity, and a reduction in the normal number of body shifts during sleep, causing discomfort and frequent arousals; (3) periodic leg movements, tremors, or medication-induced movement disorders, causing frequent and prolonged arousals; (4) abnormal muscle tone, which facilitates breathing abnormalities that may awaken the patient; and (5) disorders of circadian rhythm and the sleep-wakefulness schedule, which may arise from medications or the disease itself. Improved sleep is often achieved by treating the underlying disorder with levodopa in the evening. Any48improvement in sleep that occurs is probably due in part to increased nocturnal mobility. Some patients may also respond to other dopamine agonists (e.g., pergolide, ropinirole, or pramipexole) or selegiline. Insomnia due to involuntary movements may respond to benzodiazepines or reduced doses of dopamine agonists. For sleep-wakefulness schedule disturbances, a brief course of a short-acting benzodiazepine hypnotic may be helpful. Breathing disturbances should be approached as in other individuals; continuous positive airway pressure or upper airway surgery may be necessary. One of the more difficult aspects of sleep disorders in patients with parkinsonism is that each of the medications used can potentially disrupt sleep. Low-dose dopamine agonists facilitate sleep, but high doses lead to sleep disruption. Dopamine agonists may cause nightmares, night terrors, nocturnal hallucinations, or dyskinesias. Benzodiazepine hypnotics may exacerbate sleep apnea. Tricyclic antidepressants are often useful for insomnia in parkinsonism, particularly because of their anticholinergic side effects, but occasionally lead to an increase in periodic leg movements with arousal. These problems can usually be detected by careful history taking, but testing in the sleep laboratory may ultimately be required.
Alzheimer's Disease The cognitive decline in Alzheimer's disease is paralleled by a decline in slow-wave sleep and REM sleep and an increase in the number of nocturnal awakenings and amount of time spent 49 awake during normal sleep time. As the disease advances, there is a progressive disruption of the circadian sleep-wakefulness cycle, with reduced nocturnal sleep and increased daytime sleep. In addition to the gradual breakdown of the normal sleep process, patients with Alzheimer's disease experience the phenomenon of “sundowning.” Although there is no formal definition for sundowning, it generally consists of evening attacks of delirium in which the patient experiences emotional and perceptual disturbances with irrational thinking, disorganized speech, and agitation. The physiological basis of the deterioration of sleep in Alzheimer's disease appears to be the degeneration of brainstem and basal forebrain pathways that are crucial for initiating and maintaining sleep. Autopsy studies demonstrate degeneration of the brainstem midline raphe nuclei, locus ceruleus, and reticular formation, all of which play a critical role in sleep 49 control. Although the physiological basis for sundowning remains unclear, histological 50 evidence suggests that it may be caused by degeneration of the suprachiasmatic nucleus. Destruction of this nucleus would also explain the circadian sleep-wakefulness schedule disturbance. The first step in the treatment of sundowning is to rule out treatable causes, such as drug-induced, infectious, or metabolic disorders. Behavioral and environmental treatments should be used whenever possible. These include maintaining a constant and familiar environment, increasing daytime activity, restricting daytime sleep, and increasing exposure to bright light early in the day. Nocturnal agitation is usually treated with neuroleptics, such as haloperidol or phenothiazines. There appears to be little evidence that one neuroleptic is 51 superior to another. Because of the potential for undesirable side effects, such as orthostatic hypotension and extrapyramidal disorders (e.g., tardive dyskinesia, parkinsonism, and akathisia), neuroleptics should be used intermittently or withdrawn periodically to determine whether they are still necessary. DISORDERS OF EXCESSIVE SLEEPINESS
Sleep Apnea The most commonly diagnosed organic disorder of excessive daytime sleepiness is the 37 which has a prevalence estimated to be between 1 and obstructive sleep apnea syndrome, 52 8.5 percent. In this syndrome, sleepiness is due to sleep deprivation caused by repeated arousals from struggling against a closed airway. In the original description of the pickwickian syndrome (i.e., obesity, daytime sleepiness, and cardiorespiratory failure), sleepiness was 53 erroneously attributed to the effects of hypercapnia. Although hypercapnia is known to
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impair cerebral function, somnolence is not an outstanding feature. The true cause of sleepiness in the obstructive sleep apnea syndrome was discovered in 1965 when Gastaut 55 56 and colleagues in France, and Jung and Kuhlo in Germany, studying a series of pickwickian patients, found frequent intermittent airway obstruction during sleep, associated with repeated EEG arousals. Obstructive apnea occurs when the upper airway collapses during inspiration (rarely, during expiration). Respiratory effort continues against the closed airway until inspiratory pressures trigger an arousal. The arousal restores tone in the upper airway dilators, the genioglossus and geniohyoideus muscles, and airflow resumes. The site of airway collapse varies among patients; in approximately57,58 half it is at the level of the palate (velopharynx), and in the other Airway collapse is often most severe during REM sleep, when half it is below the palate. 59 muscle atonia of the upper60airway occurs, and is coupled with a reduced ventilatory drive to hypercapnia and hypoxia. In approximately 60 percent of patients, the apneas are more frequent and more prolonged in the supine position during NREM sleep. During REM sleep, 61 the occurrence of apnea is less dependent on position. Obstructive apnea appears in the PSG as a cessation of airflow in the nasal and oral thermistor channels, with a continuation and buildup of respiratory effort in the channels monitoring chest and abdominal motion and intercostal EMG (Fig. 32-3). As the patient struggles to overcome the obstruction, paradoxical breathing occurs and the chest and abdominal circumferences enlarge and contract out of phase with each other. If the apnea is prolonged, there is a decline in oxygen saturation as measured by pulse oximetry. An apnea is defined on the PSG as a cessation of airflow for at least 10 seconds. Other significant respiratory events include mixed apneas and hypopneas.
FIGURE 32-3 Differences between obstructive, central, and mixed apnea.
Airflow is monitored by CO2 analysis, and respiratory effort is monitored by an esophageal balloon transducer. EOG, electro-oculogram; EMG,
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electromyogram; EEG, electroencephalogram; ECG, electrocardiogram. (From Orr WC: Disorders of excessive somnolence [DOES]. p. 52. In Hauri PJ [ed]: The Sleep Disorders. Upjohn, Kalamazoo, MI, 1982, with permission.) Mixed apneas consist of an initial cessation of both airflow and effort (i.e., a central apnea), followed several seconds later by the appearance of effort without airflow (i.e., an obstructive apnea). Mixed apneas have the same significance as obstructive apneas in patients with obstructive sleep apnea syndrome. Patients with obstructive sleep apnea also experience episodic partial airway obstructions, referred to as hypopneas. Hypopneas are variously defined on the PSG as (1) a decline of more than 50 percent in airflow; (2) a decline in airflow accompanied by a decline in oxygen saturation (Sao2) exceeding 3 percent; or (3) a decline in airflow terminated by an EEG arousal. Occasionally, patients with the clinical presentation of obstructive sleep apnea syndrome appear to have central apneas on the PSG. In many instances, this is because routine respiratory monitoring techniques fail to detect low-amplitude respiratory effort. Indeed, the only definitive technique for ruling out the presence of airway obstruction is esophageal pressure monitoring (Fig. 32-3). This is accomplished by inserting an esophageal balloon transducer attached to the end of a nasogastric tube. Interestingly, patients can have the clinical findings of obstructive sleep apnea syndrome in the absence of polygraphically defined sleep apnea. This has been termed the upper airway 62,63 In such patients, esophageal resistance syndrome by Guilleminault and colleagues. pressure monitoring reveals frequent episodes of decreased pressure during inspiration that end with an EEG arousal. Recurrent arousals cause sleep deprivation. The upper airway resistance syndrome may be difficult to detect on a routine PSG because the polysomnographer has to look for subtle signs of airway resistance, such as recurrent EEG arousals, that may be associated with a buildup of snoring or increased intercostal EMG activity. Patients with upper airway resistance syndrome respond to the same therapeutic interventions used for obstructive sleep apnea. In contrast to adults, complete airway obstruction with apnea occurs less often in children with clinically significant airway resistance during sleep. In a group of 20 children with obstructive sleep apnea syndrome, a mean apnea index (apneas per hour of sleep) of 2 was 64 found by Rosen and colleagues. In contrast, oxygen desaturations occurred frequently and the mean minimum Sao2 was 66 percent (normal range in children is 92% to 100%). Clinical manifestations during sleep included loud snoring and labored breathing. Thus, the diagnosis in children depends more on changes in oxygen saturation and EEG arousals than on the presence of apneas. Snoring in any child should always raise the suspicion of obstructive sleep apnea. A useful summary measure of the severity of sleep-disordered breathing is the respiratory disturbance index (RDI), also referred to as the apnea-hypopnea index (AHI). The RDI is the number of apneas plus hypopneas that occur per hour of sleep. Although it was originally thought that obstructive sleep apnea could be diagnosed by an RDI of 5, it has become apparent that this would include almost 40 percent of normal individuals older than 60 25,32,65 and would exclude the majority of children with obstructive sleep apnea. The years number of apneas per hour of sleep (the apnea index) normally increases with age; it should 66 be less than 1 in children, less than 5 in adults aged between 20 and 60 years, and less than 10 in adults older than 60 years. The presence of daytime sleepiness correlates most closely with the degree of sleep fragmentation rather than with the number of apneas or frequency or degree of oxygen desaturation. Thus, as in the upper airway resistance syndrome, the diagnosis can be made in the appropriate clinical setting even with an RDI of less than 5, as long as there are frequent awakenings or arousals associated with other respiratory findings (e.g., crescendo snoring, bradytachycardia, oxygen desaturation). A number of symptoms arise as a direct consequence of sleep deprivation. These include impaired cognitive abilities, memory difficulties, delayed reaction times, irritability, aggressiveness, confusional awakenings, fatigue, and sexual dysfunction (reduced drive or impotence). If sleep deprivation is severe enough, there may be hypnagogic hallucinations or episodes of automatic behavior in which the patient performs complex activities with no subsequent recollection of them. Restless sleep occurs as a consequence of struggling to overcome a closed airway. During the apneic episode, body movements may be slight or massive. In the latter instance, the patient may assume an upright sitting position and make loud choking sounds as the apnea terminates. Occasionally the patient awakens in a panic-stricken state and may run breathless to a window. Bed partners often report being kicked during the night and bedcovers being torn off the bed. Excessive body movements during sleep cause excessive sweating in most patients. Nocturia occurs in approximately
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one fourth of patients and is rarely associated with episodes of urinary incontinence. Urinary incontinence is probably caused by increases in intra-abdominal pressure that occur during apneic episodes. Headache upon awakening is a frequent complaint and may be a consequence of recurrent elevations of intracranial pressure that occur with each instance of obstructive apnea. The headaches are usually bifrontal and last for 1 to 3 hours after awakening. Patients with clinically significant obstructive sleep apnea syndrome usually complain of daytime sleepiness. Less often there is a complaint of difficulty in initiating and maintaining sleep as a result of the arousing effects of airway obstruction. Rarely, there is a denial of difficulties with daytime sleepiness, even though family members and friends are well aware of the problem. With growing awareness among the lay public, patients are increasingly being brought to the physician by concerned bed partners who notice lapses in breathing or episodes of choking. More unusual presentations encountered in the hospital or emergency room include postanesthetic respiratory failure and anoxic nocturnal seizures. Patients with acute stroke may develop obstructive or central apneas with severe oxygen desaturations. The incidence of apnea in stroke is unknown, but the disorder is probably underdiagnosed. Because of the physiological consequences of obstructive apnea in stroke, treatment should be instituted without delay. Patients with severe, long-standing obstructive sleep apnea may also experience right-sided heart failure from pulmonary hypertension either caused or exacerbated by the apneic episodes. Approximately 50 percent of patients with67obstructive sleep apnea have hypertension, and as many as 7 percent have polycythemia. Nearly all patients with obstructive sleep apnea snore, and in many cases the snoring is loud enough to drive the bed partner from the bedroom. Over two thirds of patients are also 67 overweight or obese. Thus, in many instances, a presumptive diagnosis can be made upon finding an overweight patient sitting in a chair, asleep and snoring loudly in the waiting room. It should be emphasized, however, that patients need not be obese or have a history of snoring. Indeed, one of the more common surgical interventions regularly cures snoring but infrequently rids the patient of sleep apnea (see pp. 621–622). The immediate danger of sleep deprivation from this syndrome is accidental injury or death. The automobile accident rate for individuals with severe 68 obstructive sleep apnea is approximately three times that of the normal population, and a history of falling asleep while driving or at traffic lights is frequently obtained. Serious aviation and industrial accidents may also occur. He and colleagues found a 37 percent cumulative 8-year mortality in patients with obstructive sleep apnea syndrome and more than 20 69 apneas per hour, compared with a 4 percent mortality with fewer than 20 apneas per hour. Partinen and colleagues found an 11 percent mortality at 5 years in patients with obstructive sleep apnea treated conservatively 70 with weight reduction, compared with no mortality among those treated with tracheostomy. During obstructive apneas, a number of events occur that are thought to contribute to mortality and morbidity. Systolic and diastolic blood pressures increase by an average of 25 71 percent during an obstructive apnea. As has been shown by direct recordings from sympathetic nerves in patients with obstructive72sleep apnea, elevations in blood pressure are mediated by the sympathetic nervous system. The role of hypoxemia in blood pressure elevation appears to be limited, because elevations in blood pressure continue even when 73 Sao2 is maintained at levels greater than 90 percent with supplemental oxygen. That obstructive sleep apnea causes chronic hypertension is not as well established; however, its 74 treatment consistently reverses daytime hypertension in children as well as in many adults. Various cardiac arrhythmias have been reported in patients with obstructive apneas, including sinus pauses of up to 13 seconds, second-degree atrioventricular block, and ventricular ectopy, although all of these may occur in similar-aged control subjects. The most common75 arrhythmia is a bradytachycardia that results from increased vagal output during the apnea and increased sympathetic output upon resumption of breathing. Of all the effects on heart rhythm, the most serious is an increase in ventricular ectopy, which occurs when Sao2 levels 76,77 decline below 60 to 65 percent. Individuals with obstructive sleep apnea syndrome have a greater risk of stroke compared with unaffected individuals. Obstructive sleep apnea syndrome is significantly more common in patients with either acute stroke or transient cerebral ischemic attacks compared with 78 age-matched and weight-matched control subjects. Impaired cerebral blood-flow and 79 cerebrovascular autoregulation have also been reported in patients with this syndrome. Netzer and colleagues found a significant reduction in blood flow in the middle cerebral artery 80 using transcranial Doppler imaging. Reduced flow occurred in most obstructive apneas and hypopneas and infrequently during central apneas. They found a quantitative correlation between decreased blood flow and the duration or severity of hypoxemia in obstructive hypopneas, but not apneas. Several epidemiological studies indicate that snoring alone
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appears to be a risk factor for stroke. Established risk factors for stroke, hypertension, and cardiac arrhythmias are commonly associated with obstructive sleep apnea. A somewhat more tenuous link between this syndrome and stroke is the observation that approximately one third of strokes are present upon awakening and that peak occurrences of myocardial 84 infarction and stroke are between 3 a.m. and 9 a.m. Possible mechanisms for stroke in this context include reduced blood flow and impaired autoregulation, cyclical increases in 85 intracranial pressure, and anoxia during apneic episodes in combination with either atherosclerotic occlusive disease, polycythemia, or cardiac arrhythmias. Permanent cognitive impairment may also be a consequence of the obstructive sleep apnea syndrome. Montplaisir and colleagues have found that deficits in cognitive tasks requiring planning abilities, verbal fluency, and manual dexterity persist despite correction of daytime 86 sleepiness with continuous positive airway pressure. They believe that persistent cognitive dysfunction is probably due to irreversible anoxic cerebral damage. In most cases, obstructive sleep apnea appears to be idiopathic, with the main contributing factor being obesity. Fatty infiltration in the neck decreases the size of the pharyngeal lumen, which then predisposes the airway to collapse during sleep. There is often a history of weight gain that parallels the onset and severity of the disorder. Weight loss usually results in 87,88 Unfortunately, most patients achieve only limited substantial improvement in symptoms. success in weight loss by dieting alone. Gastric (bariatric) surgery may be beneficial for 89 certain patients, particularly those with extreme obesity. In approximately two thirds of patients, the apneas are more frequent or severe in the supine position. It may be helpful to outfit such patients with a shirt that has tennis balls sewn into a pocket in the back to keep them from assuming the supine position. In some cases, specific causes of obstructive sleep apnea can be identified. Neurological disorders associated with both obstructive and central sleep apnea syndromes are listed in 90 Table 32-9. Anatomical abnormalities and medical disorders associated with these syndromes are listed in Table 32-10. Most surgical disorders are diagnosed during the clinical examination, which should include inspection of the nasal passages, oropharynx, and larynx. Click here to view this table.... Click here to view this table.... The initial treatment of choice for the obstructive sleep apnea syndrome is continuous positive airway pressure (CPAP). Nasal CPAP forces air through the nose into the pharynx and acts as a pneumatic splint to keep the airway open. To use CPAP, the patient must wear either a mask that covers the nose or “nasal pillows” that rest against the nares. CPAP therapy is initiated in the sleep laboratory; pressures are gradually adjusted during the night until apneas and snoring are suppressed. CPAP pressures are usually effective within a 91 range of 7.5 to 14 cmH2O. Approximately 85 percent of patients are able to tolerate CPAP. Of those who do not, some will be able to tolerate bimodal positive airway pressure (sometimes referred to as BiPAP). The bimodal device detects exhalation and immediately reduces the positive air pressure to a preset level that is lower than the pressure during inhalation, so that breathing does not occur against resistance. The main reasons that patients are unable to tolerate CPAP or BiPAP are (1) a sensation of claustrophobia, (2) irritation from dry throat and nasal passages, (3) nasal congestion (self-limited in the majority of cases), and (4) esthetic concerns. Newer CPAP and BiPAP devices are readily portable and are relatively quiet. Irritation from dryness can be addressed by warming and humidifying the air from the CPAP device. Nasal congestion usually responds to corticosteroid or vasoconstrictor nasal sprays. A return to normal daytime vigilance as measured by the MSLT usually takes approximately 1 to 2 weeks after beginning CPAP. Although tracheostomy is no longer the therapy of choice, it is still commonly used in severe cases when CPAP is ineffective or not tolerated. The most commonly performed surgery for obstructive sleep apnea is uvulopalatopharyngoplasty (UPPP). The goal of UPPP is to increase the size of the airway via resection of the uvula, soft palate, tonsils, and redundant soft tissue within the posterior pharynx. Unfortunately, success in terms of a greater than 90 percent suppression of apneas occurs in fewer than 30 percent of patients. However, in approximately 50 percent of patients 92,93 For some patients, the number of apneas is reduced by more than 50 percent. particularly young adults facing a lifelong disorder, it may be considered as a useful adjunctive measure to other treatments, including weight loss and CPAP. The UPPP is also extremely effective for eliminating snoring. The most commonly encountered untoward effect is nasal regurgitation. In children, enlargement of the adenoids and tonsils is an important cause of obstructive sleep apnea that responds readily to surgical resection.
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Other surgical procedures that address specific anatomical defects, such as retrognathia or micrognathia, have been found to be useful adjunctive measures. Pharmacological therapy has been aimed primarily toward suppressing REM sleep with tricyclic antidepressants or stimulating respiratory drive in patients with hypoventilation at rest with medroxyprogesterone 94 acetate. Some investigators have also found acetazol-amide to be useful in patients with sleep apnea who are not overweight. At present, however, the role for pharmacological intervention is quite limited. Patients with sleep apnea should be warned that sedatives and alcoholic beverages exacerbate their condition. The danger of an accident while driving is increased if the patient has a history of recent accidents or near misses or clearly has excessive daytime sleepiness. Under such conditions, the physician is obligated to warn the patient and discourage driving until daytime vigilance can be restored. This often takes 1 to 2 weeks after the initiation of CPAP. For medicolegal reasons, instructions to the patient should be clearly documented in the physician's notes. In some locales, it may also be appropriate to report the patient's condition to the driver licensing agency or state health department, but it is advisable in such cases to discuss the legal ramifications with a local attorney. As with obstructive sleep apnea, the approach to central sleep apnea is initially directed toward treating potential underlying conditions, such as nasal obstruction, congestive heart failure, or metabolic disturbances (Table 32-9 and Table 32-10). If a treatable cause cannot be found, and there are no contraindications, treatment for adults may be initiated with acetazolamide, 250 mg four times daily, and the PSG repeated to determine the efficacy of 95 96 the response. Nasal CPAP should also be tried and may be effective in some cases. If neither of these approaches is successful,97supplemental oxygen is prescribed and may abolish or greatly diminish central apneas. Tracheostomy with mechanical ventilation may be necessary in severe cases. Again, the usefulness of ventilatory stimulant medications has not been established.
Narcolepsy The term narcolepsy was first used by Gelineau in 1880 to describe a condition of recurrent 98,99 attacks of irresistible sleep. Until the mid-twentieth century, narcolepsy was frequently misdiagnosed as a psychiatric disorder. It is now understood to be a central disorder of sleep-wakefulness regulation and REM sleep that includes excessive sleepiness, usually with cataplexy, and other REM sleep phenomena, such as a rapid transition from wakefulness to REM sleep, sleep paralysis, and hypnagogic hallucinations. The first symptoms usually occur in the second decade, with the peak age at onset between 15 and 25 years of age. However, onset may occur as early as 5 years or after 50 years of age. Excessive sleepiness is usually the presenting symptom. Cataplexy may follow the onset of sleepiness by more than 20 years or, less often, appear in advance of sleepiness. The salient feature of narcolepsy is excessive daytime somnolence. The narcoleptic patient typically takes short naps lasting for 10 to 20 minutes (rarely longer than 1 hour) that may restore vigilance for up to 2 to 3 hours. Sleep occurs most readily in monotonous environments, especially when physical activity is not required. Remarkably, many patients with narcolepsy can remain awake if engaged in a stimulating task. Sometimes the onset of sleep is precipitous. Such “sleep attacks” occur without warning in situations in which sleep rarely occurs normally (e.g., while eating, talking, or driving). The symptom that is most specific for narcolepsy is cataplexy. Cataplexy occurs in 100 approximately 70 percent of patients with narcolepsy and may precede or follow the onset of daytime sleepiness by months or years. Cataplexy is characterized by a sudden loss of muscle tone, which may last from seconds to several minutes. The distribution and severity of atonia vary from mild localized weakness (e.g., arm or leg weakness, dysarthria, buckling of the knees) to complete postural collapse. The most common cataplectic attacks are subtle and often go unnoticed by nearby individuals. As in sleep paralysis (see later), extraocular movements and respiration are largely unaffected during the attack, but there may be blurring of vision, ptosis, or rarely diplopia. If the weakness is limited to the muscles of speech, the patient may have dysarthria or stuttering attacks. If attacks are limited mainly to the arms, the patient may complain of intermittent clumsiness. Although consciousness and memory are usually preserved, prolonged attacks may be accompanied by dream-like hallucinations (visual, auditory, or tactile) or lead directly into an episode of REM sleep. Cataplectic attacks are always associated with an emotional precipitant, such as excitement, surprise, fear, anger, elation, or pride; the most common is laughter. Persistent strong emotions may even trigger a series of cataplectic attacks lasting for hours to days (status cataplecticus). The interindividual frequency of cataplexy varies widely from several attacks per year to numerous attacks each day. Attacks are more likely to occur during periods of exhaustion or sleepiness.
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As with epileptic attacks, the sudden loss of motor control may lead to serious injury. Depending on the severity and frequency of attacks, certain precautions may be necessary. Sleep paralysis and hypnagogic hallucinations occur in approximately 25 and 30 percent, 91 respectively, of all patients with the narcoleptic syndrome. Together with excessive sleepiness and cataplexy, they complete the so-called tetrad of the narcoleptic syndrome (which actually occurs in fewer than 20% of patients). Sleep paralysis is a frightening experience in which the patient is unable to open the eyes, move, speak, or take a deep breath. Fright is commonly intensified by a sensation of being unable to breathe and by simultaneous hypnagogic hallucinations. The attacks occur during the transition between wakefulness and sleep and may last from several seconds to several minutes (rarely longer than 10 minutes). With repeated attacks, the patient becomes less concerned, and the attacks are ultimately viewed simply as an inconvenience. As in cataplexy, the H reflex and tendon reflexes are suppressed or absent during the attack. The EEG is remarkable only for the apparent preservation of consciousness during patterns of drowsiness. Sleep paralysis101 also occurs in the absence of narcolepsy in approximately 5 percent of normal individuals, as a rare X-linked genetic syndrome (familial sleep paralysis), and rarely in association with the obstructive sleep apnea syndrome. Hypnagogic hallucinations occur during the transition between wakefulness and sleep and are primarily visual. The visual content may range from simple forms to fantastic scenes. Other components of the experience may include simple or complex auditory hallucinations, feelings of being touched, changes in the location of body parts, and a sensation of levitation or being outside of one's body. Awareness that these experiences represent hallucinations is usually preserved, but they may be so unpleasant that the patient begins to dread going to bed at night. Automatic behavior, memory problems, and disturbed nocturnal sleep complete the clinical picture of narcolepsy. Automatic behavior consists of semipurposeful activity associated with 33 amnesia that occurs in as many as 80 percent of patients. It occurs in monotonous environments conducive to sleep and may last from seconds to more than 30 minutes. During attacks there may be irrelevant gestures and remarks, lapses in speech, and illogical activity (e.g., placing a magazine in the refrigerator). More complex activities, such as driving, may also occur. Memory problems occur in more than 50 percent of patients owing to drowsiness and brief episodes of sleep. Indeed, both automatic behavior and memory problems are encountered in other sleep disorders as a consequence of sleep deprivation. Disturbed nocturnal sleep parallels the severity of narcolepsy and is manifested by frequent awakenings and increased body movements. Daytime sleepiness is almost always lifelong, but its severity stabilizes within several years of onset. Worsening sleepiness after a period of stability should there fore prompt reevaluation for a new sleep problem, such as sleep apnea. Cataplexy, hypnagogic hallucinations, and sleep paralysis improve with age in about one third of patients. The progressive disruption of sleep that naturally occurs with aging is accelerated in some cases of narcolepsy. The prevalence of narcolepsy varies from 1 in 102–105 600 persons in Japan, to 1 in 3,000 in North Although complaints of excessive America and Europe, to 1 in 500,000 in Israel. sleepiness are eight times more likely to be elicited in relatives of patients with narcolepsy compared with the general population, earlier reports of a high rate of familial narcolepsy appear to have been inaccurate. Guilleminault and colleagues conducted the first large-scale 106 study in which sleep recordings were used to confirm the diagnosis. They found that only 3 percent of patients had one first-degree relative with narcolepsy-cataplexy, and only 1 percent had more than one affected first-degree relative. Despite the finding of a relatively low familial incidence of narcolepsy, there is ample evidence for a genetic predisposition. The HLA-DR2 and HLA-DQw1 histocompatibility antigens on107chromosome 6 are present in 100 percent of Japanese patients with 108 narcolepsy and more than 90 percent of white patients. The DQw1 antigen is also present in more than 90 percent of blacks with narcolepsy, and DR2 is present in 109 approximately 65 percent. DR2 is present in 10 to 35 percent of general populations studied thus far. Although the association of specific histocompatibility antigens with narcolepsy raises the question of an immune-mediated process, evidence of immune system involvement is currently lacking. The genetic basis of inherited narcolepsy appears to be due to a mutation of the same gene that is now known to be responsible for canine narcolepsy, the canarc-1 gene (also referred 25 to as the hypocretin receptor 2 gene) located on chromosome 12. Hypocretin is a neuropeptide named for its location of origin in the hypothalamus and its resemblance to
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secretin. The hypocretin-2 gene normally codes for the hypocretin cell surface receptor protein. The canine model of narcolepsy is inherited in an autosomal-recessive fashion. Although most cases of narcolepsy do not appear to be genetic in origin, the discovery of hypocretin dysfunction in narcoleptic dogs makes it likely that narcolepsy can be caused by any process that disrupts hypocretin function. Because most cases of narcolepsy are not associated with obvious structural lesions, it is likely that acquired narcolepsy results from a highly specific attack that interrupts hypocretin synthesis. This is consistent with the observation that CSF levels of hypocretin-1 are significantly reduced in patients with spontaneous (nonfamilial) narcolepsy (99% specificity; 87% sensitivity). Such a selective injury could be caused by an autoimmune or metabolic-toxic disorder. Rarely, narcolepsy is caused by a structural lesion of the rostral brainstem, often in 110,111 Lesions reported to cause sleep attacks association with invasion of the third ventricle. and cataplexy have included pituitary adenoma, midbrain glioma, sarcoidosis, multiple sclerosis with bilateral hypothalamic plaques, Wernicke's encephalopathy, colloid cyst of the third ventricle, craniopharyngioma of the floor of the third ventricle, and glioma of the third 110 the “limp man ventricle. Rarely, symptoms may occur in a protracted manner, as in 111 syndrome” of continuous cataplexy reported by Stahl and colleagues. In general, tumors may cause sleep-wakefulness disturbances by the direct invasion of sleep-modulating 112 structures or as a remote effect of intracranial hypertension. Peduncular hallucinosis, characterized by vivid visual and auditory hallucinations, may resemble hypnagogic hallucinations. It usually results from a vascular lesion of the rostral brain-stem, most commonly “top of the basilar” artery occlusion. Hallucinations similar to those encountered in the syndrome of peduncular hallucinosis also occur as a side effect of levodopa medication. Prolonged episodes of repeated hypnagogic hallucinations have been misdiagnosed as 113 schizophrenia. The diagnosis of narcolepsy is relatively straightforward when cataplexy and excessive sleepiness are present. This diagnostic opportunity is sometimes missed because the manifestations of cataplexy are often subtle and are therefore ignored or not understood by the physician. The mildest motor expression may consist of a slight, brief, unilateral drooping of the eye or corner of the mouth. The history of triggering events is most reliable for attacks that follow strong positive emotional phenomena, such as laughter, sudden startle, or excitement (e.g., winning the lottery), rather than crying, sadness, or depression. Cataplectic attacks, unlike seizures or generalized myoclonus, rarely result in injury from falling because the onset develops over a period of seconds. In approximately 10 to 15 percent 33 of cases, cataplexy does not develop until 10 or more years after the onset of sleepiness. Cataplectic attacks accompanied by vivid hallucinations (with or without progression directly into REM sleep) and episodes of automatic behavior have been misdiagnosed as epileptic. Cataplectic attacks have also been misinterpreted as drop attacks associated with vertebrobasilar insufficiency or periodic paralysis. More subtle cataplectic episodes may be mistaken for myasthenia gravis. The duration of attacks, preservation of consciousness, and precipitating emotional factors help distinguish cataplexy from other disorders. A secure diagnosis of narcolepsy in the absence of cataplexy can be made when the following are present: (1) a complaint of excessive sleepiness; (2) recurrent daytime sleep almost daily for at least 3 months; (3) sleep paralysis, hypnagogic hallucinations, automatic behavior, and disrupted sleep; (4) an absence of any medical or psychiatric disorder that could explain the aforementioned symptoms; and (5) an MSLT that demonstrates either a mean sleep latency of less than 8 minutes or two or more naps with REM sleep, or a decreased CSF hypocretin-1 level (<110 pg/ml). For reliable PSG and MSLT findings, the patient should be free from any sleep-altering drugs (particularly those that interfere with REM sleep, such as amphetamines or tricyclic antidepressants) for 15 days, the sleep-wakefulness schedule should be standardized for at least 7 days prior to testing, and the MSLT should be performed on the day following the PSG. Interpretation of the sleep studies is complicated by the observation that sleep apnea and periodic limb movements 33 occur in as many as one half of individuals with narcolepsy. However, if narcolepsy is present, the treatment of these disorders will not restore daytime vigilance. It is recommended that CSF hypocretin-1 levels be measured if cataplexy cannot be clearly documented and (1) MSLT results are ambiguous, (2) an MSLT cannot be obtained (e.g., poor patient cooperation or medications that may conflict with the results cannot be stopped), or (3) coexisting neurological or other sleep disorders reduce the specificity of the MSLT findings. Because the DR2 and DQw1 histocompatibility antigens occur frequently in the general population and may be absent in some affected individuals, their role in the diagnostic evaluation is limited. The main indication for testing is in high-risk individuals in families of narcoleptic patients who are DR2- or DQw1-positive. A family member without the antigen is extremely unlikely to develop the disorder.
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The treatment of narcolepsy includes patient education. Self-help groups should be encouraged. Advice regarding safety precautions should be carefully considered and based on the severity of the disorder. It is not necessary to curtail essential activities, such as driving, if sleepiness is mild or can be anticipated and cataplectic attacks are controlled. In most cases, the initial treatment of daytime sleepiness does not include pharmaceutical agents. Strategically timed short naps lasting 15 to 20 minutes, one to three times daily, often 114 provide adequate relief for as long as 2 hours. Indeed, it has never been demonstrated that stimulant medications are more effective in achieving short-term relief from sleepiness. Exercise, even in the form of a brief walk, also has a useful alerting effect. If driving or attendance at a conference is anticipated, heavy meals should be avoided, as they tend to be sedating. Finally, caffeinated beverages in combination with behavioral strategies alone may provide sufficient relief so that medications are unnecessary. Stimulant medications are indicated if the aforementioned strategies fail. The only way of determining the efficacy of stimulant medication is the patient's perceived response (MSLT testing remains largely unchanged despite reports of clinical improvement). Unfortunately, complete relief from daytime sleepiness is rarely achieved. Treatment of daytime sleepiness is usually initiated with modafinil taken once or twice (morning and afternoon) daily as needed (a typical dose is 100 to 200 mg); unlike amphetamines or methylphenidate, its site of action is more restricted to the central nervous system (CNS) and involves the histaminergic system. Interactions with other drugs metabolized by cytochrome P-450 isoenzymes may occur. If treatment with modafinil is unsuccessful or unavailable, then methylphenidate is a reasonable alternative. It has a more rapid onset of action and is associated with fewer side effects than amphetamines. A typical starting dose in adults is 5 mg three times daily, with the daily dose then being built up, depending on response and tolerance. If methylphenidate is unsuccessful in doses of 60 to 90 mg daily, dextroamphetamine is initiated in a dose of 5 mg twice daily. Chronic stimulant use may result in addiction, habituation, irritability, psychosis, or hypertension. Habituation can often be avoided with a drug holiday for 1 day each week. Remarkably, most patients with narcolepsy are able to take stimulants for 33 decades without encountering serious side effects. Adrenergic or serotonergic antidepressants (including tricyclics) are effective in the treatment 33 of both sleep paralysis and cataplexy in more than 80 percent of patients. Treatment now is usually initiated with fluoxetine or clomipramine. Protriptyline (5 to 30 mg daily) has also been used because of its stimulant side effect that may also help in the treatment of daytime sleepiness. Other tricyclics such as imipramine, nortriptyline, and desipramine are probably equally effective in suppressing cataplexy. Newer, more selective antidepressants, such as viloxazine (which inhibits serotonin uptake) and fluoxetine (which inhibits norepinephrine uptake), are associated with fewer anticholinergic side effects and may be preferable in some cases. Rarely, tolerance develops, necessitating a 1- to 2-week drug holiday. Caution should be exercised when the physician withdraws tricyclic antidepressants because abrupt withdrawal may precipitate cataplectic attacks or even status cataplecticus. Patients who fail to respond to antidepressants may have a favorable response to sodium oxybate. It is taken as an oral liquid each night at sleep onset and often repeated again about 4 hours later. The mechanism of action is unclear but is thought to be somehow related to its effect on sleep and REM consolidation. In the United States it can only be obtained directly from the manufacturer under physician supervision following special documented counseling. It is reserved for use in antidepressant failure because of its extremely toxic potential; slight overdose can result in coma or respiratory arrest. However, in the author's experience, when given with proper counseling (and supervision in the home when needed), it is an important and highly effective alternative treatment for poorly controlled cataplexy, nocturnal sleep fragmentation, and daytime sleepiness. Disrupted sleep contributes to both daytime sleepiness and associated symptoms, such as cataplexy. Short-term sedatives are frequently used to facilitate sleep, but their effectiveness for treating daytime symptoms has not been established. Benzodiazepines, such as temazepam (Restoril) and triazolam (Halcion) or the newer nonbenzodiazepine zolpidem (Ambien), are currently the preferred agents. Sedatives may actually worsen morning sleepiness, and those with relatively long half-lives should be avoided. PARASOMNIAS Disorders associated with prominent physical phenomena during sleep, but not with the primary complaints of insomnia or daytime somnolence, are referred to as parasomnias (Table 32-1). The most common that present with neurological manifestations are discussed in this section.
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Confusional Arousals, Sleepwalking, and Sleep Terrors Confusional arousals, sleepwalking, and sleep terrors are considered arousal disorders because the patient manifests certain aspects of waking behavior yet fails to awaken fully. A common feature of the arousal disorders is that they occur during NREM sleep, particularly stages III and IV. Confusional arousals, sometimes referred to as sleep drunkenness, are characterized by inappropriate behaviors, disorientation, slowed speech, and amnesia following partial arousal from slow-wave sleep that may last from minutes to several hours. They are most likely to occur following sleep deprivation, with sedative medications, in metabolic-toxic encephalopathies, or in association with narcolepsy or sleep apnea. They are normally present in children younger than 5 years and can be precipitated by arousal from sleep during the first one third of the night. Rarely, frequent confusional arousals occur in association with brain lesions in areas subserving sleep control, including the periventricular 1 gray matter, midbrain reticular area, and posterior hypothalamus. Personal injuries have occasionally occurred, and, as in any confusional state, individuals may become aggressive if restrained. Sleepwalking (somnambulism) consists of walking and other complex behaviors occurring in stage III or IV sleep. Episodes may be relatively benign or the patient may appear frantic, attempting to escape from an imagined threat. Patients are difficult to arouse and remain in a confusional state after arousal. The prevalence of sleepwalking is between 1 and 15 percent, 1 and, as with the other arousal disorders, it is most common in children and adolescents. Rarely, the onset of sleepwalking occurs in adulthood. A genetic predisposition for sleepwalking is suggested1 by the observation that the incidence approaches 60 percent when both parents are affected. Serious injuries may result in a number of ways, including walking into the street, off a balcony, or through a window. Aggressive behavior toward others is rare in the absence of physical restraint. Rarely, homicide has been reported. The main neurological consideration in differential diagnosis is epilepsy with ambulatory automatisms; these automatisms can be distinguished clinically by their relatively short duration and by the 115 presence of epileptiform activity in the EEG. Sleep terrors, also referred to as night terrors or pavor nocturnus, are characterized by a sudden partial arousal from slow-wave sleep and a subsequent attack heralded by a piercing scream or cry with behavioral and autonomic manifestations of intense fear. Unlike nightmares, sleep terrors tend to occur during the first one third of the night, when slow-wave sleep predominates; there is little or no recollection of dream content, and the patient is difficult to arouse. Indeed, attempts to arouse the patient usually intensify the attack. The entire episode usually lasts no more than 3 to 5 minutes. Following arousal, there is confusion and amnesia for the event. Sleep terrors occur most often in children between the ages of 2 and 12. The occurrence of sleep terrors in childhood, unlike in adulthood, does not suggest the presence of psychopathology. Confusional arousals, sleep terrors, and sleepwalking all may occur in varying combinations in a given individual. Their treatment depends on the frequency and severity of their occurrence. In children, the events may be prevented by the use of a benzodiazepine (e.g., diazepam 2 to 5 mg) at bedtime. The response to psychotherapy is often favorable. Unfortunately, in adults, medications and psychotherapy often meet with mixed results. Isolated reports of success in adults with various agents, such as tricyclic antidepressants or anticonvulsants, raise the question of an undetected underlying condition (e.g., depression or epilepsy). Precipitating factors, such as sleep deprivation, loud noises during sleep, or bladder fullness, should be avoided, as should certain medications known to exacerbate or cause sleepwalking, including thioridazine, fluphenazine (Prolixin), perphenazine, desipramine, chloral hydrate, and lithium.
REM Sleep Behavior Disorder REM sleep behavior disorder is characterized by the loss of atonia during REM sleep, with elaborate motor activity and dream mentation. The behavioral activities that occur are consistent with dream enactment and may at times be violent. Frequent manifestations include leaping, running, kicking, and punching. The disorder occurs far more often in men than in women. Usually, medical attention is sought at the urging of a bed partner because of disturbed sleep or physical injury. The attacks usually occur after the first 90 minutes of sleep, at which time REM sleep normally begins. Just as there are usually four REM cycles during a normal night, attacks often occur four or more times a night. Consistent with REM sleep, patients are difficult to arouse fully during an attack, awakening is not associated with a prolonged confusional state, and there is detailed dream recall. Most patients have a typical repetitive dream, which usually consists of being attacked. Because the episodes are often
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violent, this may result in the ironic situation in which patients dream that they are116 defending a bed partner only to find, upon awakening, that they have inflicted injuries instead. REM sleep behavior disorder may present as an acute transient disturbance, usually associated with drug intoxication or withdrawal, or as a chronic disorder. The acute form has been associated with withdrawal of alcohol, meprobamate, pentazocine, and nitrazepam116 or intoxication from biperiden, tricyclic antidepressants, and monoamine oxidase inhibitors. The chronic form usually first appears in the sixth or seventh decade of life and is a progressive disorder in terms of the complexity, intensity, and frequency of expressed 116,117 One third of affected individuals have a history of neurological disorder, behaviors. including dementia, subarachnoid hemorrhage, ischemic cerebrovascular disease, olivopontocerebellar degeneration, brainstem astrocytoma, multiple sclerosis, and Guillain–Barré syndrome. Although bilateral lesions in the vicinity of the locus ceruleus might be anticipated from animal experiments, these are rarely found in affected humans. Instead, 118 involvement of suprapontine structures seems to play a more important role. The diagnosis can be made in the presence of limb or body movements associated with dream mentation and either harmful or potentially harmful sleep behaviors, dreams that appear to be “acted out,” or sleep behaviors that disrupt sleep continuity. The PSG during REM sleep typically demonstrates excessive tonic submental EMG activity and excessive 116 phasic EMG activity (Fig. 32-4). Simultaneous video monitoring reveals excessive limb or body jerking or more complex, vigorous, violent behaviors.
FIGURE 32-4 Polysomnogram (PSG) during REM sleep in a 70-year-old man
with a 6-year history of REM sleep behavior disorder following a subarachnoid hemorrhage. Chin atonia is absent, and there are abundant left and right arm movements. Rapid eye movements consistent with REM sleep are seen, but there is excessive alpha activity. (From Mahowald MW, Schenck CH: REM sleep behavior disorder. p. 389. In Kryger MH, Roth T, Dement WC [eds]: Principles and Practice of Sleep Medicine. WB Saunders, Philadelphia, 1989, with permission.) Treatment with clonazepam has been uniformly effective, emphasizing the utility of proper diagnosis. The initial starting dose is 0.5 mg and the maximal effective dose is 2.0 mg administered at bedtime. Administration up to 2 hours before bedtime is helpful in patients complaining of excessive morning sedation, limb jerking at sleep onset, or difficulty in initiating sleep. The efficacy of clonazepam is probably due to its serotonergic effects. Disinhibition of REM phasic activity in cats has been induced by serotonin-depleting drugs 116 and by lesions of serotonergic neurons of the brainstem raphe nuclei. In one reported instance, the effective dosage of 116 clonazepam was successfully reduced with the use of the serotonin precursor l-tryptophan. Habituation does not appear to be a significant problem even after years of treatment, whereas withdrawal leads to immediate relapse.
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Nocturnal paroxysmal dystonia is a heterogeneous and somewhat controversial syndrome of nocturnal attacks that all share the distinction of being marked by stereotyped dystonic, ballistic, or choreoathetoid movements that arise out of stage II sleep (or, less frequently, slow-wave sleep or the transition from slow-wave sleep to REM sleep) and often occur nightly, frequently several times per night. At least two varieties exist: in one the attacks are brief, lasting 40118to 50 seconds, whereas in the other the attacks are prolonged and last for up to 60 minutes. The short-lasting attacks begin with an EEG arousal from sleep, often preceded by a K complex. Initially, there is eye opening and neck flexion. Shortly thereafter, the patient begins to flail the limbs and trunk wildly with ballistic movements, dystonic posturing, and 119 accompanying vocalizations. The attacks may be preceded by tachycardia or bradycardia or a central apnea. Following the attack, the patient usually goes back to sleep. If the patient is awakened immediately afterward, he or she may have partial recall of the ictal events and show little evidence of postictal confusion. In some patients, similar attacks occur during wakefulness. The attacks are differentiated from epileptic seizures by the absence of ictal electrographic activity. Although the prevalence is unknown, the disorder is rare. The attacks do not subside spontaneously and have been known to occur over periods of 20 years or more. When frequent, the attacks may result in severe sleep disruption. The movements may disturb or injure the bed partner as well as the patient. Although it was originally thought that short-lasting attacks might represent a new 119 nonepileptic syndrome, it now seems more likely that they represent frontal lobe seizures. This conclusion is based on the following observations: (1) the attacks respond to carbamazepine (albeit sometimes in relatively low dosage); (2) frontal lobe seizures may also involve bizarre behavior with torsion, flailing, and side-to-side movements, vocalizations, and movements involving both hands and feet, sometimes with dystonic posturing (particularly 120,121 ; (3) frontal lobe seizures are typically when arising from supplementary motor cortex) nocturnal, brief, and repetitive; and (4) the EEG frequently fails to show epileptiform changes during frontal lobe seizures that produce behaviors resembling those seen during nocturnal 122 paroxysmal dystonic attacks. Finally, in a series of 12 patients with nocturnal paroxysmal dystonia studied with polygraphic and video monitoring, two thirds experienced focal sensorimotor daytime seizures and one third had generalized tonic-clonic seizures during 123 sleep. Attacks lasting for 2 to 60 minutes are extremely rare and differ further from shorter attacks in their poor response to carbamazepine. Prolonged motor attacks with dystonic features arising out of sleep are currently considered to be a sleep-induced movement disorder.
Epilepsy More than half of all individuals with epilepsy experience seizures during sleep. The diagnosis of sleep-related seizures depends on direct observation by a bed partner or roommate or on indirect evidence, such as a bitten tongue, blood on the pillow or bed sheets, urinary incontinence, and muscle soreness or excessive sleepiness on the following day. Many patients with generalized tonic-clonic seizures experience them only during sleep or shortly after awakening from sleep. If a pattern of nocturnal seizures has been present for years, daytime seizures are unlikely to develop. Seizures arising from the temporal lobe are more likely to progress to generalized tonic-clonic seizures during sleep than during 124 wakefulness. More than half of all patients with temporal lobe epilepsy have seizures during sleep, and in a minority they occur only during sleep. Both partial seizures and localized epileptiform activity are more likely to occur during NREM sleep than during wakefulness or REM sleep. Convulsions almost always occur exclusively during sleep in patients with benign rolandic epilepsy (childhood epilepsy with centro-midtemporal spikes), and the epileptiform EEG discharges are activated dramatically by sleep. Seizures arising from the frontal lobe during sleep may be misdiagnosed as psychogenic because of their occasionally bizarre appearance. Patients may exhibit a complex series of gestures, unusual respiratory patterns, sudden sustained changes in heart rate, or violent movements with vocalizations and may recall clearly the details of the ictal events. Features that are helpful in the diagnosis of frontal lobe seizures in such circumstances include the following: 1. Repeated stereotypic attacks throughout the night 2. Rapid recovery of consciousness and ability to respond appropriately following an attack
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3. Absence of tonic, clonic, or myoclonic movements 4. Relatively brief duration (less than 50 seconds) 5. Sudden tachycardia or bradycardia sustained throughout the attack The only identified genetic, localized epilepsy involving the frontal lobe is autosomal-dominant nocturnal frontal lobe epilepsy. The seizures occur mainly during sleep, begin in childhood, and apparently do not remit. The syndrome of epilepsy with continuous spike waves during slow-wave sleep begins with the onset of seizures in infancy or childhood. Within 1 to 2 years, a continuous or near-continuous lateralized or generalized pattern of epileptiform spikes is seen in the EEG during NREM sleep. Prior to the development of continuous nocturnal epileptiform activity, isolated epileptiform spikes may be found during wakefulness and sleep. As the EEG deteriorates, behavioral changes occur. Behavioral deterioration and occasionally aphasia 125 (Landau–Kleffner syndrome) parallel the severity of epileptiform activity. Treatment is symptomatic for seizures. In most cases, clinical and EEG improvement occurs prior to the age of 20 years. Epilepsy may be exacerbated by sleep disorders, particularly those that cause frequent arousals and thereby lead to sleep deprivation. Several studies have shown that sleep apnea treated with positive airway pressure improves seizure control. Thus, in patients with epilepsy, a sleep history should always be obtained. If there is any suspicion of sleep apnea, restless legs syndrome, periodic leg movement disorder, or other disorders causing frequent arousal, 126,127 then polysomnography should be performed. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 33 Sphincter Disorders and the Nervous System MICHAEL SWASH •
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SPHINCTER CONTROL SYSTEMS IN HUMANS Functional Anatomy of Continence Anal Continence Urinary Continence Neural Control Systems Onuf's Sacral Nucleus Suprasegmental Organization CLINICAL ASSESSMENT AND INVESTIGATION OF SPHINCTER DISORDERS Anorectal Function Anal Manometry Perineal Descent Electromyography Vesicourethral Function Urodynamics Urinary Flow Rate Urethral Pressure Profile Pelvic Floor Muscle Electromyography Other Neurophysiological Studies Pudendal and Perineal Nerve Terminal Motor Latencies Transcutaneous Spinal Stimulation Cortical Stimulation Sensory Evoked Potentials Spinal Motor Conduction Velocity DISORDERS OF PELVIC SPHINCTER FUNCTION Incontinence Frontal Lobe Lesions Brainstem Lesions Spinal Cord Lesions Lower Motor Neuron Lesions Idiopathic Stress Incontinence Sensory Abnormalities Retention Detrusor-Sphincter Dyssynergia Anismus-Type Constipation
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Lack of Propulsive Force
Disorders of the urinary and anorectal sphincters are common, consisting of urinary and fecal incontinence, or difficulty in voiding urine or feces (Table 33-1). Incontinence of urine or feces is a devastating, socially disruptive disability. People with incontinence are reluctant to go out, are fearful of making social contacts, and often become depressed and housebound. Incontinence is not a subject that patients find easy to discuss with friends or relatives, and the symptom thus often remains hidden for many months or even years before being brought to medical or nursing attention. It is particularly common in aged populations, but it should never be regarded as an invariable consequence of the normal aging process. Click here to view this table.... Urinary retention is most commonly due to mechanical obstruction of the urethra (e.g., prostatism in men) but may also result from neurological lesions causing failure of sphincter relaxation or loss of coordination of the urinary detrusor and urinary sphincter mechanisms. A similar functional disorder of the anorectal sphincter, anismus, may lead to intractable constipation. In anismus, during attempted defecation, there is failure of relaxation of the striated anal sphincter musculature. Constipation, however, is almost always associated with slowed bowel transit, whether or not anismus is present. The pathogenesis of bowel and bladder voiding disorders can be understood by knowledge of the normal control systems governing detrusor and sphincter function. SPHINCTER CONTROL SYSTEMS IN HUMANS The urinary and anal sphincter systems consist of smooth and striated muscles innervated by autonomic and somatic efferent neurons. These muscular sphincters are modulated by spinal centers with central connections that reach conscious levels. There are extensive afferent connections from sensory receptors in the bladder and urethra, and in the anal canal and 1 bowel, that relate to spinal and more rostral levels of this neuronal control system. There is a close relationship between the autonomic and the somatic nervous systems in the control of continence and the orderly evacuation of the bladder and bowel.
Functional Anatomy of Continence Anal Continence The involuntary smooth muscle sphincter of the anal canal consists of a thickened ring of smooth muscle derived from the circular layer of smooth muscle of the rectum and anal canal. Tonic contraction of this smooth muscle ring holds the inner layers of the anal canal in 2 apposition. The smooth muscle of the anal canal is richly innervated by sensory nerves and nerve 3 endings derived from the pudendal nerves. These sensory receptors subserve discriminative sensation, so that the upper anal canal functions as a sampling organ to discern the arrival of 4 fecal matter and its consistency ; thus, liquid stool, solid stool, and gas can be readily discerned in the healthy individual. The smooth muscle of the anal canal and internal anal sphincter may be particularly important for modulating sensitivity of these sensory receptors by maintaining apposition of the anal squamous epithelium. The striated anal sphincter consists of a complex ring of striated muscle fibers forming the external anal sphincter muscle. The superficial layers of this muscle ring insert into the skin of the perianal region, and the deeper layers interdigitate in the midline anteriorly and posteriorly. The external anal sphincter and the puborectalis muscles are not the major voluntary muscles of continence. The puborectalis muscle sling is the larger muscle, arising from the posterior surface of the pubis on each side and passing posteriorly beside the urethra and vagina to fuse with the opposite homologous muscle behind the anorectum at the anorectal junction. This muscle sling forms the innermost margin of the pelvic floor diaphragm, differing from the levator ani muscle diaphragm itself in that it does not insert into the sacrum. The puborectalis muscle, separated from the external anal sphincter by a fascial 5,6 layer, is innervated by direct somatic efferent nerves from the sacral plexus, whereas the external anal sphincter muscle receives its innervation from the inferior rectal branches of the pudendal nerves. In addition, there are differences in the size and fiber-type distribution of 7,8 muscle fibers in these three muscles. The external anal sphincter and puborectalis9 muscles are in a constant state of low-level tonic resting contraction, even during sleep. Tonic contraction of the puborectalis muscle
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(puboanal sling) pulls the anal canal forward toward the pubis, thus maintaining a sharp rectoanal angulation. Parks suggested that this angulation acts as a flap-valve sphincter 10 11 mechanism. Indeed, the anal canal is usually empty. There has been much subsequent controversy concerning this concept, mainly centered around whether there is a zone of high 12 pressure at the2 level of the flap valve. No such high-pressure zone has been demonstrated. Increased recruitment of the puborectalis and the external anal sphincter muscles occurs during a period of increased abdominal pressure, as with straining against a 9,13–15 Only in tabes dorsalis is the closed anal canal, coughing, and changes of posture. 9 resting tonic activity of these muscles abolished. Anorectal continence requires an effective external anal sphincter muscle and a pelvic floor that retains its normal elasticity. Urinary Continence 1,16
The mechanism of urinary continence is complex. It is dependent on tonic contraction of the periurethral striated sphincter musculature, resulting in a pressure zone in the upper 16–19 Tonic18contraction of the intramural component of the striated urethra and bladder neck. urethral sphincter is also important, and the smooth muscle of the bladder neck is an essential factor. The striated urinary sphincter musculature seems to be analogous to the external anal sphincter and puborectalis muscles, respectively, in function and innervation. The periurethral striated sphincter muscle is innervated by perineal branches of the pudendal nerves, and the intramural striated sphincter by direct motor branches of the somatic efferent pelvic nerves. Combined contraction of these two muscles causes flattening of the proximal urethra, in addition to closure and angulation of the bladder neck. Relaxation of these 1,16,20,21 muscles is necessary before micturition can commence. Like the voluntary anal sphincter musculature, the periurethral striated sphincter and intramural striated sphincter muscles are in a state of tonic18,22 basal activity and, like these The only other muscles in the muscles, they consist largely of type 1 tonic muscle fibers. human that show similar continuous basal activity are the cricopharyngeal sphincter muscles (which are responsible for closure of the upper esophagus during respiration), the muscles of the floor of the mouth (which maintain the upper airway), and the intrinsic abductor muscles of the vocal cords in the larynx. The internal urethral sphincter muscle is clearly also important in urinary continence, but its precise role in the integration of muscular activity that 1 takes place at the proximal urethra is uncertain.
Neural Control Systems As in other central motor control systems, the neural organization of the control systems for bowel and bladder sphincters consists of neural systems overlaid one on another in the spinal cord, brainstem, basal ganglia, and cerebral cortex to form a distributed network of motor systems such that each component can be23recruited into functional motor programs that are connected in parallel, rather than in series. This arrangement encourages flexibility of response and the capacity for learning and behavioral responsiveness because it allows input 24 for decision making at several functional and anatomical levels. Onuf's Sacral Nucleus The peripheral components of the innervations of the anal and urinary sphincters, including 25 both autonomic and somatic components, are organized in Onuf's sacral nuclei. These consist of bilateral symmetric groups of anterior horn cells making up a distinct nucleus in the S2 and S3 spinal segments. The Onuf nucleus is situated medially in the anterior horn on each side. The specialized groups of somatic efferent motor neurons in the ventromedial parts of the nucleus innervate the striated components of the vesical and anorectal sphincter 26,27 and the perineal muscles (e.g., the ischiocavernosus and bulbocavernosus musculature 28 muscles). The dorsal component of this nucleus contains motor neurons that innervate the periurethral striated sphincter muscle. The site of the neurons that innervate the puborectalis muscle is unknown, but since it has the same root origin it is probably adjacent to the Onuf nucleus. The neurons of Onuf's nucleus are smaller than other somatic neurons and have dense dendritic bundles that project rostrocaudally while remaining within the confines of the column 29 of the nucleus. These prominent and unusual dendritic arrays provide direct pathways for interconnection of the neurons of the nucleus. These profuse connections may provide the anatomical basis for the synchronization of neuronal activity in the nucleus for the maintenance of rhythmic and repetitive output and perhaps for metabolic and developmental 28,29 Other dendrites extend radially from the main body of the nucleus and make functions.
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contact with fibers descending rostrocaudally from brainstem and cerebral centers, especially from the ipsilateral paraventricular hypothalamic nucleus, ipsilateral caudal pontine lateral reticular formation, and caudal nucleus retroambiguus. Afferents from the pudendal nerve (e.g., muscle spindle and other muscle afferents) and input from the pudendal sensory 30,31 Muscle spindles are present, innervation of the anal canal also synapse in this nucleus. 32,33 so that primary and but only in small numbers, in the external anal sphincter muscle, secondary afferent input to this nucleus is probably relatively sparse. The neurotransmitters in these terminals are not yet characterized. Histological studies in humans have suggested that Onuf's nucleus contains both autonomic and somatic efferent neurons (see later), although 30 Holstege and Tan found that in the cat this nucleus consists only of autonomic neurons. Terminals containing leu-enkephalin, somatostatin, and vasopressin intestinal peptide are found in relation34to these neurons, but not in the somatic motor neurons just adjacent to Onuf's nucleus. Similar peptidergic terminals are found in relation to the parasympathetic neurons themselves. It has been suggested that the leu-enkephalin terminals are derived 35 from collaterals of parasympathetic neurons that innervate the bladder detrusor and perhaps the smooth muscle of the colon through connections with the enteric nervous system established from the parasympathetic innervation of the myenteric plexus (Auerbach's plexus). The parasympathetic neurons innervating colonic smooth muscle probably contain both leu-enkephalin and somatostatin. These peptides may be important in mediating reciprocal inhibition of urethral and anorectal sphincter neurons during defecation and micturition. The origin of the terminals containing vasopressin intestinal peptide is uncertain, 28 but they may represent interneuronal connections. Suprasegmental Organization The sacral nuclei subserving urinary smooth and striated sphincter and detrusor (smooth muscle) activity are modulated by descending pathways that traverse the spinal cord from the 1,36 In the human, most of these fibers belong to the corticospinal39tract and are situated brain. 37,38 The enteric nervous system is separated from in the most mesial portion of this tract. the somatic and visceral nervous systems at an early stage of ontogenesis, but is modulated by vagal and sacral parasympathetic efferents and by sympathetic efferents derived from the 40,41 Afferent fibers that subserve sensation in the bladder and urethra and thoracic outflow. presumably also in the anorectum probably travel in the superficial ventral part of the lateral 37,38 The parasympathetic and sympathetic afferents, and somatic afferents, from funiculus. the bladder and anorectum follow different afferent pathways. There have been many attempts to locate centers for the control of micturition and defecation in the central nervous system (CNS), and several supposed centers for these functions have been described in the cortex, basal ganglia, and near the third ventricle. In addition, several complex systems of neuronal circuits have been suggested as being important to micturition, involving brainstem relays with so-called spinal centers. Excitatory dysfunction in the basal 42 ganglia may produce detrusor hyperreflexia, but the urinary hesitancy and incontinence with constipation that often occurs in idiopathic Parkinson's disease is probably the result of associated degeneration in dopaminergic autonomic pathways and of neurons within the 43 bowel wall, rather than of cell loss in the substantia nigra and other basal nuclei. Connections probably exist from1 the anorectum and bladder to nuclei in the limbic system, hypothalamus, and cerebellum. 1,31,36,44–46
The brainstem systems concerned with micturition are closely integrated with those 37,38 A lateral-dorsal tegmental nucleus in the pons, rostral to the concerned with defecation. nucleus of the locus ceruleus, is probably the site of origin of the neuronal system that descends in the intermediolateral tract of the spinal cord to supply parasympathetic 38 innervation to the sacral outflow and thus to the detrusor muscle of the bladder (the voiding pathway). This autonomic outflow projects to the neurons of Auerbach's myenteric plexus in 39 the bowel wall that modulate motility of colonic and anorectal smooth 1muscle. Projections to the bladder detrusor muscle probably travel in the reticulospinal tract. Hald and Bradley tried to integrate these neuronal systems with the control of bladder function and suggested four functional loop control systems: two for the detrusor muscle and 1 two for the periurethral striated sphincter muscle. These postulated loops all involve connections through the pudendal nuclei and the pontine brainstem. Loop 1 connects the brainstem to the frontal lobe, loop 2 connects detrusor muscle afferents to the brainstem, loop 3 consists of detrusor afferents connecting with the pudendal nucleus in the sacral cord, and loop 4 consists of afferents and efferents connecting the periurethral striated muscles with the pudendal and pontine nuclei. Barrington described brainstem reflexes induced by 45,46 In bladder distention and by running water through or distending the urethra in the cat. addition, he recognized that thoracic spinal cord section would temporarily abolish micturition
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and that low thoracic section would permanently abolish it. These features are observed in humans with spinal injury, and the pathways suggested by Barrington for these reflexes have 47–49 been largely confirmed by physiological, evoked potential, and morphological studies. The work of De Groat, and of Holstege and collaborators, has done much to clarify these concepts. Barrington pointed out that the “middle pons is the level at which the motor tone of 45,46 This concept is synonymous with the modern notion of the pontine the bladder arises.” micturition center (PMC), located in the dorsolateral pons, that projects to the intermediolateral cell columns of the sacral cord segments and parasympathetic outflow. This sacral parasympathetic outflow innervates the bladder detrusor muscle. A more ventrally situated nucleus in the pons projects to the portion of the sacral Onuf's nucleus that innervates the striated urinary sphincter and the cells of the same nuclear complex that innervate the smooth nonstriated component of the urinary sphincter muscle. Thus, there is a “neural switch” in the brainstem that controls bladder emptying (detrusor contraction and sphincter relaxation) and urinary storage (detrusor relaxation and sphincter contraction). This neural switch is activated by input from small-diameter afferent fibers entering the sacral cord from the bladder, signaling bladder wall stretch as the bladder fills, which sets the system toward urinary voiding. Descending inhibition sets the system toward bladder storage. Positron emission tomography (PET) studies of storage and micturition have shown activation of the PMC area during micturition, with activation in the right frontal region. 50,51 In men but Increased right cingulate activation occurred when micturition was withheld. not in women, a region in the periaqueductal gray matter was activated prior to micturition. The cortical localization of the functions of micturition and defecation was located by Foerster, following the work of Kleist on head injuries sustained by German soldiers during 52 World War I, on the medial surface of the cerebral hemisphere in the paracentral lobule, just anterior to the central sulcus. This localization is consistent with that of the motor representation of the sacral muscles on the cortical surface and has been confirmed53in normal human subjects by transcutaneous electrical stimulation of the motor cortex. The cortical localization of the sensory input from these organs is less certain but is probably in the adjacent sensory cortex, on the medial surface of the hemisphere. Penfield and Rasmussen reported that patients experienced sensations of bladder and rectal fullness when the sensory cortex on the upper part of the medial surface of the cerebral hemisphere 54 was stimulated. The localization of the sensory input from the pelvic area can be investigated in the intact human by cerebral evoked potential studies involving stimulation of 49 the pudendal nerve (dorsal nerve of the penis or clitoris) or the pelvic detrusor nerve. 1 Stimulation of the latter nerve results in a response in the frontal lobe. The cortical 55 localization of the parasympathetic detrusor innervation of the bladder and bowel remained uncertain until the PET studies described earlier. Lesions of the superior parts of the medial surface of the hemispheres in the rolandic areas are uncommon, but frontal lobe lesions produce characteristic effects on bladder and bowel 56,57 particularly loss of social inhibition, so that micturition and defecation occur at continence, inappropriate times and places. These clinical syndromes overshadow the effects of lesions in other parts of the brain because they are so common, occurring especially frequently as a result of stroke, subarachnoid hemorrhage from anterior communicating aneurysms, frontal 56,57 Kuroiwa and associates reported that lesions of the right lobe tumors, and trauma. hemisphere were more likely to cause urgency and frequency of micturition than lesions of 58 the left hemisphere. Lesions in other parts of the brain are less likely to cause major problems with continence. Only lesions in the spinal cord, 1conus medullaris, or cauda equina are likely neurological causes of urinary or fecal retention. CLINICAL ASSESSMENT AND INVESTIGATION OF SPHINCTER DISORDERS Clinical examination is essential in providing evidence of CNS disease and in suggesting the possibility of urinary infection or colonic disorders, including fecal retention with overflow, in which the anus is often patulous and the anorectum laden with feces. In patients with urinary retention and overflow, the bladder may be palpable regardless of the underlying etiology. Inspection of the perineum may reveal local causes, such as traumatic damage to the sphincter musculature, perhaps associated with injury during childbirth, local infection, or surgical damage. In addition, the response of the perineum to coughing and straining downward (as though defecating) is a useful clinical test for weakness of the perineal musculature. When there is weakness of these muscles, the perineal plane bulges downward 59 toward the examiner during a cough, a clinical sign termed perineal descent.
Anorectal Function Clinical examination is supplemented by measurement of function and other
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neurophysiological variables. Anal Manometry Anorectal pressures can be measured with closed or open-tipped catheter probes connected to a pressure transducer. Resting anal pressure in the anal sphincter region is largely a measure of internal anal sphincter tone. The voluntary squeeze pressure corresponds to recruitment of activity in the external anal sphincter muscle. It can be sustained for only a few seconds at a time. Distention of an air-filled balloon within the rectum causes relaxation of the internal anal sphincter; this rectoanal relaxation reflex is mediated through intramural neural 40 circuits in the myenteric plexus of the anorectum. It is absent in Hirschsprung's disease, in which there is focal absence of the myenteric plexus in the anorectum, leading to obstruction of the lower bowel. Inflation of the rectal balloon also causes an initial burst of activity in the external anal sphincter muscle owing to stretch-induced activation of its muscle spindles. This inflation55reflex is absent in tabes dorsalis and in some patients with diabetic neuropathy. Perineal Descent The plane of the perineum at rest and during a straining effort can be measured with respect 60 to the plane of the ischial tuberosities by means of a perineometer. Electromyography Concentric needle electromyography (EMG) with motor unit potential analysis can be used to examine the external anal sphincter and puborectalis muscles in studies of the anal sphincter 61,62 The system and the striated urethral sphincter muscle in vesicourethral investigations. author prefers to use single-fiber EMG because fiber density is a relatively robust measure 63,64 that has good concordance between examiners and between serial investigations. 63 Furthermore, it is a good index of reinnervation in a muscle (Fig. 33-1).
FIGURE 33-1 Single-fiber electromyographic recording of the external anal
sphincter muscle. A, Normal subject. B, Idiopathic anorectal incontinence: the motor unit potentials are abnormally complex, and the fiber density is increased.
Vesicourethral Function
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Assessment of vesicourethral function has received47a great deal of attention since the pioneering studies of Denny-Brown and Robertson. Urodynamic methods are commonly applied to the investigation of voiding disorders. A number of techniques are used, especially cystometry, urine flow-rate measurement, urethral pressure profile, and integrated pelvic floor muscle EMG. These methods provide complementary information on parts of the filling, storage, and voiding cycle that constitute normal vesicourethral function. Urodynamics Cystometry, using gas or more commonly liquid (e.g., water or radiological contrast 1 medium), may be utilized to study the relationship between intravesical pressure and bladder filling volume, which represents the detrusor activity in response to a change in bladder volume. Cystometric abnormalities are not diagnostic of any underlying lesion but describe the functional disturbance itself. Five main categories of information are derived from urodynamic studies: 1. Residual urine volume. This is a measure of the completeness of bladder emptying. Postmicturition ultrasonography is the preferred noninvasive technique. 2. Bladder sensation. Normal subjects can first sense bladder filling at volumes of 100 to 200 ml. As filling continues, the desire to void increases and becomes urgent at maximal bladder capacity. Loss of these bladder sensations occurs with lesions in the peripheral nervous system or CNS and with a chronically distended, obstructed bladder. 3. Maximal bladder capacity. This varies greatly, ranging from 300 to 600 ml. Impairment of this storage capacity leads to frequency of micturition. 4. Bladder compliance. The term compliance describes the change in pressure with any given change in volume during bladder filling, corresponding to the slope of the cystometrogram. It reflects the stretch characteristics of the bladder wall. In the normal bladder, pressure should not increase by more than 10 cmH2O until full capacity is reached. Stiffening of the bladder wall after infection or radiotherapy reduces compliance, so that intravesical pressure rises more sharply than normal. This action results in urgency of micturition. 5. Detrusor contractility. Intravesical pressure results from the sum of intra-abdominal pressure and bladder detrusor pressure. The former can be measured with an anorectal pressure probe, allowing derivation of detrusor pressure by subtraction. Detrusor pressure is high when there is bladder outlet obstruction. Intra-abdominal pressure is high when there is a weak detrusor muscle, so that micturition is accomplished by abdominal straining, rather than detrusor contraction. Abdominal straining is also a compensatory feature in bladder outlet obstruction. Normal micturition is under voluntary control. The normal individual is able to sense bladder filling and to initiate or inhibit detrusor contractions. Urinary Flow Rate Measurement of urinary flow rate is an inexpensive, noninvasive method of assessing detrusor function and outflow obstruction. The rate of flow and the total volume of urine voided can be measured. Urethral Pressure Profile Open-tipped catheters can be used to measure pressure in the urethra during micturition. This method resembles that used for anorectal manometry and gives information about the length of the functional sphincter zone in the urethra (normally 2.5 to 3.0 cm in women and 4 to 6 cm in men). Abnormalities in the pressure gradient in the urethra can be directly correlated with fluoroscopic imaging of the urethra during micturition. However, there is no direct correlation between abnormalities in the urethral pressure profile and urinary incontinence. Pelvic Floor Muscle Electromyography Surface or needle EMG recordings from pelvic floor muscles can be used to monitor the function of striated muscle during cystometry and micturition. The external anal sphincter or
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urethral striated sphincter muscles are commonly studied. Basal EMG activity in the external anal sphincter muscle normally increases during micturition. Conversely, at the start of micturition, basal activity in the urethral striated sphincter muscle is inhibited at the commencement of detrusor contraction and re-established at the end of micturition. The normal patient can interrupt the flow of urine during micturition. Such interruption is accompanied by a burst of EMG activity in the urethral striated sphincter muscle. EMG activity in this muscle also increases during bladder filling and responds briskly to21changes in body posture and intra-abdominal pressure, as during that induced by coughing. This reflex modulation of activity in the urethral striated sphincter muscle is similar to that found in the external anal sphincter and puborectalis muscles and is important to the maintenance of continence during the normal stresses of daily life. Abnormalities in the relationship between modulation of EMG activity in these muscles and changes in filling pressure in the anorectum and bladder are found with functional disorders of voiding and defecation—for example, detrusor-sphincter dyssynergia and anismus (see later discussion). Study of the configuration of motor unit potentials in the urethral striated sphincter muscle has been used to detect abnormalities in the innervation of this muscle in patients with stress urinary incontinence and certain types of functional obstruction to 65 micturition.
Other Neurophysiological Studies When there are abnormalities in motor unit configuration in the external anal sphincter, puborectalis, or urethral striated sphincter muscles, it is appropriate to investigate the innervation of these muscles directly. Such investigation can be achieved with techniques that utilize standard EMG equipment. Pudendal and Perineal Nerve Terminal Motor Latencies The terminal motor latency in the pudendal and perineal nerves is a measure of function in the distal parts of the nerve supply of the external anal sphincter and periurethral striated in sphincter muscles (Fig. 33-2). The evoked compound action muscle potentials (CMAPs) 66–69 these muscles can be recorded after stimulation of the pudendal nerves in the pelvis using a finger-mounted array of recording and stimulating electrodes with fixed interelectrode distances (3.5 cm). The two stimulating electrodes are mounted at the tip of the finger, with the cathode arranged distally; the recording electrodes are mounted side by side at the base of the finger so as to be in a suitable position to pick up the response in the external anal sphincter muscle. Stimulation of the pudendal nerves is achieved on either side of the pelvis by directing the exploring finger in the rectum toward the lateral rim of the pelvis (i.e., toward the ischial spine). The onset of the stimulus is used to trigger the oscilloscope. Stimuli of square-wave pulses, 0.1 msec in duration and about 50 V (but always supramaximal), are used to find the shortest latency of the response in the external anal sphincter muscle. The perineal nerve terminal motor latency (Fig. 33-2) can be measured with a similar technique, recording the response with a pair of catheter-mounted recording electrodes placed in the urethra. Normal values for terminal motor latencies in these nerves are published 70 elsewhere.
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FIGURE 33-2 A, Pudendal nerve terminal motor latency in a normal subject. B,
Perineal nerve terminal motor latency in a normal subject. The terminal latency in this nerve is slightly longer than that in the pudendal nerve, reflecting its greater length from the point of stimulation in the perirectal space. Transcutaneous Spinal Stimulation The innervation of the puborectalis, which is derived from pelvic branches of the sacral plexus, is not accessible to intrarectal electrical stimulation techniques. The nerves innervating this and other muscles of the perineum or legs can be excited transcutaneously by applying magnetic stimulation71,72 over the cauda equina, thereby allowing the motor latency to This method has practical difficulties, however, in that these muscles to be measured. stimulation of the cauda equina through the lumbosacral bone mass is usually not supramaximal, and may not always be possible. Muscle responses in the external anal sphincter muscle (Fig. 33-3) are recorded with the finger-mounted electrode array or with an anal plug electrode. A catheter-mounted electrode can be used to assess responses in the periurethral striated sphincter muscle (Fig. 33-3). By stimulating at the L1 and L4 vertebral levels representing the conus medullaris and the lumbosacral nerve roots of the cauda equina, respectively, it is possible to assess motor conduction in the cauda equina. The latencies from L1 and L4 stimulation sites (Fig. 72–75 33-4) can be expressed as a ratio. In normal Conduction velocity in the nerve roots of subjects this ratio has a relatively low variance. 72–75 The sensitivity and the cauda equina in normal subjects was 58 m/sec (SD ±10 m/sec). reliability of these techniques has not been reported and, in investigating sphincter disorders in suspected lumbosacral spinal disease, most clinicians rely on functional testing by anorectal manometry and cystometry, and on neuroimaging of the cauda equina, rather than on neurophysiological assessment.
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FIGURE 33-3 Transcutaneous spinal (cauda equina) stimulation at the L1 and
L4 levels, with responses recorded from external anal sphincter muscle (A), puborectalis muscle (B), and periurethral striated sphincter muscle (C). Note the different latencies to these muscles from the L1 and L4 sites of stimulation, reflecting the different lengths of these lower motor neuron pathways.
FIGURE 33-4 Transcutaneous spinal stimulation. The latencies to the
puborectalis muscle are increased from the L1 level (A), but normal from the L4 level (B), suggesting a lesion in the spinal canal between these two levels. Cortical Stimulation 76–79
The sphincter musculature can be excited by electrical (now a largely outmoded method) 80 or magnetic stimulation of the motor cortex. The cortical motor representation of the striated sphincter and pelvic floor musculature is close to the median sagittal plane of the skull. Disposable surface electrodes placed within the anal canal can be used to record the response of the external anal sphincter muscle. The shortest latency of the response is at 76,78 The response is therefore probably monosynaptic, about 20 msec in normal subjects. because it occurs at a latency consistent with that of other striated muscles known to have
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corticospinal innervation, allowing for differences 77 in length of the intervening pathways. Ertekin and colleagues reported a longer latency, but this is probably attributable to the lower-powered electrical stimulator used in their experiments. Sensory Evoked Potentials The sensory pathway to the cerebral cortex can be investigated with standard evoked response techniques. Stimulation can be applied in the anorectum, at the bladder neck, at the dorsal nerve of the penis or clitoris (pudendal nerve), or at the trigone of the bladder. These methods are uncomfortable for the patient, and they have not therefore been generally applied to investigation of voiding or defecatory disorders, except in patients with spinal 81 injuries in whom sensation is impaired. Anorectal82sensory evoked potentials have proved inconsistent in form and latency in clinical studies. Spinal Motor Conduction Velocity The corticospinal fibers of the spinal cord can be excited by transcutaneous electrical 83 stimulation using the method introduced by Merton and Morton. Stimulation can be achieved at the lumbar (T12/L1 and L4), midthoracic, and cervical (C6) levels, thereby allowing calculation of the motor conduction velocity between these levels. Recording from the external anal sphincter muscles, the corticospinal motor conduction velocity between the C6 and the L1 vertebral levels in 21 normal adults with a mean age of 55 years was 67.4 84 m/sec (SD ± 9.1 m/sec). Although there was a trend for the spinal motor conduction velocity to decrease with increasing age, this was not statistically significant. DISORDERS OF PELVIC SPHINCTER FUNCTION Sphincter disorders are frequent, although often unvoiced. The two basic symptoms of sphincter dysfunction are sphincter incompetence, leading to incontinence, and incoordination between sphincter relaxation and detrusor activity, leading to retention of urine or feces (Table 33-1). Management is not considered here, but in general it consists of treatment of the underlying disorder and the symptomatic measures discussed in most standard medical textbooks.
Incontinence Surveys of the prevalence of urinary and fecal incontinence in the general population suggest that incontinence is much more common than has generally been supposed, especially 85 among women. As many as 10 percent of women older than 50 years experience two or more episodes of incontinence of urine each month. In elderly populations in nursing homes, a prevalence figure for urinary incontinence of more than 50 percent is common. Fecal incontinence is less common, but the observation of Leigh and Turnberg that 51 percent of patients presenting to a gastroenterology clinic with the complaint of diarrhea were, in reality, 86 incontinent suggests that the incidence of fecal incontinence has been greatly underestimated. Surveys have confirmed the commonly held view that incontinence is much 85–87 Most patients with incontinence have no evident more common in women than in men. neurological disorder. They experience incontinence particularly when the sphincter system is stressed, as during a cough or other sudden increase in intra-abdominal pressure. This idiopathic form of incontinence is usually called idiopathic stress urinary incontinence or idiopathic anorectal incontinence, terms that suggest ignorance of both the underlying causative factors and the functional disturbances leading to the sphincter disorder. A classification of fecal incontinence is given in Table 33-2, and a similar approach can be used to classify urinary incontinence. Click here to view this table.... Incontinence due to neurological disease itself is relatively commonly found in association with disorders of the CNS, especially dementia, multiple strokes, and multiple sclerosis. Incontinence in these patients often occurs in response to emotional or even cutaneous stimuli, sometimes as part of generalized reflex activity (e.g., in association with flexor or extensor spasms). In patients with neurological disorders such as multiple sclerosis, incontinence is often a greater threat to self-esteem than loss of mobility. Incontinence may also develop when there is damage to the motor or sensory pathways in the cauda equina (e.g., with spinal stenosis and after pelvic fractures). 88
Classifications of clinical symptoms are generally not useful in the diagnostic process. Unfortunately, it is not yet possible to construct classifications of urinary and fecal
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incontinence that are relevant to functional and anatomical concepts and can also be used in 1 clinical practice. The four-loop theory of sphincter control can be loosely related to older concepts of the uninhibited, or reflex, bladder, corresponding to lesions in the connections between the frontal region and the brainstem or sacral detrusor nucleus (loops 1 and 2) and to the motor or sensory “paralytic” bladder defects that characterize more distal (lower motor or sensory neuron) lesions. In general, it is helpful to recognize that more rostral lesions are generally associated with failure to store urine or feces, and more distal lesions with failure to void urine or feces. Thus, frontal lesions result in micturition in inappropriate circumstances, whereas conus or cauda equina lesions initially cause retention of urine, with overflow. Central lesions in brain, brainstem, or spinal cord may cause detrusor hyperreflexia (Fig. 33-5), which is characterized by detrusor contractions that occur during the filling phase of the cystometrogram. These contractions are only partially inhibited and may lead to involuntary micturition, especially if there is incompetence of the sphincter mechanism. This feature is often referred to as bladder instability or sphincter-detrusor dyssynergia by urologists. It is also found in patients in whom the normal pressure–flow relationships are disturbed by the presence of partial outflow obstruction due to prostatic enlargement or urethral stricture; a similar functional disorder occurs when the bladder wall is irritable—that is, hypersensitive, as in infection.
FIGURE 33-5 Urodynamics. In this cystometrogram (upper trace) the detrusor muscle contracts when small increments of fluid collect during the filling phase. In the normal bladder (lower trace) the detrusor muscle is relaxed during this early phase of filling; a single sharp spike of increased pressure represents a cough during the procedure.
With some disorders (e.g., multiple sclerosis), lesions may be present in both the frontal lobe white matter and the conus medullaris, accounting for any difficulty in understanding the basis of sphincter disturbances. Mathers and co-workers found electrophysiological evidence of damage to both upper and lower motor neuron pathways subserving sphincter control in 78 is more likely to develop in women with multiple sclerosis. Furthermore, incontinence 89 multiple sclerosis who have borne children, probably because of damage to the pudendal nerves. Frontal Lobe Lesions 57
Frontal lobe tumors arising from the falx cerebri or olfactory groove that impinge on the medial or inferior surface of the frontal lobe are a well-known, although rare, cause of incontinence. Classically, the tumor may present with incontinence, typically consisting of voiding at inappropriate times or inappropriate places, rather than frank urge incontinence. Incontinence also occurs in patients with intrinsic disease of the cerebral hemispheres (e.g., intrinsic tumors, multiple strokes, multiple sclerosis, or uncompensated hydrocephalus). In hydrocephalus, there is ventricular enlargement and the corticospinal and other fibers running from the cortex to the brainstem are stretched around the enlarged ventricles. The fibers to the sacral spinal cord are particularly vulnerable to this lesion; treatment may be followed by recovery of sphincter function and of the gait disorder. Incontinence in uncompensated hydrocephalus is commonly accompanied by gait apraxia, probably reflecting damage to frontal lobe motor connections, and by extensor plantar responses and other signs of mild 90 corticospinal dysfunction in the legs. There may be a mild dementia. With degenerative brain diseases, especially Alzheimer's dementia and frontotemporal dementias, the location of the lesions responsible for incontinence cannot be precisely defined but is probably “frontal” in origin. Brainstem Lesions Lesions in the brainstem (e.g., demyelination or infarction) may cause incontinence usually in
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association with pseudobulbar palsy with a prominent abnormality of affect; the latter often implies the presence of lesions rostral to the brainstem. However, pontine lesions may present with incontinence as a clinical manifestation. This reflects involvement of neurons in the pontomedullary centers concerned with suprasegmental control of Onuf's sacral nucleus and interruption of descending pathways from frontal and hypothalamic regions to this nucleus. These brainstem 30 neurons are located in the locus ceruleus and the medullary in the control of medial reticular formation. These neurons and pathways are also important 91 the enteric nervous system by the CNS, especially in relation to gut motility. Spinal Cord Lesions With spinal cord lesions, there is loss of supranuclear control of the sacral centers for micturition and defecation so that, in the absence of obstruction or infection, an automatic pattern of micturition and defecation is established. However, both micturition and defecation are abnormal in the presence of partial or complete spinal cord lesions. The absence of the normal sensation of filling of the bladder and anorectum, because afferent pathways are interrupted through the damaged cord, often results in overdistention and injury to these organs, with consequent secondary functional effects. Loss of viscoelasticity of the wall of the bladder and anorectum and loss of the normal smooth muscle responses to filling and inflation lead to abnormal compliance and incontinence (e.g., as with fecal impaction). There is thus not only reflex incontinence with impaired supraspinal control mechanisms but also loss of storage function from local effects on the bladder and anorectum. In addition, spinal lesions produce abnormalities in the reflex interrelations of the detrusor and sphincter systems, causing detrusor-sphincter dyssynergia (see later). Lower Motor Neuron Lesions Incontinence results from damage to the somatic afferent and efferent pathways to the striated sphincter musculature of the bladder neck and the external anal sphincter and pelvic floor muscles. This may occur with congenital anomalies (e.g., myelomeningocele), spondylosis, narrow spinal canal syndromes, primary or secondary sacral tumors, sacral bony anomalies, or trauma. Similarly, incontinence may occur owing to sacral plexus and nerve root lesions in proximal neuropathies (e.g., diabetic neuropathy), in association with malignant infiltration of these nerves, or with pelvic trauma. Other features (e.g., pain, weakness, and sensory loss) are major features of these syndromes. In progressive autonomic failure (Shy–Drager syndrome), there is selective damage to the innervation of the striated urinary sphincter musculature similar to that found in the abductor muscles of the larynx. The external anal sphincter seems to be spared, at least in the early stages of the disease. This observation implies selective vulnerability92within the somatic efferent component of the neurons of Onuf's nucleus in this disease. In motor neuron disease (amyotrophic lateral sclerosis) and the spinal muscular atrophies, the converse occurs in that the striated pelvic floor sphincter muscles are relatively spared, as are the external ocular muscles, the cricopharyngeal sphincter, and the diaphragmatic sphincter muscles. These features have implications for selective vulnerability in degenerative 93,94 disorders of anterior horn cells. When incontinence results from lesions in the S2 to S4 nerve roots, whether in the spinal canal or the pelvis, it is important to recognize that conventional neurological examination is normal. Sensory disturbance is evident only on testing in the gluteal cleft. The anal reflex, although much relied on, is often absent even in normal subjects, with the relatively crude technique generally used clinically. Tone is reduced in the external anal sphincter muscle during a maximal squeeze and during a cough, and there may be palpable atrophy of the puborectalis muscle. Atrophy of the posterior thigh muscles is difficult to appreciate, and tendon reflexes cannot be reliably elicited from these muscles even in normal subjects. It is in these syndromes that the electrophysiological tests, described earlier, are useful when it is being decided how far to pursue investigation. EMG features of denervation in the external anal sphincter and puborectalis muscles, and the slowing of nerve conduction in the motor innervation of the perianal sphincter muscles, provide useful data concerning the site of the causative disease process and may indicate the need for imaging of the sacral canal and 72 pelvis. Idiopathic Stress Incontinence In patients with stress urinary or fecal incontinence (idiopathic anorectal incontinence), there 95 is damage to the sphincter mechanism, often due to direct trauma sustained in childbirth,
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but also occurring during the aging process. The pelvic floor is lax and has lost its normal youthful elasticity. In addition there is often partial denervation of the striated pelvic floor sphincter muscles (Fig. 33-1), usually due to damage to the innervation of these muscles 75 during childbirth. The nerves involved are the inferior rectal and perineal branches of the pudendal nerves and the somatic, direct pelvic branches of the sacral nerves. Injury is caused by direct force applied to these nerves during passage of the fetal head through the birth canal and by stretching during elongation of the birth canal and descent of the perineum 75 as part of the normal process of childbirth. Difficulty during childbirth (e.g., prolonged labor, a large baby, and especially the application of forceps to the head and sphincter tears) is 70,75 particularly associated with damage to the perineal and pudendal nerves. Weakness of the anal sphincter, whether due to a posteriorly located tear in the muscle, denervation, or a combination of these factors, leads to incomplete closure of the anal canal and stretching of pelvic floor connective tissue. The latter is probably particularly important because it results in the inability of pelvic floor muscles to adequately tense the vagina, urethra, and anal canal and thus in failure of the sphincter closure mechanism. Incontinence may then occur with pressure stress, as in sneezing. Weakness of the pelvic floor muscle diaphragm causes loss of tone in these muscles, descent of the pelvic floor during simulated defecation straining and during coughing, and other symptoms such as genital, urinary, or anorectal prolapse, nagging pain, and difficulty with defecation because of associated anal mucosal prolapse. A pattern of straining during defecation is thus initiated that leads to frequent, pronounced perineal descent and to further recurrent stretch-induced injury to the pelvic floor muscles, 71 and eventually to the development of incontinence of feces or urine or to double incontinence. The clinical deficit depends on the relative amount of damage to the innervations of the urethral and anal striated sphincter muscles, and on any direct injury. Because the pelvic floor sphincters are weak, the anorectal and vesicourethral angles are increased (flattened), and urine and feces are voided during sudden straining, coughing, twisting, laughing, or other movements that increase intra-abdominal pressure. Not all women with stress incontinence have given birth; indeed the syndrome occurs in men, although rarely. In these patients, there is often a history of straining during defecation or of intractable constipation (see later). This form of the disorder is associated with the same features of denervation due to nerve injury as in women with childbirth injuries. Pelvic floor 60 descent during straining or coughing is also a feature. Thus, constipation or an abnormal bowel habit with a straining pattern of defecation also leads to stretch injury to the pelvic floor muscles (Fig. 33-6).
FIGURE 33-6 Algorithm of stress incontinence. Fecal and urinary incontinence
are shown associated with denervation and weakness of the pelvic floor muscles and especially of the striated sphincter muscles. This condition results from damage to the innervation of these muscles sustained during childbirth, during excessive straining at defecation, and from disease in the pelvis and cauda equina. The relative involvement of the different innervations of the sphincter muscles accounts for the occurrence of predominantly urinary and fecal incontinence. EAS, external anal sphincter; PR, puborectalis muscle; USSM, urethral striated sphincter muscle. In about 10 percent of the patients referred for investigation of stress incontinence, there is electrophysiological evidence of damage not only to the distal parts of the innervation of the pelvic floor striated sphincter muscles but also to the cauda equina nerve roots in the sacral
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spinal canal. This is probably due to lumbosacral spondylosis, but its relevance to the clinical syndrome is uncertain. It is important to recognize that the cystometric and anal manometric findings of stress incontinence do not differentiate between these patient groups, as they give information concerning only the functional state of the bladder–sphincter relationships and the compliance of the bladder and anorectal walls. They give no data on the nerve supply. Sensory Abnormalities Damage to the somatic sensory innervation of the anorectum and bladder would96be expected when there is denervation of the pelvic floor muscles resulting from neuropathy. However, the somatic sensory innervation of these organs is restricted to the anal canal itself and to the trigone of the bladder and urethra. Sensory abnormalities in these areas are well recognized in some patients with proximal diabetic neuropathy. The rectum and bladder receive sensory 1,4 innervation from the autonomic and enteric nervous systems, which is probably the main source of the sensations of filling and urgency and of visceral pain. The role of sensory deficit 97 in urinary and anorectal stress incontinence is controversial, but because continence may be partially restored by biofeedback conditioning in idiopathic anorectal incontinence, enough 98 sensory input must be present to allow access to central control mechanisms. Lack of awareness of bladder or anorectal filling could be important in some patients with autonomic neuropathies, such as in those with idiopathic visceral neuropathy and patients with progressive autonomic failure.
Retention Inability to void may be a feature of both bladder and anorectal dysfunction (Table 33-1). It may be due to sphincter incoordination in relation to the detrusor mechanism or to detrusor weakness causing loss of propulsive force. Detrusor-Sphincter Dyssynergia Successful micturition depends on adequate detrusor contraction, with synchronous relaxation of the smooth and striated urinary sphincter muscles. Detrusor-sphincter dyssynergia results from an involuntary increase in urinary sphincter tone during attempted voiding, so that the detrusor muscle contracts against a tightly closed sphincter and urine flow 36 is poor or absent. Contraction of the periurethral striated sphincter musculature can be recognized by the presence of bursts of EMG activity in this muscle during attempted micturition, at a time when intravesical pressure is high from detrusor muscle 99,100 Simultaneous pressure recordings and EMG recordings are therefore contraction. required for accurate recognition of this functional disturbance. The most commonly recognized cause of detrusor-sphincter dyssynergia is spinal cord 1 disease, the lesion being above the level of the conus medullaris. The syndrome has been explained as due to disconnection of the sacral micturition center from the brainstem and its central connections, preventing the normal integration of detrusor and sphincter muscle 101 functions. From the theoretical standpoint, detrusor-sphincter dyssynergia is of special interest because it represents dissociation of central mechanisms concerning the functional interrelation of the visceral detrusor system from the somatic sensorimotor system that 31 controls the striated external sphincter system. Little is known about the anatomy and physiology of the interactions of these two nervous systems in health or disease. The syndrome also occurs in patients with other CNS lesions, in particular, stroke, dementia, multiple sclerosis, and Parkinson's disease. However, these patients more commonly have 102 detrusor hyperreflexia with urge incontinence. Despite the assumption that detrusor-sphincter dyssynergia is due to a neurological disorder, most cases appear idiopathic in that there is no demonstrable neurological lesion. They appear in children with hesitancy of micturition, straining, and encopresis, and in otherwise healthy adults who develop voiding dysfunction after a previously normal pattern of micturition. The cause of the functional disturbance of micturition in these patients is not known. Detrusor-sphincter dyssynergia is important because it leads to an increase in intravesical pressure, with persistent postmicturition residual urine. In some patients, intermittent catheterization may be required to achieve bladder emptying and so reduce the risk of recurrent urinary tract infection. Nonetheless, there is a substantial risk of the development of hydronephrosis from the back-pressure effect on the upper urinary and renal tracts, a problem that may cause chronic renal failure if untreated (e.g., by α-blocking agents or sphincterotomy).
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Detrusor-sphincter dyssynergia must be differentiated from other disordered patterns of 1 of micturition in micturition. For example, some patients show an abnormal straining pattern 20 which other pelvic floor muscles are recruited into the act of micturition. External sphincter spasm also occurs in some patients with detrusor hyperreflexia in whom there is no evidence of any organic lesion in the detrusor innervation and no dyscoordination between the detrusor and the external urinary sphincter. Spasm1,20 of the external urinary sphincter muscle also occurs when there is urethritis or cystitis. Anismus-Type Constipation There are various causes of constipation (Table 33-3). Constipation is difficult to define, but a useful working definition states that a person is constipated if he or she strains at stool more 103 than 25 percent of defecating time or passes fewer than two stools per week. In one study, patients with constipation were given radiopaque markers in the diet. Eighty percent of the markers were visible on plain abdominal radiographs 10 days later; in normal subjects these markers are voided within 4 days. The location of the markers in the colon gives information 104 concerning the cause of the functional disorder. Click here to view this table.... Constipation may be of the slow-transit type, in which there is a delay in passage of fecal matter through the colon as a whole, or of the normal-transit type, in which colonic motility is 104,105 This normal but there is a functional obstruction to defecation at the pelvic outlet. syndrome of pelvic outlet obstruction, termed anis-mus, is a common cause of constipation, 105,106 especially in women. Defecating proctography in patients with anismus has shown that the anorectal angle retains its acuteness during attempted defecation, rather than opening to 105 allow passage of the fecal bolus. This is due to paradoxical recruitment of the puborectalis muscle during defecation, a phenomenon that is not found exclusively in pelvic outlet obstruction but that also occurs in some patients with intractable pelvic and perineal pain and 107 in those with solitary rectal ulcer syndrome. 108
A similar functional disturbance of defecation occurs in Parkinson's disease. With both anismus and Parkinson's disease, paradoxical recruitment of the puborectalis muscle is accompanied by recruitment of other pelvic floor muscles and of the glutei and anterior abdominal wall muscles. This form of constipation thus in some respects resembles a focal dystonia in the widespread muscle recruitment that occurs during the attempted motor task 108 Attempts to weaken the and in the inappropriate contraction of the puborectalis muscle. 109 puborectalis muscle by surgical division and by local injection of botulinum toxin have had some success in relieving the disordered defecation. A long history of straining at stool in patients with the anismus syndrome is associated with the later development of fecal incontinence, probably because of the perineal descent that occurs during straining. The latter can lead to progressive denervation of the pelvic floor 110 sphincter muscles and so to weakness. Lack of Propulsive Force Disease of the enteric innervation of the39,111 gut (e.g., of the colon) results in reduced motor Similarly, abnormalities in the bladder wall can activity and slowing of intestinal transit. cause weakness of the bladder detrusor muscle. Autonomic neuropathies involving the parasympathetic nervous system may also cause these symptoms. Thus, detrusor weakness and lack of intestinal motility are common features of autonomic involvement in Guillain–Barré syndrome and occur in diabetic autonomic neuropathy, in the hereditary autonomic and sensory neuropathies, and in patients with progressive autonomic failure. Weakness of the bladder detrusor muscle may occur without other clinical deficits (detrusor areflexia). Although investigation usually fails to reveal any systemic or local cause, it is often assumed that detrusor weakness implies degeneration in the parasympathetic innervation of the bladder detrusor muscle. In Chagas' disease, due to infestation with Trypanosoma cruzi, there is widespread destruction of ganglia in the myenteric plexus and of neurons in the peripheral autonomic ganglia, leading to megacolon and impaired colonic transit as one of the manifestations of the 112 gastrointestinal disorder. Megacolon is also a feature of patients with idiopathic visceral neuropathy, a syndrome in which constipation and slowed intestinal transit result from inflammatory or noninflammatory degeneration of the intrinsic neurons of the whole gut, 113–116 Some cases, with inflammatory change115 in the especially of the myenteric plexus. plexus, are associated with neoplasia, representing a paraneoplastic syndrome.
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Slow-transit constipation has been associated with degeneration of the myenteric neurons in the colon, a degenerative, noninflammatory disorder that affects young women and that may 117 even require colectomy to achieve relief. Its cause is unknown. A few families have been reported in which visceral neuropathy was the predominant clinical feature of an unclassified type of hereditary autonomic neuropathy. Hirschsprung's disease presents with colonic obstruction during the first few days or weeks of life. It is due to congenital absence of ganglion cells from a segment of the terminal portion of the bowel. This anomaly leads to massive dilatation proximal to the region of aganglionosis because peristalsis is interrupted in this region. The disorder is due to an abnormality in the migration of neurons into the gut from the neural crest during 118 development, but its pathogenesis is poorly understood, as is reviewed elsewhere. Another group of poorly understood disorders, megacolon, with extensive involvement of other parts of the gastrointestinal tract, seems to be due to degeneration of the innervation of the smooth116muscle of the gut wall, although some cases are due to a primary smooth muscle myopathy. There is detrusor areflexia and weakness, with megalocystis and megaureter. When the gut is affected peristalsis is abnormal and intestinal pseudo-obstruction develops, 117 sometimes requiring surgical excision of redundant loops of gut. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 34 Sexual Dysfunction in Patients With Neurological Disorders DAVID B. VODUŠEK • MICHAEL J. AMINOFF •
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SEXUAL FUNCTION AND THE NERVOUS SYSTEM Desire Arousal Orgasm Topographic Anatomy of Nerves in the Pelvis Change in Sexual Function with Aging EVALUATION OF PATIENTS WITH SEXUAL DYSFUNCTION AND NEUROLOGICAL DISORDERS History Clinical Examination Investigation of Genital Reaction and Arousal Investigations of Neurological Function Hormone Measurement SEXUAL DYSFUNCTION IN PATIENTS WITH NEUROLOGICAL DISEASE Head and Brain Injuries Cerebrovascular Disease Epilepsy Seizures and Sexual Symptoms Interictal Phenomena Parkinson's Disease Multisystem Atrophy Other Extrapyramidal Disorders Hypothalamopituitary Disorders Multiple Sclerosis Lesions of the Spinal Cord Cauda Equina Lesions and Lumbar Stenosis Spinal Malformations Localized Nerve Lesions Diabetic Polyneuropathy Chronic Renal Failure Other Acquired Polyneuropathies Hereditary Polyneuropathies Amyotrophic Lateral Sclerosis Hereditary Neuromuscular Diseases
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Adverse Sexual Reactions to Medications THERAPY Treatment of Neurogenic Erectile Dysfunction Oral Agents Intracavernous Injection Therapy Intraurethral Therapy Transdermal Therapy Vacuum Devices Surgical Treatment Ejaculatory Dysfunction in Men With Neurological Disorders Treatment of Abnormalities of Libido Drug Treatment in Women Treatment of Lack of Libido and Anorgasmia NEUROLOGICAL PROBLEMS ASSOCIATED WITH SEXUAL ACTIVITY Headache Transient Global Amnesia
Sexual excitement and satisfaction from adequate stimuli are a normal component of a fulfilled life. The somatic and psychosocial factors involved may be compromised by neurological disease. Sexual dysfunction may occur as the presenting symptom of a developing neurological disease (e.g., erectile dysfunction in multisystem atrophy) or as an isolated phenomenon after local nerve injury (e.g., painful penile dysesthesia after pudendal nerve lesion), or it may be due to more general effects of a neurological disorder.1It is helpful to conceptualize sexual dysfunction in neurological disease as Foley and Iverson did for multiple sclerosis: there are primary effects stemming from physiological or pharmacological factors; secondary problems related to sensorimotor, bladder, and bowel disturbances and higher brain dysfunction; and tertiary issues related to psychosocial and cultural changes resulting from the disease. Sexual disorders, such as loss of sexual desire, erectile dysfunction in men, decreased lubrication in women, and disturbances of ejaculation and orgasm, are common in neurological patients but are often neglected by physicians. Sexual functioning needs to be addressed, however, because it may be relevant for diagnosis, is a major determinant of quality of life, and may be responsive to treatment. The focus of this chapter is on the more classic neurological dimension of sexuality as a physiological function dependent on the integrity of neural control, on sexual dysfunction as a consequence of neurological disease, and on management of neurological patients with sexual dysfunction. SEXUAL FUNCTION AND THE NERVOUS SYSTEM To the neurologist, sexual behavior involves a series of neurally controlled phenomena occurring in a hormonally defined milieu. Sexuality depends also on psychosocial factors, but the neurologist's interest is necessarily focused more on physiological aspects; nevertheless, the perspective of partnership and social issues should not be forgotten. The normal sexual response is traditionally conceptualized as consisting of several phases, 2 including desire, excitation, and orgasm. Although the distinction of phases has been criticized and reformulated by different authors, it will serve to structure the relevant neuroanatomical and physiological issues discussed subsequently. Any lesion involving neural tissue relevant for sexual responses may cause dysfunction, as also may lesions of other neural structures more generally involved in control of behavior. Thus, forebrain areas regulate the initiation and the execution of sexual behavior, the medial preoptic area integrates sensory and hormonal signals, and the amygdala and other nuclei play a role in the execution and reward aspects of sexual function.
Desire Desire or sexual interest (libido) refers to the extent that an individual responds to or seeks out erotic stimuli. This varies with time and circumstances, and its measurement depends on self-ratings of such items as the frequency of spontaneous sexual thoughts, the excitement provoked by them, and the resulting behavioral response. Desire is enhanced by sexual activity itself, exciting circumstances, new sexual partners, hypomania, and certain focal brain lesions (particularly of the frontal and temporal lobes). Depressed patients may develop more 3 than their premorbid levels of sexual desire in response to antidepressant medication and there are scattered reports of increased libido with levodopa and dopamine agonists in 4 patients with Parkinson's disease. Sexual interest may be lowered by lack of opportunity, age, certain addictive or sedative drugs, malnutrition, debilitating illness, depression, epilepsy,
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and certain focal brain lesions. Animal experiments have revealed dopaminergic-stimulating and serotonergic-inhibiting mechanisms controlling sexual interest. Androgens are necessary for normal libido, although there remain some uncertainties related to this issue.5Sexual desire is apparently also associated with levels of free testosterone in women. The rhinencephalon, including the limbic cortex, is important for sexual desire and behavior. The basal hypothalamus is particularly relevant; it is affected by tissue levels of the sex steroid hormones, and loss of libido may result from lesions of it. Moreover, the hypothalamus controls the gonadotropic functions of the pituitary gland and thus prenatal development of genital organs, pubertal development, and the menstrual cycle. The medial preoptic area is involved in regulating sexual motivation and performance, and dopamine 6–8 may regulate penile erection at this level. Neurons from the paraventricular nucleus project to the thoracic and lumbosacral nuclei concerned with erection. Hypothalamospinal 9 projections are situated in the dorsolateral funiculus. Positron emission tomographic studies during normal male sexual activity have, however, shown increased regional blood flow in the 10 ventral tegmentum but not in the hypothalamus or limbic cortex.
Arousal Sexual excitement results from sensory stimuli or sexual ideation. The glans in both genders has a high receptor density: up to 80 to 90 percent of the nerve endings are free in the most superficial layer of mucosa. There are also corpuscular-type endings beneath the mucosal layer. The receptors are of two types: slowly adapting distally and rapidly adapting proximally, 11 with afferent C and A delta fibers. Surrounding the cavernous bodies are large nerve endings that resemble onions, with thick lamellae and a central nerve fiber connected to thick, myelinated nerve fibers. These nerve endings respond to deep pressure and vigorous movement. Receptors close to the cavernous bodies are influenced by the amount of engorgement of cavernous tissues so that touch may be experienced simply as touch or as a sexual stimulus depending on the degree of engorgement. Sensory information from the glans and the skin of the penis and clitoris is conveyed through bilateral branches of the pudendal nerve (the dorsal nerves of penis/clitoris). The afferents from the root of the penis (and from the anterior part of the scrotum) join the ilioinguinal nerve. Genital afferents synapse in the spinal cord via interneurons with both somatic and autonomic motoneurons; those afferents destined for supraspinal structures travel in the anterolateral funiculus. “Erotically colored” sensations from the genital region are conveyed by the spinothalamic pathways, and patients with selective damage to these tracts may complain of anorgasmia and ejaculatory failure. Orgasmic sensation is blocked by bilateral 12 anterolateral section of the spinal cord (cordotomy). Somatic sensory afferents deliver information on tactile sexual stimuli that, after synapsing in the sacral spinal cord, induce local sexual responses (i.e., erectile and glandular responses). Sensory information also passes to suprasacral regions and is operative in other reflex activity, leading to awareness of sexual excitation. Both thalamic and cortical areas receive sensory input from the genitals, and sexual feelings may be elicited when such areas are stimulated. In the primary sensory cortex the genitals are represented in the parasagittal area. Somatosensory input from other body parts (“erogenic zones”) may—subject to somatic and individual psychological factors and dependent on context—also lead to sexual excitement. Adequate sexual excitation can be achieved by stimuli delivered through cranial nerves. Although such excitation—similarly to that achieved by stimulation of sexual organs—should also be called reflex (because there may be little “intrinsic” contribution to the excitatory response), it has traditionally been called “psychogenic.” Regional cerebral blood-flow 13 measurements by positron emission tomography in eight men during visually evoked sexual arousal demonstrated activation of the inferior temporal cortex (a visual association region) bilaterally, as well as the right insula and inferior frontal cortex (regions processing sensory information and motivational state) and the left anterior cingulate cortex (involved in neuroendocrine function). Mental imagery is the “real” psychogenic activator. Cortical and subcortical structures related to the limbic system elicit erection when stimulated. Sexual excitement leads to a complex response of the autonomic nervous system, and a particular behavioral response that is different for different species and is in some psychosocial aspects culturally influenced in humans. Parasympathetic efferents from the S2 to S4 spinal segments, traveling through the pelvic plexus and cavernosal nerves, initiate erection. (The male erection has to be firm enough for vaginal penetration, and maintained
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throughout intercourse to bring about ejaculation, which in turn should deliver sperm to the 14 uterine cervix. ) Blood flow in the penile artery, or the corresponding artery in the clitoris, increases. The smooth muscle of the cavernosal sinuses in the penile corpora relax, and the helicine arterioles branching from cavernosal arteries selectively shunt blood flow to the lacunar spaces of the cavernosal bodies, filling them with blood. Subtunical venules are compressed so that corporeal venous return is restricted, resulting in increasing intracorporeal pressure. The pressure stabilizes at approximately systolic blood pressure, resulting in penile (and clitoral) tumescence and rigidity. Continued sacral parasympathetic activity maintains this 15 erection. The nerves of the corpora cavernosa have anatomical characteristics different from other nerves. The intracavernous nerves are located in fibrous tunnels into which numerous fibrous bundles are attached; this, it is thought, prevents compression of the nerves during 16 erection. Contraction of striated pelvic floor muscles, the ischiocavernous muscles in particular, brought about through pudendal nerve activity, is also important for maintaining 17 erection. In women, parasympathetic activity causes clitoral erection, engorgement of the labia, and vaginal lubrication. The lubrication during sexual arousal is due to transudation through the vaginal wall. Another source is secretion from paraurethral glands (emptying into the urethra). Increased vaginal blood-flow, lubrication, and erection of cavernous tissue in the clitoris and around the outer part of the vagina are the female homologues of the male erectile response; lubrication indeed occurs during rapid eye movement sleep in women. The response is 18 dependent on innervation and a normal estrogen level. In the periphery, the main proerectile transmitter is nitric oxide, which is co-localized with vasoactive intestinal peptide and acetylcholine; the main antierectile neurotransmitter is 9 norepinephrine. The same mechanisms are thought to be responsible for clitoral erection; nitric oxide synthetase activity has been demonstrated in nerve fibers within the human glans 19 and corpora cavernosa of the clitoris. Erections can still occur in men and animals after lesions of sacral cord and pelvic nerves. This is due to the “alternative” proerectile pathway mediated through the hypogastric nerve. This explains the so-called psychogenic erections of paraplegics with conus or cauda equina 20 lesions but preserved thoracolumbar segments. Similarly, women with injury to sacral spinal cord and an ability to perceive a pinprick21in the T12 to L2 segments may retain the capacity for psychogenic genital vasocongestion. In women with complete spinal cord injuries (SCIs) and preserved sacral segments, such a response is as a rule obtained only by manual genital 22 stimulation. Thus, the reflex–“psychogenic” dichotomy of the genital sexual response can be seen in both genders. Inhibitory influences on the sexual response also exist. A center in the rostral ventral medulla (in the region of nucleus paragigantocellularis) seems to mediate tonic inhibition of sexual 23 Descending reflexes by a direct serotonergic pathway descending to spinal centers. 24 projections from the brainstem raphe nuclei travel in the lateral funiculus. In nucleus paragigantocellularis a majority of the serotonergic 25 neurons project to the spinal cord and provide tonic inhibition of sexual reflexes in the rat.
Orgasm Seminal emission begins during arousal and, with continued sensory stimulation, orgasm is triggered, with ejaculation of the urethral contents resulting from the rhythmic phasic contractions of perineal and pelvic floor muscles. Ejaculation is effected by integrated sympathetic outflow from T11 to L2 segments traveling through the sympathetic chain and hypogastric plexus and along the pelvic and pudendal nerves, and by somatic efferents traveling through the pudendal nerves. Animal experiments have shown extensive 26 cross-innervation of the sympathetic nervous system. Although the predominant neural control of the male accessory sexual organs is sympathetic27(adrenergic and purinergic), the secretion of seminal fluid is under parasympathetic control. Sympathetic activity causes smooth muscle contraction in the seminal vesicles, vas deferens, and prostate to deliver seminal fluid to the posterior urethra; in the bladder neck to prevent retrograde ejaculation; and in the corpora cavernosa to cause detumescence. The latter “antierectile” activity is probably inhibited during erection through spinal coordination of reflex action. The female orgasmic response consists of rhythmic contractions of pelvic floor muscles, sometimes expulsions from the paraurethral glands through the urethra (so-called female
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ejaculation ), and rhythmic contractions of the uterus, fallopian tubes, and paraurethral 29 glands. Women may achieve orgasms by stimulation outside the genital region and probably do so more easily than men, but the most notable difference from men is that women may achieve multiple orgasms. Motor innervation of the pelvic floor muscles as well as the ischiocavernosus and bulbocavernosus muscles is conveyed through pudendal nerve branches from below. However, the most relevant motor innervation of the levator ani (“pelvic floor”) muscle is directly from the sacral plexus via the levator ani nerve. Electromyographic recording of the pelvic floor muscles in women during vibratory clitoral stimulation shows intermittent activity 30 associated with contractions on a background of continuous activity. During ejaculation in males, repeated bursts of electromyographic activity have been recorded that preceded and even followed expulsion of semen. The sensation of orgasm, however, is not dependent on pelvic muscle contractions. Men reported that orgasmic sensation began31before, and lasted longer than, bursts of electromyographic activity in the perineal muscles. Orgasm can be separated conceptually (but not easily physiologically) from emission and ejaculation. Ejaculation can be absent with an intact orgasm in lesions of the hypogastric plexus and under the influence of α-noradrenergic drugs. Anorgasmia is very rare in 32 otherwise normal men, but 13 percent of women between the ages of 18 and 26 years have never achieved orgasm, with the incidence declining to a minimum of 3 percent in women 33 between the ages of 51 and 64 years.
Topographic Anatomy of Nerves in the Pelvis The topographic anatomy of the peripheral nerves related to sexual function is important as preservation of these nerves at surgery is necessary for good postoperative results. The course of the pudendal nerve with its branches is relatively well appreciated, but the vulnerability of sexual (and other sacral) functions to lesions of autonomic nerves during abdominal and pelvic surgery is only slowly coming to be appreciated. In the pelvis and abdomen, autonomic structures related to genital innervation are situated in the retroperitoneal space. The superior hypogastric plexus is localized anterior to the aortic bifurcation at the level of the fifth lumbar vertebral body and sacral promontory between the common iliac arteries. It divides caudally into the right and left hypogastric nerves. Within the pelvis these nerves become the inferior hypogastric plexus, which is joined on each side by the pelvic nerves. In males, the inferior hypogastric plexus is lateral to the rectum, seminal vesicle, prostate, and the posterior part of the urinary bladder. The lesser and greater cavernosal nerves originate from the anterior part, are joined by fibers from the pudendal nerves, and pass below the pubic arch. In females, the inferior hypogastric plexus gives off uterine nerves, branches for the vagina and cervix, and connections with the paracervical plexus. Many questions regarding the neurophysiology of sexual function remain unanswered. The fine neural control of human sexual behavior by the cerebral hemispheres, brainstem, and spinal cord is far from elucidated.
Change in Sexual Function with Aging There is great variability of sexual functioning in the elderly; the frequency of intercourse as a rule decreases. Males need more time and stimuli to achieve erection and orgasm. They have a decreased sensation of impending ejaculation and decreased ejaculatory volume. 34 Their refractory period after detumescence is prolonged. Hormonal changes in menopause lead to decreased libido and thinning of the vaginal wall with decreased elasticity and lubrication. Decreased sexual thoughts and frequency of intercourse35after menopause have been more closely correlated with testosterone than estrogen levels. EVALUATION OF PATIENTS WITH SEXUAL DYSFUNCTION AND NEUROLOGICAL DISORDERS The breadth of the history and clinical examination will be tailored by the individual physician's interests and practice habits, but inquiry about sexual function should not be reserved for the male patient. With the advent of effective treatment for erectile dysfunction, many physicians take a pragmatic approach to treatment and inquire about little more than whether erectile dysfunction is present. However, there is more to sexual dysfunction than erectile dysfunction, and more to treating any dysfunction than simply giving a pill. Dysfunction in an individual patient—even in the presence of neurological disease—may be due (entirely or partially) to psychosocial, vascular, endocrine, or other causes.
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An informative account of the items to be assessed is provided in the following pages, along with a brief description of special investigations (although most of these are rarely applicable outside research protocols).
History The history should include details of neurological disease as well as any past history of cardiovascular, endocrine, psychological, and psychiatric disturbances. History of disorders of the sex organs, trauma and surgical procedures, the use of prescription drugs, smoking and alcohol habits, and possible drug abuse should also be elicited. The patient's sexual expectations, needs, and behavior should be defined as well as any misconceptions. Before diagnosing dysfunction of sexual organs, the level of actual desire should be established. The term hypoactive sexual desire disorder (HSDD) is used to define a persistent or recurrent reduction in desire for sexual activity, alone or with a partner, with inability to respond to sexual cues that would be expected to trigger a sexual response; symptoms need to be associated with personal distress. If present in men, it may be associated with impotence; in women it often occurs with the female sexual arousal disorder (FSAD), which is a persistent or recurrent inability to attain or maintain sufficient sexual excitement that causes personal 14 distress. Men should be asked about erectile function (the occurrence of nocturnal erections, morning erections, and erections evoked by genital, visual, auditory, or psychogenic stimuli) and women about vaginal lubrication. The nature of ejaculation should be determined, and in particular whether it is premature, retarded, absent, or dribbling (i.e., emissions occur through the urethra without the activity of pelvic floor muscles). Retrograde ejaculation, described as “dry ejaculation,” means that ejaculum has entered the bladder. Finally it should be clarified whether the patient can achieve orgasm, and the quality of orgasmic sensations and experiences should be noted. In some circumstances it may be helpful to interview the patient's partner. Formal questionnaires can be used to obtain standardized information on male sexual 36,37 These questionnaires mostly focus on erectile dysfunction (the persistent38 function. inability to develop and maintain an erection sufficient for satisfactory sexual activity). The 39 impact on quality of life is covered by another inventory. Questionnaires have also been formulated to assess sexual function in women, for instance the female sexual function 40 questionnaires are not strictly necessary for assessment of individual index. Formal 41 patients.
Clinical Examination Sexual development, body length and weight, changes in pigmentation and body hair, and the presence of galactorrhea should be noted. The external genitalia should be examined. Palpation of peripheral pulses (arms, legs, penis), auscultation of the heart, and blood pressure measurement are recommended. A standard neurological examination will reveal any signs of underlying neurological disease. Particular care should be given to inspection of the lower back (for nevus, hypertrichosis, or sinus), the feet (for deformity or muscle atrophy), and the sacral segments. The bulbocavernosus muscles can be palpated in the male and tested for voluntary contraction (“move the penis”) and reflex contraction. Anal sphincter and levator ani tone, voluntary contraction, and reflex contraction can be examined in both sexes by rectal examination. The cremasteric reflex (the L1 segment) and the bulbocavernosus and anal reflexes (S2 to S4/5 segments) should be tested. Neurophysiological tests are direct extensions of the clinical examination.
Investigation of Genital Reaction and Arousal In men, spontaneous and physiologically induced erection can be studied with a variety of techniques. Spontaneous nocturnal penile tumescence and rigidity can be measured in the sleep laboratory using mercury strain gauges (measuring penile expansion), visual inspection, measurement of buckling force (for assessment of rigidity), and polygraphic confirmation of sleep phases. Continuous monitoring of nocturnal penile tumescence and rigidity can be obtained by a rigidometer during normal sleeping conditions at home and also during daytime napping or in the awake, sexually stimulated state. Various low-cost screening 42 tests for nocturnal penile expansion have been proposed, but their validity is questionable. Testing for nocturnal erections, however, does not reliably distinguish psychological from central nervous system (CNS) causes of erectile dysfunction, as has been suggested by
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The afore-mentioned testing remains mainly of research interest. An intracorporeal penile injection of a vasoactive substance, such as prostaglandin E1, will induce an erection (in the absence of major vascular pathology), thus strengthening the suspicion of a neurogenic or psychogenic cause of erectile dysfunction. Intracorporeal injection of vasoactive agents has been proposed as an established diagnostic tool in patients undergoing assessment for possible neurogenic erectile dysfunction and is safe when performed by experienced 44 physicians, with an acceptable complication rate. Suspected vasogenic erectile dysfunction may require the testing of penile vasculature (blood pressure and vascular competence) by a urologist. The purpose of testing should always be defined: pharmacotesting may be sufficient for the majority of patients, and invasive tests 45 reserved for those in whom surgery is contemplated. Sexual arousal in women has not been studied extensively, and research methods have not yet been translated into clinical practice. Direct or indirect methods can be used to measure blood-flow changes in the labia and vagina. Noncontrast dynamic magnetic resonance 46 imaging (MRI) can assess female sexual arousal quantitatively. Vaginal vasocongestion to erotic stimuli may be unaccompanied by erotic feelings, and subjective indices should 47 therefore be obtained when physiological measurements are made.
Investigations of Neurological Function Special devices and algorithms can be used for quantifying sensory perception on the genital organs and in the perineum. The measurement of vibratory perception (biothesiometry; measuring the vibration perception threshold) on the penis may be48helpful in diagnosing sensory neuropathy, and has also been applied in female patients. The vibration perception threshold on the penis (glans and shaft) in neurologically healthy men is similar to that of the feet, whereas in females this threshold (best measured on the clitoris, labia majora, and 49 in the hands. Tests evaluating small-fiber function (e.g., testing perineum ) is the same as 50 for penile thermal sensation ) may be more informative about the neural control of erection. Several neurophysiological tests may be useful for assessing sacral or suprasegmental lesions (Table 34-1). Tests measuring conduction through somatic nervous pathways (motor, sensory, and reflex) might be expected to be useful because most lesions should involve both somatic and autonomic neural pathways, and abnormalities obtained on testing the former could be extrapolated to the latter. Even so, these tests are sensitive only to 51,52 demyelination and not to axonal lesions, which predominate in clinical practice. Click here to view this table.... Electromyography may demonstrate the activation patterns of striated muscles but is mainly used to differentiate normal from denervated (reinnervated) muscle, discussed in detail 51,52 Penile electromyography, despite some controversy about the source and elsewhere. 53 54 nature of the signal, 55seems to be a promising investigative technique that has also been applied to the clitoris. The lumbosacral sympathetic system may be tested by the sympathetic skin response from the perineum (and penis). Recordings should be made both in the limbs and perineum and also combined with somatic electrophysiological measurements in order that generalized and 56 localized involvement and somatic and autonomic neuropathy might be distinguished. The role in clinical practice of these and the other tests shown in Table 34-1 is limited. In terms of experience and available normative values, only electromyography (in muscles of the lower sacral myotomes) and the recording of sacral reflex responses and somatosensory evoked responses (SEPs) to pudendal nerve stimulation should be widely available 57 clinically. The pa- tients with possible or probable neurogenic sexual dysfunction in whom such testing might yield a result relevant for diagnosis and prognosis (though rarely important for decisions on therapy) are those with suspected lesions in the peripheral sacral reflex arc. In these patients, support for the presence or absence of a neurological lesion can be obtained; this may have medicolegal implications. It is necessary to point out, however, that the relationship between a neurological lesion (or, for that matter, any neurophysiological test abnormality) and sexual dysfunction is complex. In a recent study of women with multiple sclerosis, for instance, latency of pudendal (and 58 tibial) somatosensory evoked potentials failed to predict the extent of sexual dysfunction.
Hormone Measurement
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When patients with sexual dysfunction have symptoms or signs indicating endocrine dysfunction, hormone assays—or rather, endocrinological consultation—may be necessary. The hormones to be studied depend on the circumstances (sex, age, and onset and nature of symptoms). SEXUAL DYSFUNCTION IN PATIENTS WITH NEUROLOGICAL DISEASE Sexual dysfunction, such as lack of libido (in both sexes), erectile dysfunction and disturbances of ejaculation (in men), and deficient lubrication, dyspareunia, and problems 59 with orgasm (in women), is not uncommon in the general population. In patient populations with disorders of the CNS, the prevalence of sexual dysfunction is reportedly higher, although few comparative studies have been done.
Head and Brain Injuries Some cognitive impairment, personality change, and sensorimotor disability often remain after traumatic brain injury and may be accompanied by sexual dysfunction as a consequence of either the cerebral lesion or psychosocial factors. Loss of empathy and 60 focused attention are not rare. Among patients with closed-head injury admitted for 24 hours61or more, significant sexual dysfunction was found in 50 percent over a 15-year time may span. 62Decreased or increased sexual desire, erectile failure, and retarded ejaculation 63 In occur, perhaps in part as a consequence of post-traumatic pituitary dysfunction. 64 women, endocrine abnormalities are sensitive predictors of sexual dysfunction. Frontal and temporal lesions seem to result more often in sexual disturbances than parieto-occipital lesions. Hypersexuality, disinhibited and inappropriate sexual behavior, sexually aggressive behavior, and changes in sexual preference sometimes follow basal frontal and limbic brain 65 anterior temporal lesions may result in the injury and may lead to sex offences. Bilateral 66 Klüver–Bucy syndrome with hypersexuality ; pansexuality (i.e., sexual drive that is directed 6 not only toward humans but also toward animals and inanimate objects) may occur.
Cerebrovascular Disease Decline in intercourse after stroke is not unexpected; whereas 11 and 29 percent of men and women, respectively, reported no coital activity before stroke, 64 and 54 percent did so 67 afterward. The best predictor of decreased sexuality between partners is the degree of dependence in activities of daily living. From various studies, about 75 percent of patients who were sexually active before the stroke report a subsequent decrease in coital 68–70 frequency. A decline in sexual interest67–69 commonly follows stroke. Many men (50% to 65%) have erectile In one study, nocturnal erections 2 months after stroke were dysfunction after a stroke. 70 impaired in 55 percent of patients. Orgasmic dysfunction after stroke is common in men. Whereas most men were able to ejaculate before a stroke, only 29 percent could do so 71 67 afterwards in one study, and similar findings have been reported by others. Changes also occur in women. In one study, 63 percent of women reported normal vaginal lubrication before but only 29 percent did so after stroke. Similarly, only 34 percent failed to 67 achieve orgasm before stroke but 77 percent did so afterward. However, in another study, the ability to achieve 68 orgasm declined in only one third of women who remained sexually active after a stroke. The prevalence of major sexual dysfunction (decrease in libido and frequency of intercourse) is reportedly significantly greater after right than left hemisphere stroke in men with unilateral 72 lesions. Involvement of the nondominant hemisphere, especially the parietal lobe, was more often associated with a decline of desire. Hemihypoesthesia is associated with decreased 73 Hypersexuality may also occur sexual ability, possibly due to the loss of erogenous zones. 74–76 after a stroke causing frontal or temporal lobe damage. Nevertheless, among 50 men who had experienced a stroke, 82 77 percent regained the ability to have erections, with an average delay of 7 weeks in one study ; in another, both68erections and ejaculation returned to approximately 60 percent of men 8 months after stroke. Sexual problems after a stroke may be complicated by lack of coping. Diminished sexual contact relates primarily to the patients' fears of inadequacy. Cognitive impairment may also play a role. Patients and their partners may avoid sexual intercourse out of concern that another stroke may be precipitated. The heart rate during sexual activity may exceed 180 beats per minute in men and reach similar values in women; the workload during sexual activity is similar to that of climbing stairs or walking briskly. Although the exact risk of stroke
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during sexual activity is not known, it seems to be low. Patients and their partners may thus be reassured that, in resuming sexual activity, the gains in most instances outweigh any slight risks. These issues should be addressed in counseling.
Epilepsy Epilepsy is associated with sexual problems, more often in men than women. Various types of abnormal behavior, hypersexuality, and, most commonly, hyposexuality have been reported, particularly in temporal lobe epilepsy. Satisfaction with life and sexuality is better in patients who are seizure free. The extent to which social and psychological factors bear on sexual dysfunction is not clear. It is helpful to6determine whether disturbances relate to seizures or occur during the interictal period. Seizures and Sexual Symptoms Arousal and intercourse can provoke an epileptic attack through several pathophysiological mechanisms, sexual phenomena may occur as part of an epileptic seizure, and sexual behavior may change in epileptic patients. Hyperventilation can provoke generalized epileptic seizures and commonly accompanies sexual activity, thus provoking seizures. Sexual 79 fantasies as well as genital stimuli (masturbation) or orgasm may trigger reflex epilepsy. Sensations in the genital organs may be manifestations of a partial epileptic seizure arising from a genital sensory cortical area. Motor symptoms such as erection and ejaculation or the sensory experience of an orgasm may also occur. Such events may be experienced by patients as sexual or nonsexual. Pelvic sexual movements, as a part of epileptic automatisms, or compulsive masturbation in front of others may occur during or after a seizure. Complex sexual experiences may occur during an epileptic seizure in patients with complex partial epilepsy, most often in patients with temporal lobe lesions. Sexual 6 automatisms may also occur with frontal lobe lesions. Deviant sexual behaviors (e.g., exhibitionism, fetishism, or violent sexual behavior) have been related to epilepsy and interpreted as ictal phenomena. Only a few cases have been reported, but the episodic nature of the behavior and its occasional disappearance after treatment favors a causal connection between the behavior and the epilepsy. Partial complex seizures usually occurred, and lesions were present in one or both temporal lobes. Deviant behavior sometimes correlates with the presence of continuous seizure discharges in the 79 electroencephalogram (psychomotor status). Interictal Phenomena Patients with epilepsy, regardless of gender, often report a loss of sexual desire, reduced sexual activity, or80,81 inhibited sexual arousal; the prevalence of these complaints varies in Sexual interest is more reduced in patients with right than left temporal different studies. lobe epilepsy. In men with temporal lobe damage and epilepsy, however, desire is sometimes preserved but erectile function is impaired. Other disturbances of sexual function, such as ejaculatory dysfunction, decreased sexual satisfaction, and reduced sexual fantasies, dreams, and initiatives may occur in patients with complex partial epilepsy and a mesiobasal 81 delusions of a temporal spike focus, and nocturnal tumescence may be lost. Paranoid 79 sexual nature (such as of being violated) occur in some epileptic patients. Sexual function is rarely restored by surgery for epilepsy, but this has been little studied. Antiepileptic drugs, especially the older agents (phenytoin, phenobarbital, primidone, carbamazepine, and valproate), may lead to hormonal changes (particularly increased estradiol and decreased free testosterone levels in men), as well as decreased sexual desire 82–84 Menstrual irregularities are common among women with and performance in both sexes. 85 86 epilepsy. Antiepileptic drugs may influence morphology and motility of spermatozoa. The effect of the newer anticonvulsant drugs on sexual function is claimed to be less (for 87 instance, for oxcarbazepine and lamotrigine).
Parkinson's Disease Libido is commonly decreased in patients with Parkinson's disease, especially women, with 88 resulting distress to their partners. Decreased libido, however, is not directly coupled with the severity of disease. Sexual dysfunction is common even in young male parkinsonian patients. In comparison with age-matched controls, in whom the prevalence of impotence was 37.5 percent, the89corresponding number in patients with Parkinson's disease was 60 percent in one study. An inability to maintain erections occurs in approximately half of
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parkinsonian men ; nocturnal and morning erections may be absent. Many men cannot 88 ejaculate or reach orgasm, but premature ejaculation has also been reported. As for women with parkinsonism, vaginal tightness, involuntary urination, anxiety, and inhibition are more prevalent than in matched controls, and these patients are more likely to be dissatisfied 91 with the quality of their sexual experiences. The mechanisms behind sexual dysfunction in parkinsonian patients are not well understood. Studies of bladder and bowel function have demonstrated a high frequency of bladder detrusor hyperreflexia and paradoxical contractions of the striated sphincter muscles during 92 defecation, suggesting specific autonomic nervous system involvement. Depression is common in parkinsonian patients and may affect sexual activity; its treatment may further compromise sexual function. Tremor may be enhanced during sexual arousal, thereby limiting the patient. Muscle rigidity and bradykinesia may also make sexual activities more difficult and may be worse in the late evenings if dose scheduling is aimed at favoring daytime activities. Dopaminergic treatment may result in an apparent increase, or normalization, of libido without corresponding improvement in parkinsonism. A true increase in libido may occur as 93 an adverse reaction to treatment with levodopa. Spontaneous erections have been reported in patients receiving levodopa. Apomorphine treatment may result in erections and benefits 94 sexual function. Deep brain stimulation of the subthalamic nucleus has been found to have a positive influence on sexual well-being in Parkinson's disease, in that male (but not female) 95 patients were reportedly more satisfied with their sexual life.
Multisystem Atrophy Erectile failure is very common among patients with multisystem atrophy of both the 96 striatonigral and olivopontocerebellar types. In a retrospective study of 46 men with a clinical diagnosis of multisystem atrophy, 96 percent had erectile dysfunction at the time of diagnosis; it occurred alone as the first symptom in 37 percent and was part of the presenting 97 symptom-complex in 59 percent. Erectile dysfunction usually began several years before the onset of other neurological symptoms, often in patients in their early 50s or late 40s. By the time of diagnosis, 30 percent of male patients were also unable to ejaculate. It is not clear why erectile dysfunction is such an early symptom in this disease. The pathology of multisystem atrophy does involve rather selectively certain autonomic nuclei including Onuf's nucleus, which innervates both the urethral and anal sphincters. In consequence, electromyographic98,99 examination of either the urethral or anal sphincter often The reason for the selective involvement of anterior reveals significant abnormalities. horn cells in this nucleus is unknown, as is the reason that they are spared in motor neuron disease or amyotrophic lateral sclerosis.
Other Extrapyramidal Disorders In families with Huntington's disease, members who ultimately develop the disease tend to have more children than those who are spared. Approximately 10 percent of patients with Huntington's disease have increased sexual activity, sometimes associated with mania or hypomania. Habitual promiscuity and marital infidelity may be early or initial symptoms of the disease. However, patients may have difficulty in becoming sexually aroused. Paraphilias 100 such as sexual aggression, exhibitionism, and pedophilia may occur. 101
Disinhibited sexual behavior is common in patients with Gilles de la Tourette's syndrome, 102 and increased sexual activity has been reported in patients with Wilson's disease.
Hypothalamopituitary Disorders Hypothalamopituitary dysfunction is usually caused by a pituitary adenoma; less common types of tumors in this region include craniopharyngiomas, meningiomas, optic gliomas, hypothalamic hamartomas, and metastases. Three fourths of patients with hypothalamopituitary tumors have decreased or absent libido at the time of diagnosis. The figures are higher for large tumors that extend into the suprasellar region than for intrasellar tumors. Decreased libido (related to low serum testosterone levels) is also the first symptom 103 in most men with small pituitary tumors and hyperprolactinemia but is not a symptom for which patients commonly seek medical advice. Hence, the diagnosis is usually postponed until other symptoms appear, and it may be as long as a decade after the onset of changes in 104 sexual behavior before the pituitary tumor becomes apparent. Erectile dysfunction is also
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but, because of reduced sexual interest, is less distressing.
Most women with hypothalamopituitary disorders have amenorrhea. Women with hypoprolactinemia reportedly complain more commonly of loss of sexual desire than those 105 with normal serum prolactin levels. A low serum testosterone level in patients with erectile dysfunction does not necessarily signify a space-occupying lesion in the hypothalamopituitary region: a neuroimaging study of 164 impotent males and abnormal testosterone levels detected potentially serious lesions (pituitary lesions greater than 5 mm or any hypothalamic lesion) in 11 men, including 5 pituitary106 microadenomas (5 mm or more), 4 pituitary macroadenomas, and 2 hypothalamic lesions.
Multiple Sclerosis Disturbances of sexual function are common in patients with multiple sclerosis, regardless of 107 gender. Most such disturbances relate to spinal cord involvement by the disease and are generally, but not always, associated with urinary symptoms and lower limb involvement. Sexual dysfunction has also been correlated with destructive lesions in the pons, as detected 108 by magnetic resonance imaging, in patients with relapsing-remitting multiple sclerosis. 109
Although erectile dysfunction is rare initially, it becomes more common with increasing spinal cord involvement and43is a frequent problem, with estimates of its prevalence varying between110 35 and 80 percent. Interest in resuming sexual activity persists in 75 percent of patients. Spontaneous improvement in erectile function sometimes occurs. 111,112
and are often Problems with ejaculation are also frequent in men with multiple sclerosis coupled to the erectile dysfunction. Anorgasmia has been correlated with evidence on magnetic resonance113 imaging of brainstem and corticospinal abnormalities as well as with total area of lesions. In women, decreased lubrication and sensory disturbances involving the114genital region (hypoesthesia, hyperesthesia, and different types of pain) are common. Sacral-segment dysesthesias may be so severe that patients are unable to bear direct genital or nongenital contact. Electrodiagnostic data—cortical evoked potentials of the dorsal 49 nerve of the 115 clitoris —as well as measurement of vibratory thresholds in the clitoris suggest that pudendal somatosensory input is necessary for female orgasmic function, and that this may be disturbed even in early, mild multiple sclerosis. To compensate for such a loss, more direct stimulation of the anterior vaginal wall is recommended. Some patients with multiple sclerosis experience decreased libido; this problem has not been studied in depth, however, and emotional and cognitive disturbances may be contributory. Increased sexual desire occasionally constitutes a problem. Other symptoms related to multiple sclerosis, such as fatigue, depression, cognitive dysfunction, spasticity in the lower limbs, urinary and bowel disturbances, and the use of aids to manage incontinence, can inhibit sexuality, as can paroxysmal motor and sensory disturbances triggered by sexual intercourse.
Lesions of the Spinal Cord A spinal cord injury or lesion may lead to major neurological deficits that in men initially often overshadow sexual disturbances such as a loss of normal erectile and ejaculatory function and of the ability to procreate naturally. For women, the resulting sexual dysfunction is often regarded as less limiting but is definitely important. The effects on vaginal lubrication and 29 orgasm relate to the level and completeness of the lesion. After complete cord transection, reflex function in all segments of the isolated spinal cord is completely lost (spinal shock) for a variable period lasting from a few hours to several weeks. Incomplete or slowly developing lesions may be associated with little or no spinal shock. The male genital reflexes (reflex penile erection and the bulbocavernosus and cremaster reflexes) are abolished or profoundly depressed during the period of spinal shock, and erectile and ejaculatory functions are abolished. Because of the occurrence of spinal shock, it is usually impossible to predict the extent or severity of sexual dysfunction, including whether erectile and ejaculatory functions will recover in men within the first weeks after injury. With complete lesions of the spinal cord, the penis may become enlarged and semierect from passive engorgement of the corpora cavernosa due to paralytic vasodilatation after the interruption of vasoconstrictor fibers in the anterolateral tracts of the spinal cord. As spinal shock subsides, reflex activity and spasticity may develop in the lower extremities and reflex functioning is
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regained of the bladder and bowels. In patients with upper motor neuron lesions, the erection reflex becomes part of the autonomic function of the isolated cord and may appear with tactile stimuli of various types and intensity, including stimuli to the penis, independent of cerebral participation and before the reflex responses of skeletal muscles are fully 116 developed. With complete destruction of the genital reflex center in the sacral part of the conus medullaris, reflex erection and lubrication are usually lost and the striated ejaculatory muscles are paralyzed. With spinal cord lesion between the level of the lower thoracic segments and the conus, both cerebral and reflex erection and lubrication may be possible, even though the patient cannot feel the sexual organs. Loss of sacral sensation does not necessarily imply anorgasmia. Although ejaculatory contractions cannot be felt when a complete lesion of the spinal cord exists above the conus, autonomic components of the orgasm can be experienced. Hyperesthesia often occurs just above or at the level of the spinal cord lesion, and this may be used as an erogenous zone. Although bladder, bowel, and sexual dysfunction often coexist, this is not necessarily the case; sexual function may be preserved in spite of severe neurogenic bladder dysfunction, presumably owing to preservation of the thoracic sympathetic outflow. 6
A meta-analysis of 24 studies of more than 2,500 men with SCIs showed that a median of 80 percent (range, 54% to 95%) reported spontaneous erections. The percentage of SCI men reporting ejaculation with out therapeutic assistance was much lower (median, 15%; range, 0% to 52%). Fewer (26%) of the patients with complete lower sacral lesions had erectile capacity than those with complete upper cord lesions or incomplete lesions at any level (90% to 99%). However, there is much individual variation, and an accurate prognosis for future sexual function may not be possible in individual cases. Indeed, in one study no 117 significant correlation of the level and completeness of SCI with sexual function was found. Patients with incomplete SCI retain the ability for psychogenic genital vasocongestion if pinprick sensation is preserved in the21,22 T11 to T12 segments; only reflexogenic responses are After SCI, women menstruate and are able to obtained in those with complete SCI. conceive and give birth, although those with a paralyzed pelvic floor are at risk for overstretching and perineal tears. Autonomic hyperreflexia (Chapter 8) may occur in those with a lesion above T6–7. Preoccupation with future sexual performance occurs early after SCI, and it may be easier for men to accept motor deficits than sexual problems. Sexual readjustment after SCI depends 116 on the individual, on previous sexual habits, and on the cooperation of partners. In one study, sexual readjustment was closely and positively correlated with a young age at injury, frequency of 117 sexual intercourse, and willingness to experiment with alternative sexual expressions. Physical and social independence and a high mood level were further positive determinants of sexual adaptation after injury. The ability to ejaculate by masturbation or sexual intercourse is impaired in most men with severe SCI; 118 consequently, pregnancies caused by such men are rare without medical intervention. The semen of men with SCIs is characterized by small volume, low sperm count, and low sperm mobility. Reduced fertility cannot therefore be attributed completely to 119 ejaculatory dysfunction. Ejaculation can be provoked in many paraplegic men through vibratory stimulation or electrostimulation. Repeated vibration-induced ejaculations result in increased volume of semen, a larger number of motile sperms, and improved sperm penetration capacity. Insemination with autologous semen obtained in such a way has resulted in pregnancies. Collection of semen very early after the SCI makes it possible to 6 store semen of good quality for future insemination. Orgasms may occur in men with SCI but may differ from those that occurred before the 120 injury. Women with SCI may also achieve orgasm; indeed, some women with apparently complete lesions can do so, perhaps because of afferents from the cervix traveling with the 121 with SCI than in normal subjects, but vagus nerve. Latency to orgasm is greater in women 122 the descriptions of orgasm are indistinguishable.
Cauda Equina Lesions and Lumbar Stenosis Although complete lesions of the cauda equina damage the parasympathetic erectile pathways to the penis, a number of men (approximately one fourth) are still able to achieve an erection psychogenically, mediated perhaps by a sympathetic erectile pathway involving the hypogastric plexus. There are also ejaculatory disturbances (delayed or absent, but occasionally premature ejaculation), penile sensory loss, paresthesias, dysesthesias, and even pain syndromes. In a group of men with cauda equina lesions of differing causes and
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variable severity, only 15 percent reported normal sexual function. Women report loss of erotic sensation, dyspareunia, loss of lubrication, loss of feeling during vaginal intercourse, difficulties in achieving orgasm, and changes in the feeling of orgasm. Involvement of lower sacral nerve roots by any process can lead to “positive” as well as “negative” functional symptoms. Sensory symptoms and deficits involving the genitals are not necessarily accompanied by impotence. Spontaneous erections on walking have been 124 described as a consequence of symptomatic lumbar stenosis ; other postures may induce erection in afflicted men. Laminectomy solves the problem.
Spinal Malformations Any type of dysraphism may be associated with neurological symptoms that may include sexual disturbances, but data from large patient populations are lacking. Meningomyelocele as a rule gives rise, among other disturbances, to sexual dysfunction, depending on the severity of the malformation. Some boys have no genital sensations at125all, with loss of erection and orgasm; some have isolated126 erections without emission. Loss of genital sensations is the major complaint in girls. Reduced libido and impotence have been reported in patients with Arnold–Chiari malformations; the onset of sexual symptoms is generally after the development of other 127 neurological disturbances.
Localized Nerve Lesions Trauma may be the cause of pudendal nerve injury, leading to loss of penile sensation, dysesthesias, pain syndromes, and dribbling ejaculation because of perineal muscle denervation. Among long-distance cyclists, it was found in one study that 22 percent had penile sensory symptoms and 13128 percent had erectile dysfunction; symptoms were transient but persisted for up to 8 months. Erectile dysfunction may follow pelvic fracture, especially when urethral injury has occurred, owing to involvement of the neurovascular bundles. The peripheral autonomic nerves to the genitalia may be injured also by surgical procedures, leading to erectile and ejaculatory dysfunction in men and loss of lubrication in women. The sympathetic thoracolumbar fibers may be injured by retroperitoneal lymph node dissections. Pelvic plexus and cavernosal nerves may be injured by such operations as abdominoperineal resection for carcinoma, hysterectomy, radical prostatectomy, or sphincterotomy, thus significantly impairing the quality of life in patients after otherwise successful surgery. Surgeons are increasingly aware of the need to preserve relevant neural129 tissue even during radical surgery and have developed “nerve-sparing” operations. Erectile dysfunction has also been reported after injection of sclerosing agents to131treat 130 hemorrhoids and after subtrigonal injections to treat a hypersensitive bladder.
Diabetic Polyneuropathy Diabetes is the most common cause of polyneuropathy in developed countries, and the most frequent type of neuropathy is the distal symmetric sensorimotor variety, in which small nerve fibers may be involved earlier than large fibers. This polyneuropathy is frequently accompanied by autonomic involvement, and dysautonomia is occasionally the predominant clinical presentation, with bladder, bowel, and sexual dysfunction. Such severe autonomic involvement is seen almost exclusively in insulin-dependent diabetes. Hyperglycemia, and 132 some glycosylation products promote inactivation133 of nitric oxide and there seems to be a selective nitrergic neurodegeneration in diabetes. Further discussion of diabetic neuropathy is provided in Chapter 21. Sexual dysfunction, especially erectile dysfunction, is common in diabetic men. Erectile dysfunction has been reported in 9 percent of diabetic men aged 20 to 29 years, rising to 95 percent of diabetics by age 70. Overall the incidence in a population of 9500 diabetic men (20 to 70 years old) was 38 percent. Patients had the onset of impotence within the first 10 years 134 of their disease in 50 percent of cases. Men with diabetic polyneuropathy have fewer sleep-related erections, shorter tumescence time, diminished penile circumference increase, 135 and weaker penile rigidity than do nondiabetic men. Erectile dysfunction is usually considered neurogenic when there are other signs of neuropathy, although alternative etiological possibilities cannot be excluded.136There is little correlation with neurophysiological abnormalities in peripheral nerve function, although bulbocavernosus and urethroanal
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reflex latencies and penile137 (pudendal) evoked potentials are more often abnormal in impotent than potent diabetic men. Neurophysiological testing of pudendal nerve function, however, is not more sensitive in diagnosing neuropathy in impotent diabetics than limb nerve 138 conduction studies. In patients with cystopathy, retrograde ejaculation is sometimes an additional problem; failure of normal closure of the bladder neck by sympathetic activation during ejaculation leads to semen passing retrogradely into the bladder. 139
Among women, those with more diabetic complications have greater sexual dysfunction. A correlation in diabetic women of sexual dysfunction with the presence of neuropathy has 140 141 been found in some studies but not in others. Reduced sexual desire has been reported in 26 percent of women with insulin-dependent diabetes; 22 percent had decreased vaginal lubrication, and 10 percent had decreased capacity to achieve orgasm. In total, the figure for sexual dysfunction was 40 percent, compared with only 7 percent among age-matched controls. Vibration perception thresholds (hands and clitoris), reduced sweating of feet, increased gustatory perspiration, constipation, and incontinence correlated with sexual 142 dysfunction.
Chronic Renal Failure 143
The incidence of erectile dysfunction approaches 100 percent in patients with uremia. Male patients on hemodialysis have a similar prevalence of erectile dysfunction (71%) as patients 144 on peritoneal dialysis (80%). Neuropathy is not the only possible cause; primary hypogonadism has been reported, and involvement of the testes also leads to low sperm counts and azoospermia. However, even in nondiabetic men with erectile dysfunction who were undergoing hemodialysis, the etiology was usually neuropathic rather than 145 desire, endocrinological or vascular. Among women with uremia, one half have decreased146 and one third have decreased lubrication; dysfunction improves after transplantation. The prevalence of sexual dysfunction after transplantation remains high; after successful transplantation improvement of neuropathy can be expected, but revascularization of the donor kidney may diminish blood flow to the genitals. Thus, varying effects on erectile 147 On the whole, there is a tendency (dys)function after transplantation have been reported. 148 for preexistent erectile dysfunction to improve.
Other Acquired Polyneuropathies Autonomic dysfunction, including erectile dysfunction, occurs in other peripheral neuropathies, including those due to infectious agents, chemical toxins, secondary 150 149 amyloidosis, prescription or street drugs, and vitamin B1 or vitamin B12 deficiency, or those that are parainfectious or paraneoplastic. In one study of 341 consecutive men with erectile dysfunction, neurophysiological evaluation revealed a polyneuropathy in 38 percent of 151 the diabetics and 10 percent of the others. Autonomic involvement may lead to erectile dysfunction in the Guillain–Barré syndrome and was actually reported by Guillain himself in his original description of the disorder that bears 152 his name. Bladder, bowel, and sexual problems may also occur in patients with chronic inflammatory demyelinating polyneuropathy but are less common. Reversal of erectile 153 dysfunction due to penile sensory loss may follow effective treatment. In persons infected with the human immunodeficiency virus (HIV), peripheral nerve disorders occur commonly and may be accompanied by a dysautonomia. In one series of 17 consecutive patients with acquired immunodeficiency syndrome (AIDS), 9 had erectile 154 dysfunction or decreased libido. In another report, not only erectile dysfunction but also 155 ejaculatory disturbances were reported in patients with AIDS or AIDS-related complex. Slowed sural and dorsal penile sensory conduction velocities suggest that neuropathy is 156 important in the genesis of erectile dysfunction in HIV-positive men. Counseling and treatment may be especially important in AIDS patients with sexual dysfunction, since the use of condoms often precipitates the problem, and men are therefore unwilling to use protection.
Hereditary Polyneuropathies There is little information about sexual dysfunction in patients with hereditary polyneuropathies. Erectile dysfunction and ejaculatory problems may certainly occur 158 in 157 syndrome. patients with hereditary sensory neuropathy and Charcot–Marie–Tooth 159 Erectile dysfunction also occurs in primary amyloidotic polyneuropathy and
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160
adrenoleukodystrophies. Not surprisingly, men with hereditary motor and sensory neuropathy and 161 proven involvement of the pudendal nerves may nevertheless have normal sexual function.
Amyotrophic Lateral Sclerosis 162
Sexual function is normal in men with amyotrophic lateral sclerosis. Even when severe weakness makes intercourse impractical, erection and ejaculation are possible through partner masturbation, and the sensation of orgasm may be experienced as normal. These factors are highly relevant with regard to the patient's quality of life and may be important in counseling patients and their partners.
Hereditary Neuromuscular Diseases The early onset and progressive course of certain hereditary neuromuscular diseases may restrict psychosocial and psychosexual development and limit sexual activity. Nevertheless, the capacity for sexual satisfaction remains unaffected in many patients who survive to adulthood and consequently has led to more awareness of the need for appropriate counseling. In Kennedy's syndrome (X-linked bulbospinal muscular atrophy), gynecomastia is common and testicular atrophy, decreased libido, and erectile dysfunction may occur. Hypogonadism, diminished163,164 libido, and erectile dysfunction occur in certain muscular dystrophies (myotonic 165 Becker dystrophy, and autosomal progressive external dystrophy, 166 and amenorrhea may also occur in certain mitochondrial ophthalmoplegia ). Impotence 167 encephalomyopathies.
Adverse Sexual Reactions to Medications Many medications, such as antihypertensive and antidepressant agents, have adverse effects on sexuality. Reports on such adverse reactions as reported to the World Health 168 Organization centers for drug monitoring have been published. At least until recently, however, the occurrence of sexual dysfunction was rarely monitored in clinical drug trials. Further discussion of this aspect is beyond the scope of this chapter. THERAPY Sexual dysfunction associated with neurological disease often increases patients' distress. Discussion with patients and partners about their sexual life should be part of any rehabilitation strategy. In all instances, drug regimens should be reviewed for possible effects on sexual function. Sexual education, counseling, and specific suggestions about therapeutic methods are important, and should be provided by the treating physician. In a limited number of patients, referral for psychotherapy may be indicated. Methods for sexual rehabilitation in 169 the context of neurological disorders have been described.
Treatment of Neurogenic Erectile Dysfunction The development of drug treatments by the oral and intracavernous routes has revolutionized the outlook for men with erectile failure. As a last resort, surgical treatment is also possible. All these treatments are also available for neurologically impaired patients. Oral Agents Specific phosphodiesterase-5 inhibitors have been developed to treat erectile dysfunction, the first being sildenafil, which has now been used for more than 9 years by several million men. The selective inhibitors of type 5 cyclic guanosine monophosphate phosphodiesterase augment the nitric oxide–mediated relaxation pathway in penile tissues by increasing available cyclic guanosine monophosphate in the corpus cavernosum. These medications therefore do not cause erection but enhance the response 170 to sexual arousal. Sildenafil taken at bedtime also significantly increases nocturnal erections. 171,172
Sildenafil is an effective treatment for erectile dysfunction in men with diabetes, patients 173 110 174,175 multiple sclerosis, Parkinson's disease, on dialysis and after renal transplantation, 176,177 178 179 SCI, spina bifida, and familial amyloidotic polyneuropathy . In men with erectile dysfunction after radical prostatectomy, sildenafil is180 ineffective when a nerve-sparing procedure was not performed on at least one side, but it is effective if the cavernous
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nerves were spared, although it may take up to 18 months to obtain the best response. Overall, its efficacy in patients with an organic etiology of erectile dysfunction was reported to be 68 percent, being lower in diabetics (59%) and in nonselected post-prostatectomy patients 181 (43%). Sildenafil (25, 50, or 100 mg) can be taken orally 1 hour before intended sexual activity. (Significant effects have been reported between 30 minutes and 4 to 6 hours after taking the medication.) Treatment should be begun with 25 mg or 50 mg, and the same dose taken several times before it is increased. Dose-finding studies have demonstrated a dose-response curve. Sildenafil can be used repeatedly, and if used once or twice per week 181 there should be no fear of tachyphylaxis. 182
In men with diabetes mellitus or SCIs, vardenafil (5 to 20 mg) and tadalafil (2.5 to 20 mg) 183 with similar efficacy. Tadalafil has a longer half-life and is thus longer have been used 184 acting. Phosphodiesterase-5 inhibitors are contraindicated in combination with vasodilator drugs of the nitro type and nitric oxide donors, but a cardiologist can change such drug regimens in suitable patients with erectile difficulties requiring treatment. Phosphodiesterase-5 inhibitors should not be used in patients with retinitis pigmentosa. They are contraindicated in men with hypotension (blood pressure below 90/50 mmHg). Care should be taken to identify men with multisystem atrophy who may have erectile dysfunction, atypical parkinsonism, and asymptomatic postural hypotension. In our experience, an intelligent patient can use sildenafil after clear explanation, with careful planning of activity during the several hours after drug intake and performing sexual activity in the recumbent position. The most common adverse events of sildenafil are headache, flushing, and dyspepsia. Temporary visual symptoms (mainly color-vision disturbances) may occur with higher doses (100 mg). Adverse effects are mostly transitory and of minor intensity; in one study, higher rates were recorded than originally found (headache, 25.4%; heartburn, 10.5%), but no 185 serious side effects were seen. No evidence was found of effects on the myocardium or the conduction system. Evaluation of functional capacity is necessary in patients with coronary artery disease, who need to know the risks of physical (and sexual) activity. Patients who can exercise to 181 4.5 metabolic equivalents without angina or hypotension can probably the use of sildenafil in patients with safely use sildenafil. Recommendations for186 and open-label studies, no cardiovascular disease have been published. In controlled181 increased risk of cerebrovascular events has been reported, although one patient has shown 187 a temporal association of sildenafil use with a transient ischemic attack and then a stroke. Treatment with apomorphine sublingually is another therapeutic option for men with erectile dysfunction. The action is through a dopaminergic effect in the hypothalamus. Doses of 2 to 4 mg are given. Erection occurs within 10 to 25 minutes. However, in a randomized study of 188 130 men with diabetes mellitus, only 22 percent189 had a significant erectile response. Nausea is the most common adverse reaction. Yohimbine is an ancient aphrodisiac that is produced from the yohimbine tree (Pausinystalia yohimbine of the Rubiaceae family), which grows in West Africa. It is an α2-adrenergic blocker; its facilitation of sexual arousal is probably achieved by an effect on noradrenergic transmission, decreasing sympathetic activity and thereby resulting in increased penile blood inflow and reduced outflow. Pharmacologically, its action is similar to the peripheral action of reserpine, but it also has a pronounced central action and may have a mood-stimulating effect. It probably has little to offer in the presence of new, potent oral drugs. Intracavernous Injection Therapy Intrapenile injections of papaverine have been used extensively in the treatment of erectile 190 191 dysfunction in men with SCI, multiple sclerosis, or other neurogenic conditions. The required dosage of papaverine was lower than in vascular disease, and erection lasted192longer and was of better quality. Doses did not relate statistically to the level or extent of SCI. Priapism and prolonged erection were the most common acute complications but were dose related. Tunical scarring is a long-term complication that affects from 2 to 8 percent of patients after 6 months of treatment. Prostaglandin E1, papaverine, and a papaverine-phentolamine mixture all showed an efficacy rate of more than 70 percent. Acute complications such as priapism were, however, lower with prostaglandin (25%) than papaverine (65%) or a papaverine-phentolamine mixture (63%); the risk of local long-term complications was also lower with prostaglandin (8%) than with papaverine (57%) or a 193 papaverine-phentolamine mixture (12.4%).
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Prostaglandin E1 (alprostadil) is now the preferred drug for self-injection therapy in erectile dysfunction. Intracavernous injection should be taught under medical supervision before self-administration is attempted by the patient or his partner. The effect is very rapid and194 may last for 2 to 4 hours. Its efficacy in diabetic patients with impotence has been confirmed. Longer-lasting erection should be treated as priapism. Local bleeding, pain, and fibrosis may develop in the corpora cavernosa, leading to loss of effectiveness. This treatment is obviously contraindicated in patients taking anticoagulants or with hematological malignancies. Moxisylyte is an α-adrenergic blocking agent. Efficacy and tolerance for195intrapenile injection have been found encouraging in a double-blind study against placebo. Priapism as an adverse drug reaction usually has a good prognosis with conservative treatment. Painless priapism of less than 6 hours duration should be treated at first by 196 cooling. If present for more than 6 but less than 24 hours, intracavernous injection of an α-adrenergic agonist such as metaraminol is recommended. In painful priapism or with failure of conservative methods, penile puncture should be performed, at which time a cavernosal blood sample should be obtained to assess cavernosal hypoxia. Intraurethral Therapy Although intraurethral therapy with alprostadil (prostaglandin E1) seems an effective 197 treatment of erectile dysfunction, no double-blind study for neurogenic dysfunction has been reported. Transdermal Therapy Because of the complications of intracavernous injections, local noninvasive therapy is preferable. Transdermal nitroglycerin applied on the penis may allow an erection sufficient for vaginal penetration (but headache is a common side effect); it is not as effective as 198 intracavernous papaverine. Vacuum Devices Rigidity adequate for penetration occurs in 90 percent of patients with neurogenic erectile dysfunction when a vacuum device is used. Satisfaction of partners was initially reported as high (70%), but after months of treatment, and despite an increase in sexual activity, only 41 199 percent of patients were satisfied. Premature loss of rigidity and difficulty in placing and removing the constriction bands are common complaints. The most common complications are bruises, petechiae, and skin edema. The constriction band should not stay in place for longer than 30 minutes; major complications such as penile gangrene, severe erosion, and 200 cellulitis have been associated with prolonged wearing of the band. The use of a constriction band (on its own) may help patients who can obtain an erection, albeit not a durable one; the same restrictions concerning the duration of application should be observed. Surgical Treatment Penile prostheses (implanted semi-firm or inflatable rods) were used between 1970 and 1980 but they have many disadvantages and are now rarely recommended. They are not considered further here. Surgical revascularization and procedures to treat cavernous insufficiency (i.e., venous leakage) are not indicated in neurological patients.
Ejaculatory Dysfunction in Men With Neurological Disorders In cases of anejaculation/anorgasmia, vibratory stimulation may be helpful. The presence of intact dorsal201 penile nerves is necessary for orgasm achieved by penile vibratory Penile vibration has been found to have a significant antispastic effect in men stimulation. 202 with SCIs. Diabetes mellitus, retroperineal lymph node resection, and certain pharmacological agents may render the patient effectively sympathectomized, leading to failure of seminal emission or to retrograde ejaculation. Patients may respond to a variable extent to sympathomimetic pharmacological agents such as imipramine, phenylpropanolamine, or ephedrine. If retrograde ejaculation persists, sperm retrieval from the bladder is usually all that is required when insemination is contemplated. If unsuccessful, procedures such as surgical sperm
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retrieval from the testis, epididymis, or vas deferens may be necessary. Such patients are usually poor candidates for the assisted ejaculation procedure of penile vibratory stimulation because the sympathet- ic innervation necessary for seminal emission is not intact. Treatment options for insemination in other neuropathic conditions include assisted ejaculation or surgical sperm retrieval. The choice of treatment depends on the patient's ability to respond to methods of assisted ejaculation and on the quantity and quality of sperm in the ejaculate. With surgical methods, the assisted reproductive technology of intracytoplasmic sperm injection will probably be required owing to the low numbers of sperm obtained with these methods. Assisted ejaculation methods generally result in higher numbers of sperm, thus allowing for more assisted reproductive technology options. Premature (or rapid) ejaculation has been associated with myelopathy and neuropathy, but particularly with behavioral, psychological, and partner-related issues. Counseling on the use 204 of particular techniques may lead to improvement. Use of antidepressants (serotonergic agents such as clomipramine, or selective serotonin reuptake inhibitors such as sertraline or 8 paroxetine) may be successful.
Treatment of Abnormalities of Libido Hormone insufficiency, testosterone in men and estrogens in women, should always be corrected. Testosterone may also be helpful in women, but its use in fertile women is limited by the risk of masculinization. Hyperprolactinaemia should be treated. Dopaminergic drugs may also be helpful for reduced libido in some instances. For abnormally increased libido, androgen antagonists (cyproterone acetate, medroxyprogesterone acetate) may be effective. In resistant cases, neuroleptics are usually helpful.
Drug Treatment in Women Treatment of Lack of Libido and Anorgasmia No drug treatment is effective. Vibratory stimulation and dildos may be helpful in patients with genital sensory disturbances and in those with weakness or motor disorders. Sildenafil has been well tolerated in58women with neurological disorders causing lack of sexual 205 arousal, such as multiple sclerosis and SCI, with few benefits or side effects. In multiple sclerosis, there was an effect on lubrication, but quality of life did not improve significantly 58 although some women opted to continue on the drug after conclusion of the study. Clearly sildenafil does not produce the same spectacular results in women as it does in men with disturbed sexual responses related to underlying neurological disorders. In women with dysesthetic or painful sensations in the genitalia that are not alleviated by improving lubrication, antiepileptic drugs such as gabapentin, pregabalin, and carbamazepine may be helpful. Women showing signs of estrogen insufficiency should be referred to a gynecologist for hormone replacement therapy. Androgens may be considered in women with no risk of pregnancy. NEUROLOGICAL PROBLEMS ASSOCIATED WITH SEXUAL ACTIVITY
Headache When headache develops during sexual activity, and particularly if it is of sudden onset and occurs at orgasm, it can be alarming; many patients are convinced that they have had a cerebral hemorrhage. In fact, such headaches are usually benign and self-limiting. The designation benign coital cephalalgia refers to a severe, usually sudden, occipital headache that occurs at orgasm. The pain, which is pulsatile, may not206 end with the cessation of sexual activity; its mean duration is 30 minutes (10 to 180 minutes). Headache may also begin during sexual activity but before orgasm (typically 2 to 3 minutes before; so-called preorgasmic headache) and generally worsens as orgasm approaches; it may last from 10 minutes to several hours. The headache is usually occipital in location but may spread 207 diffusely. It may be pulsatile but is more often felt as pressure on the head. A dull, long-lasting, tension-type discomfort can outlast the headache. The headache may be accompanied by nausea, vertigo, and other symptoms, but often stops after cessation of sexual activity. There is no consensus as to the pathophysiology of the headaches
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associated with sexual activity. The combination of hyperventilation, the Valsalva maneuver, and exertion increases the cerebrospinal fluid pressure, which may produce traction on pain-sensitive structures, giving rise to short-duration, well-localized pain. These types of headache are rare; orgasmic headache is about four times more frequent than preorgasmic headache. Men are afflicted more often than women (3–4:1); the first peak of occurrence is early in the third decade, with the second late in the fourth decade. Comorbidity with 207 migraine, tension-type headache, and exertional headache is common. The headaches may be recurrent, but spontaneous remission is the rule. There have been no controlled 208 studies of treatment; short-term prophylaxis with indomethacin is recommended. Headaches related to sexual activity must be treated as potentially serious because subarachnoid hemorrhage may occur during sexual activity and headaches of other cause may also be exacerbated in this context. Vascular mechanisms are the probable cause of headaches that occur during sexual arousal in patients with unruptured aneurysms, cerebral tumors, and subdural hematomas. Pain due to angina pectoris or myocardial infarction may be referred to the head. Low-pressure postcoital headache, analogous to that following lumbar puncture, may also occur; symptoms are relieved by recumbency. Tearing of the arachnoid membrane with leakage of cerebrospinal fluid is the postulated cause. Postcoital migraine is well documented and may occur in patients with benign coital cephalalgia. Its character is identical to the patient's usual pattern of migraine, and the onset is postorgasmic, beginning minutes or hours after the event. On occasion, particularly in women, sexual arousal forms part of the aura of migraine. Ampoules of amyl nitrite, crushed and inhaled immediately before the event, are sometimes used in an attempt to enhance orgasm. A potent vasodilator, this drug may produce severe vascular headache. More often “sexual activity–associated” headache is nowadays a side effect of the use of phosphodiesterase inhibitors taken for treatment (or sport).
Transient Global Amnesia Transient global amnesia is usually associated with a precipitating event. “Emotional” events 209 both predominate in women, “physical” events in men. Sexual intercourse may qualify for209–211 categories and has been regularly reported among provoking events in both genders. ACKNOWLEDGMENT D. B. Vodušek acknowledges previous collaborations with C. J. Fowler and P. O. Lundberg on texts related to sexual dysfunction in neurological patients. Some of the material in this chapter appeared in the previous edition of this book in a chapter co-authored by Dr Fowler. We thank Miloš Kogej for help with manuscript preparation. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 35 Pregnancy and Disorders of the Nervous System MICHAEL J. AMINOFF •
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EPILEPSY Management of Epilepsy Obstetrical Management Interactions Between Oral Contraceptives and Anticonvulsant Agents MIGRAINE TUMORS PSEUDOTUMOR CEREBRI CEREBROVASCULAR DISEASE Occlusive Arterial Disease Occlusive Venous Disease Pituitary Infarction or Hemorrhage Disseminated Intravascular Coagulation Subarachnoid Hemorrhage From Intracranial Vascular Anomalies Intracranial Dural Arteriovenous Malformations Spinal Arteriovenous Fistulas and Malformations INFECTIONS METABOLIC AND TOXIC DISORDERS MOVEMENT DISORDERS MULTIPLE SCLEROSIS OPTIC NEURITIS TRAUMATIC PARAPLEGIA ROOT AND PLEXUS LESIONS PERIPHERAL NERVE DISORDERS Entrapment Neuropathies Traumatic Mononeuropathies Bell's Palsy Polyneuropathies MYASTHENIA GRAVIS MYOTONIC DYSTROPHY ECLAMPSIA AND PRE-ECLAMPSIA
Neurological disorders may first present during pregnancy, and their investigation and treatment may be complicated by concerns for the safety of the developing fetus. Furthermore, the natural history of certain preexisting diseases may be affected by
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pregnancy, and obstetrical management may be influenced by the neurological disturbance. These aspects are considered in this chapter. EPILEPSY Many of the pregnancies that occur in the United States are unplanned, so that regular 1 counseling of women with epilepsy during the reproductive years is important. Pregnancy may affect the natural history and management of patients with epilepsy in several ways. First, it may affect the frequency of seizures in known epileptics. In 2recent series, an increase in seizures occurred during pregnancy in3 23 to 75 percent of cases ; between 53 and 67 percent had unchanged seizure control. There is no way of predicting in advance whether or how seizure frequency will be altered during pregnancy, but certain general points can be made. Seizure frequency is more likely to increase in poorly controlled epileptic patients than in those with infrequent seizures, and any increase is most likely to occur during the first trimester. Any change in seizure frequency usually reverses after the birth of the infant, although occasional patients whose seizures increase during pregnancy remain more difficult to control thereafter. The influence of a particular pregnancy cannot be predicted by the outcome of previous pregnancies, any relationship between seizures and the menstrual cycle, or maternal age. Seizures may occur for the first time during or immediately after pregnancy and in some instances occur only in relation to pregnancy. Even in patients with such true gestational epilepsy, however, it is not possible to predict the course of subsequent pregnancies from the occurrence of seizures during one pregnancy. Status epilepticus may complicate pregnancy and sometimes occurs before there is any other evidence that seizures have become more difficult to control. It may take the form of tonic-clonic (major motor) or nonconvulsive status. The former is easy to recognize, but a transient alteration in mental status and level of arousal may not be attributed to nonconvulsive status epilepticus unless an electroencephalogram is performed. As in the nonparous woman, it is important to obtain control of the seizures rapidly, but therapeutic termination of pregnancy is usually unnecessary. There is no evidence that anticonvulsant drugs administered intravenously to treat status epilepticus affect the fetus adversely. The reason that seizure frequency sometimes increases during pregnancy is not clear, but a change in drug requirements during the gestational period may be responsible in some patients. For example, the amount of phenytoin and phenobarbital required to maintain total plasma drug levels increases during the gestational period4 and decreases during the drug puerperium. This is true for all first-line antiepileptic drugs. However, free or unbound 4 concentrations decline less often, and do so significantly only for phenobarbital. Other possible reasons for the increased dose requirements of these drugs during pregnancy include poor compliance with the anticonvulsant drug regimen, changes in drug absorption and excretion, and the dilutional effects of increasing plasma volume and extracellular fluid volume. Changes in drug absorption may relate to nausea, vomiting, or reduced gastric motility. Antacids are frequently prescribed during pregnancy and are known to adsorb to medications, preventing absorption. Thus, phenytoin absorption is reduced by5 71 percent by dimethicone, a common constituent of antacids, and by 60 percent by kaolin. An increased metabolic capacity of maternal liver and metabolism of part of the anticonvulsant dose by the fetus, placenta, or both may also be important. Folic acid therapy, prescribed routinely by many obstetricians, sometimes lowers the plasma phenytoin level. Whether hormonal factors also contribute to an increase in seizure frequency is unclear, but estrogens are epileptogenic in animals, and progesterone is said to have both convulsant and anticonvulsant properties. Finally, fatigue and sleep deprivation may influence seizure frequency during pregnancy. The reason that seizure frequency decreases in some epileptic patients is also unclear, but improved compliance with the anticonvulsant drug regimen may be responsible. A second major concern in the management of epileptic women during pregnancy is the possible effect of the seizure disorder and of anticonvulsant drugs on the developing fetus. It is difficult to determine the precise risk that a seizure disorder will also develop in the offspring of epileptic parents. The risk depends in part on whether the parental epilepsy is idiopathic (constitutional) or acquired; such risk appears to be increased among the offspring of epileptic mothers but not when only the father is epileptic. The reason for the increased risk is unclear, but genetic factors may be important, as may the consequences of maternal seizures or anticonvulsant drugs taken during pregnancy. For many years there has been concern that anticonvulsant drugs are teratogenic. Epidemiological studies are difficult to interpret because epilepsy occurs for many reasons, varies markedly in severity, may itself increase the risk of fetal malformation, and is treated
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by many drugs in different doses and combinations; environmental factors also bear on the development of fetal malformations and are difficult to control. Nevertheless, numerous reports suggest that certain anticonvulsant drugs are indeed teratogenic in humans, and the risk of malformation among the offspring of epileptic women is approximately double that for 6 Cognitive and behavioral nonepileptic women, with greater risk when polypharmacy is used. 7 development may also be affected. Trimethadione has been incriminated particularly clearly as being teratogenic and should be avoided during pregnancy; fortunately, it is now rarely used. Among the major anticonvulsant drugs in current use, phenytoin and phenobarbital may lead especially to congenital heart disease and to cleft lip and cleft palate; carbamazepine may be associated with craniofacial defects, fingernail hypoplasia, developmental delay, and neural tube defects, especially when used in combination with 8 other anticonvulsants. Valproic acid has been associated particularly with neural tube defects but also with cleft lip and palate, with 9,10 developmental delay, and with cardiovascular, genitourinary, and endocrinological disorders ; dose-dependency has been established. It is best avoided in women of childbearing potential; if pregnancy occurs in a woman taking it, amniocentesis is advised so that therapeutic abortion can be considered if the α-fetoprotein level suggests a high risk of neural tube defect. The teratogenicity of felbamate, gabapentin, lamotrigine, tiagabine, topiramate, oxcarbazepine, and vigabatrin is not known with certainty; 1,6 there is some suggestive evidence that lamotrigine and oxcarbazepine are teratogenic. The 11 combination of lamotrigine and valproate is particularly teratogenic. The mechanisms involved in teratogenesis of anticonvulsant drugs are not known but may include folate 12 production of toxic intermediary metabolites during deficiency (Fig. 35-1) or antagonism and 13 biotransformation of the parent compound. Specific oxidative intermediates such as epoxide, for example, have been suggested as the ultimate teratogen in patients receiving 13 phenytoin.
FIGURE 35-1 Percentages of pregnancy outcome in relationship to mean
serum folate levels in the first trimester dichotomized as less than 4 (subnormal) or at least 4 ng/ml. N = number of pregnancies with subnormal or normal serum folate levels. A significantly higher number of pregnancies with subnormal levels resulted in an abnormal outcome than did pregnancies with normal levels. Using Fisher's exact test, P = 0.05 for spontaneous abortion and P = 0.03 for total abnormal outcomes. (From Dansky LV, Andermann E, Rosenblatt D, et al: Anticonvulsants, folate levels, and pregnancy outcome: a prospective study. Ann Neurol 21:176, 1987, with permission.) A specific syndrome has been described among some of the offspring born to mothers taking phenytoin or phenobarbital during pregnancy and bears some resemblance to the fetal alcohol syndrome. It is characterized by prenatal and postnatal growth deficiency, microcephaly, dysmorphic facies, and mental deficiency. A similar syndrome has been ascribed to carbamazepine, and a characteristic facial phenotype in14children exposed to valproic acid or sodium valproate in utero has also been described. A clinical or subclinical bleeding disorder may occur in neonates exposed to anticonvulsant drugs in utero, without evidence of coagulopathy in the mothers. For example, Mountain and colleagues reported that 7 of 16 infants born to mothers taking anticonvulsant drugs had a 15 severe coagulopathy, 1 had a mild defect, and the remainder were normal. Factors II, VII, IX, and X were decreased in affected infants, whereas factors V and VIII and fibrinogen were normal. Bleeding usually occurred within 24 hours of birth, sometimes in unusual sites (e.g., the pleural or abdominal cavities). Bleeding has also been reported to occur in utero, leading to stillbirth. The bleeding disorder may be prevented by the maternal ingestion of vitamin K1 16 during the last month of pregnancy. The recommended dose of vitamin K is 10 mg daily for 30 days before delivery. The 5mechanism of the deficiency is held to be induction of hepatic enzymes by anticonvulsants. Because of the risk of such hemorrhagic complications, vitamin K1 (1 mg/kg intramuscularly) is sometimes given routinely to newborns of women receiving anticonvulsant drugs during pregnancy. However, more recent studies suggest that this hemorrhagic disorder is rare and that routine prophylaxis by maternal treatment with vitamin 17,18 K1 is unjustified. Alternatively, the prothrombin time of cord blood should be measured at
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delivery of such children; if it is subnormal or there is clinical evidence of bleeding during the neonatal period, intravenous vitamin K1 is then given. Treatment with infusion of fresh-frozen plasma or concentrates of factors II, VII, IX, and X is sometimes necessary as well. Maternal use of barbiturates may be associated with barbiturate withdrawal symptoms in the neonate, with restlessness, irritability, tremulousness, difficulty in sleeping, and vasomotor instability, usually beginning a week after birth. Although anticonvulsant drugs taken by the mother may be present in breast milk, their concentrations are usually too low to have any clinically significant effect on neonates. The 19 rate of transmission into breast milk varies with the drug. Breast-feeding need not be discouraged on this basis; however, when obvious sedation develops in an infant that could relate to anticonvulsants in the maternal milk, breast-feeding should be discontinued and the child observed for signs of drug withdrawal.
Management of Epilepsy Little or no information is available in the published literature to20guide decision making with regard to certain management issues in women with epilepsy. Epilepsy must be managed during pregnancy, as at other times, by prophylactic anticonvulsant drugs. Management should be by monotherapy whenever possible, with selection of the anticonvulsant that is most appropriate for seizure type. As indicated earlier, trimethadione and valproic acid are best avoided, but available data concerning relative safety and therapeutic utility of the various anticonvulsant drugs during pregnancy are insufficient to provide any more detailed guidelines at this time for the management of epileptic patients or of women wishing to become pregnant. Moreover, there is little point in substituting one anticonvulsant drug for another after the first 2 to 3 months of pregnancy because major fetal malformations will probably have occurred already if they are going to occur at all. Folate supplementation (4 mg 12 although the optimal dose is daily) may help, however, to reduce the risk of teratogenicity, 1 unclear. Outcome studies are also needed to confirm the utility of maternal vitamin K supplementation in preventing hemorrhagic complications in the newborn. It is important to monitor anticonvulsant drug treatment during pregnancy by serial measurement of plasma drug levels. Patients should be seen monthly, and as the pregnancy continues, the dose of medication may need to be increased to maintain plasma concentrations at previously effective levels. If increases are made during pregnancy, dose reductions will be necessary at some point (usually within 8 weeks) after delivery to prevent toxicity, but at a time that must be determined individually based on clinical evaluation and plasma drug levels. If patients inquire, it is appropriate to indicate that there is a slightly increased risk of fetal malformation due either to the seizure disorder itself or to the drugs used in its treatment. Nevertheless, there is still a very good chance (90% to 95%) that offspring will be normal. It must also be emphasized that the risks to both mother and fetus of noncompliance with anticonvulsant drug regimen are considerable, in that an increased seizure frequency or even status epilepticus may occur, with its associated morbidity and mortality.
Obstetrical Management Increased incidences of vaginal hemorrhage and toxemia were reported in epileptic women 21 by Bjerkedal22and Bahna, but others have found the incidence of toxemia to be unchanged. There is a significantly increased stillbirth rate in epileptic women, but the incidence of low-birth-weight infants is not increased. An increased incidence of neonatal 21 death has also been reported, perhaps owing to an increased incidence of congenital malformations, iatrogenic neonatal hemorrhage, the metabolic or toxic effects of seizures or anticonvulsant drugs, or socioeconomic factors.
Interactions Between Oral Contraceptives and Anticonvulsant Agents Certain anticonvulsants (including phenytoin, carbamazepine, felbamate, topiramate, oxcarbazepine, phenobarbital, and primidone) may alter the effectiveness of oral 19,23 Thus, the risk of contraceptive failure in contraceptives, leading to unwanted pregnancy. patients taking these anticonvulsants should be discussed in advance and documented in the patient's records; in some instances, use of an additional backup contraceptive method should be considered. The incidence of breakthrough bleeding is also increased in women taking these anticonvulsants and concurrent oral contraceptives, and such bleeding may 23 point to the possibility of contraceptive failure. Valproic acid and the newer anticonvulsants,
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zonisamide, vigabatrin, gabapentin, lamotrigine, levetiracetam, pregabalin, and tiagabine (at 1,23 It has been low doses) have not been reported to cause contraceptive failure. recommended that when oral contraception is to be used in a woman taking enzyme-inducing anticonvulsants, a formulation that includes at least 50 μg ethinyl estradiol or mestranol should be used. Oral contraceptives may also affect seizure frequency or blood levels of anticonvulsant medication, but this is less clear. MIGRAINE Migraine is often influenced by pregnancy. Most commonly, symptoms improve after the first trimester, but occasionally they worsen or occur for the first time during pregnancy. The influence of pregnancy on migraine does not depend on any relationship of migraine to the menstrual cycle. Similarly, it does not relate to the sex of the fetus or to differences in plasma progesterone levels, although there may be some relationship to changes in the pattern of circulating estrogens. Treatment of migraine during pregnancy is similar to that at other times, with emphasis on the avoidance of precipitating factors together with the use of simple analgesics as necessary. However, acetaminophen should be used in preference to aspirin because there is some evidence that aspirin use in large dosages in the later stages of pregnancy may prolong labor, increase the incidence of stillbirth, impair neonatal hemostasis, 24,25 Nonsteroidal anti-inflammatory and cause premature closure of the ductus26arteriosus. drugs are best avoided for similar reasons, except in severe cases. If acetaminophen is insufficient, partial opioid agonists may be used on a limited basis. Ergot-containing 27 preparations should be avoided when possible because of possible teratogenicity and the effect this drug may have on the gravid uterus. Propranolol is also best avoided during pregnancy when possible because animal studies have shown that it may impair fetal growth and that β-adrenergic blockade may inhibit the normal responsiveness of the fetus to asphyxia or other stresses. Other reported complications in neonates include prematurity, 28,29 respiratory depression, hypoglycemia, and hyperbilirubinemia. Many women, often with a past or family history of migraine, experience mild bifrontal headaches in the week after delivery. These headaches usually respond to simple analgesics and settle spontaneously. The association between migraine and oral contraceptive preparations is discussed in Chapter 22. TUMORS Although any type of intracranial tumor occasionally presents during pregnancy, pituitary adenomas, meningiomas, neurofibromas, hemangioblastomas, and certain vascular malformations sometimes exhibit relapses during pregnancy, with partial or complete remission occurring after delivery. The basis of this relationship is unclear, but it seems likely that pregnancy produces a slight increase in tumor size. The enlargement of certain pituitary adenomas during pregnancy may be due to the trophic effects of increased circulating estradiol. Similarly, an increase in size of meningiomas may relate to a direct trophic effect of gonadal hormones on tumor cells; sex steroid–binding sites have been found in human meningiomas, 30 but there are marked differences in their reported prevalence and concentration. Tumors with symptoms that show a consistent temporal relationship to pregnancy are usually so situated that significant neurological involvement, with the development of new symptoms or signs, occurs with only slight expansion of the underlying lesion. Thus, spinal meningiomas are more likely than convexity meningiomas to show a relationship of symptoms to pregnancy. Visual field defects are unlikely to develop during pregnancy in patients with pituitary microadenomas, but may certainly occur with larger 31 tumors. Patients with suspected intracranial neoplasms should be managed during pregnancy as at other times. Magnetic resonance imaging (MRI) is generally the best noninvasive means of establishing the diagnosis and does not involve exposing the fetus to irradiation. Essential operative treatment should not be delayed. However, surgery for pituitary adenomas or other benign tumors diagnosed toward the end of pregnancy can often be delayed until after delivery, provided that the patient is followed closely. Radiation therapy or chemotherapy may be required during pregnancy and carries a teratogenic risk for the developing fetus, especially if administered during the first trimester. If such therapy cannot be delayed to the latter half of pregnancy or postponed until after delivery, consideration may have to be given to aborting the fetus. The pregnancy itself can usually be managed normally in patients with intracranial tumors. Concerns that vaginal delivery may exacerbate any existing increase in intracranial pressure due to the tumor are usually misplaced, especially if adequate regional anesthesia is
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employed and low forceps are used, if necessary, to shorten the second stage of labor. The necessity and justification of therapeutic abortion should be considered on an individual basis in patients with malignant tumors. The long survival associated with low-grade gliomas suggests that some women with such tumors may wish to become pregnant after the diagnosis has been established. Such decisions need to be made on an individual basis, but patients with these lesions may certainly go through pregnancy without further complications. Choriocarcinoma may develop after a normal pregnancy or follow a molar, ectopic, or terminated pregnancy. Intracranial metastases are common, and hemorrhage may occur into the cerebral lesions. Early diagnosis and treatment are important for survival. PSEUDOTUMOR CEREBRI Benign intracranial hypertension has a clear association with pregnancy and is especially likely to occur during the first trimester or the postpartum period. It therefore seems sensible that women with benign intracranial hypertension should defer pregnancy until their disease is controlled and important that all pregnant patients with new-onset headaches be examined funduscopically to exclude the diagnosis. Headache and visual disturbances due to papilledema may be accompanied by diplopia from sixth nerve palsy. Investigations reveal no space-occupying lesion, but the cerebrospinal fluid (CSF) pressure is increased. The disorder is self-limiting, but it may not remit for weeks after delivery, and there may be recurrences 32 during subsequent pregnancies. Treatment, as in the nonpregnant woman, consists of measures to lower the intracranial pressure to prevent secondary optic atrophy. It may require the use of acetazolamide, furosemide, corticosteroids, repeated lumbar punctures, or a surgical shunting procedure. Optic nerve decompression and early delivery of the fetus may have to be considered if the intracranial pressure remains high despite these measures. There are no specific obstetrical complications, and a normal birth can be expected. Intracranial venous sinus thrombosis may simulate pseudotumor cerebri and is discussed later. CEREBROVASCULAR DISEASE 33,34
A significant number of pregnancy-related maternal deaths has been attributed to stroke. 35 An increased incidence of stroke has been associated particularly with the puerperium as well as with the use of oral contraceptive preparations. It is not35,36 clear, however, whether although such an pregnancy itself is associated with an increased risk of stroke, association is widely believed to exist. The extent to which any such increase relates to hormonal changes is unclear. However, sex steroids can certainly affect several physiological and metabolic factors that predispose to cerebral thromboembolic or venous infarction, as discussed in Chapter 22. Estrogens and perhaps some progestogens increase blood coagulability and platelet aggregation, increase the blood pressure, affect serum lipid profiles, 37 and may lead to pathological changes in blood vessels. Sex hormones may also predispose to aneurysm formation or rupture, as suggested by observations that early menarche38or oral contraceptive use is associated with an increased risk of subarachnoid hemorrhage, that 39 and that premenopausal the risk for hemorrhage is greatest in the perimenstrual period, 39 women are at reduced risk for subarachnoid hemorrhage. Whether pregnancy influences intracranial arteriovenous malformations (AVMs) is unclear, but it may certainly aggravate spinal AVMs (discussed on p. 680). The microangiopathic syndromes of pre-eclampsia, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome are considered briefly on p. 688.
Occlusive Arterial Disease Most cases of nonhemorrhagic hemiplegia developing during pregnancy or the postpartum 40 period are due to arterial occlusion. As in nonpregnant patients, this may relate to thrombus formation on an atheromatous plaque; inflammatory disorders such as arteritis or meningovascular syphilis; hematological disorders such as polycythemia and sickle cell disease; and cardiac disorders such as a cardiomyopathy, rheumatic or ischemic heart disease, intracardiac shunts, cardiac dysrhythmias, subacute bacterial endocarditis, use of prosthetic heart valves, and cardiac myxoma. During pregnancy, in addition, stroke may be predisposed to by anemia, hormonal factors, changes in blood coagulation factors, increased platelet aggregation, hypertension, and puerperal septicemia. The blood is said to be in a hypercoagulable state during pregnancy; there is a rise in all procoagulant factors except XI and XIII, and increased thrombin activity. Circulating inhibitors
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of coagulation, such as protein C and protein S, are reduced during normal pregnancy, and 41 The activity of the fibrinolytic antithrombin III is reduced under certain circumstances. 41 system is also reduced during pregnancy. These various changes predispose pregnant women to stroke. Other factors also become important risk factors for stroke during the gestational period. Hemoglobinopathies, for example, may lead to significant maternal morbidity during pregnancy. Thus, women with sickle cell disease are especially likely to 42 experience crises, usually vaso-occlusive, during pregnancy. Sickle cell disease is also associated with an increased incidence of obstetrical complication—including abortion, growth retardation, preterm birth, and stillbirth—although fetal wastage has been reduced 42 considerably by improved prenatal care. The presence of circulating antiphospholipid autoantibodies is similarly associated with a high rate43of maternal arterial and venous thrombotic events and of transient ischemic attacks, as well as with obstetrical complications such as a high rate of spontaneous abortion and of early-onset, atypical 44 an especially high risk for thromboembolic pre-eclampsia. Pregnancy may represent 44 disease in patients with these antibodies. A peripartum cardiomyopathy may occur during the last trimester of pregnancy or the puerperium, especially in the presence of twinning, toxemia, or postpartum hypertension; it sometimes presents with embolic phenomena necessitating anticoagulation. Its precise cause is unclear, but nutritional, hormonal, viral, and immunological mechanisms have been 45 reduction in left suggested. Subsequent pregnancies are associated with a significant 46 ventricular function and may lead to clinical deterioration and death. Rare cases have been described47of segmental cerebral vasoconstriction (“vasospasm”) of during uncertain cause in young adults. Such a postpartum cerebral angiopathy may occur 48 an otherwise normal pregnancy or the postpartum period and lead to a fatal outcome. It has been associated with hypertension and use of vasoconstrictive drugs and may be mistaken 49 for cerebral vasculitis. A reversible intimal hyperplasia of the cerebral vasculature during pregnancy has also been described as a rare cause of stroke or transient ischemic attack during the gestational 50 period, but such cases are poorly documented and hard to interpret. There are rare reports of arterial occlusion by paradoxical embolization from a pelvic vein through51a patent foramen ovale. Fat, air, or amniotic fluid embolism may also occur during childbirth but usually presents with dyspnea, shock, and acute encephalopathy. Amniotic fluid embolism is an important cause of stroke and maternal death. In the United Kingdom and France, it is the fifth and third highest direct cause of maternal death, respectively, and in Singapore an autopsy52study revealed that it was responsible for more than 30 percent of direct maternal deaths. Hemodynamic collapse and disseminated intravascular coagulopathy may lead to focal neurologic signs from cerebral hypoperfusion or hemorrhage. Plasma exchange may be helpful after initial resuscitation. The role of thrombolytic agents (e.g., tissue plasminogen activator) for treating acute ischemic stroke in pregnant women or nursing mothers is unclear. Hemorrhagic complications are more likely, especially in the first few days after delivery; any effects on the fetus and the extent to which these agents are excreted in breast milk are uncertain. As in nonpregnant women, transient cerebral ischemic attacks may precede occlusion of one of the major intracranial arteries. Neurological investigation and management should not be influenced by the pregnancy, but special shielding during radiological studies may help to protect the developing fetus. Angiographic delineation of degenerative atherosclerotic disease in a localized arterial segment that is surgically accessible may permit disobliterative surgery. If surgery is decided against or there is more widespread atherosclerotic disease, treatment with aspirin may be commenced. A cardiac source of emboli usually necessitates treatment with warfarin. This drug is associated with risks of teratogenicity and fetal wastage when used during the first trimester, and it crosses the placenta, thereby increasing the risk of hemorrhagic complications. Accordingly, patients requiring anticoagulation during pregnancy are best maintained on subcutaneous heparin, which is discontinued with the onset of labor and restarted approximately 12 hours after vaginal delivery (or 24 hours after cesarean section). The optimal management of labor and delivery in patients who have had a stroke during pregnancy is unclear. In most cases, vaginal delivery assisted by forceps is probably satisfactory. The blood pressure needs to be monitored closely, however, to avoid excessively high or low levels.
Occlusive Venous Disease
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Aseptic intracranial venous thrombosis may occur during pregnancy, during the puerperium, 53 or with the use of oral contraceptives for reasons that are unclear. It has been attributed to coagulation abnormalities, changes in the constituents of peripheral blood, and intimal damage to dural sinuses. The extent to which it relates to hormonal changes is unknown, but such changes probably have an important etiological role, as discussed in Chapters 22 and 61. In many instances there is no evidence that pelvic or leg veins were thrombosed. Intracranial venous thrombosis occurs most commonly during the third trimester of pregnancy or the postpartum period, sometimes in relation to pre-eclampsia. Although it may, in fact, occur at any time during a normal pregnancy, when it develops during the first trimester it usually is in relation to some complication such as spontaneous or therapeutic abortion. It is characterized clinically by headache, seizures, obtundation, confusion, and sometimes focal 53 neurological disturbances. Examination commonly reveals papilledema, and there may be signs of meningeal irritation from subarachnoid bleeding secondary to cortical infarction. Cerebrospinal fluid pressure is often increased, and its protein or cell content may be increased. Radiological imaging procedures (computed tomography [CT] scan, MRI, and arteriography) confirm the diagnosis and help to exclude arterial disease. 53
Treatment of intracranial venous thrombosis is controversial. Anticonvulsant drugs and antiedema agents may be helpful. Anticoagulation with dose-adjusted intravenous heparin 54,55 The role may also be worthwhile despite the risk of provoking hemorrhagic complications. of thrombolytic therapy to prevent extension of the thrombus in pregnant or postpartum women is not clear. Approximately one third of patients do not survive, and survivors may experience recurrence of thrombosis later in the same pregnancy or in subsequent ones. The outcome is better, however, than when intracranial venous thrombosis is a sequel to inherited 55 thrombophilia or systemic disease. Cesarean section may be necessary if venous thrombosis has occurred before or during labor. If it occurs early in the pregnancy, labor can generally be allowed to commence spontaneously, with forceps-assisted delivery if necessary.
Pituitary Infarction or Hemorrhage Acute infarction or hemorrhage of the pituitary gland, especially around the time of delivery, is a well-recognized complication that leads to hypopituitarism if the patient survives the acute event. The disorder may occur in patients with preexisting diabetes or in those who experience such obstetrical complications as postpartum hemorrhage with vascular collapse. It may also occur in patients with coagulopathies or a pituitary adenoma. The extent of pituitary damage governs the severity of pituitary hypofunction. The initial symptom may be failure of lactation. Emergency treatment with corticosteroids and trans-sphenoidal decompression of the intrasellar content may need to be considered to preserve life and vision. Management otherwise is with hormone replacement therapy.
Disseminated Intravascular Coagulation Disseminated intravascular coagulation may occur in patients with a variety of obstetrical complications. It is discussed in Chapter 13, and further consideration here is unnecessary.
Subarachnoid Hemorrhage From Intracranial Vascular Anomalies Subarachnoid hemorrhage may occur during pregnancy from an aneurysm or cerebral AVM. The morbidity and mortality rates are greater with the former. Although Robinson and associates suggested that56pregnancy had an adverse effect on intracranial AVMs, making 57,58 them more likely to bleed, this has not been substantiated by others. Symptoms and signs of subarachnoid hemorrhage are as in nonpregnant patients. The hemorrhage may be the first indication of the underlying lesion. An AVM is somewhat more likely than an aneurysm to be responsible if subarachnoid hemorrhage is accompanied by a major focal neurological deficit (suggesting an intracerebral hematoma). CT scan of the head is a reliable means of detecting recent subarachnoid or intracerebral bleeding and may permit the causal lesion to be identified and localized. Arteriography permits the identity of the lesion to be confirmed and provides information about its anatomical characteristics that is especially important in planning operative treatment. All of the major intracranial vessels should be opacified because feeders to AVMs sometimes arise from the contralateral side and aneurysms may be multiple. Special shielding during radiological studies is necessary for pregnant women to protect the developing fetus.
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The management of subarachnoid hemorrhage is as for nonpregnant women. Because of the high risk of rebleeding in survivors of a ruptured aneurysm, operative or endovascular treatment should not be delayed because of pregnancy if the clinical and arteriographic findings indicate its feasibility. Although ruptured AVMs may also bleed again, this may not be for months or years after the initial hemorrhage, and neurosurgical treatment can often be postponed until the pregnancy is over. The obstetrical management of survivors of a subarachnoid hemorrhage is controversial. In patients with aneurysms that have been successfully treated by surgery or in whom rupture occurred before the last trimester, pregnancy and delivery can generally be permitted to continue normally. In patients with unoperated or incompletely obliterated aneurysms that ruptured during the last trimester of pregnancy, cesarean section at 38 weeks' gestation is probably appropriate. Some have also suggested delivery by cesarean section at 38 weeks 56,59 but this measure seems unjustified. for women with AVMs, Intracranial hemorrhage during pregnancy or the postpartum period may also occur in association with hypertension, vasculitis, various hematological disorders, mycotic 60,61 62 and moyamoya disease and as a manifestation of aneurysms, cocaine abuse, 63 choriocarcinoma. Treatment is of the underlying cause. The relationship of oral contraceptive use to intracranial hemorrhage is considered in Chapter 22.
Intracranial Dural Arteriovenous Malformations Dural AVMs may present during pregnancy, sometimes after abortion, or during the postpartum period. The anomalous arteriovenous shunt may involve either the anterior-inferior group of dural sinuses (cavernous, intercavernous, sphenoparietal, superior and inferior petrosal, and basilar plexus) or the superior-posterior group (superior and inferior 64 sagittal, straight, transverse, sigmoid, and occipital). Anomalies involving the former group lead typically to unilateral orbital or head pain, diplopia, a proptosed or red eye, tinnitus, or some combination of these symptoms. Malformations involving the superior-posterior dural sinuses may lead to subarachnoid hemorrhage, increased intracranial pressure, tinnitus, seizures, or focal neurological deficits due to cerebral ischemia. In either case, there may be papilledema, and a bruit is often present either over the eye (with involvement of the anterior-inferior sinuses) or about the mastoid region or ear (superior-posterior sinuses involved). Arteriography is necessary to localize the shunt with certainty and determine its anatomical features. With shunts to the anterior-inferior dural sinuses, embolization of feeding vessels may help preserve vision or relieve intolerable symptoms. Ligation or embolization of feeding vessels is often helpful in relieving symptoms from shunts to the superior-posterior dural sinuses, and a direct surgical approach is also sometimes feasible.
Spinal Arteriovenous Fistulas and Malformations Spinal fistulas and AVMs are usually either dural or intradural in location. They may lead to spinal subarachnoid hemorrhage or to a myeloradiculopathy that can either present acutely or develop insidiously. Symptoms usually are progressive. At least one half of the survivors of subarachnoid hemorrhage from these spinal lesions have further episodes of bleeding, and 65 one half of the subsequent survivors bleed again unless the underlying lesion is treated. Similarly, once there is any functional impairment in the legs due to the myeloradiculopathy, disability is likely to worsen, so that 50 percent of patients become unable to walk at all or 65 require two sticks or crutches to do so, within 3 years. Cord or root symptoms may show a characteristic relationship to exercise or posture and occasionally to pregnancy or the menstrual cycle. Typically, examination reveals a mixed upper and lower motor neuron deficit in the legs, often with an associated sensory disturbance that occasionally has a radicular distribution. There may be a coexisting cutaneous malformation that sometimes relates segmentally to the spinal lesion. A spinal bruit may be present. Unruptured dural arteriovenous fistulas and spinal AVMs probably produce symptoms by causing venous hypertension. Although they are usually extramedullary, their draining veins connect with veins draining the spinal cord. The increased venous pressure leads to a reduction in the arteriovenous pressure gradient across the cord and thus to a reduction in 65 spinal blood-flow. Pressure on pelvic or abdominal veins by the gravid uterus could aggravate symptoms of caudally situated dural arteriovenous fistulas and AVMs by
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obstructing venous return to the heart, thereby reducing still more the arteriovenous pressure gradient across the cord. Whether anemia and hemodilution are also partly responsible for exacerbations of symptoms during pregnancy is unclear, and it is not known whether sex hormones exert direct trophic influences on these lesions. Advances in imaging procedures have revealed that the nidus of many spinal vascular lesions is situated durally, and these lesions are thus readily accessible to embolization or surgical intervention. Treatment is indicated in patients with progressive symptoms, functional incapacity, or a history of hemorrhage. Treatment is clearly more difficult for vascular anomalies located anteriorly or within the cord, but in some of these, also, the actual nidus of the lesion is dural and thus operable. INFECTIONS A variety of organisms may infect the nervous system, as discussed in Chapters6640 to 49. Pregnancy is reportedly associated with a depression of cell-mediated immunity that may interfere with resistance to specific infectious agents (as well as permitting fetal retention), thereby endangering maternal health. Treatment of various infections may also be complicated during pregnancy because of the need to avoid certain antimicrobial agents if possible. When infection occurs during pregnancy, it may pose risks to the developing fetus from the infective organism and the drugs used in its treatment. Thus, obstetrical management may be complicated. Pregnancy increases the susceptibility of women to clinical poliomyelitis, but it is not clear whether this is because pregnant women are more susceptible to the initial viral infection or to invasion of the nervous system. Weakness tends to be more severe and widespread when poliomyelitis develops during the late stages of pregnancy. Poliomyelitis affects the course of pregnancy. During the first trimester, spontaneous abortion may occur with apparently mild nonparalytic attacks of the disease or in conjunction with a febrile reaction in its acute phase. Abortion or fetal loss may also occur during later stages of pregnancy, but usually in conjunction with severe poliomyelitis. Successful pregnancy may occur, however, even in 67 patients who are dependent on continuous noninvasive positive pressure ventilation. The uterine muscle is not paralyzed in women with poliomyelitis, and labor can usually be managed as in normal women unless there are specific obstetrical indications for cesarean section or induction of labor. Normal offspring can be anticipated, although neonatal poliomyelitis may occur. Neonatal involvement within the first 5 days of life is generally assumed to follow transplacental transmission of the virus and is associated with a 50 percent or greater mortality rate. Tetanus is an important complication of abortion or delivery, especially in developing 68 countries, and is associated with a high mortality rate. In addition to treating the tetanus, any retained products must be evacuated from the uterus, and hysterectomy is sometimes necessary. Neonatal tetanus results from contamination of the umbilical cord, and in some areas 69 the mortality rate is a high (but uncertain and geographically variable) proportion of all births. Infants are usually diagnosed within 10 days; the history is typically that of increased irritability for up to 48 hours, followed by cessation of sucking and crying, accompanied by convulsions and often by fever. Improved maternity facilities and the active immunization of women who are pregnant or of childbearing age are important public health measures to 70 counter this disorder. Maternal infection with Listeria monocytogenes may lead to abortion or stillbirth and in neonates to either an early-onset, predominantly septicemic infection or a late-onset, 71 predominantly meningitic or meningoencephalitic infection. The bacteriological and serological findings suggest the diagnosis, and treatment is with appropriate antibiotics. Maternal rubella, especially during the first trimester, may lead to congenital fetal malformations. Ocular abnormalities, seizures, mental retardation, deafness, focal neurological deficits, and other abnormalities, including cardiac anomalies, occur in a variety of combinations. Much more rarely, a panencephalitic illness has been reported during the second decade of life in patients with congenital rubella and leads to pyramidal and extrapyramidal signs, seizures, and dementia. High antibody titers to rubella virus occur in the blood and CSF, and the virus may be isolated from the brain. The topic is reviewed in detail 72 elsewhere. Congenital toxoplasmosis may lead to meningoencephalitis, chorioretinitis, obstructive hydrocephalus, and cerebral calcification. Pregnant women should therefore be advised to keep away from cat feces and to avoid ingestion of raw or undercooked meat or eggs. Fetal infection with cytomegalovirus may lead to a variety of somatic manifestations.
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Neurological involvement may be manifested by cerebral malformation, microcephaly, mental retardation, seizures, obstructive hydrocephalus, cerebral calcification, deafness, chorioretinitis, or some combination of these disorders. Neonatal infection with herpes simplex virus leads primarily to visceral involvement. When there is neurological involvement, manifestations may include seizures, irritability, increased intracranial pressure, depressed level of consciousness, and motor deficits. Maternal syphilis is an important disorder to recognize and treat. It is associated with an increased rate of spontaneous abortion and increased perinatal mortality. Offspring of affected mothers may have symptomatic congenital syphilis. Infection may also occur at birth if infants come into contact with an infective lesion. The clinical features of congenital neurosyphilis are similar to those of neurosyphilis in adults. They may become apparent at any time after the first few weeks of life, or they can be delayed for several years. Treatment is of the underlying infection, penicillin being the drug of choice. Fetal infection usually occurs in the second half of pregnancy. Thus, treatment at an early stage of pregnancy generally prevents fetal involvement, emphasizing the importance of serological testing during antenatal care. Details of treatment are provided in Chapter 41. Tuberculous meningitis may occur during pregnancy and 73 is then associated with higher mortality and neurological morbidity rates than otherwise. Its treatment is discussed further in Chapter 42. Children born to women with acquired immunodeficiency syndrome (AIDS) are at risk for development of the disease after an interval that varies from several 74 months to several years. Infection may occur Children infected transplacentally may be born with congenital AIDS. 75 not during fetal development but at birth or from breast milk. Neurological manifestations of the disorder are particularly frequent in such children and are due to a progressive encephalopathy that leads to developmental delay or regression, with evidence of cortical atrophy on neuroimaging studies. Calcification of the basal ganglia also occurs. Other manifestations of the disease include failure to thrive, interstitial pneumonitis, hepatosplenomegaly, and increased susceptibility to bacterial infections. Secondary opportunistic infections of the immunocompromised mother are potentially a risk to the fetus or child. The availability of effective antiretroviral agents and access to infant formula (to prevent postnatal transmission through breast milk) have reduced the 76,77 incidence of perinatal infections with human immunodeficiency virus in developed countries. Because some of the antiviral agents used for AIDS may be teratogenic (in many instances 78,79 infants born of no pharmacokinetic or safety data related to pregnancy are available), mothers treated with them during pregnancy may have nervous system malformations from the virus itself, from the medications used in its treatment, or both. The virus invades endothelial cells, causes a vasculitis, and leads to microinfarcts in the fetal brain; its teratogenic effects depend upon the developmental stage of the fetus when it is exposed to the virus, but even late gestational exposures may affect brain development. Children of women infected with human T-cell leukemia virus, type I (HTLV-I) may acquire the infection through breast-feeding and develop a resulting myelopathy in adult life. This is considered further in Chapter 47. METABOLIC AND TOXIC DISORDERS In parts of the world where malnutrition is common, many pregnant women have a deficient intake of diverse nutrients including proteins, vitamins, and minerals. The incidence of malformed fetuses is high in this circumstance, but it is generally not possible to recognize the specific deficiency that is responsible. Fetuses exhibit intrauterine growth retardation, and organ development, including that of the brain, is sometimes affected. Clinical presentation of the neurological manifestations of vitamin B12 deficiency (myelopathy, polyneuropathy, mental changes, optic neuropathy) do not differ during pregnancy, but any accompanying megaloblastic anemia may be obscured by folic acid supplements. As in the nonpregnant patient, treatment is with parenteral vitamin B12 to arrest progression and correct reversible neurological deficits. Maternal vitamin B12 deficiency during pregnancy may lead to similar deficiency in neonates, exacerbated in breast-fed infants by the reduced content of vitamin B12 in maternal milk. Clinically, such infants exhibit apathy, developmental delay or regression, involuntary movements, cutaneous pigmentation, and megaloblastic anemia. Treatment is with vitamin supplementation. Phenylketonuria, with its autosomal-recessive inheritance, is an important cause of mental retardation. Neonatal screening programs can identify affected infants so they can be treated
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before intellectual function deteriorates. Affected women have a high rate of spontaneous abortion. Offspring of untreated women have a high incidence of facial dysmorphism, developmental delay, microcephaly, and congenital heart disease. Dietary treatment before conception or as soon as possible thereafter may prevent or lessen some of these 80–83 To ensure that the diagnosis is not missed, antenatal screening for maternal features. phenylketonuria, or testing at the first antenatal visit of women with a positive family history, low intelligence of uncertain cause, or a history of microcephalic offspring is justifiable. The homozygous offspring of an affected mother requires a diet low in phenylalanine, but the most appropriate nutritional management of heterozygotes is less certain. In any event, the affected mother should avoid breast-feeding because of the high concentration of phenylalanine in her milk. Many toxins and drugs are teratogenic and may affect the developing nervous system. The teratogenic effects of antiepileptic drugs taken during pregnancy were considered earlier. Excessive maternal alcohol intake may lead to the fetal alcohol syndrome, in which intrauterine growth retardation and dysmorphic facies are common, but cerebral abnormalities (cortical changes, hypoplasia or agenesis of the corpus callosum, and 84,85 Excessive microcephaly) may lead to seizures, mental deficiency, and motor deficits. vitamin A intake early in gestation may be teratogenic (facial86abnormalities, microcephaly, Many other agents that are and perhaps meningomyelocele and Chiari II malformation). 79 seemingly innocuous to the mother may affect the fetus, and the topic is too extensive to be reviewed here. Most drugs are not labeled for use in pregnancy, and there are few or no data on human fetal effects at the time of marketing. The use of medication or recreational agents during pregnancy should therefore be as limited as possible. MOVEMENT DISORDERS Movement disorders of any type may occur during pregnancy, as at other times. Comment here is restricted to those related more specifically to pregnancy or posing obstetrical problems. Chorea gravidarum occurs most often in primigravidas, frequently without evidence of preceding streptococcal infection, as a variant of Sydenham's chorea. Approximately two thirds of patients have a history of chorea or rheumatic fever, and most of the others have signs of rheumatic heart disease. Symptoms usually begin early in pregnancy; they remit after delivery but may recur during subsequent pregnancies. Altered patterns of circulating sex hormones during pregnancy may account for the chorea by their effects on previously damaged basal ganglia (Chapter 22). Such a notion is supported by the observation that the chorea improves after delivery or abortion, as sex hormone levels return to prepregnancy 37 values, and by the occurrence of chorea in women taking oral contraceptives. The prognosis relates to cardiac complications. The neurological disorder generally benefits from bed rest and sedation. It is not an indication for termination of pregnancy, and there are no specific obstetrical complications. Chorea developing for the first time during pregnancy does not necessarily represent a variant of Sydenham's chorea. Huntington's chorea may occasionally present during pregnancy, and chorea may also develop at this time as a result of systemic lupus erythematosus, polycythemia vera rubra, thyrotoxicosis, hypocalcemia, encephalitis, cerebrovascular disease, or Wilson's disease, or as a drug-induced reaction. Further discussion is provided in Chapter 59. Chorea may be induced by oral contraceptives, sometimes in women with preexisting abnormalities of the basal ganglia. It usually begins approximately 3 months after contraceptives are started, tends to evolve subacutely, may be asymmetric or unilateral, and settles with discontinuation of the causal agent. Its pathophysiological basis is unknown, but vascular mechanisms, immunological mechanisms, and a hormone-dependent alteration in central dopaminergic activity have been proposed. A number of pregnant women have the restless legs syndrome, usually during the latter part 87 of pregnancy, for uncertain reasons. Among pregnant Japanese women, almost 20 percent 88 ; the corresponding number in reportedly have symptoms of restless legs syndrome 89 pregnant women in northern Italy was 27 percent. Unpleasant creeping sensations occur in the legs and occasionally the arms, usually at night or during relaxation, leading to a compelling need to move about. The cause is unknown. Neurological examination reveals no abnormalities. Treatment of coexisting anemia or iron deficiency may improve symptoms, and treatment with diazepam or clonazepam is sometimes worthwhile. Other drugs that may be helpful include carbidopa-levodopa (Sinemet), bromocriptine, carbamazepine, propranolol, 87 baclofen, and opiates, but these drugs are usually best avoided during pregnancy.
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Symptoms generally resolve spontaneously in the first few weeks postpartum. Untreated Wilson's disease, an autosomal-recessive disorder, is associated with a high miscarriage rate, but pregnancy poses no special problems in patients receiving adequate chelation treatment. Penicillamine therapy may be associated with mesenchymal birth defects, but a number of reports document an uneventful pregnancy with birth of a normal 90–92 When acute dystonia infant in patients treated with penicillamine or zinc sulphate. develops during pregnancy, the most probable cause is use of a dopamine antagonist antiemetic or neuroleptic, such as metoclopramide. In patients with long-standing dystonia of either the idiopathic or secondary variety, there is no evidence that pregnancy affects the neurological outcome adversely. Pregnant patients with dystonia should be offered genetic counseling if the disorder has a hereditary basis; the conduct of labor depends on the severity and nature of the abnormal posturing. Parkinson's disease may develop in women who are still young enough to bear children, and concerns are sometimes expressed about the possible effects of pregnancy on the neurological disorder. A detailed study has shown no consistent effect on overall parkinsonian disability, although some patients did show a worsening of their neurological symptoms; among the series of patients that was studied, there was no increase in the 93 incidence of obstetrical complications or fetal defects. MULTIPLE SCLEROSIS The classic, unpredictable relapses and remissions that occur in multiple sclerosis make it difficult to determine whether pregnancy influences the disorder. However, several epidemiological studies have suggested that there is 94–96 an increased frequency of relapses Neither pregnancy itself nor the during the 3 to 6 months immediately after childbirth. 96–98 In some number of pregnancies affects the degree of subsequent neurological disability. 99 studies multiple sclerosis did not seem to influence the course of pregnancy or childbirth, but in others it was associated with smaller babies for age and more frequent deliveries 100 involving the use of forceps, vacuum extractors, or cesarian section than in controls. Patients receiving beta-interferon therapy when they became pregnant had a higher rate of 101 fetal wastage (miscarriages or stillbirths) and of low-birth-weight babies. If possible, patients should stop beta-interferon therapy before becoming pregnant; failure to do so, however, does not necessarily imply a bad outcome, and most patients will produce a healthy 102 infant. Glatiramer acetate and mitoxantrone should also be avoided by women who are pregnant or trying to become pregnant. Pregnant women with multiple sclerosis are often concerned about development of the disease in their offspring. Although multiple sclerosis may indeed show a familial incidence, this association is uncommon and tends to involve siblings rather than different generations, so that firm reassurance can generally be given. Pregnancy and parenthood should not be discouraged unless the patient is incapable of coping with the demands involved. Neurological management during pregnancy is as at other times, but patients with sphincter disturbances or a paraparesis may pose particular problems. The method of delivery should be guided by obstetrical factors alone. OPTIC NEURITIS Optic neuritis of any type may occur fortuitously during pregnancy. Optic nerve involvement is a rare complication of hyperemesis gravidarum, and uncontrollable vomiting may necessitate termination of pregnancy. Optic nerve involvement may occur during pregnancy or the postpartum period in patients with multiple sclerosis or tumors that enlarge slightly during the gestational period. Genetic counseling is important if there is a history of hereditary optic atrophy. TRAUMATIC PARAPLEGIA When spinal injury occurs during pregnancy, the patient must be investigated and managed with her own best interests in mind. Despite concerns that radiological studies might affect the developing fetus, such studies should not be postponed if indicated neurologically. Patients with established paraplegia should be educated about (1) the importance of avoiding urinary infection by ensuring a minimal amount of residual urine after micturition, and (2) the best means of avoiding pressure sores. Unless a paraplegic woman has a gross impairment of renal function, however, she need not be discouraged from pregnancy if she wishes to have a family. Care should be taken to prevent anemia during pregnancy. The conduct of labor is complicated in paraplegic women. With complete cord lesions above
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T10, onset of labor is unrecognized and labor is painless. For this reason, the cervix is usually examined at each antenatal visit after approximately the 26th week of pregnancy; patients are hospitalized if the cervix is dilated, or routinely after about 32 weeks of pregnancy. With cord lesions below T10, uterine contractions are accompanied by normal pain sensations. Complete cord lesions above T5 or T6 may be associated with autonomic hyperreflexia. Headache, sweating, nasal congestion, hypertension, reflex bradycardia, and cutaneous vasodilatation and piloerection above the level of the lesion are often conspicuous during the uterine contractions of labor, becoming especially marked just before delivery. If unrecognized, the disorder is sometimes mistaken for pre-eclampsia. Symptoms have been attributed to release of catecholamines. Treatment in the past has included reserpine (to deplete catecholamines from sympathetic nerve terminals), atropine, clonidine, glyceryl trinitrate, or hexa-methonium. Continuous lumbar epidural anesthesia can block or prevent autonomic hyperreflexia. Cesarean section is not necessarily indicated by the paraplegia itself but may be required if there is bony deformity of the spine or pelvis. Forceps delivery may be necessary to compensate for paralysis of muscle involved in the expulsive efforts of the second stage or to shorten delivery time because of severe hypertension. Paraplegic and even quadriplegic patients have a normal milk ejection reflex during suckling and can breast-feed their infants. ROOT AND PLEXUS LESIONS Low back pain is common during pregnancy and usually unrelated to serious underlying neurological cause, so that management is generally conservative. Acute prolapse of a lumbar intervertebral disc, for example, is rare during pregnancy. Management of the acute prolapse is as in nonpregnant women, but it is important to distinguish the disorder from conditions simulating it. This may require imaging—recent published guidelines indicate that MRI during pregnancy is without known adverse effects on the fetus, but the use of contrast 103 agents is best avoided if possible. Compressive injuries of the lumbosacral plexus may occur during labor and can be difficult to distinguish from an acutely prolapsed lumbar intervertebral disc. However, the latter is associated with tenderness and rigidity of the lumbar spine, sciatica, and signs of root tension. Electrophysiological studies may also clarify the diagnosis, depending on whether there is evidence of involvement of the paraspinal muscles (which are supplied proximally from the nerve roots). Lumbosacral plexus lesions result from compression by the fetal head or obstetrical forceps of the roots of the sciatic nerve. This injury is especially likely when there is minor disproportion or when midforceps are used during delivery because of malpresentation. Anatomical features of the pelvis that predispose to this complication include a straight sacrum; a flat, wide posterior pelvis; posterior displacement of the transverse diameter of the inlet; wide sacroiliac notches; and prominent ischial spines. Symptoms are usually unilateral and develop immediately after delivery. There is often predominant involvement of peroneal fibers, as reflected by the distribution of motor and sensory findings. With mild injuries, the prognosis for recovery is excellent, but recovery may be prolonged and incomplete if axonal degeneration has occurred. Electrophysiological studies therefore assist in determining prognosis. Treatment of severe cases with calipers and a night cast prevents contractures. Despite an obstetrical lumbosacral plexus palsy, delivery in subsequent pregnancies need not be by cesarean section. However, cesarean section is appropriate if the infant is large or there are premonitory symptoms suggesting nerve compression with attempted engagement of the fetal head during the last 4 weeks of pregnancy. Brachial plexopathy may occur on a familial basis, and in some of the reported cases there has been a clear association of attacks with pregnancy or the puerperium; inflammation, 104 probably immune-based, appears pathogenic at least in some instances. PERIPHERAL NERVE DISORDERS
Entrapment Neuropathies Two entrapment neuropathies are especially likely to occur during pregnancy. Carpal tunnel syndrome occurs often, possibly because of fluid retention. Nocturnal pain and paresthesias in the hand disturb sleep. Weakness of the thenar muscles occurs in more advanced cases. The clinical and electrophysiological features of the disorder do not require description here. When the syndrome develops during pregnancy, it most often does so in the third trimester (although it may present earlier), and typically settles within approximately 3 months of
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delivery, often within 2 weeks 106; however, symptoms with onset in early pregnancy are less likely to improve after delivery. Treatment should be conservative. The use of a nocturnal wrist splint is often helpful for alleviating symptoms; the splint is placed on107 the dorsal surface with the aim of maintaining the wrist in a neutral or slightly flexed position. Salt restriction, local injection of corticosteroids into the carpal tunnel, or treatment with diuretics sometimes helps. The patient should be reassured about the benign nature of her symptoms. Surgical division of the anterior carpal ligament is usually unnecessary unless symptoms become intolerable or continue to progress in the weeks after delivery. In some instances, carpal tunnel syndrome develops in the puerperium; it may then relate to the position of the hand and wrist during breast-feeding. Treatment is conservative, but the wearing of wrist splints at such a time may be difficult. Entrapment of the lateral femoral cutaneous nerve is also common during pregnancy, 108 especially in its later stages, and leads to the syndrome of meralgia paresthetica. Pain, paresthesias, and numbness occur about the outer aspect of the thigh, usually unilaterally, and are sometimes relieved by sitting. Clinical examination reveals no abnormality except in advanced cases, when cutaneous sensation may be disturbed in the affected area. Symptoms generally settle spontaneously within a few weeks of delivery, and the patient can therefore be reassured. In rare instances, however, the pain has reportedly been so severe that labor has been induced early. Local injection of hydrocortisone about the region where the nerve lies medial to the anterior superior iliac spine may provide temporary benefit. Symptomatic relief may also follow treatment with low-dose tricyclic antidepressants; anticonvulsant drugs such as carbamazepine are best avoided during pregnancy.
Traumatic Mononeuropathies A number of isolated nerve lesions may occur as a complication of various obstetrical maneuvers. Lower-limb nerve injury has been associated with nulliparity and a prolonged 109 second stage of labor. The obturator nerve may be injured when the patient is in the lithotomy position because of angulation as the nerve leaves the obturator foramen. It may 110 also be compressed between the fetal head and the bony pelvic wall. Similarly, an isolated femoral neuropathy may occur by angulation and pressure from the inguinal ligament when the thighs are markedly flexed and abducted, as when anesthetized patients are placed in the lithotomy position; stretch of the nerve by excessive hip abduction and external rotation may also occur. The saphenous nerve is sometimes injured by pressure from leg braces when the patient is improperly suspended in the lithotomy position. The most common cause of sciatic nerve palsy is a misplaced deep intramuscular injection, but this nerve can also be injured by stretch when a patient is placed in stirrups on the obstetrical table. To avoid such injury, the knee and hip joints should be well flexed and extreme external rotation of the hip avoided. The common peroneal nerve may be injured in the region of the head of the fibula by 111 pressure from the leg braces of the obstetrical table, especially in anesthetized women. The clinical features of all these neuropathies are well known and are not recapitulated here. Damage during labor and delivery to the innervation of the sphincter muscles in the pelvic floor may be responsible for stress incontinence of urine or feces, as discussed in Chapter 33.
Bell's Palsy Idiopathic lower motor neuron facial palsy is common and shows a definite association with pregnancy, speculatively attributed by some to fluid retention, a viral inflammatory reaction, or 112 pregnancy-related immunosuppression. Approximately 85 percent of cases occurred during the third trimester of pregnancy or the puerperium. The onset of Bell's palsy during pregnancy has been related to hypertensive disorders, implying that patients who develop Bell's palsy during pregnancy should be monitored closely for hypertension or 113 pre-eclampsia. Although most patients with Bell's palsy recover completely without treatment, such recovery may be less likely for women with a complete palsy developing 114 during pregnancy than for the general population. Despite questions concerning the validity of trials assessing its therapeutic efficacy, treatment with corticosteroids is generally prescribed for Bell's palsy, especially if a poor prognosis is anticipated because of severe pain or a clinically complete palsy and if patients are seen within the first week of the disorder.
Polyneuropathies There is no specific polyneuropathy of pregnancy, but any type may occur during the gestational period. Nutritional deficiency is probably the most likely cause in patients from one
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of the developing nations or in those with hyperemesis. There may be evidence of peripheral nerve involvement in patients with hyperemesis gravidarum complicated by Wernicke's encephalopathy and sometimes by Korsakoff's syndrome. Diagnosis is confirmed by finding a marked reduction in blood transketolase activity and a marked thiamine pyrophosphate effect. As in nonpregnant women, treatment is with thiamine, 100 mg being given once intravenously and then intramuscularly for several days until a satisfactory diet is ensured. Vitamin B12 deficiency was discussed earlier (see p. 682). Guillain–Barré syndrome may occur during any stage of pregnancy. A Scandinavian epidemiological study has suggested that the disorder has a lower incidence during 115 pregnancy but an increased incidence in the first month of the postpartum period. It may be associated with antecedent infections such as with Campylobacter jejuni or 116,117 cytomegalovirus. Its course is not influenced by pregnancy. Approximately 3 percent of patients have one or more relapses, sometimes several years after the initial illness, and they 118 occasionally occur in relation to pregnancy. There has been a case reported of a mother with cytomegalovirus-related acute inflammatory neuropathy that developed approximately 10 weeks before delivery of a healthy infant who, in turn, developed a neonatal inflammatory 119 neuropathy after several days. The author is unaware of other cases of both maternal and fetal or neonatal involvement. Serial ultrasonographic fetal monitoring has sometimes been performed but usually reveals 120 Early ventilatory normal fetal movement, even when paralysis is severe in the mother. 121 support may be helpful in preventing fetal hypoxia. Hypotensive episodes due to autonomic involvement may necessitate volume expansion to ensure adequate placental perfusion. The maternal outcome appears unaffected by early delivery. The Guillain–Barré syndrome is treated as in nonpregnant women; experience with plasmapheresis or intravenous immunoglobulin therapy, however, is more limited. Delivery may require forceps or assisted extraction devices because of weakness of the abdominal muscles, which may reduce the ability to increase the intra-abdominal pressure voluntarily; uterine contractions are normal. One study suggested that there is an increased risk of relapse of chronic inflammatory 122 demyelinating polyneuropathy during pregnancy. Most relapses occur late in pregnancy or in the puerperium. There are no specific fetal complications. Treatment is as in nonpregnant women, but concerns regarding plasmapheresis and intravenous immunoglobulin merit reiteration; there is further concern about the use of azathioprine, cyclosporine, and cyclophosphamide, which may retard fetal growth and have other adverse effects, including potential teratogenicity. Multifocal motor neuropathy with conduction block may be exacerbated during pregnancy but responds to 123 intravenous immunoglobulin therapy; after pregnancy, power reverted to its previous level. Pregnancy may lead to acute exacerbations in the hepatic type of porphyria. The usual neurological manifestation is a polyneuropathy that is predominantly motor but sometimes has pronounced autonomic accompaniments. Cerebral manifestations may also occur. In many patients with hepatic porphyria, however, pregnancy is well tolerated. Relapses may occur at any time, but are most likely during early pregnancy and may then lead to spontaneous abortion. Patients with this disorder who are contemplating pregnancy must therefore understand the implications and uncertain outcome, and they must be monitored closely during the gestational period. Caution must also be exercised in the medications used during and after labor because they may provoke exacerbations. MYASTHENIA GRAVIS Myasthenia gravis, an autoimmune disorder of neuromuscular transmission, is associated most commonly with antibodies against muscle nicotinic acetylcholine receptors; in seronegative cases, antibodies against muscle-specific kinase (MuSK) are often present. Exacerbations of myasthenia gravis may occur in relation to the menstrual period. The disorder may be influenced in an unpredictable manner by pregnancy, and the effect of pregnancy may vary in124 the same patient on different occasions. Pregnancy does not worsen the long-term outlook. The severity of the myasthenia at the time of the pregnancy does not predict the occurrence of exacerbation or remission. Remission occurs during pregnancy 125 in approximately one third of cases, relapse in another one third, and no change in the remainder. A significant additional 126 number of relapses occur in the postpartum period, when they tend to be particularly severe. Relapses may occur at any time during the pregnancy. Severe relapse of the disorder may suggest the need for termination of pregnancy, but termination does not necessarily lead to clinical benefit. The myasthenia must be treated effectively but, as indicated earlier, the safety (to mother or fetus) of cholinesterase inhibitors, immunosuppressive agents, plasmapheresis, and intravenous immunoglobulins during pregnancy is not completely clear; the potential risks of such treatment, however, must be
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balanced against the risks to both mother and fetus of myasthenic crisis. Plasmapheresis or intravenous immunoglobulin therapy has been used safely and effectively in myasthenic 125 patients during pregnancy. Myasthenia gravis has little effect on pregnancy itself, unless it leads to maternal respiratory inadequacy; weakness of the respiratory muscles may be exacerbated by a restriction of diaphragmatic excursions by the growing fetus. There is sometimes a marked contrast between the strength of uterine contractions during the second stage of labor and the severity of skeletal muscle weakness. Enemas should not be given because they may precipitate a myasthenic crisis. The vacuum extractor is often used to shorten the second stage of 125 labor. Cesarean section is best reserved for patients in whom it is indicated for obstetrical reasons. Regional anesthesia rather than general anesthesia is desirable, and the use of muscle relaxant drugs should be avoided if possible. Magnesium sulfate should not be used in myasthenic patients with toxemia because of its effects on neuromuscular transmission. In a population-based cohort study, no significant differences were found in perinatal mortality, mean gestational age, or birth weight between the offspring of myasthenic and 128 nonmyasthenic women. Breastfeeding is not contraindicated. Neonatal myasthenia, a transient disorder that may relate to placental transfer of maternal antibodies against acetylcholine receptors, occurs in approximately 10 to 15 percent of the newborn infants of myasthenic women, regardless 124 of the duration or severity of the maternal illness or anti–acetylcholine receptor antibody titer. Infants of myasthenic mothers should therefore be watched carefully for clinical signs of the disorder: a poor cry, respiratory difficulties, weakness in sucking, feeble limb movements, and a weak Moro reflex. Symptoms generally become apparent within the first 3 days of birth but are not usually evident immediately after birth. The neonatal disorder can be treated with anticholinesterase drugs if necessary, and it usually subsides within 6 weeks of delivery. Its occurrence in one child does not imply that subsequent children born to the same mother will have the disorder. The transient neonatal form of myasthenia is distinct from congenital myasthenia, which is rare, occurs in children born to healthy mothers, and is a life-long disorder that varies in type with age of onset, severity, and pathogenesis. MYOTONIC DYSTROPHY The weakness and myotonia of myotonic dystrophy type 1 may worsen during pregnancy, and the course of the disorder sometimes appears to accelerate during the gestational period. Women with early-onset myotonic dystrophy129are more likely to experience a complicated pregnancy than those with later onset. A number of obstetrical complications have been reported, including threatened, spontaneous, and habitual abortion; ectopic pregnancy; and placenta praevia. Perinatal loss (stillbirths or neonatal deaths) is increased and has been related to congenitally affected fetuses and associated complications of the 129 130 pregnancy. Hydramnios has been attributed to diminished fetal swallowing. Premature onset of labor in patients with myotonic dystrophy has sometimes been attributed to abnormalities of uterine muscle. The uterus may fail to contract normally during labor, so that the first stage is prolonged, and retention of the placenta and postpartum hemorrhage may occur. Skeletal muscle weakness may also lead to difficulties during the second stage of labor. If anesthesia is required for obstetrical reasons, depolarizing muscle relaxant drugs should be avoided because they may cause myotonic spasm, and nondepolarizing drugs are given in reduced dosage to patients who are taking quinine for their myotonia. Electrocardiographic monitoring facilitates the early recognition of cardiac arrhythmias, to which patients with myotonic dystrophy are prone, and which may require a pacemaker. 130 General anesthetics may lead to marked respiratory depression, and regional analgesia is the preferred method of management. Type 2 myotonic dystrophy (CCTG expansion in intron 1 of the ZNF9 gene) may first become manifest during pregnancy, with worsening occurring in subsequent pregnancies, for uncertain reasons. When initial symptoms occur before or during pregnancy, marked improvement131,132 often follows delivery, with a recurrence of symptoms in subsequent In one series, preterm labor occurred in 50 percent of pregnancies and pregnancies. was more likely in women who developed the first symptoms or a deterioration of the myotonic dystrophy during pregnancy compared with those in whom an influence of gestation on the disease course was inapparent. No increased obstetric risk was found, and early 131 pregnancy loss rate was normal. Myotonic dystrophy type 1 may occur congenitally among the offspring of mothers with the disease. Magee and colleagues calculated that the risk of a child having congenital myotonic dystrophy is 59 to 100 percent if the maternal CTG expansion is greater than 1 to 4 kb, as
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opposed to 17 percent if the expansion is less than 1 kb. An affected mother is more likely to have a child with congenital myotonic dystrophy in a first pregnancy if she has multisystem disease when pregnant, age at onset is less than 30 years, her father is the affected parent, and CTG expansion is more than 1 kb; however, even133subclinically affected women with low repeat sizes can have congenitally affected offspring. Recurrence risk to further children is high if an affected woman has given birth to133one child with congenital myotonic dystrophy and has been estimated as nearly 100 percent. There may be a history of hydramnios or reduced fetal activity during late pregnancy. Affected infants may die within hours or a few days of birth. Clinical features of the disorder in such infants include facial diplegia, hypotonia, respiratory distress, feeding difficulties, delayed motor development, and mental 130 retardation. Talipes is also common. Myotonia is absent clinically in neonates with the congenital form of myotonic dystrophy but is uniformly present in children 10 years or older. 131,134 Myotonic dystrophy type 2 has not been reported in congenital form. In congenital myotonic dystrophy, transmission is generally via the mother. The data suggest that the disorder results from the combination of the gene 130 responsible for the disorder in adults, with some additional maternally transmitted factor. The gene causing myotonic dystrophy type 1 is on chromosome 19q13.2-q13.3 and has variable penetrance; increasing numbers of triplet repeat expansions govern development of clinical disease. Genetic counseling is an important consideration for women with myotonic dystrophy who are contemplating pregnancy. Counseling and planning of pregnancy may be difficult in patients with mild mental retardation or behavioral disturbances. Prenatal detection of the disorder provides the opportunity for abortion of an affected fetus. ECLAMPSIA AND PRE-ECLAMPSIA Reference has not been made in this chapter to eclampsia (defined as the occurrence of seizures or coma in a patient with pre-eclampsia), which is usually treated by obstetricians rather than neurologists. The neurological manifestations of pre-eclampsia or eclampsia include headache, tinnitus, diplopia, visual blurring, scotomas, and transient blindness that may arise cortically. The pathophysiological basis of the seizures or coma that occurs in patients with eclampsia is unclear, but the cerebral dysfunction has been attributed to a number of factors, including intensive vasoconstriction, endothelial damage, cerebral edema, and disseminated intravascular coagulation in the cerebral microcirculation. The relationship between hypertension, seizures, and cerebral dysfunction is unclear and unpredictable, but a further increment in the previously elevated blood pressure or an exacerbation of headache may be noted. Imaging (CT scans or MRI) may reveal cerebral edema, ischemia, infarction, or hemorrhage, and angiographic evidence of vasospasm is sometimes found; the radiological findings resemble those in hypertensive encephalopathy. Treatment generally consists of controlling hypertension, preventing convulsions, and reducing cerebral edema. In extreme cases, termination of pregnancy may be necessary. In general, seizures can be controlled with intravenous diazepam, with the addition of phenytoin if necessary. Many obstetricians prefer to use magnesium sulfate to control eclamptic seizures, and some 135,136 justification exists for this approach, which may be superior in this context to phenytoin 137 or diazepam. A common regimen is to administer 10 g intramuscularly followed by 5 g intramuscularly every 4 hours, depending on renal output. The aim is to achieve a serum magnesium level of 5 to 8 mEq/L. Other therapeutic approaches reflect obstetrical management and include prompt delivery, and need not be recapitulated here. Pre-eclampsia (hypertension, proteinuria, and edema, occurring between the 20th week of gestation and 48 hours postpartum) may present with a variety of manifestations due to involvement of such different organs as the kidney, liver, heart, central nervous system (CNS), or blood-clotting system. There is increasing evidence that pre-eclampsia relates to endothelial dysfunction secondary to excessive amounts of circulating factors released by the 138–141 and to a subclinical, chronic consumptive coagulopathy. It may be clinically placenta impossible to distinguish between pre-eclampsia and either thrombotic thrombocytopenic purpura or the hemolytic-uremic syndrome. Hematologically, however, pre-eclampsia is characterized by disseminated intravascular coagulation and reduction of plasma antithrombin III activity, in contrast to thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. The so-called HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), a variant of pre-eclampsia, frequently has major neurological consequences such as intracerebral hemorrhage. The reversible posterior leukoencephalopathy syndrome is sometimes considered to be indicative of eclampsia, even when there are no other features of eclampsia (proteinuria, 142 hypertension). It is characterized by the gradual onset of headache, confusion or an impairment of consciousness, visual changes, and seizures, associated with edema of the
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posterior cerebral (parieto-occipital) white matter on imaging studies. The MRI findings consist most often of 143 punctate or confluent areas of increased signal on proton density and T2-weighted images. Treatment is as for pre-eclampsia or eclampsia. Thrombotic thrombocytopenic purpura is characterized by fever, Coombs-negative hemolytic anemia, thrombocytopenic purpura, fluctuating neurological involvement, and renal disease, and it may simulate pre-eclampsia. Its neurological features are discussed in Chapter 13. Thrombotic thrombocytopenic purpura may develop during the antepartum period, often before approximately 24 weeks of gestation, and may result in infant death, although successful treatment may permit prolongation of the pregnancy. Treatment is by plasma infusion, plasma exchange, or plasmapheresis. Platelet transfusions should be avoided 144 because they may trigger an exacerbation. Antiplatelet agents (such as aspirin or dipyridamole) usually are not effective, but treatment with corticosteroids may be helpful. Postpartum hemolytic-uremic syndrome is similar to thrombotic thrombocytopenic purpura, and many consider it within the same spectrum. Weiner has recommended that if the differential diagnosis is between thrombotic thrombocytopenic purpura and pre-eclampsia and the gestational age is 34 weeks or greater, 122 the plasma antithrombin III activity level should be determined and the patient delivered. The correct diagnosis will probably be pre-eclampsia, in which case the plasma antithrombin III activity level is diminished and the patient will begin to recover soon after delivery. If the antithrombin III level is normal and the patient does not recover quickly, it should be assumed that the correct diagnosis is thrombotic thrombocytopenic purpura, and plasma therapy should be initiated. If the patient is less than 28 weeks pregnant when the problem presents, the plasma antithrombin III activity level should be measured before delivery, and if the fetal condition is satisfactory, plasma therapy should be tried. If the patient's response is rapid, a diagnosis of thrombotic thrombocytopenic purpura is supported. By contrast, if there is no response to therapy, the probable diagnosis is pre-eclampsia and the patient should be delivered. Previous
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Table of Contents This Chapter by Chapters
Keyword Index
Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 36 Drug-Induced Disorders of the Nervous System FRANK L. MASTAGLIA •
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HEADACHE Vascular Headaches Medication Overuse Headache Benign Intracranial Hypertension (Pseudotumor Cerebri) Aseptic Meningitis STROKE SEIZURES COMA ENCEPHALOPATHY NEUROPSYCHIATRIC DISORDERS Behavioral Toxicity Delirium and Confusional States Affective Disorders Psychoses Hallucinatory States Cognitive Impairment MOVEMENT DISORDERS Dystonic-Dyskinetic Reactions Akathisia Tardive Dyskinesia and Other Disorders Choreoathetosis Parkinsonism Neuroleptic Malignant Syndrome Tremor Tics Myoclonus CEREBELLAR SYNDROMES OTOTOXICITY VISUAL DISORDERS Pupillary Changes Refractive Changes Retinopathy Optic Neuropathy Disorders of Color Vision
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Cortical Blindness Diplopia Nystagmus DISORDERS OF TASTE AND SMELL SPINAL DISORDERS AUTONOMIC DISORDERS Postural Hypotension Bladder Dysfunction Sexual Dysfunction NEUROMUSCULAR DISORDERS Peripheral Neuropathies Antineoplastic Drugs Antimicrobial Agents Antirheumatic Drugs Cardiovascular Drugs Lipid-Lowering Agents Hypnotic and Psychotropic Drugs Other Drugs Neuromuscular Transmission Disorders Muscle Disorders Lipid-Lowering Agents Acute Rhabdomyolysis Mitochondrial Myopathies Dyskalemic Myopathies Inflammatory Myopathies Glucocorticoid Myopathy Acute Quadriplegic Myopathy Autophagic Myopathies Malignant Hyperpyrexia Myalgia and Cramps Drug-Induced Myotonia Other Drugs
Adverse drug reactions are a frequent cause of morbidity and admission to hospital and a 1 major burden on the health care budget. The introduction in many countries of spontaneous reporting schemes has led to increasing awareness of such reactions and has played an important role in identifying new drug hazards and risk factors that predispose to them. Drug reactions commonly involve the nervous system, resulting in a variety of disorders that may be serious and even life-threatening and that may mimic many naturally occurring neurological disorders. Unlike many of the latter, most drug-induced disorders are potentially reversible if the offending agent is identified and withdrawn. It is therefore essential that the possibility of an iatrogenic condition should be considered in any patient with neurological symptoms, and a full drug history should always be obtained with this possibility in mind. The spectrum of drug-induced neurological disorders is very wide, ranging from disturbances of neuromuscular or autonomic function to seizures, movement disorders, and syndromes of raised intracranial pressure, stroke, cognitive dysfunction, and encephalopathic states. HEADACHE Drugs may cause headache by inducing vasodilation, raised intracranial pressure, or aseptic 2 meningitis and may exacerbate a preexisting headache disorder such as migraine. In addition, medication-induced headache accounts for the symptoms of up to 8 percent of 3 4 patients with headache and is often unrecognized.
Vascular Headaches Many drugs can cause vascular headaches by inducing vasodilation. These include antihistamines, sympathomimetic agents, amyl nitrate, nitroglycerin, nicotinic acid, hydralazine, prazosin, pentoxifylline, cyclandelate, nifedipine, perhexiline, theophylline, 5 aminophylline, terbutaline, and dipyridamole. Similar headaches may also occur after withdrawal of various drugs, including amphetamines, ergotamine, caffeine, methysergide, octreotide, and benzodiazepines. 6
Headache may also occur during treatment with cyclosporine, bromocriptine, dopamine, and the nonsteroidal anti-inflammatory drugs indomethacin, phenylbutazone, naproxen, 5 ketoprofen, diclofenac, alclofenac, and ibuprofen, particularly when treatment is first begun. Severe and persistent headache may also occur in some patients treated with H2-receptor
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antagonists (e.g., cimetidine and ranitidine) and with the proton pump inhibitors (e.g., omeprazole and lansoprazole). Severe headaches associated with hypertension may develop when patients taking monoamine oxidase inhibitors are treated with amphetamines, imipramine, ephedrine, or other sympathomimetic agents or consume foods with a high tyramine content. Headache is also a common transient reaction7 after vaccination and intravenous immunoglobulin therapy, particularly in migraine sufferers. Oral contraceptives and female hormonal preparations may cause migrainous headaches or 8 exacerbate a preexisting migrainous tendency, as may vasodilators, cyclosporine, and some of the other drugs already discussed.
Medication Overuse Headache This is now recognized as being the third most frequent form of headache encountered in 9,10 and one which is often unrecognized A paradoxical increase in frequency clinical practice of headaches commonly occurs in migraine or11–13 cluster headache sufferers taking excessive on a regular basis and is an indication for ergotamine-containing preparations or14triptans gradual withdrawal of the medication. Chronic analgesic dependency may have a similar effect in patients with migraine or tension headaches, leading to rebound headaches and 15 chronic daily headache.
Benign Intracranial Hypertension (Pseudotumor Cerebri) A number of drugs have been associated with the development of benign intracranial hypertension, which is characterized by headache, papilledema, and at times, diplopia and impairment of vision. These include oral contraceptives, estrogens and progestational 16 agents, growth hormone, anabolic steroids, various antibiotics (tetracyclines, minocycline, ampicillin, nalidixic acid, nitrofurantoin), nonsteroidal anti-inflammatory agents (naproxen, ibuprofen, indomethacin), vitamin A and retinoids (isotretinoin, etretinate), danazol, amiodarone, perhexiline, thyroxine, ketamine, nitrous oxide, and corticosteroids (or 5,17 corticosteroid withdrawal).
Aseptic Meningitis Drug-induced aseptic meningitis has been associated most frequently with the use of 5,18–20 particularly in patients with nonsteroidal anti-inflammatory drugs or cotrimoxazole, systemic connective tissue diseases, and may occasionally occur with other antimicrobial 21 ciprofloxacin, and cephalosporins, and agents, such as sulfasalazine, penicillin, amoxicillin, 22–24 Aseptic meningitis may also develop after with carbamazepine and pentoxifylline. 7 intravenous immunoglobulin therapy but is uncommon. Intrathecal administration of anesthetic agents, contrast media, methylprednisolone, methotrexate, and cytarabine may 23 also cause aseptic meningitis. STROKE 25
Women taking oral contraceptives have an increased risk of cerebral venous thrombosis 5 and ischemic stroke, although the absolute risk is small. The risk of stroke was found to be greater with the higher dose estrogen preparations but was not significantly increased in women taking low-dose oral contraceptives, although there was a positive interaction with 26,27 Oral contraceptives have also been implicated in causing cigarette smoking. 5 subarachnoid hemorrhage, particularly in women who smoke. Postmenopausal estrogen or estrogen-progestogen replacement therapy has not been associated with an increased risk of 28,29 The30risk of ischemic stroke is increased in women treated with tamoxifen for stroke. breast cancer. The inappropriate use of antihypertensive drugs is an important cause of iatrogenic stroke, particularly in the elderly and in patients with cerebrovascular disease. These drugs should be used with caution, particularly in individuals with previous symptoms of cerebral ischemia, and should only be administered when there is sustained and significant elevation of blood pressure. Patients taking anticoagulant drugs have an increased risk of intracerebral and other forms of intra-cranial hemorrhage, particularly with poorly controlled or long-term therapy. In addition,31 patients with heparin-induced thrombocytopenia have an increased risk of ischemic stroke. The use of aspirin for primary or secondary prevention of ischemic stroke has been
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considered to be a possible risk factor for intracerebral hemorrhage, although a recent 32 case-control study did not support this. Intracerebral or subarachnoid hemorrhage may occur after intravenous, oral, or intranasal administration of33amphetamines and related compounds that can cause acute elevation of in patients taking diet pills, blood pressure. Intracranial hemorrhage has also been reported 34 decongestants, and stimulants containing phenylpropanolamine, and pseudoephedrine. Intracerebral hemorrhage or ischemic stroke may occur in individuals taking high doses of 35,36 and of cocaine, amphetamines, methylphenidate, or ephedrine-containing preparations heroin. These drugs, as well as phenylpropanolamine, pseudoephedrine, oxymetazoline, allopurinol,23penicillin, and ergot alkaloids, have also been associated with cerebral vasculitis. Cerebral and myocardial ischemia may occur in patients given cisplatin-based combination 37 associated chemotherapy. Combination chemotherapy including l-asparaginase has been 38 The risk of with the development of cerebral venous or arterial thrombosis and hemorrhage. 39 cerebral and other ischemic lesions is increased with overuse of ergotamine. SEIZURES Many drugs may induce seizures in healthy individuals and especially in those with 23,40,41 (Table 36-1). In a42large hospital series, preexisting epilepsy or a low seizure threshold drug-induced seizures accounted for 1.7 percent of all seizure cases. In this series, single (45%) or multiple (40%) generalized seizures occurred and 15 percent of patients developed status epilepticus. Generalized seizures with focal features were common, and simple partial seizures occurred in only 4 percent of patients. The drugs most frequently implicated were 42 isoniazid, insulin, lidocaine, and psychotropic medications. In a survey of seizures associated with drug intoxication and poisoning in the San Francisco Bay area, the most frequent causes were tricyclic antidepressants, psychostimulant drugs, theophylline, and 43 isoniazid. Some drugs are more likely than others to cause seizures, particularly those administered in high doses by the intrathecal or intravenous routes and those that cross the blood–brain barrier. In the case of a number of the drugs listed in Table 36-1, seizures have been reported only rarely and the association remains circumstantial. Click here to view this table.... A number of factors predispose to the occurrence of drug-induced seizures. Patients who have such seizures often have a family history of epilepsy, suggesting that they may have a genetically determined low seizure threshold. Individuals with preexisting cerebral or systemic disease may also have a lowered seizure threshold. Penicillin-induced seizures are more likely to develop with high-dose intravenous or intrathecal administration of the drug and in patients with renal failure who develop high blood levels due to reduced excretion. Other drugs that may accumulate as a result of renal failure and cause convulsions include meperidine, imipenem, nalidixic acid, cephalosporins, cimetidine, lithium, and 44 erythropoietin. Seizures have been reported to occur in 1.5 to 6 percent of patients treated with cyclosporine, especially in renal or liver transplant patients who have high blood levels of 6 the drug. Intravenous administration of lidocaine, mepivacaine, or theophylline may cause convulsions, 5 especially in patients with liver disease or heart failure. A number of therapeutic agents such as oxytocin, carbamazepine, and selective serotonin reuptake inhibitors (SSRIs) may induce 5,45 Withdrawal of benzodiazepines, barbiturates, tricyclic seizures by causing hyponatremia. antidepressants, alcohol, or baclofen is an important cause of seizures, particularly if these drugs are discontinued too abruptly. Withdrawal of anticonvulsant drugs in epileptic patients is an important cause of seizures or status epilepticus and should always be carried out gradually. Conversely, excessively high doses and serum concentrations of phenytoin, carbamazepine, and other anticonvulsants may aggravate epilepsy or induce new seizure types or status 46–48 Carbamazepine may aggravate absences or myoclonic or atonic seizures. epilepticus. Benzodiazepines may induce tonic seizures and status epilepticus in patients with Lennox–Gastaut syndrome. Valproic acid and vigabatrin may occasionally induce status 23 epilepticus. Gabapentin may have an adverse effect on myoclonic epilepsy, as may 49 topiramate on focal epilepsy, and tiagabine may induce nonconvulsive status epilepticus. The convulsant effects of isoniazid, aminophylline, local anesthetics, phencyclidine, and 42 seizures even with 51 meperidine are dose related. A number of other drugs may cause 50 antidepressants ; therapeutic doses and blood levels. These include theophylline ; tricyclic 42 and phenothiazines, which induce seizures in 1 to 2 percent of patients. The aliphatic
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phenothiazines chlorpromazine, promazine, and prochlorperazine are more likely to induce 5 seizures than those of the piperazine group, such as fluphenazine and trifluoperazine. Seizures of different types have also been reported in patients treated with the newer 40 neuroleptic drugs clozapine, olanzapine, risperidone, and sertindole. In addition to the tricyclic antidepressants and monoamine oxidase uptake inhibitors, the tetracyclic drug mianserin has also been implicated in causing seizures, as have a number of the 40 SSRIs (e.g., fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, and venlafaxine). COMA Drugs are a common and important cause of coma, which may result from accidental overdosage of drugs such as insulin or oral hypoglycemic agents in patients with diabetes mellitus or, more frequently, from self-administered overdosage with hypnotics, sedatives, 52 antidepressants, analgesics, or various drug combinations. Other drugs that may produce depression of consciousness and coma include phenothiazines, salicylates, acetaminophen (which produces53severe hepatic damage with resulting coma), paraldehyde, 54 5,55 chlormethiazole, acyclovir, valproic acid, and intrathecal baclofen. Certain neurological findings are characteristic of drug-induced coma. The pupils are typically small and reactive but may be dilated and fixed in severe barbiturate intoxication, or pinpoint in opiate poisoning. The corneal reflexes are preserved but may be lost in profound drug-induced coma. Ocular movements, both spontaneous and reflex, are depressed at an early stage, particularly with barbiturate, tricyclic, and phenytoin intoxication, the eyes being typically fixed and divergent without spontaneous roving eye movements and with impaired or 52 absent oculocephalic (doll's head) or oculovestibular (caloric) reflexes. Muscle tone is usually reduced and the deep tendon reflexes depressed, with flexor plantar responses, although in some cases there may be hypertonia, hyperreflexia, decerebrate posturing, and extensor plantar responses, particularly if there has been superadded hypoxia. Muscle twitching, choreoathetosis, myoclonus, and seizures may occur in coma caused by tricyclic 52 agents. The electroencephalogram (EEG) usually shows diffuse slowing of cerebral rhythms or, in cases of barbiturate or benzodiazepine intoxication, prominent generalized beta activity. Alpha-pattern coma, which is characterized by alpha activity with an altered distribution and reactivity, or a combination of alpha and beta activity, occurs in some cases of intoxication 53 with benzodiazepines or chlormethiazole. ENCEPHALOPATHY Certain drugs such as lithium and acyclovir may cause a diffuse disturbance of cerebral function, leading to tremor, asterixis, myoclonus, seizures, ataxia, mental confusion, and obtundation, at times progressing to coma. Such a syndrome may be caused by lithium 56 toxicity but may occur even when blood levels are within the therapeutic range. In some patients with lithium toxicity, the combination of cognitive impairment, myoclonus, mutism, primitive reflexes, and periodic sharp-wave complexes in the electroencephalogram may 57 resemble Creutzfeldt–Jakob disease. Although the neurological abnormalities are usually reversible when treatment is discontinued, cerebellar dysfunction and other neurological 56 deficits may persist and are irreversible in some cases. A reversible myoclonic encephalopathy has been reported in patients with a prolonged exposure to bismuth-containing preparations. This was first reported from Australia in 58 colostomy patients taking bismuth subgallate orally, and there have been subsequent reports of a similar syndrome developing in patients using other oral preparations and 59 bismuth-containing cosmetic creams. A myoclonic encephalopathy may also be caused by aluminum toxicity in patients with renal failure who are undergoing regular hemodialysis 23 60 (dialysis encephalopathy) and with overdosage with carisoprodol. 51
Other drugs that may cause an encephalopathy include penicillin and cephalosporins when administered in high doses, particularly in patients with renal failure, lidocaine and its oral analog tocainide, benzodiazepines in patients on hemodialysis, vigabatrin, valproic acid, phenytoin, carbamazepine, baclofen, isoniazid, levodopa, mefloquine, sulfonamides, podophyllin, the antineoplastic agents l-asparaginase, thymidine, 5-fluorouracil, carmustine (PALA), cytarabine, fludarabine, (BCNU), mechlorethamine, N-phosphonacetyl-l-aspartic acid 23 and doxorubicin and intrathecal metrizamide and iohexol. A severe progressive leukoencephalopathy characterized by dementia, dysarthria, ataxia, and paralysis, at times followed by seizures, coma, and death, may occur in patients treated with high-dose intrathecal, intraventricular, or intravenous methotrexate, particularly if cranial or craniospinal radiotherapy has previously been administered. A posterior
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leukoencephalopathy associated with headache, seizures, cortical blindness, and lesions in the parieto-occipital regions of the brain has been increasingly recognized in patients treated 6 with cyclosporine. The condition is often associated with hypertension and high blood levels of the drug and is usually reversible. Leukoencephalopathy may also occur in patients treated with cisplatin, cytarabine, 5-fluorouracil, fludarabine, ifosfamide, amphotericin B, interferons, 23 interleukin-2, levamisole, tacrolimus, and arsenical drugs such as melarsoprol. NEUROPSYCHIATRIC DISORDERS Psychiatric adverse drug reactions are common in clinical practice and may take various 61–63 forms.
Behavioral Toxicity This term has been used to cover various nonspecific symptoms such as listlessness, drowsiness, insomnia, irritability, restlessness, anxiety, euphoria, mild depression, excitement, vivid dreams and nightmares, increased sensitivity to light and sound, mood changes, and impaired psychomotor performance, which may occur during treatment with a 61,62 Although such symptoms may be the prelude to a more florid wide range of medications. delirious state, they usually subside gradually if the dose of the drug is reduced. They are encountered most frequently in patients treated with tricyclic agents, lithium, amphetamines, phenothiazines, barbiturates, glucocorticoids, cholinergic drugs, levodopa, anticonvulsants, and some antihistamines. Similar symptoms may be caused by withdrawal of a number of drugs such as benzodiazepines and SSRIs.
Delirium and Confusional States Drugs are an important cause of delirium and confusional states, which are characterized by a fluctuating level of consciousness, diminished awareness, impairment of attention and 61 memory, disorientation, and at times, illusions, hallucinations, and paranoid delusions. The elderly are particularly prone to such reactions, presumably being predisposed by the presence of age-related degenerative cerebral changes. A wide range of drugs may produce these reactions, the tranquilizers and hypnotics collectively being the most important groups. Other important causes include the benzodiazepines, antiparkinsonian drugs, and antidepressants, including the SSRIs, which have been associated with the serotonin 23,64 The last results most frequently from an interaction between seroto-nergic syndrome. drugs and monoamine oxidase inhibitors or tricyclic agents and is characterized by an altered mental state with confusion, agitation, tremor, myoclonus, shivering, hyperreflexia, 64–66 Abrupt withdrawal of SSRI drugs may incoordination, diaphoresis, diarrhea, and fever. also result in a confusional or delirious state associated with twitching, hypertonia, and sensory symptoms.
Affective Disorders Depressive reactions are common during drug therapy. Reserpine and subsequently methyldopa were among the first drugs recognized to cause depression. Depression is less common in patients treated with some of the newer antihypertensive agents such as clonidine, propranolol, and the calcium-channel blockers verapamil and nifedipine. Depression may also occur in patients receiving corticosteroids but is less common than euphoria. It is the most common psychiatric symptom in patients receiving levodopa. Other drugs that may induce depression include oral contraceptives, anabolic steroids, digoxin, indomethacin and naproxen, sulfonamides, retinoids, disulfiram, antituberculous drugs (in particular cycloserine), antineoplastic drugs, histamine H2 antagonists, antiepileptic drugs, baclofen, barbiturates, benzodiazepines, phenothiazines, butyrophenones, and 23,61 interferons. 61 Benzodiazepine, amphetamine, and fenfluramine withdrawal may also cause depression. Although some degree of euphoria is 61 common in patients on various drugs, actual manic or hypomanic reactions are uncommon. Such reactions may, however, occur in patients treated with glucocorticoids or corticotropin, anabolic steroids, thyroid hormone, captopril, chloroquine, isoniazid, ranitidine and cimetidine, levodopa and other dopaminergic agents, baclofen, opiates, pentazocine, monoamine oxidase inhibitors, tricyclic agents, iproniazid, cyclosporine, sympathomimetic amines, amphetamines, benzodiazepines, procyclidine, 23,61 Agitation and 64 hypomania may also occur in the phenylpropanolamine, and hallucinogens. serotonin syndrome associated with the use of SSRI drugs.
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Various drugs have been reported to cause paranoid and schizophreniform psychotic reactions characterized by delusions, hallucinations, and emotional61,63 and thought disorder in Although the the absence of impaired consciousness, particularly in the elderly. drug-induced disorders closely resemble the naturally occurring psychoses, individuals who develop these conditions do not appear to be predisposed to develop idiopathic psychotic disorders subsequently.
Hallucinatory States 61
Certain drugs may cause hallucinations without other features of delirium or psychosis. The hallucinations, which are usually visual, tend to be extremely vivid, are often colored, and are 61 often of animals, sometimes having a microptic or lilliputian dimension. The drugs most frequently involved include tricyclic agents, benzodiazepines, vigabatrin, bromides, methylphenidate, atropine and other anticholinergic drugs after parenteral or even topical administration into the eye, ephedrine, amantadine, bromocriptine, pergolide, levodopa, digoxin, diltiazem, β-adrenergic blockers, prazosin, captopril, disopyramide, pentazocine, buprenorphine, indomethacin, salicylates, cimetidine, aminophylline, acyclovir, and 61 cyproheptadine, as well as cannabis and lysergic acid diethylamide (LSD). Hallucinations, usually auditory and less often visual, are also a feature of withdrawal from alcohol, barbiturates, benzodiazepines, and baclofen.
Cognitive Impairment A number of drugs may cause transient memory impairment—for example, clioquinol, isoniazid, baclofen, and drugs with a central anticholinergic action, such as benzhexol and antidepressant drugs. More severe, but still reversible, cognitive impairment that may mimic dementia may develop in some patients with chronic intake of benzodiazepines, barbiturates, bromides, and67chlorpromazine, with anticonvulsant overdosage in epileptics, and with 61 glucocorticoid and interleukin administration. A number of antiepileptic drugs may have adverse effects on cognitive functions. Some earlier studies suggested that these were less likely to occur with carbamazepine or sodium valproate than with phenytoin or phenobarbital. However, more recent studies in epileptic patients and healthy volunteers have shown that, 68 at therapeutic serum concentrations, the adverse effects are comparable for these four drugs. The newer antiepileptic drugs gabapentin, lamotrigine, vigabatrin, tiagabine, remacemide, 68,69 and topiramate appear to have fewer cognitive effects than the older agents. MOVEMENT DISORDERS Several groups of drugs may induce involuntary movements or abnormalities of movement, posture, or70–73 muscle tone resembling those associated with naturally occurring extrapyramidal All of the major classes of conventional neuroleptic drugs (phenothiazines, disorders. reserpine, benzoquinolizines, thioxanthenes, and butyrophenones) 74 as well as a 75 number of the clozapine, and more recently introduced atypical neuroleptics such as risperidone, 76 77 olanzapine, and the tricyclic agents, SSRIs, and dopaminergic antiparkinsonian medications have the ability to induce such syndromes, which may take a number of different 78,79 (Table 36-2). These drugs also have the potential to aggravate preexisting forms extrapyramidal disorders such as Parkinson's disease and should therefore be avoided or used with caution in such patients. Click here to view this table.... The reported incidence of drug-induced extrapyramidal disorders varies considerably according to the diagnostic criteria used and the patient groups studied. It is well recognized that there is a marked individual variability in the susceptibility to these reactions; some patients develop side effects even after small doses of a drug, whereas many others take much higher doses and are unaffected. The factors responsible for this variable susceptibility are poorly understood, but age, gender, and genetic factors seem to play a part.
Dystonic-Dyskinetic Reactions An acute dystonic reaction is a well-recognized complication of treatment with neuroleptic drugs such as the phenothiazines and butyrophenones, as well as the tricyclic antidepressants, metoclopramide, and, less frequently, phenytoin, carbamazepine, propranolol, chlorzoxazone,80ondansetron, fluoxetine, and the calcium-channel blockers flunarizine and cinnarizine. The onset is usually within the first few days of starting treatment and may be quite abrupt and alarming. The dystonia may be confined to the muscles of the head and neck, causing facial grimacing, trismus, abnormal movements and
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spasms of the tongue, oculogyric crises, orofacial dyskinesias, torticollis, and retrocollis; or it may be more generalized, with slow writhing movements of the limbs and more prolonged tonic contractions of the axial and limb muscles leading to opisthotonos, lordosis, tortipelvis, and a bizarre gait. The bizarre and protean nature of the manifestations may lead to a mistaken diagnosis of hysteria, tetanus, tetany, or epilepsy. The incidence of this type of extrapyramidal reaction has been estimated to be of the order of 2.5 percent in patients 81 lower in patients treated with treated with neuroleptic drugs and is considerably 82 metoclopramide, prochlorperazine, and haloperidol. Despite their dramatic and at times alarming nature, the acute dystonias are usually self-limited and remit once the drug is discontinued. Severe reactions may be terminated by the intravenous administration of benztropine or diazepam. Acute dyskinetic reactions involving the lips, face, and tongue, and at times the limbs and trunk, occur commonly in parkinsonian patients treated with levodopa and are dose related. These dyskinesias may develop early during the course of treatment with levodopa (or with various dopamine agonists), and they respond to a reduction in dose. With prolonged treatment, dyskinesias become an increasing problem, tending to occur at times of maximal response to the levodopa and alternating with periods of akinesia and severe rigidity (the “on-off” phenomenon). The administration of smaller, more frequent doses of levodopa, or a reduction in the overall dose and the introduction of a dopamine agonist, is sometimes helpful in alleviating this common complication of prolonged levodopa therapy; the on-off phenomenon may also be reduced by concomitant treatment with a catechol-O-methyltransferase inhibitor or amantadine. However, in more severe cases it may be necessary to consider deep brain stimulation.
Akathisia Akathisia is a state of motor restlessness that is characterized by an uncontrollable urge to 83 move about, pace, or even run incessantly. The condition is seen particularly in patients taking dopamine-blocking agents such as phenothiazine derivatives (e.g., fluphenazine, trifluoperazine, and prochlorperazine) and less frequently with the butyrophenones, benzodiazepines, tricyclic agents, SSRIs, levodopa, lithium, monoamine oxidase inhibitors, 5 and vigabatrin. It may also occur with amoxapine and oxazepam withdrawal. The reported incidence of akathisia in groups of patients treated with antipsychotic drugs has ranged from 83 12.5 to 45 percent. Akathisia may also be associated with other extrapyramidal manifestations, such as parkinsonism, tremor, and dystonia. It usually remits within days or weeks of withdrawal of the neuroleptic drug, but it may persist for several months and is occasionally permanent. The most effective treatment for akathisia is to withdraw the offending drug or lower the dose of the medication. Benztropine or diphenhydramine are usually effective in controlling akathisia when given by the intramuscular or 79 intravenous route, and propranolol, amantadine, and clonidine are effective when given orally.
Tardive Dyskinesia and Other Disorders This distinctive involuntary movement disorder occurs most frequently after prolonged treatment with dopamine antagonists, particularly antipsychotic drugs, but also with metoclopramide, promethazine,72prochlorperazine, amoxapine, perphenazine, flunarizine and cinnarizine, and tricyclic agents. Some early studies found tardive dyskinesia in up to 50 percent of patients treated with antipsychotic drugs, but the frequency84appears to be declining since the introduction of the second-generation antipsychotic agents. In contrast to the acute dystonic-dyskinetic syndrome, tardive dyskinesia usually develops after more than 12 months of continuous therapy, although it has been reported with periods as short as 3 months; it occasionally develops after cessation of therapy. The condition is more common and more severe in the elderly, in whom it is less likely to remit than in younger individuals. The condition typically takes the form of an orobuccal dyskinesia with lip smacking and pursing; sucking; jaw opening and closing; protruding, side-to-side, or writhing movements of the tongue; and facial grimacing. The movements tend to be rather stereotyped and, when severe, may interfere with speech or swallowing. In some cases more generalized choreoathetotic movements of the limbs and trunk and repetitive foot tapping are present, and the condition may resemble Huntington's chorea. Less frequently, dystonic posturing of the neck and myoclonic jerking of the distal extremities are also present, and concomitant akathisia or parkinsonism may occur. Dystonia or dyskinesia may also occur with abrupt 85 withdrawal of clozapine.
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Tardive dystonia may be focal or more generalized and may involve the neck, jaw, limbs, or trunk. It is distinguished from the more frequent orobuccal dyskinesia by the dystonic nature of the disorder and is often more disabling. Other tardive syndromes include akathisia, 71 chorea, myoclonus, tremor, tics, or oculogyric crises. The pathophysiological basis for tardive dyskinesia has not been clearly established. The most widely held theory is that, as a result of prolonged dopamine receptor blockade in the corpus striatum, a state of hypersensitivity to endogenous dopamine develops owing to 72 changes in receptor properties or numbers. The severity of tardive dyskinesia is variable, and the condition is not often disabling. It may remit in up to 40 percent of cases, even on continued therapy. In cases where it is possible to withdraw the offending drug, there is usually gradual resolution over a period of several weeks or months, but in some cases the condition persists. Occasionally, remission may occur even several years after withdrawal of antipsychotic drugs. Interruption of therapy when dyskinesia first develops may be beneficial, but there is some evidence that 71,72 repeated interruption leads to an increased prevalence and persistence of dyskinesia. Although many pharmacological agents have been used to treat tardive dyskinesia, none has proved consistently beneficial. The drugs used include, on the one hand, agents with an effect on dopaminergic transmission, such as tetrabenazine, bromocriptine, and levodopa, and on the other hand, drugs with cholinergic action, including deanol, choline, and lecithin. Other drugs reported to be beneficial in some cases include baclofen, propranolol, diazepam, tocopherol, sodium valproate, and the calcium-channel blockers verapamil and diltiazem.
Choreoathetosis A number of drugs may produce chorea, which is characterized by irregular, multifocal, 5 nonstereotyped, semipurposive “fidgety” or jerky movements. At times, chorea is associated with the slower, more sinuous movements of athetosis, or with dystonia. These involuntary movements are thought to result from dopamine overactivity or cholinergic underactivity in the basal ganglia. Chorea or choreoathetosis has been reported with phenytoin intoxication, other anticonvulsants (ethosuximide, valproic acid, carbamazepine, phenobarbital) and clonazepam withdrawal, anticholinergic drugs (e.g., high doses of benzhexol), tricyclic agents, fluoxetine, amphetamines, methylphenidate, amoxapine, pemoline, cimetidine, theophylline, aminophylline, lithium, methadone, antihistamines, cyclosporine, oxymetholone, 23 chorea is rare and may intrathecal baclofen, and oral contraceptives. Contraceptive-induced 86 occur with either high- or low-dose estrogen preparations. Some patients who develop this condition have a past history of rheumatic chorea. In some women, the occurrence of contraceptive-induced chorea may be followed by the development of chorea gravidarum.
Parkinsonism Drug-induced parkinsonism can occur at all ages but is most frequent in the elderly and is probably the most common drug-induced movement disorder. The condition resembles idiopathic Parkinson's disease very closely, bradykinesis usually being the most prominent feature, with a variable degree of facial masking, rigidity, tremor, and gait disturbance. Although tremor has been said to be less frequent than in idiopathic Parkinson's disease, in some series the incidence of tremor has been as high in cases of drug-induced 87 parkinsonism. The drugs most frequently implicated are the neuroleptics, including almost all of the phenothiazines (the most frequent being prochlorperazine), haloperidol, the tricyclics, metoclopramide, lithium, and the calcium-channel blockers (cinnarizine, flunarizine, 88,89 and verapamil). The condition is usually reversible after drug withdrawal or dose reduction. In a group of 48 cases, Stephen and Williamson found that symptoms resolved over a mean period of 7 87 weeks (1 to 36 weeks). Five patients who initially improved subsequently went on to develop idiopathic parkinsonism after an interval of 3 to 18 months, suggesting that the drug had unmasked a latent form of idiopathic parkinsonism. In a study of 36 cases of88 parkinsonism induced by calcium-channel blockers, Garcia-Ruiz and co-workers found that although most patients improved after stopping the drug, tremor usually persisted. In patients who need to continue on neuroleptic therapy, administration of anticholinergic agents such as benzhexol or benztropine may reverse the parkinsonian symptoms. 5 Levodopa may aggravate an underlying psychotic disorder and should be used with caution. In some cases spontaneous improvement occurs even if the causative agent is continued. Prophylactic treatment with anticholinergic agents is not advocated, since it may predispose
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to the development of an irreversible form of tardive dyskinesia.
Neuroleptic Malignant Syndrome The neuroleptic malignant syndrome is a serious and potentially lethal complication of treatment with antipsychotic drugs. It is characterized by hyperpyrexia, severe muscular rigidity, bradykinesis,90–92 tremor, autonomic manifestations, and elevation of serum creatine The drugs most frequently implicated are haloperidol, fluphenazine kinase (CK) activity. and other phenothiazines, thioxanthenes, or combinations of these drugs with each other or with lithium, metoclopramide, loxapine, or tricyclic agents. Clozapine and olanzapine have 93,94 The condition may occur with both high and low doses of either also been implicated. high- or low-potency neuroleptic drugs and may develop after neuroleptic therapy is begun, after an increase in dose, or after the introduction of a second, more potent drug. A similar syndrome has been reported also after abrupt levodopa withdrawal in patients with 95 Parkinson's disease. Although in mild forms of the condition complete recovery may occur within days or weeks of stopping the causative drug, in severe cases metabolic acidosis, myoglobinuria, renal failure, coagulation defects, respiratory failure, shock, seizures, and coma may develop. A mortality rate of up to 20 percent has been reported in some series. Persisting neurological sequelae 90 occur in up to 10 percent of survivors. The underlying pathophysiological mechanism is uncertain, but the current view is that the condition is due to profound dopamine receptor blockade in the striatum and in thermoregulatory and vasomotor centers in the hypothalamus. Treatment involves discontinuation of the causative drug together with vigorous cooling, restoration of fluid and electrolyte balance, and management of any other complications. Specific measures that may be beneficial in reversing the rigidity and akinesia include the use of levodopa, pancuronium, bromocriptine, or dantrolene, or a combination of these drugs. Anticholinergic drugs and nifedipine have also been reported to be effective in some cases.
Tremor 96
Various groups of drugs may cause or aggravate tremor. These include β-adrenergic agonists (e.g., salbutamol, salmeterol); sympathomimetic drugs (e.g., ephedrine, pseudoephedrine, phenylpropanolamine); antiseizure agents (e.g., sodium valproate); antidepressants and mood stabilizers (e.g., tricyclics, SSRIs, lithium); neuroleptic agents (e.g., phenothiazines, butyro-phenones); anti-arrhythmics (amiodarone, procaina-mide, mexiletine); chemotherapeutic agents (e.g., doxorubicin, cytarabine, thalidomide); and immunosuppressants (e.g., cyclosporine, tacrolimus) as well as thyroxine, glucocorticoids, hypoglycemic agents, levodopa, amphetamines, theophylline, and aminophylline. A postural tremor of the hands, head, and trunk resembling essential tremor is not 97 uncommon in patients treated with sodium valproate. The tremor usually develops over a period of several months and remits when the drug is stopped or the dose is reduced. Treatment with propranolol or amantadine may alleviate the tremor. Cimetidine and terfenadine may 98 induce a severe postural and action tremor by aggravating physiological or essential tremor. Postural or action tremor is an early manifestation99of lithium intoxication and is also common in patients taking therapeutic doses of the drug. A postural tremor has 6 been reported in up to 40 percent of patients on cyclosporine. Asterixis may occasionally occur in patients treated with phenytoin, phenobarbital, carbamazepine, sodium valproate, 23 methyldopa, ceftazidime, lithium, or tocainide.
Tics A syndrome resembling Gilles de la Tourette's syndrome has been reported after the 5 administration of dextroamphetamine, methylphenidate, pemoline, or haloperidol in children. Other antipsychotic drugs as well as opiates, clonazepam, carbamazepine, phenobarbital, 72 and fluoxetine have also been reported to cause tics.
Myoclonus Drug-induced myoclonus is uncommon but may occur in patients treated with antipsychotic and tricyclic antidepressant drugs or lithium carbonate. Myoclonus has been reported in 104 100,101 102 103 propofol, vigabatrin, fluvoxamine, chlorambucil, patients105 treated with clozapine, opioids, antibiotics (e.g., penicillin, ticarcillin, carbenicillin, imipenem, cephalosporins), and
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calcium-channel blockers. A clinical picture resembling that of Creutzfeldt–Jakob disease with myoclonus, tremor, cerebellar and extrapyramidal manifestations, cognitive impairment, and periodic sharp-wave complexes in the electroencephalogram has been reported in 57 induced myoclonic jerks in the upper limbs have patients with lithium toxicity. Posturally107 been described in patients on phenytoin and with long-term antipsychotic drug therapy and may be associated with tardive dyskinesia in some patients. CEREBELLAR SYNDROMES Various drugs may cause truncal ataxia, incoordination, and other manifestations of cerebellar dysfunction. Sedatives (e.g., chloral hydrate, barbiturates, benzodiazepines, and paraldehyde) and anticonvulsants (e.g., phenytoin, carbamazepine, primidone) are most often responsible, their effects being dose dependent. Individual tolerance to these drugs varies considerably, but in general symptoms are more likely to develop when high doses are administered too quickly. Ataxia may occur with high doses of most tranquilizers, including diazepam, chlordiazepoxide, and meprobamate; signs of cerebellar dysfunction may be caused more rarely by phenothiazines, monoamine oxidase inhibitors, reserpine, thioxanthenes, and lithium. The latter may cause an isolated cerebellar ataxia or a more diffuse encephalopathy, even with blood levels within the therapeutic range. These disorders are usually reversible when the causative agent is withdrawn or the dose adjusted, but there are occasional reports of permanent cerebellar atrophy or dysfunction in patients treated with 108 lithium or phenytoin. These drugs may also aggravate or unmask a preexisting cerebellar disorder. A cerebellar syndrome has also been reported in bone marrow and liver transplant recipients 6 treated with cyclosporine. A reversible cerebellar syndrome has been described in patients with leukemia or lymphoma treated with high doses of cytarabine; in some patients the drug 109 has also been causes an irreversible cerebellar degeneration. Cerebellar dysfunction 110 reported in cancer patients treated with high- or low-dose fluorouracil, in patients with impaired renal function receiving colistin, and in association with a peripheral neuropathy in some patients taking nitrofurantoin or perhexiline. OTOTOXICITY Over 100 drugs are known to have 111 ototoxic effects, causing damage to the cochlear or vestibular portions of the inner ear. Tinnitus is usually the earliest symptom of cochleotoxicity and, when persistent, is suggestive of impending hearing loss. Vestibulotoxicity may result in vertigo, oscillopsia, and impairment of balance particularly in the dark. The most important ototoxic drugs are the aminoglycoside antibiotics, which may cause inner ear damage that is often irreversible after parenteral, oral, or even topical administration. Since these agents are excreted112 through the kidneys, ototoxicity is more likely to develop in patients with renal insufficiency. All the aminoglycosides can damage both the cochlear and vestibular portion of the inner ear; some (e.g., neomycin, kanamycin, amikacin, and vancomycin) are more cochleotoxic, whereas others (e.g. gentamicin, streptomycin) are preferentially vestibulotoxic; tobramycin is equally vestibulotoxic and cochleotoxic. Vertical oscillation of the surroundings on movement (“bobbing oscillopsia”) is highly characteristic of the vestibular disturbance produced by the aminoglycoside antibiotics. Hearing loss affects the high frequencies initially and is usually irreversible. It may develop within a few days of beginning treatment but is more often delayed and may even develop after administration of the drug has ceased. As a group, the aminoglycosides cause a degeneration of the sensory hair cells of the cochlea, the outer hair cells being most severely affected, accounting for the preferential loss of high frequencies, whereas gentamycin selectively destroys vestibular hair cells, severely impairing vestibular function without 112 affecting auditory function. It is important to have a high level of awareness of this serious complication, to monitor blood levels of the drug, to avoid prolonged courses of gentamycin, and to discontinue the drug if any symptoms of vestibulotoxicity develop. However, some patients may develop irreversible vestibulotoxicity even when blood levels of gentamycin are maintained within the recommended range, and the onset of symptoms may be 112,113 delayed. Other ototoxic antibiotics include minocycline (which is almost exclusively vestibulotoxic), colistin, polymyxin B, erythromycin (which may cause reversible deafness after oral or intravenous administration), metronidazole, vancomycin, and rarely, procaine penicillin, cephalexin, and chloramphenicol. The loop diuretics furosemide, ethacrynic acid, and bumetanide may also cause ototoxicity,
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especially in patients with renal or hepatic impairment or who are also taking an aminoglycoside antibiotic. Salicylates, in particular aspirin, may cause tinnitus, deafness, and vertigo when the serum concentration approaches 300 mg/L. Hearing loss is usually reversible, although recovery may be delayed or incomplete and there are occasional reports of permanent hearing loss. There are also reports of deafness after the use of salicylate-containing ointments. Quinine may cause tinnitus and reversible low-tone hearing loss in a small proportion of patients taking the drug; an idiosyncratic mechanism seems to be involved. Prolonged high-dose administration of chloroquine may cause tinnitus and perceptive deafness that is usually irreversible. A number of cytotoxic drugs including cisplatin, vincristine, misonidazole, bleomycin, and mustine hydrochloride may also cause hearing loss. Cisplatin has been reported to cause a high incidence of tinnitus and high-tone hearing loss; recording of brainstem 114 auditory evoked potentials is helpful in detecting early involvement of the auditory pathway. 115
Other ototoxic drugs include quinidine, deferoxamine, and the β-adrenergic blocker practolol, which caused combined sensorineural deafness and conductive hearing loss due to serous otitis media when it was in general use. There are also rare reports of hearing loss or vestibular dysfunction in patients taking propoxyphene, naproxen, indomethacin, sulindac, 116 metoprolol, nortriptyline, propylthiouracil, flecainide, and interferon-α. VISUAL DISORDERS Drug-induced visual disorders may result from effects on the pupil, refractive mechanisms, retina, optic nerve, and central visual pathways.
Pupillary Changes Parasympathomimetic drugs such as carbachol117 and neostigmine produce miosis, as may morphine, chloral hydrate, and phenothiazines. Mydriasis is more often drug induced and potentially more serious because it may precipitate an attack of acute angle-closure glaucoma in susceptible individuals. Drugs that may cause mydriasis and cycloplegia with blurring of near vision include anticholinergics, antihistamines, monoamine oxidase inhibitors, tricyclic antidepressants, chlorpropamide, indomethacin, hexamethonium, fenfluramine, oral contraceptives, amphetamines, and lysergic acid derivatives.
Refractive Changes In addition to the drugs mentioned earlier that may cause cycloplegia and induced hypermetropia, certain drugs may cause a transient myopia as a result of fluid shifts between the lens and the aqueous humor. These include oral diuretics (chlorothiazide, hydrochlorothiazide, chlorthalidone, and acetazolamide), tetracyclines, sulfonamides, corticosteroids and corticotropin, stilbestrol, phenytoin, thiamine, bromocriptine, and 117 arsenicals, as well as insulin and oral hypoglycemic agents in diabetics.
Retinopathy Chloroquine and related drugs such as hydroxychloroquine, mepacrine, and amodiaquine may cause a pigmentary maculopathy and retinopathy with central and peripheral field defects and impairment of central vision after prolonged administration. Patients treated with these drugs should have regular neuro-ophthalmic examinations as well as electroretinography and electro-oculography to detect early signs of retinopathy. Phenothiazines in high doses may produce a progressive choroidoretinopathy; cardiac glycosides, methylphenidate, and cephaloridine have also been reported to cause pigmentary retinopathy. Macular edema may be caused by oral contraceptives and, rarely, by chlorothiazide and acetazolamide. Other drugs that may interfere with vision through effects on the retina include indomethacin, quinine, tamoxifen, ethambutol, diethylcarbamazine, and vigabatrin, which has been found to cause symptomatic—or more often 118,119 asymptomatic—visual field constriction with prolonged administration.
Optic Neuropathy Optic neuropathy leading to optic atrophy occurred as part of the subacute myelo-opticoneuropathy (SMON) syndrome associated with use of clioquinol that was 23 120 prevalent in Japan. A number of antimicrobial agents including linezolid, chloramphenicol, isoniazid, paraminosalicylate, streptomycin, ethambutol, sulfonamides, 117 griseofulvin, dapsone, and chlorpropamide may also cause optic neuropathy. In the case
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of chloramphenicol, this may be prevented by the prophylactic administration of vitamin B12. Prolonged high-dose treatment with the iron-chelating agent deferoxamine has been reported to cause optic neuropathy with marked reduction in visual acuity, loss of color vision, and 115 delayed visual evoked potentials in addition to hearing loss. Other drugs implicated in causing optic neuropathy include amiodarone, chlorambucil, cisplatin, 5-fluorouracil, vincristine, penicillamine, disulfiram, phenylbutazone, indomethacin, ibuprofen, naproxen, benoxaprofen, morphine, monoamine oxidase inhibitors, retinoids, organic arsenicals, 23,121–124 cardiac glycosides, ergotamine, dideoxyinosine, omeprazole, and interferon-α.
Disorders of Color Vision Disturbances of color vision may result from the effects of drugs on the retinal cone receptors or from optic nerve dysfunction. Xanthopsia (yellow vision) may be caused by a number of drugs, including sulfonamides, streptomycin, methaqualone, barbiturates, digitalis derivatives, 117 thiazide diuretics (in particular, chlorothiazide), and the anthelmintic agent santonin. Other drugs that may cause altered color vision include nalidixic acid, oral contraceptives, cannabis, 117 LSD, and the older-generation anticonvulsants troxidone and paramethadione.
Cortical Blindness Cortical blindness may rarely occur after episodes of severe hypotension during anesthesia or after treatment of hypertension and has also been reported as a complication of 117 chemotherapy during childhood or of excessive doses of salicylates or barbiturates. It may also occur as6part of a posterior leukoencephalopathy syndrome in patients treated with cyclosporine.
Diplopia Certain drugs commonly cause diplopia by leading to breakdown of a latent squint. These include benzodiazepines, indomethacin, chlorpropamide, quinine,117 methaqualone, may be fenfluramine, tricyclic antidepressants, and anticonvulsant drugs. Rarely, diplopia 23,117 due to an extraocular muscle palsy, gaze palsy, or internuclear ophthalmoplegia.
Nystagmus Drug-induced nystagmus is common, particularly in hospital practice. Horizontal vestibular nystagmus is commonly found in patients on high doses of barbiturates, benzodiazepines, anticonvulsants, and other sedative and hypnotic drugs. It is a useful sign of toxicity in patients on anticonvulsant therapy but may occur even with therapeutic doses of some of the other drugs. Other drugs reported to cause nystagmus include monoamine oxidase inhibitors, salicylates, gold, neostigmine, chlordiazepoxide, fenfluramine, and amitriptyline, as well as 23,117 Lithium and various other the ototoxic antibiotics and a number of 125 other medications. drugs may cause downbeat nystagmus. DISORDERS OF TASTE AND SMELL 126
Drug-induced disorders of taste are common. Many drugs may cause metallic, bitter, or salty taste sensations (phantogeusia) or distortions of taste. These include biguanides, ethambutol, vitamin D, gold, allopurinol, penicillin, metronidazole, tinidazole, lincomycin, clindamycin, terbinafine, aspirin, and phenindione. A number of other drugs may cause a reduction or loss in taste, the perception of sweetness being most often affected. These include d-penicillamine (which causes marked hypogeusia in up to 30 percent of patients; this is corrected by the administration of copper), levodopa, captopril, enalapril, etidronate, oxyfedrine, methimazole, carbimazole, thiouracil, phenylbutazone, amphotericin B, griseofulvin, terbinafine, azathioprine, salazosulfapyridine, chlormezanone, carbamazepine, and baclofen. Distortion of the sense of smell or complete anosmia, which may be irreversible, has been associated with the administration of a number of drugs including amoxicillin/clavulanate potassium (Augmentin), intranasal beclomethasone, captopril, doxycycline, and erythromycin. For a more complete list of drugs that can affect smell and taste, the reader is referred to the 126 review by Ackerman and Kasbekar. SPINAL DISORDERS Intrathecal injections of certain drugs may be complicated by infective or aseptic meningitis,
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adhesive arachnoiditis, or toxic effects of the drug on the spinal cord or nerve roots. Intrathecal injection of corticosteroid preparations such as methylprednisolone (Depo-Medrol) can cause an acute meningeal reaction that is thought to be due to the polyethylene glycol detergent in the preparation and is associated with back and leg pain and paresthesias, bladder dysfunction, and a polymorphonuclear pleocytosis and raised protein concentration in 127 methylprednisolone has also been implicated in causing the cerebrospinal fluid. Intrathecal 128 a chronic adhesive arachnoiditis. Other drugs that may be toxic when given intrathecally include baclofen, lidocaine, morphine, chymopapain, methotrexate, cytarabine, and 23 radiological contrast materials. Epidural injections are not associated with such reactions unless there is inadvertent penetration of the dura. Spinal anesthesia is associated with a low incidence of lower-limb numbness, paresthesias, or weakness that is attributable to toxic effects of the anesthetic 129 agent or accidental injury to the lumbosacral roots. Symptoms usually develop immediately after the operation and may persist in126 some cases. The incidence of such complications is even lower after epidural anesthesia. A syndrome of myeloneuropathy with sensory dysesthesias, Lhermitte's sign, leg weakness and spasticity, ataxia, and130 sphincter disturbances has been described after prolonged exposure to nitrous oxide. The condition is thought to be due to the inhibitory effects of nitrous oxide on vitamin B12 utilization and, in some cases, hematological changes of vitamin B12 deficiency are also found. Recovery usually occurs after exposure to nitrous oxide is stopped. Lhermitte's sign has also been reported in association with peripheral neuropathy in 131 patients treated with high doses of cisplatin. Spinal cord compression due to increased extradural adipose tissue has been reported rarely 132 in patients on prolonged corticosteroid therapy. Cord compression may also occur as a result of hemorrhage into the extradural space in patients who are receiving anticoagulants. Acute transverse myelopathy may occur in heroin addicts and is attributed to ischemia due to vasculitis. Spinal cord infarction has also been reported as a result of accidental injection of penicillin into the superior gluteal artery during intramuscular injections in the gluteal 133 region. AUTONOMIC DISORDERS
Postural Hypotension Many drugs may precipitate or aggravate postural hypotension, resulting in “giddiness,” falls, or syncope; focal cerebral ischemic events sometimes occur in patients with cerebrovascular disease. The drugs that most frequently produce this side effect are the antihypertensive agents, vasodilators, diuretics, tricyclic antidepressants, and levodopa.
Bladder Dysfunction Drugs with an anticholinergic action may cause urinary retention by inhibiting parasympathetic postganglionic cholinergic neurons and decreasing bladder tone, particularly 5 if there is already some degree of bladder outflow obstruction due to prostatic hypertrophy. These include atropine, hyoscine, propantheline, benzhexol, benztropine, methixene, orphenadrine, dicyclomine, and other belladonna derivatives. In addition, tricyclic antidepressants and phenothiazines may cause difficulty with micturition and may precipitate acute urinary retention because of their anticholinergic effects. Other drugs that may cause urinary retention include monoamine oxidase inhibitors, disopyramide, ephedrine, salbutamol, 5 terbutaline, and theophylline. A number of other drugs may also interfere with the control of micturition and cause urinary incontinence. These include prazosin, metoprolol, benoxaprofen, depot phenothiazines, 5 clonazepam, and the combination of phenoxybenzamine and methyldopa.
Sexual Dysfunction Many drugs interfere with normal sexual function, causing loss of or decreased libido, impotence, impaired ejaculation, or orgasmic dysfunction. The drugs implicated in causing 134,135 Those most commonly involved are these side effects have been reviewed elsewhere. antihypertensive agents, tricyclic antidepressants, monoamine oxidase inhibitors, major tranquilizers, antihistamines, and anticholinergics, as well as baclofen, cimetidine, clofibrate, disopyramide, bromocriptine and other dopamine agonists, and levodopa.
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NEUROMUSCULAR DISORDERS Many drugs have adverse effects on the peripheral nervous system, neuromuscular junctions, or muscles, resulting in sensory symptoms, weakness, or fatigability. Patients with a preexisting neuromuscular disorder are more likely to develop such adverse effects.
Peripheral Neuropathies Various drugs136 used in clinical practice may interfere with peripheral nerve function and cause a neuropathy. The risk of drug-induced neuropathy is greater in patients with diabetes mellitus or alcoholism, in individuals with a preexisting neuropathy, and in those treated with a combination of more than one potentially neurotoxic drug. Some drugs have an effect principally on sensory nerve function, causing peripheral paresthesias and, in some cases, other signs of a sensory neuropathy. Conversely, other drugs such as dapsone and gold may produce a predominantly motor neuropathy with absent or inconspicuous sensory findings. Most drugs, however, produce a mixed sensory and motor neuropathy that manifests initially with sensory symptoms, and signs of motor involvement only develop at a later stage if the drug is not stopped. Muscle pain and cramps are prominent early symptoms in some cases. The tendon reflexes may be preserved in the early stages but are subsequently depressed or lost, even when motor involvement is absent or inconspicuous. In general, drugs that cause peripheral neuropathy do so by interfering with neuronal or axonal function or with Schwann cell function or, less frequently, through a vascular effect. Localized forms of neuropathy may occur as a complication of intramuscular, intravenous, or intra-arterial injections of certain drugs. Antineoplastic Drugs The Vinca alkaloids, platinum compounds, taxanes, and suramin have the greatest potential 137 to cause neuropathy. Vincristine and other Vinca alkaloids that interfere with intracellular microtubules are particularly neurotoxic. Most patients treated with these drugs for long enough will develop a sensorimotor polyneuropathy with early loss of tendon reflexes and in some cases 110,138 postural hypotension and constipation due to autonomic nervous system Muscle cramps may be a prominent symptom in the early stages, and in involvement. some cases an associated painful proximal myopathy develops. Recovery may occur if the drug is stopped or the dose is reduced, but areflexia and mild sensory symptoms usually persist. In some patients treated with vincristine or other antineoplastic agents such as cisplatin, symptoms of neuropathy may not develop until after the course of treatment is completed or may continue to progress despite the cessation of treatment. This phenomenon 137 has been referred to as “coasting.” The platinum compounds are all potentially neurotoxic and can cause a predominantly sensory neuropathy that may be painful and in severe cases is associated with impaired proprioception and ataxia. Cisplatin and carboplatin have toxic effects on dorsal root ganglion neurons and cause a primary neuronopathy rather than an axonopathy. Oxaliplatin, which has been shown to interfere with axonal ionic conductance, causes transient sensory symptoms after intravenous administration but persisting symptoms may develop after 137,139 repeated infusions. The taxanes paclitaxel and docetaxel, which act by causing aggregation of microtubules, can cause a predominantly sensory or sensorimotor axonal neuropathy affecting large-diameter 140 of other neurotoxic drugs such as myelinated sensory and motor fibers. Coadministration 141 group of cisplatin increases the risk of neuropathy. The recently introduced epothilone 142 drugs, which also act on microtubules, may also cause a peripheral neuropathy. Misonidazole and other compounds that are chemically related to metronidazole and used as radiosensitizing agents in cancer therapy may also induce a sensory neuropathy. Suramin produces a dose-related axonal sensorimotor neuropathy associated with lamellar inclusions 136 in dorsal root ganglia and Schwann cells. Podophyllin derivatives, which have been used to treat disseminated malignancy and also are constituents of certain laxative preparations and topical agents, may cause a peripheral neuropathy of variable severity, which is sometimes associated with signs of spinal cord involvement. A severe demyelinating peripheral neuropathy has been reported after high-dose therapy with cytarabine in patients with 143 leukemia. Various agents including corticosteroids, ACTH, antioxidants, and growth factors have shown 137 limited success in preventing or reversing chemotherapy-induced neuropathy. A recent 144 randomized controlled trial of vitamin E, however, did show a neuroprotective effect.
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Recent experimental studies have shown that erythropoietin and immunophilin ligands such 145 as tacrolimus may be neuroprotective. Antimicrobial Agents A number of antimicrobial drugs may cause a peripheral neuropathy. The best-known example is the mixed sensorimotor neuropathy caused by isoniazid, which is due to the effect of the drug on pyridoxine metabolism and which can be prevented by administering vitamin B6 supplements. Ethambutol may cause a sensory or sensorimotor neuropathy or an optic neuropathy. Ethionamide and streptomycin may rarely also cause a peripheral neuropathy, although in the case of streptomycin this is less frequent than the ototoxic effects of the drug. Peripheral neuropathy is a well-documented complication of treatment with nitrofurantoin and is more likely to develop in patients with renal insufficiency. The neuropathy is usually of a mixed sensorimotor type but occasionally is predominantly motor. Chloramphenicol may 136 rarely cause a mild sensory neuropathy. Although peripheral neuropathy was a well-recognized complication of treatment with sulfonamides in the past, none of the drugs in current clinical use has this effect. There have been several reports of a 136 reversible sensory neuropathy in patients treated with metronidazole for prolonged periods. Peripheral neuropathy was also part of the SMON syndrome caused by clioquinol that was prevalent in 146 Japan during the 1950s and 1960s and has been reported only rarely from other countries. 135 A peripheral neuropathy has147 also been reported in patients treated with fluoroquinolones and sodium stibogluconate. Antirheumatic Drugs Peripheral neuropathy is a well-recognized complication of gold treatment in patients with rheumatoid arthritis, occurring in 0.5 to 1 percent of patients. Motor involvement is prominent, with inconspicuous sensory symptoms. The onset may be abrupt and the progression rapid, so that in some cases the condition mimics the Guillain–Barré syndrome, particularly in 148 patients who develop facial diplegia and have elevated cerebrospinal fluid protein levels. A sensory or mixed peripheral neuropathy has been reported in patients with149rheumatoid arthritis treated with the recently introduced disease-modifier leflunomide. Chloroquine may cause a mild sensorimotor neuropathy as well as a more severe proximal myopathy in some cases. A neuropathy may also occur rarely in patients treated with d-penicillamine, but this is less common than the myasthenic syndrome that may occur in patients on long-term treatment with this drug. There has also been 148 a report of the Guillain–Barré syndrome developing in a patient on d-penicillamine. A mixed sensorimotor neuropathy may develop in patients treated with colchicine for long periods and is usually 150 associated with a proximal myopathy. Cardiovascular Drugs A demyelinating sensorimotor polyneuropathy occurred in about 0.1 percent of patients 148 treated with the coronary vasodilator perhexiline, which is no longer widely used. Associated findings in some cases included papilledema, dysgeusia, deafness, cerebellar signs, autonomic dysfunction, and raised cerebrospinal fluid protein levels. A demyelinating sensorimotor neuropathy is also well documented in patients treated with the antiarrhythmic agent amiodarone. Streptokinase has been associated with the development of the 151 develop in patients treated with Guillain–Barré syndrome. Peripheral neuropathy may rarely152,153 disopyramide, hydralazine, flecainide, enalapril, and captopril. Lipid-Lowering Agents Although the occurrence of peripheral neuropathy was not detected in the initial large statin trials, a number of reports have subsequently documented the development of neuropathy in 145,154,155 This has usually been an axonal patients treated with various statin drugs. sensorimotor polyneuropathy, but there have also been single case reports of a156 neuropathy and of a resembling Guillain–Barré syndrome developing after initiation of statin therapy 157 reversible small-fiber neuropathy. In Australia the National Adverse Drug Reactions Advisory Committee has received reports of 281 patients with peripheral neuropathy or 158 symptoms consistent with a neuropathy that were attributed to statins since 1993. Most of these cases were associated with the use of simvastatin or atorvastatin and, less frequently, pravastatin and fluvastatin. Many patients had other co-morbidities such as diabetes mellitus or chronic renal failure, which may have been a contributory factor in causing the neuropathy. However, recovery on withdrawal of the statin drug was noted in approximately one half of the
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cases. In other cases, symptoms have been reported to persist for months or even years 155 after withdrawal of the statin. Population-based studies in the United Kingdom and Denmark have159,160 shown an increased incidence of idiopathic peripheral neuropathy in patients However, the confounding effects of glucose intolerance and taking statins. hyperlipidemia could not be excluded in these studies, and the true incidence of statin-induced neuropathy remains uncertain. A mild reversible sensory neuropathy has been reported with bezafibrate treatment, and a 161,162 motor neuropathy with clofibrate. Hypnotic and Psychotropic Drugs There have163 been occasional reports of peripheral neuropathy developing in patients taking methaqualone, glutethimide, imipramine, amitriptyline, lithium carbonate, and phenelzine, 148 perazine. Administration of the antidepressant drug zimeldine was associated with the development of the Guillain–Barré syndrome in Sweden, the risk of developing this condition 164 being increased 25-fold in patients taking the drug. Other Drugs 148
Various other drugs have occasionally been implicated in causing a peripheral neuropathy. A mild peripheral neuropathy with depression of the tendon reflexes and minor sensory changes may occur in patients on long-term treatment with phenytoin but is only rarely symptomatic. Disulfiram, used in the treatment of alcoholism, may cause a sensorimotor polyneuropathy of axonal type as well as optic neuropathy. Dapsone, used in the treatment of leprosy and of certain dermatological conditions, may cause a predominantly motor peripheral neuropathy after prolonged high-dose therapy. A sensory or mixed axonal neuropathy is well documented in patients with various chronic dermatological conditions 165–167 treated with thalidomide. Chronic administration of high doses of pyridoxine has been reported to cause a severe sensory polyneuropathy of insidious onset and course, and paresthesias may develop even in 168 some patients taking conventional doses of this vitamin. Recent studies in a rat model have investigated the mechanism of the neuropathic effects of megadoses of pyridoxine and 145 gene therapy approaches to treatment with growth factors. An inflammatory demyelinating polyneuropathy occurred in some patients with the eosinophilia-myalgia syndrome caused by contaminated preparations of l-tryptophan. Almitrine bismesylate, a drug used in the treatment of chronic respiratory insufficiency, may cause a sensory polyneuropathy. There have been a number of reports of 169,170 an axonal polyneuropathy developing in hepatitis C patients treated with interferon-α. A reversible 171 sensorimotor neuropathy has also been reported with high doses of deferoxamine. 172
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A number of drugs including gangliosides, streptokinase, zimeldine, d-penicillamine, interferon-α, captopril, and danazol, as well as epidural anesthesia, have been associated 173,174 with the development of the Guillain-Barré syndrome. A demyelinating neuropathy resembling chronic inflammatory demyelinating polyneuropathy has been reported in patients 175,176 in patients treated with the tumor treated with the immunosuppressive agent tacrolimus, 177 necrosis factor–α blockers etanercept and infliximab, and in a patient treated with 178 interferon-α. Trigeminal neuropathy has been reported in a patient with hepatitis C virus infection treated 179 with interferon-α. Peripheral neuropathy has 180 also been reported in a number of patients with multiple sclerosis treated with interferon-β. Dichloroacetate may bring on or worsen peripheral neuropathy in patients with the syndrome of mitochondrial myopathy, lactic 181 acidosis, and stroke-like episodes (MELAS).
Neuromuscular Transmission Disorders A variety of drugs used in clinical practice may interfere with neuromuscular transmission by causing a postsynaptic block or through a presynaptic effect on transmitter release, as occurs 148,182 (Table 36-3). The most frequently encountered clinical syndrome is with botulinum toxin the postoperative respiratory depression that sometimes occurs in patients being treated with aminoglycoside antibiotics or with drugs that potentiate the action of muscle relaxants used during anesthesia. Many of the drugs shown in Table 36-3 may also unmask or aggravate a preexisting myasthenic disorder by further reducing the safety factor for transmission at the neuromuscular junction and should therefore be avoided or used with caution in such
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patients. In particular, the choice of antibiotics for use in myasthenic patients is important. Aminoglycosides, tetracyclines, sulfonamides, and polypeptide antibiotics should be avoided, whereas cephalosporins, macrolides, and penicillins (with the exception of ampicillin) are considered to be safe to use. Patients with myasthenia or Lambert–Eaton myasthenic syndrome are also excessively sensitive to the effects of muscle relaxants, and the occurrence of prolonged postoperative respiratory depression may be the first indication that the patient has a disorder of neuromuscular transmission. Deterioration of myasthenia and even myasthenic crisis have been reported after administration of botulinum toxin 183,184 injections. Click here to view this table.... A syndrome clinically indistinguishable from myasthenia gravis may develop in some patients 185 treated with d-penicillamine for prolonged periods. These patients develop acetylcholine receptor antibodies in the serum, similar to those found in naturally occurring myasthenia gravis, suggesting that the drug initiates an autoimmune response through an effect on immunoregulatory mechanisms or, possibly, by altering the antigenic properties of the 148 through an immune acetylcholine receptor. Other drugs reported to induce myasthenia 185–187 mechanism include interferon-α, captopril, and thiopronine. An association between the commencement of statin treatment and the development of autoimmune myasthenia gravis 188 has recently been reported. However, the role played by the statin in such cases remains uncertain.
Muscle Disorders A variety of drugs may cause muscular symptoms through a direct toxic effect on skeletal muscle (Table 36-4). In the case of other drugs that are not intrinsically myotoxic, myopathy may develop as a result of an immunological process, severe hypokalemia or ischemia, muscle compression (crush syndrome) from prolonged periods of immobility after drug 189,190 overdosage, or excessive neural driving. Click here to view this table.... Lipid-Lowering Agents Myopathy is an important side effect of treatment with the 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors (statins) and fibrate drugs that 191 interfere with the biosynthesis of cholesterol. The risk of developing myopathy was shown to be increased 8-fold in patients on statins and 42-fold in patients on fibrates in a 192 case-control study in the United 193 Kingdom. Myopathy may also develop in patients treated with high doses of nicotinic acid, and there are reports of myalgia and myopathy developing in some194 patients treated with ezetimibe, which blocks cholesterol absorption from the small intestine. Statins may cause asymptomatic hyperCKemia or a more severe necrotizing myopathy with myalgia and proximal muscle weakness. Symptoms usually resolve over a period of a few 195 weeks once the drug is discontinued but may persist in some patients. The risk of myopathy is greater with the lipophilic statins such as simvastatin, atorvastatin, and lovastatin than with the hydrophilic compounds such as pravastatin. Acute rhabdomyolysis is the most severe form of statin myopathy and was associated particularly with the use of cerivastatin, which was withdrawn from the market in 2001 after the occurrence of over 100 fatal cases; it also occurs rarely with the other statin drugs, with an estimated mortality rate of 0.15 per 1 196 million prescriptions. Statin myopathy is more likely to develop in the elderly, with high drug doses, and in patients with diabetes, hypothyroidism, renal failure, or hepatobiliary disease. Other risk factors include coadministration of statins with a fibrate drug (e.g., gemfibrozil) and 197 with drugs that compete with or inhibit the CYP3A4 enzyme system. These include cyclosporine, macrolide antibiotics, azole antifungal agents, calcium-channel blockers, SSRI 198 antidepressants, and a number of other drugs, as well as grapefruit juice, which should be avoided or restricted during statin therapy. Genetic factors may also predispose to 199 susceptibility. In patients whose symptoms fail to improve following withdrawal of the statin, further investigations including a muscle biopsy should be performed as statins may rarely induce or 200 or an unmask a previously asymptomatic mitochondrial or other metabolic myopathy 195 There has also been a report of rippling muscle immune-mediated inflammatory myopathy. 201 disease brought on by simvastatin.
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Acute Rhabdomyolysis This is the most serious form of drug-induced myopathy. It has been associated with statin treatment and with a number of other drugs. Acute rhabdomyolysis may also occur following self-administration of heroin, cocaine, and other narcotic drugs, with alcohol intoxication, and in patients with drug-induced coma, seizures, dyskinesias, or the neuroleptic malignant syndrome (see p. 703). Severe muscle pain, tenderness, and weakness usually develop over a period of 24 to 48 hours and may be associated with marked limb swelling and the development of a secondary compartment syndrome. The serum CK level is markedly elevated, and myoglobinuria is an early feature and may lead to acute oliguric renal failure. Muscle biopsy shows widespread muscle fiber necrosis. The prognosis for recovery is generally good, but some patients die as a result of multiple organ failure. The management of patients with acute rhabdomyolysis is primarily supportive, with careful monitoring of renal function and fluid and electrolyte balance and early treatment of any metabolic derangements. Monitoring of intracompartment pressures is important in patients with muscle swelling as some patients will require fasciotomy and muscle decompression. Mitochondrial Myopathies A myopathy characterized by ragged-red fibers, cytochrome c oxidase–negative fibers, and abnormal mitochondria with paracrystalline inclusions was described in patients with the acquired immunodeficiency syndrome (AIDS) on long-term treatment with zidovudine 195,202–204 The myopathy is characterized by myalgia, fatigue, proximal or generalized (AZT). muscle weakness and atrophy, and elevated serum CK levels; it usually improves when the drug is withdrawn. In some patients there is an associated inflammatory myopathy, and it may be difficult to distinguish the two conditions. This myopathy has been shown to be due to 205 inhibition of mtDNA replication and mtDNA depletion in muscle fibers. 206
A mitochondrial myopathy has also been reported in some patients taking statins. These cases differ from the more common form of statin myopathy in demonstrating normal serum CK levels. Mitochondrial abnormalities and reduced cytochrome c oxidase activity also occur in the myopathy induced by germanium, which is a constituent of a number of dietary supplements 207,208 and elixirs. Dyskalemic Myopathies Severe hypotonic weakness with depression of tendon reflexes and marked elevation of serum creatine kinase activity may develop in patients who become hypokalemic. This may occur as a result of treatment with diuretics or nasal sprays containing fluoroprednisolone, or as a result of purgative abuse or the consumption of large quantities of licorice or licorice extracts, which are ingredients of some traditional Chinese drugs and which contain the 190 myopathy may also potent mineralocorticoid analogue glycyrrhizinic acid. Hypokalemia and 209 complicate treatment with amphotericin B due to renal tubular acidosis. Profound muscle weakness due to hyperkalemia may occur in patients taking potassium-retaining diuretics. Inflammatory Myopathies Drugs may occasionally initiate an immunemediated inflammatory myopathy. The best known are d-penicillamine and interferon-α, both of which have been associated with the development of polymyositis or dermatomyositis as well as other autoimmune disorders such 210,211 In the case of d-penicillamine, the occurrence of myositis has as myasthenia gravis. 210 been associated with the HLA-B18, B35, DR4 haplotype. In most of the reported cases, the myositis has improved promptly on withdrawal of the medication, but in some a course of corticosteroids therapy has been required. An immune-mediated inflammatory myopathy has 212 also been reported195 as a complication of treatment with streptokinase and more recently with statin therapy. A condition referred to as macrophagic myofasciitis was first recognized in the 1990s in 203 France, where over 130 cases were documented, and has also been reported from other parts of the world. It is characterized by diffuse myalgia, arthralgia, and fatigue, with a good response to corticosteroid therapy, and is now thought to be caused by intramuscularly 203 injected vaccines containing aluminium hydroxide. An interstitial form of myositis characterized clinically by muscle pain, stiffness, and mild weakness has been reported rarely in patients treated with procainamide, hydralazine,
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phenytoin, levodopa, cimetidine, leuprolide, or propylthiouracil. An interstitial form of eosinophilic myositis and fasciitis characterized by severe myalgia, edema and induration of the skin, and a peripheral blood eosinophilia was reported in the early 1990s in patients taking l-tryptophan as a hypnotic (the eosinophilia-myalgia syndrome). The condition was most prevalent in the United States, where more than 1,500 cases were reported, and was 213 attributed to a chemical contaminant. Glucocorticoid Myopathy Myopathy is a common complication of prolonged treatment with glucocorticoids and is probably the most common drug-induced myopathy in clinical practice. A symptomatic myopathy is most likely to develop in patients treated with 9αfluorinated corticosteroids such as triamcinolone, betamethasone, and dexamethasone but may also occur when other corticosteroids are administered for prolonged periods. Patients treated for long periods with more than 10 mg of prednisolone per day, or its equivalent of another corticosteroid, may develop a myopathy. Those taking daily doses of 40 mg or more of prednisolone are at 214 particular risk, whereas patients on an alternate-day regimen are not usually affected. The muscles of the pelvic girdle and thighs are most severely affected; myalgia may occur but is not usually a feature. Muscles innervated by the cranial nerves are spared, but involvement of the laryngeal muscles leading to dysphonia has been reported in patients using inhaled corticosteroids such as beclomethasone. Diaphragmatic weakness may develop in asthmatic 214 patients taking corticosteroids, and weakness of the respiratory muscles has been reported in patients 215,216 with chronic obstructive pulmonary disease and in cancer patients treated Serum CK levels are usually normal and elevated levels should with corticosteroids. suggest the possibility of an inflammatory or other type of myopathy. Muscle biopsy shows selective atrophy of type II muscle fibers. Glucocorticoid myopathy is usually reversible if administration of the drug is stopped or the dose reduced, or attenuated if an alternate-day regimen is implemented. Anabolic steroids and B-group vitamins have been shown to prevent the development of myopathy in rats but not in humans. Glucocorticoid-induced muscle atrophy and weakness can be prevented at 217 Growth hormone and least partially or reversed by a regular program of physical training. 218 insulin-like growth factor–1 have also been reported to be protective. Acute Quadriplegic Myopathy This condition, which has also been referred to as “acute steroid myopathy” or “critical illness myopathy,” has been encountered particularly in severe asthmatics and in liver- or heart-transplant patients treated with high intravenous doses of glucocorticoids usually in 219–221 It is characterized combination with nondepolarizing neuromuscular blocking agents. clinically by profound generalized muscle weakness, hypotonia, and depressed tendon reflexes. Weakness of the respiratory muscles often leads to difficulties in weaning from the respira tor. The serum CK level is usually moderately elevated but may be normal. Muscle biopsy shows nonspecific changes including atrophy, necrosis, and central loss of ATPase activity in muscle fibers. However, electron microscopy shows a selective loss of thick (myo-sin) filaments that is characteristic of the condition. Its electrophysiological hallmark is a markedly reduced excitability of muscles with direct electrical stimulation. Nerve conduction studies are normal, apart from a reduction in amplitude of the compound muscle action potentials, but should always be performed to exclude critical illness neuropathy, Guillain–Barré syndrome, or a myasthenic disorder. Gradual recovery usually occurs over a period of several months with the help of an intensive program of physiotherapy and physical activity. Further details are provided in Chapter 52. Autophagic Myopathies A number of drugs with amphiphilic cationic properties may cause autophagic degeneration 189 and accumulation of phospholipids in muscle and other tissues. These include chloroquine and hydroxychloroquine, which can cause a painless proximal myopathy or neuromyopathy after prolonged periods of administration, and perhexiline and amiodarone, which lead to the development of a demyelinating sensorimotor peripheral neuropathy with an associated 222 proximal myopathy in some patients. Malignant Hyperpyrexia Malignant hyperpyrexia is a condition in which susceptible individuals may develop a potentially fatal state of severe generalized muscular rigidity, hyperpyrexia, metabolic
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acidosis, and myoglobinuria when exposed to certain anesthetic agents or other drugs. Susceptibility is usually transmitted as an autosomal-dominant trait and may be associated with either a clinically apparent or a subclinical myopathy. Mutations in the ryanodine receptor gene (RYR1) on chromosome 19q account for over 70 percent of susceptible 224,225 individuals. A number of other susceptibility loci have also been reported, and mutations have also been found in the CACNA1S gene that encodes the α1-subunit of the 224,225 voltage-gated dihydropyridine receptor. The most reliable method of identifying individuals at risk in affected families is still by the demonstration of abnormal sensitivity of muscle tissue to halothane and caffeine (the so-called in vitro contracture test). A similar susceptibility to anesthetic reactions may rarely also occur in patients with Duchenne or Becker muscular dystrophy, myotonia congenita, myotonic dystrophy, central core and multiminicore disease, and hypokalemic periodic paralysis. The malignant hyperpyrexia crisis is thought to be due to an intrinsic abnormality of the excitation–contraction coupling mechanism in skeletal muscle, as a result of which exposure to anesthetic agents leads to the excessive release of calcium ions from the sarcoplasmic reticulum, causing sustained myofibrillar contraction. Management involves the urgent administration of dantrolene, cooling, correction of fluid and electrolyte balance, and prompt 224 treatment of other complications. Myalgia and Cramps Many drugs have been reported to cause muscle pain, stiffness, and cramping that are reversible when the drug is withdrawn (Table 36-5). In some cases, serum CK activity may be elevated transiently. Similar symptoms may occur in patients with drug-induced myotonia and 148,189 Muscle pain may also be the initial symptoms of a more severe necrotizing myopathy. and fasciculations are commonly induced by suxamethonium during anesthesia. Fasciculations and myokymia have also been reported in patients treated with gold or 226,227 d-penicillamine. Click here to view this table.... Drug-Induced Myotonia A number of drugs may induce myotonia in humans or experimentally in animals. These include the lipid-lowering agents 20,25-diazacholesterol, clofibrate, triparanol, and zuclomiphene. In addition, some drugs may exacerbate a preexisting myotonic disorder or unmask previously undetected myotonia. These include the depolarizing muscle relaxants such as suxamethonium, which may markedly exacerbate myotonia during general anesthesia, the β-adrenergic blockers (e.g., propranolol and pindolol), and β2-agonists (e.g., fenoterol and ritodrine). A number of diuretics including furose mide, ethacrynic acid, mersalyl, and acetazolamide can induce myotonia 228 in animals and should be used with caution in patients with genetic forms of myotonia. Other Drugs Myopathy is an uncommon complication of treatment with the antifibrinolytic agent 148,190 ε-aminocaproic acid. Muscle weakness is a common side effect of treatment with emetine in patients with amebiasis, and229,230 a severe myopathy has been reported in individuals A proximal myopathy with myalgia and using ipecac syrup as an emetic agent. myasthenic features and marked elevation of the serum CK activity has been reported in drug abusers consuming large quantities of the cough-suppressant codeine linctus, one of the components of which is squill, which contains the cardiac glycosides scillarin A and B that 231 inhibit the cell membrane sodium-potassium pump. Other drugs that have rarely been implicated in causing a myopathy include rifampicin, 232 mercaptopropionyl glycine, vidarabine, cimetidine, tetracycline, griseofulvin, sulfasalazine, 233 209,234 ethchlorvynol, finasteride, retinoids (etretinate and isotretinoin) and interferon-α. Severe muscle fibrosis and contracture may develop after repeated intramuscular injections in illicit drug abusers or after prolonged courses of antibiotic injections. ACKNOWLEDGMENT I am grateful to S. Moncrieff for her expert secretarial assistance and literature review. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 37 Alcohol and the Nervous System ROBERT O. MESSING •
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Previous ALCOHOL INTOXICATION AND WITHDRAWAL Intoxication Minor Withdrawal Syndrome Withdrawal Seizures Delirium Tremens DEMENTIA Pellagra Marchiafava–Bignami Disease Acquired Hepatocerebral Degeneration Alcoholic Dementia WERNICKE'S ENCEPHALOPATHY KORSAKOFF'S AMNESTIC SYNDROME ALCOHOLIC CEREBELLAR DEGENERATION CENTRAL PONTINE MYELINOLYSIS ALCOHOLIC NEUROPATHY ALCOHOLIC MYOPATHY Acute Necrotizing Myopathy Chronic Myopathy ALCOHOL AND STROKE
Who could have foretold, from the structure of the brain, that wine could derange its functions? Hippocrates The ability of alcohol to interfere with neuronal function is no longer a surprise, but the wide variety of alcohol-related neurological disorders and their underlying mechanisms remain puzzling. As illustrated in Figure 37-1, alcohol abuse has been implicated in neurological diseases affecting every level of the neuraxis, including brain, peripheral nerve, and muscle. Despite its protean nature, alcoholic neurological disease often involves discrete anatomical structures or1,2cell populations, suggesting that multiple, discrete pathophysiological processes are at work.
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FIGURE 37-1 Alcohol-related disorders affecting different levels of the neuraxis.
Intoxication results from acute, pharmacological effects of alcohol, and altered neurotransmission in γ-aminobutyric acid and glutamate systems may be especially important 3 in this respect. Adaptation at the cellular level to alcohol's acute effects leads to clinical withdrawal syndromes when alcohol intake is reduced or terminated; these syndromes may result from chronic up-regulation of calcium channels or glutamate receptors and from 4–6 adaptive changes in GABAergic neurotransmission. A direct, cytotoxic action of alcohol has been proposed as a pathogenetic mechanism in alcoholic myopathy and fetal alcohol syndrome, whereas7 other neurological complications appear unrelated to the amount of alcohol consumed. Several neurological disorders are related to systemic effects of alcohol (e.g., hepatic cirrhosis, nutritional deficiency, electrolyte disturbances); these include dementia due to pellagra or acquired hepatocerebral degeneration, Wernicke's encephalopathy, Korsakoff's amnestic syndrome, cerebellar degeneration, central pontine myelinolysis, and polyneuropathy. Genetic factors may also operate in the pathogenesis of alcohol-related neurological disease. 8 First, evidence exists for an inherited predisposition to alcoholism in certain individuals. In addition, genetically determined predilections could explain why individual alcoholics develop a particular neurological disorder or escape neurological complications altogether. Although genetic factors may influence the occurrence of these disorders, the role of alcohol itself is primary: not all at-risk individuals develop either alcoholism or neurological complications, and cessation of alcohol abuse can arrest or reverse neurological deficits in many instances. The clinical features of the major alcohol-related neurological disorders are summarized in this chapter. ALCOHOL INTOXICATION AND WITHDRAWAL
Intoxication Early signs of alcohol intoxication include euphoria, mood swings, loss of9 social inhibition, mild ataxia, nystagmus, dysarthria, flushing, tachycardia, and mydriasis. In nonalcoholics, measurable signs of intoxication occur with blood concentrations greater than 31 mg/dl (6.5 mmol/L). Impaired coordination occurs at blood alcohol levels above 100 mg/dl (21 mmol/L) and is followed by findings of central nervous system depression as blood levels increase.
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Blood levels above 300 mg/dl (65 mmol/L) can lead to coma, hyporeflexia, respiratory compromise, and hypotension. Although the behavioral effects of alcohol generally correlate with blood concentrations, tolerance may occur rapidly and greatly modify the clinical response. Acute tolerance may develop during a single bout of drinking, causing the drinker to become sober at blood 10 alcohol concentrations higher than those at which intoxication developed. In chronic alcoholics, the tolerance may be great enough to permit sobriety at blood concentrations well above 100 mg/dl. Urso and associates measured11blood alcohol levels of 120 to 540 mg/dl (mean, 268 mg/dl) in 65 sober alcoholic patients. Thus, concentrations of alcohol that are lethal in nonalcoholics may fail to intoxicate alcoholics. Lethal blood alcohol concentrations are also higher in alcoholics, and blood levels of 730 to 1,510 mg/dl have been measured in 12,13 patients who later recovered from alcoholic coma.
Minor Withdrawal Syndrome 14
Characteristic symptoms of alcohol withdrawal follow abrupt cessation of drinking. Tremulousness is the most common early symptom, becoming most marked 24 to 36 hours after the last drink. The tremor is generalized, resembles an accentuated physiological tremor, and is accompanied by signs of autonomic hyperactivity such as arousal, tachycardia, flushing, and hyperreflexia. These signs are associated with elevated blood and urinary catecholamine levels and increased levels of catecholamine metabolites in the cerebrospinal 15,16 fluid (CSF).
Withdrawal Seizures 17
Seizures may occur shortly after chronic ethanol intake is suddenly discontinued. Alcohol withdrawal seizures are usually associated with a history of daily alcohol consumption, but briefer drinking sprees may also culminate in seizures. Generalized tonic-clonic seizures are most common; focal seizures occur in 5 to 24 percent of cases and suggest an etiology other than alcohol withdrawal. More than 90 percent of seizures occur within 7 to 48 hours after cessation of drinking. Approximately 60 percent of patients have more than one seizure, but fewer than 15 percent have more than four. Status epilepticus is unusual and occurs in only 3 percent of cases, but alcohol withdrawal 18 was responsible for approximately 15 percent of all cases of status epilepticus in one series. The period of risk for withdrawal seizures is short: less than 6 hours in 85 percent of cases and less than 12 hours in 95 percent. Some patients manifest photomyoclonic and photoparoxysmal responses on the electroencephalogram during the convulsive period. Anticonvulsant therapy is usually not required for alcohol withdrawal seizures. In patients with repeated seizures, benzodiazepines (e.g., diazepam, chlordiazepoxide, and lorazepam) 19,20 21–23 whereas20phenytoin does not. Phenobarbital has been prevent seizure recurrence, reported effective in uncontrolled series, but controlled trials comparing it with benzodiazepines are lacking. Although inexpensive, it has a long half-life and may pose a greater risk of causing 19 respiratory depression than benzodiazepines, especially when it is combined with alcohol. Valproic acid and carbamazepine attenuate withdrawal seizures in animals and reduce withdrawal14,24 symptoms in humans, but their25role in treatment of alcohol 24 Topiramate and baclofen also reduce alcohol withdrawal seizures is unclear. withdrawal symptoms in humans, but it is not yet known whether they are effective against withdrawal seizures. Status epilepticus due to alcohol withdrawal is a medical emergency and should be treated with anticonvulsants in the same fashion as status epilepticus due to any other etiology. It is important to recognize that alcoholics are at risk for a variety of other treatable conditions that may cause status epilepticus, including occult head trauma, meningitis, hypoglycemia, hyponatremia, and other drug ingestions.
Delirium Tremens Approximately 20 percent of patients become delirious 2 to 5 days after ethanol withdrawal, and in up to one half of these patients the syndrome of delirium tremens may develop, 26 with marked confusion, hallucinations, tremor, hyperpyrexia, and sympathetic hyperactivity. The risk for development of delirium tremens is higher in alcoholics with heavy daily alcohol intake, prior alcohol withdrawal seizures or delirium, decreased serum chloride and potassium concentrations, elevated serum levels of alanine aminotransferase and γ-glutamyltransferase, and findings of tachycardia (>100 bpm), ataxia, and polyneuropathy on 26–28 admission. The major threat to life is from associated illnesses or injuries, hyperthermia,
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dehydration, and hypotension. Although initial studies reported mortality rates as high as 15 26 percent, with current treatment rates have fallen to 1 percent or less. A variety of sedatives, anticonvulsants, sympatholytics, and neuroleptics have been administered to patients with 20,26 Several double-blind studies alcohol withdrawal delirium, usually in uncontrolled trials. have suggested that benzodiazepines are effective in controlling the symptoms of alcohol 27,28 A recent meta-analysis found sedative-hypnotics (diazepam, withdrawal. chlordiazepoxide, pentobarbital, paraldehyde, and barbital) better than neuroleptics in reducing mortality from alcohol withdrawal delirium, with a relative risk of 6.6 (95% CI, 26 1.2–34.7). The dose of medication required to control symptoms can vary greatly among different patients and over time in the same patient. A typical regimen is to administer 5 to 10 mg of diazepam intravenously every 5 to 10 minutes until the patient is lightly somnolent, followed 26 by 5 to 20 mg every few hours as needed to control delirium and agitation. Shorter acting benzodiazepines such as oxazepam or lorazepam may be safer in patients with liver 29 disease. Although there are not measurable differences in efficacy between individual sedative-hypnotic drugs, patients refractory to benzodiazepines may respond to addition of a different class of sedative-hypnotic (e.g., propofol or pentobarbital). Neuroleptics, such as haloperidol, may be used for severe agitation but should only be administered as adjunctive therapy with sedative-hypnotics. Fluid and electrolyte abnormalities can be severe and require prompt therapy. Dehydration accompanying delirium tremens may lead to circulatory collapse, requiring replacement of up to 4 to 10 L of fluid during the first 24 hours. Hypomagnesemia is common and should be treated with magnesium sulfate (1 g intravenously every 6 hours during the first day in patients with adequate renal function). Potassium should be included in intravenous solutions because hypokalemia may be exacerbated by glucose administration and cause cardiac arrhythmias. DEMENTIA Several disorders may cause dementia in alcoholic patients. With these conditions, cognitive function is impaired in a diffuse and nonspecific fashion.
Pellagra Pellegra, which results from deficiency of nicotinic acid (niacin) or its amino acid precursor, 30 tryptophan, may produce dementia in alcoholics. The disorder is uncommon in developed countries30,31 because of fortification of processed foods with niacin. Neuropathological involve mainly the large neurons of the motor cortex, although changes are also changes seen elsewhere in the cortex, in large neurons of the basal ganglia, in cranial motor and deep cerebellar nuclei, and in anterior horn cells. Affected neurons appear swollen and rounded, with eccentric nuclei and loss of Nissl substance. Axonal damage is too minor to account for 31 the chromatolysis, which is more likely related to metabolic effects on nerve cell bodies. Systemic manifestations of pellagra include diarrhea, glossitis, anemia, and erythematous cutaneous lesions that appear in sun-exposed areas. Early mental symptoms of irritability, depression, fatigue, insomnia, and inability to concentrate are nonspecific and suggest a psychiatric disorder. However, the later development of confusion, hallucinosis, or paranoid ideation confirms the presence of an encephalopathy, and is usually accompanied by spastic weakness and Babinski signs. Tremor, rigidity, polyneuropathy, optic neuritis, and deafness may also be present. Pellagra responds readily to administration of niacin, although cerebral symptoms may not be completely reversible. Further details are given in Chapter 17.
Marchiafava–Bignami Disease Marchiafava–Bignami disease was first described in 1903 in wine-drinking Italian men but has since been observed among people of many nationalities and with consumption of all 30,32 In this rare disorder, there is destruction of myelin mainly in types of alcoholic beverages. the corpus callosum and anterior commissure. Exceptionally, lesions extend laterally to involve the centrum semiovale, and in some instances the middle cerebellar peduncles are demyelinated. Neurons in layer 3 of the cerebral cortex may be replaced by gliosis, possibly owing to disruption of callosal fibers. The disorder is usually diagnosed postmortem because the clinical signs are nonspecific, though magnetic resonance imaging (MRI) has made the diagnosis more feasible during life. Most patients are alcoholics of long standing and many have associated malnutrition or liver disease, although the disease has appeared in a few nondrinkers. The etiology is not known. Symptoms may present acutely with seizures and coma often accompanied by signs of upper motor neuron dysfunction, or may follow a subacute course with gait disturbance, dysarthria, hyperreflexia, cognitive impairment,
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neuropsychiatric symptoms, and signs of interhemispheric disconnection. Patients may show minimal impairment of consciousness or may progress to stupor or coma. MRI shows T2-hyperintense swelling of the corpus callosum followed later in the course by callosal 33,34 T1-weighted images may show atrophy, as well as cortical and subcortical atrophy. hypointense necrotic lesions of the corpus callosum. Motor deficits, such as pyramidal tract signs and gait disturbance, tend to recover with abstinence from alcohol and improved nutrition, but many patients show residual cognitive impairment and a disconnection 30,33 Patients who develop coma carry the greatest risk of serious disability or syndrome. death, whereas those with little impairment in consciousness may recover with only mild 33 disability.
Acquired Hepatocerebral Degeneration Alcoholic liver disease may be accompanied by acquired hepatocerebral degeneration, a disorder associated with liver failure due to many causes, and with neuropathological lesions 35,36 Brains of affected individuals show diffuse, patchy necrosis similar to Wilson's diease. with microcavitation at the junction of cerebral gray and white matter, and a loss of neurons and myelinated fibers in the basal ganglia and cerebellum. Protoplasmic type II (Alzheimer) astrocytes are increased in number, and Opalski cells may be present. Patients are often demented and show reduced attentiveness and diminished ability to concentrate on problems, retain new facts, and sustain mental activity. Motor signs always accompany the dementia and include cerebellar ataxia, dysarthria, tremor, dystonia, myoclonus, and choreoathetosis. Mild corticospinal tract deficits may also be present, and occasional patients show signs of a myelopathy. A mild form of the disorder may occur with parkinsonian features 36 that include rigidity, bradykinesia, and impaired gait and posture, but normal cognition. In some cases, the neurological findings precede recognition of liver disease by several years. The deficits are irreversible, the rate of progression is variable, and the course is often punctuated by superimposed episodes of reversible hepatic encephalopathy. Death usually occurs as a complication of advanced liver disease or intercurrent infection rather than from the neurological disorder.
Alcoholic Dementia Dementia unrelated to the foregoing disorders has been recognized in alcoholics for several years. Numerous psychometric studies have shown cognitive impairment to be common in 37 alcoholics. Parker and colleagues found performance on tests of abstraction ability also to be impaired in social drinkers, and the degree of impairment was 30,39 correlated with the amount 38 have argued that of alcohol consumed per drinking occasion. Some investigators unrecognized Korsakoff's syndrome (see later)40,41 accounts for most cases of cognitive claim that alcohol is directly toxic to the impairment among alcoholics, whereas others brain and induces structural nervous system abnormalities that account for dementia. In rodents, chronic alcohol consumption can lead to learning41,42 deficits, altered dendritic Postmortem studies have morphology, decreased synaptic density, and neuronal loss. attempted to document the existence of alcohol-induced dementia by quantifying changes in brain weight and size, and the number of cortical neurons in alcoholics. Torvik and associates compared the brain weights of 545 male alcoholics and 586 age-matched control subjects 40 and found that the brains of alcoholics weighed an average of 31 g less. Skullerud found a 70- to 90-g reduction in brain43weight in alcoholics that was independent of the presence of liver disease or malnutrition. Harper and Kril compared brains from 25 alcoholics and 44 control patients and found that there was a statistically significant loss of brain tissue in chronic alcoholics, which was worse in patients with associated thiamine deficiency or liver 44 the number of neurons in the frontal cortex disease. Harper and associates also found that 45 was significantly reduced in chronic alcoholics. Computed46–54 tomography (CT) and MRI studies have shown decreased brain size in In the CT studies, the incidence of atrophy ranged from 7 to 100 percent alcoholics. 50 among alcoholics and48–52 heavy social drinkers, and atrophy tended to be greater in alcoholics MRI studies show widespread volume loss affecting cortical than55,56 in nonalcoholics. 46 and white matter. In addition, MRI studies show deficits in several subcortical gray 57 structures, including the corpus callosum, pons, cerebellar hemispheres and vermis. These regions are less affected in patients with uncomplicated alcoholism free of alcohol-associated electrolyte and nutritional disturbances when compared with patients with clinically defined syndromes such as Marchiafava–Bignami disease, alcoholic cerebellar degeneration, and 57 may be observed with greater central pontine myelinolysis. White matter abnormalities 58 sensitivity and detail using diffusion tensor imaging.
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Neuropsychiatric abnormalities correlate poorly with structural abnormalities on MRI49,51,53 or CT 49,51,52 Neither variable correlates well with the duration or pattern of drinking.51,54,57 scans. Imaging and neuropsychiatric abnormalities are partly reversible during abstinence. However, Carlen and colleagues found that54improving CT parameters correlated poorly with changes in psychometric test performance. Mechanisms that account for volume loss and recovery during abstinence have been postulated to reflect changes in brain water, but recent longitudinal studies using MR spectroscopy have shown increases in N-acetyl aspartate and in phospholipids in59,60 certain brain regions, suggesting recovery of neurons and white matter during abstinence. Several biochemical and physiological abnormalities require many weeks to resolve after alcohol withdrawal. In chronic alcoholics, CSF acidosis may persist for weeks after62the last 61 drink, and evoked response abnormalities may require up to 3 weeks to recover. In longitudinal studies, Parsons has found 37 that neurocognitive deficits in recovering alcoholics remit slowly over 4 years of abstinence. Thus, it appears that although alcohol can be toxic to the brain, several radiological and neuropsychiatric abnormalities observed in alcoholics are partially reversible. WERNICKE'S ENCEPHALOPATHY Wernicke's encephalopathy is an acute disorder manifested by ophthalmoplegia, gait ataxia, 63–65 Neuropathological findings include demyelination, glial and and a confusional state. vascular proliferation, hemorrhage, and necrosis, which particularly affect gray matter regions of the thalamus, hypothalamus, brainstem, and cerebellum. An underlying disorder that predisposes to malnutrition appears to be common to all cases. Alcoholism is the most frequent predisposing factor, but persistent vomiting due to a variety of causes, starvation, and malignancy or other chronic systemic diseases have also been implicated. A detailed account of its clinical features is provided in Chapter 17. The link between malnutrition and Wernicke's encephalopathy is a deficiency of vitamin B1 (thiamine). With chronic alcoholism, decreased dietary intake of thiamine may be compounded by alcohol-induced defects in intestinal absorption, metabolism, and hepatic storage of thiamine. However, the manner in which thiamine depletion produces neurological dysfunction is unknown. Thiamine pyrophosphate is a required cofactor for at least four enzymes involved in intermediary metabolism: pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, transketolase, and branched-chain α-ketoacid dehydrogenase. Several investigators have reported heterogeneity of transketolase affinity for thiamine or variant 66–69 which could provide a basis for preferential vulnerability of certain forms of transketolase, alcoholic patients to thiamine deficiency. Thiamine phosphates have also been suggested to have a role in axonal conduction or synaptic transmission. Experimental thiamine deficiency 70–73 is characterized by widespread depression of glucose metabolism in gray matter regions, 72 which may be accompanied by enhanced metabolism in white matter tracts ; 73 a later phase of gray matter hypermetabolism may precede the onset of histological lesions. 63
Ocular abnormalities in Wernicke's encephalopathy may take a variety of forms. The most common is nystagmus, which almost always exhibits a horizontal component; vertical nystagmus is less common, and rotatory nystagmus is rare. Ocular palsies are also frequent, particularly lateral rectus palsy, which is usually bilateral. Horizontal or horizontal and vertical gaze palsies are often seen. Ptosis and internuclear ophthalmoplegias are rare, and loss of pupillary reactivity does not occur. Ataxia results from disease in the superior cerebellar vermis and vestibular nuclei. Consequently, the gait is most severely affected. Only a few patients exhibit limb ataxia, such as is revealed by finger-to-nose or heel-knee-shin testing; dysarthria is unusual. The acute confusional state is nonspecific. As with other metabolic encephalopathies, there is typically sedation, disorientation, and inattention, and the level of consciousness may fluctuate. The ability to incorporate new memories is severely impaired. Most patients with Wernicke's encephalopathy have an associated polyneuropathy at the time of presentation. Hypothalamic involvement occasionally leads to hypothermia or hypotension. Coma may occur. The diagnosis of Wernicke's encephalopathy is established by the clinical findings and the response to thiamine74,75 (discussed later). However, acute, reversible MRI abnormalities have and may be helpful for diagnosing mild cases or those with atypical also been described clinical features. In patients who present with ophthalmoplegia, ataxia, and confusion, the differential diagnosis includes sedative drug intoxication and structural lesions in the posterior fossa.
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Wernicke's encephalopathy is, at least in theory, a preventable disorder. One widely 76 discussed approach is the fortification of alcoholic beverages with thiamine. Although thiamine hydrochloride is stable in alcoholic beverages, it is poorly absorbed by alcoholic patients; thiamine propyldisulfide, which is well absorbed, is unstable. Thus, new analogues combining the desirable properties of these two compounds will have to be developed before this approach is technically feasible. Prevention of iatrogenically induced Wernicke's encephalopathy is more easily achievable. Iatrogenic conditions associated with Wernicke's 77 78 79 kidney dialysis, and the administration disease include persistent vomiting, malnutrition, 80 of large amounts of oral hypoglycemic agents. Such patients at risk for nutritional deficiency should receive thiamine regardless of whether clinical signs of Wernicke's encephalopathy are present. Treatment of Wernicke's encephalopathy is by repletion of thiamine. Patients should be hospitalized and receive 100 mg of thiamine intravenously daily for several days. Outpatient therapy with 50 mg of oral thiamine per day should follow, although in alcoholic patients absorption of the vitamin is likely to be impaired. The prognosis of Wernicke's encephalopathy depends on the prompt institution of appropriate treatment. The overall mortality rate is high, with figures in the range of 10 to 20 percent commonly cited. After the institution of treatment, ocular and gaze palsies begin to improve within hours to days, and nystagmus, gait ataxia, and confusion within days to weeks. Long-term sequelae include residual nystagmus or gait ataxia (alcoholic cerebellar degeneration; see later) in approximately 60 percent of patients and a chronic memory disorder (Korsakoff's amnestic syndrome; see next section) in more than 80 percent. KORSAKOFF'S AMNESTIC SYNDROME Korsakoff's syndrome is a selective disorder of memory (amnestic syndrome) that typically arises in chronic alcoholics in the wake of one or more episodes of Wernicke's encephalopathy. The63distribution of histopathological lesions is identical to that seen in acute considerable progress has been made toward understanding Wernicke's disease. Although81–83 it is not known how a disorder of memory is produced in the biological basis of memory, Korsakoff's syndrome. Some authors have proposed that memory impairment in Korsakoff's syndrome is due to selective damage to ascending noradrenergic pathways by brainstem and 84 diencephalic lesions, whereas others have postulated that an increase in NMDA receptor function permits excitotoxicity leading to thalamic and hypothalamic lesions and memory 85 impairment. A causal relationship between (acute) Wernicke's encephalopathy due to thiamine deficiency and (chron-ic) Korsakoff's syndrome is generally assumed. However, this issue is not 86 resolved. For example, Korsakoff's syndrome was rarely a consequence of Wernicke's disease in malnourished prisoners of war in the Pacific theater during World War II. A review of cases of nonalcoholic Wernicke's encephalopathy found that patients who developed subsequent amnestic syndromes showed a substantial improvement in memory over time 86 compared with alcoholics with Wernicke's encephalopathy. This may be because the duration of malnutrition is briefer in nonalcoholics than is usually the case in chronic alcoholics or because alcohol itself contributes to development of the syndrome. The latter is supported by the finding that alcoholics who develop Wernicke's encephalopathy after a period of vomiting perform better on tests of memory than those without vomiting, possibly 87 because emesis helps to clear alcohol from the body. The disability afflicting patients with Korsakoff's syndrome is one of the most striking in clinical neurology. There is both impaired retrieval of previously established, especially recent, memories (retrograde amnesia) and inability to incorporate new memories (anterograde amnesia). Immediate recall, tested by having patients immediately repeat what is said to them, is intact. Patients are typically disoriented to time and place. Hospitalized patients are characteristically unaware of their room numbers or hospital floor, how long they have been in the hospital, what they had for their last meal, or who visited them. At the same time, very distant memories may be preserved in detail. Some patients appear to be stuck in time, insisting that the year is one from decades past. Patients with Korsakoff's syndrome appear to be unaware of their deficit and commonly attempt to reassure the examiner that nothing is seriously wrong. Confabulation, the invention of material to fill in gaps in memory, is often but not invariably seen. Other aspects of cognitive function may exhibit subtle 63 impairment, but alertness and language are intact. Patients with Korsakoff's syndrome may show evidence of other alcohol-related neurological disorders. Nystagmus and gait ataxia related to past bouts of Wernicke's disease are common, as are signs of a peripheral neuropathy.
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Korsakoff's amnestic syndrome is a clinical diagnosis. This relatively selective memory disorder must be distinguished from the more global cognitive impairment that occurs in dementia due to a variety of causes. The differential diagnosis of a chronic amnestic syndrome resembling Korsakoff's syndrome includes pancerebral hypoxia or ischemia, bilateral posterior cerebral artery strokes, herpes simplex virus encephalitis, paraneoplastic limbic encephalitis, and brain tumors in the vicinity of the third ventricle. Although acute Wernicke's disease should always be treated with thiamine, the effectiveness of thiamine88in preventing the subsequent development of the chronic amnestic syndrome is uncertain. Similarly, thiamine has not been shown to be effective for the treatment of established Korsakoff's syndrome, although patients with this disorder may improve 86 spontaneously. ALCOHOLIC CEREBELLAR DEGENERATION In some alcoholic patients, a chronic cerebellar syndrome develops that, like Korsakoff's63 amnestic syndrome, may represent a long-term sequela of Wernicke's encephalopathy. In common with Wernicke's and Korsakoff's syndromes, alcoholic cerebellar degeneration is 89 usually attributed to nutritional deficiency and specifically to depletion of thiamine. However, it has also been suggested that the disorder may result from a direct toxic effect of alcohol on 90 the cerebellum or from electrolyte abnormalities associated with alcoholism. The neuropathological basis of alcoholic cerebellar degeneration consists of loss of cerebellar cortical neurons, especially Purkinje cells, with particular predilection for the anterior and superior vermis; the anterior and superior cerebellar hemispheres are affected 89 pathological process is strikingly similar to that less often. The distribution of this cerebellar 63 seen in Wernicke's encephalopathy, providing an important clue that the two disorders may be pathophysiologically linked. The natural history of alcoholic cerebellar degeneration is variable. The syndrome usually occurs in the setting of chronic alcoholism of 10 years' or more duration. The most frequent mode of onset is with cerebellar ataxia that progresses steadily for weeks to months. A more gradually progressive disorder that evolves over years is also common. Less often, a mild and stable deficit that has been present for years may become suddenly worse. Although gait ataxia is the most prominent manifestation of both alcoholic cerebellar 63 degeneration and Wernicke's encephalopathy, the pattern of involvement in the two disorders may otherwise differ. Limb ataxia, which is absent in most patients with Wernicke's syndrome, is usually detectable in alcoholic cerebellar degeneration. Examination of such patients typically discloses severe involvement of the legs, with milder involvement of the arms. Dysarthria, which is usually mild, is also more frequent in alcoholic cerebellar degeneration. In contrast, nystagmus is present far less often than in Wernicke's encephalopathy. Uncommon manifestations of alcoholic cerebellar degeneration include hypotonia, ocular dysmetria, and postural tremor. Patients with alcoholic cerebellar degeneration may also exhibit signs of a polyneuropathy (see later). Alcoholic cerebellar ataxia is a clinical diagnosis. The CT scan or MRI may show cerebellar cortical atrophy, but laboratory findings usually are helpful only for excluding other causes of ataxia. Conditions that must be considered in the differential diagnosis of subacute or chronic cerebellar ataxia in middle life include multiple sclerosis, hypothyroidism, paraneoplastic cerebellar degeneration, idiopathic cerebellar or olivo-pontocerebellar atrophies, Creutzfeldt–Jakob disease, and posterior fossa tumors. Like alcoholic cerebellar degeneration, many of these disorders can produce ataxia preferentially affecting the gait. Ataxia due to alcoholic cerebellar degeneration often stabilizes or improves with cessation of 91 drinking and improved nutritional status, although the relative importance of these two factors is uncertain. Patients with this condition should receive parenteral thiamine. CENTRAL PONTINE MYELINOLYSIS Central pontine myelinolysis is manifested by rapidly evolving paraparesis or quadriparesis, pseudobulbar palsy, and impaired consciousness. Certain aspects of the disorder92are discussed in Chapter 19. It was first described by Adams and associates in 1959, although a German-language report of pontine demyelination in a patient with Wilson's disease 27 93 years earlier has recently been 93 confirmed. A history of alcoholism is common and found in of 39 percent of affected patients. Recent liver transplantation accounts for 17 percent 93 cases and as many as 7 percent of patients with burns may develop the disorder. Less
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often it develops after prolonged use of diuretics, psychogenic polydipsia, pituitary surgery, or 94 urological surgery. Central pontine myelinolysis is mainly an iatrogenic disorder, and its appearance coincided with the widespread use of intravenous therapy for correction of fluid and electrolyte 93,94 Hyponatremia frequently precedes central pontine myelinolysis, and disorders. 93–95 Norenberg aggressive correction of hyponatremia appears to be the precipitating factor. and colleagues retrospectively studied the records of 12 patients with autopsy-proven central pontine myelinolysis and provided the most convincing evidence for a link between 96 hyponatremia and the disorder. All of these patients had been hyponatremic, and their serum sodium levels had been raised by more than 20 mEq/L over 1 to 3 days. Eleven patients became hypernatremic (serum sodium level >147 mEq/L) during treatment. Signs of central pontine myelinolysis developed 3 to 10 days after correction of the serum sodium. In a control group of nine hyponatremic patients without pontine myelinolysis at autopsy, the serum sodium level had increased more slowly or to lower maximal levels. A causal relationship between rapid correction of hyponatremia and central99pontine myelinolysis was 97 98 established in the 1980s by studies in rats, rabbits, and dogs. Well-documented rapid correction of hyponatremia has now been identified in approximately 22 percent of human 93 of central pontine myelin-olysis in cases. However, the existence of well-documented cases93,100,101 indicates that rapid patients with hypernatremia or normal serum sodium levels correction of hyponatremia is not the only cause of this neurological disorder in humans. The characteristic pathological lesion in central93pontine myelinolysis is bilaterally symmetric, focal destruction of myelin in the ventral pons. Gocht and Colmant reviewed 58 cases and found that in approximately 50 percent characteristic lesions were present outside the basis 102 pontis, and in half of these cases extrapontine lesions were found without pontine lesions. Extrapontine myelinolysis has been observed in the cerebellum, thalamus (especially the lateral geniculate body), external and extreme capsules, basal ganglia, deep layers of cerebral cortex and adjacent white matter, and rarely in the fornix, anterior commissure, 93 subthalamic nucleus, amygdala, optic tract, and spinal cord. Histologically, there is severe loss of myelin, and oligodendroglia are reduced in number. Neurons and axons are relatively spared, although axonal swelling and neuronal shrinkage may occur, particularly in the center of lesions. There is no inflammation, and blood vessels appear normal. Coexistent illnesses often influence the clinical manifestations of central pontine myelinolysis, making it difficult to diagnose this disorder. Furthermore, small lesions detected postmortem 93 can be asymptomatic, and the disorder is therefore often not recognized before death. 95 Nevertheless, certain clinical features are typical of reported cases. Central pontine myelinolysis often evolves over several days to weeks in a severely ill patient, and mental confusion is a prominent feature in almost all cases. Demyelination of pontine corticobulbar fibers leads to early dysarthria or mutism. Spastic quadriparesis and pseudobulbar palsy are common, occurring in more than 90 percent of symptomatic cases. If lesions extend into the midbrain, medulla, or pontine tegmentum, there may be papillary and oculomotor signs, depressed consciousness or coma, and dysfunction of cranial nerves. Progressive demyelination of corticospinal and corticobulbar tracts in the basis pontis may produce a locked-in syndrome. Extrapontine lesions can cause ataxia, parkinsonism, choreoathetosis, 94,95 Cognitive and behavioral symptoms have also been reported and include and dystonia. restlessness,93emotional lability, apathy, agitation, insomnia, paranoia, delusions, rage, and disinhibition. 103
The CSF is normal in up to 72 percent of patients. Elevated CSF pressure, increased protein concentration, and mononuclear pleocytosis occur in a few. Immunoglobulins are 104 CT brain scans may be normal or may normal, but myelin basic protein may be elevated. 105–107 105 and extrapontine lucencies. Clinical recovery can show nonenhancing pontine 107 precede resolution of CT findings by as much as 18 months. MRI scans may be normal during the first 2 weeks of illness, but eventually affected regions appear hyperintense on T2-weighted images and hypointense on corresponding T1-weighted images, and usually do 95 visualization not enhance with gadolinium. Because MRI is more sensitive and allows better 94 of the brainstem, it is preferable to CT for imaging central pontine myelinolysis. Although the disorder had historically been considered to carry a93poor prognosis, recent addition, several autopsy series have shown that many cases are asymptomatic. In104,107,108 Menger and Jorg symptomatic patients have shown improvement after 1 to 4 weeks. found in a group of 44 patients that 32 survived and 11 recovered completely, and outcome did not correlate with the severity108 of neurological deficits during the acute phase of illness or with the degree of hyponatremia. Therefore, all patients with suspected central pontine myelinolysis should be supported aggressively because substantial improvement may occur after several weeks.
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Over the past 20 years there has developed a consensus on the treatment of hyponatremia to minimize the risk of myelinolysis. Severe hyponatremia (<120 mEq/L), if it develops rapidly, can cause severe, life-threatening symptoms such as coma and seizures, and demands prompt treatment. If hyponatremia occurs slowly, however, symptoms are generally less severe and include malaise, nausea, headache, lethargy, and confusion. In rats, the brain adapts to hyponatremia over the course of several days by losing electrolytes and other osmolytes, including phosphocreatinine, myo-inositol, and several amino acids, so that brain 109,110 Once the brain adapts, it is vulnerable to volumes return to normal within 2 to 3 weeks. 111–112 In a study by Ayus osmotic stress that occurs with rapid correction of the hyponatremia. and co-workers, factors contributing to myelinolysis in treated hyponatremic patients included an increase in serum sodium level to normal or hypernatremic levels during the first 48 hours 113 More or a change in serum sodium level of more than 25 mmol/L during the first 48 hours. 114,115 recent case reviews have concluded that 12 mmol/L or more over 24 hours is too rapid. Several treatment recommendations have been proposed, but the general consensus appears to be that central pontine myelinolysis94can be avoided by increasing the serum sodium level by no more than 8 mmol per day. ALCOHOLIC NEUROPATHY Neuropathy is the most frequently encountered chronic neurological disorder related to 116 alcohol117 abuse. Both nutritional deficiency and a direct, toxic, dose-dependent effect of alcohol have been invoked as etiologies. Support for a toxic effect of ethanol comes from 118,119 studies in rats demonstrating hyperalgesia following several weeks of ethanol ingestion. 120 Axonal degeneration appears to be the principal pathogenetic process. Segmental demyelination also occurs and may be secondary to the primary axonal disorder or a consequence of concomitant nutritional deficiency. Alcoholic neuropathy usually presents after several years of alcohol abuse as a distal, symmetric, sensorimotor polyneuropathy that is gradual in onset. Symptoms include weakness, pain, paresthesias, muscle cramps, numbness, gait ataxia, and burning 120 dysesthesias. Neurological examination may reveal any combination of reflex, sensory, and motor abnormalities, with predominant involvement of the legs. Absent or decreased reflexes and impaired vibration sense are virtually universal findings. Defective appreciation of light touch and weakness are also seen in most patients. Pain and temperature sensation are affected less often, and autonomic dysfunction and cranial nerve involvement are comparatively rare. In addition to the neurological abnormalities, affected limbs may exhibit 120 edema, hyperpigmentation or ulceration of the skin, and bony deformities. Nerve conduction studies are useful for documenting the presence of neuropathy and for demonstrating the predominantly axonal pathological process. Laboratory studies on blood and CSF can exclude other causes of polyneuropathy—for example, diabetes, chronic inflammatory polyradiculoneuropathy, uremia, dysproteinemia, and vasculitis. Vitamin (especially thiamine) supplementation and abstinence from alcohol can often arrest the progression of alcoholic polyneuropathy and in some cases lead to clinical improvement. Neuropathic pain may respond to anticonvulsants or tricyclic antide-pressants. Rarely, alcoholic neuropathy develops acutely over several days with severe weakness, 121 absent tendon reflexes, and multimodal sensory loss in the limbs. This condition can be distinguished from acute inflammatory demyelinating neuropathy (Guillain–Barré syndrome) by the absence of bulbar and respiratory muscle weakness, normal or only mild elevations in cerebrospinal fluid protein concentration, and electrophysiological and pathological findings of axonal damage. With abstinence from alcohol, most patients regain their ability to walk after several months. ALCOHOLIC MYOPATHY 120–123
Chronic alcoholism has adverse effects on both skeletal and cardiac muscle. Two distinct clinical presentations of alcoholic myopathy are recognized, one acute and the other chronic.
Acute Necrotizing Myopathy An acute, necrotizing myopathy may develop over the course of 1 to 2 days in the setting of heavy binge drinking. Symptoms include muscle pain and weakness, which may be asymmetric or focal in nature. Neurological examination shows tender, swollen muscles in the affected areas. Weakness is a prominent finding, is commonly proximal in distribution, and may be associated with dysphagia. Signs of congestive heart failure may be present.
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Laboratory abnormalities include moderate to severe elevation of serum creatine kinase levels and in some cases myoglobinuria. The electrocardiogram may reveal arrhythmias or conduction defects. Electromyography discloses myopathic changes in configuration and recruitment of motor unit potentials, as well as fibrillation potentials. The muscle biopsy shows necrosis of muscle fibers. Acute alcoholic myopathy must be distinguished from other causes of acute weakness in alcoholic patients, such as hypokalemia and hypophosphatemia. In the former condition, weakness is not accompanied by muscle pain, and myoglobinuria does not occur. Hypophosphatemia closely reproduces the clinical features of acute alcoholic myopathy and 124 may contribute to its pathogenesis. Consequently, serum potassium and phosphorus concentrations should always be measured in acutely weak alcoholic patients. Complications of acute alcoholic myopathy, such as cardiac disturbances and renal compromise due to myoglobinuria, should be treated urgently. Electrolyte abnormalities should be monitored carefully and corrected if necessary. Muscle pain and tenderness may improve with analgesics. Abstinence from alcohol appears to be important for recovery 120 because resumption of intake during convalescence can cause symptoms to recur. The role of nutritional factors in promoting recovery is less clear, but a nutritionally adequate diet should be ensured. Recovery within weeks to months is the rule, but some patients exhibit residual weakness and cardiac conduction abnormalities.
Chronic Myopathy Much more common is chronic alcoholic myopathy, which develops insidiously over weeks to 120,123 In animal and cell-culture months, and is seen in 40 to 60 percent of alcoholic patients. studies,122 alcohol reversibly inhibits initiation of translation and protein synthesis in skeletal muscle. Chronic alcoholic myopathy is characterized by proximal leg weakness with relative preservation of the reflexes. In contrast to the acute necrotizing alcoholic myopathy discussed previously, muscle pain is inconspicuous or absent. Where the clinical diagnosis is uncertain, chronic alcoholic myopathy can be distinguished from polyneuropathy by 125 electromyography or by a muscle biopsy showing selective atrophy of type II muscle fibers. Cessation of drinking and an improved diet are associated with clinical improvement over several months in most cases. ALCOHOL AND STROKE 126
Epidemiological studies suggest that alcohol consumption influences the risk of stroke. For intracerebral and subarachnoid hemorrhage, the risk increases linearly with increasing daily alcohol intake. Possible explanations for this association include alcohol-induced disorders of coagulation or fibrinolysis, thrombocytopenia or impaired platelet function, and acute or chronic hypertension. Heavy alcohol consumption may also adversely influence the outcome after aneurysmal subarachnoid hemorrhage by increasing the risk of rebleeding or of 127 vasospasm. In contrast, the relationship between daily alcohol intake and ischemic stroke is J-shaped. Thus, moderate drinking—two or fewer drinks per day—appears to reduce ischemic stroke risk compared with that observed in nondrinkers, whereas less temperate drinking patterns predispose to ischemic stroke. The protective effect of small amounts of alcohol has been attributed to elevated levels of prostacyclin, decreased platelet activation, enhanced fibrinolysis, and increased levels of high-density lipoprotein cholesterol. In some but not all studies, the protective effect is more significant for red wine, possibly due to phenolic components of wine that promote vasodilation, impair plaque formation, and have 128 antioxidant activity. Mechanisms that could be responsible for an increased risk for ischemic stroke in heavy drinkers include alcohol-related cardiomyopathy or arrhythmias, alcohol-induced hypertension, the increased incidence of cigarette smoking in heavy drinkers, rebound thrombocytosis occurring with alcohol withdrawal, and hypercoagulable 126,129 states. Because not all episodes of focal cerebral ischemia culminate in permanent deficits, the acute pharmacological effects of alcohol could contribute to reducing the risk of stroke by protecting ischemic but still viable neural tissue. In this regard, several studies have shown that ethanol protects cultured cerebral neurons from injury induced by excitotoxic amino acid neurotransmitters, such as glutamate, that have been implicated in ischemic neuronal 130–132 Conversely, chronic exposure to high concentrations of ethanol may up-regulate death. excitatory amino acid 131,133 receptors on cerebral neurons, as has been demonstrated in cultured thereby increasing neuronal susceptibility to infarction. cerebral cortical cells, ACKNOWLEDGMENTS
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The author's work is supported by grant AA013588 from the U.S. Public Health Service, contracts DAMD17-03-1-0058 and WB1XWH-06-1-0159 from the U.S. Department of the Army, and funds provided by the State of California for medical research on alcoholism and substance abuse through the University of California, San Francisco. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 38 Neuropsychiatric Complications of Substance Abuse GEORGE A. RICAURTE • J. WILLIAM LANGSTON • UNA D. McCANN •
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HEROIN COCAINE METHAMPHETAMINE EPHEDRINE METHYLENEDIOXYMETHAMPHETAMINE (“ECSTASY”) LYSERGIC ACID DIETHYLAMIDE MARIJUANA INHALANTS Volatile Organic Solvents Nitrous Oxide Alkyl Nitrites PHENCYCLIDINE CONCLUDING COMMENT
Substance abuse is among the most prevalent of all neuropsychiatric disorders. Complications of illicit drug use are common and depend upon the particular psychoactive drug in use, the mode by which it is consumed, and occasionally, the setting in which it is taken. The purpose of this chapter is to review known neurological and psychiatric complications of commonly abused illicit drugs. The drugs to be discussed are heroin, cocaine, methamphetamine, ephedrine, methylenedioxymethamphetamine, lysergic acid diethylamine (LSD), marijuana, solvent inhalants, phencyclidine, and the well-known drug contaminant 1-methyl-4-phenyl-tetrahydropyridine (MPTP). HEROIN Heroin, the diacetyl derivative of morphine, is widely abused, and such abuse has inevitably been associated with many deaths and visits to the emergency room. Heroin is smoked, sniffed, or injected, either subcutaneously (“skin popping”) or intravenously. When taken intravenously, heroin produces a warm flushing of the skin along with an intensely 1 pleasurable sensation. These and other pharmacological effects of heroin result principally from the actions of the drug on opiate receptors in the gastrointestinal tract and central 2 nervous system (CNS). Through its actions on the CNS, heroin relieves pain, suppresses cough, depresses respiration, and clouds the sensorium. In the gut, heroin interferes with intestinal motility. Another well-known effect of heroin is pupillary constriction, an effect that is
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probably mediated at the level of the autonomic portion of the oculomotor complex. 1
Hallmarks of heroin overdose are coma, pinpoint pupils and respiratory depression. Of these, respiratory depression is the most pressing concern. It can be readily and quickly reversed by the opioid antagonists naloxone or nalmefene. Because of the short plasma half-life of naloxone (approximately 60 to 90 minutes) relative to the long half-lives of many opioids, close monitoring of patients is required when this agent is used, and some patients will require repeated doses. Nalmefene, which has a longer plasma half-life (approximately 11 hours) has been added to the pharmacological armamentarium of many emergency3 departments and is now perceived by many to represent a significant clinical advance. Neurological complications associated with heroin misuse can be subdivided into those that stem from noninfectious sources and those that are of infectious origin. Those of noninfectious origin arise mostly from cerebral hypoxia, secondary to hypoventilation and 4 5,6 hypotension produced by heroin overdose. 7,8These include cerebral infarction and acute or heroin overdose in the delayed posthypoxic leukoencephalopathy. Cerebral infarction after 5 noninfected 9,10 patient may also involve direct11vascular compression, possible vasculitis or or thromboembolic events. Direct effects of heroin on cerebral blood vasospasm, vessels await further investigation. Neurological complications observed in heroin abusers that are related to infection include meningitis, cerebral abscess, embolic infarcts (in patients with endocarditis), and human 12 immunodeficiency virus (HIV)–related neurological disturbances. The role of intra-venous drug use in the proliferation of HIV is well known and is considered a major public health problem. Other neurological complications associated with heroin abuse include myelopathy (primarily 13 14 seizures, and extrapyramidal dysfunction secondary to at the cervical and thoracic levels), 11,15,16 Again, these neurological complications are likely secondary to basal ganglia injury. hypoxic-ischemic insult related to respiratory depression and hypotension. Reversible 17 parkinsonism in the setting of tetrahydrobiopterin deficiency has also been noted. In addition, a18progressive ventral pontine syndrome following heroin abuse has been described ; its underlying basis is not well understood. Peripheral nerve disorders have also been noted in heroin abusers. Usually they can be attributed to prolonged compression of nerves during periods of stupor or to direct trauma 19 from injection. The appearance of brachial and lumbosacral plexopathies after heroin use is difficult to explain on this basis, however. In these cases, local infections, rhabdomyolysis, 20 and autoimmune processes have been implicated as etiological factors. There is no evidence that heroin or other opiates are directly neurotoxic to the brain. However, there are numerous reports of individuals who developed an acute toxic spongiform leukoencephalopathy associated with inhalation of preheated heroin (“chasing the 21,22 The cause of this leukoencephalopathy is not known with certainty, but it is dragon”). believed to be 22 related to a toxic derivative produced in the heating process of the free base form of heroin. Severe neuropsychiatric deficits are rarely seen in ordinary opiate addicts. A study in which detailed neuropsychiatric assessments were conducted in seven heroin addicts maintained on pharmaceutical heroin for an average of 32 years revealed mild and inconsistent cognitive deficits and mild or no abnormalities on23computed tomography (CT) scans when subjects were compared with matched controls. More recent studies are in keeping with these earlier 24 observations. Postmortem neuropathological evaluation of the brains of heroin addicts reveals abnormalities that would be anticipated from hypoxic-ischemic injury (including ischemic neuronal loss, enhanced glial fibrillary acid protein, and microglial proliferation) 12 rather than evidence of direct neurotoxic effects of heroin. 25
Several pharmacological approaches are available for the treatment of opioid dependence. One involves therapy with opiate agonist drugs that have a longer duration of action than heroin and can be taken orally; methadone, a full opioid agonist, falls into this category. Another orally active opioid drug increasingly used in the treatment of opioid dependence is buprenorphine, a partial opioid agonist. In addition to agonist drugs, opiate antagonists have been tried in the treatment of opiate dependence (naltrexone). Because opiate antagonists can precipitate acute withdrawal in the opiate-dependent individual, use of narcotic antagonists should be limited to opiate-free subjects seeking to prevent relapse. Yet another approach calls for cessation of opiate use (“detoxification”). A series of rapid and ultrarapid 26 detoxification procedures are evolving. The long-term efficacy of these procedures remains to be determined.
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COCAINE Cocaine, either as the hydrochloride salt or as a free base (“crack”), continues to be one of the most widely abused illicit drugs. The hydrochloride salt of cocaine can be self-administered orally, intranasally, or intravenously, whereas the free base form of cocaine is smoked. Over the years, abuse of cocaine has been associated with a number of neuropsychiatric complications, most of which are referable to its central stimulant and sympathomimetic effects. In particular, cocaine stimulates catecholaminergic neurotransmission by blocking27reuptake inactivation of dopamine and norepinephrine, both in the brain and in the periphery. Cocaine27also produces local anesthetic effects by acting at voltage-dependent sodium ion channels. Largely because of these pharmacological effects, moderate doses of cocaine increase alertness, raise blood pressure, cause 28 mild hyperthermia, reduce appetite and thirst, and induce a euphoric sense of well-being. In higher or repeated doses, cocaine can produce 29,30 hypertension, hyperpyrexia, rhabdomyolysis, cardiac arrhythmias, and sudden death. 30 In some instances, serious adverse effects of cocaine develop even after modest doses. Signs of recent cocaine ingestion include dilated pupils and tachycardia. Common neurological complications of cocaine 31–34 abuse include seizures, tremor, headache, The mechanisms by which cocaine and various types of cerebrovascular accidents. causes stroke are not entirely clear, but increased blood pressure and vasospasm are 32,34,35 36 Cocaine also causes platelet activation and aggregation and thrombus suspected.37 38,39 formation. Cases of vasculitis associated with cocaine abuse have been reported. Cerebrovascular complications of cocaine often occur in individuals later found to have some 40,41 predisposing factor such as hypertension, aneurysm, or arteriovenous malformation. Other neuropsychiatric complications associated with cocaine abuse include dystonic 42 43 reactions, exacerbation of preexisting movement disorders such as tics, paranoia, 44 delirium, and a psychotic state that may resemble nascent schizophrenia in a young adult. In addition to the previously mentioned neuropsychiatric complications, cocaine has been 45–47 These reported to produce persistent (up to 6 months) alterations in cerebral blood-flow. 48 alterations partially reverse with abstinence. In one study in which blood-flow abnormalities persisted for at least 6 months of abstinence from cocaine, an association was 47 found between deficits in cerebral blood-flow and abnormal neuropsychiatric function. Along with blood-flow alterations, neuroimaging studies have demonstrated altered cerebral glucose 46,49 The regional distribution of metabolic metabolism in abstinent cocaine abusers. alterations does not coincide with that of blood-flow alterations, suggesting that the two phenomena are probably distinct. The clinical significance of these imaging abnormalities remains to be determined. Treatment of acute cocaine intoxication must be tailored to the individual patient. Furthermore, it is important to recognize that polysubstance abuse is the rule rather than the exception. Repeated seizures should be treated50with intravenous diazepam (usually after intubation for potential laryngospasm or apnea). Sodium bicarbonate is indicated in the setting of51,52 acute acidosis. Beta-blockade leading to unopposed alpha-stimulation should be Rather, nitroglycerin, a calcium-channel blocker, or intravenous phentolamine avoided. should be considered to reduce malignant hypertension. In cocaine-related brain ischemia, thrombolysis is not routinely indicated, because it does not overcome vasospasm and can increase the risk of intracranial hemorrhage associated with hypertension secondary to 30 cocaine intoxication. In contrast, use of an antiplatelet agent such as aspirin to prevent further thrombus formation is appropriate. Agitation is best controlled with a benzodiazepine (e.g., diazepam). Successful treatment of cocaine dependence remains a major challenge. A variety of agents are now under active investigation. These include dopamine uptake inhibitors (bupropion, methylphenidate), dopamine receptor blockers (risperidone), monoamine oxidase inhibitors (selegiline), GABAergic drugs (gabapentin, topiramate), and drugs whose mechanism of 53,54 action is not entirely clear (modafinil). METHAMPHETAMINE Over the last decade, methamphetamine abuse has reached epidemic proportions in various parts of the United States. Like cocaine, methamphetamine is a powerful sympathomimetic agent. However, rather than acting primarily by blocking the reuptake inactivation of dopamine and norepinephrine, methamphetamine acts principally by 55 releasing dopamine and norepinephrine from dopaminergic and noradrenergic nerve endings. Compared with cocaine, methamphetamine has a longer duration of action (typically more than 1 hour
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compared with less than an hour for cocaine). Methamphetamine is also a relatively weak inhibitor of the enzymatic inactivation of catecholamines (dopamine and norepinephrine) by 55 monoamine oxidase. 56
In the illicit drug market, methamphetamine is known as “speed,” “crystal meth,” or “crank.” In addition, a purified crystalline or solid form is known as “ice.” Depending on the form, methamphetamine can be taken orally, intravenously, inhaled, or smoked. Some individuals take extremely high dosages of methamphetamine intravenously over prolonged periods. These “runs” of methamphetamine use sometimes last for up to 3 or 457days, during which the drug user often forgoes eating, sleeping, or drinking to a large degree. Clinical clues to chronic methamphetamine abuse include poor personal hygiene, cachexia, and erratic, often violent, behavior. One of the most notorious neurological complications of methamphetamine abuse is 58,59 In addition to hemorrhagic stroke, methamphetamine abuse has intracranial hemorrhage. 60 been associated with ischemic stroke. Although elevations in blood pressure likely play a role in some methamphetamine-related strokes, it is important to note that not all patients have an elevated blood pressure at the time of presentation. Vasoconstriction is another mechanism by which methamphetamine may produce brain ischemia. Vascular abnormalities referred61,62 to as “amphetamine-induced vasculitis” have been described However, the relationship between methamphetamine and in methamphetamine abusers. necrotizing vasculitis is complicated. Adulterants in methamphetamine preparations have63 been implicated, but vasculitis has been observed in patients taking pure amphetamines. Infectious agents injected during the intravenous administration of nonsterile drug solutions62 have also been suggested to play a role in the etiology of amphetamine-induced vasculitis. However, vasculitis has been observed in individuals who have taken the drug orally and who 63 has also been reported have had no signs or symptoms of infections. Necrotizing vasculitis64,65 Therefore, use of following the use of other psychostimulant drugs, such as ephedrine. methamphetamine and related drugs should be suspected in any young adult presenting with unexplained stroke (hemorrhagic or ischemic) or CNS vasculitis. 66
Other notable neuropsychiatric complications of methamphetamine abuse include seizures, 67,68 67–69 choreiform movement disorder, headache, hypertension, and hyperpyrexia. Alterations in mental 69 status also occur. These usually take the form of anxiety, agitation, and severe acute mental status changes may include paranoia, aggressive behavior. More 67–69 These complications of methamphetamine abuse are typically delirium, and psychosis. self-limiting (i.e., they resolve after the 70–72 drug is discontinued). However, persistent psychosis In addition, subacute depression lasting for a few has been observed in some instances. 73,74 days after cessation of methamphetamine abuse has been reported.
Clinical management of methamphetamine intoxication depends on the presentation. As alluded to previously, signs and symptoms of methamphetamine toxicity are often self-limiting and usually require only routine supportive care and observation. When pharmacological intervention is deemed necessary, haloperidol is the agent of choice for countering the central stimulant effects of methamphetamine when they lead to paranoia, chorea, or 75,76 Since hyperpyrexia is potentially lethal, it should also be treated with hyperpyrexia. whole-body cooling. Repeated seizures should be treated with intravenous diazepam. In this setting, intubation for potential apnea or laryngospasm should be considered. In patients with malignant hypertension, a peripheral α–receptor blocking agent, such as phentolamine, can be used. Nitroprusside and calcium-blocking agents are also effective in this setting. Acidification of the urine with ammonium chloride can be used to promote renal excretion of methamphetamine. Animal studies have shown that administration of repeated or high doses of methamphetamine produces lasting decreases in brain dopamine and serotonin neuroaxonal 77–79 Anatomical studies indicate that these neurochemical deficits are markers in animals. 79,80 related to destruction of dopaminergic and serotonergic axon terminals. 81–84 Methamphetamine-induced neurotoxicity also appears to occur in humans, although more data are needed. The functional consequences of methamphetamine-induced neurotoxicity remain largely unknown. In spite of what might have been expected, there is little evidence that chronic methamphetamine abuse leads to a parkinsonian state, probably because the size of the dopaminergic lesion is insufficient. By contrast, chronic use of methamphetamine has been associated with a variety of cognitive changes including deficits in learning, selective attention, delayed recall, processing speed, 85–87 working memory, verbal memory, manipulation of information, and cognitive inhibition. Cognitive deficits in methamphetamine abusers may be influenced by numerous factors including the severity of dependence, other drug use, and comorbid conditions. Because of
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these potentially confounding factors, the precise role of methamphetamine in these cognitive alterations is not entirely clear. EPHEDRINE Ephedrine is another amphetamine analogue that is subject to misuse. Both illicit synthetic and licit botanically derived formulations of ephedrine are available. Plant-derived preparations such as ma huang (Ephedra sinica), once widely marketed as dietary 88 supplements and promoted for weight loss, body building, and increased energy, were 89 banned by the U.S. Food and Drug Administration (FDA) in 2004, but their legal status is still under review. These preparations of ephedrine typically contain a mixture of ephedrine alkaloids and caffeine, as well 90 as other ingredients that may influence the pharmacological and toxic effects of ephedrine. As with methamphetamine, adverse effects of ephedrine and ephedra alkaloids are generally referable to overstimulation of the central and sympathetic nervous systems. Common symptoms include hyperactivity, tremulousness, agitation, anxiety, and palpitations. More serious adverse effects include stroke, seizures, psychosis, malignant hyperthermia, and 91–94 Posterior reversible encephalopathy, secondary to increased blood sudden death. 95 pressure, has recently been reported after ephedra overdose. This syndrome is characterized by seizures, mental status changes, and visual disturbances that typically recede once blood pressure is controlled. A case-control study linked96the use of the ephedrine analogue phenylpropanolamine to the risk of hemorrhagic stroke. Not surprisingly, neurological complications associated with 97 phenylpropanolamine also include acute hypertension, stroke, seizures, and psychosis. Recognition and management of ephedrine intoxication parallel that of methamphetamine 98 and other amphetamine-type stimulants such as MDMA, which are discussed in the next section. Ephedrine and phenylpropanolamine may give rise to a positive drug screen for amphetamine. METHYLENEDIOXYMETHAMPHETAMINE (“ECSTASY”) Methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a synthetic drug structurally related to both the stimulant methamphetamine and the hallucinogen mescaline. Presently, much of the use of MDMA takes place in the setting of clubs or large dance parties (“raves”),99where individuals may consume multiple doses of MDMA over the course of 8 to 10 hours. As the 100,101 repeated dosing can lead to metabolism of MDMA exhibits nonlinear kinetics, disproportionate rises in plasma MDMA concentrations, which, in turn, can produce more pronounced effects. In addition to stimulating the sympathetic nervous system (via catecholamine release), MDMA releases brain serotonin and thus indirectly activates a variety of central serotonin 102,103 Shortly after MDMA ingestion (typically oral), users report a sense of receptors. well-being and closeness to others. Physiological effects include mydriasis, tachycardia, increased blood pressure,104hyperthermia, hyperreflexia, decreased hunger and thirst, nystagmus, and bruxism. As with use of other amphetamines, use of MDMA has been associated with various neurological complications. These include ischemic and hemorrhagic 107–109 cerebral 104–106 ; intracerebral, subdural, or subarachnoid hemorrhage ; cerebral venous infarction 110 111,112 As with sinus thrombosis ; cerebral edema; and coma, sometimes resulting in death. methamphetamine, some of these complications (e.g., strokes) may be related to preexisting 113 arteriovenous malformations or hypertensive surges and others (e.g., sinus thrombosis) to severe dehydration secondary to vigorous physical activity (such as dancing) in crowded, overheated settings. Other reported neuropsychiatric difficulties associated with MDMA use or abuse include panic 114–116 117–119 117,118,120 psychosis, major depressive disorder, and memory or cognitive disorder, 121–125 In most of these case reports, the role of preexisting conditions and disturbance. polydrug use represent confounding factors. Less well understood adverse effects of MDMA are hyponatremia (often in the setting of 126,127 inappropriate antidiuretic hormone secretion128,129), marked elevation in serum creatine 130,131 and malignant hyperthermia. Of kinase (CK) in the absence of muscle injury, these, malignant hyperthermia has received particular attention because it is hypothesized to occur more frequently with MDMA than with other stimulants (e.g., methamphetamine) and because of the setting and use patterns of MDMA. This may be because, as noted earlier,
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MDMA is often used in crowded, hot settings while individuals are engaging in vigorous activity. Thus, this combination of heat, physical activity, and concomitant dehydration are likely to increase the risk for MDMA-related hyperthermic reactions. Left untreated, MDMA-induced malignant hyperthermia can rapidly develop into a cluster of serious complications, including disseminated intravascular coagulation, rhabdomyolysis, renal 130 failure, and sometimes death. A large body of preclinical research indicates that MDMA selectively damages brain serotonin 102–104 Because doses of neurons in a variety of species, including nonhuman primates. MDMA that produce neurotoxicity in primates overlap with those that are used by some humans, a number of researchers have sought to determine whether humans also sustain MDMA-induced neurotoxicity. In controlled studies, MDMA users have been found to132 have selective reductions in 5-hydroxyindoleacetic acid (5-HIAA) of the cerebrospinal fluid 133 similar to those seen in squirrel monkeys with documented MDMA-induced neurotoxicity. Similarly, human MDMA users have been shown to have reductions in brain serotonin 134,135 transporters, 136 as found in baboons with documented MDMA-induced serotonin neurotoxicity. Although the functional consequences of MDMA-induced toxicity to brain serotonergic neurons are not certain, several groups have found cognitive deficits in MDMA users, particularly on memory tasks (see earlier). Further studies are needed to determine whether these functional abnormalities are direct consequences of MDMA-induced serotonin neurotoxicity. Treatment of MDMA intoxication, like that of methamphetamine, depends on the presenting signs and symptoms, and should follow similar guidelines. There have been no controlled studies regarding treatment of chronic neuropsychiatric sequelae associated with MDMA use. LYSERGIC ACID DIETHYLAMIDE 137
Lysergic acid diethylamide (LSD), which activates brain serotonergic neuronal systems, continues to be a commonly abused illicit drug. Low doses of LSD are associated with mild 138 affective lability, visual illusions, and heightened perception. There is considerable variability in the effects of LSD, both within the same individual at different times and between different individuals. Although dose is not unimportant,139 the setting in which LSD is taken can have a profound influence on its psychoactive effects. LSD has been associated with persistent adverse neuropsychiatric consequences, the most 140 severe being chronic psychosis. The psychotic syndrome seen following LSD use can be variable, involving either a clear affective component with140mood swings, mania, grandiosity, 139,140 or a more schizophrenic-like picture. Although the neurobiological and religiosity basis of vulnerability to LSD-induced psychosis is not known, it is generally thought that individuals with previous personal or family histories of a psychotic illness or severe affective disorder are at a higher risk for the development of this syndrome. In addition to psychosis, LSD can lead to a phenomenon known as “hallucinogen persisting 138 perception disorder.” This phenomenon can take the form of a flashback, where the individual reexperiences an LSD-like state when not under the acute pharmacological 141 142 influence of the drug, or of persistent, continuous visual disturbances. A variety of intermediate syndromes have also been described involving somatic, perceptual, or 143 emotional distortions that occur distant in time from the acute LSD experience. The best studied of these hallucinogen persisting 138,144 perception disorders are the persistent It has been hypothesized that these visual disturbances reported by some LSD users. persistent visual abnormalities involve small inhibitory GABAergic interneurons receiving 145 serotonergic input. In this setting it has been proposed that an intense LSD-generated current leads to a loss of inhibitory GABAergic influences on neurons responsible for the altered visual experiences. The acute psychotic or unpleasant psychological effects (e.g., severe anxiety, paranoia) of 146 LSD are often best treated using benzodiazepines, such as 146 oral diazepam. Antipsychotics should be avoided because they may aggravate symptoms. In addition, benzodiazepines 139 can also be useful in the treatment of hallucinogen persisting perception disorder, though chronic use should be avoided, particularly in someone with a strong history of drug abuse or dependence. MARIJUANA The principal psychoactive component of marijuana is delta-9-tetrahydrocannabinol (THC), but the marijuana plant contains other chemicals, some of which are related to THC. Although marijuana is generally smoked, it can also be taken orally. In recent years, elegant
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studies have led to the characterization of an endogenous cannabinoid system, and at least two types of cannabinoid receptors (CB1 and CB2) susceptible to pharmacological blockade 147 have been identified. The CNS effects of marijuana vary, depending on dose and route of administration, but moderate doses of marijuana typically produce changes in mood, impair motor coordination, 148 alter cognitive abilities, and engender a different sense of time. Psychopharmacological effects of marijuana are perhaps best characterized as mildly psychedelic, but the effects clearly differ from those of true hallucinogens. Cardiovascular effects most commonly noted 149 after marijuana are a mild increase in heart rate and a reddening of the conjunctiva. Effects on the endocrine and immune systems have also been reported, but their significance is as yet unclear. 150
Effects of marijuana on the nervous system include impaired coordination and gait. High doses of marijuana cause disorientation, confusion, and, if doses are high enough, a frank toxic psychosis. More commonly, this complication occurs after oral ingestion. Typically, the sensorium clears entirely within days, and therapeutic intervention is not required. A withdrawal syndrome associated with cannabis dependence has been described and consists 151 of irritability, anxiety, marijuana craving, and sleep disturbance. Two recent reviews summarize case reports pointing to a possible relationship between 152,153 The mechanism by which marijuana use and cerebrovascular ischemia and infarction. marijuana could produce cerebral ischemia in young adults without other predisposing conditions is unclear, but vasospasm seems to be the most likely mechanism, as 154 vasoconstrictive effects of THC have been documented in animals. A variety of techniques and animal species have been employed by researchers investigating potential long-term neurological sequelae of marijuana use. Studies in rodents revealed neuronal changes in the CA3 region of the hippocampus months after chronic drug 155 is unclear. A second study also reported exposure, but the significance of these findings 156 neuronal alterations in the hippocampus of rats. Early studies conducted in rhesus monkeys exposed to marijuana smoke for 6 months also suggested that marijuana exposure 157 However, could lead to ultrastructural changes in hippocampal and septal brain regions. 158 later studies in a larger number of monkeys failed to confirm these results. Notably, the exposure regimen in these more recent primate studies was specifically designed to parallel 156 that used previously in rats. Given these conflicting results, it is not possible to state unequivocally whether chronic marijuana exposure induces neurotoxic changes in the hippocampus. In humans, chronic marijuana use has been reported to lead to an amotivational syndrome characterized by apathy, dullness, lack159,160 of ambition and drive, cognitive disturbance, and a Controlled studies designed to test this general loss of goal-directed behavior. 161,162 There has also been some possibility, however, failed to confirm these reports. disagreement regarding the development of persistent cognitive deficits in chronic marijuana users, with some investigators163finding that cognitive deficits are entirely reversed following an cognitive deficits abstinence period of 28 days, and others finding persistent dose-related 164 in abstinent individuals who were previously chronic marijuana users. A number of reports have suggested that marijuana use is associated with more severe psychiatric symptoms in 165–167 but it is not clear whether marijuana use is a patients with a psychiatric condition, precipitant, correlate, or consequence of psychiatric symptoms. Thus, at present, it is still not clear whether marijuana use, particularly chronic marijuana use, leads to long-term neuropsychiatric impairments. INHALANTS Inhalant abuse is prevalent in many parts of the world. In part, this is due to the ready availability of inhalants. Abused inhalants include volatile organic solvents, nitrous oxide, and volatile alkyl nitrites. Each of these is discussed in turn.
Volatile Organic Solvents These are found in many common household products including some glues, paint thinner, lighter fluid, and spot removers. Some people breathe the fumes of organic solvents directly from the container; others put organic solvents on rags or in plastic bags, which they then place over the nose or head. The principal active ingredients in organic solvents are simple carbon-based molecules (e.g., benzene, toluene, hexane, acetone, butane, and ethyl 168,169 The mechanism by which solvent inhalants produce psychoactive effects is chloride). not well understood. Acute neurobehavioral effects of organic solvents include
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lightheadedness, giddiness, and a hot, flushed, exhilarated feeling.
Acute neurological manifestations of solvent intoxication include ataxia, dysarthria, diplopia, 170,171 Respiratory depression may occur, along with nystagmus, and mental status changes. increasing disorientation and confusion that may evolve to loss of consciousness. 170 Confusional states related to solvent inhalation may persist for days. Death may result from suffocation as a direct result of the application methods described earlier. The principal neurological disorders associated with chronic organic solvent abuse are 170 peripheral neuropathy, ataxia, and dementia. Neurological abnormalities may vary depending upon the solvent involved. For example, a distal, symmetrical sensorimotor polyneuropathy has often been described in individuals who sniff glues containing 172,173 Typically, the neuropathy stabilizes and partially resolves after solvent abuse hexane. has been curtailed, but it may persist for months. Generally, the more extensive the abuse, the longer it takes for the neuropathy to resolve, and resolution may be incomplete. Ataxia has been associated174 with toluene abuse, and is most likely secondary to cerebral has also been associated with a white matter derangement. Toluene abuse175 neurological complications of leukoencephalopathy that leads to dementia. Other reported 176 177 chronic toluene abuse are internuclear ophthalmoplegia and optic atrophy. Treatment of acute solvent inhalant intoxication may be difficult, as no specific antidotes are available. In the agitated patient, diazepam can be used for sedation. Aside from this measure, only routine supportive respiratory and cardiovascular measures can be provided.
Nitrous Oxide Nitrous oxide (“laughing gas”) is a commonly used anesthetic agent. This liquified gas is also 178 subject to abuse. Whipped cream propellants (“whip-its”) containing nitrous oxide can be readily obtained or prepared. The most prominent psychoactive effect of nitrous oxide is a sense of well-being; continued exposure may produce paresthesias, hearing distortion, and 179 gait ataxia, all of which are reversible after use is discontinued. Neurological complications secondary to chronic nitrous oxide exposure are primarily related to a vitamin B12–deficient state. The precise mechanism by which nitrous oxide causes vitamin B12 deficiency is not completely understood, but effects on S-adenosyl methionine (SAM) production, methylmalonyl conversion to succinyl coenzyme A, and cyanocobalamin 180 metabolism have all been postulated. Regardless of the precise mechanism, the net effect is vitamin B12 deficiency with its known attendant neurological complications including 181 182,183 184,185 neuropathy, myelopathy, and encephalopathy. Individuals deficient in vitamin B12 appear to be more susceptible to the neurological complications of nitrous oxide 185 abuse. However, neurological deficits may also develop in the absence of vitamin B12 186 deficiency. Neurological problems typically resolve with vitamin B12 supplementation and cessation of nitrous oxide abuse.
Alkyl Nitrites Alkyl nitrites such as amyl nitrite are also inhaled for recreational purposes. However few, if any, neurological complications have been reported in association with abuse of alkyl nitrites. PHENCYCLIDINE Phencyclidine (PCP) is one of a group of arylcyclohexylamines that also includes the dissociative anesthetic, ketamine, and dizocilpine (MK-801). PCP was first synthesized in the 1950s and was marketed as a surgical anesthetic. Its use in surgical settings was abruptly discontinued when approximately half of the patients who received it 187 were noted to develop a psychotic syndrome that sometimes persisted for more than a week. The mechanism of action of PCP is both unique and complex and includes glutamate 188 N-methyl-d-aspartate (NMDA)–type receptor antagonism. Overall, PCP produces a mixture of stimulant, depressant, and psychedelic effects. Lower doses of PCP induce a giddy, drunken feeling with euphoria resembling alcohol intoxication, although marked anxiety and 189–191 Higher doses emotional outbursts are frequently seen in the emergency room situation. may produce dysarthria, ataxia, increased deep tendon reflexes, decreased pain sensation, 191,192 tachycardia, raised blood pressure, flush ing and sweating, and altered perception. 193 Malignant hyperthermia after PCP intoxication has been reported. PCP can also produce nystagmus (either190,191 horizontal or vertical) and, in some cases, PCP intoxication progresses to The combination of nystagmus and hypertension in an otherwise stupor and coma.
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healthy young adult should alert the physician to the possibility of PCP intoxication. Remarkably, some patients intoxicated with PCP are vigilant but unresponsive, and they can be mistaken for being catatonic or in a state of akinetic mutism. Neurological complications of PCP intoxication include major motor seizures, focal dystonias, 190,191 It is important to remember that PCP exerts anesthetic effects and athetoid movements. and that patients may therefore complain of numbness. It is generally thought that the combination of anesthesia and mental status changes (e.g., hallucinations and formal thought disorder) accounts for cases of self-mutilation that have been reported in association 194 with PCP. There have been several reports of chronic PCP users who195,196 developed persistent cognitive Abrupt lapses into impairments, particularly in the area of short-term memory. confusional states occurring weeks or months after PCP ingestion have also been reported; occasionally these have a “schizophrenic-like” quality. PCP intoxication may persist for 197 days, since the half-life of PCP after overdose may be prolonged for as long as 3 days. The half-life of PCP can be shortened by acidifying the urine with ammonium chloride. However, this measure should not be taken if rhabdomyolysis is an intercurrent problem. Instead, aggressive hydration and diuretics are indicated. Control of psychotic behavior can generally be accomplished in a quiet environment and by the judicious use of haloperidol. Phenothiazines should be avoided because their anticholinergic effects may aggravate those of PCP. When severe agitation or seizures occur, diazepam is 197 the drug of choice. Olney and colleagues reported that single doses of198 PCP and related compounds (MK-801 and ketamine) led to selective neurotoxicity in rats. In particular, neurons located in layers III and IV of the posterior cingulate and retrosplenial cortex were observed to have abnormal cytoplasmic vacuolization that was directly correlated with the potency of noncompetitive NMDA blockade. These neurotoxic changes were at first believed to be transient. However, higher doses of MK-801 were observed to lead to changes persisting for at least 48 hours after drug administration. More recent studies indicate that PCP can produce neuronal degeneration in many cerebrocortical and limbic regions, possibly by disinhibiting multiple 199 converging excitatory pathways. Whether these effects are related to the psychotogenic effects of PCP or its putative long-term effects on memory remains to be determined. CONCLUDING COMMENT Commonly abused illicit drugs can produce a wide range of neurological complications, some of which may be permanently disabling or fatal. For this reason, it is important to include illicit drug abuse in the differential diagnosis of acute neuropsychiatric syndromes. However, it is important to be aware that polysubstance abuse is the rule rather than the exception. Therefore, identification of an illicit substance on a drug screen or by history should not be considered diagnostically conclusive, because the presence of other illicit substances (whether taken wittingly or as a contaminant) can complicate both the clinical presentation and treatment of a drug-induced neuropsychiatric syndrome. This is exemplified by the so-called MPTP story. In 1983, there was an unusual outbreak of parkinsonism among young intravenous heroin abusers. In these cases, it was determined that in an effort to synthesize a synthetic heroin analog, clandestine chemists had synthesized a compound tainted with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a potent neurotoxin that destroys dopamine-containing cells in the pars compacta of the substantia nigra, the primary site of 200 pathology in Parkinson's disease. Not surprisingly, shortly after heroin addicts began using what they believed was a new synthetic heroin, a number of them developed a striking neurological syndrome that had all the cardinal features of Parkinson's disease, including marked bradykinesia, rigidity, loss of postural reflexes, and tremor at rest. These patients not only responded to standard dopamine replacement therapies but also developed the typical complications of levodopa therapy, including peak dose dyskinesias and on-off 201 phenomena. This unfortunate series of events serves to highlight the perils associated with illicit drug synthesis and consumption. It should be recognized that the landscape of illicit drugs is constantly changing, and “small” modifications of a parent compound can be associated with profoundly different consequences. Therefore, it seems likely that the present review of potential neuropsychiatric complications of commonly abused illicit drugs will always be in need of updating as novel psychoactive substances emerge in the illicit drug subculture. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 39 Neurological Complications of Toxin Exposure in the Workplace GARETH J. PARRY •
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BASIC TENETS OF NEUROTOXICOLOGY CLINICAL SYNDROMES OF NEUROTOXICITY Acute Encephalopathy Chronic Encephalopathy Structural Diseases of the CNS Toluene Abuse Carbon Monoxide Intoxication Heavy Metal Exposure Nitrous Oxide Organophosphates Toxic Neuropathy SCREENING AT-RISK WORKERS FOR NEUROTOXICITY Clinical History Clinical Examination Electrodiagnostic Testing Electroencephalography Evoked Potentials Electromyography and Nerve Conduction Studies Neuropsychological Evaluation Other Laboratory Testing CLINICAL SYNDROMES ASSOCIATED WITH SPECIFIC OCCUPATIONAL NEUROTOXINS Organic Solvents CNS Effects Peripheral Neuropathy Heavy Metals Lead Arsenic Other Neurotoxic Metals Organophosphates Neurotoxicity From Inhibition of Acetylcholinesterase Neurotoxicity From Inhibition of Neuropathy Target Esterase Acrylamide Toxic Gases
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Only a few of the tens of thousands of chemicals used in industries in the United States have 1 been shown to be neurotoxic. Furthermore, even those with proven neurotoxic potential in the laboratory are rarely demonstrably toxic to humans in the workplace. This is a tribute as much to the resiliency of the human organism as to preventive measures taken by industry. Nonetheless, many cases of human neurotoxicity resulting from industrial exposure are documented each year and probably many more go unrecognized. There is probably a level of neurotoxic injury that is inevitable in industrial societies of our time, and the chief weapon in limiting its spread is constant vigilance on the part of the medical and paramedical professions. In this chapter, discussion is concentrated on those instances in which neurotoxicity has been proven by rigorous scientific investigation. This is not meant to imply that the many other postulated instances are factitious but only that no definite conclusions can be reached until more information is forthcoming. BASIC TENETS OF NEUROTOXICOLOGY Establishing that a particular chemical is neurotoxic or that a certain clinical syndrome is due to exposure to a neurotoxin is no easy task. Spencer2–4 and Schaumburg have proposed an evolving series of useful rules to follow in this regard (Table 39-1). These serve only as a guide and should not be arbitrarily applied. For the purpose of further discussion, they can be considered in the form of the following questions, which should be posed when the possible neurotoxic basis of a neurological disorder is being evaluated: Click here to view this table.... 1. Does the suspected neurotoxin produce a consistent pattern of neurological dysfunction in exposed humans? It is rare for only one or a few workers similarly exposed to a given toxin to have symptoms and signs of intoxication. There will certainly be some variation in the severity of the clinical syndrome, based on age, sex, genetic makeup, and the presence of co-existing disorders such as diabetes, renal disease, liver disease, and preexisting neurological disease, but all workers usually have some clinical evidence that they have been exposed to a neurotoxic chemical. Involvement of a single worker may have several explanations. First, the clinical syndrome may not be due to a toxin; the symptoms of intoxication are often so nonspecific that any of a large number of systemic, neurological, and psychological disorders may have identical symptoms. Second, if the illness is due to a toxin, the intoxication may not have taken place at work; abuse of drugs and alcohol is so ubiquitous that the development of a syndrome of neurointoxication may be due to recreational exposure. In addition, there is potential for exposure to other toxins from hobbies. Finally, the exposure may be the result of an unusual or unique work habit; a lone affected individual may not use a mask or may not wash after exposure to a neurotoxin. A visit to the workplace by an appropriately trained individual may be necessary to unearth a habit that is resulting in excessive exposure. Although this first rule certainly should be rigorously applied, it is of limited usefulness in occupational intoxications. By far the most common effect of intoxication (real or imagined) on the nervous system is a rather stereotypical but entirely nonspecific syndrome of encephalopathy; patients complain of headache, dizziness, numbness, paresthesias, weakness, difficulty in concentrating, memory loss, and sleep disturbances. Such symptoms are common to a wide variety of neurological and psychological conditions. Furthermore, in outbreaks of proven intoxication, a syndrome of mass hysteria may result once the symptoms are publicized by the media, as they almost invariably are in such situations; large numbers of individuals may then acquire identical symptoms even in the absence of exposure. This first rule, then, is useful primarily in evaluating objective findings rather than symptoms, and although it is sensitive, it is not specific. This rule also presumes an accurate knowledge of the range of clinical phenomena that may occur after exposure to a single neurotoxin. For example, massive, short-term exposure to acrylamide causes an encephalopathy with seizures, confusion, hallucinations, and cognitive impairment as well as a cerebellar ataxia, whereas a somewhat lower level of chronic exposure causes a sensory axonopathy with distal sensory loss. 2. Can the neurotoxic syndrome be reproduced experimentally in animals under similar conditions of exposure? All too often, a substance is labeled neurotoxic based on animal data derived from exposure to much higher levels and for much longer periods than those likely to be experienced by humans. In human neurotoxicology, there is a strong dose–response relationship, and the argument that there may be a form of neurological “allergy” to very low levels of toxic chemicals is 5 unpersuasive and unsupported by experimental evidence. The inability to reproduce similar neurotoxic disease experimentally in animals does not rule out neurotoxicity in
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humans, because differences in species susceptibility are well documented. Moreover, the cognitive and functional disturbances that are so common in humans are hard to 6 reproduce in animals. In addition, it is important to be aware that mixtures of chemicals may produce a neurotoxic syndrome at concentrations of individual chemicals that are harmless. This enhancement of neurotoxicity by chemicals that may not themselves be neurotoxic is best exemplified by the mixture of n-hexane and 7 methyl ethyl ketone. When an attempt was made to reduce the toxicity of a mixed organic solvent by lowering the concentration of the known neurotoxin n-hexane with the addition of methyl ethyl ketone, which is not neurotoxic, there was an outbreak of neuropathy. Subsequent experimental studies conclusively demonstrated that methyl 8 ethyl ketone markedly potentiated the neurotoxicity of n-hexane. 3. Are there reproducible pathological or pathophysiological findings in the nervous system in either humans or animals? This stringent requirement, if applied arbitrarily, would eliminate the many neurotoxic syndromes for which the pathological or pathophysiological basis is unknown. 4. Can demonstrable pathological or pathophysiological abnormalities of the nervous system account for the observed neurological or behavioral syndrome? Demonstration that a substance is neurotoxic does not necessarily mean that it accounts for the observed clinical syndrome. For example, electrodiagnostic demonstration of an unequivocal peripheral neuropathy obviously does not provide a satisfactory explanation for a disturbance of cognitive function. 5. Is there a temporal relationship between exposure to the neurotoxin and the suspected neurotoxic illness? Neurotoxic illnesses almost always occur at the time of exposure or very shortly thereafter. A number of toxic neuropathies (arsenic, thallium, organophosphates) occur after a delay, but this is only of 2 to 3 weeks. Moreover, in many cases, improvement eventually occurs when the exposure is terminated, although it may be incomplete. It is well to be aware of the phenomenon of “coasting,” in which continued deterioration occurs for a period of days to weeks after 9–11 The temporal relationship between exposure and illness is termination of exposure. much easier to establish with acute intoxications than with chronic ones, although in some cases improvement of symptoms over weekends or during a vacation may be an important clue to work-related exposure to a neurotoxin. Of course, psychological symptoms related to dissatisfaction with work or disputes with supervisors or co-workers and symptoms of malingering are also likely to improve over weekends and on vacations. 6. Is the clinical syndrome nonfocal? Most neurotoxic syndromes involve a functional depression or overt degeneration of neural elements or their supporting cells (glia, Schwann cells) that is diffusely distributed. Occasionally, a focal presentation may lead to the unearthing of an unsuspected diffuse condition, so it is well to be vigilant. For example, a toxic polyneuropathy may present with symptoms of carpal tunnel syndrome. Thus, neurotoxic diseases resemble many other metabolic and degenerative diseases of the nervous system. A corollary to this is that neuroimaging studies are nearly always normal, and the results of electrodiagnostic studies, though often abnormal, are extremely nonspecific. These techniques of investigation are primarily used to rule out other disorders with similar clinical features. These general considerations are important to bear in mind when evaluating patients with suspected neurotoxic illnesses. CLINICAL SYNDROMES OF NEUROTOXICITY Neurotoxic syndromes can reflect dysfunction of either the central nervous system (CNS) or the peripheral nervous system.
Acute Encephalopathy The most common clinical neurological syndrome that results from intoxication is an acute but nonspecific encephalopathy. In its mildest form, the main symptoms are headache and an associated sense of lightheadedness; these resolve within minutes to hours after the exposure is terminated. Neurological examination is usually normal, even during the period of maximal symptoms. In a more severe form, there may also be confusion and irritability, impaired judgment, alteration in the level of consciousness, rotatory dysequilibrium, tinnitus, numbness and paresthesias, ataxia, a sense of weakness, and nausea and vomiting; recovery may take 24 hours or more but is usually complete. Standard clinical neurological
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examination is often normal, although there may be nystagmus and ataxia. Neuropsychological examination, which is more sensitive, is likely to be abnormal but, because recovery is rapid and complete, is seldom performed. If exposure continues, alteration in the level of consciousness supervenes and may progress to coma; seizures may also occur. If this stage is reached, morbidity and mortality increase sharply. Any recovery that occurs is often more protracted and sometimes incomplete. This acute neurological syndrome usually provides little diagnostic challenge, at least in workplace exposures, because the history of exposure is promptly forthcoming. Often many workers are affected and there may be a variety of non-neurological manifestations, such as irritation of the eyes, mucous membranes, and skin, as well as shortness of breath; with severe encephalopathy, concomitant systemic effects may also be severe and include such manifestations as pulmonary edema and circulatory collapse. These complications, which in themselves cause severe neurological dysfunction independent of the neurotoxicity of the chemical or chemicals involved, contribute significantly to morbidity and mortality.
Chronic Encephalopathy The encephalopathy that results from chronic exposure to neurotoxins is not well characterized. In fact, there is no incontrovertible evidence of a chronic neurotoxic encephalopathy. The most commonly cited symptoms are mild and nonspecific. They include headache, dizziness or lightheadedness, difficulty in concentrating, memory impairment, irritability, sleep disturbances (both insomnia and hypersomnolence), loss of libido, depression, paresthesias, and weakness. Although these symptoms are usually mild and may sound relatively innocuous, they are often disproportionately disabling. Such symptoms may be caused by any of a number of medical diseases unrelated to toxin exposure or by exposure to toxins unrelated to the workplace (e.g., alcohol and many other drugs of abuse). Furthermore, identical symptoms may occur with primary psychological diseases and may easily be claimed by malingerers. The routine neurological examination in these patients is invariably normal. Laboratory investigation is not much more rewarding. The electroencephalogram (EEG) may be mildly 12 abnormal, but the results are as nonspecific as the symptoms. Evoked potentials (EPs) have also reportedly been abnormal, but the changes are often minimal and of questionable significance. For example, in one study the reported abnormalities in visual EPs (VEPs) involved only the amplitude of the responses, which are notoriously unreliable, and there was 13 only a small group of control subjects. A wide variety of neurobehavioral abnormalities has been described, but the findings are inconsistent and the interpretation of neuropsycho-logical tests is, as yet, inexact. Moreover, premorbid testing has almost never been performed. Despite the skepticism expressed by many, the presence of a wide variety of abnormalities of function, as manifested by the results of neuropsychological and electrodiagnostic studies, supports the existence of this syndrome but provides little insight into its pathogenesis. The pathological basis of this syndrome is obscure.
Structural Diseases of the CNS There is a remarkable paucity of proven neurotoxic diseases that affect the structure of the CNS. There are even fewer in which the intoxication is thought to result from exposure in the workplace. Nonetheless, the existence of definite pathological changes occurring as the result of massive exposure to toxins by accident, abuse, or suicidal or homicidal intent provides further support for the concept that milder forms of these syndromes may occur with occupational exposure. For most of these disorders, final confirmation of the pathological nature of the intoxication is lacking, but there are either consistent, objective clinical abnormalities or abnormalities of neuroimaging or electrodiagnostic studies. Toluene Abuse Chronic toluene abuse gives rise to dementia—which may be overt or subclinical—ataxia, 14 dysarthria, nystagmus, tremor, and spasticity. The clinical syndrome to date has been confined to individuals who abuse toluene, and possibly other organic solvents or solvent mixtures, in very large doses. Magnetic resonance imaging (MRI) shows cerebral, cerebellar, and brainstem atrophy and widespread periventricular white matter lesions. Brainstem auditory EPs (BAEPs) may be abnormal, even when there are no other clinical or neuroimaging abnormalities, prompting some to suggest that the BAEP may be useful for 14 screening at-risk workers. A similar syndrome has never been seen with occupational exposure to these same chemicals. This difference probably reflects the prolonged exposure to very large doses that occurs during abuse, but contamination of the solvents with other
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toxins or the concomitant administration of other chemicals and drugs may also play an important role. An extrapyramidal syndrome has also been described with massive exposure to a solvent 15 mixture, the predominant component (60%) of which was toluene. Immediately after the intentional inhalation of the solvent mixture, the subject developed an acute encephalopathy that resolved spontaneously. Two days later, she had severe parkinsonism and akathisia. She also had signs of pyramidal involvement. The parkinsonism responded well to levodopa but persisted throughout the 3 months of follow-up. A computed tomography (CT) scan of the brain was normal. Positron emission tomography (PET) showed reduced striatal dopamine D2-receptor ligand binding with normal fluorodopa uptake, suggesting damage to the postsynaptic receptor. A milder but otherwise similar16case has been reported with accidental ingestion of solvent mixtures not containing toluene, indicating that other organic solvents may be toxic to the nigrostriatal system. Carbon Monoxide Intoxication Carbon monoxide intoxication also causes structural brain damage, but again this usually occurs after massive accidental or suicidal poisoning outside the workplace. The mechanism of the brain injury is anoxia; carbon monoxide competes with oxygen for binding sites on the hemoglobin molecule and has a much greater affinity for hemoglobin than does oxygen. The oxygen-carrying capacity of blood is therefore greatly reduced, and tissue hypoxia results. Chronic low-level exposure may cause the syndrome of chronic encephalopathy described earlier, but there are no documented pathological abnormalities. Acute high-level exposure leads to the various stages of acute encephalopathy described earlier. Severely intoxicated individuals may never recover consciousness and at autopsy are found to have cerebral 17 edema with focal or diffuse necrosis of the cerebral cortex and occasionally the cerebellum. Bilateral necrosis of the globus pallidus is considered the pathological hallmark of carbon monoxide intoxication, but it also occurs with other ischemic-hypoxic cerebral insults. In approximately 10 percent of cases, usually in those severely intoxicated, there is partial or complete recovery, followed days or even weeks later by a secondary deterioration. Patients have delirium and multifocal neurological signs, often with spasticity or rigidity. Many patients progress to a mute akinetic state and ultimately die, but some recover partially or even 18 completely after a period of weeks to months. Pathological studies show, in addition to the widespread necrosis described previously, extensive zones of demyelination in the subcortical white matter. Heavy Metal Exposure Prolonged exposure to certain heavy metals causes various well-characterized clinical syndromes for which a pathological substrate has been identified. Manganese
Exposure to manganese, usually by inhalation during mining, results in the syndrome of “manganese madness,” with hallucinations, emotional instability, and bizarre behavior. With continued exposure, patients manifest weakness, dysarthria, ataxia, tremor, and later an extrapyramidal syndrome that can closely resemble Parkinson's disease, although dystonia 19 study indicated that welders have an and tremor may be its only features. A recent 20 increased risk of developing parkinsonism, and it is postulated that this is the result of chronic inhalation of manganese. After exposure is terminated, patients may stabilize or improve, but progression of the extrapyramidal syndrome sometimes continues for years. 21 Pathological studies show degeneration of the basal ganglia. Mercury
Exposure to both organic and inorganic mercury also causes characteristic neurological syndromes. Inorganic mercury causes a delirium that was well recognized in the felt-hat industry of the nineteenth century and gave rise to the expression “mad as a hatter”; it is often accompanied by tremor (“hatter's shakes”), weakness, and paresthesias. Chronic organic mercury poisoning leads to paresthesias, ataxia, and visual loss. Pathological studies show degeneration of22the cerebral and cerebellar gray matter, particularly involving the calcarine (visual) cortex. Mercury has also been implicated in the pathogenesis of peripheral neuropathy, but there is no reliable electrodiagnostic or pathological confirmation, suggesting 23 that the paresthesias have a central origin.
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Lead
Lead causes an encephalopathy with high-level exposure, but this is seldom seen in the workplace. The brain is congested and edematous, and there is variable neuronal degeneration. Evidence is emerging that accelerated neurodegeneration may result from chronic industrial exposure to lead. A series of recent reports has documented the fate of a 24–26 Exposure group of industrial workers exposed to both organic and inorganic lead. occurred before 1991 and, at the time of evaluation, no worker continued to be exposed to any form of lead in the workplace. The earlier studies documented a progressive decline in neurobehavioral measures that correlated with tibial lead levels measured by x-ray fluorescence. In the most recent report, total and regional brain volume and the volume of white matter lesions were measured by MRI. Exposed workers showed an increase in white matter lesions of hyperintensity on T2-weighted images and a reduction in total and regional brain volume measures. The loss of brain volume was equivalent to about 5 additional years of aging. This is the first demonstration that chronic lead exposure may lead to loss of brain tissue and, importantly, that the loss of tissue may be progressive, continuing for years after the exposure has ceased. Unresolved is whether the loss of brain tissue is a direct result of lead toxicity on the brain or is a result of hypertension induced by lead nephropathy. Chronic exposure to lead and mercury has been implicated in the pathogenesis of amyotrophic lateral sclerosis, and aluminum toxicity has been held to contribute to the pathogenesis of Alzheimer's disease, but the evidence is not persuasive. Nitrous Oxide Chronic intoxication with nitrous oxide produces a myeloneuropathy that is clinically identical 27 to subacute combined degeneration of the spinal cord due to vitamin B12 deficiency. The clinical syndrome has been seen only with recreational use of the drug in very large doses over prolonged periods. It has nevertheless been suggested that dentists and dental assistants may be intoxicated owing to leakage of gas during dental anesthesia. The clinical syndrome consists of spastic paraparesis, sensory ataxia, and sphincter disturbances. It results from inactivation of vitamin B12 leading to impaired methionine synthesis. Serum vitamin B12 levels may be normal or low, but methylmalonic acid levels are always elevated. Organophosphates Some of the organophosphates produce a myeloneuropathy that results from their ability to inhibit an enzyme called neuropathy target esterase (NTE), discussed on page 762. Patients have a severe neuropathy, but as the neuropathy resolves, signs of spinal cord dysfunction appear, leading to spastic paraparesis.
Toxic Neuropathy Perhaps the most widely studied and best understood of the clinical syndromes that result from toxin exposure in the workplace is peripheral neuropathy. The best understood and characterized neuropathic syndrome is that which occurs as a delayed effect of massive single or short-term repeated exposure. Such exposure to certain heavy metals (most notably arsenic and thallium) and some organophosphates is followed after 1 to 3 weeks by the subacute development of distal sensory loss and weakness. The metal neuropathies tend to be predominantly sensory, but the organophosphate neuropathy is predominantly motor and there is additional involvement of the pyramidal tracts. Autonomic functions are usually spared. In these disorders, the predominant pathological effect of the toxin is to cause that portion of the axon farthest from the cell body to degenerate. The terms distal axonal neuropathy, dying-back neuropathy, distal axonopathy, and central-peripheral distal axonopathy are synonymous and are referred to as distal axonopathy in this chapter. As a result of this pattern of pathological involvement, symptoms and signs are initially confined to the distal legs and progress proximally to a degree determined by the severity of the intoxication. The primary sensory neuron sends axons not only into the periphery but into the spinal cord, and both degenerate toward the cell body. The central extensions of the sensory neurons enter the spinal cord and some ascend in the posterior columns as far rostrally as the cuneate and gracile nuclei in the caudal brainstem; these distal but centrally directed axons, because of their great length, are often among the first to degenerate. For example, the earliest manifestation of acrylamide intoxication, at least 28 in experimentally intoxicated primates, is degeneration of these central extensions. This has
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important implications for recovery because regeneration does not occur in the CNS; if the axonal degeneration is severe, recovery will be incomplete despite effective regeneration of the peripheral nerves. Chronic exposure to many of these and other chemicals also causes neuropathy. For example, heavy metals, acrylamide, some organophosphates, and many organic solvents cause progressive axonal degeneration after chronic exposure. In addition, minor abnormalities of nerve conduction can be demonstrated in individuals who are chronically exposed to other neurotoxins in the workplace, but there is little evidence to support the concept that these inevitably progress to clinical neuropathy. Nonetheless, prudence dictates that a high level of vigilance be maintained at all times to minimize risk. SCREENING AT-RISK WORKERS FOR NEUROTOXICITY There are three important reasons for screening workers who are or may have been exposed to neurotoxins. In the first instance, it may permit the prevention of further intoxication if early neurological dysfunction is detected at a time when clinical symptoms and signs are covert—measures could be taken to prevent further exposure by whatever means necessary. Second, at times of recognized outbreaks of a neurotoxic disorder, screening may permit the identification of individuals who have been exposed to lower levels of the neurotoxin than overtly affected workers. Finally, in instances in which intoxication is claimed, screening techniques may have a role in documenting neurological involvement in those workers claiming to have been affected as well as documenting any subclinical involvement of fellow workers similarly exposed. As indicated earlier, all similarly exposed workers should have at least some of the symptoms and signs of intoxication. Therefore, screening of fellow workers may provide invaluable diagnostic information in a case of suspected exposure. Each of the screening techniques discussed in the following sections has serious limitations: each is insensitive, nonspecific, time-consuming, expensive, nonstandardized, or poorly tolerated by patients. However, they are all that is available; one of the greatest needs in neurotoxicology is a simple, inexpensive, and reliable29method for objectively evaluating the nervous system in situations of minimal dysfunction.
Clinical History A detailed history is the cornerstone on which an accurate diagnosis of neurotoxic illness is based. In the clinical evaluation of any individual, a brief occupational history is an integral part of the complete medical history. This is especially important in the evaluation of patients with neurological diseases of obscure etiology. If exposure to toxins is suspected, a comprehensive and accurate list of chemicals used in the workplace should be obtained from the patient or employer. Exposure at past places of employment should also be considered as a cause of symptoms, at least if they are of long standing, although neurotoxic disease almost always appears shortly after exposure. The situations in29which exposure to any potential neurotoxin may have taken place should be explored. This involves inquiry about (1) ventilation in the work environment; (2) the provision, use, cleaning, and discarding of protective clothing; (3) the provision and use of facilities for washing after exposure; and (4) the area in which food is stored and the likelihood of its contamination. The most common routes of exposure in the working environment are inhalation and through the skin; ingestion is much less frequent. It may be necessary to visit the workplace to clarify many of these issues, because the patient is often unaware of potentially hazardous habits. Contrary to popular belief, smaller companies and cottage industries, rather than giant corporations, are more likely to be using hazardous techniques and procedures to the detriment of their workers, who are often poorly educated. It is also necessary to question co-workers of the patient, either in person or indirectly, to determine whether they have similar symptoms, and it may be necessary to examine those individuals who work in a closely similar environment. A detailed history is also important when co-workers without symptoms are being screened for possible exposure to a known neurotoxin. In such situations, questioning may be more focused, based on the symptoms in recognized cases; self-administered, standardized symptom question-naires may be useful and time-saving.
Clinical Examination Routine clinical examination of the nervous system is of limited utility as a screening technique. It is notorious for interobserver and intraobserver variability, even for such apparently objective measures as the presence of tendon reflexes. The principal role of the examination is therefore to exclude other conditions. As mentioned earlier, neurotoxic
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disease is almost never focal, and the presence of focal neurological abnormalities should raise doubt about a diagnosis of intoxication. Other coexisting non-neurological disorders may also be found during the routine medical examination. There have been many attempts to quantitate neurological function for the purpose of screening individuals for subtle neurological dysfunction and following improvement or deterioration of patients with overt neurological deficits. Most of these have concerned 30 quantitation of sensory function. Most human toxic neuropathies preferentially affect large myelinated axons, which mediate vibratory and proprioceptive sensations, and attempts have concentrated on objectively and quantitatively evaluating vibration threshold. Arezzo and 31 co-workers studied one such system in a group of acrylamide-exposed workers. Testing was done by local nurses at each of two plants, and the results were highly reproducible both between and within subjects. The authors emphasized the simplicity and speed of the evaluation, but, at least as described, the testing appears to have been neither; no details are given of the time taken for testing or for training the paraprofessional personnel, and a detailed protocol was followed to ensure reproducibility and accuracy. Nonetheless,32,33 the results of this study and of several others using similar technology and procedures indicate that the method is accurate, noninvasive, and painless and that it can be administered by paraprofessionals, unlike many other methods of evaluating function in large-diameter afferent fibers. Quantitative methods of evaluating small-diameter fibers, using temperature threshold sensitivity, have also been developed, but these are both time-consuming and less 34 reproducible and therefore less applicable to screening large populations of patients. Fortunately, toxic neuropathies and other toxic neurological conditions are less likely preferentially to affect small rather than large fibers. Quantitative tests of motor function, including strength and coordination, have been developed but remain too cumbersome to apply to large populations as screening devices.
Electrodiagnostic Testing There are several electrophysiological methods of evaluating the function of the nervous system, with varying degrees of sensitivity and specificity. The EEG and various types of EPs can be used to assess CNS function, whereas electromyography (EMG) and nerve conduction studies can be used similarly to evaluate the function of peripheral nerves. These techniques are important in evaluating individual patients with known or suspected neurotoxic 35 disease. They have also enabled a more thorough characterization of the pathophysiological basis for many neurotoxic disorders and have become an essential component in evaluating neurotoxic disorders in the experimental laboratory. However, they have major limitations. First, each of these procedures is time-consuming, is physician-intensive, and requires expensive sophisticated electronic equipment. Second, although EMG and nerve conduction studies can be performed in the field, the quality of the recordings may be poor; EEGs and EPs can be recorded only in the clinical laboratory. Third, EMG and nerve conduction studies are poorly tolerated by many subjects because they are painful. Finally, a high level of expertise is needed to interpret many of the results; this is particularly true of EMG, in which there is often under-reporting of abnormalities, and of EEG, where there is often over-reporting of nonspecific changes. Electroencephalography The EEG is abnormal in most patients with acute toxic/metabolic encephalopathy, commonly showing a diffuse slowing of background activity that may be continuous or intermittent. Focal slowing may occasionally be seen and does not exclude a toxic etiology. The changes are nonspecific and do not distinguish between toxic and nontoxic forms of encephalopathy or between different toxic states. In patients with chronic encephalopathy, the EEG is much less likely to be abnormal. The EEG is therefore of little practical use in screening patients for neurotoxic injury. Evoked Potentials Sensory EPs provide some measure of the functional integrity of various afferent pathways in 35 the CNS. More complex polysynaptic pathways can be evaluated using event-related potentials of long latency, but these techniques have not been fully validated and their role in neurotoxic disease is investigational. Sensory EPs provide a means of determining the speed of conduction (expressed as latency) along fiber tracts in the CNS. The amplitude of EPs varies so much in normal subjects that it cannot be relied on to detect abnormalities. Most
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neurotoxins produce axonal degeneration, and this causes changes in amplitude but little change in latency of responses; accordingly, EPs are relatively insensitive to neurointoxication. Rosenberg and co-workers found that some toluene abusers had prolonged BAEP latencies when there were no other clinical or neuroimaging abnormalities; they suggested that the technique might be useful in screening for subclinical intoxication in the setting of 36 occupational exposure. However, there has been no validation of the technique in this situation. Seppalainen and co-workers found abnormalities in amplitudes but not the13latencies of the electroretinogram and VEP in people chronically exposed to organic solvents. Similarly, Estrin and co-workers reported abnormalities of the P300, one of the complex, polysynaptic, event-related potentials, in patients exposed to ethylene oxide, but they also 37 showed abnormalities only of amplitude, not of latency, and thus of questionable validity. These are intriguing examples of the role of EPs as a research tool but in no way support the use of EPs as a method of screening workers exposed to neurotoxins. Electromyography and Nerve Conduction Studies Nerve conduction studies remain the gold standard for evaluating peripheral nerve function, supplemented when necessary by needle EMG. The techniques, when used by experienced personnel, are quantitative, accurate, and reproducible. They can be used to evaluate both conduction velocity and amplitude of the bioelectric signals and are thus useful in situations of both axonal degeneration and demyelination; axonal degeneration results in reduced amplitudes of compound action potentials, whereas demyelination causes conduction slowing. These techniques do, however, have several drawbacks. First, they are painful and are not always well accepted by individuals without symptoms of intoxication. Second, if the results are to be reliable, skilled personnel are required both to perform the studies and interpret the results. Third, they require expensive equipment. Nevertheless, it is feasible to use these techniques when screening for neuropathy. Whether nerve conduction studies give better results than the less expensive, painless quantitative sensory testing, using the techniques outlined earlier, is unresolved. However, abnormalities detected by means of quantitative sensory testing should certainly be corroborated by traditional electrodiagnostic testing. Quantitative sensory testing can simply demonstrate that an abnormality exists, whereas electrodiagnostic evaluation can more clearly define the most likely underlying pathological process and thus give invaluable information concerning etiology.
Neuropsychological Evaluation There have been steady advances in the accuracy and reproducibility of neuropsychological 38 testing in recent years, and these have improved its usefulness as a screening device. The tests are highly sensitive to subtle cognitive dysfunction but are not diagnostic of toxic encephalopathy. Traditional psychometric testing takes approximately 3 hours per patient to perform. The most important element is a detailed history, without which interpretation of the results is unreliable. Attempts have been made to speed up the process, without sacrificing accuracy and sensitivity, by the use of self-administered questionnaires and computer-driven testing, but the process remains time-consuming. Baker and colleagues developed a computer-based system for evaluating memory, visual/motor function, vocabulary, and mood 39,40 They described the technique as that incorporated symptoms and history of exposure. rapid, but the entire test took over an hour to administer. They found that the results compared favorably with other methods and that there was excellent stability of the results when applied to normal subjects over 4 to 6 months. Bowler and associates took portions of several widely used neuropsychological tests and developed a composite screening battery that could be administered in under an hour and yet retained good correlation with a more 41 detailed analysis. However, these tests are still time-consuming and, although they are useful for the evaluation of individual patients suspected of having neurotoxic exposure, they are less helpful in screening large numbers of individuals.
Other Laboratory Testing The role of traditional laboratory testing in screening for neurotoxic disorders is minimal. The excretion of heavy metals in the urine or their presence in other tissues can be measured in workers with suspected exposure, but most other toxins are rapidly metabolized and difficult to detect. With organophosphate intoxication, the levels of certain enzymes may be affected, but this is of little use for screening purposes. Routine laboratory testing may reveal abnormalities of liver, renal, or bone marrow function, but these are nonspecific, and by the time they show abnormalities, intoxication is already advanced. Nerve biopsy can
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demonstrate the highly specific changes of solvent-induced neuropathy but is rarely indicated in the evaluation of patients with neuropathy and is never indicated for screening purposes. CLINICAL SYNDROMES ASSOCIATED WITH SPECIFIC OCCUPATIONAL NEUROTOXINS
Organic Solvents Intoxication with organic solvents is a major public health problem because these chemicals are ubiquitous. Individual solvents or mixtures of different solvents are used in some way in practically every workplace. They are used for cleaning and degreasing and for thinning other liquids, as well as in the manufacture of many other chemical products. Their neurotoxicity results almost entirely from their use as cleaners, degreasers, and thinners. A major problem in identifying solvent intoxication is that the composition of solvent mixtures is often unknown, particularly in smaller industries. This problem is compounded by ignorance of, or indifference to, the potential for intoxication of exposed workers. Most organic solvents are highly volatile liquids with high lipid solubility. The major route of exposure is by inhalation, so the potential for exposure to toxic levels is greatest in poorly ventilated areas. Pulmonary absorption of these chemicals is greatly increased by exercise, which increases blood flow to the lungs, making lower environmental concentrations potentially toxic. Some absorption also takes place through the skin; those chemicals that are both lipid and water soluble and are somewhat less volatile have a greater potential for absorption by this route. Conversely, the most volatile solvents are less likely to be absorbed through the skin because most of the chemical evaporates before significant amounts can be absorbed. CNS Effects Almost all organic solvents, because of their high lipid solubility, enter the brain rapidly, where they act as nonspecific CNS depressants. There is good correlation between the lipid solubility of a solvent and its action as a CNS depressant. Lipid solubility increases with the length of the carbon chain, the number of double bonds (i.e., the degree of unsaturation), and the number of halogen or alcohol substitutions. Acute exposure to practically any of the organic solvents can cause the syndrome of toxic/metabolic encephalopathy described previously. Treatment entails removal of the individual from exposure; recovery occurs within minutes to hours, usually without sequelae, although headache may persist for several days. If acute exposure is of sufficient severity and duration to cause coma, recovery may be incomplete, probably because of hypoxic brain damage rather than a direct action of the chemical. Whether a syndrome of chronic encephalopathy results from long-term exposure to organic solvents is controversial, as has already been discussed. Several epidemiological studies have suggested that there is increased prevalence of neuropsychological dysfunction in spray painters,42,43 who are chronically exposed to solvents used as thinners, but the evidence Recent studies have emphasized the high prevalence of insufficient is unconvincing. effort in individuals being tested for the neuropsychological effects of chronic solvent 44,45 Psychometric testing is critically dependent on full cooperation of the test exposure. subjects, making interpretation unreliable of data obtained from subjects exerting insufficient effort. Nonetheless, even after controlling for poor effort, abnormalities have been found that 45 suggest subtle cognitive effects of chronic toxin exposure. Perhaps the most persuasive example of toxic encephalopathy with chronic exposure to organic solvents is the chronic encephalopathy that has been described after long-term exposure to carbon disulfide, used 46 primarily in the manufacture of cellophane and rayon. As discussed earlier, there have been many cases of incompletely reversible encephalopathy that have resulted from exposure to toluene or mixtures of chemicals containing toluene. All the cases have resulted from massive exposure during recreational use rather than industrial exposure. However, it is possible that the syndrome of chronic encephalopathy described in spray painters could have been caused by toluene. Most of these individuals have been exposed to solvent mixtures, the composition of which is usually unknown or at least unreported, and toluene is commonly a constituent of mixed organic solvents. An argument against the existence of toluene encephalopathy is that no abnormalities have been seen in 47 the brains of chronically exposed animals. The clinical syndrome of toluene intoxication consists of a neurobehavioral disorder with memory loss, attention deficits, and apathy, associated with cerebellar and pyramidal tract signs. Latencies of BAEP components are prolonged in approximately one half of cases and are occasionally abnormal even when the neurological examination and MRI are normal. MRI
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demonstrates abnormalities in approximately one third of cases, showing cerebral atrophy, loss of gray/white contrast, and an increased periventricular signal. Improvement occurs with prolonged abstinence, but some patients have been followed for almost 1 year of proven abstinence without completely returning to normal. There have been periodic reports of structural abnormalities of the brain on imaging studies in patients with chronic solvent exposure, mainly consisting of slight cerebral atrophy, but methodological shortcomings of most studies do not allow48reliable conclusions to be drawn, Mild abnormalities of magnetic as emphasized by the review of Ridgway and colleagues. 49 resonance spectroscopy have also been reported, suggesting chronic metabolic abnormalities, but these require corroboration. Peripheral Neuropathy Only a few of the hundreds of organic solvents or solvent mixtures used in industry have been shown to be toxic to peripheral nerves. The major culprits are n-hexane, methyl n-butyl ketone (MnBK), and carbon disulfide. Trichlorethylene causes cranial neuropathy but not a diffuse neuropathy. There has been a single outbreak of neuropathy after exposure to the 50 plastic-foaming catalyst 2-t-butylazo-2-hydroxy-5-methylhexane. This discussion focuses on the hexacarbons n-hexane and MnBK because several outbreaks of neuropathy have been traced to their use. Furthermore, both are metabolized to 2,5-hexanedione, which is largely or entirely responsible for the neuropathic effect. Neuropathy results from repetitive and prolonged exposure to n-hexane, usually in concentrations in inhaled air of greater than 100 ppm: the threshold limit value (TLV) for the workplace in the United States is 50 ppm. The TLV for MnBK is 5 ppm. Methyl ethyl ketone, a common constituent of organic solvent mixtures, is not neurotoxic in itself but potentiates the 8 neurotoxic properties of n-hexane and MnBK. Clinically, the hexacarbon neuropathies are distal axonopathies. The earliest symptoms are sensory; there is an insidious onset of symmetric numbness in the toes and later the fingers. If exposure continues, the numbness migrates proximally; it may reach as far as the knees but rarely extends higher. There is less weakness, but in advanced cases mild footdrop and weakness and atrophy of the intrinsic hand muscles may develop. The motor features rarely predominate. The neuropathy has evolved slowly in all cases resulting from industrial exposure. With the much larger exposures occurring during recreational use, the neuropathy evolves more rapidly and may be more extensive, with proximal weakness; it may superficially resemble Guillain–Barré syndrome, although the evolution is usually slower. Examination confirms that there is significant cutaneous sensory loss, with relative preservation of vibration sense and proprioception. Distal reflexes usually are absent or reduced, but more proximal reflexes are preserved. Autonomic dysfunction has not been described with industrial exposure. The solvent neuropathies always improve when the exposure stops, but continued 51 deterioration (coasting) for a period of weeks to months almost invariably occurs. The degree and rapidity of recovery depend on the severity of the neuropathy. Recovery is by way of axonal regeneration, which is a slow and inefficient process, and patients with severe neuropathy may recover incompletely over 2 to 3 years. Milder cases re-turn to normal within a few months. Electrodiagnostic screening is useful in the detection of subclinical hexacarbon neuropathy. In a major outbreak of MnBK neuropathy in Ohio, 43 percent of cases had characteristic 9 electrophysiological abnormalities in the absence of symptoms and signs of neuropathy. The most consistent abnormalities in all patients, regardless of severity, were found with needle EMG. There were fibrillation potentials and positive sharp waves, indicating active denervation, in distal leg muscles. Most patients, even those mildly involved, also had slowing of motor conduction velocity. Although the hexacarbon neuropathies are distal axonopathies, the slowing of conduction velocity is greater than that usually seen in axonal neuropathies, for reasons discussed later. The pathological features of the hexacarbon neuropathies have been extensively studied in both humans and animals. In animals chronically intoxicated with n-hexane (or 2,5-hexanedione), there are many swollen axons, which are filled with maloriented neurofilaments, mitochondria, neurotubules, and smooth endoplasmic reticulum, as a result of a defect in axonal transport. These axonal enlargements are first seen on the proximal side of the nodes of Ranvier in the distal part of the axon. Because of this enlargement of the paranodal portion of the axon, there is retraction of myelin from the node and, ultimately, segmental demyelination. It is because of this secondary demyelination that the conduction
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velocity is disproportionately slowed. With time, the axons degenerate distal to these enlargements. In keeping with the concept that these are distal axonopathies, similar changes are seen in the most rostral sensory axons in the dorsal column of the spinal cord, which are the most distal extensions of the primary sensory neuron whose cell body is in the dorsal root ganglion. Identical changes are seen in sural nerve biopsies taken from humans with hexacarbon neuropathy and were also seen in the gracile fasciculus of the rostral spinal cord in autopsy tissue taken from a glue sniffer. The pathogenesis of these pathological changes is thought to be cross-linking of axonal neurofilament proteins interfering with axonal 52 transport. Neuropathy can also result from exposure to tri-chloroethylene and possibly also to perchloroethylene, organic solvents that are extensively used in the dry-cleaning industry as degreasing agents. The neuropathy was recognized decades ago when trichloroethylene was 53 used as an anesthetic agent. The neuropathy is extremely unusual in that it is confined to the cranial nerves. Initial involvement is restricted to the trigeminal nerve, with early onset of facial numbness or dysesthesias and later weakness of the muscles of mastication. The lower cranial nerves are occasionally involved, and optic neuropathy may also occur. Recovery occurs over a period of months, with the 54 sensory deficit receding toward the center of the face until only the tip of the nose is involved, indicating that this too is a distal axonopathy but one that is confined to cranial nerves. Patchy facial sensory loss and absent 55 develop after only a corneal reflexes may persist indefinitely. Trigeminal neuropathy may 54 few minutes of exposure to high concentrations of trichloroethylene. It is doubtful that exposure to pure trichloroethylene causes trigeminal neuropathy; rather, the neuropathy results from the spontaneous decomposition product dichloroacetylene, which is formed when trichloroethylene is exposed to alkalis.
Heavy Metals Many heavy metals have been shown to have neurotoxic potential. In contrast to the highly volatile organic solvents that are rapidly eliminated from the body and cause neurotoxicity primarily after ongoing, intensive exposure, the heavy metals tend to accumulate in the body tissues, particularly bone, over prolonged periods of low-level exposure. Toxicity may therefore result from many years of exposure to low levels in the working environment, and recovery may be extremely delayed because of the long time-course of elimination of the metal from the body. Accidental exposure to higher concentrations can also cause well-recognized syndromes of neurotoxicity. In addition to their well-documented neurotoxicity, the heavy metals produce a plethora of systemic effects, particularly on the hematopoietic and gastrointestinal systems. The heavy metals that have been documented to cause neurotoxicity and the clinical syndromes that result from intoxication are shown in Table 39-2. All these intoxications are rare in the industrial setting, at least in their overt form. The heavy metals to which there is the greatest likelihood of exposure are lead and arsenic; the remaining discussion concentrates on these. Click here to view this table.... Lead Lead is toxic to the central and peripheral nervous systems in both its organic and its inorganic form. Industrial exposure is mainly to inorganic lead and is chiefly by way of inhalation of fine particulate matter, but lead may also be absorbed after ingestion. An increasing amount of lead is present in the air, released through the combustion of fossil fuel to which organic lead has been added to improve its combustion. It is estimated that almost one-half million metric tons of lead are dispersed into the atmosphere every year by this means. Industrial exposure to lead must be considered in this context. Lead Encephalopathy
Acute occupational exposure to lead results mainly in systemic effects involving the hematopoietic, gastrointestinal, and renal systems, sparing the nervous system. Lead encephalopathy, with headache, seizures, stupor, and coma—related to increasing cerebral edema—is much more common in acutely or subacutely exposed children and is therefore beyond the scope of this56–58 review. Long-term exposure to low levels of lead can cause a and recent studies indicate that progressive cerebral atrophy chronic encephalopathy, 24–26 The manifestations mainly consist occurs even long after exposure has been terminated. of abnormalities of neuropsychological and neurophysiological testing. Clinical symptoms of apathy, insomnia, loss of libido, memory loss, and difficulty in concentrating occur more commonly in the exposed cohorts.
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Lead Neuropathy
Chronic exposure to lead causes neuropathy. The neuropathy develops only after several years of exposure in most cases. In the 16 patients with clinical neuropathy reported by 59 Cullen and colleagues, only 2 had been exposed for less than 4 years. Similarly, Rubens and colleagues found that the average duration of exposure in subjects with lead neuropathy 60 was 22 years and no individual had been exposed for less than 10 years. Nerve conduction abnormalities are found after only 2 years of exposure, but it is uncertain whether these 61 of conduction velocity increases with the duration progress to overt neuropathy. The slowing 62 neuropathy does not develop in of exposure and with the blood lead level, but clinical 63,64 individuals with blood lead levels below 70 μg/dl ; the maximum allowable blood lead level in exposed workers in the United States is 60 μg/dl. The classic form of lead neuropathy is unique in its clinical manifestations. It is predominantly motor, affects the arms more than the legs, affects the extensors of the wrists and fingers much more than other muscles, and is often asymmetric. In these characteristics, it differs from all other toxic neuropathies, which are distally accentuated and therefore affect the feet first, are almost always predominantly sensory, and are usually symmetric. Weakness of the interossei and footdrop do occur occasionally with lead neuropathy, but these are unusual and late features. This form65of lead neuropathy occurs with shorter periods (on average 5 years) of intense exposure. A more typical toxic neuropathy occurs with more protracted 60,65 exposure, almost invariably greater than 10 years and often for as long as 20 years. Individuals with lead neuropathy almost always have involvement of other organ systems. There is usually a microcytic, hypochromic anemia; basophilic stippling of red blood cells is not always present and is not specific for lead poisoning. Lead interferes with hemoglobin synthesis by inhibiting the enzyme δ-aminolevulinic acid (δALA) dehydrase, and the enzyme substrate (i.e., δALA) begins to appear in the urine when the blood lead level reaches 40 to 50 μg/dl, which is below the level at which neuropathy results. Therefore, neuropathy should not be diagnosed if the urinary δALA is normal. An increased body lead load should also be demonstrated, either an increased blood lead level or increased 24-hour urinary excretion. None of these measures is useful if exposure to lead is no longer ongoing; they represent exposure to lead over the preceding weeks to months. Past excessive exposure to lead can be measured through its accumulation in teeth or bones, but this is seldom practical. It has been suggested that lead excretion in response to a dose of the chelating agent ethylenediaminetetra-acetic acid (EDTA) can be used to establish an excessive body lead 66 load, but this method has not been widely validated. The pathological basis of lead neuropathy in humans is unknown, primarily because the disease in its overt form has become rare since the advent of good methods for the morphological study of peripheral nerves. The problem is compounded by the fact that different laboratory animals react differently to lead poisoning. The early development of slowed conduction velocity suggests that the primary pathological process in humans is 67 demyelination, as occurs in rats. Indeed, there is a slight but statistically significant increase in paranodal and segmental demyelination in humans with lead poisoning, but not enough to 68 that in overt neuropathy the account for the clinical findings. However, it is clear 65 predominant abnormality is axonal degeneration. The primary treatment of lead neuropathy, as with all intoxications, is to remove the individual from the toxic environment. All people exposed to lead in the workplace should be regularly screened by determination of the blood lead level so that any individual with an increased level can be removed from the environment before overt neuropathy develops. It is currently recommended that individuals with a single blood level above 60 μg/dl or with three consecutive monthly levels above 50 μg/dl be removed from exposure. If the blood level is below 40 μg/dl, the level should be tested every 6 months; for levels above 40 μg/dl, monthly 69 surveillance is recommended. Chelation therapy with EDTA or penicillamine is effective in 70 accelerating removal of lead from the body and should be given to all patients with overt neuropathy. The current recommended treatment is to administer EDTA followed by oral 71 been compared penicillamine. Another oral agent, 2,3-dimethyl succinic acid (DMSA), has 72 with EDTA and found to be equally effective, at least by anecdotal report. Preliminary studies have shown that chelation therapy with zinc supplementation (400 mg zinc sulfate daily) resulted in73a more rapid correction of abnormal hematologic parameters than did chelation alone. Regardless of the treatment chosen, it should be continued until a steady-state level of lead excretion has been achieved. Arsenic Arsenic may enter the body by inhalation during smelting of arsenic-containing ores or by
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ingestion of contaminated food or water. The principal effect of arsenic intoxication is peripheral neuropathy. Encephalopathy and a wide variety of systemic effects occur with both acute and chronic intoxication; as with all other industrial poisons, the role of arsenic in the pathogenesis of chronic encephalopathy is controversial and is therefore not addressed further. Arsenic neuropathy is in marked contrast to lead neuropathy. It is more typical of toxic neuropathies in general in that it is a pre-dominantly sensory, distal axonopathy. It may occur after exposure to high concentrations of arsenic, usually by ingestion with suicidal74or homicidal intent, or as a chronic complication of long-duration low-level exposure. After acute intoxication there are usually prominent gastrointestinal symptoms that are followed, within 1 to 3 weeks, by the onset of neuropathy. The earliest symptoms are sensory, with numbness, burning, and tingling in the feet and later, as the symptoms migrate proximally, the legs, hands, and arms. Pain may be severe. In advanced cases there may be sensory ataxia, but cutaneous sensory symptoms usually predominate. Weakness is usually present but is overshadowed by the sensory symptoms, at least in milder cases. With more severe intoxication, there may be marked limb and truncal weakness, including respiratory failure. Autonomic instability may occur but is usually minor and of little consequence. Examination confirms the sensory loss and weakness, which, in contrast to lead neuropathy, is strikingly symmetric and distally accentuated. This is the clinical picture of a distal axonopathy. With repeated lower level exposure, the neuropathy may evolve somewhat more slowly. With chronic exposure, the sensory predominance is even more apparent and the neuropathy evolves in an insidious manner, over many weeks to months. In addition to the gastrointestinal symptoms, other systemic effects are usually seen. Hyperkeratosis and desquamation of the skin, particularly of the palms and soles, or redness and swelling of the hands and feet are common. In chronic poisoning, there may be patchy areas of both increased and decreased skin pigmentation. Transverse gray lines in the nails (Mees' lines) are common with acute or repeated exposure but are not specific for arsenic. Proteinuria or more severe renal failure may also develop. Anemia is common, and there may be a more severe pancytopenia. As with lead neuropathy, there may be basophilic stippling of red blood cells. If the history of arsenic exposure is not forthcoming, the acutely evolving form of the neuropathy may be mistaken for Guillain–Barré syndrome, with the initial gastrointestinal 75 symptoms being mistaken for a prodromal illness. The confusion may be compounded by the fact that the cerebrospinal fluid protein is often elevated without an increase in cells, the albuminocytological dissociation that is characteristic of Guillain–Barré syndrome. The electrodiagnostic findings in acute arsenic neuropathy superficially resemble those of Guillain–Barré syndrome as well. The predominant abnormality reflects the underlying axonal degeneration, but there is also an element of toxic demyelination that results in electrodiagnostic abnormalities characteristic of an acute demyelinating neuropathy. Clues to the correct diagnosis include desquamation of the skin, depression of the bone marrow, and development of Mees' lines in the nails, although the latter appear only after several weeks. The diagnosis of arsenic neuropathy requires the demonstration of arsenic in blood, urine, or tissues. Arsenic is rapidly cleared from the blood and measurement of blood levels is seldom diagnostically helpful unless very recent acute exposure is suspected. Urine excretion of 76 arsenic is elevated for weeks or even months after a single dose. With chronic intoxication, the urine excretion usually exceeds 25 μg/24 H, and this is the most reliable means of monitoring exposure in at-risk occupations. In individuals with a diet extremely high in fish, higher levels may be found because of the accumulation of arsenic in the flesh of fish. Arsenic is cleared from blood into tissues and in particular is bound to keratin of growing hair or nails. Because these tissues are slowly turned over, arsenic may be found there for months or even years. This is particularly true for slow-growing hair, such as pubic or axillary hair. This is important when exposure is not suspected until long after the 77 event. Arsenic does not appear in these tissues for 4 to 6 weeks after a single exposure, so levels may be useful in timing the exposure. Treatment of arsenic neuropathy primarily consists of removing the individual from exposure. Hastening the excretion of arsenic from the body by chelation has a theoretical role, but it has not been shown to increase the rate of recovery from neuropathy; it probably should be reserved for the treatment of severely intoxicated individuals with marked systemic effects. Recovery from arsenic neuropathy is protracted, occurring over months to years. Prognosis is directly related to the severity of the neuropathy; mild cases recover completely, but a residual deficit is common with severe neuropathy. Other Neurotoxic Metals
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Mercury
Mercury may cause toxicity in both its organic and inorganic forms. Organic mercury intoxication usually results from ingestion of methyl mercury and causes a syndrome characterized by optic neuropathy with constriction of visual fields, hearing loss, cerebellar signs, and dementia or organic psychosis. There are also prominent paresthesias that may 78 although LeQuesne and be due to peripheral nerve or dorsal root ganglion involvement, 23 colleagues suggested that these too are central in origin. Inorganic mercury is poorly absorbed from the gastrointestinal tract and is mainly absorbed by way of inhalation of the vapor during smelting; this is the major source of occupational exposure. Inorgan-ic mercury can also cause a toxic encephalopathy whose major features are toxic psychosis and tremor. Peripheral neuropathy, resembling acute or chronic inflammatory polyneuropathy, has been linked to both forms of mercury, but the evidence is scanty. Mercury has also been implicated in the pathogenesis of some cases of motor neuron disease, but the evidence for this is even less persuasive. Manganese
Manganese intoxication 79 results from inhalation of dust or vapor occurring during the mining or smelting of manganese. The earliest manifestation is a toxic psychosis with later development of headache, weakness, dysarthria, tremor, and incoordination. Finally, an extrapyramidal syndrome characterized by dystonia or parkinsonism may develop. One 19 report has emphasized that progression may continue even after exposure is terminated. Tin 80
Tin, in its organic form, may cause intoxication through inhalation or ingestion. The major manifestations are those related to the marked elevation of intracranial pressure. There is headache, often accompanied by nausea and vomiting, visual disturbances related to papilledema, convulsions, and coma. Focal neurological signs sometimes develop. The symptoms develop rather suddenly after a latent period of 4 to 7 days after acute exposure. Recovery is slow and often incomplete except in the mildest cases. Tin causes severe interstitial cerebral edema as well as intramyelinic edema in the CNS and peripheral nervous system.
Organophosphates Organophosphates are neurotoxic by virtue of their ability to inhibit acetylcholinesterase (AChE), which accounts for their central neurotoxicity, and neuropathy target esterase (NTE), formerly known as neurotoxic esterase, which accounts for the delayed neuropathy that occurs after exposure to many of these compounds. The ability to inhibit NTE is used to screen new organophosphates for potential neurotoxicity. However, although inhibition of NTE is essential for the development of peripheral neurotoxicity, not all organophosphates that inhibit NTE cause neuropathy. The other factors that determine which NTE-inhibiting organophosphates are neurotoxic are unknown. Different organophosphates have differing potencies against these enzymes, although almost all have some anticholinesterase effects. Those that are used as insecticides and rodenticides have the most activity against AChE and relatively weak activity against NTE. The quintessential NTE inhibitor is triorthocresyl phosphate (TOCP), an additive to gasoline, mineral oil, and plastics, which has minimal activity against AChE; several pesticides also have NTE-inhibiting properties. Most organophosphates are readily absorbed through the skin as well as by inhalation and ingestion. Neurotoxicity usually results from acute exposure, either as a single event or after repeated short-term exposure. Both animal and human data support the contention that long-term neurobehavioral and cognitive problems may persist for years following a single acute 81 exposure. 81 Whether chronic low-level exposure results in any health risk remains unproven. Neurotoxicity From Inhibition of Acetylcholinesterase Exposure to organophosphates that are AChE inhibitors results in a clinical syndrome that reflects increased activity of acetylcholine at cholinergic synapses, both centrally and peripherally. Because AChE is inhibited at these sites, acetylcholine released from the presynaptic nerve terminal is not degraded normally and its action at the postsynaptic membrane is prolonged. The clinical manifestations resulting from acetylcholinesterase
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inhibition are shown in Table 39-3. Click here to view this table.... The earliest manifestations (type I or early syndrome) represent inhibition of AChE at CNS 81 cholinergic receptors and postganglionic parasympathetic receptors (muscarinic). The CNS effects begin with behavioral changes, mainly agitation, and progress to convulsions. There may be life-threatening peripheral muscarinic effects such as bradycardia and hypotension, sometimes progressing to complete cardiovascular collapse. Effects on the bronchial tree result in bronchospasm, increased secretions, and occasionally florid pulmonary edema. Non–life-threatening peripheral muscarinic effects include miosis, diarrhea or even involuntary defecation, urinary urgency or incontinence, and increased salivation and lacrimation. The nicotinic (neuromuscular junction) effects include muscle fasciculations and weakness. In severe intoxications, death from respiratory paralysis may occur. The combination of convulsions with weakness of respiratory muscles is particularly dangerous. The cholinergic effects of organophosphate poisoning usually begin within hours of exposure, although in mild cases they may be delayed for 2 to 3 days. In the intermediate (type II) syndrome, which occurs a few days after exposure, there may be recurrence of the acute respiratory failure that has initially responded well to aggressive 82,83 This is often accompanied by multiple cranial treatment with atropine and pralidoxime. neuropathies and weakness of neck flexion and proximal limb muscles. Unlike the acute syndrome, these intermediate effects do not respond to atropine or pralidoxime. Most patients with the type II syndrome go on to have neuropathy (see later). An acute, reversible extrapyramidal disorder has also been attributed to organophosphate 84 poisoning following massive exposure. The evidence that chronic low-level exposure to organophosphates in the workplace may produce an extrapyramidal syndrome is less persuasive and is based primarily on epidemiological surveys. For example, two case-control 85 86 studies of Parkinson's disease in Germany and Taiwan showed an increased prevalence 85 of Parkinson's disease in individuals exposed to organophosphate pesticides. In one study, there was also an increased prevalence of Parkinson's disease in relatives, leading the investigators to conclude that interaction of environmental and genetic factors may lead to development of the disease. Recognition of AChE inhibition seldom presents a diagnostic dilemma except in the mildest cases, at least in the workplace. There is usually a clear history of exposure, and the clinical syndrome is highly characteristic. There are even more characteristic electrophysiological 87 abnormalities associated with inhibition at the nicotinic receptor. The earliest sign is repetitive firing of the compound muscle action potential in response to a single electrical 88 stimulus delivered to a motor nerve. Later, there is a decremental response of the muscle to repetitive stimulation of the motor nerve. AChE activity can be measured in plasma or red blood cell—preferably the latter because this most closely reflects neurotoxicity—to confirm suspected intoxication and to monitor exposure in at-risk occupations. Primary treatment of AChE-related intoxications is with agents that block the action of acetylcholine at postsynaptic receptors such as with intravenous atropine. A test dose of 0.5 mg is given; this would cause tachycardia and mydriasis in normal people but has virtually no effect in an organophosphate-intoxicated individual. Atropine can then be given repeatedly in doses of 1 to 2 mg intravenously until signs of atropine toxicity develop. Because atropine can precipitate cardiac arrhythmias, an effect potentiated by hypoxemia, treatment should always be given in the intensive care unit with the patient intubated and monitored. Unfortunately, atropine has no effect on the nicotinic neuromuscular receptors and so is ineffective treatment for weakness and respiratory paralysis. Neither does it moderate the CNS effects of agitation and convulsions. It is useful only for controlling the diarrhea, incontinence, and excessive salivation and lacrimation. 89 If intoxication is recognized early, administration of pralidoxime chloride may be effective. Pralidoxime acts by accelerating the cleavage of the bond between the organophosphate and AChE and restoring AChE activity to normal. Therefore, effectiveness is independent of receptor 90 type, and the drug may also cross the blood–brain barrier and have a beneficial central effect. The complex that forms between the organophosphate and cholinesterase is initially reversible, but with time, irreversible configurational changes take place that have been termed aging. Once the 91 complex has “aged,” the enzyme is permanently deactivated and pralidoxime is ineffective. The most important treatment of organophosphate intoxication is supportive care, including artificial ventilation and anticonvulsant medication if necessary. Neurotoxicity From Inhibition of Neuropathy Target Esterase
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Inhibition of NTE causes a distal axonal neuropathy after acute or repeated exposure to some organophosphates. The onset of the neuropathy is typically delayed for 1 to 3 weeks 92,93 Preceding cholinergic symptoms may be mild or even absent. The after exposure. earliest symptoms are cramping calf pain and burning or tingling in the distal extremities, mainly the feet. Weakness develops early and is unusually severe, in contrast with most toxic neuropathies. It also involves distal muscles initially but progresses proximally: occasionally truncal muscles are involved, including the respiratory muscles. There may be ataxia out of proportion to the weakness, suggesting particular involvement of proprioception. Distal reflexes are absent, and more proximal reflexes are usually depressed. Cranial nerves are not involved, and autonomic function is spared. With time, severe distal muscle atrophy develops. The neuropathy evolves in a subacute fashion and the nadir is usually reached within 2 to 3 weeks of the onset of symptoms. Thereafter, patients improve slowly but steadily; the extent of improvement of the neuropathy is directly related to the severity of the neuropathic deficit at the nadir. Unfortunately, there is always CNS involvement in patients with organophosphate-induced neuropathy, although this is usually obscured by the severe peripheral neuropathy in the early stages. As the neuropathy improves, the CNS signs are 94,95 Most unmasked and the overall prognosis usually depends on the severity of CNS injury. commonly, there is significant spasticity, and often there is also ataxia. Diagnosis of organophosphate-induced neuropathy is not difficult if a history of exposure is forthcoming. Intoxication should be considered in any acutely evolving distal axonopathy even in the absence of a history of exposure. Unfortunately, there are no pathognomonic signs of organophosphate intoxication. Clinically and electrophysiologically, the neuropathy is little different from any other distal axonopathy, although there is an unusual degree of motor involvement. Electrodiagnostic studies confirm distal axonal degeneration, and there is also some slowing of conduction velocity, but these features are nonspecific. By the time the neuropathy develops and the patient comes to medical attention, red blood cell cholinesterase levels have returned to normal and all clinical and electrophysiological signs of AChE inhibition have resolved. The NTE in lymphocytes can be measured, but the technique 96 is not widely available. Measurement of lymphocyte97NTE levels has been suggested as a means of monitoring for chronic excessive exposure.
Acrylamide Acrylamide in its nontoxic polymeric form is widely used as a grouting agent and flocculator. It is the acrylamide monomer that is neurotoxic, and most cases of poisoning occur during the manufacture of the monomer or during the polymerization process at the work site. Acrylamide may be absorbed by inhalation or ingestion and through the skin. The latter is probably the major route of absorption in the workplace. Clinically apparent intoxication in the workplace usually arises as the result of either a single, massive, accidental exposure or repeated exposure over short periods. Chronic exposure to low levels of acrylamide in 98 animals produces neuropathy, but this has not been established in humans. Unlike almost all other toxins discussed in this chapter, there are few systemic toxic effects of acrylamide. It may produce a mild exfoliative dermatitis and some weight loss, but its serious toxicity is confined to the nervous system. Furthermore, the only meaningful toxicity is to the peripheral nervous system, causing a distal axonopathy. There is a mild encephalopathy with acute 99 exposure, and the ataxia that accompanies the neuropathy has prompted some to suggest a cerebellar disorder, although a sensory ataxia is a more plausible explanation. Nonetheless, there is Purkinje100 cell degeneration in animals experimentally exposed to high concentrations of acrylamide. Like most toxic neuropathies, acrylamide neuropathy is a predominantly sensory neuropathy and is strikingly length-dependent. Initial complaints are of numbness and hyperhidrosis of the distal extremities, particularly the feet, associated with unsteadiness of gait. The ataxia of gait is out of proportion to the weakness and probably reflects the predilection of acrylamide for the large myelinated proprioceptive fibers in peripheral nerves. There is also a disproportionate loss of reflexes, further indicating involvement of large-diameter afferent fibers from muscle spindles. Distal weakness is present but is not so severe as the sensory involvement. Cranial nerves are spared. Apart from the hyperhidrosis, there are no signs of autonomic instability, despite clear evidence of involvement of 101 sympathetic and parasympathetic nerves in experimentally intoxicated animals. There are no specific diagnostic tests to establish acrylamide as the cause of the neuropathy. If no history of exposure is forthcoming, the diagnosis is essentially impossible to establish; the key to diagnosis is a high index of suspicion and a thorough occupational history. There is no treatment for acrylamide intoxication other than removal from the toxic environment. Once exposure is terminated, there is steady improvement; functional recovery is complete in mild cases, although some reflex loss may be permanent.
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It is difficult to monitor for acrylamide exposure in the workplace. Acrylamide is rapidly eliminated from the circulation, metabolized to incompletely characterized end products, and eliminated from the body in the urine. Monitoring by means of measuring urinary metabolites has been unsuccessful. Because its entire meaningful toxicity is to peripheral nerves, excessive exposure can be monitored by testing peripheral nerve function. This task is made easier because of the preferential involvement of large myelinated fibers whose function can be accurately and reproducibly monitored with nerve conduction studies or quantitative measures of vibration threshold. Both have been used to monitor for excessive exposure in the workplace.
Toxic Gases Any gas that is present in sufficient concentration in the inhaled air can have a narcotizing effect. Perhaps the most common gas to cause problems in the workplace in this regard is carbon dioxide. Carbon monoxide is a more potent poison because of its high affinity for hemoglobin, which results in its accumulation in the circulation and a prolonged recovery phase. The early symptoms of both carbon dioxide and carbon monoxide poisoning are headache, irritability, difficulty in concentrating, and defects in judgment, all of which are signs of a mild encephalopathy. Recovery is usually rapid and complete except when there is progression to coma and convulsions, which is rare with occupational exposure. Toxicity of nitrous oxide was discussed previously (p. 753). Whether chronic, unintentional exposure in the workplace can result in myeloneuropathy has not been established, but it seems unlikely. Other gases have been suggested to have primary toxicity to the102 CNS, independent of the level of any hypoxia produced, but the evidence remains scanty. Further comment is therefore confined to ethylene oxide. Ethylene oxide is a gas that acts as an alkylating agent; it is therefore useful for sterilizing heat-sensitive objects. It is established as being toxic to the peripheral nervous system after high-level (i.e., >250 ppm) single or intermittent exposure. Prolonged exposure to lower levels may also be toxic to both peripheral nerves and the CNS; hospital sterilization workers exposed to low levels for many years with occasional exposure to much higher concentrations have been reported to have an increased prevalence of neurobehavioral 103,104 37 and some105 neurophysiological abnormalities, although these contentions abnormalities have not gone unchallenged. Chronic exposure in humans and animals causes a predominantly sensory, distal axonal neuropathy with a predilection for large myelinated 106,107 so that vibration and position sense are particularly affected, and there is axons, widespread reflex loss, which may be permanent. The human neuropathy is usually mild, and recovery is excellent once exposure is terminated. No other treatment is available or necessary. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 40 Acute Bacterial Infections of the Central Nervous System KAREN L. ROOS •
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ACUTE BACTERIAL MENINGITIS Etiology Clinical Presentation Diagnosis Differential Diagnosis Herpes Simplex Virus Encephalitis Arthropod-Borne Virus Encephalitis Rocky Mountain Spotted Fever Focal Infectious Intracranial Mass Lesions Subarachnoid Hemorrhage Treatment Empirical Antimicrobial Therapy Specific Antimicrobial Therapy Newer Antimicrobial Agents Dexamethasone Therapy Prevention BRAIN ABSCESS Etiology Clinical Presentation Diagnosis Differential Diagnosis Treatment SUBDURAL EMPYEMA AND EPIDURAL ABSCESS Etiology Clinical Presentation Diagnosis Treatment SPINAL EPIDURAL ABSCESS Etiology Clinical Presentation Diagnosis Treatment SEPTIC INTRACRANIAL THROMBOPHLEBITIS Etiology
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Clinical Presentation Diagnosis Treatment
The acute bacterial infections of the central nervous system (CNS) include meningitis, brain abscess, subdural empyema, epidural abscess, and septic venous sinus thrombosis. The etiology, clinical presentation, diagnosis, and treatment of each of these bacterial infections are discussed in this chapter. ACUTE BACTERIAL MENINGITIS Bacterial meningitis is an acute purulent infection in the subarachnoid space that is associated with an inflammatory reaction in the brain parenchyma and cerebral vasculature. The epidemiology of acute bacterial meningitis in children and adults has changed in the last 15 years. The Haemophilus influenzae type b (Hib) vaccine has dramatically reduced the incidence of meningitis in infants and children. The most common causative organisms of bacterial meningitis are Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, group B streptococci, and gram-negative bacilli. H. influenzae causes meningitis in unvaccinated children and adults. There is an increased incidence of penicillinand cephalosporin-resistant pneumococcal meningitis and an increasing incidence of N. meningitidis strains with moderate resistance to penicillin and a decreased susceptibility to ampicillin. The discussion that follows emphasizes the current epidemiology of acute bacterial meningitis, the best diagnostic tests to perform on cerebrospinal fluid (CSF), the use of dexamethasone as adjunctive therapy, and the present recommendations for the use of chemoprophylaxis and vaccination.
Etiology The most common etiological organisms of acute bacterial meningitis in children and adults are S. pneumoniae and N. meningitidis. Prior to the routine use of the Hib conjugate vaccine, Hib was the most common cause of bacterial meningitis in children in the United States, accounting for approximately 70 percent of cases of bacterial meningitis among children 1 younger than 5 years. The incidence of Hib invasive disease among children aged 4 years or less has declined by 98 percent since the introduction of the Hib conjugate vaccine for routine use in children aged 181,2months or older in December 1997, and in infants aged 2 months or older in October 1990. H. influenzae type b remains a cause of bacterial meningitis in older adults, immunocompromised patients, and patients with chronic lung disease, splenectomy, 2 leukemia, or sickle cell disease. Children too young to have completed a primary Hib vaccination series are also at risk for Hib meningitis. S. pneumoniae is the most common cause of meningitis in adults older than 18 years. A number of predisposing conditions increase the risk of pneumococcal meningitis, the most common of which is pneumonia. Acute and chronic otitis media, alcoholism, diabetes, splenectomy, hypogammaglobulinemia, and head trauma with basilar skull fracture and CSF rhinorrhea are also important predisposing conditions. Currently, approximately 44 percent of clinical isolates of S. pneumoniae in the United States have either intermediate or high levels 3 of resistance to penicillin. There is an increasing incidence of isolates of S. pneumoniae that are resistant to the third-generation cephalosporins cefotaxime and ceftriaxone. It is imperative that all isolates of S. pneumoniae be tested for penicillin and cephalosporin susceptibility and that a repeat lumbar puncture be performed 48 hours into antimicrobial 4 therapy for penicillin-resistant pneumococcal meningitis to document microbiological cure. The quadrivalent meningococcal conjugate vaccine is expected to decrease the incidence of meningococcal meningitis due to N. meningitidis among college students, but it does not provide immunity to N. meningitidis serogroup B. N. meningitidis strains with moderate or relative resistance to penicillin and a decreased susceptibility to ampicillin have been reported 5 from a wide variety of geographic locations. The Enterobacteriaceae (Proteus species, Escherichia coli, Klebsiella species, Serratia species, and Enterobacter species) cause meningitis in older adults; in adults with underlying diseases, such as cancer, diabetes, alcoholism, congestive heart failure,6 chronic lung disease, and hepatic or renal dysfunction; and in neurosurgical patients. L. monocytogenes is a cause of meningitis in individuals with impaired cell-mediated immunity from age (adults older than 60 years), organ transplantation, pregnancy, malignancy, chronic illness, or immunosuppressive therapy. The routine use of trimethoprim-sulfamethoxazole as a prophylactic agent for the prevention of Pneumocystis carinii pneumonia reduces the risk of L. monocytogenes infection and, therefore, has had the added benefit of decreasing the incidence of L. monocytogenes meningitis in individuals with
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the acquired immunodeficiency syndrome (AIDS). Staphylococcus aureus and coagulase-negative staphylococci are the predominant organisms causing meningitis as a complication of invasive neurosurgical procedures, particularly shunting procedures for hydro-cephalus, and as a complication of the use of subcutaneous Ommaya reservoirs or lumbar puncture for the administration of intrathecal chemotherapy. Streptococcus agalactiae, or group B streptococcus, is a leading cause of bacterial meningitis and sepsis in neonates and is increasingly recognized7 in two groups of adults: puerperal women and patients with serious underlying diseases.
Clinical Presentation Fever, headache, and stiff neck constitute the classic triad of symptoms and signs of bacterial meningitis. Patients are also typically lethargic or stuporous, and the level of consciousness may deteriorate while the patient is being evaluated in the emergency room. Nausea, vomiting, and photophobia are common complaints. Seizure activity occurs in approximately 40 percent of patients and typically occurs at either the onset or within the first few days of the illness. A stiff neck, or meningismus, is the pathognomonic sign of meningeal irritation. Meningismus is present when the neck resists passive flexion. Kernig's sign and Brudzinski's sign are also classic signs of meningeal irritation. Kernig's sign is elicited with the patient in the supine position. The thigh is flexed on the abdomen, with the knee flexed. Attempts to passively extend the leg elicit pain when meningeal irritation is present. Brudzinski's sign is elicited with the patient in a supine position and is positive when passive flexion of the neck results in 8 spontaneous flexion of the hips and knees. Increased intracranial pressure is an expected complication of bacterial meningitis and is the major cause of obtundation and coma in this disease. The most common signs of increased intracranial pressure in bacterial meningitis are an altered level of consciousness and papilledema. Cerebral arteritis and septic venous thrombosis of the cerebral dural sinuses and cortical veins are also complications of bacterial meningitis and present as focal neurological deficits or new-onset seizure activity. The rash of meningococcemia begins as a diffuse erythematous maculopapular rash resembling a viral exanthem, but the lesions rapidly become petechial. This rash can be differentiated from the rash of a viremia in that petechiae are found on the trunk and lower extremities in meningococcemia. Petechiae may also be found in the mucous membranes and conjunctiva and occasionally on the palms and soles. Other infectious diseases that may manifest with a petechial, purpuric, or erythematous maculopapular rash like that of meningococcemia include enteroviral meningitis, Rocky Mountain spotted fever, West Nile fever encephalitis, bacterial endocarditis, echovirus type 9 viremia, and pneumococcal or H. influenzae meningitis.
Diagnosis The diagnosis of bacterial meningitis is made by examination of the CSF. The necessity of neuroimaging prior to lumbar puncture has been debated for years. Neuroimaging prior to lumbar puncture should be performed in any patient with an altered level of consciousness, papilledema, focal neurological deficits, an immunocompromised state, or new-onset seizure activity. When the clinical presentation is suggestive of bacterial meningitis, blood cultures should be obtained and dexamethasone and empirical antimicrobial therapy initiated immediately. If the patient is being treated with antibiotics, there is no risk in delaying lumbar puncture until after neuroimaging has been performed. Antibiotic therapy for several hours prior to lumbar puncture does not alter the CSF white blood cell (WBC) count or glucose concentration enough to allow a diagnosis of bacterial meningitis to be overlooked, and it is not likely to sterilize the CSF enough to prevent the isolation of a microorganism on Gram's stain or in culture. The classic CSF abnormalities in bacterial meningitis are (1) an increased opening pressure, 3 (2) a pleocytosis of polymorphonuclear leukocytes (10 to 10,000 WBCs/mm ), (3) a decreased glucose concentration (<45 mg/dl or CSF/serum glucose ratio of <0.31), and (4) an increased protein concentration. A CSF sample should be analyzed, using Gram's stain and bacterial culture. The Gram stain, developed by Hans Christian Joachim Gram, a Danish bacteriologist, is positive in 70 to 90 percent of untreated cases of bacterial meningitis. The polymerase chain reaction (PCR) has not been as well studied for the diagnosis of bacterial
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meningitis as it has been for the diagnosis of viral CNS infections. There have been increasing reports, however, of the usefulness of PCR in detecting bacterial DNA from N. 9,10 meningitidis, H. influenzae, S. pneumoniae, S. agalactiae, and L. monocytogenes in CSF. A broad-range PCR can detect small numbers of viable and nonviable organisms in the CSF. When the broad-range PCR is positive, a PCR that uses specific bacterial primers to detect the nucleic acid of S. pneumoniae, N. meningitidis, E. coli, L. monocytogenes, H. influenzae, and S. agalactiae should be done. It is anticipated that the broad-range PCR may eventually 11 be used to exclude the diagnosis of bacterial meningitis. The latex particle agglutination (LA) test for the detection of bacterial antigens of S. pneumoniae, N. meningitidis, H. influenzae type b, group B streptococcus, and E. coli K1 strains in CSF is useful for making a diagnosis of bacterial meningitis in patients who have been pretreated with oral or parenteral antibiotics and in whom Gram's stain and CSF culture are negative, but it is being replaced by the PCR assay. The LA test has a specificity of 96 percent for S. pneumoniae and 100 percent for N. meningitidis. It has a sensitivity of 69 to 100 percent for the detection of S. pneumoniae in CSF and a sensitivity of 33 to 70 percent for the detection of bacterial antigens of N. meningitidis in CSF. It is important to emphasize, however, that a negative LA test for bacterial antigens does not exclude bacterial meningitis, and this test is not recommended for making a decision about whether to continue or discontinue empiric antibiotic therapy. The Limulus amebocyte lysate assay is a rapid diagnostic test for the detection of gram-negative endotoxin in CSF and thus for making a diagnosis of gram-negative bacterial meningitis. This test is reported to have a sensitivity of 99.5 percent 12–14 In clinical practice, and a specificity of 86 to 99.8 percent, but it is not routinely available. when bacterial meningitis is a possibility, most physicians treat with empirical therapy until the results of bacterial cultures are negative. If there are petechial skin lesions, biopsies should be performed. The rash of meningococcemia results from the dermal seeding of organisms with vascular endothelial damage, and biopsy may reveal the organism on Gram's stain. As stated, raised intracranial pressure is an expected complication of bacterial meningitis. Lumbar puncture should be performed with a 22- or 25-gauge needle, and a minimal amount of CSF removed for analysis. Approximately 6 ml of CSF is sufficient to obtain a cell count, determine glucose and protein concentrations, and analyze the sample using Gram's stain, culture, and PCR or LA methods. An additional 1 ml of CSF can be sent to the PCR laboratory to analyze it for viral DNA, specifically herpes simplex virus (HSV) DNA, because HSV-1 encephalitis is the leading disease in the differential diagnosis of bacterial meningitis.
Differential Diagnosis Herpes simplex virus encephalitis is an important consideration in the differential diagnosis of bacterial meningitis, and arthropod-borne viral encephalitis should be included during the summer and early fall months while mosquitoes are biting. Focal intracranial mass lesions and subarachnoid hemorrhage also need to be included in the differential diagnosis of bacterial meningitis. Herpes Simplex Virus Encephalitis The clinical presentation of HSV encephalitis (discussed in detail in Chapter 44) includes hemicranial headache, fever, behavioral abnormalities, focal or generalized seizure activity, and focal neurological deficits (e.g., dysphasia, hemiparesis with greater involvement of face and arm, and superior quadrantic field defects). The symptoms of HSV encephalitis typically evolve over several days, and the presentation is not so acute as that of bacterial meningitis. In patients with HSV encephalitis, on T2-weighted and fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), high signal intensity lesions are seen in the medial and inferior temporal lobe extending up into the insula. The absence of an abnormality on MRI 48 hours after symptom onset should prompt consideration of another diagnosis. There is a distinctive electroencephalographic (EEG) pattern in HSV encephalitis, consisting of periodic, stereotyped, complexes from one or both temporal areas that occur at regular intervals of 1 to 2 seconds. The periodic complexes are typically observed between day 2 and day 15 of the illness. Examination of the CSF3 reveals an increased opening pressure, a lymphocytic pleocytosis of 5 to 500 cells/mm , a mild to moderate elevation in the protein concentration, and a normal or mildly decreased glucose concentration. There may be red blood cells or xanthochromia, findings that reflect the hemorrhagic nature of the encephalitis. Results of CSF viral cultures for HSV-1 are almost always negative. The PCR is typically positive within 72 hours of symptom onset and then declines after the first week. If an initial CSF HSV PCR is negative within the first 72 hours of symptoms and HSV remains a major diagnostic consideration, the CSF should be resampled as the initial result may be a false
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negative. Cerebrospinal fluid and serum samples should be sent for HSV IgG antibody titers. Antibodies to HSV appear in CSF approximately 8 to 12 days after the onset of symptoms and can be detected for at least 30 days. A serum:CSF HSV-1 antibody ratio of less than 20:1 is considered diagnostic of intrathecal synthesis of antibodies and HSV encephalitis. Arthropod-Borne Virus Encephalitis During the summer and early fall months when mosquitoes are biting, arthropod-borne viral encephalitis (discussed in Chapter 44) should be included in the differential diagnosis. In the United States, the La Crosse virus, the St. Louis encephalitis virus, and the West Nile virus are the most common causes of arthropod-borne viral encephalitis. Eastern equine encephalitis virus causes the most severe arthropod-borne viral encephalitis, and the fatality rate is high. Japanese encephalitis virus is the most common cause of arthropod-borne human encephalitis worldwide. Venezuelan equine encephalitis virus is endemic in South America and is a rare cause of encephalitis in Central America and the southwestern area of the United States, particularly in Texas. The clinical presentation of arthropod-borne viral encephalitis, regardless of the specific virus, is fairly characteristic. The onset of encephalitic symptoms may be preceded by an influenza-like prodrome of fever, malaise, myalgias, nausea, and vomiting. This is followed by symptoms of headache, confusion, stupor, and occasionally convulsions. Focal neurological deficits and focal seizure activity have been reported in cases of encephalitis caused by eastern equine encephalitis virus and La Crosse virus. Patients with West Nile virus encephalitis may have conjunctivitis or a maculopapular or roseolar rash. Patients with West Nile virus or St. Louis virus encephalitis may have an acute asymmetric flaccid weakness or tremors, myoclonus, or parkinsonian features. Japanese encephalitis virus tends to infect the basal ganglia and the thalamus, and patients present with tremors during the acute disease, with a parkinsonian-like syndrome occurring in survivors. Either neuroimaging is normal or there are nonspecific abnormalities in arthropod-borne viral encephalitis. Focal abnormalities in the basal ganglia and the16thalamus have been reported in eastern equine, Japanese, and West Nile virus encephalitis. Examination of the CSF in arthropod-borne viral encephalitis demonstrates a polymorphonuclear leukocytic pleocytosis or a lymphocytic pleocytosis. The CSF glucose concentration is normal. Based on criteria established by the U.S. Centers for Disease Control and Prevention, a confirmed case of arboviral encephalitis is defined as a febrile illness with encephalitis during a period when arboviral transmission is likely to occur, plus at least one of the following criteria: (1) fourfold or greater rise in serum antibody titer between the time of acute illness and 4 weeks later; (2) isolation of virus from tissue, blood, or CSF; or (3) specific immunoglobulin M (IgM) antibody in cerebrospinal fluid. La Crosse virus has not been isolated from CSF. St. Louis encephalitis virus, eastern equine encephalitis virus, and western equine encephalitis virus are rarely isolated from CSF. A CSF PCR assay is available for the detection of West Nile virus nucleic acid. A positive test confirms the diagnosis, but a negative test does not exclude it, since the test has a low sensitivity. The detection of West Nile virus IgM in CSF is considered the most sensitive diagnostic test for West Nile virus encephalitis. A presumptive case of arboviral encephalitis is defined as a compatible illness, plus either a stable elevated serum antibody titer to an arbovirus (≥320 by hemagglutination inhibition, ≥128 by complement fixation, ≥256 by immunofluorescent assay, or ≥160 by plaque-reduction neutralization test) or specific IgM antibody in serum by enzyme immunoassay. The exception to the latter is West Nile virus. West Nile virus IgM antibodies may persist in serum for a year or more after exposure to the virus and cannot be used for definitive diagnosis of recent infection. Rocky Mountain Spotted Fever Rocky Mountain spotted fever is caused by the bacteria Rickettsia rickettsii. The disease begins with high fever, prostration, myalgias, headache, and nausea and vomiting. The rash is characteristic and is initially a diffuse erythematous maculopapular rash that appears 2 to 4 days after the onset of symptoms. It typically begins at the wrist and ankles and then spreads distally, including the palms and soles, and proximally within a matter of a few hours. Diagnosis is made by immunofluorescent staining of skin biopsy specimens or by detection of IgM and IgG antibodies. Focal Infectious Intracranial Mass Lesions
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Focal infectious intracranial mass lesions, including brain abscess, subdural empyema, and epidural abscess, are discussed later in this chapter but should be included in the differential diagnosis of bacterial meningitis. The presence of a focal infectious intracranial mass lesion is suggested by focal or generalized seizure activity or focal neurological deficits on examination and is ruled out by neuroimaging. Subarachnoid Hemorrhage The possibility of a subarachnoid hemorrhage should also be included in the differential diagnosis of acute bacterial meningitis. The clinical presentation of a subarachnoid hemorrhage is characterized by the explosive onset of a severe headache or a sudden transient loss of consciousness followed by a severe headache. Because of the presence of blood in the subarachnoid space, nuchal rigidity is frequently present. A dilated nonreactive pupil is suggestive of a subarachnoid hemorrhage from an aneurysm of the posterior communicating artery. When a subarachnoid hemorrhage has occurred, a computed tomography (CT) scan may demonstrate blood in the basal cisterns. If the CT scan is normal, the spinal fluid should be examined for red blood cells and xanthochromia. Red blood cells are present in the CSF within minutes of the rupture of an intracranial aneurysm. A sample of the blood-tinged CSF should be centrifuged. The supernatant obtained has a yellow or xanthochromic color within 2 to 4 hours of the subarachnoid hemorrhage. Xanthochromic spinal fluid may also be seen when the CSF protein concentration is elevated (above 150 mg/dl), and therefore it can be seen in bacterial meningitis.
Treatment Empirical Antimicrobial Therapy When bacterial meningitis is suspected, antimicrobial therapy is initiated immediately after blood cultures are obtained and before the results of CSF Gram's stain and culture and antimicrobial susceptibility tests are known. Empirical therapy should be based on the possibility that the patient has penicillin- and cephalosporin-resistant pneumococcal meningitis and should include a combination of cefotaxime or ceftriaxone plus vancomycin. Acyclovir is added to the empirical regimen to cover HSV because HSV encephalitis is the leading disease in the differential diagnosis (Table 40-1). Ampicillin should be added to cover L. monocytogenes if the patient is over the age of 60 years or immunosuppressed. If the patient has been treated with trimethoprim-sulfamethoxazole for prophylaxis of toxoplasmosis or P. carinii pneumonia, it is less likely that the meningitis is due to L. monocytogenes. Meningitis that complicates a neurosurgical procedure, epidural anesthesia, or intrathecal chemotherapy should be treated empirically with a combination of vancomycin plus ceftazidime, cefepime, or meropenem. Vancomycin is used to cover staphylococci and ceftazidime, cefepime, or meropenem to cover gram-negative bacilli, specifically Pseudomonas aeruginosa. The doses of each of the antimicrobial agents are provided in Table 40-2, which shows both pediatric and adult dosing categories. Click here to view this table.... Click here to view this table.... Specific Antimicrobial Therapy All CSF bacterial isolates should be tested for antimicrobial susceptibility. In experimental models of bacterial meningitis, the maximal bactericidal activity occurs when the antibiotic concentration is 10 to 30 times greater than the minimal bactericidal concentration of the 17 microorganism in vitro. Pneumococcal Meningitis
Antimicrobial therapy for pneumococcal meningitis is initiated with a third-generation cephalosporin and vancomycin. Some strains of pneumococci are sensitive to penicillin. All CSF isolates of S. pneumoniae should be tested for sensitivity to penicillin and the third-generation cephalosporins. Once the results of antimicrobial susceptibility tests are known, therapy can be modified accordingly (Table 40-3). According to the guidelines of the National Committee for Laboratory Standards, an isolate of S. pneumoniae is considered to be highly resistant to penicillin with a minimal inhibitory concentration (MIC) of at least 2 18 μg/ml. An isolate of S. pneumoniae is considered to have intermediate resistance to penicillin with an MIC of 0.1 to 1 μg/ml and to be susceptible to penicillin with an MIC of less
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than 0.1 μg/ml. Penicillin G can be used to treat susceptible strains of S. pneumoniae. For S. pneumoniae meningitis, however, more rigid guidelines are applied. An isolate is defined as penicillin-susceptible when the MIC is ≥0.06 μg/ml, to have intermediate resistance when the MIC is 0.1 to 1.0 μg/ml, and to be highly resistant when the MIC is ≥1.0 μg/ml. Isolates of S. pneumoniae that have MICs ≥0.5 μg/ml are defined as susceptible to the cephalosporins (cefotaxime, ceftriaxone, cefepime). Those with MICs of 1 μg/ml are considered to have intermediate resistance, and those with MICs ≥2 μg/ml are considered resistant. For meningitis due to pneumococci, when the MICs of cefotaxime or ceftriaxone are ≥0.5 μg/ml, treatment with cefotaxime or ceftriaxone is probably adequate. If the MICs are ≥1 μg/ml, vancomycin is the antibiotic of choice. Rifampin can be added to vancomycin for its synergistic effect because it is highly active against most penicillin-resistant pneumococci, but rifampin is inadequate as monotherapy because resistance develops rapidly when it is used alone. Click here to view this table.... For pneumococcal meningitis, a repeat lumbar puncture should be performed 24 to 48 hours after the initiation of antimicrobial therapy to document eradication of the pathogen. Consideration should be given to using intraventricular vancomycin in patients not responding to parenteral vancomycin. The intraventricular route of administration is preferred over the intrathecal route because adequate concentrations of vancomycin in the cerebral ventricles are not always achieved with intrathecal administration. Intraventricular and intrathecal vancomycin is safe and is not associated with a risk of seizure activity. A 2-week course of intravenous antimicrobial therapy is recommended for pneumococcal meningitis. Meningococcal Meningitis
Penicillin G or a third-generation cephalosporin (Table 40-3) remains the antibiotic of choice for meningococcal meningitis. Isolates of N. meningitidis with moderate or relative resistance to penicillin (defined as a penicillin MIC of 0.1 to 1.0 μg/ml) and decreased susceptibility to ampicillin have been reported from a wide variety of geographic locations (Spain, South Africa, North Carolina). Penicillin resistance in N. meningitidis is due in part to alterations in 5 the penicillin-binding proteins. All CSF isolates of N. meningitidis should be tested for penicillin and ampicillin susceptibility. If antimicrobial susceptibility testing demonstrates that the isolate is a relatively penicillin-resistant strain of meningococcus, and in areas with a high prevalence of meningococci with decreased susceptibility to penicillin, cefotaxime or ceftriaxone should be used. A 7-day course of intravenous antibiotic therapy is adequate for most uncomplicated cases of meningococcal meningitis. The index case and all close contacts should receive chemoprophylaxis with a 2-day regimen of rifampin (600 mg every 12 hours for 2 days in adults and 10 mg/kg every 12 hours for 2 days in children older than 1 year). Rifampin should not be used in pregnant women. Alternatively, adults can be treated with one dose of ciprofloxacin (750 mg) or one dose of azithromycin (500 mg). Close contacts are defined as individuals who have had contact with nasopharyngeal secretions either through kissing or sharing toys, beverages, or cigarettes. Staphylococcal Meningitis
Meningitis caused by S. aureus or coagulase-negative staphylococci is treated with nafcillin or oxacillin. Vancomycin is the drug of choice for methicillin-resistant staphylococci and for patients allergic to penicillin. The CSF should be monitored during therapy, and if the spinal fluid continues to yield viable organisms after 48 hours of intravenous therapy, intraventricular vancomycin, 10 mg once daily for children and 20 mg once daily for adults, should be added. Listeria Monocytogenes Meningitis
Meningitis due to L. monocytogenes is treated with ampicillin for at least 3 weeks. Gentamicin should be added to ampicillin in critically ill patients. Meningitis caused by this organism is seen less often today in immunosuppressed patients than in the past because the trimethoprim-sulfamethoxazole administered to them as a prophylactic agent to prevent P. carinii pneumonia and toxoplasmosis is bactericidal against L. monocytogenes. Enterobacteriaceae Meningitis
Meningitis caused by the Enterobacteriaceae, including Proteus species, E. coli, Klebsiella species, Serratia species, and Enterobacter species, is treated with a third-generation cephalosporin, either cefotaxime or ceftriaxone, for 3 weeks.
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Pseudomonas Aeruginosa Meningitis
The third-generation cephalosporins cefotaxime, ceftriaxone, and ceftazidime are equally efficacious for the treatment of gram-negative bacillary meningitis, with the exception of meningitis caused by P. aeruginosa. Meningitis resulting from infection with this organism is treated with ceftazidime, cefepime, or meropenem in a 3-week course of intravenous antibiotic therapy. Newer Antimicrobial Agents Meropenem is a carbapenem antibiotic structurally related to imipenem but reportedly with 19 less seizure proclivity than imipenem. In experimental models, meropenem has bactericidal activity similar to that of the combination of ceftriaxone and vancomycin against 20 penicillin-resistant S. pneumoniae. Safety and efficacy of meropenem were compared with those of cefotaxime in a prospective randomized trial of 190 children with bacterial meningitis (caused by H. influenzae, S. pneumoniae, and E. coli). Seizures occurred within 24 hours before antibiotic therapy in 16 of 98 patients (16%) randomized to receive meropenem, and in 6 of 92 patients (7%) randomized to receive cefotaxime. In patients without seizures before therapy, seizures occurred during treatment in 5 of2182 patients (6%) receiving meropenem and in 1 of 86 patients (1%) receiving cefotaxime. Meropenem is highly active in vitro against L. monocytogenes. Meropenem is also active against multidrug-resistant 21–23 gram-negative bacteria and is effective in cases of meningitis caused by P. aeruginosa. The dose of meropenem is 1 to 2 g intravenously every 8 hours for adults; the pediatric dose is 40 mg/kg every 8 hours. The number of patients enrolled in clinical trials of meropenem for bacterial meningitis has not been sufficient to date to correctly assess the efficacy of this antimicrobial agent in the treatment of bacterial meningitis or its epileptogenic potential. Cefepime is a broad-spectrum fourth-generation cephalosporin with in vitro activity similar to that of cefotaxime or ceftriaxone against the common meningeal pathogens H. influenzae, S. pneumoniae, and N. meningitidis, and greater activity against Enterobacter species and P. 24 aeruginosa. The dose of cefepime is 2 g intravenously every 8 hours in adults. In clinical trials, cefepime has been demonstrated to be equivalent to cefotaxime in the treatment of pneumococcal and meningococcal meningitis, but its efficacy in bacterial meningitis caused by penicillin- and cephalosporin-resistant pneumococcal organisms has not been established. Dexamethasone Therapy The use of dexamethasone as adjunctive therapy in bacterial meningitis comes from present understanding of the pathophysiology of the neurological complications of bacterial meningitis. The critical event in the pathogenesis of bacterial meningitis is the inflammatory reaction in the subarachnoid space to the invading meningeal pathogen. It is not the pathogen itself that causes the neurological complications. In bacterial meningitis, brain 25 damage progresses long after the CSF has been sterilized by antibiotic therapy. The lysis of bacteria with the release of bacterial cell wall components in the subarachnoid space is the initial step in the induction of the inflammatory process and the formation of a purulent exudate in the subarachnoid space (Fig. 40-1). Components of bacterial cell walls, such as lipopolysaccharide molecules (endotoxin), a cell wall component of gram-negative bacteria, and teichoic acid and peptidoglycan, cell wall components of the pneumococcal species, induce meningeal inflammation by stimulating the production of inflammatory cytokines and chemokines by microglia (CNS macrophage-equivalent cells), astrocytes, monocytes, microvascular endothelial cells, and white blood cells in the CSF space. There are a number of pathophysiological consequences that result from the presence of the inflammatory cytokines in CSF. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) act synergistically to alter the permeability of the blood–brain barrier. This allows for the leakage of serum proteins and other molecules into the CSF, contributing to the formation of a purulent exudate in the subarachnoid space. The purulent exudate obstructs the flow of CSF through the ventricular system and diminishes the resorptive capacity of the arachnoid granulations in the dural sinuses. This leads to obstructive and communicating hydrocephalus and interstitial edema. The exudate also surrounds and narrows the diameter of the lumen of the large arteries at the base of the brain, and inflammatory cells infiltrate the arterial walls (vasculitis). The inflammatory cytokines recruit polymorphonuclear leukocytes from the bloodstream and upregulate the expression of selectins on cerebral capillary endothelial cells and leukocytes, which allow for leukocytes to adhere to vascular endothelial cells and to subsequently migrate into the CSF. The results of experimental models of meningitis suggest that bacterial eradication is not a leukocyte-dependent phenomenon. Neutrophils degranulate and release toxic metabolites that contribute to cytotoxic edema, cell injury, and death. The adherence of
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leukocytes to cerebral capillary endothelial cells increases the permeability of blood vessels, allowing for the leakage of plasma proteins into the CSF and further contributing to the inflammatory exudate in the subarachnoid space.
FIGURE 40-1 Inflammatory cascade leading to the neurological complications
of bacterial meningitis. CSF, cerebrospinal fluid; SAS, subarachnoid space. (Reprinted by permission of Karen L. Roos, MD, Indiana University Hospital, Indianapolis.) Dexamethasone exerts its beneficial effect by inhibiting the synthesis of IL-1 and TNF at the level of mRNA and by decreasing CSF outflow resistance and stabilizing the blood–brain barrier. The rationale for giving dexamethasone prior to antibiotic therapy is that dexamethasone inhibits the production of TNF if administered to macrophages and microglia before they are activated by endotoxin, both by diminishing the quantity of TNF mRNA in response to endotoxin and by preventing its translation. Dexamethasone is unable to regulate TNF production once induction occurs. Scientists working in the area of the molecular basis of neurological injury in bacterial meningitis have been interested in dexamethasone because of its beneficial effects on inhibiting the synthesis of the inflammatory cytokines. There have been a number of clinical trials dating back to 1950 that were designed to evaluate the efficacy of corticosteroids in reducing mortality and morbidity in bacterial 26 27 28 meningitis. It was the work of Tauber and co-workers in 1985 and Lebel and co-workers in 1988, however, that renewed interest in corticosteroid therapy for bacterial meningitis. A meta-analysis of randomized, concurrently controlled trials of dexamethasone therapy in childhood bacterial meningitis published from 1988 to 1996 confirmed the benefit of dexamethasone for H. influenzae type b meningitis if begun with or before intravenous 29 antibiotics and suggested a beneficial effect for pneumococcal meningitis in children. In interpreting the results of the clinical trials conducted to date, certain important variables must be considered. The timing of the first dose of dexamethasone differs greatly among clinical trials. In clinical trials where dexamethasone was administered prior to antibiotic therapy, it 30,31 As has been discussed, dexamethasone inhibits the has been shown to be efficacious. synthesis of the inflammatory cytokines. Once bactericidal antibiotics have lysed bacteria so that bacterial cell wall components are present in the subarachnoid space, the production of the inflammatory cytokines has begun. Maximal benefit from dexamethasone therapy is thus dependent on timing. A common criticism of the dexamethasone trials is that in the majority of cases, the causative organism of the meningitis was H. influenzae type b. This is no longer one of the more common etiological organisms of bacterial meningitis because of the success of the Hib conjugate vaccine. Present understanding of the molecular basis of the neurological complications of bacterial meningitis, however, does not suggest that the pathophysiology of
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the neurological complications varies with the meningeal pathogen, with the exception of how the microorganism gains access to the CNS. An additional concern about the use of dexamethasone in the therapy for bacterial meningitis is the effect of dexamethasone on the penetration of antibiotics into the CSF. Meningeal inflammation appears to improve the penetration of vancomycin. By decreasing meningeal inflammation, dexamethasone could reduce the penetration of vancomycin into the CSF. In a prospective, randomized clinical trial of bactericidal activity against cephalosporin-resistant pneumococci in CSF in children with acute bacterial meningitis, vancomycin in a dosage of 60 mg/kg daily reliably penetrated the CSF when the children were treated concomitantly with dexamethasone (0.6 mg/kg daily, 32 divided into four doses for 4 days). The third-generation cephalosporins and rifampin penetrate the CSF extremely well, even in the presence of dexamethasone. The American Academy of Pediatrics recommends the consideration of dexamethasone for bacterial meningitis in infants and children aged 2 months or older. The recommended dose is 0.6 mg/kg daily in four divided doses (0.15 mg/kg/dose) given intravenously for the first 4 days of antibiotic therapy. The first dose of dexamethasone should be administered before or at least with the first dose of antibiotics. Results of clinical trials of dexamethasone therapy in children have demonstrated its efficacy in decreasing meningeal inflammation and neurological sequelae and in reducing the incidence of sensorineural hearing loss. The efficacy of dexamethasone as adjunctive therapy in adults was demonstrated in a prospective, randomized, placebo-controlled, double-blind, multicenter trial of 301 adults with bacterial meningitis. Dexamethasone 10 mg was administered intravenously 15 to 20 minutes before the first dose of an antimicrobial agent and then given every 6 hours in a dose of 10 mg for 4 days. Such therapy was associated with a reduction in the proportion of patients with unfavorable outcomes (15% versus 25%, P = 0.03) and in the proportion who died (7% 33 versus 15%, P = 0.04). The recommended dose is 0.6 mg/kg daily in four divided doses for the first 4 days of antimicrobial therapy, with the first dose administered 10 to 20 minutes before or at least concomitant with the first dose of antibiotic. Dexamethasone therapy is recommended for all adults with suspected or proven bacterial meningitis. For the reasons cited earlier, dexamethasone is most beneficial if given before or concomitantly with the first dose of antibiotic. Dexamethasone is not likely to be of much benefit if started 24 hours or more after antimicrobial therapy has been initiated.
Prevention The Advisory Committee on Immunization Practices recommends that college freshmen be vaccinated against meningococcal meningitis with a tetravalent (MenA,C,W135,Y) meningococcal polysaccharide vaccine. MenC polysaccharide vaccine would also be effective. During an outbreak of meningococcal disease, individuals who have not been previously vaccinated should be treated with chemoprophylaxis. As many as 33 percent of secondary cases of meningococcal disease develop within 2 to 5 days of presentation of the index case. Vaccination is not a substitute for chemoprophylaxis to prevent secondary disease, because there is an insufficient amount of time for development of the optimum effect of vaccination, which requires approximately 1 to 2 weeks for good antibody 34 production. Adults and adolescents who have not been vaccinated but have been exposed to an individual with meningococcal disease can be treated with rifampin, 600 mg twice daily for 2 days. Children are treated with rifampin, 10 mg/kg twice daily for 2 days. Alternatively, adults can be treated with ciprofloxacin, 750 mg, one single dose orally, or azithromycin, 500 mg, one single dose orally. Ciprofloxacin is not recommended in children and adolescents because it has been associated with arthropathy, although it is doubtful that a single dose of ciprofloxacin would cause this adverse effect. Vaccination against pneumococci is recommended for three at-risk populations: adults older than 65 years, adults with chronic underlying diseases (cardiopulmonary diseases, renal diseases, diabetes mellitus, splenectomy, and CSF fistula), and immunocompromised patients over 10 years of age. Individuals infected with 34 the human immunodeficiency virus (HIV) should also be vaccinated against pneumococci. BRAIN ABSCESS A brain abscess is a focal suppurative infection in the brain parenchyma that begins as a 35 localized area of cerebritis and develops into a collection of pus surrounded by a capsule. The most common sources of brain abscess are dental and sinus infections. Previously, chronic otitis media was a common predisposing condition for brain abscess, but aggressive treatment of otitis media has led to a decrease in the incidence of otogenic-related brain abscess. Bacteria are not a common cause of brain abscess in immunosuppressed patients because of routine prophylaxis with antibiotics during episodes of neutropenia. The single
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exception to this is Nocardia asteroides, which is the causative organism in an increasing number of cases of brain abscess in patients with defects in cell-mediated immunity.
Etiology As stated, the most common source of brain abscess is sinusitis or dental disease. Brain abscesses that arise from intracranial extension of paranasal sinus infection are usually caused by microaerophilic streptococci and anaerobic organisms (Bacteroides species, 35 Fusobacterium species, and anaerobic streptococci) and Haemophilus species. Bacterial infection in the paranasal sinuses spreads intracranially to the frontal or temporal lobe either36 by retrograde thrombophlebitis of the diploic veins or via a contiguous area of osteomyelitis. Brain abscesses associated with a dental procedure or dental abscesses are also typically due to microaerophilic streptococci and anaerobic organisms. Anaerobic organisms predominate in abscesses caused by dental infection. A brain abscess may arise from direct extension of mastoid infection or via retrograde thrombophlebitis of the emissary veins within the temporal bone from mastoiditis. Middle ear infections can cause temporal lobe abscess by direct spread of infection through the tegmen antrum or petrous portion of the temporal 36 bone. Brain abscesses that arise from middle ear infections are most often due to Streptococcus species, Enterobacteriaceae, Bacteroides species (including B. fragilis), and P. aeruginosa. A brain abscess may develop from hematogenous dissemination of microorganisms from a remote site of infection such as the heart, the lungs, the abdomen, or 36 the urinary tract. Metastatic abscesses are often multiple. Metastatic abscesses tend to form primarily in areas supplied by the middle cerebral artery (i.e., posterior frontal or parietal lobes). These abscesses are usually located at the interface of gray-white matter, where capillary blood-flow is slowest. A common cause of brain abscess in infants and children is cyanotic congenital heart disease, with tetralogy of Fallot and transposition of the great vessels being the most frequent anomalies cited. As a general rule, a brain abscess develops only in an area of ischemic or devitalized brain tissue. The polycythemia that occurs with cyanotic congenital heart disease causes intravascular thrombosis and reduces the rate of blood flow in the microcirculation in the brain, leading to brain hypoxia or infarction. In addition, the presence of a right-to-left shunt precludes the filtering of virulent bacteria by the lungs. Bacteria reach the brain and are able to establish infection in 37,38 areas of focal cerebral damage from microinfarction with Anaerobic and microaerophilic streptococci are most often reduced tissue oxygenation. 39 recovered in abscesses associated with congenital heart disease. Neonatal brain abscesses occur as a complication of meningitis, a predisposing condition that is uncommon in older children and adults. The most common causative organisms of bacterial brain 36 abscess in neonates and infants are Proteus species and Citrobacter species. Brain abscess is an uncommon complication of neonatal group B streptococcal or E. coli meningitis. Bacterial brain abscess is not a common intracranial infection in immunosuppressed patients because of the use of prophylactic antibiotics in patients who are neutropenic. When a bacterial brain abscess develops in the first month after organ transplantation, the source40 is usually infection in a surgical wound, the lungs, or the urinary tract or in intravenous lines. Nocardia asteroides is a branching, filamentous, rod-shaped aerobic, gram-positive 41 bacterium within the order Actinomycetes. Nocardia asteroides is found in soil and decaying vegetables. Infection is acquired by inhalation, and the organism spreads from the lungs to 42 the brain. Risk factors for the development of a Nocardia brain abscess include cytotoxic chemotherapy, pregnancy, corticosteroid therapy, organ transplantation, and lymphatic 41 malignancy. Immunosuppressed patients receiving prophylactic therapy with trimethoprim-sulfamethoxazole to prevent P. carinii pneumonia are less likely to have Nocardia as the causative organism of brain abscess, because prophylaxis with this antimicrobial agent can prevent nocardial brain infection. A brain abscess may develop as a complication of penetrating head trauma or a neurosurgical procedure. S. aureus is the most common pathogen recovered from post-traumatic brain abscesses, which are frequently multiloculated and may contain foreign 35 bodies. A brain abscess following a neurosurgical procedure is typically due to staphylococci or gram-negative bacilli.
Clinical Presentation Headache is the most common presenting complaint in patients with a brain abscess. Fever occurs in fewer than 50 percent of patients. One third of patients present with new-onset focal or generalized seizures. The findings on neurological examination are related both to the site
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of the abscess and to the presence of increased intracranial pressure. Hemiparesis is a common localizing sign of a frontal or parietal lobe abscess. A temporal lobe abscess may be associated with dysphasia or a visual field deficit (upper homonymous quadrantanopia). A patient who has a cerebellar abscess presents with nystagmus and ataxia. When the brain abscess is complicated by increased intracranial pressure, there may be papilledema, deficits of cranial nerves III and VI, and an alteration in consciousness ranging from lethargy to irritability, confusion, or coma.
Diagnosis Cranial MRI is the best neuroimaging procedure for demonstrating a brain abscess, especially one that is in an early (cerebritis) stage. On T2-weighted images, cerebritis is evident as an area of increased signal intensity. A mature brain abscess appears hypointense to CSF on T1-weighted MRI and shows ring enhancement following administration of intravenous gadolinium. On T2-weighted images, a mature brain abscess has a central area of pus that is hyperintense to CSF, is surrounded by a well-defined hypointense capsule, and 35 has a surrounding area of edema that is hyperintense to CSF. Diffusion-weighted MRI and magnetization transfer ratios (MTRs) are helpful in differentiating a brain abscess from other types of cystic lesion. A brain abscess is hyperintense on diffusion-weighted MRI with low 43 the MTR of a brain abscess is higher than that of a ADC values. On MT imaging, 44 non-abscess cystic lesion. On contrast-enhanced CT, the mature abscess has the appearance of a low-density lesion with a sharply demarcated, dense ring of contrast enhancement surrounded by a variable hypodense region of edema. In both the early (cerebritis) and mature stages, a marginal ring of density is present on contrast-enhanced images; however, in the cerebritis stage, the enhancing ring forms an inhomogeneous “halo.” As the abscess matures, its margin becomes more discrete and the associated enhancement more homogeneous. There may be diffusion of contrast medium into the low-density center of an abscess in the cerebritis stage. The etiological organism of a brain abscess is determined by stereotactic needle aspiration. This procedure not only provides diagnostic specimens for Gram's stain and culture but also permits therapeutic drainage of pus. Lumbar puncture should be avoided in patients with known or suspected focal intracranial infections because of the danger of herniation and because the diagnostic yield is low. About 50 percent of patients with a brain abscess have a peripheral leukocytosis, and 60 percent have an elevated erythrocyte sedimentation rate.
Differential Diagnosis The differential diagnosis of a brain abscess includes focal structural or space-occupying lesions, such as tumor, stroke, subdural empyema, and superior sagittal sinus thrombosis.
Treatment All abscesses that are larger than 2.5 cm in diameter or that are causing significant mass 45 effect should be drained by stereotactic aspiration. Antibiotic therapy is based on culture and sensitivity testing of the specific etiological organism of the brain abscess. Empirical antibiotic therapy should be based on a knowledge of the organisms most frequently encountered with the suspected etiology of the brain abscess until the results of culture and 36 sensitivity studies are available (Table 40-4). Click here to view this table.... Abscesses originating from the paranasal sinuses are caused predominantly by microaerophilic streptococci, anaerobic organisms (Bacteroides species, Fusobacterium species, and anaerobic streptococci), and Haemophilus species. A combination of penicillin G, a third-generation cephalosporin, and metronidazole is recommended. The doses of the antimicrobial agents are provided in Table 40-2. A brain abscess associated with dental disease is treated with a combination of penicillin G plus metronidazole to cover streptococci and Bacteroides fragilis. A brain abscess that complicates otitis media or mastoiditis may be caused by Streptococcus species, Bacteroides species (including B. fragilis), Enterobacteriaceae, or P. aeruginosa. A combination of penicillin G, metronidazole, and ceftazidime is recommended. Cerebral abscesses due to bacteremia from a pyogenic lung infection, urinary sepsis, or an intra-abdominal source of infection are treated with a combination of penicillin G, metronidazole, and ceftazidime until the results of culture and antimicrobial susceptibility tests are available. A brain abscess that develops in association with endocarditis is most often caused by S. aureus or microaerophilic streptococci. Empirical therapy should include a combination of nafcillin or vancomycin plus a third-generation
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cephalosporin (cefotaxime). The most common organisms isolated when brain abscess complicates cyanotic congenital heart disease are viridans streptococci (microaerophilic streptococci), anaerobic streptococci, and occasionally Haemophilus species. A combination of penicillin G and cefotaxime plus metronidazole is recommended. Penicillin G covers microaerophilic streptococci. Metronidazole has excellent bactericidal activity against strict anaerobes, excellent oral absorption, and excellent penetration into CSF and brain abscess cavities, but streptococci and aerotolerant anaerobes are resistant to metronidazole. Cefotaxime is added to cover Haemophilus species. Cefotaxime is the preferred third-generation cephalosporin because it and its lipophilic metabolite, desacetylcefotaxime, have excellent antibacterial activity and 35 penetrate and accumulate within abscess cavities. Brain abscesses complicating neurosurgical procedures are usually due to staphylococci or gram-negative organisms. Empirical therapy should be a combination of vancomycin plus ceftazidime. The most common pathogens recovered from brain abscesses that complicate penetrating head injuries are staphylococci and gram-negative bacteria. Anaerobes and Nocardia species may also be recovered. Empirical therapy should include a combination of vancomycin, ceftazidime, and metronidazole. A brain abscess is treated with a 6- to 8-week course of parenteral antimicrobial therapy, followed by an additional 2- to 3-month course of oral antimicrobial therapy. Either a CT scan or MRI can be45performed every 2 weeks and should also be performed at any sign of clinical deterioration. A small amount of enhancement may still be seen on imaging for several months after the abscess has been successfully treated. The majority of abscesses can be managed with stereotactic aspiration and therapeutic drainage in combination with antimicrobial therapy. There are two exceptions to this rule. An abscess that is in the cerebritis stage and has not become encapsulated may respond to antimicrobial therapy alone. The other exception is a brain abscess due to N. asteroides. These usually require surgical excision and therapy with trimethoprim-sulfamethoxazole. Corticosteroids are recommended only for those patients with significant cerebral edema and associated mass effect causing increased intracranial pressure. Steroids should not be given routinely to patients with brain abscesses, as they delay the encapsulation of the abscess. Because of the high risk of focal or generalized seizures, patients should be treated with prophylactic anticonvulsant drugs during their course of antimicrobial therapy and for at least 3 months after resolution of the abscess. Consideration can then be given to tapering and discontinuing anticonvulsant therapy. SUBDURAL EMPYEMA AND EPIDURAL ABSCESS Subdural empyema is a collection of pus in the space between the dura and the arachnoid (Fig. 40-2). A cranial epidural abscess develops in the space between the dura and the inner table of the skull (Fig. 40-3). A subdural empyema is a more malignant and life-threatening infection than is an epidural abscess.
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FIGURE 40-2 Schematic appearance of a subdural empyema.
FIGURE 40-3 Cranial epidural abscess located in the space between the dura
and the inner table of the skull.
Etiology Paranasal sinusitis, especially frontal sinusitis, is the most common predisposing condition 46 for subdural empyema. Septic thrombophlebitis of the mucosal veins of the sinuses results in retrograde extension of infection with drainage of bacteria into the dural venous sinuses 47 and cortical veins and the formation of a subdural empyema. Subdural empyema may also result (1) from direct infection of the subdural space during a neurosurgical procedure, such as drainage of a subdural hematoma, (2) as a complication of head trauma, or (3) from infection of a subdural effusion. It rarely develops from hematogenous dissemination of bacteria from a distant focus of infection. An epidural abscess may develop as a complication of a craniotomy or a compound skull fracture or as the result of spread of infection from the frontal sinuses, middle ear, mastoid, or 48 orbit. When an epidural abscess develops as a complication of a craniotomy, it is either as a result of direct infection of the epidural space or as a complication of a contiguous area of osteomyelitis that developed from infection of a wound or bone flap. A cranial epidural abscess rarely results from hematogenous seeding of the epidural space from a distant site 48 of infection. Aerobic and microaerophilic streptococci and anaerobic bacteria are the most common causative organisms of subdural empyema or epidural abscess that develops as a complication of sinusitis, middle ear infection, or mastoiditis. A subdural empyema or an epidural abscess that develops as a complication of craniotomy, compound skull fracture, or drainage of a subdural hematoma is usually caused by S. aureus, coagulase-negative staphylococci, or gram-negative organisms. A subdural effusion may be a complication of bacterial meningitis in infants and children. This is typically a self-limited process that resolves as the meningitis resolves. Occasionally, a subdural effusion may become infected. It is then a subdural empyema, and the causative organism is the organism responsible for the meningitis.
Clinical Presentation Headache is the most common complaint at the time a patient presents with a subdural empyema and is initially localized to the side of the subdural infection. It may be accompanied by fever and symptoms of sinusitis or otitis media. The evolution of a subdural empyema tends to be remarkably rapid. There are no septations in the subdural space. As a result, the purulent exudate can spread quite extensively. The headache may become more severe and generalized; focal neurological deficits or seizures may also occur. Contralateral hemiparesis or hemiplegia is the most common focal neurological deficit. Seizures begin as partial motor (jacksonian) seizures but then become secondarily generalized. Over the
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course of a few49days, the level of consciousness decreases from somnolence to stupor and finally to coma. In a review of subdural empyema arising from sinusitis in 18 patients, headache was present in 15 patients (83%), fever in 17 patients (94%), focal neurological signs in 17 patients (94%), nuchal rigidity in 14 patients (78%), altered level of consciousness in 10 patients (56%), seizures in 10 patients (56%), and sinus tenderness or periorbital 46 swelling in 7 patients (39%). The clinical presentation of an epidural abscess is distinctly different from that of a subdural empyema. The patient is not as ill, and there is rarely rigidity of the neck or focal neurological 49 signs. The patient typically presents with an unrelenting hemicranial headache with persistent fever. Focal neurological deficits, seizures, and signs of increased intracranial pressure do48not develop until the infection spreads into the subdural space (subdural empyema).
Diagnosis Cranial MRI is the procedure of choice for demonstrating the lesion because it is free from bony artifacts adjacent to the inner table of the skull and readily demonstrates extracerebral fluid collections. T1-weighted cranial MRI postgadolinium and T2-weighted MRI are the best imaging studies for demonstrating subdural empyema or cranial epidural abscess. Subdural empyema has a slightly higher signal intensity than does CSF on T1-weighted images. The administration of gadolinium enhances the rim of the empyema and separates the empyema from the subjacent brain parenchyma. The empyema appears as a crescent-shaped lesion of higher signal intensity than that of CSF on T2-weighted MRI. On T1-weighted MRI, an epidural abscess has a signal intensity that is between that of normal brain parenchyma and CSF. Following the administration of gadolinium, a significant enhancement of the dura is seen on T1-weighted images. An epidural abscess appears as a lentiform or crescentic purulent fluid collection that is hyperintense to CSF on T2-weighted images. Lumbar puncture should not be performed in patients with subdural empyema or epidural abscess. The etiological organism is identified by Gram's stain and culture of pus obtained either via burr holes or by craniotomy.
Treatment Immediate neurosurgical drainage of a subdural empyema or a cranial epidural abscess is the definitive step in the management of these infections. At surgery, Gram's stain and culture of the purulent material is performed. Empirical antimicrobial therapy pending the results of Gram's stain and culture should cover aerobic and microaerophilic streptococci, anaerobic bacteria, staphylococci, and gram-negative bacilli and include a combination of a third-generation cephalosporin (cefotaxime or ceftriaxone), metronidazole, and nafcillin or vancomycin. Ceftazidime should be substituted for cefotaxime or ceftriaxone in neurosurgical patients because it provides better coverage of Pseudomonas species. Antibiotic coverage can be modified when the results of Gram's stain and bacterial culture and sensitivity testing are known. A 4-week course of intravenous antibiotic therapy is recommended for subdural empyema, followed by a 2-week course of oral antibiotic therapy. A cranial epidural abscess is treated for 3 weeks with parenteral antibiotics in the absence of osteomyelitis, and for 6 to 8 weeks when it is a complication of a contiguous area of osteomyelitis. SPINAL EPIDURAL ABSCESS An epidural abscess may develop in the spinal epidural space (Fig. 40-4). The most common locations for a spinal epidural abscess are the posterior midthoracic region between the fourth and the eighth thoracic vertebrae (Fig. 40-5) and the lower lumbar epidural space. This is because the anteroposterior width of the50spinal epidural space is greatest from approximately T4 to T8 and from L3 to S2. Anterior abscesses occur less often than do posterior abscesses and usually occur at the cervical level.
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FIGURE 40-4 An abscess in the epidural space posterior to the spinal cord.
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FIGURE 40-5 Axial postcontrast T1-weighted magnetic resonance imaging
(MRI) through an upper thoracic vertebral body. This demonstrates focal low-intensity signal from an extra-axial fluid collection consistent with an epidural abscess (white arrow), which displaces the spinal cord posteriorly (black arrows).
Etiology A spinal epidural abscess develops in the space outside the dura mater but within the spinal canal as the result of hematogenous spread of bacteria from a remote site of infection to the epidural space (e.g., secondary to skin infection, urinary tract infection, intra-abdominal infection, pelvic inflammatory disease, pneumonia, endocarditis, or infections in intravenous lines), by direct extension from a contiguous infection (e.g., an area of osteomyelitis in an adjacent vertebral body), by direct infection of the epidural space during spine surgery or epidural anesthesia, or by direct extension of infection from decubitus ulcers, infected abdominal wounds, retropharyngeal abscesses, or psoas muscle abscesses. Immunosuppression from chronic disease (such as diabetes or chronic renal insufficiency), AIDS, corticosteroid therapy, and immunosuppressive therapies are increasingly reported as predisposing conditions for spinal epidural abscess formation. The etiological organism of the spinal epidural abscess is predictable from the predisposing condition. A spinal epidural abscess that arises from hematogenous dissemination from a skin infection or infections in intravenous lines, or as a complication of spine surgery or epidural anesthesia, is caused in the majority of cases by S. aureus. Infection that reaches the epidural space by hematogenous spread of bacteria from a genitourinary infection or intra-abdominal infection to the paravertebral venous plexus is usually caused by gram-negative bacilli.
Clinical Presentation Patients with a bacterial spinal epidural abscess present with a classic neurological syndrome 51 that was described by Heusner in 1948. Back pain is the initial symptom, followed within 2 to 3 days by radicular pain in the extremities or pain in an intercostal thoracic dermatomal distribution. As the disease progresses, paresis of appendicular muscles is associated with loss of sensation below the level of the lesion and loss of bowel and bladder control. Finally, there is complete paralysis of appendicular muscles and loss of all sensory modalities below the level of the lesion (i.e., a sensory level). The majority of patients also have an elevated temperature. The possibility of a spinal epidural abscess should be considered in any patient with fever, back pain (especially focal vertebral pain and tenderness), and radicular pain in the extremities or pain in a thoracic dermatomal distribution.
Diagnosis Gadolinium-enhanced MRI is the diagnostic procedure of choice for spinal epidural abscess. At the very least, MRI of the thoracic and lumbar region should be obtained to visualize the extent of the epidural abscess, and it is reasonable to obtain images of the cervical region as well. A lumbar puncture should not be performed at the site of a possible abscess because of the risk of spread of infection from the epidural to the subarachnoid space. The majority of patients have an elevated peripheral white blood cell count, and blood cultures may demonstrate the organism.
Treatment A spinal epidural abscess is treated with immediate laminectomy, with decompression and drainage of the epidural space. Empirical therapy depends on the predisposing condition. Because S. aureus is the most common etiological agent, and given the increasing incidence of community- and hospital-acquired methicillin-resistant S. aureus, empiric therapy should include vancomycin. In the postneurosurgical patient, a third-generation cephalosporin with antipseudomonal activity should be added to the empirical regimen to cover gram-negative bacilli. When a spinal epidural abscess is the result of local extension from an adjacent infection, such as a decubitus ulcer, empirical therapy should cover S. aureus and gram-negative bacilli. If the source is an abdominal infection, anaerobic coverage with metronidazole should be added. Once a specific organism has been isolated, the antibiotic regimen can be modified based on the results of sensitivity studies. The duration of
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intravenous antibiotic therapy is usually 3 to 4 weeks in the absence of osteomyelitis, and 6 to 52 8 weeks when vertebral osteomyelitis is present. SEPTIC INTRACRANIAL THROMBOPHLEBITIS Septic intracranial thrombophlebitis is a bacterial infection of the cortical veins and sinuses with venous thrombosis. This is a complication of bacterial meningitis, subdural empyema, epidural abscess, or infection in the skin of the face, paranasal sinuses, middle ear, or mastoid. Textbooks tend to treat septic intracranial thrombophlebitis as a distinct entity, but in reality clinicians rarely diagnose this as a distinct entity and, in fact, probably underdiagnose it as a complication of bacterial meningitis or subdural empyema. The availability of noninvasive neuroimaging procedures, such as magnetic resonance venography and CT angiography, for demonstrating dural sinus thrombosis may increase the recognition of this complication of bacterial meningitis.
Etiology The superior sagittal sinus is the largest of the venous sinuses (Fig. 40-6). It receives blood from the frontal, parietal, and occipital superior cerebral veins and the diploic veins, which communicate with the meningeal veins. Infection can spread from the meninges (bacterial meningitis) to the superior sagittal sinus via the diploic veins, especially in cases with purulent exudate near areas of the superior sagittal sinus. The cerebral veins and venous sinuses have no valves; therefore, blood within them can flow in either direction. The superior sagittal sinus drains into the transverse sinus. The transverse sinuses also receive venous drainage from small veins from both the middle ear and the mastoid cells. The transverse sinus becomes the sigmoid sinus before draining into the internal jugular vein. Septic transverse–sigmoid sinus thrombosis can be a complication of acute and chronic otitis media or mastoiditis. Infection spreads from the mastoid air cells to the transverse sinus via the emissary veins or by direct invasion.
FIGURE 40-6 The major cerebral venous sinuses.
The cavernous sinuses are inferior to the superior sagittal sinus at the base of the skull (Fig. 40-5). Bacteria in the sphenoid and ethmoid sinuses can spread to the cavernous sinuses via the small emissary veins. The sphenoid and ethmoid sinuses are the most common sites of primary infection resulting in septic cavernous sinus thrombosis. In sick patients, dehydration from vomiting and hypercoagulable states contribute to the formation of thrombosis in the cerebral venous sinuses. Immunological abnormalities, including the presence of circulating antiphospholipid antibodies, can also contribute to cerebral venous sinus thrombosis. Thrombosis of a dural sinus can be associated with thrombosis of the cortical veins that drain blood into and out of the sinus. The latter complication may result in small parenchymal hemorrhages.
Clinical Presentation Patients with septic thrombosis of the superior sagittal sinus have headache, nausea and vomiting, weakness of the lower extremities with bilateral Babinski signs, focal or generalized
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seizures, and an alteration in the level of consciousness. There may be a rapid development of stupor and coma. The signs and symptoms of septic cavernous sinus thrombosis are fever, headache, frontal and retro-orbital pain, and diplopia. The oculomotor nerve (cranial nerve III), trochlear nerve (cranial nerve IV), abducens nerve (cranial nerve VI), and ophthalmic and maxillary branches of the trigeminal nerve all pass through the cavernous sinus; therefore, the classic signs of a septic cavernous sinus thrombosis are ptosis, proptosis, and extraocular dysmotility due to deficits of cranial nerves III, IV, and VI. Hypo- or hyperesthesia of the ophthalmic and maxillary divisions of the fifth cranial nerve and a decreased corneal reflex may be detected. Patients with septic transverse sinus thrombosis may present with Gradenigo's syndrome, which is characterized by otitis media, sixth nerve palsy, and retro-orbital or facial pain.
Diagnosis The diagnosis of septic venous sinus thrombosis is suggested by an absent flow void within the sinus on MRI and is confirmed by magnetic resonance venography, CT angiography, or the venous phase of cerebral angiography.
Treatment Septic venous sinus thrombosis has traditionally been treated with antibiotics and hydration and by removal of infected tissue and thrombus in septic lateral or cavernous sinus thrombosis. Anticoagulation with dose-adjusted heparin is reported to be beneficial in patients with aseptic venous sinus thrombosis and is used in the treatment of septic venous sinus thrombosis in bacterial meningitis when patients are worsening despite antimicrobial therapy and intravenous fluids. Good clinical results have been reported with catheter-directed urokinase therapy and intrathrombus infusion of recombinant tissue plasminogen activator for aseptic venous sinus thrombosis, but there has not been enough experience with these therapies for septic venous sinus thrombosis to make recommendations regarding their use. As stated, this complication is probably underrecognized and underreported in bacterial meningitis. In patients with bacterial meningitis and lower extremity weakness or a decreased level of consciousness, the use of noninvasive magnetic resonance venography and CT angiography may increase the recognition of this complication, prompting the use of other therapeutic modalities in addition to antibiotics and hydration for the management of this complication in critically ill patients. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 41 Spirochetal Infections of the Nervous System JOHN J. HALPERIN •
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SYPHILIS Background Diagnosis Clinical Features Treatment LYME DISEASE Background Clinical Features General Neuroborreliosis Diagnosis Treatment and Outcome
Spirochetes cause a broad range of human illnesses, including relapsing fever, yaws, pinta, leptospirosis, and periodontal disease. Although leptospirosis and relapsing fevers can cause severe headaches and myalgias in conjunction with high fever and severe systemic illness, only two spirochetal infections target the nervous system specifically: syphilis and Lyme disease. Therefore, these two are the focus of this chapter. Both have achieved great notoriety. The similarities between them have been emphasized repeatedly and probably excessively. However, important aspects of each are instructive when one considers the other. Probably the greatest similarity is that both have become the subject of popular mythology and have been blamed for far more than they could possibly have done. Syphilis swept Europe at a time when medicine had yet to understand such fundamental concepts as the germ basis of infection. Even early in the twentieth century, the pre-eminent physicians of the time referred to syphilis as the great imitator that could cause all manner of illness. It must be remembered that at that time, little was understood about cerebrovascular disease or other types of neurological disorders. As late as the 1950s and beyond, anecdotal reports appeared about neurosyphilis having been diagnosed on the basis of silver stains of brain tissue—a highly problematic methodology since fibrillar structures normally present in the brain stain with silver and have a corkscrew-like appearance. Similarly, Lyme disease has been blamed for innumerable “quality-of-life” ailments. At a time when science has sequenced the human genome, can detect subtle structural abnormalities with magnetic resonance imaging (MRI), and has developed an immense and powerful
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pharmacopoeia, many find it difficult to accept that medicine has limitations and, in particular, cannot provide simple biological answers to and remedies for a constellation of common and distressing symptoms, variably known over the years by terms such as neurasthenia, chronic fatigue syndrome, and fibromyalgia, among others. In this setting, some have chosen to extrapolate from the known phenomenology of Lyme disease, emphasizing the areas of similarity between these symptom complexes and Lyme disease and ignoring the far more glaring differences. Nevertheless, there are fascinating similarities between syphilis and Lyme disease that deserve emphasis, as they presumably reflect basic biological properties of spirochetes. Both infections can be extremely chronic, despite the presence of easily demonstrable antibodies targeted against major epitopes. Presumably, this relates to the spirochetal properties of both limiting the range of antigens expressed on their surface and of changing the expressed epitopes over time, as conditions require. Both disorders are spread almost exclusively by intimate contact with a vector, reflecting the very limited ability of spirochetes to survive in vitro. Both begin with prominent, angry-looking cutaneous abnormalities that are surprisingly painless, the lack of pain presumably reflecting the peculiarities of the limited local host immune response. Both disseminate widely and rapidly, easily broaching the blood–brain barrier, probably reflecting their own inherent motility and adherence to cell-surface molecules. Both seed the nervous system frequently but cause neurological disease only in a small subset of those seeded. Most important, both bacteria have remained sensitive to fairly simple antibiotics. The innumerable references to their protean manifestations reflect an approach to neurology based on phenomenology rather than pathophysiology. Each infection causes a discrete set of pathogenic disorders. The specific manifestations in any given individual depend on the particular part of the nervous system involved, but the disorders are pathophysiologically related. SYPHILIS
Background Syphilis, caused by Treponema pallidum, became prominent in Europe shortly after the return of Columbus from the New World. Known at the time (in some circles) as “the French pox,” the mode1 of transmission was recognized early on. In the Breviary of Health (1547, cited by Tramont ), a brief list of other infrequent mechanisms is followed by the unequivocal statement that “specially it is taken when one pocky person doth synne in lechery the one with another.” At that time, as with other newly introduced infectious diseases, the morbidity and mortality associated with syphilis were high. Then, presumably as the most susceptible hosts died and the bacteria self-selected for strains that could persist without killing or incapacitating their hosts, the bacteria and humankind settled into their current symbiotic relationship. Currently, there are about 8,000 cases of primary and secondary syphilis each 2 year in the United States.
Diagnosis Diagnosis was originally clinical and rested on recognition of the characteristic chancre—a painless, ulcerated, indurated lesion at the site of primary infection that typically heals spontaneously. The lesion contains numerous spirochetes; one of the best methods of diagnosis is to scrape the lesion, place the scrapings in saline on a slide, and view the motile spirochetes with a dark-field microscope. In patients not seen at the time of the chancre, diagnosis initially rested on the recognition of one of the large number of clinical syndromes attributed to this disease. Further improvement of diagnostic accuracy could not be achieved until appropriate laboratory technologies were developed. Identification of the causative organism early in the twentieth century was an important first step, but to this day culturing T. pallidum remains problematic; growing T. pallidum in vitro remains essentially impossible, although inoculation into susceptible animals provides an indirect method of propagating the organism. However, the spirochete has now been very well characterized. Its length varies from 6 to 20 μm; its diameter is about 0.18 μm. It is shaped in a regular helix and exhibits 4corkscrew motility, 3 propelled by its flagella. Its entire genome has now been sequenced. Despite this intimate knowledge of the spirochete, laboratory confirmation of infection, particularly after resolution of the chancre, remains dependent on serological tests. Although numerous variations of these tests exist, all fall into one of two groups. Screening is done
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with an indirect test, testing for “reaginic” antibodies, in essence, anticardiolipin antibodies. The reason that patients with this infection have high titers of anticardiolipin antibody remains unknown, but presumably reflects an interaction of the spirochete with host lipoproteins and other lipids. Tests such as the Wasserman reaction, rapid plasma reagin (RPR), Venereal Disease Research Laboratory (VDRL), and Hinton tests all fall into this group. These tests have very high sensitivity but, as indirect measures of infection, lack specificity. Patients who have positive screening test results are then tested with specific antitreponemal tests, such as the FTA-Abs (fluorescent treponemal antibody, absorbed against nonpathogenic treponema to decrease cross-reactivity) or the MHA-TP test (microhemagglutination for T. pallidum). Interestingly, efforts to use differential immunoglobulin G (IgG) and IgM measures of antibody have not been very helpful in determining disease activity, much as for Lyme disease. In general, response to therapy is assessed by measuring titers of indirect antibody. Typically, the serum titer in a VDRL or similar test declines steadily after successful treatment and eventually becomes negative in most cases. When serological testing was introduced early in1 the twentieth century, seroprevalence rates of 8 to 14 percent were reported in major cities. It was at that time that the medical literature blossomed, attributing all manner of disease to syphilis. It seems likely (at least to this author) that at least some of this was misattribution due to coincidentally positive serological tests, much as occurs in Lyme disease–endemic areas5 today (where, coincidentally, seroprevalence rates of 5% to 15% are common ). Diagnosis of nervous system disease relies heavily on examination of the cerebrospinal fluid (CSF), which is recommended in the assessment of any patient with primary or secondary syphilis 6,7 and clinical suspicion of central nervous system (CNS) involvement or with tertiary syphilis. Invasion and infection of the CNS typically elicit 8increased protein concentration or a CSF pleocytosis, with an increased proportion of B cells. Rarely there is mild hypoglycorrhachia. Active disease typically elicits production of reaginic antibodies (VDRL) in the CSF. Chronic infection and stimulation of the immune response within the CNS typically result in increased IgG concentration in the CSF as well as production of oligoclonal bands. 9 Synthesis of specific anti–T. pallidum antibody can often be demonstrated in the CSF. Successful treatment usually leads to resolution of all these abnormalities. CSF-based diagnosis is usually straightforward but can, in some circumstances, be quite problematic. The CSF VDRL test is considered highly specific—the presence of a positive CSF VDRL result is regarded as diagnostic of CNS syphilis. (A CSF RPR test has far more false-positive results.) This specificity is probably related to the fact that the methodology is rather insensitive in that a fairly high concentration of antibody is needed for the test to be judged positive. Thus, the presence of a positive VDRL in the CSF is unlikely to be an artifact of contamination of CSF with peripheral blood immunoglobulins. One potential diagnostic problem arises, however, in that although the CSF VDRL typically declines after successful treatment, it may remain positive for an extended period of time. In this circumstance, the return of the CSF white blood cell count and protein concentration to normal is usually taken as evidence of adequate treatment. With the far more (technically) sensitive methods used to detect actual antitreponemal antibodies (FTA-Abs, MHA-TP), contamination is a more important issue. False-positive results can occur for one of at least three reasons. Antibodies against antigenically similar organisms (e.g., Borrelia burgdorferi) can cross-react. More important, if the lumbar puncture is traumatic, peripheral blood can contaminate the specimen, resulting in artifactual elevations in antibody titers. Probably most important, however, is the fact that some peripheral blood immunoglobulin always finds its way into the CSF. In the absence of CNS inflammation, there is minimal if any intrinsic production of antibodies within the CNS. However, CSF IgG concentration is typically 2 to 3 mg/dl, approximately 0.2 percent of peripheral blood IgG concentration, representing the small amount of serum immunoglobulin that normally leaks through the blood–brain barrier. Just as in testing CSF Lyme serologies, standard testing conditions (diluting CSF 1:5 for the FTA-Abs, for example) are selected to compensate for this leakage. However, artifacts may arise in two important circumstances. In patients with high serum FTA-Abs titers, CSF titers may be positive simply by virtue of the small amount of specific antibody that normally filters in. Second, in the presence either of CNS inflammation or of blood–brain barrier breakdown for other reasons, the amount of peripheral blood immunoglobulin leaking into the CNS may be greater than assumed, resulting in an apparent increase in the concentration of the tested antibody but actually simply reflecting an overall and nonspecific increase in all antibody levels. These considerations notwithstanding, the CSF FTA is a highly sensitive if not entirely specific 8 marker of neurosyphilis.
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The absence of an absolute gold standard test for the diagnosis of neurosyphilis has resulted in controversy, differing recommendations for diagnostic strategies, and varying estimates of the sensitivity and specificity of different CSF tests. Whereas the CSF VDRL test is thought to be 100 percent specific, estimates of its sensitivity vary widely, depending on the alternative criteria used to define neurosyphilis. Screening CSF samples using the FTA-Abs and considering patients to have probable neurosyphilis if they have (1) a positive CSF FTA-Abs result, (2) a consistent clinical syndrome, and (3) elevation in either the CSF cell count or protein concentration, or both, leads to an estimated sensitivity of the CSF VDRL of 27 10 as the primary criterion percent. Performing a similar analysis, but using the CSF MHA-TP 11 and comparing the CSF MHA-TP, CSF FTA-Abs, and CSF VDRL, suggests that the sensitivity of the CSF VDRL is about 40 percent, but that of the CSF MHA-TP is substantially 12 greater than that of the FTA-Abs. However, there is evidence that as many as one third of human immunodeficiency virus (HIV)–seronegative individuals with positive serum VDRL results will have inflammatory changes in the CSF, but no serological (CSF VDRL or FTA-Abs) evidence of neurosyphilis, calling into doubt the assumptions underlying the first two conclusions. Theoretically, a more definitive approach would be to determine whether antibodies targeted against T. pallidum are actually being produced within the CNS. Although a variety of techniques can be used, conceptually this is accomplished by measuring the antibody concentration in CSF and serum, normalizing for the relative total immunoglobulin concentrations in both, and determining whether specific antibody is disproportionately 13 should have very represented in the CSF. This approach, used in many other infections, 9,14–17 Despite the intuitive high specificity, although, again, sensitivity is difficult to define. appeal of this approach, sensitivity estimates have varied widely, depending on underlying assumptions, making its applicability uncertain at this time.
Clinical Features After initial inoculation of spirochetes, the organism disseminates rapidly. Within weeks of infection, a typically painless, indurated lesion, the chancre, develops at the site of infection. These lesions contain large numbers of spirochetes and are highly infectious. Untreated, they typically subside spontaneously over weeks. This early, localized disease constitutes primary syphilis. Over the ensuing few months, spirochetes disseminate, setting the stage for secondary syphilis. In this phase, there is a high antigen load, often with a significant spirochetemia. Spirochetes can invade any organ of the body but have a particular predilection for the skin (with secondary lesions, particularly involving the palms and soles); lymph nodes (particularly the epitrochlear nodes); the kidney (with an immune complex–mediated glomerulonephritis); and the CNS (seeded in between 25% and 40% of infected individuals). As many as 40 percent of untreated patients develop a lymphocytic meningitis. As in other basilar meningitides, the cranial nerves, particularly II to VIII, can be compromised. Intracranial pressure may be increased. The disease then typically enters a latent phase, during which infection—and the immune 15 response to it—persist. In the majority, the host immune response clears the infection. In a small subset, late or tertiary complications develop. In some, this consists of disseminated granulomas, known as gummas, that can occur anywhere in the body, causing focal symptoms depending on location. Patients may develop gummas in the brain, causing local structural damage and symptoms; these tend to be relatively benign but can be confused with neoplasms or other processes. Some develop an endarteritis obliterans in the vasa vasorum of the ascending aorta, causing characteristic aneurysmal dilatation. Although neurological involvement is generally divided into early or late (secondary or tertiary) manifestations, there is some variability in how different pathophysiological entities are grouped. The acute meningitis, with or without cranial nerve involvement, typically occurs during acute spirochetal dissemination, and it is considered part of secondary (acute disseminated) disease. All other manifestations occur later in the disease, in what might be termed late disseminated infection (“tertiary syphilis”), although some tend to occur earlier in this “late” phase, others later. Symptomatic nervous system involvement ultimately occurs in 4 to 6 percent of untreated 18,19 patients and tends to take one of several forms. One of the earlier occurring late manifestations is meningovascular syphilis, in which the characteristic obliterative endarteritis involves the intracranial vasculature, causing strokes. Although the resultant clinical phenomena are described as protean, they are no more protean than in other cerebrovascular disease—differences reflect the site of damage, not the mechanism. Several other characteristic abnormalities may occur. Those not due to vasculitis are
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collectively referred to as parenchymal neurosyphilis. Involvement of the upper brainstem and surrounding basilar cisterns can lead to Argyll Robertson pupils, small irregular pupils that do not react to light but do to accommodation. Optic atrophy can develop slowly, presumably owing to both increased intracranial pressure caused by the meningitis and local infiltration of the optic nerves. Tabes dorsalis, consisting of damage to the dorsal roots, the dorsal root ganglia, and the posterior columns, results in marked loss of proprioception, as well as “lightning-like” shooting radicular pain. The gait is typical of that in individuals with proprioceptive loss—slapping, with poor awareness of the location of the feet in space. Loss of the dorsal root ganglion neurons and dorsal roots leads to loss of reflexes and diminished pain awareness, potentially leading to repeated injuries to lower extremity joints with severe cumulative damage (Charcot joints). One of the most fascinating disorders associated with late neurosyphilis is the late dementia, referred to as general paresis of the insane, or GPI. Initial symptoms are described as personality changes with delusions and hallucinations; seizures and myoclonus may occur. Involvement tends to be frontotemporoparietal, with a slowly progressive dementia. Considered a consequence of long-standing meningitis, the pathology is rather subtle. Inflammatory changes are seen in the ventricular walls (granular ependymitis). There is brain atrophy, ventricular enlargement, and neuronal loss, with some reactive gliosis. Parenchymal inflammation is usually rather limited, without evidence of multiple infarcts—in brief, the degree of CNS dysfunction seems out of proportion to the evidence of disease activity. In recent years, however, MRI studies have sometimes demonstrated fairly widespread 20 abnormalities. Since the early 1980s, the HIV epidemic has led to a resurgence of neurosyphilis, raising new concerns about both the biology of the infection and its treatment. In HIV-infected patients, early disease and asymptomatic disease each account for about one third of the cases of 21 coexisting neurosyphilis. Of patients with early disease, one half have meningitis and one fourth have meningovascular syphilis. Of those with late-stage disease, the majority have general paresis, and a small subset has tabes. Finally, congenital infection still occurs, unfortunately. This happens most commonly during 1 early stages of maternal infection, when spirochete dissemination is still actively occurring. Treatment during the first 4 months of gestation usually protects the fetus; after that, death of the fetus or newborn, or congenital infection, can result. The common manifestations of newborn infections include “snuffles” (rhinitis due to mucocutaneous involvement) and a diffuse rash that is unusual in that it involves the palms and soles as well as skin at mucoepithelial junctions. Involvement of the liver is common, as are osteochondritis and perichondritis, most typically manifested as a “saddle nose” and “saber shins.” Unusual, centrally notched, peg-shaped upper teeth (“Hutchinson's incisors”) occur, as does frontal 22,23 bossing. IgM assays can be useful for diagnosis.
Treatment 6,24
Treatment of early syphilis remains remarkably effective with simple regimens. Primary, secondary, and latent syphilis (without CNS involvement and of less than 1-year duration) are generally treated with a single dose of intramuscular benzathine penicillin (2.4 million units). Treatment for 2 weeks with oral doxycycline (100 mg twice daily) has been recommended for patients allergic to penicillin, although few studies have evaluated this approach; 6 recommendations are usually for desensitization to penicillin if at all possible. When the nervous system is involved, high doses of intravenous penicillin are generally required (10 to 14 days, 3 to 4 million units every 4 hours). Curiously, for many years, weekly intramuscular injections of benzathine penicillin were used. This is still one of the recommended alternative regimens for neurosyphilis, even though the demonstrable levels in the CNS are 25–27 presumably reflecting the efficacy of this regimen outside subtherapeutic for T. pallidum, the blood–brain barrier and the rather low incidence of late neurosyphilis in untreated individuals. An acceptable alternative is procaine penicillin 2.4 million units intramuscularly 6 daily, with probenecid 500 mg orally four times daily for 10 to 14 days. Ceftriaxone has been suggested as an alternative in patients 28–31 allergic to penicillin and may be useful, although few studies have demonstrated its efficacy. Treatment has been particularly challenging in patients co-infected with HIV. Not only may syphilis cause considerably more serious symptoms, it may be much more difficult to 32,33 Patients who have received full courses of usually curative doses of eradicate. intravenous penicillin have developed clear-cut relapses, even32when initial treatment was at a time when the patient was not severely immunocompromised. This suggests that treatment may not eliminate these spirochetes entirely, but reduces the bacterial burden to a number that normally can be controlled by the patient's immune system.
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LYME DISEASE
Background The term Lyme disease was coined in the mid-1970s to describe a disorder affecting children living near Lyme and34Old Lyme, Connecticut, who developed what appeared to be juvenile rheumatoid arthritis. Careful epidemiological studies by Steere's group demonstrated that this disorder developed following bites by hard-shelled Ixodes ticks, particularly when the bites were followed by a slowly enlarging erythroderm. It was soon recognized that this rash was identical to the one described early in the twentieth century in the European literature, known as erythema chronicum35migrans (ECM or, more recently, EM), also known to develop following bites of Ixodes ticks. Moreover, it became apparent that those affected frequently developed all or part of a triad of neurological disorders—lymphocytic meningitis, cranial 36 neuritis, and painful radiculoneuritis.37 A virtually identical syndrome had been described in38 the 1920s by two French physicians and expanded on in 1941 by a German neurologist, becoming known as Garin–Bujadoux–Bannwarth syndrome. The 1941 report even associated the disorder with “rheumatism.” By the late 1970s, it was clear that the American syndrome bore a distinct similarity to that described in Europe, although American patients appeared to have more prominent rheumatological symptoms and European patients appeared to have more striking nervous system abnormalities. 39
In 1982, Willy Burgdorfer isolated a novel spirochete from Ixodes ticks collected on Shelter Island, New York (directly across Long Island Sound from Connecticut), and the following year it was clearly established 40,41 that this organism, named B. burgdorferi, was the agent Shortly thereafter, Eva Asbrink in Sweden identified a responsible for Lyme disease. 42 virtually identical organism as the agent responsible for European borreliosis. Subsequent studies have permitted the subdivision of this group of Borrelia (referred to collectively as B. 43 burgdorferi sensu lato) into at least three subspecies. The strain responsible for North American disease has been termed B. burgdorferi sensu stricto, whereas European disease is attributed primarily to two strains, known as Borrelia garinii, responsible for most cases of neuroborreliosis, and Borrelia afzelii, responsible for several unique cutaneous abnormalities. These strain differences are believed to be responsible for the somewhat different range of presentations seen in Europe and North America. B. burgdorferi spirochetes differ somewhat morphologically44from T. pallidum. They range in length from 10 to 30 μm and are 0.2 to 0.5 μm in diameter. Like treponemes, they are helical in shape and propel themselves through medium or tissue with flagella. Lyme disease occurs worldwide, primarily in areas in which Ixodes ticks coexist with a reservoir of infected animal hosts and potential human victims. The tick goes through a 2-year life cycle. After hatching into a larva, it will feed once, typically on a small mammal, such as a field mouse. If this mouse has previously been infected, the tick may ingest spirochetes and itself become infected. After feeding, the larva matures into a nymph, which will then have its requisite meal. As blood enters the infected tick's gut, spirochetes already present start to proliferate. Over a period of 24 to 48 hours, they migrate to the tick's salivary glands, from which they can be injected into the new host, again transmitting infection. This process typically requires 24 to 48 hours of sustained attachment and feeding—briefer encounters with ticks are highly unlikely to result in infection. The tick ultimately partakes of one last meal, this time as an adult. This typically occurs on a larger mammal, such as a deer, bear, or sheep—the species of choice giving rise to the popular name given the tick. Since the tick responsible for Lyme disease in the northeastern with deer, some control United States (Ixodes scapularis) is most closely associated 45 strategies have focused on reducing the deer population. Although this may be helpful in 46 lowering tick density, host elimination must be nearly complete. Similar strategies are less practical elsewhere. In much of the world, sheep provide the predominant large host; elimination of these commercially important animals would be impractical. On the West Coast a tick that may feed on reptiles of the United States, the principal vector is Ixodes pacificus, 46 or a broad range of other hosts. Other control strategies, such as providing rodents—the principal reservoir host—with acaricide-containing nesting material, springtime acaricide spraying to eliminate nymphs, and creation of dry barriers between wooded and residential areas, have met with varying success. In most endemic areas, ticks feed primarily during warmer months, placing human victims at greatest risk of contracting this infection from spring through autumn. The more temperate California climate leads to less seasonal variation. Interestingly, although Lyme arthritis was characterized only in the 1970s, identical cases of recurrent, nontraumatic knee arthritis were recognized years earlier in eastern Long Island,
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where this was known as Montauk knee. In fact, there is a growing body of evidence that Lyme disease was introduced to the United States when a herd of deer was brought to Long Island, New York, from Europe early in the twentieth century, an interesting counterpoint to the theory that Columbus imported syphilis to Europe from the New World. The disease appears to have spread slowly from Long Island to Connecticut, and then to contiguous regions, and is now endemic along much of the eastern seaboard of the United States from Massachusetts to Delaware. A second endemic focus exists in the upper Midwest, and a third in northern California. These three regions account for the vast majority of cases of Lyme 47 disease in the United States (Fig. 41-1).
FIGURE 41-1 Lyme disease cases in the United States, 1992 to 1998. (From
Surveillance for Lyme Disease—United States, 1992–1998. MMWR Morb Mortal Wkly Rep 49:1, 2000.)
Clinical Features General Lyme disease typically begins with a virtually pathognomic rash, known as erythema migrans, occurring at the site of the tick bite, generally developing within 1 month of infection. Although the rash is erythematous and occasionally swollen, it typically is remarkably asymptomatic. Untreated, it may expand so that it is many inches in diameter, ultimately spanning an entire limb or occupying much of the trunk (Fig. 41-2). Between one half and two thirds of adults with Lyme disease recall having such a rash; in children, who are presumably under the 48 watchful eye of a parent, the rash is seen in as many as 90 percent of infected individuals. Since the rash may occur on parts of the body not readily seen and is asymptomatic, it is not surprising that a significant number of patients have no recollection of having had a rash. Like the chancre, it can resolve spontaneously without treatment, although treatment clearly speeds resolution. Also like the chancre, the rash contains innumerable spirochetes, particularly at the leading edge. Unlike T. pallidum, however, it is possible to culture B. burgdorferi in vitro, although this requires a specialized medium that is not commonly available in most microbiology laboratories.
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FIGURE 41-2 Erythema migrans, extending across much of the lower back.
The spirochetes typically disseminate rapidly after inoculation. This secondary spread differentiates acute localized Lyme disease, analogous to primary syphilis, from early disseminated infection, analogous to secondary lues. Dissemination is often accompanied by fever and diffuse myalgias and arthralgias, identical to those seen in other bacteremias, often referred to as a “flulike” syndrome. Notably, this flulike syndrome does not include upper respiratory or gastrointestinal symptomatology. With dissemination, the rash may become multifocal, and other organ systems may become involved. Other cutaneous abnormalities occur infrequently in North America, but more commonly in Europe. Acrodermatitis atrophicans develops late in European borreliosis and consists of “tissue paper–like” atrophy of the skin, which becomes reddish-purple in hue. Borrelia lymphocytoma, a thickening of the skin due to a dense lymphocytic infiltrate, typically involving the earlobe or the areola of the breast, similarly occurs frequently in Europe but rarely in the United States. About 5 percent of patients develop cardiac conduction abnormalities (typically heart block in 49–51 an otherwise healthy young adult). Occasional cases of myositis have been described. Mild elevations of serum creatine kinase are not uncommon, although frank muscle weakness is distinctly unusual. The myositis is typically focal, presents particularly with pain 52,53 and swelling, and often occurs adjacent to areas of skin, joint, or nerve involvement. As in virtually every other known infection, a certain number of individuals become infected but do not become symptomatic or develop minor symptoms that are self-limited and indistinguishable from other summertime febrile illnesses. The precise frequency with which 5 this occurs is indeterminate, but probably is substantial. Unlike syphilis, congenital infection does not appear to be a significant problem. Despite anecdotal54,55 reports, no characteristic “congenital Lyme disease syndrome” has been Epidemiological studies have failed to demonstrate any increase in adverse identified. outcomes among women with positive serologies who have not had clinical evidence of acute infection. In a few instances, infants born to women who had experienced acute infections during pregnancy have themselves been infected, so aggressive treatment in this circumstance is appropriate. Neuroborreliosis A total of 10 to 15 percent of infected patients will develop neurological abnormalities, most 36,37,56 The commonly a lymphocytic meningitis, cranial neuropathy, or painful radiculitis. neurological syndromes can be conceptualized as preferentially affecting the peripheral nervous system or the CNS, although overlap occurs. Manifestations of each vary widely, depending on the specific site and severity of involvement. However, pathophysiological mechanisms are limited to a small number of phenomena. The CNS is often seeded early in infection (Table 41-1). Precise estimates are difficult because patients do not routinely undergo CSF examination. However, it is highly likely that 57–59 In many the CNS is infected in many individuals, but the infection clears spontaneously.
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patients, acute infection is marked by an acute lymphocytic meningitis. Headache and neck stiffness are quite variable in severity and do not correlate well with the degree of CSF pleocytosis. Typically, the CSF contains 50 to several hundred lymphocytes per cubic millimeter, with mild (50 to 150 mg/dl) elevations in CSF protein concentration. CSF glucose concentration is typically normal. Although culture of B. burgdorferi is technically possible, generally CSF cultures are positive in less than 10 percent of patients with unequivocal Lyme 60 meningitis, probably reflecting the very low number of spirochetes free in the CSF. Click here to view this table.... Although this meningitis typically is benign and manifests primarily as a headache, in children 61,62 with increased intracranial a disorder resembling pseudotumor cerebri may occur, pressure. This generally occurs either with or following Lyme meningitis and presumably relates to impaired CSF resorption, to increased vascular permeability mediated by cytokines and therefore increased pressure, or to both. On rare occasion, this has resulted in significant 63 visual impairment. Although seeding of the CNS, with a reactive meningitis, is relatively common, actual infection of the brain or spinal cord parenchyma (encephalomyelitis) is extremely rare, 64,65 In these rare probably affecting fewer than 1 in 1,000 infected, untreated individuals. individuals, there is generally clear clinical and MRI evidence of focal parenchymal 66 preferentially (probably reflecting preferential involvement, usually affecting the white matter 67,68 Patients may present with focal signs that binding of B. burgdorferi to oligodendroglia). depend on the site of involvement, although a myelopathy tends to be common.69Anecdotal case reports have described a remarkable range of neurological presentations. Establishing a causal relationship in such circumstances can be challenging. A number of case reports have suggested that, as in meningovascular syphilis, strokes70may be caused by Lyme disease, but the evidence of a causal relationship is tenuous ; if a meningovascular form of Lyme disease exists, it must be rare. Similarly, numerous reports have suggested that optic 71 neuritis may occur in rare instances of neuroborreliosis. Despite the potential severity of CNS involvement, antimicrobial therapy is usually highly effective. As with any disorder of the nervous system, scarring may leave residual deficits, but treatment in most cases will arrest any further worsening and usually results in significant clinical improvement. The final and most controversial CNS72–75 syndrome has been a chronic confusional state, In more severely affected patients, this may reflect referred to as Lyme encephalopathy. a mild form of encephalitis. In such individuals, the CSF is virtually always abnormal and brain MRI may demonstrate focal abnormalities. In others, who have prominent non-neurological involvement (most typically active, recurrent oligoarthritis), a mild confusional state occurs that is similar to that seen in patients with other chronic inflammatory disorders in whom there is a sense of chronic fatigue and malaise with blunting of intellect 76,77 An important corollary of this, however, is that it is difficult to attribute and memory. confusional states to Lyme disease in the absence of either systemic inflammation or abnormal CSF. Unfortunately, this concept has been extrapolated to describe a disorder referred to as “chronic Lyme disease.” Such patients probably fall into one of at least three groups. Rare patients with true CNS infection will fail to respond to standard courses of antimicrobial 77,78 Other individuals who therapy. In these, a second course may well end the symptoms. clearly have Lyme disease and are microbiologically cured continue to manifest chronic and nonspecific symptoms. The etiology of these symptoms is totally unclear. However, these patients do not respond to additional antibiotics, but often respond to symptomatic treatment of their symptoms with various combinations of exercise, “wellness education,” and medications including anti-inflammatory and antidepressant agents. Often, a sleep disorder is a prominent part of this syndrome and correcting this can be beneficial. Finally, this group undoubtedly includes patients whose symptoms were never caused by Lyme disease in the first place. These individuals require careful evaluation to determine the original cause of their symptoms and then appropriate treatment. It needs to be emphasized in this context that no systematic study has ever indicated that Lyme disease causes psychiatric disease, beyond 79–82 ; in fact, a systematic study of the usual difficulties associated with being chronically ill more than 900 psychiatric patients in a Lyme disease–endemic83area suggested that no specific psychiatric disorder was associated with this infection. The cranial nerves are at particular risk in Lyme disease. As in syphilis and other forms of basilar meningitis, cranial nerves VII and VIII are particularly at risk, although cranial nerves III through VI may also be involved. The lower cranial nerves are sometimes involved,
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although much less frequently. Lyme disease is one of the few disorders commonly associated with bilateral facial palsies (along with sarcoidosis and Guillain–Barré syndrome). Because these cranial neuropathies generally occur fairly early in infection and because, in the most commonly involved areas, climate dictates that ticks feed primarily from spring through autumn, patients presenting with facial palsies in summer and autumn in endemic areas should undergo serological screening for Lyme disease. Those with positive serologies should probably undergo CSF examination, with the treatment regimen depending on the results. Although lymphocytic meningitis commonly accompanies Lyme disease–associated cranial84,85 nerve palsies, the actual site of nerve involvement is probably peripheral in most 86 ; as a result, oral treatment regimens are often sufficient. cases The peripheral nervous system (Table 41-2) is probably involved even more frequently than 36,73,87–89 Most dramatic is the syndrome of Garin–Bujadoux–Bannwarth. Patients the CNS. with this syndrome often have severe radicular pain that can mimic precisely a mechanical radiculopathy. Truncal radiculopathies occur and may lead to much diagnostic confusion. The CSF is often, although not invariably, abnormal. Weakness in the same nerve root distribution may be minimal or severe. A clue to this atypical etiology of a radiculopathy may be involvement of more than one dermatome. Click here to view this table.... 89
Even more common is a milder but more diffuse polyneuropathy. This typically is not painful, but presents as a more mundane distal neuropathic sensorimotor syndrome, with both positive and negative symptoms. Some patients may develop a plexopathy or a typical mononeuropathy multiplex. Interestingly, electrophysiological and pathological studies indicate that all these syndromes are due to a mononeuropathy multiplex. Notably, in the rhesus macaque monkey, the only accurate model of human neurological Lyme disease, 90 virtually all infected animals develop a mononeuropathy multiplex that subsides over time. Finally, occasional patients have been described with a disorder resembling Guillain–Barré 91–93 Clinically, these individuals have had a rapidly progressive polyneuropathy, syndrome. with ascending paralysis, but they generally have had a more prominent CSF pleocytosis than typically occurs in Guillain–Barré syndrome, and electrophysiological changes, in most cases, have not demonstrated clear-cut evidence of demyelination.
Diagnosis Accurate diagnosis requires recognition of the clinical syndrome, a reasonable 94,95 Although much has epidemiological likelihood of exposure, and laboratory confirmation. 96,97 overall, it is comparable with been said about the inaccuracy of testing for Lyme disease, other serological testing. Although there remain technical arguments about the best antigen to use, the most useful criteria for defining positive and negative results, and the precise methodology to use, it is likely that more of the difficulty arises from misinterpretation of test results than from inaccurate ones. Laboratory diagnosis relies primarily on serological diagnosis—the demonstration of antibody in peripheral blood that adheres to B. burgdorferi. The sensitivity of microbiological culture remains low (except in erythema migrans, where it is unnecessary) and probably reflects the small number of spirochetes present in readily accessible specimens from patients. The polymerase chain reaction (PCR) assay has remained problematic, probably for the same reason (in addition to contamination-related issues and false-positive results). Antigen detection methods are commercially available, but lack reproducible validation in 98,99 the scientific but this literature. Immune complexes containing Borrelia antigens have been described, observation, similarly, has not been widely reproduced. Hence, most laboratories rely on enzyme-linked immunosorbent assays (ELISAs) to quantitate immunoreactivity. In addition to the technical limitations listed previously, several particular problems confront serological testing for Lyme disease. First, the disease is focally endemic. In highly endemic areas, such as areas of Long Island, 10 percent or more of the population may have been exposed. In contrast, in nearby Manhattan, there were more cases of malaria in 1998 than of 100 Lyme disease. This highly varying background prevalence has a major effect on the positive and negative predictive values of test results, which depend on the background prevalence. (For example, in areas with a Lyme disease prevalence of 1 in 100,000 and a statistically defined negative cutoff of 3 standard deviations, 1 sample in 1,000 will be a false positive, but only 1 in 100,000 will be a true positive.) Second, as with any antibody-based testing, it must be remembered that it takes several weeks or months to develop a detectable antibody response in blood. Thus, negative results are common at the time of the erythema migrans, but as with the syphilitic chancre, the rash by itself is sufficiently diagnostic to
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mandate immediate antibiotic treatment. Third, unlike other serological tests, most clinicians rely on a single Lyme disease ELISA value rather than on comparing acute and convalescent titers. This is reasonable in syphilis, where screening reaginic tests are typically positive only during active infection, and is understandable insofar as there is a desire to treat Lyme infection as soon as possible. However, it makes test interpretation difficult in patients who have had prior infection and have a persistently elevated titer. As in most infections, the immune system usually continues to generate detectable antibodies for an extended period after the infection has resolved, making the relevance of the infection to current symptoms difficult to judge. Finally, as with most serological 101 tests, some cross-reactions occur. An effort to address this has produced using a two-step test procedure, comparable with that used in HIV infection,102 even more confusion. First, the criteria for positive and negative Western blots (Table 41-3) were defined almost entirely in individuals with positive ELISA results; therefore, these measures cannot necessarily be applied in individuals with negative ELISA results. Second, the criteria were derived statistically to provide very high specificity, sacrificing considerable sensitivity. Therefore, a negative Western blot does not exclude Lyme disease, but it is one more bit of data that must be considered in the diagnosis. Click here to view this table.... As in syphilis, spinal fluid studies can be extremely useful, but they also are the source of considerable confusion. Most, if not all, patients with active CNS infection will have elevations in the CSF white blood cell count, protein concentration, or both. Chronic infection is often accompanied by increased local production of antibodies, resulting in an increased relative CSF IgG concentration and even oligoclonal bands. In most acute cases (about 90%) and in many patients with chronic CNS Lyme disease (at least 50% and possibly more), synthesis of specific anti–B. burgdorferi antibodies in the CNS can be demonstrated by appropriately 72,73,103,104 comparing concentrations of specific antibody in CSF and serum. Simple measurement of antibody concentration in the CSF alone can be very misleading in individuals with blood–brain barrier breakdown, CNS inflammation from other causes, or positive peripheral blood Lyme disease serologies, as discussed previously in considering CSF serologies in syphilis.
Treatment and Outcome As with any infection, prevention is usually simpler than treatment. Infected ticks occur in relatively restricted locales, and avoidance is therefore a feasible strategy. Those who cannot or choose not to can limit their risk by wearing light-colored clothing that covers as much of the body as possible, making it easier to spot the very small, responsible ticks. Because ticks must be attached and feeding for 24 to 48 hours before infection is likely, a careful tick check at the end of the day is highly effective. Attached ticks should be removed by placing a fine forceps between the tick and the skin, and gently pulling back. Efforts to suffocate ticks in petroleum products or burn them with a lit cigarette are counterproductive. Use of insecticides-acaricides can help, but repeated exposures, particularly in children and with higher-concentration products, can lead to significant systemic absorption and can be neurotoxic. A vaccine was available but has been withdrawn from the market, primarily 105,106 because of poor sales. Antimicrobial therapy is highly effective, regardless of disease duration and severity. Popular mythology about the organism hibernating invisibly, only to resurface years later, is an intriguing theoretical possibility, but from a practical perspective is irrelevant. Patients with the characteristic rash should be treated immediately with oral medication (Table 41-4), regardless of the results of serological testing. Those with more disseminated disease may 107 108 and there are excellent data that Lyme arthritis and well respond to oral regimens, 109 86 meningitis will also usually respond well to oral regimens, particularly with doxycycline. As a practical matter, most U.S. practitioners are reluctant to use oral regimens when there is any evidence of CNS involvement (particularly CSF abnormalities), and such patients are 110 almost always treated with parenteral third-generation cephalosporins (Table 41-4). The optimal duration of treatment remains unclear. No randomized 111,112 trial has demonstrated any However, anecdotal advantage of prolonging parenteral treatment beyond 2 weeks. evidence from all major centers treating patients indicates that this is occasionally insufficient. As a result, courses of 3 to 4 weeks are routinely used and, under exceptional circumstances, repeated. Despite common practice at some centers, there are no data to support longer courses or the use of more toxic antimicrobials. Several studies have now addressed the role of longer courses of antimicrobial therapy in patients with continuing but 113,114 nonspecific symptoms; no sustained benefit was found over conventional treatment.
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Two studies from Lyme disease–endemic areas should be highly reassuring. Systematic case-control studies from Connecticut and Nantucket Island, Massachusetts, both areas highly endemic for Lyme disease, provide clear evidence that long-term outlooks of treated patients are excellent. Although many patients who have been diagnosed as having Lyme disease and have undergone treatment appear to develop the same transient symptoms as do normal control subjects, they attribute them to Lyme disease and therefore find them more distressing. However, by all objective measures, the treated patients appear indistinguishable from healthy, uninfected individuals. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 42 Tuberculosis of the Central Nervous System JOHN M. LEONARD •
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MENINGITIS Pathogenesis Pathology Clinical Presentation Symptoms and Signs Atypical Features Tuberculous Meningitis and HIV Infection Diagnosis Cerebrospinal Fluid Examination Neuroradiological Evaluation Differential Diagnosis TUBERCULOMA SPINAL TUBERCULOUS ARACHNOIDITIS THERAPY Antituberculous Chemotherapy Recommended Regimen Toxicity Adjunctive Therapy Corticosteroids Surgery Paradoxical Worsening on Therapy Prognosis and Outcome CONCLUDING COMMENT
Tuberculosis in all its forms remains a challenging clinical problem and a public health issue of considerable magnitude. The World Health Organization (www.who.int/mediacentre/factsheets/fs104/en/) has estimated that 14.6 million persons in the world have active tuberculosis and about 9 million new cases arise each year. Rates of new infection vary widely from country to country in relation to socioeconomic conditions; for example, the incidence is approximately 5 cases per 100,000 population in the United States, compared with rates in excess of 200 cases per 100,000 in some developing countries of Asia and Africa. The incidence of tuberculosis in the United States has declined steadily over the past 50
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years, except for the period 1985 to 1992 when an estimated 64,000 “excess cases” of tuberculosis were diagnosed. This was attributed to several factors: the expanding human immunodeficiency virus (HIV) epidemic, the increase in the prevalence of poverty and homelessness, 1–3 and the immigration of persons from high-prevalence countries of Asia and South America. For 2005, a total of 14,093 new cases (4.8 cases per 100,000 population) were reported in the3 United States. The rate was 8.7 times higher among foreign-born than U.S.-born persons. Tuberculosis of the central nervous system (CNS) accounts for 1 to 2 percent of all cases of tuberculosis and about 8 percent of all forms of extrapulmonary infection in immunocompetent individuals. Although pulmonary tuberculosis in the United States has been on the decline, the number of reported cases of meningeal tuberculosis has changed little over the past decade, about 180 to 200 per year, and the case fatality ratio remains high 4,5 at 15 to 40 percent. CNS tuberculosis may be considered as comprising three clinical categories: meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis. These three forms of CNS infection are encountered with about equal frequency in regions of the world where the incidence of tuberculosis is high and the prevalence of postprimary dissemination is common 6,7 among children and young adults. In Europe and North America, extrapulmonary infection is seen primarily in adults with reactivation disease, and the dominant CNS category is meningitis. MENINGITIS
Pathogenesis The now classic studies of Rich and McCordock demonstrated that meningeal tuberculosis results from rupture into the subarachnoid space of an adjacent older, caseous focus of 8 infection situated within the substance of the brain, meninges, or adjacent bone. In a meticulous autopsy series, one or more such foci were found in 77 of 82 cases of tuberculous meningitis. These critically located tuberculous foci (tubercles) are established in the brain and other tissues during the bacillemia that follows primary infection or late-reactivation tuberculosis elsewhere in the body. The number, character, and location of lesions in the brain vary from case to case. The proximity to the surface of the brain, rapidity of progression, and rate at which encapsulation follows acquired immune resistance determines the clinical consequence. The chance occurrence and progression of a suitably located subependymal tubercle is the critical event in the development of tuberculous meningitis. The widespread and dense distribution of infectious foci in progressive miliary tuberculosis greatly increases the chance that a juxtaependymal tubercle will be established and from this 9 critical location break through into the subarachnoid space. This is the usual sequence in childhood tuberculous meningitis, as infants and young children are especially susceptible to progressive hematogenous dissemination after primary infection. Adults also develop CNS infection in association with clinically apparent progressive miliary disease, or from other less apparent or entirely hidden foci of chronic organ tuberculosis as well. Reactivation of latent foci with resultant secondary hematogenous dissemination may be intermittent or chronic and progressive. In either circumstance, the spread of bacilli to distant organs produces scattered tubercles of varying size and encapsulation, including some adjacent to the subarachnoid space. Subependymal foci arising in this manner may remain quiescent, harboring bacilli for months or years, having the potential to destabilize into the subarachnoid space as a result of local injury or general depression in host immunity. Advanced age, alcoholism, drug-induced immunosuppression, lymphoma, and acquired immunodeficiency syndrome (AIDS) all impair cellular immunity and, in persons with smoldering chronic organ tuberculosis, lead to the syndrome of reactivation and late generalized tuberculosis. In an excellent summary of this syndrome, careful postmortem examination revealed meningeal involvement in 54 percent of 10 patients studied. A significant proportion of adult cases have no demonstrable extracranial infection or apparent defect in host immune function. Occasionally, there is a history of head trauma some weeks or months prior to the onset of symptoms, suggesting that intracranial caseous foci may be destabilized by physical factors.
Pathology The pathological changes observed in the CNS result from an intense hypersensitivity reaction induced by the presence of organisms and associated antigenic material in the substance of the brain and subarachnoid space. Three features dominate the pathological
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process and account for the clinical manifestations: (1) proliferative, predominantly basilar arachnoiditis, (2) vasculitis of arteries and veins traversing this exudate, and (3) disturbance 8,11 of cerebrospinal fluid (CSF) circulation or resorption leading to hydrocephalus. Proliferative arachnoiditis is most marked at the base of the brain and, in a matter of days, produces a thick, gelatinous exudate extending from the pons to the optic chiasm. With chronicity, the optochiasmic zone of arachnoiditis comes to resemble a fibrous mass encasing adjacent cranial nerves and penetrating vessels. Vasculitis with resultant thrombosis and hemorrhagic infarction may develop in vessels that traverse the basilar or spinal exudate or are located within the brain substance itself. The vascular inflammatory reaction is initiated by direct invasion of the adventitia by mycobacteria or by secondary extension of the adjacent arachnoiditis. An early polymorphonuclear reaction followed by infiltration of lymphocytes, plasma cells, and macrophages leads to progressive destruction of the adventitia, disruption of elastic fibers, and extension of the inflammatory process to involve the intima. Eventually, fibrinoid degeneration in small arteries and12veins produces aneurysms, multiple thrombi, and focal hemorrhage in some combination. Depending on the location and extent of the vasculitis, a variety of stroke syndromes may 13 result. Involvement of perforating vessels to the basal ganglia and pons can produce movement disorders or simulate lacunar infarcts. Multiple lesions are common, and areas of ischemic injury most frequently involve the basal ganglia, cerebral cortex, pons, and cerebellum. In a review of the pathological features of intracranial tuberculous vasculitis, Poltera found phlebitis in 22 cases and varying degrees of arteritis in 20 of 27 cases studied, including 8 patients with an obstructive tuberculous thrombophlebitis associated with 14 hemorrhagic cerebral infarction. Intracranial vasculitis is a common feature of autopsy studies and a major determinant of residual neurological deficits in those recovering after therapy. Extension of the inflammatory process to the basilar cisterns may impede CSF circulation hydrocephalus in most cases that have been and resorption, leading to communicating 15 symptomatic for longer than 2 to 3 weeks. Less frequently, obstruction of the aqueduct develops from contraction of exudate surrounding the brainstem, inflammation of the ependymal lining of the ventricles, or a strategically placed brainstem tuberculoma. In far advanced cases, increased intracranial pressure can cause brainstem compression and tentorial herniation.
Clinical Presentation Symptoms and Signs Typically, the illness begins with a prodrome of insidious onset characterized by malaise, lassitude, personality change, intermittent headache, and low-grade fever. This is followed, usually within 2 to 3 weeks, by more prominent neurological symptoms and signs, such as meningismus, protracted headache, vomiting, confusion, cranial nerve palsies, and long-tract signs. The pace of illness may accelerate rapidly at this stage; confusion gives way to stupor and coma, seizures may occur, and multiple cranial nerve palsies and hemiparesis or 16–18 In most untreated cases, death supervenes within hemiplegia are common in late stages. 5 to 8 weeks of the onset of illness. The occasional patient follows a more indolent, slowly progressive course over weeks or months. The symptoms and signs compiled in a well-studied series are presented in Table 42-1. In children, the condition is characterized early by irritability, loss of interest in play, restlessness, and anorexia; headache 19 is less common and vomiting often much more prominent, especially in the very young. Generalized seizures are more common in children and are apt to be an early or presenting symptom. Click here to view this table.... For purposes of prognosis and therapy, it is useful to categorize patients on presentation, based on mental status and focal neurological signs. Stage 1 comprises patients who are conscious and rational, with or without meningismus but with no focal neurological signs or evidence of hydrocephalus; stage 2 patients exhibit lethargy and confusion and may have mild focal neurological signs such as cranial nerve palsy and hemiparesis; stage 3 illness includes signs of advanced illness such as 7delirium, coma, seizures, multiple cranial nerve palsies, dense hemiplegia, and paraplegia. The clinical stage on presentation is related to duration of illness, although some patients progress rapidly to advanced stages within a few days. The response to treatment is much influenced by the clinical stage at the time therapy is initiated.
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Atypical Features In some adults, the prodrome may be a slowly progressive dementia over months or even years, characterized by personality change, social withdrawal, loss of libido, and memory deficits. At the other end of the spectrum, patients may present with an acute, rapidly progressive meningitic syndrome indistinguishable from pyogenic bacterial meningitis. At times, this accelerated form is superimposed on a chronic dementing illness. Seizures and focal neurological disturbances such as cranial nerve palsy or hemiparesis may occur early and dominate the clinical presentation. Of the cranial nerves, the sixth is the most commonly involved, followed by the third and the fourth. Instances of internuclear ophthalmoplegia have been observed, characterized by adduction paresis of one or both eyes on lateral gaze, often 20 with nystagmus of the abducting eye and failure of convergence. Occasionally the symptoms and signs of hydrocephalus (headache, papilledema, diplopia, and visual disturbance) precede the signs of meningeal irritation. Udani and Dastur have described an encephalitic course in children characterized by stupor, 21 coma, and convulsions without signs of meningitis. The CSF may show a mild pleocytosis and protein elevation or may be entirely normal. This syndrome of “tuberculous encephalopathy” is also encountered occasionally in adults. Tuberculous Meningitis and HIV Infection Co-infection with HIV has been reported in 21 percent of patients with extrapulmonary 22 tuberculosis in the United States. Although CNS tuberculosis has not yet become a widespread problem in persons with AIDS, there are reports to23–26 indicate that meningitis occurs Among 52 AIDS patients with greater frequency in HIV patients with active tuberculosis. with tuberculosis seen by Bishburg and associates over a 3-year period, 10 had CNS 23 disease. The clinical spectrum included meningitis, tuberculoma, and cerebral abscess. In a study of 455 HIV-positive patients with tuberculosis, 10 percent developed meningitis compared with 2 percent of HIV-negative patients, and HIV-positive patients accounted for 59 24 percent of cases of tuberculous meningitis seen during the study period. Dube and colleagues compared the clinical features, laboratory findings, and in-hospital mortality rates in patients having tuberculous meningitis with or without HIV infection. Intracerebral tuberculomas were more common in the HIV-infected group (60% compared with 14%); otherwise, co-infection with HIV did not alter the clinical manifestations, CSF findings, or 25 response to therapy.
Diagnosis Few problems in medicine so critically challenge the physician's diagnostic acumen and clinical judgment as the patient with CNS tuberculosis. Once the possibility of tuberculous meningitis has been considered, the central task is rapid and thorough assessment of supporting evidence followed by a prompt decision regarding empirical therapy. Clues to the diagnosis include a positive family history of tuberculosis, recent exposure to others with active tuberculosis (especially in cases involving children and immunosuppressed adults), a history of recent head trauma, and alcoholism. Evidence of active tuberculosis elsewhere in the body, observed in 20 to 70 percent of cases, provides the most reliable basis for the presumptive diagnosis in patients with CNS disease. A meticulous physical examination with careful attention to abnormal findings is essential. Significant but easily overlooked clues include lymphadenopathy, spinal and other joint lesions, splenomegaly, scrotal mass, and draining fistulas. In patients with generalized (miliary) infection, careful funduscopic examination often shows choroidal tubercles, a valuable diagnostic clue. These are multiple, 27 ill-defined, raised yellow-white nodules (granulomas) of varying size near the optic disc. Abnormalities on chest radiography, including miliary infiltrate and, less commonly, hilar adenopathy or upper lobe nodular infiltrates, occur in most childhood cases and in approximately 50 percent of adults. Patients with tuberculous meningitis may exhibit mild anemia and leukocytosis, but often the complete blood count and even the erythrocyte sedimentation rate are entirely normal. Hyponatremia and other biochemical features 28 of inappropriate secretion of antidiuretic hormone have been observed in some cases. The tuberculin skin test is of limited utility. A positive skin test is nonspecific but supports the diagnosis; however, the reaction is commonly absent in all forms of active tuberculosis. Cerebrospinal Fluid Examination
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Careful examination of the CSF is the key to diagnosis in most instances. The opening pressure is usually elevated, the fluid is clear or “ground glass” in appearance, and, on standing, a delicate, weblike clot often forms. The typical CSF formula shows elevated 29 protein and low glucose concentrations as well as mononuclear pleocytosis. The CSF protein concentration ranges from 100 to 500 mg/dl in most patients, is less than 100 mg/dl in 25 percent, and is more than 500 mg/dl in 10 percent. Patients with subarachnoid block may exhibit extremely high protein concentrations, in the range of 2 to 6 g/dl, associated with xanthochromia and a poor prognosis. The CSF glucose concentration is usually low, being less than 45 3mg/dl in approximately 80 percent of cases. The CSF cell count is between 100 3 than 100 cells/mm in approximately 15 percent, and and 500/mm in most patients, less 3 between 500 and 1,500 cells/mm in 20 percent. Although the characteristic cellular reaction is lymphocytic, early in the course of meningitis the findings are often atypical with only a few cells, a mixed pleocytosis, or polymorphonuclear predominance. Cases with an atypical cellular reaction at the onset evolve in the direction of more typical findings on repeat CSF examination. Misinterpretation of this sequence as improvement or as response to antibacterial therapy (when an erroneous diagnosis of pyogenic meningitis is being entertained) can have serious consequences. On occasion, an initial mononuclear pleocytosis may briefly change in the direction of polymorphonuclear predominance when therapy is initiated (“therapeutic paradox”), a change that may be associated with clinical deterioration. Bacteriology
Specific diagnosis rests on the demonstration of Mycobacterium tuberculosis in the CSF. Cultures are positive in approximately 75 percent of cases but require weeks for detectable growth. Consequently, the careful examination of a stained smear of CSF for acid-fast organisms is the most effective means of making the diagnosis promptly. The importance of repeated careful examination and culture of CSF specimens cannot be overemphasized. In one carefully defined series, the incidence of a positive smear was 37 percent on examination of the first specimen but increased to 87 percent when up to four serial CSF specimens were examined, even though some patients had already received antituberculous 17 therapy before the first smear was positive. In a more recent prospective study, designed specifically to evaluate the effectiveness of careful bacteriological technique, acid-fast bacilli were seen on smear in 77 of 132 adult patients (58%) and cultured from 94 of 132 (71%). 30 The overall sensitivity of smear and culture was 82 percent. It is recommended that a minimum of three CSF samples be submitted for smear and culture. It is not necessary to defer treatment as the yield remains high for several days after the institution of antituberculous chemotherapy. The sensitivity17,30,31 of the smear for acid-fast : bacilli can be optimized by attention to the following guidelines 1. Acid-fast organisms can be demonstrated most readily in a smear of the clot or sediment. 2. It is best to use the last fluid removed at lumbar puncture, taking 10 to 15 ml. 3. If no clot forms, the addition of 2 ml of 95 percent alcohol (so that the alcohol mixes with only the upper portion of the CSF) gives a heavy protein precipitate that, on centrifuging, carries bacilli to the bottom of the tube. 4. Of the centrifuged deposit of CSF, 0.02 ml should be applied to a glass slide in an area not exceeding 1 cm in diameter and stained by the standard Kenyon or Ziehl–Neilsen method. 5. Between 200 and 500 high-power fields should be examined (approximately 30 minutes), preferably by more than one observer. The use of fluorescent staining as a rapid screening device is advantageous, but simultaneous staining with the Ziehl–Neilsen or Kenyon stain is also advisable in view of the importance of diagnostic accuracy. Nucleic Acid Amplification Technique
A promising new diagnostic approach has been the nucleic acid–based amplification test that relies on the polymerase chain reaction (PCR) for the rapid detection of specific bacterial 32 DNA in clinical specimens. Although simple, rapid, and appealing in principle, the reliability of PCR for the identification of mycobacteria is not well established, primarily because of problems with methodology and lack of an effective system for monitoring sensitivity and
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specificity. In a blind comparison study of seven laboratories, the rate of false-positive results ranged from333 to 20 percent, and levels of sensitivity also varied widely among different participants. With respect to PCR testing of CSF for mycobacteria, there are few studies comparing PCR with Ziehl–Neilsen stains and cultures in large series of patients with suspected or confirmed infection. In one such study reported from South Africa, the sensitivity of PCR testing was 60 percent in 15 patients classified as having definite or probable 34 tuberculous meningitis. In a recent meta-analysis of nucleic acid amplification tests used for the diagnosis of tuberculous meningitis, the pooled sensitivity was 56 percent and the 35 specificity was 98 percent. CSF should be submitted for PCR testing whenever clinical suspicion is sufficiently high to warrant empirical therapy and initial stains for acid-fast bacilli are negative, recognizing that a negative PCR test result neither excludes the diagnosis nor obviates the need for continued treatment. Neuroradiological Evaluation Computed tomography (CT) and magnetic resonance imaging (MRI) have greatly enhanced understanding of pathogenesis, clinical assessment, and management of all forms of CNS 36 tuberculosis. CT can define the presence and extent of basilar arachnoiditis, the presence of cerebral edema and infarction, and the presence and course of hydrocephalus. In two large, community-based series from India and Turkey, hydrocephalus was demonstrated in 75 percent of patients, basilar meningeal enhancement in15,37 38 percent, Hydrocephalus cerebral infarcts in 15 to 30 percent, and tuberculomas in 5 to 10 percent. was associated with a longer duration of symptoms before treatment and was seen more often in children than adults. CT findings were of prognostic significance and useful to monitor the effectiveness of adjunctive therapy such as corticosteroids and neurosurgical shunting procedures. In the series from India, patients with an entirely negative scan recovered completely on antituberculous therapy; those with mild or moderate basilar exudate showed some improvement with early ventriculoatrial shunting; and those with a 15 severe degree of basilar exudate did not do well even with shunt surgery. The following observations can be derived from a review of several CT studies to date. In patients presenting with tuberculous meningitis, approximately 30 percent of those with stage 1 and 8 percent with stage 2 have a normal scan. Virtually all stage 3 patients have abnormalities, including hydrocephalus. Accordingly, a normal contrast-enhanced CT scan in a drowsy patient makes tuberculous meningitis unlikely. Serial studies have demonstrated that hydrocephalus alone is uncommon and carries a good prognosis. However, hydrocephalus combined with marked basilar enhancement is indicative of advanced meningitis and implies a poor prognosis. Marked basilar enhancement, indicative of an extensive basilar meningitis, is often associated with vasculitis and portends serious risk of 37,38 basal ganglia infarction. MRI is the preferred imaging modality for defining lesions of the basal ganglia, midbrain, and 39,40 In a careful prospective study of 27 childhood cases, including clinical, brain-stem. radiological, and pathological findings, Schoeman and co-workers found MRI superior to CT in delineating focal infarcts of the basal ganglia and diencephalon and in defining the 39 presence and extent of associated lesions in the brainstem. The character and severity of brainstem abnormality, as defined by MRI, correlated well with clinical evidence of brainstem disease. Differential Diagnosis Differential diagnosis of CNS tuberculosis includes a variety of inflammatory, vascular, and neoplastic conditions of the CNS. The classic clinical presentation of granulomatous meningitis—fever, encephalopathy, meningeal signs, and a CSF formula characterized by lymphocytic pleocytosis, lowered glucose concentration, and high protein content—can be caused by tuberculosis, fungal infection, syphilis, and brucellosis. The syndrome is also encountered among patients with parameningeal suppurative foci related to sphenoid sinusitis, brain abscess, and endocarditis. Patients with herpes simplex and mumps encephalitis pose the greatest challenge because they may present with fever, rapid neurological deterioration, and mild lowering of the CSF glucose concentration, as discussed in Chapter 44. Careful evaluation for tuberculosis is warranted in every patient suspected of any of the other diagnoses listed in Table 42-2. Click here to view this table.... Error or delay in diagnosis may result from atypical CSF findings, such as minimal
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abnormalities of glucose and protein concentration or predominance of neutrophils. Repeat examination of the CSF frequently shows a declining glucose level, an increasing protein concentration, and a shift to mononuclear predominance. It is helpful to bear in mind that CSF protein concentrations in excess of 150 mg/dl are rarely seen in viral meningitis and 42 should always raise suspicion of tuberculous or fungal infection. TUBERCULOMA Tuberculomas are conglomerate caseous foci in the substance of the brain that develop from deep-seated tubercles acquired during a recent or remote episode of hematogenous dissemination. Centrally located, active lesions may reach considerable size without 8,43 Under conditions of poor host resistance, this process may result in producing meningitis. focal areas of cerebritis or frank abscess formation, but the more usual course is coalescence of caseous foci and fibrous encapsulation (tuberculoma). If they are defined radiologically as lesions apparent on CT or MRI, then clinically silent single or multiple granulomata are seen commonly in cases of tuberculous meningitis and often in miliary tuberculosis without meningitis. The characteristic CT finding is a nodular enhancing lesion 44,45 The MRI appearance depends on the stage of with a central hypodense region. tuberculoma: focal cerebritis is manifest by nonspecific edema and ill-defined enhancement, whereas a caseating lesion typically shows central hypointensity and peripheral enhancement on T2-weighted images. It is now evident that macroscopic parenchymal lesions are more common in miliary tuberculosis and tuberculous meningitis than previously suspected. These lesions usually disappear with medical therapy, although cases have been reported in which tuberculomas developed and progressed early during the course of antituberculous 46–48 therapy. In contrast to lesions demonstrated by CT or MRI but producing no symptoms, clinical tuberculomas presenting as intracranial mass lesions are distinctly uncommon in the West. However, in India and other parts of Asia, especially among children, intracranial 49 tuberculomas account for 20 to 30 percent of all intracranial space-occupying lesions. The usual clinical picture is that of a space-occupying lesion in the brain; symptoms of systemic illness and meningeal inflammation are usually lacking. Approximately 30 percent have 49–51 evidence of tuberculosis outside the CNS. The diagnosis and management of intracranial tuberculoma have been greatly advanced by the availability of CT scanning. Contrast enhancement is essential. Early stages are characterized by low-density or isodense lesions, often with edema out of proportion to the mass effect and little encapsulation. At a later stage, well-encapsulated tuberculomas appear 45,52 CT is especially as isodense or hyperdense lesions with peripheral ring enhancement. helpful in assessing the presence of cerebral edema and the risk of herniation and for 50 monitoring response to medical therapy. In areas of the world where intracranial tuberculoma is a common cause of space-occupying lesions of the brain, a presumptive etiological diagnosis is often made based on clinical and epidemiological considerations. Surgical intervention for diagnostic and therapeutic purposes has, in the past, often been complicated by severe, fatal meningitis. Although pretreatment with antituberculous chemotherapy now effectively reduces the risk, conservative medical 49,50,53 Surgery for purposes other management is preferable to early surgical intervention. than diagnosis may be required when lesions are critically located and produce obstructive hydrocephalus or compression of the brainstem. Corticosteroids aid in selected cases in which cerebral edema out of proportion to the mass effect contributes to altered mental 50 status or focal neurological deficits. SPINAL TUBERCULOUS ARACHNOIDITIS Tuberculous arachnoiditis or tuberculoma may arise at any level of the spinal cord in association with breakdown of a “Rich” focus in the cord or meninges or by extension from an adjacent area of inapparent spondylitis. The inflammatory process is usually confined locally, gradually producing partial or complete encasement of the spinal cord in a gelatinous or 43 fibrous exudate. In other cases, tuberculomas of the extradural, intradural, or intramedullary space may produce symptoms of a local tumor. Patients usually present with some combination of nerve root and cord compression signs secondary to impingement by the advancing arachnoiditis. Wadia and Dastur, in an exhaustive analysis, used the term radiculomyelopathy, emphasizing that the clinical manifestations are more neurological than infectious, protean in nature, and associated with an ascending54or transverse radiculomyelopathy of variable pace at single or multiple levels. Most of their cases evolved within 2 months; some reached maximum severity within 2 to 5 days and others developed over years. Symptoms include pain, hyperesthesia, or paresthesias in the distribution of the
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nerve root; a lower motor neuron paralysis; and bladder or rectal sphincter incontinence. On occasion, the granulomatous mass or abscess may be confined largely to the epidural space, producing symptoms of cord compression with no evidence of meningeal inflammation. An associated vasculitis may result in thrombosis of the anterior spinal artery and infarction of the cord. Regardless of whether the underlying lesion is localized to the epidural, meningeal, or extramedullary levels, all forms of tuberculous spinal arachnoiditis may cause subarachnoid block 41,55 characterized by high concentrations of protein in the CSF with or without a cellular response. The diagnosis of spinal tuberculous arachnoiditis should be considered in the patient with any combination of the following clinical and laboratory features: subacute onset of spinal or nerve root pain; rapidly ascending transverse myelopathy or multiple-level myelopathy; increased CSF protein concentration and cell count; extensive filling defects on myelography or signs of arachnoiditis or epidural space infection by MRI, usually with a spinal block; and evidence of tuberculosis elsewhere in the body. Surgical intervention and tissue biopsy are often required for diagnosis. Some patients progress from an initial spinal syndrome to tuberculous cranial meningitis terminally. THERAPY
Antituberculous Chemotherapy The decision to begin antituberculous chemotherapy must be made promptly, often based on clinical suspicion rather than direct evidence of mycobacterial infection because prognosis depends greatly on the clinical stage at which treatment is initiated. More harm results from delay, even of only a few days, than from inappropriate therapy so long as efforts are continued to confirm the diagnosis. There are no randomized trials to establish the optimal drug combination, dose, and duration of treatment for tuberculous meningitis. The principles are those that govern the 56 management of pulmonary tuberculosis. In meningeal tuberculosis, the number of organisms is small and the challenge is to deliver bactericidal drugs to the site of infection, beginning as promptly as possible in order to forestall the tissue damage that results from the host response to infection. On theoretical grounds, there is reason to expect that combination drug therapy should enhance sterilization of the CSF; however, the primary goals of multiple drug therapy are to cover the possibility of drug resistance, reduce the risk of emerging resistance during therapy, and treat more effectively any non-CNS foci of disease. The “first-line” drugs are listed here, followed by the recommended regimen. Isoniazid, rifampin, and pyrazinamide are bactericidal, can be administered orally, penetrate inflamed 57 meninges, and achieve CSF concentrations required for activity against sensitive strains. Isoniazid is the cornerstone of treatment. It diffuses readily into CSF and achieves concentrations many times that required for bactericidal activity, in the presence or absence of meningeal inflammation. The recommended dose for children is 10 mg/kg daily; for adults, it is advisable to begin with 10 mg/kg daily (maximum 600 mg) until a favorable course has been established and then adjust to the usual adult dose of 300 mg daily. Pyridoxine, 25 to 50 mg daily, should be given concurrently to avoid the neurological complications of isoniazid-induced pyridoxine deficiency. An injectable form of isoniazid is available when this drug cannot be administered by mouth or nasogastric tube. It may be administered by 58 intramuscular injection or intravenous bolus infusion (300 mg over 5 to 10 minutes). Rifampin is active early against rapidly dividing organisms but achieves reliable CSF concentrations only in the presence of meningeal inflammation. Because rifampin is active also against semidormant organisms, its major contribution may relate to the resolution of residual foci in the CNS and elsewhere in the body. The daily dose in children and adults is 10 mg/kg (maximum 600 mg). An intravenous formulation of rifampin is available on a “compassionate use” basis58from the manufacturer. It is administered at usual dose (600 mg in adults) in 500 ml saline. Studies of pulmonary tuberculosis have demonstrated that the addition of pyrazinamide (25 to 35 mg/kg) to regimens that include isoniazid and rifampin produces a more powerful antituberculous effect without increasing the incidence59of hepatotoxicity when the duration of pyrazinamide therapy is restricted to 2 months or less. CSF penetration is excellent in the presence or absence of inflammation, and the drug is highly active against intracellular mycobacteria. It is recommended that pyrazinamide be included in the treatment regimen for meningitis during the first 2 months of therapy. In children, the daily dose is 15 to 20 mg/kg (maximum 2,000 mg). In adults, the dose is based on weight: 40 to 55 kg, 1000 mg; 56 to 75
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kg, 1,500 mg; 76 to 90 kg, 2,000 mg. With the advent of other effective, less toxic agents, there is less dependence on streptomycin than in the past, when its addition to isoniazid was designed to enhance sterilization and reduce the risk of clinical relapse from resistant organisms. Even in the presence of inflamed meninges, streptomycin penetrates the CSF poorly and is most efficacious when intramuscular (1 g/day) is combined with intrathecal (50 mg in 10 to 15 ml 60 saline) administration. Streptomycin merits consideration in selected situations such as limited access to alternative drugs, suspicion of multidrug resistance, management of patients in whom other combinations are obviated by hepatotoxicity, and when clinical deterioration (stage 2 to stage 3) proceeds rapidly despite therapy with a more conventional regimen (see later). Ethambutol is a weak drug that reaches the subarachnoid space in moderate concentration. Its major toxicity, optic neuritis, occurs in as many as 3 percent of patients receiving 25 mg/kg but is rare at the recommended daily dose of 15 mg/kg. When ethambutol is used, it61is advisable to check visual acuity, red-green color vision, and visual fields if possible. Recommended Regimen Guidelines published by American and British societies and by the Centers for Disease Control and Prevention recommend an initial intensive phase of treatment with four drugs for 2 months, followed by a62,63 prolonged continuation phase with two drugs for 7 to 10 months for The initial four-drug regimen includes isoniazid, rifampin, drug-sensitive infection. pyrazinamide, and either ethambutol or streptomycin. Isoniazid and rifampin alone are given during the continuation phase if the isolate is fully susceptible or the risk of drug resistance is small and the clinical course satisfactory. In the usual case of drug-sensitive infection, the recommended total duration of therapy is 9 to 12 months. If pyrazinamide is omitted or not tolerated, treatment should be extended to 18 months. The possibility of drug-resistant infection should be anticipated in high-risk individuals such as those from areas of the world where tuberculosis is endemic, the homeless, and in those having received previous antituberculous drugs or with known exposure to persons harboring resistant organisms. The impact on therapeutic outcome is variable, depending on whether 64 the isolate is resistant to isoniazid or rifampin or both. The best drug combination for resistant infection is uncertain and to some extent depends on the particular sensitivity pattern of a given case. The second-line drugs ethionamide and cycloserine penetrate well and may be useful. The fluoroquinolones have good activity against mycobacteria. In addition to streptomycin, other aminoglycides such as kanamycin and amikacin are effective and have 65 been given for this purpose by intrathecal injection. The duration of treatment should be extended to 18 to 24 months. Toxicity The rate of hepatotoxicity in adults receiving isoniazid is on the order of 1 percent and doubles with the addition of rifampin. Rifampin is a powerful inducer of hepatic P-450 oxidative enzymes, which, in turn, accelerate the conversion of isoniazid to toxic 66,67 Alcoholic liver disease does not modify the indications for isoniazid and metabolites. rifampin. When hepatic toxicity develops during treatment with isoniazid-rifampin, it is often possible to reintroduce one or both drugs successfully, in serial fashion, 68 after 2 to 3 weeks have elapsed and results of liver function tests have returned to normal. Rifampin accelerates the metabolism of a number of important pharmacological agents (cortisol, cyclosporine, warfarin, theophylline, methadone, phenytoin, ketoconazole, and oral contraceptives), with clinically important results. As an example, patients receiving phenytoin for control of seizures need careful monitoring of serum levels. Pyrazinamide, as mentioned, does not add to the hepatotoxicity of isoniazid and rifampin. It may cause arthralgia associated with hyperuricemia and, rarely, frank gout.
Adjunctive Therapy Corticosteroids The role of corticosteroids in the management of tuberculous meningitis has long been a matter of great clinical interest and some uncertainty. Past studies bearing on this issue were flawed by small patient numbers and failure to stratify the severity of illness groups according
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to specific neurological manifestations. There is at present a growing body of clinical data demonstrating that69–72 adjunctive corticosteroid therapy is beneficial in children and adults with This is the practice in most major clinical centers of Europe and of CNS tuberculosis. countries in Asia and Africa, where corticosteroids are administered routinely to patients with clinical stage 2 and 3 disease. Humphries, analyzing an extensive (199 patients) and well-studied experience from China, reported mortality figures of 11 and 61 percent, respectively, for stage 2 and 3 patients treated without corticosteroids, and of 5 and 30 69 percent, respectively, in corticosteroid-treated patients. Girgis and associates reported, from Egypt, a reduction in mortality rates in drowsy patients from 50 to 15 percent with corticosteroid treatment (P < 0.04) and from 33 to 14 percent (P < 0.02) in those who lived 70 long enough to receive 10 days of treatment. In a prospective, randomized study in young children, corticosteroids improved survival rate and intellectual outcome, and enhanced resolution of basilar exudate and tuberculomas. A modest although not statistically significant decrease in the incidence of 71 basal ganglia infarcts (16% versus 24%) was observed in the corticosteroid-treated group. A randomized, double-blind trial conducted in Vietnam compared dexamethasone with 72 placebo in 545 patients older than 14 years. A significant reduction in mortality was seen in the dexamethasone-treated group (32% versus 41%). The benefit was most apparent for patients with stage 1 (17% versus 30%) and stage 2 (31% versus 40%) disease. No mortality benefit was evident in 98 HIV-infected patients nor in patients with stage 3 disease. A follow-up survey of survivors at 9 months, evaluated by questionnaire, failed to demonstrate a reduction in residual neurological deficits or disability in the treated group. Adjunctive corticosteroid therapy is recommended for all patients with convincing epidemiological or clinical evidence of tuberculosis of the CNS, the possible exception being adults with early mild stage 1 disease. Complications for which corticosteroids are thought to be most beneficial are increased intracranial pressure, cerebral edema, stupor, focal neurological signs, and spinal block. Specific clinical indications based on urgent warning signs include the following: patients progressing from one stage to the next at or before the start of chemotherapy; CT evidence of marked basilar enhancement (portends a high risk of basal ganglia infarction); moderate or advancing hydrocephalus; spinal block or incipient block (CSF protein >500 mg/dl and increasing); and intracerebral tuberculoma when edema is out of proportion to the mass effect and there are any clinical signs. It is recommended that either dexamethasone or prednisone is administered according to the following dose schedules. For dexamethasone, the dose is 8 mg daily for children weighing less than 25 kg, 12 mg/day for adults and children weighing more than 25 kg, given for 3 weeks and then tapered off gradually over the following 3 to 4 weeks. For prednisone, the dose is 2 to 4 mg/kg daily for children and 60 mg/day for adults, given for 3 weeks and then tapered gradually over the following 3 to 4 weeks. The decision to use corticosteroids should rest on a strong presumptive or positive diagnosis. Caution is advisable in the face of diagnostic uncertainty, especially in cases in which fungal CNS infection is considered a strong possibility The expected benefit from corticosteroids must be weighed carefully against the potential for adverse consequences, bearing in mind that initial improvement in clinical signs may be nonspecific. In select cases, the addition of systemic antifungal therapy is advisable until a specific etiological diagnosis is reached. Surgery Hydrocephalus is a common complication of tuberculous meningitis, with the propensity for sustained increased intracranial pressure leading to permanent neurological damage. The combination of corticosteroid therapy and serial lumbar puncture and diuretics may suffice 73 while awaiting the early response to chemotherapy, as assessed by serial imaging studies. However, surgical decompression of the ventricular system should not be delayed in the very ill and in those74,75 with progressive neurological impairment in spite of conservative management.
Paradoxical Worsening on Therapy In a widely quoted article, Teoh and co-workers reported 10 patients and collected 12 more from the literature in whom symptomatic new tuberculomas developed, with neurological 48 deterioration, during the course of effective drug therapy for tuberculous meningitis. The latent period between the initiation of treatment and onset of neurological deterioration ranged from 2 weeks to 18 months. Watson and associates reported 5 more cases76of paradoxical tuberculoma development in a series of 22 cases of CNS tuberculosis.
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Although several of the patients reported had initially been treated with corticosteroids, it is not possible from the details to determine whether these complications had developed on the full dose or after discontinuation of corticosteroid therapy. Most patients improved with continued conservative management including reinstitution or increase in the dose of corticosteroid therapy.
Prognosis and Outcome The clinical outcome in any individual case is greatly influenced by age, duration of illness, clinical stage at the initiation of therapy, and the extent and character of optochiasmic arachnoiditis and vascular complications. The influence of the stage of disease on outcome is illustrated in Table 42-3. In general, when specific antituberculous treatment is started before patients progress 17 beyond stage 1 or early stage 2 disease, cure rates of 85 to 90 percent may be achieved. Age younger than 5 years and older than 50 years is associated with a poor prognosis. The observed mortality rate exceeds 50 percent in patients older than 50 16,77 The incidence of residual neurological deficits years and in those with stupor and coma after recovery from tuberculous meningitis varies from 10 to 30 percent in recent series. Late sequelae include cranial nerve deficits, gait disturbance, hemiplegia, blindness, deafness, learning disability, dementia, and various syndromes of hypothalamic or pituitary 17,78 dysfunction. Click here to view this table.... CONCLUDING COMMENT Tuberculosis of the CNS is uncommon in the West, potentially devastating, but an eminently treatable disorder. Current drugs are highly effective when therapy is initiated early, before the onset of altered mentation or focal neurological deficits. Prompt recognition and consideration of empirical therapy are therefore of paramount importance. Patients with subacute meningitis syndrome and CSF findings of low glucose concentration, elevated protein, and mononuclear pleocytosis should be treated immediately if there is evidence of tuberculosis elsewhere in the body or if prompt evaluation fails to establish an alternative diagnosis. Serial examination of the CSF is the best diagnostic approach; smear and culture for acid-fast bacilli yield positive results for days after antituberculous drugs have been administered. In a patient with compatible clinical features, CT or MRI evidence of basilar meningeal enhancement combined with any degree of hydrocephalus is strongly suggestive of tuberculous meningitis. Serial CT or MRI is useful for following the course of hydrocephalus and tuberculoma, particularly in reference to the need for, and response to, adjunctive therapy with corticosteroids and surgery. The recommended chemotherapy regimen for known or presumed drug-sensitive infection is isoniazid and rifampin in all patients, together with pyrazinamide and ethambutol for the first 2 months. Adjunctive corticosteroid therapy is effective in managing a variety of complications and reduces mortality in patients with stage 2 and 3 disease. Surgical shunting should be considered early in the patient with hydrocephalus and symptoms of increased intracranial pressure. Tuberculomas are best treated medically.
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 43 Neurological Complications of Leprosy THOMAS D. SABIN • THOMAS R. SWIFT •
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GENERAL MANIFESTATIONS NEUROPATHOLOGY LEPROUS NEURITIS LEPROMATOUS LEPROSY TUBERCULOID LEPROSY BORDERLINE LEPROSY TREATMENT
The acid-fast organism Mycobacterium leprae, the cause of leprosy, was the first pathogen conclusively linked to a human disease, a discovery made by Dr. G. Armauer Hansen in 1 “reductive 1874. The genome of the organism was recently elucidated and showed dramatic 2 evolution” with loss of the metabolic machinery that other mycobacteria retain. The organism must live within human cells. Single nucleotide polymorphisms indicate that leprosy originated in East Africa3 and passed on to Europe and Asia before explorers brought the disease to West Africa. The genome has also been found in ancient remains of the Near East from biblical times. The number of active cases in the world has recently fallen dramatically from 10 to 20 million in 1970 to 286,063 in 2005 because 4patients are now rapidly classified as “cured” with brief courses of multidrug therapy (MDT). The long-term validity of this optimistic trend, however, relies on the assumption that the relapse rate will be very low. No corresponding drop in incidence has yet occurred, but the hope of the World Health Organization program is to 5 eliminate leprosy by effecting a critical decrease in infectious bacteria within the population. The leprosy bacillus is unique in two important ways. First, it is the only bacterial pathogen that regularly invades peripheral nerves. Recent studies have provided details regarding the molecular biology underlying this neurotropism of M. leprae, which is unique among bacteria. An α-dystroglycan in the G domain of the α2 chain of laminin in the basal lamina of the 6 Schwann cell–axon unit is a specific binding target for M. leprae. After entering the Schwann cell, the organism commandeers the kinase kinase 7MEK kinase cascade, causing proliferation of more potential victim Schwann cells. Macrophages are the other major target cell. Second, M. leprae multiplies at temperatures that are 7° to 10°C lower than the core body
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temperature of 37°C. These two factors account for several important clinical features of the disease. All patients with leprosy have some degree of nerve involvement, making leprous neuritis a significant cause of treatable neuropathy in the world. Visible deformities from involvement of facial structures, eyes, nerves, bones, and skin result in stigmatization and 9 social ostracism. The diagnosis of leprosy is often missed by physicians, leading to a delay in treatment during which progressive neuropathy, visual loss, and deformity may occur. GENERAL MANIFESTATIONS Leprosy may be spread by aerosol or rarely 5by skin-to-skin contact; fortunately, more than 95 percent of individuals are naturally immune. Animal reservoirs have10been found in chimpanzee, sooty mangaby, cynomolgus macaque, and armadillo. In susceptible patients, the organisms rapidly gain access to cooler dermal tissues, primarily cutaneous and subcutaneous nerves and nerve networks, skin appendages, sweat glands, and erector pili 11 muscles. Leprosy occurs in three major forms: tuberculoid, borderline, and lepromatous. The type of leprosy that develops depends on the degree of host resistance rather than on the bacterium. these do not play a role in There are some intraspecific genetic variations in M. leprae, but 12 the severity of the disease, which is the same for all three types. In patients with high resistance, the leprosy that develops is called tuberculoid (or TT) or paucibacillary. A single patch of skin is involved by a granulomatous infiltrate, often with enlargement of underlying nerve trunks, but systemic dissemination does not occur, bacterial organisms are few, and self-healing is the rule. The skin lesions have raised edges and may have one or more satellite lesions (Fig. 43-1). Within these lesions, nerves are destroyed in an epithelioid granulomatous reaction. Often, a superimposed inflammatory response, known as a reversal reaction, occurs within the lesion either spontaneously or in response to drug treatment. Such a reaction reflects altered immunological responsiveness by the host to the organism and often results in bacteriological clearing of the lesions.
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FIGURE 43-1 Tuberculoid (TT) leprosy. There is complete anesthesia within
this lesion, which has a raised erythematous border and a pale, dry center. (Courtesy of Gillis W. Long Hansen's Disease Center, Carville, Louisiana.) In contrast, patients with multibacillary leprosy (called lepromatous or LL) have little or no resistance, and bacilli are disseminated throughout the body through a continuous 13 bacteremia, multiplying to extremely high numbers. There is little histological evidence of host resistance; histiocytes are literally packed with huge numbers of organisms that proliferate in cool areas of the body: the skin, upper respiratory tract, anterior one third of the 14 eye, superficial nerves, testes, and other tissues. Beading of corneal nerves may be seen. While bacilli may be deposited passively in the deeper, and therefore warmer, vital organs, such as the lungs, heart, liver, kidneys, and brain, there is little evidence of bacterial proliferation or pathological tissue reaction at those sites. Clinically, patients present with skin infiltration, particularly prominent in the cool areas, such as facial promontories, ears, dorsal forearms, legs, nasal mucosa, and scrotum (Fig. 43-2). Biopsy sample examination and skin scrapings of such tissues reveal innumerable acid-fast organisms. Without treatment, lepromatous leprosy continues to progress, eventually leading to severe deformities in most cases. At times spontaneously, but more often in response to antibacterial treatment, a reaction known as erythema nodosum leprosum occurs. Clinically, this is a very severe form of erythema nodosum and is a result of the deposition of antigen-antibody complexes in the walls of small arteries. Erythema nodosum leprosum occurs in areas where large amounts of mycobacterial antigen are present. The resulting inflammatory lesions can be devastating to the cornea and anterior eye, peripheral nerves, testes, and skin, producing multiple painful erythematous nodules (Fig. 43-3), leading to frank ulceration in some cases. During the course of erythema nodosum leprosum, iritis, neuritis, and orchitis occur and may be more damaging than the underlying leprosy itself. Erythema nodosum leprosum is a complex immunological reaction occurring with the production of cytokines such as tumor necrosis
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15–17
factor α (TNF-α). It is ironic that the circulating antibodies to mycobacterial antigen, constituting the host's only immunological responsiveness to the offending organism, appear not to benefit the host, but paradoxically to result in additional tissue damage.
FIGURE 43-2 Lepromatous (LL) leprosy. There is infiltration of the cooler facial
promontories, such as the ears, upper lip, chin, and supraorbital and malar areas. (Courtesy of Gillis W. Long Hansen's Disease Center, Carville, Louisiana.)
FIGURE 43-3 Erythema nodosum leprosum. Painful subcutaneous nodules
cover the face and trunk (not shown) and the extremities. (Courtesy of Gillis W. Long Hansen's Disease Center, Carville, Louisiana.) In the third type of leprosy, called borderline leprosy (or BB), a variable spectrum of disease occurs, depending on the degree of host resistance. In patients having low resistance, the disease resembles lepromatous disease (BL), whereas in those with higher resistance it resembles tuberculoid disease (BT). Patients with borderline leprosy have less skin involvement than those with lepromatous disease and may have more circumscribed skin
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lesions, but they have more skin lesions than patients with tuberculoid disease (Fig. 43-4). A 18,19 Increasingly in leprosy form of “pure neuritic” leprosy occurs without visible skin lesions. work, the terms paucibacillary and multibacillary are used in an attempt to simplify disease classifications and treatment decisions.
FIGURE 43-4 Borderline (BB) leprosy. The widespread symmetric skin lesions
are hypesthetic. (Courtesy of Gillis W. Long Hansen's Disease Center, Carville, Louisiana.) In the spectrum of borderline leprosy, immunity may change, with patients worsening, their disease becoming more like lepromatous (BL) disease (downgrading reaction), or evolving more toward the tuberculoid (BT) form (reversal reaction). Such shifts in the spectrum of disease may occur spontaneously or in response to drug treatment or intercurrent medical conditions, such as underlying neoplasms or secondary infections. Considering the extent of infection with human immunodeficiency virus (HIV) in leprosy-endemic areas, it is fortunate that no increase in leprosy has been associated with acquired immunodeficiency syndrome (AIDS), which may, however, precipitate reversal or downgrading reactions in leprosy 20 patients. NEUROPATHOLOGY In tuberculoid leprosy, the few organisms present in peripheral nerves evoke a strong granulomatous response with early and severe nerve damage, fortunately limited to the few nerves involved. In lepromatous leprosy, the overwhelming majority of organisms are present neuropathological and electrophysiological data show in Schwann cells (Fig. 43-5), but 21 substantial axonal destruction,22 and some of the demyelinating lesions themselves may be secondary to axonal changes. The complex immunological parasite–host interactions are
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gradually emerging as the basis for nerve damage.
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11,12
FIGURE 43-5 Sural nerve biopsy, lepromatous leprosy (LL). Acid-fast stain
reveals numerous organisms in endoneurial vacuoles. (Courtesy of Gillis W. Long Hansen's Disease Center, Carville, Louisiana.) In addition to the damage to nerves caused by the invasion of M. leprae, there are several types of leprosy reactions in which there is a sudden and often sustained increase in immune response to bacilli or products released by dead bacilli. Erythema nodosum leprosum occurs only in multibacillary leprosy and appears to be a clinical example of the Arthus phenomenon, 23 with consumption of complement and an intense vasculitis. The vasculitis is most severe in the regions of greatest bacterial density and therefore may result in a devastating acute 24 neuritis. There is a high amount of TNF-α in the blood with debilitating systemic symptoms. Although the nerve lesions of leprosy tend to be permanent, prompt treatment of reactions 21,25 It is also unclear to what extent or by what may improve neurological deficits. mechanisms erythema nodosum leprosum produces nerve damage, but it is likely that cytokines released by immunocompetent cells are important. Exogenous interferon-gamma (IFN-γ) used in an attempt to treat leprosy has caused erythema nodosum leprosum in 15,17 patients, who then have increased release of15,16 TNF. Thalidomide, which controls erythema Thalidomide also reduces elevated numbers nodosum leprosum, reduces TNF secretion. + 26 of CD4 lymphocytes in the blood of patients with erythema nodosum leprosum. During erythema nodosum leprosum, 26 there is a loss of suppressor cell function and an increase in leprosum and interleukin-2 (IL-2) production. Cyclosporine suppresses erythema nodosum 27,28 A recent report restores suppressor cell activity, possibly by its effect on macrophages. describes the effectiveness of infliximab, a monoclonal antibody that inhibits the production of TNF-α, in suppressing erythema nodosum leprosum in a single patient in whom corticosteroid and thalidomide therapy had failed. Presumably it would be effective in reactive 29 states in other varieties of leprosy in which TNF production is increased. In the higher-resistance tuberculoid and border-line cases, reactions are related to increase in tissue-mediated immune factors. There is infiltration of the lesions with IFN-γ and CD4 lymphocytes producing TNF-α, which causes local30redness, swelling, and rapid loss of function in any nerve coursing through the lesion. LEPROUS NEURITIS A meticulous neurological examination yields definitive diagnostic information of this treatable neuropathy. The diagnosis is based on the recognition of two interplaying themes that, although they produce limitless combinations in individual cases, capture the unique nature of this neuropathy once they are discerned. Both of these themes rest on the fact that M. leprae is the only bacterium that consistently invades peripheral nerves. The first of the two diagnostic themes is based on another biological feature of M. leprae: it 8,31,32 has a highly thermosensitive growth rate that is optimal at 27° to 30°C. The organism does not reproduce at all at core body temperature. This feature limits leprosy to involvement of only superficial nerves. The distinction between the “superficial” neuropathy of leprosy and a distal polyneuropathy is vital for correct diagnosis. This has been a source of confusion
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because long nerves tend to innervate cooler parts of the body. In leprosy, nerve damage is limited to intracutaneous nerve endings and networks and to the named nerves of gross anatomy at certain segments along their length where they course closest to the cooler 33 surface of the body. Since M. leprae cannot proliferate at core body temperature, peripheral nerves that are situated in deep tissues under or close to muscles, nerve roots, and the central nervous system (CNS) are not actively involved. The second diagnostic theme relates to host factors that determine the immune resistance to the invasion and proliferation of bacilli. This host resistance has resulted in the classification of leprosy into the three subtypes mentioned earlier and is the other major determinant of the clinical features including nerve damage. LEPROMATOUS LEPROSY There is very little evidence of tissue-mediated immune responses to M. leprae in lepromatous leprosy, and lepromin skin testing is negative. The organism proliferates most rapidly in the coolest tissues, and there is a constant blood-stream dissemination of 13 organisms. In untreated cases, this type of leprosy becomes widespread and symmetric within superficial tissues and may involve large areas of the skin, the anterior chamber of the eye, the upper respiratory tract, and the testes, as well as superficial nerves. Sensory loss is largely due to destruction of intracutaneous nerve endings and first appears in cool areas, such as the dorsal surfaces of the hands, dorsomedial surfaces of the forearms, dorsal surfaces of the feet, and ventrolateral aspects of the legs, as well as in the pinnae of the ears, 34,35 (Fig. 43-6). The tip of the nose, malar areas, and especially the helices and earlobes buttocks are often the next to show intracutaneous sensory loss (Fig. 43-7). There is a stage with sparing of the soles of the feet and palms of the hands, which may be due in part to the insulating effect of the thickened corium in these areas. If the patient is examined at the right stage, a distinct change in sensation at the cuticular border can sometimes be found in the hands or feet. When the intracutaneous pattern has evolved to this point, nerve trunk deficits supervene. Involvement of a 10- to 15-cm segment of the ulnar nerve proximal to the olecranon groove is most common, but the segment just proximal to the wrist may also be affected. Further paralysis is seen with damage to (1) the median nerve in the segment where it assumes a superficial position just proximal to the transverse carpal ligament (Fig. 43-8), (2) the peroneal nerve where it courses around the fibular head, (3) the branch of the peroneal nerve to the extensor digitorum brevis, and (4) the posterior tibial nerve at the level 33 of the ankle. There is also a unique patchy paralysis of the most superficial facial nerve twigs, causing lagophthalmos and paralysis of some segments of the orbicularis oris and of 36 the medial aspects of the corrugators of the forehead.
FIGURE 43-6 Lepromatous leprosy (LL). Sensation is diminished in cool zones
of the face, trunk, and extremities.
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FIGURE 43-7 Lepromatous leprosy (LL). Sensation is preserved in warm areas:
axillae, palms, antecubital fossae, inguinal region, gluteal cleft, and center of back and chest.
FIGURE 43-8 Lepromatous leprosy (LL). Enlargement of the median nerve
proximal to the carpal tunnel is shown. (Courtesy of Dr. Paul Brand and Gillis W. Long Hansen's Disease Center, Carville, Louisiana.) With progression of the intracutaneous sensory loss, this pattern is more easily recognized by the areas of sparing that include the intergluteal fold, the perineum, the anterior neck, under the scalp hair, the posterior creases at the attachment of the ears to the head, the axillae, the sternal area, and the center of the back where skin overlies the “warm” paraspinal muscles and the concavity overlying the spinous processes where cross-radiation of heat occurs. Sparing may be found in the webs of the toes or fingers and the antecubital and popliteal fossae (Fig. 43-9). A careful search may reveal unique features, such as sparing under constantly worn items of clothing (e.g., under a watchband or at a belt line) and even in small 37 cutaneous vascular malformations. A patient with chronic hemiplegia developed 38 lepromatous leprosy with skin lesions limited to the cooler hemiplegic side. Sensory examination of the distal extremities alone may result in confusion with a distal sensory polyneuropathy; therefore, the search must include the ears, nose, and malar areas in order to detect the pattern of temperature-linked sensory loss. This differential diagnosis is also suggested by the preservation of muscle stretch reflexes. Even total destruction of the mixed sensorimotor nerves at the sites outlined earlier would fail to disrupt the arcs for the usually elicited tendon reflexes. Despite the appearance of an extensive sensorimotor neuropathy with clawed toes, footdrop, and clawed hands, preserved tendon reflexes are the rule. Rarely, radial nerve involvement affects the segment that emerges from under the triceps, 4 to 6 cm proximal to the elbow. There are paralysis and atrophy in the wrist and finger extensors, whereas the triceps, brachioradialis, and anconeus muscles tend to be spared. The differential diagnosis of leprous neuritis is summarized in Table 43-1. Click here to view this table....
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FIGURE 43-9 Lepromatous leprosy (LL). There is sensory sparing of the scalp,
in the axillae and the groin, in the center of the back and the chest, and in the antecubital fossae. A variety of cutaneous lesions are associated with lepromatous leprosy, and they are most abundant and prominent in the areas where bacilli are most common in the cooler tissues. There is no precise linkage between those skin lesions and the intracutaneous sensory loss. Because the tissue immune response to the bacilli in lepromatous leprosy is very indolent, the neuropathy evolves over many years. Nerves that are grossly enlarged and infiltrated with abundant bacilli may still function well. These enlarged nerves are more liable to recurrent trauma, and measures must occasionally be taken to prevent the addition of mechanical damage to these already vulnerable nerves. TUBERCULOID LEPROSY At the other end of the spectrum of host response to infection with M. leprae is tuberculoid leprosy. There is a vigorous tissue-mediated immune response to the invasion of bacilli that 5 greatly limits the spread and proliferation of M. leprae. Only rare organisms are found in the resulting epithelioid granuloma, and nerve damage occurs as the lesion develops. The 39 lesions contain abundant activated CD4 T cells that produce IFN-γ. This means that the neurological picture is generally one of a clearly demarcated patch of sensory loss and absent sweating corresponding with a visible skin lesion that is usually hypopigmented, with an elevated border (Fig. 43-1). Bacteria have often been cleared from the center of these lesions but are still detectable in biopsy samples at the perimeter. Results of lepromin skin testing are positive in this form of the disease. Temperature has only a “permissive” role, in the sense that the lesions must occur in a region where the bacilli can reproduce; tissue temperature does not otherwise determine the precise nature of the neuropathy, as it does in lepromatous disease. Local bacillary invasion of nerves and the immediate immune tissue response are the two factors that result in focal, limited, and asymmetric disease. There is a tendency for self-healing in this type of leprosy. A named mixed, motor, or sensory nerve near a solitary tuberculoid patch may also be affected. These observations have suggested that M. leprae can travel from the intracutaneous endings back to the major nerve supplying the area of anesthetic skin. The major mixed nerves that are most commonly affected are the ulnar, median, peroneal, and facial. Subcutaneous sensory nerves near the tuberculoid patch are most likely to be enlarged, but one should also palpate for enlargement of distant nerves, such as the superficial cutaneous radial, digital, sural, and posterior auricular nerves. The tissue response within nerves may be so intense that there is necrosis and formation40of a “cold” abscess. Intense local pain results, requiring surgical drainage of the abscess. Calcification resulting in radiographically detectable linear streaks within nerves may also41 occur, and enlarged nerves may be demonstrable on computed tomography (CT) scans. Anhidrosis is always present within tuberculoid lesions; injections or iontophoresis of
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cholinergic agents into the area may be helpful in establishing the diagnosis. BORDERLINE LEPROSY
Many patients have clinical and pathological features that fall between polar tuberculoid and 5 lepromatous leprosy, and their conditions are thus classified as borderline leprosy. Such patients demonstrate unending permutations in the roles of tissue temperatures and host resistance in the pathogenesis of their nerve dysfunction. The immunological reactivity in these patents is unstable, and a drift toward one of the polar patterns occurs over time. The neurologist experienced in leprosy can place patients along a spectrum paralleling a pathological classification by the pattern of cutaneous sensory loss. Cases of pure neural leprosy with no skin lesions are usually of the borderline type; they are revealed by a good neurological examination and can be confirmed with nerve biopsy or polymerase chain 30 reaction (PCR) testing. Patients with borderline features that are nearer to tuberculoid disease have several skin lesions that tend to be larger and less distinctly demarcated than those in the pure tuberculoid cases. As one moves away from the tuberculoid end of the spectrum, there is less overlap of the sensory deficit with the visible skin lesion. In the midrange of borderline leprosy, lesions may be quite large and begin to coalesce with insensitivity covering a large area of the body, but they retain geographical borders that do not closely reflect tissue temperature gradients beyond a general tendency to spare the warmest parts of the body (Fig. 43-10). Sensory maps in such cases may show extensive intracutaneous loss that does not conform to the disruption of named peripheral nerves, nerve roots, or any known neuropathy. Further movement toward lepromatous disease is revealed by symmetry of neural deficits and the loss of linkage between the perimeters of skin lesions and areas of sensory loss. A definite tendency toward temperature-linked patterns of sensory loss emerges, but these are not as perfectly symmetric and graduated as in pure lepromatous disease.
FIGURE 43-10 Borderline leprosy (BB). Sensory loss occurs in the skin lesions.
Skin lesions tend to affect cooler areas. TREATMENT The treatment of leprosy is threefold: (1) drug treatment aimed at the eradication of M. leprae, (2) drug treatment of leprosy reactions, and (3) rehabilitation, cosmetic and restorative procedures, and prevention of further deformity consequent to loss of sensation. The drug treatment of leprosy is changing. Since 1940, sulfones have been the mainstay of treatment, replacing chaulmoogra oil, which had only limited antimycobacterial action. However, with sulfone treatment, many patients developed recurrent disease after periods during which they were apparently free from bacteria. The organisms found at recurrence 43 were shown to be sulfone resistant using the mouse footpad test.
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In addition, sulfones themselves may produce peripheral neuropathy and other idiopathic and 44 dose- related side effects, such as hemolysis and, rarely, agran-ulocytosis. Another useful drug is clofazimine (Lam-prene, B663), a rimino phenazine dye, and this drug may be helpful 5 in suppressing erythema nodosum leprosum. However, it discolors the skin and is therefore unacceptable to many patients, and its hepatotoxicity is a major side effect. In patients with tuberculoid or single skin lesions, current guidelines of the World Health Organization suggest45a single-dose combination of rifamycin 600 mg, ofloxacin 400 mg, and minocycline 100 mg. In paucibacillary intermediate disease, rifamycin 600 mg monthly and dapsone 100 mg daily are both given for 6 months. With low-resistance disease (low-resistance borderline and lepromatous leprosy), triple therapy with dapsone, rifamycin, and clofazimine is advocated. Rifamycin 600 mg monthly, clofazimine 300 mg monthly, 45 clofazimine 50 mg daily, and dapsone 100 mg daily are given for 12 to 14 months. For the most recent treatment recommendations, biopsy interpretation, patient referrals, or suggestions for management, the reader should contact the Gillis W. Long Hansen's Disease Center in Carville, Louisiana. The treatment of leprosy reactions is important because of the threat that such reactions pose to the patient. Leprosy reactions are of three types. Erythema nodosum leprosum is treated with high-dose corticosteroids (prednisone 60 to 80 mg or more daily), particularly if accompanied by neuritis, or with thalidomide 300 to 400 mg daily. Thalidomide is available in the United States at no charge through arrangements with the Gillis W. Long Hansen's Disease Center. (Female patients receiving thalidomide must take absolute precautions to prevent pregnancy because the drug 15,16 induces phocomelia in offspring.) Thalidomide +reduces + the secretion 26 of TNF-α by monocytes and causes a decrease in the ratio of CD4 to CD8 lymphocytes. When erythema nodosum leprosum is controlled, the dose of thalidomide is tapered to 100 mg daily. Long-term thalidomide treatment may also cause or worsen 46,47 A recent report describes the use of infliximab in resistant peripheral neuropathy. 29 erythema nodosum leprosum in a single patient. Reversal reactions, which may be very intense, are treated with high-dose corticosteroids as necessary. Clofazimine in a dose of 200 to 300 mg daily is also of value in treating reactions, in addition to being antibacterial. After the reaction is controlled, the dose can be tapered to 100 mg daily. It is important to note that thalidomide or high doses of corticosteroids are required to treat erythema nodosum leprosum. In tuberculoid and high-resistance borderline leprosy, a reversal reaction consists of a sudden increase in tissue-mediated immunity, with flaring of the skin lesions and acute neuritis. Corticosteroids (but not thalidomide) are effective in these reactions. Rehabilitation of leprosy patients is difficult because the associated stigma makes patients reluctant to come forward for treatment. Many such patients who have cosmetic and crippling deformities involving the face, eyes, eyelids, eyebrows, ears, nose, hands, and feet may benefit from surgical restorative procedures. The attendant peripheral neuropathy, with loss of temperature and pain sensation and of sweating but with preservation of motor function, creates the risk of progressive damage to hands and feet from painless injury followed by ulceration, infection, osteomyelitis, and eventually bone resorption. Such patients must be instructed in the care of the hands, feet, and eyes to prevent secondary disability resulting from the neuropathy, in a manner similar to patients with other neurological conditions in which pain sensation is lost but power is retained, such as syringomyelia, hereditary sensory and autonomic neuropathies, amyloid neuropathy, certain cases of diabetic neuropathy involving small fibers, and other conditions. In fact, patients with these neurological conditions can often be found in leprosariums, where they are mistakenly believed to have leprosy because the mutilating deformities are so similar. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 44 Nervous System Complications of Systemic Viral Infections LARRY E. DAVIS •
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VIRAL MENINGITIS Enteroviruses Mumps Virus Herpes Simplex Virus Type 2 Human Immunodeficiency Virus Treatment of Viral Meningitis VIRAL ENCEPHALITIS Diagnosis of Encephalitis Herpes Simplex Encephalitis West Nile Neuroinvasive Disease Treatment of Viral Encephalitis PARALYTIC POLIOMYELITIS Postpolio Syndrome PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY HERPES ZOSTER (SHINGLES) POSTVIRAL ENCEPHALOMYELITIS (ACUTE DISSEMINATED ENCEPHALOMYELITIS) Measles Chickenpox Management of Postviral Encephalomyelitis TRANSVERSE MYELITIS AND MYELOPATHY OPTIC NEURITIS DEAFNESS AND VERTIGO GUILLAIN–BARRÉ SYNDROME CREUTZFELDT–JAKOB DISEASE
Evolution has protected the brain from infections in ways different from those of other organs. One would expect the brain to be an easy target for viral infections because it is an immunoprivileged organ. The brain lacks a lymphatic system, and it has few immunological cells migrating through the brain parenchyma. Normal cerebrospinal fluid (CSF) has fewer than five lymphocytes per cubic millimeter and has only about 0.5 percent of the amount of 1 antibody that is present in serum. As a consequence, many viruses replicate in the central nervous system (CNS) when they are directly inoculated into the brain. The resulting brain infection can be severe, whereas the same viral infection of other organs may be mild. For example, herpes simplex virus (HSV) infection in labial skin causes a localized small blister,
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but infection in brain causes a severe encephalitis. Despite the potential vulnerability of the brain, most systemic viral infections do not cause CNS disease because they do not reach the CNS. To reach the CNS, viruses must overcome several major protective systems. First, viruses entering the body do not have the opportunity to infect nerves directly. To reach the CNS, all viruses must first establish a primary site of replication. Viruses that enter the gastrointestinal tract (e.g., enterovirus) 2 establish a primary site of replication in the oral pharynx and gastrointestinal tract. Viruses that enter via the respiratory system (e.g., mumps3 virus) establish local replication in the upper respiratory tract and regional lymph nodes. Viruses that enter the body via inoculation (e.g., ARthropod BOrne viruses, or arboviruses) establish local replication in vascular 4,5 endothelium and regional lymph nodes. During the primary viral infection, the host's normal defense system comes into play to counteract the local infection. The few viruses that do successfully reach the CNS do so by two major routes: blood and peripheral nerves. Hematogenous spread is the most common. Following primary viral replication, a viremia often develops and this allows secondary tissues to become infected and results in a systemic illness. Despite the viremia, most viruses still do not reach the CNS because of several factors. Virus particles, like other colloidal particles in the blood, are efficiently cleared by the reticuloendothelial system. For example, the reticuloendothelial system can clear more 6 than 90 percent of an arbovirus viremia within 1 hour. Within days, the host humoral immune system–immunoglobulin M (IgM) antibodies against the virus and cellular immune systems (macrophages and lymphocytes) actively participate in clearing the virus from infected tissues and blood. The blood–brain barrier also prevents viruses from entering the CNS. The morphological blood–brain barrier consists of cerebral capillaries that have tight junctions between cells to 7 prevent egress of plasma and white blood cells (WBCs). These tight junctions prevent viral particles from escaping the capillary lumen. In addition, cerebral blood vessels are surrounded by tight astrocytic footplates. The occasional viral infection that does bridge the blood–brain barrier appears to do so by either infecting and replicating within capillary endothelial cells, with release of progeny virions into the brain, or by infecting choroid plexus 2 epithelial cells. Capillaries in the choroid plexus have fenestrations, but the adjacent choroid epithelial cells have tight junctions. Thus, viruses such as mumps appear to reach the CSF by infecting choroid plexus epithelial cells, with subsequent release of progeny virions into the 8 CSF. The efficiency with which these defense systems prevent viruses from infecting the CNS is remarkable. Less than9 1 percent of nonimmune children infected with wild-type poliovirus develop poliomyelitis, and less 4than 1 percent of individuals infected with West Nile virus develop neuroinvasive disease. A few viruses are transported to the CNS via peripheral nerves. With rabies, there is local virus replication in muscle following inoculation from the animal bite. As the muscle infection spreads,10virus eventually reaches synapses at the neuromuscular junction or muscle spindle. After viral attachment to presynaptic membranes, the virus is transported via retrograde axoplasmic flow to the brainstem, spinal cord, or dorsal root ganglion, and from there, it spreads throughout the CNS. There is some evidence that herpes simplex encephalitis (HSE) may be the result of exacerbation of latent virus in the trigeminal ganglion 11 and spread to the brain via branches of the trigeminal nerve. Poliovirus appears to reach the spinal cord both from a viremia and via retrograde axoplasmic flow within the axon of an 12 anterior horn cell following virus entry at the neuromuscular junction. In animals and possibly humans, viral infections of epithelial cells of the upper respiratory system occasionally reach the brain via peripheral infection of olfactory or trigeminal nerves and retrograde axonal advance to the brain. The human immunodeficiency virus (HIV) may reach the brain inside an infected macrophage that passes into the brain. These unusual neural routes circumvent the reticuloendothelial system and blood–brain barrier. When a virus infects the CNS, the cellular immune system and the humoral immune system appear to have important roles in clearance of the virus, depending on the virus. With experimental viral meningitis, the meningeal infection elicits an inflammatory response that 13 14 contains mainly T lymphocytes that are specifically immune mediated. Similarly, with experimental viral encephalitis, the inflammatory response includes specifically 15 immune-mediated lymphocytes. The cellular immune system is critical in eliminating many viruses from the brain. However, for arboviruses, such as West Nile virus, specific antibody 16 appears more important than immune lymphocytes to clear the virus from brain. The brain is not a homogeneous organ, such as the liver. Viral infections directed toward different brain locations or cell types in the CNS result in differing symptoms and signs.
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Viruses that infect leptomeningeal cells 17 cause a meningitis, whereas viruses that infect neurons and glia cause an encephalitis. Even subtypes of neurons (e.g., those of the motor system) can be preferentially infected by viruses, such as poliovirus, giving rise to an illness in which muscle weakness predominates. The time course of spread of the viral infection varies from virus to virus. Some viruses, such as echovirus, give rise to a brief (about 118 week) infection of the leptomeninges and are cleared promptly by the immune system. Other viruses, such as measles (rubeola virus), occasionally cause a chronic infection, 19 subacute sclerosing panencephalitis, that slowly progresses over months to years. Some viruses, such as varicella-zoster virus, can escape immune surveillance20by becoming latent in dorsal root ganglion neurons following the primary chickenpox infection. Decades later, they can reactivate and cause shingles, an acute neuritis involving a dermatome. In summary, most viruses that cause systemic illnesses in humans do not reach the CNS. When they occasionally do so, they cause a variety of diseases with differing symptoms and signs and varying time courses. The focus of this chapter is on the common and important nervous system syndromes that occur with or following systemic viral infections. Table 44-1 lists the major viruses that infect humans and estimates the frequency (per 100,000 systemic viral infections) of a variety of nervous system syndromes that can develop. Click here to view this table.... VIRAL MENINGITIS Viral meningitis, the most common viral infection of the CNS, is due to a viral infection of leptomeningeal cells. Viral meningitis is often discussed together with aseptic meningitis. Aseptic meningitis includes viral meningitis plus transient meningeal inflammation from other causes, such as bacteria that do not grow in routine cultures (Leptospira icterohaemorrhagiae, Treponema pallidum, Mycoplasma pneumoniae), parasites (Toxo-plasma gondii), Rickettsia (human monocytic ehrlichiosis), and parameningeal 17 infections. In addition, a number of drugs, such as trimethoprim-sulfamethoxazole, ibuprofen, carbamazepine, intravenous immunoglobulin, and the murine monoclonal 21 Lyme meningitis from anti-body OKT3, have caused an acute aseptic meningitis syndrome. 22 Borrelia burg-dorferi and meningitis from two Ehrlichia organisms that cause human monocytic ehrlichiosis and human granulocytic ehrlichiosis are becoming increasingly 23,24 It is important to recognize these three infections, common in parts of the United States. as treatment with doxycycline eliminates the infection. However, most cases of aseptic meningitis are due to a variety of viruses (Table 44-2). Click here to view this table.... Each year more than 8,000 cases of aseptic meningitis are35reported to the Centers for incidence of aseptic Disease Control and Prevention (CDC) in Atlanta, Georgia. The annual 36,37 Most cases occur in meningitis has varied from 11 to 27 cases per 100,000 individuals. children and young adults during summer and early fall. The etiology of the viral meningitis varies by geographic region, age of patient, year, and season. For adults in developed countries, a rough distribution is enteroviruses (30%), HSV type 2 (20%), varicella-zoster 38,39 virus (10%), arboviruses (3%), HIV (1%), HSV type 1 (1%) and unknown (35%). 25,26
Regardless of the viral etiology, the symptoms and clinical signs are similar. The illness is characterized by the abrupt onset of fever, headache, nuchal rigidity, and, occasionally, nausea, vomiting, and photophobia (Table 44-3). Patients may experience lethargy and irritability, but obtundation and coma should not occur. The headache is particularly intense and usually is the most dramatic feature. However, in young children and infants and individuals with immunosuppression, it may be less prominent. Click here to view this table.... The peripheral WBC count may be normal or elevated. A lumbar CSF sample may have a normal or mildly elevated opening pressure. The CSF always contains a pleocytosis, usually 3 the ranging from 50 to 2,000 WBCs/mm. On the first day that the patient has symptoms, 38,40 The CSF may contain mainly neutrophils, but lymphocytes rapidly come to predominate. CSF glucose level is usually normal, but mildly depressed levels have occasionally been reported in patients with mumps,17varicella-zoster, HSV type 2, and lymphocytic choriomeningitis (LCM) viruses. If the CSF glucose level is below 25 mg/dl, bacterial or fungal causes should be seriously considered. In patients with viral meningitis, cultures of the CSF should not grow bacteria or fungi, which should also not be seen on Gram's stain of the CSF sediment; bacterial or fungal antigens should not be detected in CSF. The
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electroencephalogram (EEG) is usually normal but occasionally shows mild background slowing. Marked asymmetries or seizure foci should not be seen. Computed tomography (CT) scans and magnetic resonance imaging (MRI) of the brain are typically normal. The clinical diagnosis of aseptic meningitis is thus based on the presence of typical clinical and laboratory features that may occur in association with a mild systemic illness (rashes, parotitis, orchitis, diarrhea, myalgia, herpangina, or pharyngitis). To determine the etiology of the viral meningitis, the specific virus must be identified by virus isolation, polymerase chain reaction (PCR) assay for viral nucleic acid, or serological studies. Samples of CSF obtained 37,41 The virus early, preferably during the first day of illness, often contain a recoverable virus. may also be recovered from other body sites. Enteroviruses and mumps virus can be isolated from throat swabs or stool, HSV type 2 from a genital herpetic lesion, and LCM virus from urine. It is often possible to isolate these viruses from non-CSF sites during the first week of illness. The ability to amplify small amounts of viral nucleic acid from CSF using the PCR technique has revolutionized the diagnosis of viral CNS infections. CSF PCR is rapid, inexpensive, and only minimally invasive. False-positive CSF PCR results are rare when tests are performed according to strict standards in experienced laboratories with rigorous attention to procedures designed to avoid specimen contamination and to verify the specificity of amplification products. The sensitivity of CSF PCR varies with different viruses, and can be dramatically influenced by the timing of specimen collection in relation to onset of illness. 42 43 Nevertheless, PCR assays for enteroviruses and HSV type 2 are considerably more sensitive in detecting these viruses than conventional viral isolation methods. Clinicians are still faced with the daunting task of ordering individual PCR tests for each virus of potential interest. Recently, ‘‘multiplex” CSF PCR assays have been developed that use multiple primers simultaneously in a single reaction mixture to amplify nucleic acid from a group of viruses. Although this is a powerful technique, it is becoming apparent that caution must be used in the interpretation of some results. In one study, more than one virus was 44 detected in CSF in 10 percent of 88 samples. When the nucleic acid of two infectious 45 agents are found, usually only one infectious agent is the cause of the illness. Detection of nucleic acid from multiple infectious agents increases when the patient is immunocompromised. Although all the reasons are still unclear, some dual infections stem from detection of latent lymphotrophic viruses, such as Epstein–Barr virus (EBV), in CSF inflammatory cells or from reactivation of latent viruses in the CNS. In addition, PCR detection of infectious agents is occasionally found in44CSF when the clinical suspicion of a viral infection is deemed low and the CSF is normal. Thus, clinical judgment must be used both in determining when to order diagnostic PCR assays of the CSF and in interpreting the findings. Serological studies of acute and convalescent serum (obtained 3 to 6 weeks after the acute serum sample) may be useful in establishing meningitis due to mumps, arbovirus, HIV, and LCM viruses. Serological studies for diagnosing enterovirus infections are seldom performed because of technical difficulties requiring the use of neutralization tests. As a group, patients with viral meningitis generally make a complete recovery within 1 to 2 weeks. However, there have been occasional reports of permanent sequelae in small children, 25 including mental retardation, deafness, cranial nerve palsies, and aqueductal stenosis.
Enteroviruses In the United States, enteroviruses account for as many as 80 percent of cases of viral 46 picornavirus family and are small (30 nm meningitis in children. Enteroviruses belong to the 47 in diameter, the size of a ribosome) RNA viruses. Initially, enteroviruses were subdivided into echoviruses and coxsackieviruses. Newly isolated enteroviruses are now assigned numbers as enteroviruses (e.g., enterovirus 71 or EV 71). Enteroviruses have a worldwide distribution and often cause epidemics, primarily during the summer and early fall. The enterovirus subgroup is stable at room temperature, stable at acidic pH as low as 3.0, and resistant to lipid solvents because it lacks a lipid envelope. These viruses are thus well suited for survival in water and sewage and are transmitted by the fecal-oral or hand-to-mouth routes. 47
Enteroviruses initially replicate in the gastrointestinal tract. This replication is asymptomatic or causes a mild gastroenteritis or pharyngitis. A secondary viremia then develops, with subsequent tissue infections that may involve regional lymph nodes, skeletal muscle, myocardium, pericardium, brown fat, skin, lung, pancreas, and leptomeninges. Patients with enterovirus infections may develop rashes, pericarditis, myocarditis, myalgia, orchitis, herpangina, arthritis, polymyositis, hemolytic-uremic syndrome, nephritis, insulin-dependent
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diabetes mellitus, respiratory symptoms, and conjunctivitis. When enteroviruses invade the CNS, most patients develop meningitis. The fever, headache, and stiff neck typically last 1 to 3 weeks in older children and adults but can persist for prolonged periods in patients with hypogammaglobulinemia. Enterovirus can be isolated from the CSF during the first 1 or 2 days of meningitis, from throat for several days, and from stool for a few weeks. Because asymptomatic enterovirus infections are common in summer, enterovirus isolation from throat or stool does not make a definitive diagnosis of enterovirus meningitis. Today the most sensitive and fastest method of identification of enterovirus RNA from CSF uses a reverse transcriptase–PCR assay. This method identifies all strains of enteroviruses but does not distinguish between the strains. Virus isolation and neutralization typing are necessary to determine the specific strain. Occasional strains of enteroviruses have been reported to cause a poliomyelitis syndrome, meningoencephalitis, cerebellar ataxia, transverse myelitis, and Guillain–Barré syndrome. For example, enterovirus 71 has caused numerous cases of meningoencephalitis with acute 48 flaccid paralysis and neurogenic pulmonary edema. Children with X-linked hypogammaglobulinemia may develop a chronic meningitis and have difficulty in eradicating the enterovirus infection from CSF and stool and develop a chronic persistent infection.
Mumps Virus 49
Worldwide, mumps virus is the most common cause of viral meningitis. In developed countries, the incidence of mumps meningitis is low because of the widespread administration of mumps vaccine to children. However, minor outbreaks of mumps in older children and young adults have occurred in the United Kingdom and United States in the past few years. Most cases have occurred in individuals who were never vaccinated or received only one dose of the mumps vaccine in childhood. Mumps virus is a large (100 to 600 nm in diameter), roughly spherical RNA paramyxovirus that spreads primarily via respiratory 3 droplets. Initial replication is within the upper respiratory tract and regional lymph nodes. A viremia disseminates the virus to parotid glands and occasionally to submaxillary glands, testes, ovaries, mammary glands, and the leptomeninges. The parotitis usually occurs 16 to 18 days after exposure to27the virus. About one half of all individuals with mumps parotitis develop CSF pleocytosis. In some, the meningeal infection is asymptomatic, whereas in others, a typical viral meningitis develops. The meningitis usually occurs 2 to 10 days after 28 the onset of the parotitis, but it may rarely precede the parotitis or even occur without it. In most patients, the meningitis spontaneously resolves within 2 weeks, and full47,50 recovery cerebellar occurs.51Occasionally, individuals develop complications, including deafness, 52 53 ataxia, cortical blindness, and aqueductal stenosis with obstructive hydrocephalus. 28 Among patients with a CNS mumps infection, 1 to 5 percent develop meningoencephalitis. Available pathological studies suggest that the meningoencephalitis may result from direct55 54 viral invasion of the brain or from a postviral encephalitis with perivenous demyelination. Although most of these individuals recover completely, occasional patients are left with permanent sequelae.
Herpes Simplex Virus Type 2 In young, sexually active adults with viral meningitis, HSV type 2 should be considered. This virus accounts for 0.5 to 5.0 percent of viral meningitis in all ages but up to 20 percent in adults. At the time of the first attack of genital herpes, about 36 percent of women and 11 percent of men29have signs and symptoms of meningitis, including fever, headache, and of these individuals subsequently develop nuchal rigidity. Approximately 20 percent 56 recurrent attacks of aseptic meningitis. HSV type 2 is the most common cause of recurrent aseptic meningitis. Many affected individuals have never had a history of genital herpes and lack genital lesions at the time of 43 Although virus can often be isolated from CSF during the the second attack of meningitis. 30 56 first attack of HSV meningitis, it is seldom isolated from CSF in recurrent43attacks. However, the viral DNA can frequently be detected in CSF by PCR assay.
Human Immunodeficiency Virus Primary HIV meningitis should be considered in young adults with meningitis, particularly if they are homosexual males or have a history of intravenous drug abuse and have a coexistent mononucleosis-like syndrome (see Chapter 45). It is of importance that these individuals usually do not have antibodies to HIV during the acute meningitis but develop 32 antibody 1 to 3 months later during convalescence. In the acute stage, the diagnosis can be made by PCR detection of HIV viral RNA in acute serum.
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Treatment of Viral Meningitis Treatment of most cases of viral meningitis is symptomatic. Analgesics may be required for individuals with severe headaches, and antiemetics for those with considerable nausea and 18 vomiting. Hospitalization is seldom required except when the vomiting is severe enough to cause dehydration or when bacterial meningitis cannot be completely excluded. If an acutely ill patient has CSF containing low glucose levels or a pleocytosis in which neutrophils predominate, it may not be possible initially to rule out bacterial meningitis. In these cases, it is often prudent to hospitalize the patient and treat the individual with antibiotics over the first day. By the second day, the patient usually feels better, the initial CSF bacterial cultures are sterile, and a 40 repeat lumbar puncture shows that the CSF pleocytosis now contains mainly lymphocytes. For mild to moderately severe HSV meningitis, the treatment is usually symptomatic. In more severe cases, treatment with acyclovir, 15 to 30 mg/kg divided into three doses per day, may 57 be given slowly intravenously over 1 hour for 5 to 10 days. This treatment should be given early in the illness to have maximal benefit. Oral acyclovir, 200 mg five times daily, is sufficient to treat genital herpes. It is difficult, however, to achieve high enough CSF concentrations of the drug when given orally to be beneficial in HSV meningitis. An oral prodrug of acyclovir, valacyclovir, has better oral bioavailability than acyclovir and may lead to better CSF acyclovir levels. In patients with recurrent HSV meningitis, it may be useful to give the patient oral acyclovir or valacyclovir to keep at home and take with the onset of symptoms of aseptic meningitis. Pleconaril, an antiviral drug designed to block enteroviruses from attacking and entering host 58 cells, may be of benefit in severe enteroviral infections in immunosuppressed individuals. Unfortunately, studies suggest limited value in the treatment of typical enterovirus 59 meningitis and no value in the treatment of acute poliomyelitis. The drug has not received U.S. Food and Drug Administration (FDA) approval. Therefore, treatment remains symptomatic. Because enterovirus meningitis can rapidly be diagnosed using a PCR assay of CSF for enteroviral RNA, hospitalization may not be required unless the patient is dehydrated from fever and vomiting or it is necessary to exclude a more serious form of meningitis. One study reported that use of the enterovirus PCR assay in the emergency department in children with aseptic meningitis resulted 60 in significantly less antibiotic use, shorter length of hospitalization, and lower hospital costs. VIRAL ENCEPHALITIS Viral encephalitis is due to a viral infection of the brain parenchyma. The viral infection causes widespread death of neurons and glia, with accompanying inflammation and edema. Each year in the United States, between 1,000 and 5,000 61 cases are reported to the CDC. Most of the cases occur during the summer and early fall. Viral encephalitis occurs worldwide, with a particularly high incidence in the tropics. Table 44-4 outlines the major viruses that cause encephalitis in the United States and lists some of their distinguishing characteristics. However, studies of encephalitis from Europe and the United States using comprehensive diagnostic methods report identifying an etiology in only about 50 percent of 85–87 cases. Click here to view this table.... The hallmark of encephalitis is the abrupt onset of deterioration of mental status, low-grade headache, and fever (Table 44-5). Encephalitis differs from meningitis in that18the patients have prominent mental symptoms and minimal signs of meningeal irritation. The mental changes may include confusion, delirium, or lethargy that fluctuates and can progress to 27,66,74 On stupor and even coma. Seizures often occur and may be generalized or focal. physical examination, patients may demonstrate hyperreflexia, mild spasticity, and Babinski signs. Papilledema is occasionally present. Some patients develop focal neurological signs, including hemiparesis, cranial nerve palsies, aphasia, ataxia, tremor, dysarthria, and cortical 66 blindness. Depending on a variety of factors, including patient age (the very young and the elderly do worst) and particular strain of the virus, the encephalitis may be mild or severe. Click here to view this table.... Many patients have a prodromal illness several days before the onset of the encephalitis. The prodrome may include parotitis (mumps) or fever, malaise, and myalgias (arboviruses). However, no prodromal illness develops in HSV encephalitis. 88
Laboratory findings in viral encephalitis vary. The leukocyte count is often elevated in the blood. Blood urea nitrogen, creatine kinase, and transaminase levels may be elevated
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(particularly with arbovirus encephalitis). Hyponatremia may occur from inappropriate 66 secretion of antidiuretic hormone. A lumbar puncture shows a normal or elevated opening pressure. The CSF usually contains five to several hundred WBCs per cubic millimeter, 75 which are mainly lymphocytes. In occasional cases, the CSF is acellular or hemorrhagic. The CSF glucose is usually normal, whereas the protein level is elevated in the 89 range of 50 to 200 mg/dl. Bacterial cultures are sterile. Viruses are seldom isolated from CSF. The EEG is always abnormal and typically shows diffuse background slowing with occasional epileptiform or electrographic seizure activity. If 2-Hz, high-voltage periodic complexes develop in the temporal lobe area, the possibility of HSV encephalitis is increased. Early in the illness, MRI studies may show areas of increased signal on T2-weighted and diffusion-weighted images, 90 which can be multifocal or mainly in the frontal or temporal lobes. The CT scan is often normal early in the illness,75but later it shows areas of increased vascular permeability, necrosis, or hemorrhage.
Diagnosis of Encephalitis During an epidemic, the diagnosis of a classic case of encephalitis is not difficult. However, sporadic cases may be difficult to distinguish from cases of metabolic encephalopathy. The presence of fever, headaches, fluctuating mental changes, focal neurological signs, or 18 seizures (particularly if focal) favor encephalitis over encephalopathy. Similarly, the presence of a blood leukocytosis, CSF pleocytosis, and focally abnormal areas on the EEG, brain scan, or MRI favor encephalitis over encephalopathy. In years past, all cases of encephalitis were treated symptomatically, and the diagnosis was 70 made during convalescence with the use of serological tests. With the advent of specific antiviral drugs, such as acyclovir for treating HSV encephalitis, there is now a need to determine rapidly the etiology of the encephalitis. Several factors may help to narrow the list of possible viruses. In the United States, arbovirus encephalitis occurs predominantly during the summer and fall, when the vector (mosquito or tick) is present. Similarly, cases of arbovirus encephalitis usually cluster and may develop into epidemics. Occasionally, the prodromal illness is of help. The presence of parotitis suggests mumps meningoencephalitis. Rashes may accompany Colorado tick fever, varicella-zoster (dermatomal rash), or Rocky Mountain spotted fever (Rickettsia) infections. Thrombocytopenia may develop from Rocky Mountain spotted fever, lymphocytic choriomeningitis, and Colorado tick fever infections. Many serological tests for encephalitis require acute and convalescent sera and therefore are 89 not helpful early in the illness. Recently, an immunoglobulin (Ig) M antibody capture enzyme-linked immunosorbent assay71(MAC ELISA) has been developed for detecting early antibody to arboviruses, but not HSV. Currently West Nile neuroinvasive disease is diagnosed in a patient with acute 62 encephalitis or myelitis by detection of IgM antibodies to West Nile virus in serum or CSF. Detection of viral nucleic acid in CSF or other tissues using PCR is becoming a rapid, sensitive, and specific method for the early detection of many viruses that cause encephalitis. 88 It is now the standard method for diagnosis of herpes simplex and enterovirus encephalitis but has not become standard for arbovirus encephalitis.
Herpes Simplex Encephalitis Encephalitis from HSV type 1 is the most common cause of sporadic encephalitis. Unfortunately, HSE has no characteristics that easily distinguish it from other types of 75,76 HSE occurs worldwide, during all seasons and at all ages. However, one encephalitis. third of cases occur in individuals younger than 20 years and 50 percent occur in those older than 50 years. HSE75has no characteristic prodromal illness and no specific serum or CSF laboratory findings. Isolation of the virus from the mouth is not helpful, as it commonly occurs in any individual with an acute febrile illness. MRI has been helpful in suggesting the diagnosis. It frequently demonstrates edema or necrosis in one or both medial temporal lobes 91 in the first few days of illness. When early MRI abnormalities are seen in the temporal lobe, the possibility of HSE increases, but this90abnormality is not diagnostic. Cranial CT often does not become abnormal for several days. Attempts to develop early antibody serological tests for HSE have been difficult. Most individuals have previously been infected with HSV during childhood, and therefore most older children and adults have serum IgG antibodies to HSV. IgM antibody in HSE seldom develops. Intrathecal HSV antibody synthesis and low ratios of CSF/serum HSV antibody titers do develop76,77 in patients with HSE but take one or more weeks and thus are not helpful for early diagnosis.
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In the past, brain biopsy with isolation of HSV from the brain tissue was the standard method 76,89 At present, use of the PCR assay of CSF for the presence of making a definite diagnosis. of HSV DNA fragments has become the standard and is widely available. In the first 4 days of encephalitis, the PCR test of CSF is positive in 92 more than 95 percent of cases, and HSV DNA can be detected in about 80 percent at 1 week. A few patients with proven HSE may have a PCR assay of the CSF that is negative initially but becomes positive for HSV on a second CSF examination. Patients of all ages with sporadic encephalitis of unknown cause should be considered as having possible HSE. It is now being recognized that atypical clinical 93 pictures occur in about 15 percent of patients with positive PCR assays of the CSF for HSV. In general, these patients present with milder encephalitis that progresses more slowly and has a better prognosis, even if acyclovir treatment is delayed. However, MRI frequently shows abnormalities in the temporal lobe.
West Nile Neuroinvasive Disease In recent years, West Nile neuroinvasive disease has become the most common cause of 62 encephalitis in the United States and has occurred in almost every one of the contiguous states. More than 4,000 cases have been reported to the CDC since 1999 when West Nile virus, an arbovirus, appeared in the United States. In nature, the virus cycles between many 63 types of birds and many strains of mosquitoes. Human infections occur when a mosquito carrying the virus bites a human. Since the virus is mosquito borne, cases of West Nile neuroinvasive disease develop mainly in the summer and fall and often in clusters. Unusual infections also occur following transfusions of blood infected with West Nile virus, after 62,94 infected organ transplants, or by transplacental spread. About 80 percent of West Nile virus infections are asymptomatic, 20 percent result in mild febrile illness called West Nile fever, and 1 to 2 percent develop West Nile neuroinvasive disease. The risk of developing this disease increases in the elderly and those who are immunosuppressed, such as in patients who are transplant recipients; it is quite uncommon in children. The majority of patients with West Nile neuroinvasive disease develop typical 62,95 About 10 percent of encephalitis that is mild to moderate in severity, but death may occur. patients also 96 develop flaccid paralysis of one or more limbs that resembles paralytic poliomyelitis. In the CNS, the virus predominantly infects neurons, particularly in the brainstem. When the virus invades the spinal cord, anterior horn neurons are mainly infected. 3 The CSF typically shows a pleocytosis of 50 to 200 lymphocytes/mm , normal glucose concentration, and mildly elevated protein level. As noted previously, detection of IgM antibody to West Nile virus in CSF or serum is the usual method of establishing the diagnosis.
Treatment of Viral Encephalitis 70
Treatment of all types of viral encephalitis requires excellent symptomatic care. Patients should be placed in an intensive care unit early in the illness because the encephalitis may progress rapidly. If seizures develop, anticonvulsant drugs such as phenytoin should be given. Increased intracranial pressure often develops as a consequence of vascular engorgement and cerebral edema, but placement of an intracranial pressure monitor is seldom necessary. Treatment of increased intracranial pressure consists of nasotracheal intubation with hyperventilation from a mechanical ventilator. Arterial partial pressure of carbon dioxide (Pco2) should be maintained between 25 and 30 mmHg. Mannitol, at a dose of 0.25 to 0.50 g/kg, may be given intermittently as an intravenous bolus to control pressure. Serum osmolality should be monitored to ensure that it is maintained below 320 mOsm/L. Use of corticosteroids is controversial, as much of the cerebral edema appears to be cytotoxic, which usually does not respond to corticosteroids. All patients should receive excellent nursing care to prevent decubitus ulcers, corneal abrasions, and contractures. Optimal oxygenation of the patient should be maintained. During convalescence, patients may require physical therapy and speech therapy. Neuropsychological testing is often needed to assess intellectual damage. The length of convalescence varies with the severity of the illness, but several months may be required. There is now an effective antiviral treatment for HSE. Acyclovir has been found to inhibit HSV thymidine kinase and effectively interferes with both type 1 and 2 HSV replication. Acyclovir has considerably less potency against other members of the herpesvirus family. The earlier in 74,76 Patients the course of encephalitis that the acyclovir is given, the better is the outcome. who are lethargic at the start of therapy do better than those who are comatose. Acyclovir not only increases the number of patients who survive but also improves the quality of survival. The acyclovir should be given as 30 mg/kg per day divided into three doses. It is given intravenously and slowly (over at least 1 hour) because rapid administration can cause acute
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renal toxicity, particularly in a dehydrated patient. In patients receiving acyclovir, the urine output should exceed 100 ml/hr. Acyclovir should be given for 14 to 21 days. A longer treatment period may be necessary if the patient is immunosuppressed or taking corticosteroids since relapses after a shorter course occur occasionally. Because acyclovir is most effective when given early, the drug is often administered when the diagnosis if first suspected and continued until the result of the PCR assay of CSF for HSV is known. If another diagnosis is established or the CSF PCR assay is negative and MRI does not demonstrate typical temporal lobe involvement, administration of acyclovir usually may be discontinued. Currently, there are no antiviral medications for arbovirus infections, so treatment is symptomatic. The acute illness generally lasts 1 to 3 weeks. Convalescence is slow, taking months for recovery of cognition. 4,66,70
Rabies encephalitis The prognosis of viral encephalitis depends on the etiological agent. is usually fatal. Eastern equine, Japanese B, Murray Valley, and Russian spring-summer encephalitides are usually severe, with mortality rates as high as 20 to 40 percent; permanent neurological sequelae are seen in as many as 50 percent of survivors. These neurological sequelae include dementia, seizures, and focal neurological deficits such as hemiparesis, aphasia, cranial nerve palsies, and ataxia. West Nile neuroinvasive disease, Western equine encephalitis, St. Louis encephalitis, California encephalitis, and mumps encephalitis are moderately severe, with a 2 to 10 percent mortality rate; 5 to 10 percent of patients are left with permanent sequelae. Venezuelan equine encephalitis and Colorado tick fever viruses cause mild encephalitis from which full recovery occurs. PARALYTIC POLIOMYELITIS Poliovirus does not infect glia or all neurons but selectively infects specific neuronal 97 populations, mainly of the motor system. Instead of developing encephalitis, patients develop an illness characterized by weakness and atrophy of skeletal muscles. Although most cases of paralytic poliomyelitis are due to infection with poliovirus, occasional cases have been reported due to enterovirus or arbovirus. In the United States, paralytic poliomyelitis from wild virus currently does not occur. From 1960 to 2000, poliomyelitis occasionally developed as a complication of administration of the live oral polio vaccine 9 (Sabin vaccine). However, in developing countries, such as Africa and Asia, that do not widely administer the vaccine, poliomyelitis from wild virus still occurs. Although most poliovirus infections result in asymptomatic illness, approximately 1 in 1,000 young children 9 who are infected develop paralysis. In adults, the risk may be as high as 1 in 100 infections. In patients who develop paralysis, the incubation period is 4 to 10 days. The illness begins 9,28 Some with malaise, headaches, and fever followed 1 day later by neck and back stiffness. 2 to 5 days later, the weakness begins. Patients often complain of stiff, sensitive, painful muscles. A progressive asymmetric flaccid weakness develops, typically with greater involvement of the proximal than distal muscles. Legs are more often affected than arms. Atrophy begins in involved muscles about 5 to 7 days after the onset of weakness and progresses over several weeks. The muscles of the thorax and trunk occasionally are severely involved. About 10 to 15 percent of patients develop pharyngeal and laryngeal muscular weakness, along with a facial diplegia. In rare patients, there is involvement of the reticular formation, thalamus, and hypothalamus, with lethargy, respiratory difficulties, and 97 3 20 to 500 WBCs/mm , mildly elevated autonomic instability. The CSF typically contains 9 in the protein concentration, and normal glucose level. Initially, neutrophils predominate 98 CSF, but the fluid soon converts to contain predominantly lymphocytes. Other routine laboratory tests are usually normal. Poliomyelitis should be suspected in any patient with rapidly progressive, asymmetric weakness and CSF with a lymphocytic pleocytosis. The diagnosis can be confirmed by 9 isolating the poliovirus from the throat or stool specimens or from the spinal cord at autopsy. Poliovirus is rarely isolated from CSF. All poliovirus isolates from patients should be sent to reference laboratories to determine whether the virus is wild type or vaccine-like. Since 2000, only the inactivated poliovirus vaccine (Salk) is administered in the United States, but many countries including Mexico continue to use the live oral poliovirus vaccine. There is no specific antiviral treatment for poliomyelitis. Patients should be hospitalized and 98 watched carefully for respiratory complications. If the vital capacity decreases to less than 30 to 50 percent of predicted volume, if respirations become irregular or labored, or if arterial oxygen tension decreases, the patient should be placed on assisted ventilation. Patients with severe paralysis often experience rapid resorption of bone with increased serum and urinary calcium that can result in nephrolithiasis or bladder calculi. Adequate hydration and
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acidification of the urine should be ensured to prevent the formation of urinary stones. Patients with severe muscle weakness usually require extensive physical therapy during convalescence. Death occurs in about 8 percent of patients, usually from bulbar involvement. In survivors, strength begins to increase a few weeks after the acute illness ends. By 6 months, 80 percent of young patients have made a good or full recovery. The prognosis is somewhat poorer for older children and adults. Poliomyelitis can be effectively prevented through immunization with either killed (Salk) 99 100 trivalent poliovirus vaccine or live (Sabin) trivalent poliovirus vaccine. However, use of the killed vaccine requires repeated boosters of the vaccine throughout life to maintain effective immunity. Live poliovirus vaccine, on the other hand, should not be given to individuals with a possible immunodeficiency because they are at increased risk of developing paralytic 100–103 poliomyelitis.
Postpolio Syndrome It is now recognized that individuals with a history of poliomyelitis years earlier are at risk of 104,105 The clinical features of the postpolio syndrome include developing late complications. progressive weakness, fatigue that does not correlate with the weakness, and muscle and joint pains. Joint problems include arthritis, tendinitis, bursitis, and ligament strain from incorrect posture and use of the joints. The neurological signs may include new muscle weakness, fasciculations, cramps, respiratory insufficiency, sleep apnea, dysarthria, and dysphagia. Individuals at particular risk are those who were older at the onset of the acute poliomyelitis, had severe disease, and were very active after their recovery. Currently, the diagnosis of postpolio syndrome requires a credible history of poliomyelitis, partial recovery, a minimum of 10 years of stability, and progressive weakness that cannot be explained otherwise. Numerous studies have failed to find any evidence of poliovirus persistence as the cause of the progressive weakness. Current hypotheses include loss of the branching axons of anterior horn cell neurons that sprouted to reinnervate skeletal muscle fibers whose axons were lost during the acute poliomyelitis or death of the enlarged motor neurons that sprouted and subsequently died due to excessive metabolic demand. At present, there is no specific treatment for the syndrome, but careful physical therapy with exercise to strengthen weak muscles does not seem to accelerate disease progression. At times, splints and other orthopedic appliances may be of benefit. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Progressive multifocal leukoencephalopathy is a rare progressive demyelinating disease of the CNS white matter that usually develops in adults with impaired immune responses, such 106,107 However, recently a few cases have as acquired immunodeficiency syndrome (AIDS). developed in adults receiving immunosuppressive therapy for multiple sclerosis and Crohn's disease with natalizumab, a humanized neutralizing monoclonal antibody directed against 108 alpha 4 integrin expressed by leukocytes. The disease appears to result from recrudescence of a previous childhood infection with a papovavirus (JC strain), and 109 antibodies to the JC strain are found in most normal adults. The initial signs and symptoms usually indicate multifocal lesions in the cerebral hemispheres, but often the signs from one hemisphere predominate. The onset is insidious, often with a slowly progressive hemiplegia, dysarthria, personality change, or homonymous hemianopia. Fever, headache, and meningismus are not present. The disease steadily progresses to death over 6 months to several years. The CSF is normal, and the EEG usually shows nonspecific slowing. Cranial MRI and CT show multifocal areas of discrete white matter damage (Fig. 44-1). No laboratory 110 or serological test is diagnostic. A clinical diagnosis can now be made in an immunosuppressed patient with a characteristic clinical history, MRI with white111matter lesions, and CSF that contains DNA fragments of the JC virus by PCR assay. It should be noted that occasional patients with AIDS have had CSF that was positive for JC virus by PCR assay in the absence of clinical signs or typical MRI changes. The diagnosis can also be made by brain biopsy, with electron microscopic identification of intranuclear inclusions within oligodendrocytes or of papovavirus virions within oligodendrocytes. Virus can be isolated 106,107 No from brain biopsy sample by inoculation onto human fetal glial tissue culture cells. effective antiviral treatment is available, but improving the patient's immune status may slow the rate of disease progression.
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FIGURE 44-1 Sagittal T1-weighted (A) and axial T2-weighted (B) magnetic resonance imaging (MRI) at the level of the occipital lobes, showing multifocal areas of discrete white matter change in a patient with progressive multifocal leukoencephalopathy.
HERPES ZOSTER (SHINGLES) Varicella-zoster virus, a member of the herpes family of viruses, causes herpes zoster (shingles). Herpes zoster typically develops in patients who, decades earlier, had a primary infection with varicella-zoster virus as chickenpox. 112 Following the primary infection, the virus The incidence of herpes zoster ranges becomes latent within neurons of sensory ganglia. 113,114 Most cases are seen in patients older from 1.3 to 4.8 cases per 100,000 person-years. than 50 years. The precipitating cause of herpes zoster is unknown in many cases. However, systemic cancer, irradiation of the vertebrae, immunodeficiency, spinal trauma, and old age are recognized as precipitants. The patient usually experiences a sharp, burning discomfort in a dermatomal distribution for 2 to 5 days before the onset of the rash. A localized redness with red macules that become 114 vesicles develops in the same dermatomal pattern. New vesicles usually appear over the first 2 days, but occasionally continue to appear over the first week. The vesicles evolve to pustules and form crusts in 2 weeks. Often, the regional lymph nodes become swollen. The distribution of herpes zoster is usually unilateral and involves a single dermatome. The rash appears on the trunk in 50 percent, on the head in 20 percent, on the arms in 15 percent, and on the legs in 15 percent of cases. Over the next month, the dermatomal pain slowly disappears, leaving a residual hypalgesia or hyperalgesia. Treatment of acute herpes zoster depends on the severity and location of the dermatomal
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rash and immunocompetence of the individual. Individuals with a mild rash may require only 115 symptomatic treatment with non-narcotic analgesics. Individuals with severe zoster rash, especially 115 involving the face, or who are suspected of being immunodeficient require antiviral 116 orally three times daily for 10 to 14 days, treatment. Treatment with famciclovir 500 mg 117 acyclovir 800 mg orally 5 times daily for 10 days, or acyclovir 7.5 mg/kg given slowly 118 intravenously over 1 hour 3 times per day for a total of 7 days has been shown to shorten the period of acute dermatomal pain, to accelerate cutaneous healing of the rash, and to prevent virus dissemination. However, these drugs have not been shown to reduce the incidence or severity of postherpetic neuralgia. The use of zoster immunoglobulin has not been shown to be beneficial. The use of prednisone 40 to 60 mg daily for 10 days plus an antiviral drug during the acute rash may lessen the pain of acute shingles when given with an 119 antiviral drug, but it does not prevent postherpetic neuralgia. It is now possible to prevent shingles in the elderly by immunizing the person with a live attenuated varicella-zoster, Oka strain, virus vaccine (Zostavax) that was approved by the FDA in 2006. A major study demonstrated that elderly healthy individuals who received the varicella vaccine had a 61 percent reduction in the incidence of shingles and a 67 percent reduction120 in the incidence of postherpetic neuralgia compared to those receiving a placebo. Complications from acute herpes zoster develop from spread of the virus to the eye (herpes 121 122 roots or motor nerves, spinal cord (myelitis), brain zoster ophthalmicus), the anterior 80 123 (small- or large-vessel vasculitis), and the entire body (disseminated zoster). Herpes zoster auricularis or Ramsay Hunt syndrome, in which there is involvement of motor fibers of the facial nerve, is characterized by marked peripheral facial weakness, with pain 124 and vesicles appearing over the skin of the external pinna and external auditory canal. Varicella-zoster virus occasionally causes a progressive white matter viral infection involving a small-vessel vasculitis with small ischemic infarctions and demyelination from infection of 125 oligodendrocytes. The CNS infection usually occurs in immunocompromised patients who experienced shingles in the previous month. A large-vessel vasculitis of the internal carotid or large cerebral arteries also can occur, producing a sudden contralateral hemiplegia or 126 ipsilateral central retinal artery occlusion. Most patients will have had shingles, usually involving the face, 1 to 2 months earlier. Diagnosis usually can be made by a cerebral arteriogram demonstrating arteritis and a CSF PCR assay positive for varicella-zoster DNA fragments. Limited anecdotal cases suggest that patients respond to treatment with acyclovir administered intravenously in a dose of 15 to 30 mg/kg for 10 to 14 days. Postherpetic neuralgia, pain in the distribution of the rash that persisted longer than 3 months, is a dreaded complication of shingles and occurs in 9 to 14 percent of patients with 127,128 In one third of these individuals, the pain persists for a year or more. The herpes zoster. incidence of postherpetic neuralgia increases with age. About 10 to 20 percent of patients older than 60 years develop postherpetic neuralgia. Three types of pain occur. Burning pain is a steady, burning, boring, or tearing aching pain, whereas lancinating pain is paroxysmal, jabbing, and ticlike; allodynia is severe discomfort brought on by touching or lightly rubbing the involved skin with clothing. The pathogenesis of postherpetic neuralgia is unknown, and the pain is difficult to treat. Several drugs help to reduce but do not eliminate the pain of postherpetic neuralgia.129The most commonly used drugs are nortriptyline up to 100 to 150 mg 130 up to 900 mg daily in divided doses, gabapentin daily in divided doses, oxcarbazepine 131 up to 2,400 mg daily in132 divided doses, and divalproex sodium up to a dose of 1,000 mg daily in divided doses. Lidocaine patches or capsaicin cream to the rash area are only occasionally helpful. POSTVIRAL ENCEPHALOMYELITIS (ACUTE DISSEMINATED ENCEPHALOMYELITIS) It is apparent that some viruses appear capable of damaging the nervous system by mechanisms other than conventional viral replication (viral encephalitis) (Table 44-6). Acute disseminated encephalomyelitis (ADEM) is the abrupt development of multiple neurological 207 signs related to a monophasic, inflammatory, demyelinating disorder of the CNS. ADEM occurs most commonly in children, but adult cases are recognized. In solitary case reports, 207 many different viruses have been associated with ADEM (reviewed elsewhere ). Vaccination with live virus vaccines (measles, rubella, vaccinia) or killed virus vaccines (influenza, rabies) also occasionally has been reported to cause a similar postvaccinal encephalopathy or encephalomyelitis. Although associated with a variety of viruses, postviral encephalomyelitis has several features in common. The neurological symptoms typically begin during the late stages of the primary illness, the neurological illness is monophasic, and the clinical disease207,208 is characterized by depressed levels of consciousness and multifocal Fever develops in half and seizures in one fourth. The pathology is neurological signs.
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one of inflammatory perivascular infiltrates, localized edema, and demyelination. Lesions that are seen best on T2-weighted MRI are usually multiple, bilateral, asymmetric, and localized mainly in the subcortical white matter, thalamus, and basal ganglia. Click here to view this table.... Measles is thought to have the highest rate of postviral encephalomyelitis (100 cases per 124,209 Varicella-zoster virus has an incidence of about 10 cases 100,000 primary infections). per 100,000 primary infections, but many are a localized cerebellar ataxia. Rubella has an incidence of about 5 cases per 100,000 primary infections. Neurological complications 210 following influenza virus often present as an encephalopathy (normal MRI and CSF) but ADEM is recognized.
Measles Uncomplicated measles frequently has neurological manifestations. Many children complain of headache, myalgia, lethargy, and photophobia. An abnormal EEG, demonstrating 209 pathological slowing of the background activity, occurs in about 50 percent of individuals. In 10 percent, lumbar puncture demonstrates a CSF pleocytosis. Behavioral disturbances are thought by some to occur211,212 more frequently during the months immediately following However, other studies have shown no significant increase in uncomplicated measles. 213,214 The etiology of the mental retardation or minor neurological signs following measles. acute neurological manifestations of measles is unknown, and rubeola virus has not been isolated from CSF or brain. About 1 per 1,000 individuals develop encephalomyelitis associated with measles. This neurological illness begins 2 to 7 days after the onset 133–138 of rash, usually when the rash is fading Older children and adults are and the child is recovering from the primary measles. disproportionately affected. The common clinical signs include depressed levels of consciousness, seizures, and focal neurological signs, including hemiparesis, paraparesis, and ataxia. Less common signs include cranial nerve palsies, choreoathetosis, and myoclonus. The EEG is abnormal, showing diffuse slow activity. The CSF typically shows a mononuclear cell pleocytosis with protein elevation. However, the CSF is normal in approximately one third of patients. Contrast-enhanced CT scans are usually normal, whereas MRI may demonstrate focal areas of increased signal intensity, primarily in cerebral white matter and the brainstem. Pathological studies have shown multiple focal areas of perivenous mononuclear cell cuffing 136 and demyelination. In more severe cases, perivenous hemorrhage, edema, and adjacent nerve cell damage may occur. Viruses have only rarely been isolated from CSF or brain in 215 was not found in the brains of 10 patients who died with these patients, and viral antigen 216 Intrathecal synthesis of rubeola virus antibody rarely postmeasles encephalomyelitis. 134 occurs. Thus, the pathology, virology, and immunology of postmeasles encephalomyelitis differ considerably from the findings in more conventional viral encephalitis and from two other CNS complications of measles, subacute sclerosing panencephalitis and progressive measles encephalitis.
Chickenpox Varicella-zoster virus causes uncomplicated chickenpox in most children. Occasional children, however, develop CNS symptoms as they are recovering from chickenpox, most 133,137,138,145 Limb and gait ataxia appear an average of commonly an acute cerebellar ataxia. 21 days after the onset of the rash. The CSF may contain a mononuclear pleocytosis and increased protein concentration. The pathology of this acute cerebellar ataxia is unknown.
Management of Postviral Encephalomyelitis Patients with severe postviral encephalomyelitis should be hospitalized in an intensive care unit. There is no proven specific treatment. High-dose corticosteroids, such as dexamethasone (1 mg/kg per day intravenously), methylprednisolone (10 to 30 mg/kg per day intravenously) or prednisone (40208 to 60 mg daily orally in adults) are often administered for 5 to 10 days during the acute illness. Other investigative treatments include plasmapheresis and intravenous γ-globulin. Symptomatic treatment for controlling body temperature, seizures, and intracranial pressure should be undertaken. The use of intracranial pressure monitoring may be worthwhile. If intracranial pressure is increased, the use of hyperventilation and intravenous mannitol, 0.25 to 0.5 g/kg, in boluses may be helpful.
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The prognosis of patients with mild ADEM or acute cerebellar ataxia is good, with recovery 133,137,138 Individuals with severe encephalomyelitis, typically occurring over several months. particularly from measles, carry a worse prognosis with a mortality rate of 25 percent, and many survivors have permanent neurological sequelae that include mental retardation, 137 behavioral problems, spasticity, ataxia, hemiparesis, and paraparesis. Up to one third of older children and adults initially diagnosed with ADEM have subsequent episodes and are 207,208 diagnosed as having multiple sclerosis. TRANSVERSE MYELITIS AND MYELOPATHY 146,158,160
Transverse myelitis is a clinically recognized entity that follows viral infections. The disease affects persons of158,160 all ages, but the incidence appears somewhat increased during Transverse myelitis has been reported to occur following the second decade of life. several viral infections and vaccines (Table 44-6), but in the majority of instances, an antecedent infection cannot be recognized. The initial symptoms usually include fever, pain in the back and legs, muscle weakness, sensory disturbances, and sphincter dysfunction. The tendon reflexes are usually decreased or absent during the acute stage, and the affected limbs have diminished muscle tone. The extent of leg weakness ranges from difficulty in walking to paralysis. Over the next several weeks, most patients develop hyperactive reflexes, spasticity, and extensor plantar responses. The interval between the first symptom and maximal neurological deficit ranges from hours to 1 to 2 weeks. Usually, a sensory level is identified in the patient, most often in 167 the thoracic segments but occasionally in the cervical or lumbar segments. Most patients present with a CSF pleocytosis and elevated protein concentration. The pleocytosis may have a predominance of either neutrophils or lymphocytes. The CSF protein levels may be as high as 500 mg/dl. However, about one fourth of patients present with normal CSF. Myelography is normal, but MRI of the spinal cord often demonstrates focal areas of increased signal within the cord that range over several vertebral segments. Since patients rarely die during the acute illness, there are limited pathological studies that 217 show focal areas of necrosis, inflammation, or perivenous demyelination. The criteria for the diagnosis usually include the following: (1) an acutely developing paraparesis, with motor, sensory, and sphincter disturbances; (2) spinal segmental levels of sensory disturbances; (3) a stable, nonprogressive clinical course after the acute phase; (4) no evidence of spinal cord compression; and (5) the absence of other known neurological diseases that affect the spinal cord, such as syphilis, severe back trauma, encephalitis, and 160 malignant disease with spinal metastases. Patients should be hospitalized, usually in the intensive care unit. Catheterization of the 218 bladder is often necessary. High-dose corticosteroids are often given, but their efficacy is not proven in randomized trials. Additional empirical treatments include plasmapheresis, intravenous γ-globulin, and even immunosuppressive drugs. About one third of158,160 patients make a good recovery, one third make a moderate recovery, and one third do poorly. Occasionally, in adults, the acute transverse myelitis is the first episode of multiple sclerosis 219 or, rarely, neuromyelitis optica. OPTIC NEURITIS Several viral infections have been associated with optic neuritis (Table 44-6), but most cases 220 are idiopathic. The incidence is about 3 per 100,000 people per year. As the primary viral infection is subsiding, the patient develops a subacute progressive loss of central vision with 164 decreased visual acuity. The visual loss is unilateral in about 75 percent of patients. Patients may complain of drabness or desaturation of colored objects, especially red objects, and decreased appreciation of brightness in the involved eye such that a swinging light from the normal eye to the eye with optic neuritis induces dilation of the pupil (Marcus Gunn phenomenon). Retrobulbar pain, exacerbated by eye movement, is usually present. The retina and optic disc appear normal (retrobulbar optic neuritis) in two thirds of patients or show evidence of papillitis. With papillitis, the disc is edematous with blurred margins, and the retina is edematous, often with flame hemorrhages. Visual evoked potentials may be unobtainable, attenuated, or prolonged in latency. CT scan and skull radiographs are usually normal but T2-weighted MRI may demonstrate increased signal within the optic nerve. The CSF is usually normal. Spontaneous recovery of vision usually occurs in 4 to 12 weeks. Intravenous methylprednisolone hastens recovery of visual function but does not affect 164 that oral prednisone alone may increase long-term visual outcome. There is some concern 221 the risk of subsequent attacks of optic neuritis. Most patients make a good recovery, but some individuals are left with a relative central visual defect or a pericentral visual defect and slightly decreased color vision. Visual acuity usually returns to better than 20/40, and most
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patients maintain good to excellent visual function for over 10 years. About 40 percent of 219,223 adult patients subsequently develop multiple sclerosis or, rarely, neuromyelitis optica. The risk of multiple sclerosis is increased to 56 percent in patients in whom brain164,220 MRI demonstrated one or more white matter lesions suggestive of multiple sclerosis. DEAFNESS AND VERTIGO Mumps, measles, varicella-zoster, influenza, and HSV infections have been those most often 224 associated with acquired deafness and vertigo. During the primary infection or as it is subsiding, patients experience the abrupt onset of unilateral sensorineural hearing loss, vertigo, or both. Patients may complain of tinnitus, nausea, and vomiting, which may be severe. Otitic pain is uncommon. On examination, the patient usually exhibits deafness or a high-frequency sensorineural hearing loss, often with hypoactive caloric responses on the involved side. The vertigo typically resolves over weeks, but the hearing loss may be permanent. The inner ear damage may result from direct viral invasion of the inner ear or possibly from an immune-mediated process. Rubella and cytomegalovirus can cause 186,189 With the congenital hearing loss, which may suddenly worsen 5 to 20 years later. advent of sensitive assays, such as PCR, to detect viral nucleic acid, herpes sim plex, cytomegalovirus, and varicella-zoster viral DNA has been detected within endolymphatic or 225,226 227 or auditory or vestibular ganglia in both normal patients and perilymphatic fluid patients with sudden hearing loss, vestibular neuritis, and Meniere's disease. This may suggest that latent herpes viruses are involved in these illnesses. However, their exact role, if any, in the pathogenesis of these illnesses remains uncertain. GUILLAIN–BARRÉ SYNDROME Guillain–Barré syndrome (GBS) 228,229 has been divided into four types, with acute idiopathic 230 and acute motor axonal neuropathy (AMAN) being inflammatory neuropathy (AIDP) the most common types. In North America and Europe, AIDP accounts for more than 90 percent of cases, whereas in Asia and Central and South America, AMAN accounts for one 231 231 third of cases. The clinical features are similar, but the pathology is different. In AIDP, there is multifocal mononuclear cell infiltration of peripheral nerves that corresponds to the clinical deficit. The macrophage immune attack is primarily directed against myelin. Focal areas of segmental demyelination are usually seen throughout the peripheral nerves as the disease progresses. In AMAN, macrophages invade the nodes of Ranvier where they insert between the axon and the surrounding Schwann cell membrane, leaving the myelin sheath intact. In severe cases of AMAN, the involved axon degenerates. During the past decade, studies have strongly implicated bacterial and viral infections inducing antibodies that cross-react with neural antigens leading to Guillain–Barré syndrome. infections as a likely cause Attention has primarily focused 167–169 on Campylobacter jejuni bacterial 169,170 of AMAN and cytomegalovirus, Epstein–Barr virus, and nonspecific upper 232 respiratory illnesses as likely causes of AIDP. Case reports also have associated other viruses and vaccines (Table 44-6). Viruses have not been successfully isolated from involved peripheral nerves, but cytomegalovirus DNA has been identified by PCR in the CSF of 31 231 percent of cytomegalovirus-seropositive patients with Guillain–Barré syndrome. Guillain–Barré syndrome occurs during all seasons, affects both children and adults, and 231–234 Patients characteristically complain of involves males slightly more often than females. leg and foot paresthesias and weakness at the onset of the232–234 illness. Over the next 7 to 10 In most patients, the days, the patient develops a progressive flaccid weakness. weakness begins in the legs and ascends proximally. Initially, tendon reflexes are somewhat depressed, and they typically disappear as the illness progresses. Objective sensory loss is usually minor, involving vibration and position sense in the feet. Mentation is normal. In about 25 percent of patients, the weakness may progress, and respiration is sufficiently impaired that assisted ventilation is required. As discussed in Chapter 8, autonomic disturbances are common and may be life threatening, particularly cardiac arrhythmias and marked 235,236 Fever, lymphadenopathy, and splenomegaly are usually fluctuations in blood pressure. absent. The CSF is under normal pressure and is acellular, usually with an elevated protein 232 concentration. Infectious agents are not isolated from the CSF. Initially, motor nerve conduction231,237 velocities may be normal or depressed only slightly, but F and H waves are often Over the next several weeks, motor nerve conduction velocities become abnormal. markedly slowed. Most patients with this clinical picture have Guillain–Barré syndrome. However, diphtheria polyneuropathy, poliomyelitis, vasculitis, chronic inflammatory demyelinating polyneuropathy, tick paralysis, porphyria, and acute toxic neuropathies must be considered in the differential
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diagnosis. The pathogenesis of Guillain–Barré syndrome is unknown, but current evidence suggests both AIDP and AMAN result from abnormal immune responses. AIDP resembles experimental autoimmune neuritis, which is predominantly caused by T cells directed against peptides from231 the myelin proteins P0, P2, and PMP22 plus involvement of antibodies and complement. In AMAN, there is even stronger evidence that the weakness is triggered by antibodies to gangliosides on the axolemma that target macrophages to invade the axon at 231 the node of Ranvier. As noted previously, specific bacteria and viruses are thought to trigger the autoimmune event. It should be noted, however, that Guillain–Barré syndrome can 238 occur in individuals who are partially immunosuppressed. Patients with Guillain–Barré syndrome should be hospitalized, usually in an intensive care unit. Because the weakness may progress rapidly to involve the respiratory muscles, the patient's respiratory status must be assessed frequently. Respiratory assistance should be instituted at the first signs of dyspnea, usually when the vital capacity decreases to less than 800 ml or a decrease in blood oxygen saturation occurs. Nasotracheal intubation should be the first step, but prolonged respiratory failure may require a tracheostomy. Cardiac monitoring should be undertaken, as life-threatening cardiac arrhythmias may occur, 235,236 particularly during nasotracheal suction or when the patient is moved about in bed. Early treatment with plasma exchange or intravenous immunoglobulin (IVIg) is equally effective in reducing the time on a ventilator, shortening the time to ambulation, and 231 volumes of plasma improving return of full strength by 1 year. Patients usually receive five 231 exchange over 1 to 2 weeks or IVIg at a daily dose of 0.4 g/kg for 5 days. Since plasma exchange carries a somewhat higher complication rate, IVIg has become more popular. The 239 use of corticosteroids is not beneficial. 231,232
Prognosis is generally good, but 5 to 10 percent of patients still die. Excellent recovery occurs in more than 75 percent of survivors, but 20 percent of patients are left with some residual weakness. Recovery begins after a plateau phase of several weeks and may continue for up to 24 months. Persistent fatigue is a common residual in adults. Children tend to make a faster and better recovery than older adults. Histological studies have shown that remyelination of involved peripheral nerves occurs during recovery. Recurrences of Guillain–Barré syndrome are rare. CREUTZFELDT–JAKOB DISEASE It is now recognized that Creutzfeldt–Jakob disease (CJD) results from a special class of infectious agents, called unconventional agents or proteinaceous infectious particles 240–243 This class of infectious agents causes CJD, variant CJD, 244–246 kuru, (prions). In animals, Gerstmann–Straussler syndrome, and fatal familial insomnia in humans. scrapie, bovine spongiform encephalopathy, and chronic wasting disease of deer and elk are the most common. CJD is the most common prion disease in humans and has a worldwide distribution, with an 244 incidence of 1 to 2 cases per million population per year. The average age at onset is 60 years. Most cases are sporadic, but 12 percent cluster in families. Both sexes are equally involved. 247,248
The onset is insidious, with the The clinical features fall broadly into three phases. development of mental deterioration. The patient typically becomes forgetful and nervous, with a decline in work performance. A relentless, slowly progressive dementia then develops. Progressive memory loss, parietal lobe dysfunction, and dysphasia often develop. Behavioral disturbances include the appearance of personality change, apathy, irritability, depression, and paranoia. Systemic signs, such as fever, meningismus, adenopathy, and splenomegaly, do not develop. Headaches are rare. In the second phase, more than 85 percent of patients develop myoclonic jerks—involuntary, repetitive muscular contractions that are quick, shocklike, and of sufficient severity to cause visible displacement of limbs. They may be stimulus sensitive. Some patients develop spasticity with Babinski signs, whereas others develop cortical blindness, severe ataxia, or amyotrophy. In the third phase, the patient develops severe dementia, wasting, and spasticity. The clinical course to death usually ranges from 6 months to 2 years. The CSF is acellular, with a normal protein content. CSF and serum immunoglobulin levels are normal. The EEG is distinctly abnormal in 75 percent of cases, usually in the later stages of the illness. The tracing is characterized by repetitive, periodic, stereotyped, bilaterally 249 synchronous sharp waves, usually occurring at a frequency of 1 to 2 per second. They are often associated with myoclonic jerks. On cranial MRI, diffusion-weighted and
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fluid-attenuated inversion recovery imaging often demonstrate multifocal subtle foci of 250 hyperintensity in the putamen, caudate, thalamus, and gray matter of the cerebral cortex. Later in the illness, diffuse brain atrophy is seen on CT and MRI. The clinical diagnosis of CJD is usually made on the basis of a rapidly progressive dementia and development of myoclonic jerks coupled with laboratory tests demonstrating a characteristic EEG, 14-3-3 protein on CSF electrophoresis, and hyperintensities seen on 244 MRI. However, to date, there is no simple diagnostic test that is specific for CJD. Confirmed diagnosis requires characteristic brain histopathology and staining with specific prion antibody or demonstration of prions from homogenized brain by immunodiagnostic procedures. The conformation-dependent immunoassay245 appears to be the most sensitive and specific for brain tissue but is not sensitive for CSF. 246
The pathology appears to be confined to the nervous system. There is diffuse atrophy of the brain. Histologically, there are extensive loss of neurons, prominent astrocytic gliosis, conspicuous absence of inflammatory changes, and a characteristic spongiform change. This spongiform appearance is due to vacuoles located in the cytoplasm of neurons and astrocytes. Electron microscopy does not identify infectious particles in the brain. Technically, prions are not viruses but are included in this chapter because they are infectious particles. The characteristics of 240,241 this unique infectious sialoglycoprotein, called a It is of low molecular weight, hydrophobic, prion protein (PrP), are becoming clearer. 247,248 and tightly bound to membranes. The particle appears to amplify within the cytoplasm 243 and lacks a nucleic acid. The infectious agent appears not to stimulate a humoral or cellular immune response. Infectivity of the agent is not destroyed by common virucidal agents, such as ultraviolet light, formalin, β-propiolactone, and 100°C heat. However, it is 2 destroyed by autoclaving for 1 hour at 125°C at 20 lb/in or by soaking infected tissues for at least 1 hour in 2 M sodium hydroxide. More is becoming known about the pathogenesis of these unique infectious and inherited diseases. Current evidence strongly suggests that the nucleic acid for the prion lies cwithin a 240,246 The gene normally produces a cellular protein called PrP that is host's chromosome. found mainlyc in neuronal membranes. Under conditions that are not well characterized, the normal PRP can alter its three-dimensional structure to become the infectious prion or cjd PrP . Thus, the abnormal protein has the same amino acid sequence as that of the normal protein but is folded in a manner that alters its function and ability to be degraded. Somehow, c the abnormal protein can also induce normal PrP to refold into the abnormal configuration. Accumulation of prions in neurons leads to death of the neuron and to clinical disease. The presence of specific mutations in the PrP gene increases the likelihood of production of abnormal PrP. Furthermore, it appears that there are several three-dimensional configurations that the PrP protein can adopt, each producing a different clinical illness. Thus, CJD may develop because of a specific mutation in the host's PrP gene or by inoculation of infectious prions into an individual. Iatrogenic spread of CJD has been documented via infected244,248 corneal grafts, dural grafts, and growth hormone prepared from human pituitary Accordingly, patients who die from unexplained dementia should not be organ glands. donors. The infectious agent does not appear to be in saliva, urine, or stool. Therefore, spouses or individuals who are caring for the patient are not at increased risk of contracting the disease. The patient does not require isolation, but needles, blood, and CSF should be 251 considered infectious and should be autoclaved before being discarded. In general, animal prion diseases, such as scrapie, have not been thought to transmit to humans. However, there is considerable evidence that bovine spongiform encephalopathy 245 (mad cow disease) may rarely transmit to humans and cause a fatal illness. More than 150 cases of variant CJD, mainly from the United Kingdom, are thought to have resulted from consumption of infected beef containing prions. Such cases are primarily in younger individuals and present with psychiatric signs before the more classic features of CJD 244 disease develop. At present, no effective treatment exists for any prion disease. The mean time to death from clinical onset of sporadic CJD is 5 months, and 90 percent die within 1 244 year. ACKNOWLEDGMENTS The author is supported by the Neurology and Research Services, Veterans Administration Medical Center, and the Departments of Neurology, Neuroscience and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 45 AIDS and the Nervous System JOSEPH R. BERGER •
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MENINGITIS Viral Meningitis HIV Meningitis Bacterial Meningitis Mycobacterial Infections Treponemal Infection Listerial Infection Other Bacterial Meningitides Fungal Meningitis Cryptococcal Meningitis Other Fungal Meningitides Parasitic Meningitis Lymphomatous Meningitis GLOBAL ENCEPHALOPATHY Viral Encephalopathy HIV Encephalopathy (AIDS Dementia Complex) Cytomegalovirus Encephalitis FOCAL NEUROLOGICAL DYSFUNCTION OF CENTRAL ORIGIN Brain Disease With Mass Effect Toxoplasma gondii Infection Other Infectious Diseases Primary CNS Lymphomas Cerebrovascular Disease Brain Disease Without Mass Effect Progressive Multifocal Leukoencephalopathy SPINAL CORD DISEASE HIV-Associated Myelopathy HTLV-I–Associated Myelopathy PERIPHERAL NEUROPATHY MYOPATHY
Clinically apparent and frequently debilitating neurological disease is common with infection by human immunodeficiency virus type 1 (HIV), the etiological agent of the acquired immunodeficiency syndrome (AIDS). In the era before highly active antiretroviral therapy
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(HAART), in excess of 50 percent of persons infected with HIV developed symptomatic neurological disease. Early studies1,2 detected an incidence of neurological complications with AIDS of approximately 40 percent, but these studies were retrospective in nature and performed at a time in the course of this pandemic when life expectancies were considerably shorter and many of the neurological illnesses associated with the infection were unrecognized. Subsequent studies demonstrated significantly higher rates of neurological 3 disease. In 1996, HAART became the standard of care. The effect of this therapy on the incidence of neurological disease remains uncertain. Some studies have suggested both a change in 4,5 the spectrum and a decline in the frequency of many HIV-associated neurological of neurological disorders that disorders, whereas others report an incidence and spectrum 6 essentially parallels that observed in the pre-HAART era. The frequency with which neurological disease is observed at autopsy is substantially higher than in clinical studies, and in some series, neuropathological7,8 abnormalities have been demonstrated in more than 90 percent of patients dying of AIDS. Not surprisingly, careful neurological examination, even in the absence of specific complaints by the HIV-infected patient, frequently reveals evidence of central nervous system (CNS) or peripheral nervous system dysfunction. A novel clinical disorder that followed the introduction 9of HAART has been referred to as the immune reconstitution inflammatory syndrome (IRIS). IRIS is characterized by new or worsening symptoms of AIDS-associated opportunistic infections, malignancies, or other noninfectious complications due to an increased inflammatory reaction that paradoxically occurs as HIV viral loads decline and CD4 lymphocyte counts recover. Neurological disease consequent to IRIS has been well described. Initiating HAART before the CD4 lymphocyte count decreases to less than 100 cells/ml has been recommended to avoid this 10 complication. Neurological disease typically occurs with advanced disease and profound immunosuppression; however, it may also be the harbinger of AIDS. The frequency with which neurological disease heralded AIDS in the pre-HAART era ranged from 10 to 20 3,11 Whether that is also true with earlier diagnosis and more effective treatment is percent. unknown. It is estimated that there are approximately 1.2 million persons with HIV infection in 12 and one fourth are unaware of their the United States, roughly 1 in every 250 persons, 12 infection. Annually, 40,000 persons become infected with HIV in the United States. These numbers indicate that the burden of neurological disease associated with HIV/AIDS remains high. Not only is the spectrum of neurological disorders that complicate HIV infection extremely broad (Table 45-1), but also any part of the neuraxis may be affected. In general, the illnesses affecting the nervous system can be classified into those that are believed to be the direct result of HIV and those that result from other identifiable etiologies. Among the disorders in the former category are encephalopathy, myelopathy, peripheral neuropathy, and inflammatory myopathy. Their relative frequencies are depicted in Table 45-2. The illnesses in the latter category are chiefly a consequence of the severe abnormalities of cellular immunity accompanying AIDS. Infectious complications, particularly, cerebral toxoplasmosis and cryptococcal meningitis, are among the most common complications (Table 45-3). As a rule, these opportunistic neurological infections are the consequence of a dissemination or recrudescence of a latent or persistent infection rather than a recently acquired one. Often these infections relapse after initially successful therapy. Therefore, secondary antibiotic prophylaxis is warranted in certain infections, such as Toxoplasma encephalitis and cryptococcal meningitis. Other causes of neurological disease seen in association with the immunosuppression of HIV infection include primary and metastatic neoplasms, metabolic-nutritional disorders, and cerebrovascular complications. Click here to view this table.... Click here to view this table.... Click here to view this table.... In evaluating and treating HIV-infected patients with neurological disease, the physician must remain aware of the fact that the severely immunocompromised patient with AIDS often has two or more different illnesses responsible for neurological impairment. Furthermore, the neurological problems of HIV-infected persons may be the consequence of common neurological problems, such as migraine and herniated intervertebral disc with associated radiculopathy rather than related to HIV/AIDS. A high degree of vigilance is warranted, but these ordinary problems should not be overlooked. MENINGITIS
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Headache, signs of meningeal irritation, cranial nerve palsies, and other neurological symptoms and signs with or without fever generally herald more ominous disorders resulting from a broad array of microbial pathogens or from lymphomatous infiltration of the meninges. Radiographically, meningitis may be suspected by contrast enhancement of the subarachnoid space on computed tomography (CT) or magnetic resonance imaging (MRI). This enhancement of the subarachnoid cisterns can be either diffuse or focal, but its absence does not preclude the diagnosis. Other radiographic features seen in association with meningitis include communicating hydrocephalus, arterial or venous infarctions due to vasculitis, sinus thrombosis, and brain abscesses. The diagnosis of meningitis necessitates cerebrospinal fluid (CSF) examination. In HIV-infected patients with suspected meningitis, the CSF examination is incomplete without thorough microbiological studies including fungal and mycobacterial cultures and stains, India ink and cryptococcal antigen studies, and the Venereal Disease Research Laboratory (VDRL) test. Viral cultures, particularly for cytomegalovirus (CMV), should also be considered. Polymerase chain reaction (PCR) for Mycobacterium tuberculosis, herpes simplex viruses 1 and 2, CMV, and varicella-zoster virus 13 are also helpful in establishing the diagnosis. Cytological investigation is also essential in light of the relative frequency of lymphomatous meningitis.
Viral Meningitis HIV Meningitis The frequency of clinically apparent HIV meningitis is substantially lower than is suggested by the observation of an otherwise unexplained CSF pleocytosis or the findings of meningeal inflammation at the time of autopsy. In a minority of individuals, acute meningitis may accompany primary infection with HIV. This acute viral illness, indistinguishable from many other viral illnesses, is characterized by fever, generalized lymphadenopathy, pharyngeal injection, splenomegaly and splenic tenderness, maculopapular rash, and urticaria. It typically 14,15 before seroconversion to HIV, an14,16 event that develops within 3 to 6 weeks of infection, or averages 8 to 12 weeks after exposure. With this acute infection, a meningitis 17 meningoencephalitis may supervene, with headache, meningismus, photophobia, generalized seizures, and altered mental state. CSF examination reveals an increased protein concentration (more than 100 mg/dl), mononuclear pleocytosis (more than 200 3 16 cells/mm ), and normal glucose content. HIV may be isolated from the blood and CSF, but viral cultures are notoriously insensitive. The presence of HIV can be more reliably demonstrated by finding p24 antigen in the CSF or by amplifying HIV RNA by PCR. Routine examination of the CSF in asymptomatic individuals infected with HIV commonly reveals abnormal CSF parameters, including a sterile pleocytosis. A study of HIV-infected U.S. Air Force personnel (80% entirely asymptomatic clinically) revealed some CSF 18 abnormality in 63 percent. Among the CSF abnormalities frequently detected were mononuclear pleocytosis, increased protein concentration, increased immunoglobulin G 18 (IgG), and the presence of oligoclonal bands. The presence of myelin basic protein is unexpected. The CSF abnormalities do not appear to be predictive of the subsequent 18 development of neurological disease, and their interpretation requires caution.
Bacterial Meningitis Mycobacterial Infections Infection with M. tuberculosis, Mycobacterium avium-intracellulare, and, rarely, other atypical 19 mycobacteria occurs frequently in AIDS and is often extrapulmonary. The frequency of CNS involvement varies with the organism and the population studied. Haitians, American blacks, 20 and intravenous drug abusers appear to be the risk groups that have the highest incidences of mycobacterial infection. In Miami, 2.4 percent of HIV-infected patients with CNS disease 3 had CNS tuberculosis. In underdeveloped countries, the frequency with which CNS tuberculosis complicates HIV infection greatly exceeds its prevalence in the United States. In addition to meningitis, the clinical spectrum of CNS tuberculosis associated with HIV 21 22 infection includes cerebral abscesses and tuberculomas and spinal cord abscess. The most common clinical manifestations of tuberculous meningitis in AIDS include seizures, 21 altered mental status, fever, and meningismus. Although HIV infection increases the risk of meningitis with M. tuberculosis, it may not alter the clinical manifestations or response to 14 therapy. In contrast to M. tuberculosis, which most often presents as meningitis, M. avium-intracellulare typically causes single or multiple mass lesions. Ring-enhancing lesions 21 and hypodense areas are seen on CT scan. The CSF may, on occasion, be normal or
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emphasizing the value of brain biopsy in establishing the diagnosis in some
All HIV-seropositive patients should be skin-tested for tuberculosis and, if positive, should be treated. In those with active tuberculosis, a regimen involving three or more drugs is required for a minimum of 9 months. Recent descriptions of multidrug-resistant M. tuberculosis raise concerns about the adequacy of this treatment regimen, and drug sensitivity testing should be performed in all cases. In regions where multidrug-resistant organisms have been isolated, a more extensive regimen is probably required. Atypical mycobacterial infection requires a 23 and may necessitate experimental antimicrobials, such as rifabutyn and four-drug regimen 24 clofazimine. Treponemal Infection Neurosyphilis must always be considered in patients with HIV infection, even in the absence of neurological disease. In some populations, between 1 to 6 percent of all18,25–27 HIV-infected ; this is patients have neurosyphilis as defined by a positive VDRL test in the CSF probably an underestimate of the true incidence of neurosyphilis in AIDS because of the 28 relative insensitivity of this test. An acute, symptomatic, syphilitic meningitis during the course of secondary syphilis is not uncommon. A decrease in the latent period for the development of certain neurosyphilitic manifestations, such as meningovascular syphilis and general paresis, has been suggested. Johns and colleagues noted the development of meningovascular syphilis within 4 months of primary infection despite the administration of 29 accepted penicillin regimens. Relapse of neurosyphilis in HIV-infected individuals after 30 appropriate doses of benzathine penicillin for secondary syphilis has also been noted. Other unusual manifestations of 31 syphilis that have been reported in association with HIV infection 32 Bell's palsy and severe include unexplained fever, bilateral33optic neuritis with blindness, 34 syphilitic meningomyelitis, syphilitic bilateral sensorineural hearing loss, 35 36 polyradiculopathy, and syphilitic cerebral gumma presenting as a mass lesion. Although still controversial, concomitant HIV infection appears to alter the natural course of 37–39 syphilis. Treatment of syphilis requires the administration of intravenous, high-dose aqueous penicillin G (12 million U/day or more) for 10 to 14 days. Successful therapy of neurosyphilis with 33 doxycycline 100 mg twice daily for 21 days in an HIV-infected person has been reported. CSF examinations following treatment should be repeated at 6-month intervals over the succeeding 2 years. Ideally, the CSF cell count should be normal and the protein concentration lower, but the presence of concomitant HIV infection may alter the expected CSF resolution in successfully treated patients. The CSF VDRL titer should decline, but the CSF VDRL may remain reactive in low titer. Listerial Infection Despite a profound impairment of cellular immunity, the incidence of Listeria monocytogenes infection appears to be less with AIDS than with other causes of impaired cell-mediated 40 41 immunity. Listeria infection may result in meningitis or brain abscess and appears to have a predilection for the brainstem. In any case of meningitis of unknown cause occurring in a patient with AIDS, the antibiotic regimen should include agents effective against L. 42 monocytogenes, such as ampicillin, high-dose penicillin, or trimethoprim-sulfamethoxazole. Other Bacterial Meningitides Both infections that are typically associated with cellular immunodeficiency, such as Salmonella, and those more commonly seen with humoral immunodeficiency, such as43 Streptococcus pneumoniae, are seen with increased frequency in patients with AIDS. Pneumococcal meningitis is particularly common among HIV-infected children in 44 underdeveloped regions of the world. These and other less common causes of meningitis must be considered in any AIDS patient presenting with meningitis.
Fungal Meningitis Cryptococcal Meningitis 45
The estimated incidence of cryptococcosis in patients with AIDS varies between 1.9 and 11 2 percent. Blacks and intravenous drug abusers appear to have higher rates of this illness than other people. Cryptococcal meningitis, the chief clinical consequence of cryptococcal
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infection in patients with AIDS,3,46,47 may be the heralding illness or may occur simultaneously with In some communities, cryptococcal meningitis is more other opportunistic infections. common 40 than toxoplasmosis as the presenting neurological illness associated with HIV infection. Symptomatically, headache is almost universally noted in patients with cryptococcal meningitis. Other frequently observed clinical features include nausea and vomiting, photophobia, blurred vision, fever, mental status changes, and meningismus. Cranial nerve palsies, hemiparesis, language disturbances, seizures, cerebellar findings, and psychosis occur with lesser frequencies. In one series of 25 patients with AIDS and cryptococcal meningitis, headache was present in 88 percent, fever in 84 percent, meningeal signs in 36 percent, mental status changes in 12 percent, and other neurological findings 40 Though unusual, (cranial nerve palsies, papilledema, ataxia, and seizures) in 10 percent.1,48,49 focal neurological findings may be observed with cryptococcal disease. Cryptococcal meningitis is among the most common of the neurological disorders associated 50 51 with IRIS. The illness generally starts within 3.5 months of initiation of HAART and typically exhibits higher CSF opening pressures, glucose levels, and white blood52cell counts than patients with typical HIV-associated Cryptococcus neoformans meningitis. Pathological examination reveals a basilar, chronic meningitis that is typically neither particularly thick nor exudative. Diffuse or focal opacifications of the leptomeninges and brain edema may be noted by gross examination. Small (2- to 3-mm) nodules may be observed studding the meninges, particularly in the interpeduncular fossa and in the sulci. Cystic lesions composed of clusters of budding yeast and displaying little surrounding inflammation or reactive gliosis may be seen throughout the brain, chiefly in the superficial layers of the cerebral cortex. When macroscopic in size, they are referred to as cryptococcomas. Lumbar puncture typically reveals an increased opening pressure, mononuclear pleocytosis, increased protein content, and depressed glucose level. However, two or three of the standard CSF parameters (protein, glucose, cell count) may be normal in48,53 up to 50 percent of 40 and the these individuals. An India ink study is positive in more than 70 percent positivity rate of CSF48cryptococcal antigen, CSF culture, and serum cryptococcal antigen exceeds 90 percent. When cryptococcal meningitis is suspected, blood should be cultured and serum assayed for the presence of cryptococcal antigen. Cultures of other extraneural 53 sites, such as bronchoalveolar lavage fluid, may also be positive. Radiographic imaging is typically unremarkable. More often than not, a brain CT scan does not reveal evidence of the 54–57 In one series, mass lesions (cryptococcomas) and hydrocephalus pathological process. were each observed in approximately 10 percent of patients and diffuse cerebral edema in 58 another 3 percent. 48
The mortality of cryptococcal meningitis is about 30 percent. Many of the factors that predict a poor prognosis (positive India ink test, a low CSF leukocyte count, a positive blood culture, the presence of C. neoformans at extraneural sites, high CSF cryptococcal antigen titers, 54 CSF hypoglycorrhachia, and an increased CSF opening pressure) are present in AIDS. One study found that the most important predictor of poor outcome was an abnormal mental 59 controversy, however, status at the time of diagnosis. There remains considerable 53 regarding the importance of these predictors of survival. The standard treatment of cryptococcal meningitis consists of intravenous amphotericin B (0.6 to 1 mg/kg per day) for a minimum of 6 weeks. However, a comparative study of amphotericin B (0.4 mg/kg) intravenously with or without flucytosine to 59 oral fluconazole 200 No benefit of mg/day showed similar rates of treatment success (40% versus 34%). 59 flucytosine was detected. Although oral fluconazole appears to be the equivalent of 59 intravenous amphotericin B in the treatment of uncomplicated cryptococcal meningitis, there remains considerable debate regarding the use of fluconazole as initial therapy. The current recommendation regarding treatment of cryptococcal meningitis is to use amphotericin B (0.7 mg/kg per day) with or without flucytosine (100 to 150 mg/kg per day). At the completion of 2 or more weeks, this therapy may be supplanted by oral fluconazole at 400 mg/day for 8 to 10 weeks. If at the end of this time, the CSF culture is negative for C. neoformans, the fluconazole dose may be reduced to 200 mg/day and continued indefinitely as secondary prophylaxis to prevent relapse. Half of the patients who are48not treated with maintenance therapy following completion of their initial therapy relapse. The prostate has been suggested as the site for redissemination of infection because at least 20 to 30 percent of AIDS patients who have completed successful treatment for cryptococcal meningitis have positive urine cultures for C. 60 neoformans. Oral fluconazole or itraconazole appears to be equally effective in reducing recurrent cryptococcal meningitis; however, prophylactic therapy with antifungal agents 61 appears to have no effect on overall survival.
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Other Fungal Meningitides Other fungal infections, including Candida, may also result in meningitis in AIDS patients. Although more than 50 percent of AIDS patients develop oropharyngeal or esophageal candidiasis, it is rarely observed in the brain at autopsy. Meningitis secondary to 62,63 in the absence mucormycosis has been observed in parenteral drug abusers with AIDS of the classic triad of ophthalmoplegia, necrotic nares, and diabetes insipidus. Large intracerebral lesions with associated vascular involvement are hallmarks of this typically fatal 49 disease. Similarly, CNS Aspergillus fumigatus has been seen in AIDS, but brain abscesses requiring surgical excision are a more common form of presentation than meningitis. Other 40 fungal meningitides64rarely observed with AIDS include histoplasmosis, coccidiomycosis, and blastomycosis.
Parasitic Meningitis Toxoplasmosis may, on rare occasions, cause a ventriculomeningitis in the absence of mass 65 lesions. This clinical picture can be very confusing, and the diagnosis is rendered even more problematic by the difficulty in isolating the organism from CSF. PCR for T. gondii may 66,67 In addition to T. gondii, other CNS parasitic infections have been reported in be helpful. 68,69 association with HIV infection, including Chagas' disease (Trypanosoma cruzi) and 70 paracoccidiomycosis.
Lymphomatous Meningitis Among patients with AIDS, 5 percent ultimately develop71systemic lymphoma; approximately one third of the latter have a neurological presentation. The most common form of neurological illness occurring in association with AIDS-related systemic lymphoma is lymphomatous leptomeningitis, which may be either asymptomatic or symptomatic. The frequency of unsuspected lymphomatous meningitis occurring in AIDS-related lymphoma 71 approaches 20 percent. Accordingly, lumbar puncture is mandated in all AIDS patients with systemic lymphoma. Of these patients, 5 to7210 percent will also have cranial or peripheral nerve involvement and paraspinal masses. The clinical features of symptomatic lymphomatous leptomeningitis include headache, altered mental status, seizures, cranial neuropathies, and radiculopathies. Cranial neuropathies are not infrequent in association with HIV infection, but the potential etiologies of cranial neuropathy occurring with AIDS are extremely diverse (Table 45-4). Click here to view this table.... The most likely mode of entry73of the lymphomatous cells into the CNS is direct spread from contiguous extraneural sites. The high frequency of lymphomatous bone marrow infiltration argues for dissemination from the medullary cavity through the dura and into the 73 subarachnoid space. The neurological manifestations of AIDS-associated lymphomatous meningitis, particularly cranial neuropathy, may be exquisitely responsive to the administration of corticosteroids. Appropriate treatment requires intrathecal chemotherapy. GLOBAL ENCEPHALOPATHY Both an alteration in cognitive abilities and a decline in level of consciousness may occur in the setting of HIV infection. The former, currently attributed to a direct effect of HIV infection, is usually insidious in nature but on occasion may present in precipitous fashion. Alterations in level of consciousness are often associated with focal neurological abnormalities and typically result from mass lesions of the brain, usually opportunistic infections or lymphoma. The evaluation of a global encephalopathy complicating HIV infection requires a thorough physical and neurological examination; laboratory studies that assess electrolytes and renal, liver, and thyroid function; syphilis serologies; vitamin B12 and folate levels; cranial MRI, preferably with gadolinium or, alternatively, CT with a double dose of contrast and delayed scanning; and CSF analysis (unless contraindicated) with recording of opening pressure, measurement of total cell and differential counts, determination of protein and glucose levels, detailed microbiological studies, and cytology.
Viral Encephalopathy HIV Encephalopathy (AIDS Dementia Complex) Several appellations have been attached to the unique, progressive, dementing illness
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2,74
recognized shortly after the initial description of AIDS, including subacute encephalitis, AIDS dementia complex,75HIV encephalopathy, and, more recently, HIV-associated major cognitive/motor disorder. The exact incidence of this encephalopathy in HIV-infected individuals is unknown. Of 144,184 persons with AIDS reported to the Centers for Disease Control (CDC) between September 1, 1987, and August 31, 1991, there were 10,553 (7.3%) reported to have HIV encephalopathy: in 2.8 percent of the adult patients with AIDS and 5.3 75 percent of children with AIDS, HIV encephalopathy was the initial manifestation of the disease. In 2,3 other studies, HIV encephalopathy was the initial AIDS-defining illness in 0.8 to patients, and it has been detected in 4.0 percent of patients at the 2.2 percent of adult AIDS 76 The annual incidence in AIDS patients has been reported to be time of diagnosis of AIDS. 76,77 By the time of death, approximately one third of AIDS patients between 7 and 14 percent. 75 although estimates in excess of 50 percent have been will exhibit this dementia, 78 of this disorder has been suggested to be suggested. An apparent decline in the incidence 77,79 Since the introduction of HAART, the the result of the widespread use of zidovudine. incidence of this disorder appears to be decreasing. The incidence of pathological features concordant with HIV encephalopathy that have been observed at autopsy has varied in different series but in general is substantially higher than the estimates based on clinical 7,80–85 data. Considerable controversy has surrounded the issue of whether lesser degrees of cognitive impairment accompany HIV infection in its earlier stages. In general, large prospective longitudinal studies that have employed limited screening batteries have suggested that the occurrence of these abnormalities is no more frequent than in a suitably matched control population without HIV infection. However, smaller studies that have employed more extensive neuropsychological screening measures and electrophysiological tests suggest an increased prevalence over the control population. Whether the presence of these cognitive abnormalities predicts the development of AIDS dementia complex remains uncertain. There clearly appears to be a group of individuals with minor cognitive problems who do not progress over long periods of follow-up; however, the same observation has been made for 86 individuals meeting the criteria for significant cognitive disturbance. Brain atrophy characterized by sulcal widening and ventricular dilatation is commonly observed at autopsy in patients with HIV encephalopathy. Meningeal fibrosis may also be present. Histologically, the most common and distinctive feature of this illness is pallor of the white matter, chiefly seen in a paravascular distribution and often accompanied by an 87 astrocytic reaction. The favored location for this demyelination is the periventricular and central white matter. Multinucleate giant cells, the pathological hallmark of the disease, 78 probably result from direct virus-induced cell fusion. Other microscopic features include microglial nodules, diffuse88astrocytosis, and perivascular mononuclear inflammation. Thinning of the neocortex and neuronal loss on quantitative assessment in specific brain 89 regions have also been noted. In general, the pathological features correlate poorly with the clinical symptoms. The presence of diffuse myelin pallor and multinucleate giant cells seem 76 to correlate best. HIV encephalopathy typically78,90–95 occurs in the context of advanced immunosuppression and but it may be the presenting or even sole manifestation of coexistent systemic disease, HIV infection before96–98 the infected individual exhibits any other illnesses characteristic of The encephalopathy is characterized by an insidious onset of impaired immunity. disturbed intellect. Fatigue and malaise, headaches, increasing social isolation, and loss of sexual drive are noted. On rare occasion, the disorder begins abruptly and progresses rapidly. Symptoms include forgetfulness, difficulty in concentrating and reading, and a slowness in thinking, with an accompanying decline in job performance. Depression is 78 Sleep disturbance is not frequently considered, but dysphoria is typically absent. 99 100–102 uncommon, and both focal and generalized seizures have been described. The hallmarks of advanced AIDS, namely, wasting, alopecia, seborrheic dermatitis, and generalized lymphadenopathy, are typically apparent. The mental status examination reveals a slowing of mental processing (bradyphrenia) and other features consistent with a subcortical dementia. Abnormalities of both saccadic and pursuit eye movements are 103–107 Facial expression is diminished, and the voice is often hypophonic and 108 common. monotonous. Coordination is impaired, consistent with involvement of the basal ganglia. Fine movements are performed slowly and imprecisely. Bradykinesia, postural instability, slow and clumsy gait, and altered muscle tone are noted. In many respects, this disorder shares many features characteristic of Parkinson's disease, and some investigators maintain 109 that it is chiefly a disorder affecting the basal ganglia and forebrain. CSF studies show a mononuclear pleocytosis in one fifth of individuals, with counts usually 3 96 less than 50 cells/mm . An increased protein concentration, but usually less than 200 mg/dl,
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is observed in two thirds. Intrathecal synthesis of HIV-specific antibody and oligoclonal 112 111 bands are frequently present but are not predictive of the development of CNS disease. Potential surrogate markers in the CSF for HIV encephalopathy include an elevated HIV p24 113,114 and elevated levels of β2-microglobulin, neopterin, and quinolinic acid. The antigen 115 isolation of HIV from CSF is not a useful marker for HIV-related neurological disease. 116,117 However, quantitative HIV RNA PCR appears to correlate with disease severity. The latter is not regarded as a diagnostic marker, but may be helpful in explaining whether advancing dementia in the face of systemic viral suppression by antiretrovirals is the consequence of “CNS viral escape” (J. McArthur, personal communication). The most important aspect of radiographic imaging of the brain118 in patients with suspected The most commonly HIV encephalopathy is to exclude other neurological disorders. 1,108,119,120 MRI may show reported abnormality on CT scan of the brain is cerebral atrophy widespread involvement of large areas of white matter or smaller “patchy'' or “punctate'' 121 lesions as well as atrophy (Fig. 45-1). Neither the electroen-cephalogram (EEG) nor other electrophysiological studies are particularly useful diagnostic tools in HIV-infected individuals with HIV encephalopathy, despite assertions to the contrary. Detailed neuropsychological batteries, however, are often invaluable in determining whether there is an associated depression and in gauging the extent of the impairment and the response to therapy.
FIGURE 45-1 A, T1-weighted magnetic resonance image (MRI) of patient with AIDS dementia showing marked cerebral and cortical atrophy. B, T2-weighted MRI of the same patient showing extensive hyperintense signal abnormalities in the white matter. 122,123
Anecdotal clinical reports suggesting improvement in HIV encephalopathy with 90,124 and in zidovudine administration have been confirmed in controlled trials in adults 125 The response appears to require higher doses of zidovudine than are routinely children. 126 claim that HAART has a substantial salutary effect on HIV used. Some investigators 127–129 A longer duration of HAART therapy (more than 18 months) correlated encephalopathy. 128,129 Others have failed to find a robust response of HIV with better cognition. 130,131 The pattern of neurocognitive deficits may be different with encephalopathy to HAART. HAART, and some have suggested that some neuropsychological functions improve while others deteriorate, perhaps reflective of “burnt out” damage rather an active intracerebral 132 process. Cytomegalovirus Encephalitis CMV not infrequently results in retinitis, pneumonitis, gastroenteritis, hepatitis, and 133 encephalitis in persons with advanced immunosuppression due to AIDS. Pathological evidence of its presence in the brains of AIDS patients with neurological disease was found in 2 36 percent of patients in one study. Evidence of this involvement included neuropathological findings (i.e., microglial nodules, cytomegaly, and typical CMV inclusions), disseminated CMV infection, or serological evidence of previous CMV infection. Despite histopathological and virological evidence implicating CMV in the etiology of an HIV-associated encephalitis, the clinical features of CMV encephalitis in the AIDS population remain poorly characterized and clinical recognition is difficult. Indeed, CMV may localize to 134,135 Although imaging studies and analysis CNS tissues without significant clinical sequelae. of CSF may reveal abnormalities in many patients, none has been specific enough to allow a definitive diagnosis of CMV encephalitis. Kalayjian and colleagues argue that CMV
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ventriculoencephalitis in AIDS has sufficiently distinct clinical and pathological features to 136 allow identification. These features include previous or concomitant CMV retinitis or other serious CMV infection; altered mental status; nystagmus; cranial neuropathies; ventriculomegaly on neuroimaging; periventricular enhancement on CT scan; increased 3 periventricular signal intensity on T2-weighted MRI; CSF pleocytosis (up to 18,666 cells/mm , often with substantial numbers of polymorphonuclear cells); increased CSF protein (exceeding 50 mg/dl) and hypoglycorrhachia (less than 40 mg/dl). A multifocal CNS 137 138 disorder and isolated brainstem dysfunction have been observed with CMV encephalitis. Other clinical syndromes associated with CMV in AIDS are polyradiculoneuropathy,136 vasculitic neuropathy, myelopathy, and adrenal insufficiency with concomitant hyponatremia. Typically these illnesses occur after the onset of other AIDS-defining illnesses and in the 136 presence of low CD4 lymphocyte counts. Anecdotal reports support the use of ganciclovir, a selective guanosine analogue, and foscarnet for CMV encephalitis. FOCAL NEUROLOGICAL DYSFUNCTION OF CENTRAL ORIGIN Focal neurological disturbances, such as hemianopia, hemiparesis, and hemianesthesia, occurring with HIV infection may result from a variety of lesions affecting the cerebrum. These lesions can be broadly classified in their order of frequency as opportunistic infections, tumors, and cerebrovascular disease. The most common opportunistic infections in this category are Toxoplasma encephalitis and progressive multifocal leukoencephalopathy. With rare exception, brain tumors occurring with AIDS are primary CNS lymphomas, although other primary CNS tumors and metastatic tumors have been reported. It is not unlikely that the latter malignancies are more common than in the general population as a consequence of impaired tumor immunosurveillance in AIDS. In the HIV-infected patient with focal neurological signs, either a cranial MRI with gadolinium or a double-dose, delayed brain CT scan is mandated. The presence or absence of mass effect on radiographic imaging is extremely helpful in determining the etiology of the lesions.
Brain Disease With Mass Effect Toxoplasma encephalitis is the most common cause of focal intracranial mass lesion in HIV infection, followed in frequency by lymphoma. An approach to the management of intracranial mass lesions occurring with HIV infection is found in the algorithm shown in Figure 45-2. Less common causes of intracranial lesions with mass effect are pyogenic abscess, syphilitic gumma, Candida abscess, Nocardia abscess, cryptococcoma and cryptococcal pseudocysts, other fungal and parasitic diseases, and vascular-occlusive lesions.
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FIGURE 45-2 Algorithm for the management of intracranial mass lesions
occurring with human immunodeficiency virus (HIV) infection. CT, computed tomography; PET, positron emission tomography; SPECT, single-photon emission computed tomography. (Based on preliminary recommendations of a working group of the American Academy of Neurology on Mass Lesions in AIDS. From Berger JR: Quality Standards Subcommittee of the AAN: evaluation and management of intracranial mass lesions in AIDS. Neurology 50:21, 1998, with permission.) Toxoplasma gondii Infection Approximately 20 to 30 percent of AIDS patients in the United States will develop Toxoplasma encephalitis, although these numbers may be decreasing due to primary prophylaxis in HIV-infected persons with positive toxoplasmosis serology and profound immunosuppression. Usually, these patients present with focal neurological symptoms and signs often superimposed on a global encephalopathy. A prodrome of fever and malaise may occur for several days to weeks before the onset of the neurological illness. Mild hemiparesis 139 is the most common focal139 finding. Confusion, lethargy, brainstem and cerebellar disorders, of chorea in AIDS patients is believed to be and seizures are not rare. The appearance 140 virtually pathognomonic of toxoplasmosis. CT scan of the brain (Fig. 45-3) usually reveals multiple nodular or ring-enhancing lesions 139,141,142 Occasionally the CT scan is normal or reveals only a with edema and mass effect. hypodense lesion that fails to enhance with contrast. Most lesions occur in the basal 142,143 139 and the cerebral hemispheres, particularly the frontoparietal lobes. MRI ganglia 144 reveals discrete areas of increased signal intensity on T2-weighted images. The CT scan is probably the best radiographic method to judge the response to therapy. Although generally abnormal, the CSF findings in these patients are nonspecific. An elevation of CSF
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protein concentration (50 to 200 mg/dl) is seen in the majority,3and one third show a mononuclear 3pleocytosis (usually not exceeding 100 cells/mm ). Cells counts in excess of of another disease. Serological studies for 100 cells/mm suggest the presence145 146,147 A presumptive toxoplasmosis are typically elevated, but this is not invariable. diagnosis is made on the basis of the response to antitoxoplasmosis therapy, but brain biopsy is the only unequivocal means to establish the diagnosis. Excisional biopsies usually 148 show tachyzoites on routine histology, particularly in the periphery of the necrotic lesion.
FIGURE 45-3 A 33-year-old HIV-positive man presented with a seizure and
right hemiparesis. A, Contrast-enhanced CT scan shows edema in the basal ganglia bilaterally, with abnormal central enhancement, more marked on the left than on the right. The ventricles and sulci are excessively prominent for a patient of this age, consistent with the global parenchymal volume loss of HIV encephalopathy. B, A more superior image shows a ring-enhancing lesion with surrounding vasogenic edema in the left frontal lobe. The patient's anti-Toxoplasma titer was positive, and he responded well to a course of toxoplasmosis-specific therapy, supporting the diagnosis of toxoplasmosis. (Courtesy of Nancy Fischbein, MD, University of California, San Francisco.) A trial of therapy for toxoplasmosis of 2 to 3 weeks' duration in those patients with suspected Toxoplasma encephalitis is recommended. These patients should be carefully monitored clinically and radiographically for resolution of their lesions. If the therapy fails to effect clinical and radiographic improvement, brain biopsy should be performed. The use of corticosteroids may confuse the interpretation of this therapeutic trial, and their use should be avoided in this context. The current recommended therapy for Toxoplasma encephalitis is combination therapy of sulfadiazine and pyrimethamine, a dihydrofolate reductase inhibitor. The pyrimethamine is administered orally in an initial loading dose of 200 mg, followed by 50 to 75 mg daily, and the 149 sulfadiazine is administered as 4 to 6 g daily divided into four equal doses. Folinic acid, 5 to 10 mg daily, is needed to diminish bone marrow suppression. Side effects of these 150 medications are common, occurring in as many as 60 percent of patients. If sulfadiazine is unavailable, an alternative preparation is sulfisoxazole. In patients not tolerating sulfa medications, clindamycin 2.4 g daily can be substituted. The risk of relapsing Toxoplasma encephalitis is high, warranting the use of secondary prophylaxis. Agents employed for prophylaxis of Pneumocystis carinii pneumonia, namely trimethoprim-sulfamethoxazole and pyrimethamine-sulfadoxine, significantly reduce the risk of developing Toxoplasma 151 encephalitis. Other Infectious Diseases Infection with Nocardia asteroides, a gram-positive, weakly acid-fast bacillus, may occasionally result in brain abscess in AIDS patients. Treatment is often unsuccessful. Other causes of cerebral mass lesions of infectious origin seen in AIDS include mass lesions associated with brain abscesses due to mixed bacterial flora, Aspergillus, and the agents responsible for mucormycosis; tuberculous abscesses and tuberculomas due to M. tuberculosis or M. avium-intracellulare; cryptococcomas and cryptococcal pseudocysts; and syphilitic gummas.
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Primary CNS Lymphomas In the setting of HIV infection, the incidence of primary CNS lymphomas increases dramatically. As many as 0.6 percent of patients will present with these tumors concurrent 152 Estimates with the diagnosis of AIDS, and ultimately 2 percent develop the disease. 153 suggest that its incidence currently exceeds that of low-grade astrocytomas. These tumors are mostly of B-cell origin and both large-cell immunoblastic and small noncleaved 154 lymphomas are seen. Of potential etiological significance is the observation that Epstein–Barr virus (EBV) expression can be demonstrated in virtually all cases of 155 AIDS-related primary CNS lymphomas. Primary CNS lymphoma typically presents with confusion, lethargy, memory loss, hemiparesis, speech and language disorders, seizures, and cranial nerve palsies, in 91 descending order of frequency. The lesions are often multiple, and involvement of the meninges is frequently demonstrated by cytological examination or at the time of postmortem examination. On CT scan, most lymphomas are either hyperdense or isodense, round or oval 156 CSF masses with homogeneous contrast enhancement and variable surrounding edema. 13 analysis by PCR for EBV is diagnostically helpful. Distinguishing primary CNS lymphoma from toxoplasmosis and other infectious brain mass lesions is often difficult. An algorithm (Fig. 45-2) has been suggested by a working group of the American Academy of Neurology for evaluating brain mass lesions in AIDS. These tumors respond both clinically and radiographically to whole-brain irradiation. A regimen of 4,000 rads administered over 3 153 and regimens employing chemotherapy have weeks has been successfully employed, 157 157 been reported. The average survival is less than 4 months, with death often due to concurrent illnesses related to the immunodeficiency. Cerebrovascular Disease The spectrum of cerebrovascular disease that has been reported in association with AIDS is hemorrhagic disorders. In autopsy series, broad (Table 45-5) and includes both ischemic and 158 159 rates as high as 19 percent have been reported. In a case-control autopsy series, cerebrovascular disease was detected at autopsy in 8 percent of HIV-infected individuals but did not appear to occur significantly more frequently in HIV-infected persons than in age- and sex-matched controls with other terminal illnesses. Concomitant heart disease, particularly nonbacterial thrombotic (marantic) endocarditis, was frequent in both groups. Infectious vasculitis, especially meningovascular syphilis, must always be considered in the differential 160 diagnosis of these disorders. Vasculitis secondary to HIV infection has been reported. Click here to view this table....
Brain Disease Without Mass Effect The most common causes of intracranial lesions without mass effect in HIV-infected patients are progressive multifocal leukoencephalopathy, HIV encephalopathy, and CMV encephalitis. Of these disorders, only progressive multifocal leukoencephalopathy typically presents with focal neurological disturbances. MRI is the imaging study of choice, owing to its superior contrast resolution and marked sensitivity in detecting lesions that affect the white matter. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy is the result of infection of the brain with JC virus, a papovavirus. Before the AIDS pandemic, it was a rare disease, almost invariably occurring in association with the immunosuppression associated with lymphoproliferative disorders. Current estimates suggest that 2 to 5 percent of all patients with AIDS will develop 8,158 it. In approximately one fourth of AIDS patients with progressive multifocal leukoencephalopathy, the illness is the presenting manifestation of their immunosuppression. Limb weakness is the most common initial manifestation, followed in frequency by cognitive dysfunction, visual loss, gait161 disturbance, limb incoordination, speech or language disturbance, and headache. CT scan of the brain typically, although not invariably, reveals nonenhancing, hypodense white matter lesions without mass effect. These white matter lesions without mass effect are chiefly located in the centrum semiovale, predominantly in the 158 T2-weighted spin-echo MRI is highly sensitive parieto-occipital region and the cerebellum. 162 8 to 9 percent of the lesions in AIDS in detecting these lesions (Fig. 45-4). Approximately 161,162 The CSF is usually normal, although a show faint contrast enhancement by CT or MRI. mild increase in protein concentration, the presence of myelin basic protein, an increase in
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IgG, and a pleocytosis (9 to 25 mononuclear cells/mm ) have all been reported. The presence of an increased opening pressure or significant CSF pleocytosis should raise serious concerns about the diagnosis. Diagnostic confirmation requires either brain biopsy or 163 a positive CSF PCR for JC virus coupled with the appropriate clinical and radiographic findings. The disorder is characterized pathologically by demyelination; giant astrocytes with pleomorphic, hyperchromatic nuclei; and altered oligodendrocytes containing enlarged nuclei that stain abnormally densely with hematoxylin and harbor ill-defined inclusion bodies. JC virus can be directly demonstrated by electron microscopy or by in situ hybridization. The mean survival of patients with progressive multifocal leukoencephalopathy in AIDS is 3 to 6 158,161 Long-term161survival with nearly complete neurological recovery is observed in 7 months. 164 to 9 percent of patients. Low CSF titers of JC virus by quantitative PCR and the constellation of progressive multifocal leukoencephalopathy as the heralding manifestation of AIDS, contrast enhancement on radiographic imaging, and a high CD4 count are predictors 165 of prolonged survival. HAART improves the survival of HIV-associated progressive multifocal leukoencephalopathy, particularly in previously drug-naive patients. A significant improvement in survival in HAART-treated patients 166 with AIDS-associated progressive but has not been observed multifocal leukoencephalopathy has been reported, 167 universally. Antiretroviral therapy affects survival by restoring the immune system and not by a primary effect on JC virus. However, worsening symptoms and new lesions on MRI associated sometimes with mass effect and contrast enhancement may occur with IRIS complicating progressive multifocal leukoencephalopathy and 171 displays a significant 168–170 172 Survival is unaffected by cytosine arabinoside, interferon-alpha, or mortality.173 174 cidofovir. The apparent importance of the serotonin receptor 5HT2A for JC virus entry into cells suggest the possibility that serotonin-blocking agents may be of value.
FIGURE 45-4 T2-weighted MRI of brain of patient with progressive multifocal
leukoencephalopathy, showing extensive hyperintense signal abnormalities in the posterior regions of both hemispheres. SPINAL CORD DISEASE Spinal cord disease is frequent in HIV infection. A unique HIV-associated vacuolar myelopathy is the chief cause of myelopathy. The diagnosis of this disorder, like that of HIV encephalopathy, is one of exclusion. A number of other myelopathies may also occur with
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HIV infection including infectious myelopathies (due to CMV, herpes simplex type 2, herpes zoster, human T-lymphotropic virus type I [HTLV-I], mycobacteria, Treponema pallidum, and epidural abscesses), vascular myelopathies, epidural and intramedullary tumors, and a demyelinating myelopathy (Table 45-6). Click here to view this table.... For diagnostic and therapeutic purposes, it is useful to categorize spinal diseases occurring with HIV infection into two major groups, those that are the result of a mass lesion and those occurring in the absence of a mass lesion. The most common mass lesion affecting the spinal cord is lymphoma. Spinal lymphoma may present as (1) an intramedullary lesion, (2) meningeal lymphomatosis, (3) an epidural mass lesion, (4) bony metastases, and (5) some combination of these presentations. Other causes of mass lesions affecting the spinal cord are epidural and intramedullary nonlymphomatous tumors, intramedullary infections, and epidural abscesses. Epidural abscesses are most often seen in parenteral drug abusers and the most common organism isolated is Staphylococcus aureus.
HIV-Associated Myelopathy This unique degeneration of the spinal cord is seen at autopsy in more than 20 percent of 104 patients dying of AIDS. Usually, it begins insidiously and is characterized by leg weakness, gait impairment, paresthesias and vague leg discomfort, and bladder and bowel incontinence. Like HIV encephalopathy, HIV-associ-ated myelopathy generally occurs with advanced immunosuppression. Casual recording of the patient's symptoms often results in their being attributed to intercurrent illnesses and associated debilitation. However, neurological examination reveals spastic paraparesis, lower-extremity hyperreflexia (except when diminished as a result of concomitant peripheral neuropathy), gait ataxia, and impaired sensation, with vibratory and position sense being disproportionately affected. Lower-extremity involvement may be asymmetric. A discrete sensory level is distinctly unusual. HIV-related vacuolar myelopathy is seldom associated with abnormalities on MRI but, on rare occasion, spinal cord atrophy and hyperintense signals on T2-weighted images may be observed. Although gross examination of the spinal cord in this disorder is normal, histological examination reveals loss of myelin and spongy degeneration with 175,176 relative axonal Microglial nodules preservation, particularly affecting the dorsal and lateral columns. and HIV-laden multinucleate giant cells can be detected, but the correlation between the presence and degree of HIV infection and the spinal177pathology is poor. A metabolic disorder akin to vitamin B12 deficiency has been suggested. No treatment has demonstrated unequivocal value in178 HIV-related vacuolar myelopathy. Trials with high-dose l-methionine showed no efficacy. Other spinal cord disorders attributed to HIV include179an acute 175 and a myelopathy occurring at the time of primary infection, spinal myoclonus, 180,181 relapsing-remitting myelopathy that may accompany optic neuritis.
HTLV-I–Associated Myelopathy HTLV-I is recognized with increasing frequency in the HIV-infected population. It is transmitted in the same fashion 182–184 as HIV. Co-infection has been associated with an HTLV-I–associated myelopathy. 185 A similar myelopathy has been observed in a person co-infected with HIV and HTLV-II. HTLV-I–associated myelopathy is discussed further in Chapter 47. It is clinically indistinguishable from HIV-associated myelopathy. PERIPHERAL NEUROPATHY HIV infection is associated with a diverse group of peripheral neuropathies (Table 45-7). The exact role of HIV in the etiopathogenesis of these neuropathies remains obscure, and other factors such as concomitant infections, nutritional deficiencies, metabolic disorders, and side effects of drugs may be responsible for some of them. Prospective neurological evaluation may reveal evidence of peripheral neuropathy in up to 50 percent of patients with advanced HIV infection. Click here to view this table.... Although other types of peripheral neuropathy may be observed, the peripheral neuropathies associated with HIV infection can be divided into three major groups: a distal, symmetric peripheral neuropathy; an inflammatory demyelinating peripheral neuropathy; and a mononeuritis multiplex. The most common is a distal, symmetric sensorimotor neuropathy that typically develops in the late stages of the disease. Patients complain of often
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debilitating, painful dysesthesias and numbness of the feet. When present, distal weakness is generally mild; muscle stretch reflexes are depressed or absent. The sensory loss is greatest for vibratory perception, but other sensory modalities may be affected. Nerve conduction velocities are usually slightly decreased and sensory action potentials are either absent or of low amplitude, suggesting an axonal neuropathy, although features of demyelination may also be seen. Nerve biopsy may reveal epineural and endoneural perivascular inflammation 186 with axonal degeneration or demyelination. Symptomatic therapy with carbamazepine, phenytoin, tricyclic antidepressants, mexiletine, and topical capsaicin are of variable benefit. HAART,187,188 lamotrigine, and recombinant nerve growth factor have been demonstrated to be of benefit. Both acute Guillain–Barré syndrome and 143,189 a chronic, relapsing polyradiculoneuropathy may Nerve conduction studies are compatible with occur as a consequence of HIV infection. a demyelinating neuropathy. CSF examination reveals a normal to increased protein concentration (but usually 3less than 200 mg/dl) with a mild mononuclear pleocytosis (usually no more than 50 cells/mm ) or, more rarely, a normal cell count. Therefore, in contradistinction to typical Guillain–Barré syndrome, a CSF albuminocytological dissociation occurs in only a minority of affected individuals. Plasmapheresis may be beneficial in those 143 patients with chronic relapsing polyradiculoneuropathy, and high-dose intravenous immunoglobulin may be associated with striking improvement. On rare occasion, mononeuritis multiplex may be observed with HIV infection. Cranial, 189 peripheral, or spinal nerves may be affected. The disorder has been attributed to immune complex deposition resulting in a necrotizing vasculitis. Other causes of mononeuropathy, such as herpes zoster, CMV, and lymphomatous nerve root infiltration, must be excluded. 156,190
presents a striking picture. Progressive polyradiculomyelopathy that occurs due to CMV This illness is characterized at onset by lower extremity and sacral paresthesias. Progressive paraparesis ensues rapidly, with concomitant areflexia, ascending sensory loss, and 191 sphincter dysfunction. Although reported rarely as an early manifestation of HIV infection, it generally occurs with advanced immunodeficiency. An important clue to the presence of this potentially treatable illness is a polymorphonuclear pleocytosis in the CSF. CMV190 can be Rarely, detected in the CSF by culture, immunohistochemistry, and in situ hybridization. 190 cytomegalic cells may be seen in the CSF. A painful neuropathy has been attributed to a CMV-associated dorsal root ganglionitis, and CMV may also result in a disorder like 192 Guillain–Barré syndrome. Ganciclovir and foscarnet are the treatment modalities for these CMV-related conditions, but favorable reports have been anecdotal. MYOPATHY Skeletal muscle disease associated with HIV infection can be classified in four groups: (1) HIV-associated myopathies, (2) muscle complications of antiretroviral and other therapies, (3) 193 opportunistic infections and tumor infiltrations, and (4) rhabdomyolysis. Since the 193 introduction of HAART, the prevalence of these disorders appears to have decreased. Several forms of myopathy have been recognized in association with HIV infection. Among the most common is a polymyositis, which is clinically indistinguishable from idiopathic polymyositis. This disorder is characterized by proximal muscle weakness, myalgias, 194,195 Weight loss and excessive fatigability, and an increase in serum creatine kinase level. wasting, particularly of gluteal muscles, are often evident. Electromyographic features mirror those seen with idiopathic polymyositis. Muscle biopsy reveals fibrous tissue proliferation, necrosis,195 and phagocytosis of muscle fiber accompanied by an intense inflammatory infiltrate. The treatment of HIV-associated polymyositis parallels that of polymyositis in the non–HIV-infected person and includes the use of corticosteroids and other 196 immunosuppressive agents. Inclusion-body myositis, nemaline myopathy, and diffuse infiltrative lymphocytosis syndrome are among the other myopathic disorders observed with 193 HIV infection. Another form of myopathy has been attributed to zidovudine therapy. This illness is chiefly characterized by muscle wasting and proximal weakness and tends to occur 197 in individuals who have been treated with high doses of the drug for more than 6 months. It typically occurs in individuals who have received high cumulative doses of zidovudine and is 198 consistently associated with depletion of mitochondrial DNA (mtDNA), presumably as a consequence of the drug's ability to inhibit γDNA polymerase, an enzyme involved in mtDNA replication. Some investigators have suggested that HIV polymyositis predisposes to the 194 Other drugs used in treating HIV or200 its development of zidovudine-related myopathy. 199 complications, such as the statins, tenofovir, and trimethoprim-sulfamethoxazole, have also been associated with muscle disease, including rhabdomyolysis. A disorder referred to as the HIV-associated neuromuscular weakness syndrome that is
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characterized by weakness and elevated lactic acid levels has been reported with 201 antiretroviral therapy, particularly d4T (stavudine). This illness is characterized by hepatic steatosis, pancreatitis, and lactic acidosis and displays electrophysiological and pathological features of both peripheral nerve and muscle disease. Muscle biopsy in these patients has 201 revealed both inflammation and mitochondrial changes. 193Lipid accumulation in muscle resembling that of Reye's syndrome has been observed. The syndrome has been attributed to depletion of mtDNA and impaired oxidative phosphorylation due to selective 202 inhibition of DNA polymerase-γ by nucleoside analogues. In the largest series of this entity 201 to date, death occurred in 20 percent of patients with follow-up. The absence of prospective studies precludes any meaningful comments regarding the best therapeutic approach, although the offending antiretroviral medications should be discontinued and the acidosis aggressively treated. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 46 Neurological Complications of Organ Transplantation and Immunosuppressive Agents ROY A. PATCHELL •
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NEUROLOGICAL COMPLICATIONS COMMON TO ALL TRANSPLANTATION TYPES Long-Term Effects of Immunosuppressants Direct Neurological Side Effects Neurological Infections Lymphoproliferative Disorders Seizures NEUROLOGICAL COMPLICATIONS ASSOCIATED WITH SPECIFIC TRANSPLANTATION TYPES Renal Transplantation Bone Marrow Transplantation Cardiac Transplantation Pulmonary Transplantation Hepatic Transplantation Pancreatic Transplantation
Organ transplantation, which began in the early 1950s with renal transplantation, has developed into one of the great advances in modern medicine. Over the past 50 years, transplantation has become the treatment of choice for many otherwise fatal diseases. Advances in tissue matching, improvements in surgical technique, and new immunosuppressive agents have increased both the number and type of transplantations performed. Kidney, bone marrow, heart, lung, liver, and pancreas transplants are now used regularly in the treatment of end-stage disease. Three types of transplants exist: syngeneic (identical twins), allogeneic (different genetic origins), and autologous (patient's own tissue). Of these, allogeneic transplants are the most common, although autologous transplants of bone marrow have become common in conjunction with chemotherapy. When a new organ is implanted in the same anatomical site as the old one (e.g., liver transplantation), the transplant is said to be orthotopic. When the organ is transplanted into a site that was not the original location of the organ being replaced, the transplant is heterotopic. Advances in immunology and transplant technique have allowed longer survival for transplant recipients, but this has resulted in the emergence of a number of neurological problems in
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these patients. Depending on the type of organ transplanted, 30 to 60 percent of transplant 1–4 recipients develop neurological problems. The neurological complications of organ transplantation can be divided into two major categories: (1) those common to all allogeneic transplants, due primarily to the effect of long-term immunosuppression, and (2) those specific to particular transplant types, due either to the underlying disease, which led to the need for a transplant, or some phenomenon that is peculiar to the transplantation technique. NEUROLOGICAL COMPLICATIONS COMMON TO ALL TRANSPLANTATION TYPES
Long-Term Effects of Immunosuppressants Syngeneic and autologous transplants do not require immunosuppression; however, most transplants are allogenic, and, therefore, most transplant recipients require some degree of chronic, lifelong immunosuppressive therapy to prevent rejection of the transplanted organ. Immunosuppressive agents and the resulting immunosuppression may affect the nervous system either directly or indirectly. The major neurological complications of immunosuppression are direct neurotoxic side effects of immunosuppressive drugs, infections, and the development of de novo malignancies. Direct Neurological Side Effects Cyclosporine
Cyclosporine is one of the most commonly used agents to prevent rejection and is employed for both chronic maintenance immunosuppression and for the treatment of acute organ 3 selectively inhibits helper and cytotoxic T cells by rejection. The drug binds to calcineurin and 5,6 blocking antigen-induced T-cell activation. There is also an inhibition of lymphokine production and release. Renal and hepatic toxicity and hypertension are the most serious systemic complications of the drug. Cyclosporine toxicity is one of the most common causes of neurological problems after organ transplantation, with 15 to 40 percent of patients experiencing some type of neurological side 5–8 effect. Although higher blood levels of cyclosporine are generally associated with side effects, there is no simple correlation between blood level and the development of any specific neurological complication. Other factors in combination with cyclosporine increase the risk of developing neurological problems; these risk factors include cranial radiation, hypocholesterolemia, hypomagnesemia, β-lactam antibiotic therapy, high-dose 5–10 corticosteroids, hypertension, and uremia. Tremor is the most common neurological complication of cyclosporine and is present in up to 7–9 within days of the start of 40 percent of patients. The tremor is usually mild and develops 11 cyclosporine. It is usually caused by sympathetic activation, but patients with cyclosporine-induced encephalopathy or leukoencephalopathy may also experience tremor. In addition, tremor may be a part of a syndrome of generalized cerebellar dysfunction. Most of the serious neurological toxicity of cyclosporine is due to its tendency to produce 5–8 hypertension. The hypertension that nearly always complicates cyclosporine use is due in part to renal toxicity, but, to a larger extent, it is due to the tendency of cyclosporine to stimulate the sympathetic nervous system by an unknown mechanism. The encephalopathy of cyclosporine toxicity is roughly correlated with blood levels, but it is 7,8 better correlated with the rate of change in blood pressure from the patient's baseline level. Cyclosporine neurotoxicity may be thought of as a forme fruste of hypertensive encephalopathy. It is characterized by tremor, abnormalities in mental states ranging from mild inattention to coma, seizures, and various visual syndromes characteristic of dysautoregulation in distal arterial 7,8 territories of the posterior circulation. These include visual hallucinations, visual field deficits, visual agnosia, Balint's syndrome (the triad of simultanagnosia, abnormalities in visually directed reaching, and difficulties with voluntary eye movements), and cortical 7–9 blindness with denial of deficit (Anton's syndrome). Magnetic resonance imaging shows increased signal on T2-weighted images in the occipital white matter, a finding that may be quite evanescent and does not represent stroke. Flow studies such as single-photon emission computed tomography demonstrate that this is due to 6–8 increased flow with extravasation of water. These findings are identical to those found in patients with hypertensive encephalopathy, including the syndrome of toxemia of pregnancy. It should be emphasized that the patient's blood pressure need not be very high (i.e., need not be in the range of malignant hypertension) for this syndrome to occur. The pathogenesis appears to be related to the rate of change of blood pressure combined with loss of cerebral
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autoregulation rather than the absolute level of blood pressure. Lowering of blood pressure by any means, including but not limited to lowering the blood level of cyclosporine, will result in resolution of the clinical syndrome and the imaging abnormalities. 12
Cyclosporine is epileptogenic and causes seizures in 2 to 6 percent of patients receiving 6,8,9 The seizures may be focal or generalized and are usually (but not invariably) associated it. with high serum levels of the drug. Hypertension, hypomagnesemia, hypocholesterolemia, aluminum overload, and the concomitant administration of high-dose corticosteroids have 5,8,9 been identified as aggravating or precipitating factors. Neuralgia and neuropathy are less common complications of cyclosporine. Sensory disturbances consisting of paresthesias, dysesthesias, and hyperesthesias of the distal extremities (especially hands) are more common than weakness. Nerve conduction and electromyographic abnormalities are rarely present, although evidence of combined 8,13 demyelination and axonal damage has been reported. The treatment for all the direct neurotoxic side effects of cyclosporine is either to decrease the dose or to eliminate the drug entirely, if possible. Fortunately, nearly all the direct side effects (including the most severe encephalopathies and motor syndromes) are usually completely reversible after stopping the drug. Tacrolimus
Tacrolimus (previously known as FK506) is an immunosuppressive agent that is used for 14 long-term immunosuppression. The drug is used with a frequency equal to that of cyclosporine and has a mechanism of action similar to that of cyclosporine, with similar 15 neurological and systemic side effects. Neurological side effects are somewhat less common but resemble those of cyclosporine and consist of tremor, anxiety, restlessness, 7,15,16 Approximately one third of patients who insomnia, nightmares, and paresthesias. receive parenteral tacrolimus develop headache; oral administration is only rarely associated with headaches. As with cyclosporine, most neurotoxic side effects of tacrolimus reverse completely after the drug is withdrawn. Corticosteroids
Corticosteroids were the first immunosuppressive agents used in transplantation and continue to be used for long-term immunosuppression and to treat acute rejection. Corticosteroids affect both cellular and humoral immunity and expose patients to a greater risk of opportunistic infection than do the newer immunosuppressive agents that are relatively T-cell specific. The systemic side effects of corticosteroids are many and are not reviewed here. The most common neurological side effects of corticosteroids are myopathy, steroid psychosis, and problems resulting from corticosteroid withdrawal. The exact frequency of corticosteroid myopathy is unknown, but many patients on moderate-dose corticosteroids 9,17 The syndrome is develop some signs of myopathy 2 to 3 weeks after the start of therapy. 18 characterized by proximal muscle weakness that is most severe in the hip girdle. Treatment is to discontinue the corticosteroids (if possible) or to change to a nonfluorinated corticosteroid and decrease the dose. The myopathy usually resolves completely in 2 to 8 9,19 months after corticosteroid therapy is stopped. Psychiatric complications occur frequently in patients taking corticosteroids; many patients develop mild psychiatric symptoms, which may include anxiety, 20 insomnia, irritability, More severe acute difficulties with concentration and memory, and mood changes. 21 psychiatric syndromes occur in about 3 percent of patients. The phrase steroid psychosis refers to several psychiatric syndromes that are associated with corticosteroids. Severe psychiatric reactions usually take the form of affective disorders, schizophrenia-like 20 syndromes, or delirium. The treatment of steroid psychosis involves stopping the drug (if possible) or changing over to dexamethasone (the corticosteroid least likely to cause steroid psychosis) and reducing the dose. In addition, affective syndromes may respond to lithium, and schizophrenia-like syndromes are treatable with major tranquilizers. Withdrawal from corticosteroids also may cause neurological complications, including myalgias and arthralgias 22 consisting of headache, lethargy, and (steroid pseudorheumatism), and a syndrome 23 nausea, with or without a low-grade fever. Spinal cord or cauda equina compression from epidural lipomatosis caused by 24,25 This rare complication usually corticosteroids has been reported in transplant recipients. 24 does not occur in patients taking less than the equivalent of 30 mg/day of prednisone.
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Clinical manifestations include back pain, myelopathy, and radiculopathy. The usual treatment is surgical decompression,25although simply stopping the corticosteroid therapy has been reported to improve symptoms. OKT3 Monoclonal Antibody (Muromonab-CD3) +
26,27
OKT3 is a monoclonal antibody directed against CD3 lymphocytes. Its major neurological side effect is aseptic meningitis, which occurs in about 5 percent of patients during the first 3 days of exposure to the drug. Cerebrospinal fluid analysis shows a lymphocytic pleocytosis with normal glucose and normal or slightly elevated protein concentrations. The syndrome is self-limited and benign. Lumbar puncture and culture of the cerebrospinal fluid should be performed to exclude a bacterial or fungal meningitis before OKT3-induced aseptic meningitis is diagnosed. The mechanism of the meningeal inflammation is probably part of a cytokine release syndrome or an allergic process similar to that occurring in some patients placed on nonsteroidal28anti-inflammatory drugs such as ibuprofen or treated with intravenous immunoglobulin. A more severe syndrome with variable degrees of mental status derangement, including seizures, may occur even more 29 rarely. It is associated with neuroimaging evidence of cerebral edema, but it is also self-limited and benign, even if the OKT3 is continued. OKT3 use also predisposes patients to develop lymphoproliferative processes (including lymphoma), a side effect that appears to be dose related. Antithymocyte and Antilymphoblast Globulins
Antithymocyte globulin (ATG) and antilymphoblast globulin (ALG) are antisera directed against thymocytes or lymphocytes. Rarely, patients develop an aseptic meningitis similar to 7,9 that seen with OKT3, which is also self-limited and benign. Azathioprine
Azathioprine is an antimetabolite that suppresses both cell-mediated and humoral immunity. Although used less frequently now that more specific immunosuppressants are available, the drug is still used for long-term immunosuppression. The main systemic side effects are 7,9 myelosuppression and hepatotoxicity. There are no direct neurotoxic side effects, although the nervous system may be affected secondary to infection or liver failure. Neurological Infections Patients who receive long-term immunosuppression are at increased risk of developing infections. Neurological infections occur in 5 to 15 percent of all transplant recipients but are more important clinically than that number implies because about half of the central 30,31 nervous system (CNS) infections that occur in immunocompromised patients result in death. Nearly every conceivable organism has been reported to infect transplant recipients, but about 75 percent of the cases are due to infection with Listeria monocytogenes, 31 Cryptococcus neoformans, or Aspergillus fumigatus. Transplant recipients are at increased risk of infection for several reasons, the most important of which is the immunosuppression necessary to prevent rejection of the allograft. However, factors other than exogenous immunosuppressive agents also contribute to the risk of infection. After transplantation, patients often have indwelling catheters, endotracheal tubes, and other portals of entry for infection. The patients' underlying diseases and their complications (especially hyperglycemia and uremia) contribute to the net state of immunosuppression. In addition, certain infections (especially viruses) also cause 30,31 The single most important risk factor for developing suppression of the immune system. post-transplantation CNS infection is the magnitude and length of time of immunosuppression. CNS infections in immunocompromised hosts may be difficult to recognize, as the usual signs of infection, such as fever and meningismus, may be subtle or absent in such patients, as these signs depend on a vigorous immune response to the infection. Because the usual 32 signs of CNS infection may be absent and because nearly any organism—bacterium, fungus, parasite, or virus—may be responsible, the clinician should have a high suspicion index for infectious causes of neurological deterioration in any transplant recipient. A few clues may be of help in determining the likely organism. An infection outside the nervous system should alert the clinician to a possible neurological
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infection. Skin lesions may be found to harbor Cryptococcus, and lung infection suggests Aspergillus, Nocardia, or Cryptococcus. Acute meningitis is often due to L. monocytogenes, whereas chronic meningitis, often with cranial nerve palsies, suggests tuberculosis or fungal organisms. A progressive multifocal syndrome with hemiparesis, visual symptoms, ataxia, dysarthria, and dementia should raise the specter of progressive multifocal leukoencephalopathy caused by the JC polyomavirus. A localized mass lesion (e.g., a brain abscess) is often due to multiple organisms, including anaerobes, but the predominant organism in the immunocompromised patient is usually Aspergillus, Nocardia, or Toxoplasma. 30–32
Another clue to the causative organism is the time period after transplantation. In the early period (up to 1 month after transplantation), CNS infections are rare. When infections are present, they usually were present before the transplantation, acquired from the donor organ, or related to surgical complications of the transplantation procedure or the presence of indwelling catheters. These infections are usually due to common pathogens that are found in the general (nonimmunosuppressed) population. If opportunistic infections occur during the first month after transplantation, there is usually some problem with the transplant recipients' environment (e.g., Aspergillus in the air supply). In the intermediate period (between 1 and 6 months after transplantation), the net state of immunosuppression is usually at its peak because of prolonged immunosuppressive therapy and the immunomodulating effect of common viral infections. During this period, the risk of CNS infection is greatest. Two types of infections predominate—viruses and opportunistic organisms. Viruses (especially cytomegalovirus [CMV] and Epstein–Barr virus [EBV]) are themselves immunosuppressive, and infections with these agents predispose patients to develop infections with opportunistic organisms, including L. monocytogenes, A. fumigatus, 30,31 and Nocardia asteroides. Most late infections (more than 6 months after transplantation) fall into three categories: the lingering effects of an infection acquired earlier, opportunistic infections related to long-term immunosuppression, or the return to a pattern of infection similar to that seen in nonimmunosuppressed individuals. Most lingering infections are caused by viruses. Examples of lingering CNS infections are progressive chorioretinitis from cytomegalovirus 30,31 and B-cell lymphoproliferative disease in the form of EBV-associated CNS lymphomas. Opportunistic infections that develop more than 6 months after transplantation tend to occur in patients with chronic allograft rejection who have been maintained on higher-than-usual doses of long-term immunosuppressive agents (cyclosporine, corticosteroids) and have received additional antirejection therapy (usually with OKT3, ATG, or ALG). These patients are at the greatest risk of developing opportunistic CNS infections. C. neoformans, L. monocytogenes, and N. asteroides are the most common organisms causing opportunistic CNS infections in this group of patients. Most instances of cryptococcal meningitis that occur 30 in transplant recipients are found in these patients. Not all patients who survive for longer than 6 months after transplantation are at a substantially increased risk of developing opportunistic infections. Patients who are maintained on minimal long-term immunosuppression and whose post-transplantation courses have been free of chronic viral infections or the need for excessive antirejection therapy have only a slightly increased risk of infection. In these patients, the organisms causing CNS infections are usually the same as those present in the nonimmunosuppressed population. Lymphoproliferative Disorders Lymphoproliferative syndromes occur after prolonged immunosuppression. Early reports identified an in- crease in 33,34 non-Hodgkin's lymphomas in transplant recipients, especially but many of these apparently malignant lymphomas lacked the primary CNS lymphomas, histological and genotypic characteristics of true lymphomas. Currently, post-transplantation lymphoproliferative disorder is a description used to cover the wide spectrum of abnormal proliferations of B lymphocytes ranging from “benign” diffuse polyclonal lymphoid hyperplasia 35,36 CNS involvement occurs in 15 to 25 percent of to malignant monoclonal lymphoma. 34,37 The38CNS is the only site of patients with post-transplantation lymphoproliferative disorder. detectable disease in about 85 percent of cases that involve the CNS. Post-transplantation lymphoproliferative syndromes are strongly associated with EBV infection (even though primary CNS lymphomas in immunocompetent people are not 33 necessarily associated with this virus). These B-cell lymphomas arise deep in the brain with
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a propensity for the perivascular spaces. CNS lymphoma is distinguished from progressive multifocal leukoencephalopathy by the fact that the former produces mass effect and is enhanced with gadolinium on magnetic resonance imaging. Therapy for CNS involvement by post-transplantation lymphoproliferative disorder consists of reduction in immunosuppression, antiviral therapy, conventional cytotoxic chemotherapy, radiotherapy, and33,34,39,40 other experimental therapies (e.g., anti–B-cell antibodies and Treatment of CNS involvement begins with reduction of interferon-alpha). immunosuppression. Antiviral therapy may be tried, but standard radiotherapy and 36,40 The result of treatment of CNS chemotherapy are often the only practical treatments. disease is difficult to assess because no large series have been reported, but there is no 40 doubt that CNS involvement makes the prognosis extremely poor. The overall survival rate of patients who develop post-transplantation lymphoproliferative disorder is only about 30 34,37 percent.
Seizures Seizures are a common neurological complication after organ transplantation and occur in 6 1,41 The most common causes of seizures are drugs (especially to 36 percent of patients. cyclosporine and OKT3), metabolic derangements, and hypoxic-ischemic injury (usually producing seizures in the first weeks after heart, lung, or liver transplantation). Infections, infarcts, and tumors are less frequent causes. Often, the seizure disorder is transient and requires no treatment other than reduction in the dose of cyclosporine, correction of any responsible metabolic problem, or treatment of any underlying infection. Long-term treatment with chronic antiepileptic drugs is undesirable in transplant recipients because many of the older major anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine) interfere with the metabolism of the most commonly used immunosuppressive agents because of induction of the hepatic cytochrome oxygenase 42 P-450 system. Adding an anticonvulsant may cause a variable decrease in cyclosporine levels, and the dose of cyclosporine sometimes has to be increased when older anticonvulsants are started. Patients who have had only a single seizure should not be started on long-term anticonvulsants. For short-term acute management of status epilepticus, the benzodiazepines are the least likely to interfere with cyclosporine metabolism (although 41 benzodiazepines do cause some increased degradation). These drugs have an advantage in that they can be given either orally or intravenously. In patients who require long-term treatment with anticonvulsants, the choice of agent to use has become easier with the introduction of newer anticonvulsants that have oral and intravenous formulations and do not induce hepatic enzymes, such as valproate, gabapentin, and levetiracetam. However, valproate should be avoided in patients with liver transplants because of potential hepatotoxicity. In general, phenytoin should be avoided because of its interference with cyclosporine levels and adverse effect on engraftment. NEUROLOGICAL COMPLICATIONS ASSOCIATED WITH SPECIFIC TRANSPLANTATION TYPES
Renal Transplantation The first successful human renal transplantation occurred in 1954 when Murray and 43 associates transplanted a kidney from one identical twin to another. Renal transplantation has now developed into the best therapy for most patients with end-stage renal disease, and the kidney is the most frequently transplanted organ. For kidney transplantations, there is virtually a 100 percent 1-year patient survival rate and an approximately 90 percent graft survival rate. The 5-year survival rate for nondiabetic renal transplant recipients is more than 44 30 percent of renal transplant recipients develop neurological 90 percent. Approximately 45–52 (Table 46-1). complications Click here to view this table.... Renal transplantation is most often performed in patients with glomerulonephritis (membranous or membranoproliferative), diabetes mellitus, and hypertensive renal disease. Other underlying diseases include polycystic kidney disease, lupus erythematosus, amyloidosis, analgesic nephropathy, and obstructive nephropathy. The toxic effects of pretransplantation uremia can cause subclinical neurological impairment and leave the 47,53 In addition, uremia nervous system vulnerable to subsequent injury after transplantation.
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may recur after transplantation. Many of the underlying diseases, especially diabetes and hypertension, are associated with accelerated atherosclerosis and predispose patients to 53 develop cerebrovascular complications before and after transplantation. Most of the neurological complications of renal transplantation are due to the underlying 53 disease for which the transplantation was performed. For example, polycystic kidney disease may be associated with multiple cerebral berry aneurysms, hypertension with ischemic and hemorrhagic stroke, lupus erythematosus with antineuronal antibodies and mental state changes, and uremic encephalopathy with hepatorenal syndrome. Rapid correction of hyponatremia may lead to central pontine myelinolysis, a syndrome that can range in severity from mild quadriparesis to deep coma or even death and can now be easily demonstrated in the pons or in extrapontine sites by magnetic resonance imaging. The renal transplantation procedure itself is relatively benign. Neurological complications, other than those caused by anesthesia or intraoperative hypotension, consist of arterial and 53 peripheral nerve venous thromboses and peripheral nerve injuries. The most common 54–56 The usual cause is injuries involve the femoral and lateral femoral cutaneous nerves. intraoperative compressive injury due to pressure from self-retaining retractors. In a few patients, the caudal spinal cord is supplied by branches of the internal iliac arteries rather than by intercostal arteries; in these patients, 55 when the iliac artery is used to supply blood to the allograft, spinal cord ischemia may result. Several characteristics of renal transplant recipients make their overall complication rate different from that of other organ transplant recipients. Many renal transplant recipients have some degree of vascular compromise either as a result of their underlying disease (hypertension,53diabetes) or because of emboli associated with underlying atherosclerosis or heart disease. The most common post-transplantation neurological complications in this patient population are cerebrovascular events; these occur in approximately 9 percent of all 46,47,50,51 renal transplant recipients. 57
Acute rejection of the renal allograft can produce an encephalopathic syndrome. Neurological manifestations consist of a nonfocal encephalopathy with headache, altered mental status, and seizures. Systemic manifestations are fever, weight gain, renal failure, and swelling and tenderness of the graft. This syndrome has been described only in renal transplantations, and the mechanism has not been identified; it is likely, however, that the syndrome is caused by soluble neuroactive immune factors (e.g., cytokines) released during the rejection process. A similar syndrome occurs as a side effect of OKT3.
Bone Marrow Transplantation 58
Bone marrow transplantations became a viable treatment option in the late 1960s. With improvements in tissue matching, immunosuppression, and supportive care, bone marrow transplantation has developed into an important method of treatment for aplastic anemia, certain inborn errors of metabolism, and a variety of hematological, lymphoreticular, and solid malignancies. Today, bone marrow transplantation is the second most common type of organ transplantation. Most of the associated neurological complications59occur in allogeneic transplants, which usually require long-term immunosuppression. Neurological complications occur in 60 to 70 percent of allogeneic bone marrow recipients (Table 46-2) 50,51,59–69 and are the cause of death in 5 to 10 percent. Click here to view this table.... The underlying diseases for which allogeneic bone marrow transplantations are performed may be the cause of neurological problems. Leukemias recur in the CNS in up to 1559,60,63,70 percent of patients undergoing bone marrow transplantation for acute lymphocytic leukemia and produce neoplastic meningitis. In addition, patients with malignancies have sometimes received prior radiation and chemotherapy that may result in neurological damage. The procedure for bone marrow transplantation is the most benign of all transplantation procedures. No anesthesia or incisions are required. The donor's bone marrow is infused intravenously, and there are usually no immediate complications. In the past, toxic 60,70 myelolethal preparatory regimens often caused neurological complications. Modern preparatory regimens consisting of alkylating agents (usually cyclophosphamide) with or without small doses (<2,000 cGy) of total-body irradiation rarely cause acute neurological problems. However, even the relatively low doses of cranial radiation used in bone marrow transplantation may71produce permanent cognitive dysfunction in long-term survivors, especially children.
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The timetable of infection after bone marrow transplantation differs from that after other types 1,31,60 Patients are usually more severely immunosuppressed at the time of of transplantations. transplantation because of the underlying diseases (e.g., aplastic anemia, leukemia) and the myeloablative preparatory regimen. After the transplantation, patients are granulocytopenic for about 1 month, until the new marrow begins to function. During this period, bacterial (especially gram-negative), viral (especially herpes simplex virus [HSV]), and fungal infections may become established. Even after apparent hematological recovery, immunological abnormalities of both cell-mediated and humoral immunity persist for up to 1 67,72 In this second period, viral infections (especially cytomegalovirus) and protozoan year. infections (especially Toxoplasma gondii) become more common. Patients usually require less long-term immunosuppressive therapy than patients undergoing other transplantations, and sometimes immunosuppression may be discontinued after successful engraftment if no graft-versus-host disease is present. Perhaps as a consequence, the prevalence of post-transplantation lymphoproliferative disorders with CNS involvement is lower than with 1,33,34 other types of trans-plantations. A major problem after bone marrow transplantation is the development of graft-versus-host disease, which occurs in up to 40 percent of patients with human73leukocyte antigen (HLA)–matched and 75 percent of HLA-mismatched transplants. This complication results from an attack on host tissue by immunologically competent lymphocytes. Although most frequently associated with bone marrow transplantation, it also occurs occasionally after liver transplantation and, in severely immunosuppressed patients, after blood transfusions containing lymphocytes. Acute graft-versus-host disease occurs within 3 months after transplantation and is characterized by rash, diarrhea, and liver dysfunction; no neurological complications have been associated with it. Chronic graft-versus-host disease develops in 35 to 40 percent of patients undergoing bone marrow transplantation who survive longer than 100 days and is characterized by a syndrome that has features in common with some autoimmune disorders 73 (especially scleroderma) with multisystem involvement. Chronic graft-versus-host disease has been implicated in several neuromuscular and 74,75 Polymyositis that is neurological complications after bone marrow transplantation. clinically indistinguishable from the idiopathic form has been reported. Treatment directed against graft-versus-host disease with immunosuppressive agents usually results in 74,75 In improvement of symptoms. Myasthenia gravis has also been described in this context. these patients, the clinical picture is the same as that of classic autoimmune myasthenia gravis, and all reported cases have had elevated acetylcholine receptor antibody levels. Acetylcholine receptor antibodies appear to develop as part of the graft-versus-host disease process and are not due to the transfer of active B-cell clones from donor to recipient. Usually, there is good response to cholinesterase inhibitors and immunosuppressive agents. Peripheral neuropathies have also been associated with chronic graft-versus-host disease. The clinical findings are similar to those of chronic inflammatory demyelinating polyneuropathy. Most patients respond to immunosuppressive therapy. Cerebrovascular complications are a relatively frequent problem after bone marrow transplantation. Cerebral infarcts are found in 4 to 13 percent of patients at autopsy, and underlying nonbacterial thrombotic endocarditis or infective endocarditis is often the 60,61,76–81 In some autopsy series, nonbacterial thrombotic endocarditis60,61,76 has been cause. 60,61,76,79 and occurs after both allogeneic and present in 4 to 9 percent of patients 77,78 autologous bone marrow transplantations. The reason for the increased prevalence of nonbacterial thrombotic endocarditis in bone marrow recipients is unknown, although the cardiac lesion is associated with disseminated 82 intravascular coagulation and with other hypercoagulable states. After bone marrow 83,84 transplantation, various abnormalities in patients' natural anticoagulants occur frequently and probably predispose patients to develop the cardiac abnormality. It is of note that despite prolonged thrombocytopenia and abnormalities in coagulation, significant cerebral hemorrhages are relatively rare after bone marrow transplantation.
Cardiac Transplantation The first human heart transplantation was performed in 1967 by Christiaan Barnard in South 85 Africa. Cardiac transplantation is used to treat medically intractable dilated, hypertrophic, restrictive, and ischemic cardiomyopathies, as well as some patients with rheumatic heart disease. These conditions predispose patients to develop cerebral embolic events, chronic brain hypoperfusion, hypoxia, and metabolic abnormalities. Neurological complications are 50,86–98 (Table frequent after cardiac transplantation and occur in up to 60 percent of patients
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46-3). Click here to view this table.... The heart transplantation procedure is a major cause of neurological complications. During transplantation, patients are often on a bypass pump for several hours and may be subjected 53,89,99 During the transplant procedure, patients to long periods of hypotension and hypoxia. are also at risk for developing emboli from blood clots or air. Autopsy series have shown that up to 50 percent of patients have focal cerebral infarcts or evidence of diffuse 50,86,88,90–98 Ischemic insults suffered during the transplantation hypoxic-ischemic injury. procedure show themselves in the perioperative period as either focal neurological deficits or as nonfocal encephalopathies and are usually accompanied by seizures. Peripheral nerve injuries are another relatively common complication of the transplantation 86,97 The most frequently encountered procedure and occur in about 13 percent of patients. lesions are brachial plexus injuries caused by retraction of the chest wall during surgery or as a result of catheterization injury. The phrenic nerve also may be damaged by retraction or by 86,100 the practice of packing the heart in ice during the transplantation. Although the pattern and timetable of CNS infections are similar to those seen in other types of transplantations, the side effects of immunosuppression are more common and severe in cardiac transplant recipients because higher doses of immunosuppressive agents are often 101 94 used. Toxoplasma infections account for a higher percentage of CNS infections (12%) than in other transplantations, and the source of infection is sometimes the donor organ itself. Post-transplantation lymphoproliferative disorders with CNS involvement is more common after cardiac transplantation (especially heart/lung transplantation) than after other types of 34,37,101,102 transplantation. After transplantation, patients continue to be at risk of stroke due to cardiac emboli, underlying atherosclerosis, and arrhythmias. Syncope may also occur; the most frequent causes are arrhythmias and coronary artery spasm. Further discussion of the neurological complications of cardiac transplantation may be found in Chapter 3.
Pulmonary Transplantation 103
The first successful lung transplantation was performed in the mid-1980s, and lungs are now transplanted either singly or bilaterally by themselves or along with hearts (heart/lung transplantation). For50transplantation involving lung alone, the 1-year survival rate is on the order of 80 percent. The505-year survival rate for heart/lung transplant recipients is complications are frequent after lung transplantation approximately 82 percent. Neurological50,103,104 (Table 46-4). and occur in 45 to 60 percent of patients Click here to view this table.... Lung transplantations are used to treat a variety of end-stage lung diseases, including emphysema, other severe chronic obstructive pulmonary diseases, cystic fibrosis, α1-antitrypsin deficiency, and idiopathic pulmonary fibrosis. Many of the neurological complications are related to chronic hypoxia or the resumption of hypoxia after the graft 53 fails. Seizures and metabolic/hypoxic encephalopathies are the most common neurological 105,106 Seizures have been reported to occur in 22 to 27 complications of lung transplantation. 105,106 percent of patients. The lung transplantation procedure is the cause of several neurological complications, including stroke and diffuse hypoxic-ischemic brain damage. Cerebrovascular complications 50 are found in more than 50 percent of autopsied lung transplant recipients. Peripheral nerves are also occasionally damaged by the transplantation surgery. Phrenic nerve damage 107 (usually 100 unilateral) was found in 3 percent of patients in one large series and 7.4 percent in another. Lung and heart/lung transplantations require the largest doses of short- and long-term immunosuppressive agents of any type of transplantation, and so it is not surprising that cyclosporine toxicity and the side effects of immunosuppression are more common in lung 50 and heart/lung transplantations. In a large autopsy series, neurological infections were found in 10 percent of lung transplant recipients and 14 percent of heart/lung patients. Post-transplantation lymphoproliferative disorders involving the CNS have been found in 7 50 percent of patients at autopsy.
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Hepatic Transplantation 108
The first successful human liver transplantation was performed in 1963. Hepatic transplantation is used to treat chronic advanced liver disease, which may be due to cholestatic diseases (e.g., primary biliary cirrhosis and sclerosing cholangitis), hepatocellular diseases (e.g., alcoholic or viral hepatitis), vascular diseases (e.g., the Budd–Chiari syndrome), hepatic malignancies (e.g., hepatoma, cholangiocarcinoma, and isolated hepatic metastasis as may be seen in carcinoid tumor), fulminant hepatic failure (e.g., due to viral hepatitis or drug-induced liver damage with halothane or gold), and metabolic liver diseases (e.g., antitrypsin53,109 deficiency, Wilson's disease, glycogen storage diseases I and II, and Liver transplant recipients frequently suffer neurological complications. protoporphyria). 50,108–114 to Reported frequencies range from 20 to 50,115,116 30 percent of patients in clinical series (Table 46-5). more than 80 percent in autopsy series Click here to view this table.... Because of the shortage of organs, patients frequently wait a considerable time for transplantation. By the time of transplantation, patients are often critically ill, with many having 53 some degree of metabolic encephalopathy due to chronic liver failure. The encephalopathy may continue if the transplantation is unsuccessful or may recur if the transplanted liver fails. Also, before transplantation, patients often have coagulopathies because of liver failure and are prone to develop CNS hemorrhages both before and after transplantation. The liver transplantation procedure itself is not benign. Because of blood loss during the procedure, patients often require massive replacements of blood and electrolytes and suffer 53 prolonged periods of hypotension, which may cause diffuse hypoxic-ischemic damage to the brain or watershed infarctions.Intraoperative infarctions may also be caused by air embolism or arterial embolism. During the transplantation procedure, peripheral nerves may be injured, and one report 117 indicates that brachial plexus injuries occur in 5.8 percent of patients. Injuries to the brachial plexus may be caused by damage related to axillary dissection done for the 117 to placement of femoral-axillary venous bypasses ; however, neuropathies due117–119 catheterization injuries, nerve compression, and surgical retraction also occur. The side effects of immunosuppression after liver transplantation are similar to those seen in other types of transplantations. Liver transplantations differ in that higher doses of antirejection agents are commonly used, and the frequency of post-transplantation lymphoproliferative disorders with CNS involvement is second only to that present in cardiac and heart/lung transplantations. In addition, because liver transplant recipients have more of the factors associated with cyclosporine toxicity (e.g., hypocholesterolemia, hypertension), the direct neurotoxic side effects of cyclosporine are more common and severe. For this reason, tacrolimus is increasingly used as the primary immunosuppressive agent in liver transplantation. An unusual neurological complication that occurs at an increased rate in liver transplant recipients is central pontine myelinolysis. This has been found consistently in 7 to 13 percent 50,120–122 and has also been reported to occur of autopsied liver transplant recipients 50,123 124 and cardiac transplant recipients. The disorder consists of infrequently in renal 124 demyelination in the pons, although extrapontine demyelination may also occur. The cause has not been determined conclusively, but the disorder has been associated with rapid 125 correction of hyponatremia. During the liver transplantation procedure, patients almost always experience an abrupt increase in serum sodium concentrations caused by the rapid replacement of intraoperative blood loss with intravenous fluids and blood products that 124–127 contain high amounts of sodium. The clinical manifestations of central pontine myelinolysis (as discussed in Chapter 19) are 124 altered mental status or coma, pseudobulbar palsy, and quadriplegia ; however, after liver transplantation, these clinical findings are often masked by other neurological or systemic problems. As a result, the diagnosis is often discovered only at autopsy, although the diagnosis can be made antemortem by magnetic resonance imaging. There is no specific treatment, although avoidance of rapid changes in serum sodium concentration by using low-sodium intravenous fluids and blood products may help prevent this complication.
Pancreatic Transplantation 128
The first pancreas transplantation was performed in 1966. Pancreatic transplantations are performed in patients with type 1 diabetes mellitus who have extensive end-organ
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129,130
damage. Most pancreas transplantations are done in conjunction with renal transplantations and are performed either simultaneously or in patients who already have a functioning renal transplant. The major goal of pancreatic transplantation is not merely to make patients insulin independent but to prevent or reverse the secondary complications of diabetes by making patients truly euglycemic. Whole-pancreas transplants cause patients to become euglycemic within hours after transplantation, and there is a greater than 90 percent graft survival rate at 130 1 year. Neurological complications are relatively frequent after pancreatic transplantation. In a small series of 15 patients, Kiok found that 60 percent of patients suffered neurological 131 problems (Table 46-6). Click here to view this table.... All pancreatic transplant recipients have severe diabetes with end-organ involvement, including nephropathy, retinopathy, and peripheral neuropathy. Many patients also have evidence of peripheral or cerebrovascular disease. In addition, because most patients have end-stage renal disease secondary to diabetes, they may also experience the neurological complications associated with renal failure. Nearly all patients have some degree of peripheral or autonomic neuropathy at the time132,133 of 131 have demonstrated that the peripheral neuropathies, transplantation. Several studies 134 including autonomic neuropathies, improve after pancreatic transplantation. Neurological complications related to the transplantation procedure are rare. Kiok reported no complications130 from the transplantation procedure in his series on neurological complications ; however, 26 percent of patients later suffered either focal ischemic strokes or global hypoxic/ischemic events during subsequent surgical procedures unrelated to the transplantation procedure. Pancreatic transplants require a relatively high level of immunosuppression, and complications related to immunosuppression and antirejection agents are similar in frequency to those present in hepatic or cardiac transplantation. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 47 HTLV-I Infection and the Nervous System JOHN W. ENGSTROM •
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HISTORY EPIDEMIOLOGY Geographical Distribution of Infection Incidence and Prevalence of Myelopathy Transmission CLINICAL AND LABORATORY FEATURES Symptoms and Signs Systemic Manifestations Clinical Neurophysiology Neuroimaging Cerebrospinal Fluid Serology Hematology DIFFERENTIAL DIAGNOSIS PATHOLOGY AND PATHOGENESIS Pathology Pathogenesis PREVENTION AND TREATMENT Prevention Immunomodulation Symptomatic Treatment
Infection with human T-lymphotropic virus type I (HTLV-I) can cause an insidiously progressive and debilitating myelopathy, a fatal T-cell leukemia or lymphoma, or most 1,2 commonly remains indolent in the large pool of asymptomatic, infected individuals. Spread of the responsible virus can be prevented. HTLV-I myelopathy is a model for a chronic, 2 progressive central nervous system (CNS) disease caused by a retroviral infection. Current knowledge of the epidemiology, clinical and laboratory features, pathology, pathophysiology, prevention, and therapy of HTLV-I myelopathy is summarized in this chapter. The HTLV-II virus has similar genetic and structural features but less commonly causes disease. HISTORY A heterogeneous group of patients from the tropics with progressive thoracic myelopathy was
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described in 1964; their disorder was labeled “tropical spastic paraparesis.” In retrospect, some of these patients represent the earliest known cases of HTLV-I myelopathy. HTLV-I infection was directly associated with human disease in 1980 when the retrovirus was 4 isolated from a patient with mycosis fungoides. Gessain and colleagues subsequently reported in 1985 that patients with tropical spastic paraparesis had antibodies to HTLV-I and suggested that HTLV-I, or a related virus, was contributing to the pathogenesis of the 5 disorder. A clinically similar myelopathy associated with HTLV-I antibodies in the serum and cerebrospinal fluid (CSF) of Japanese patients was named HAM (HTLV-I-associated 6 and Osame recognized that tropical myelopathy) by Osame and colleagues. In 1988, Roman 7 spastic paraparesis and HAM were the same disease. The term HTLV-I myelopathy, or HAM, is used now in preference to these other designations. EPIDEMIOLOGY 8
It is estimated that 10 to 20 million persons are infected worldwide. The average age at onset of the myelopathy is approximately 40 years, but the prevalence of the myelopathy increases with age 9–11 in endemic areas. Symptomatic myelopathy may11begin between the ages Women are affected more than men (1.5:1). of 20 and 70 years.
Geographical Distribution of Infection Infection with HTLV-I is endemic in the Caribbean, South Japan, South America, and 12,13 equatorial Africa, with infection rates as high as 1 to 2 percent of the adult population. HAM has become a significant public health problem in developing countries that lack preventive, diagnostic, and supportive services for disabled individuals and asymptomatic carriers. In nonendemic areas, the infection is sporadic; the prevalence is 0.079 per 100,000 14 Swiss blood donors. Japan is exceptional among nonequatorial regions in exhibiting a high prevalence of HTLV-I infection; most infected persons are from the islands of Kyushu or 11,15 Okinawa.
Incidence and Prevalence of Myelopathy The calculated lifetime risk of HTLV-I myelopathy among seropositive patients is between 16 0.25 and 2 percent. The calculated lifetime risk for the development of acute T-cell leukemia or lymphoma is 1 to 4 percent. The biological factors responsible for development of myelopathy or hematological malignancy in only a small subset of infected individuals are unknown. The calculated annual incidence of the myelopathy on Kyushu, Japan, is 0.04 per 100,000 11 inhabitants, and the calculated prevalence is 8.6 per 100,000 inhabitants. The available incidence and prevalence data underestimate the scope of the problem. Accurate estimates of the incidence and prevalence of HAM worldwide are hindered by nonuniform reporting of the disease and limited availability of neurological diagnostic resources in many endemic areas. The incidence and prevalence figures of the myelopathy in Japan have been expressed per 100,000 HTLV-I–seropositive persons per year. The annual 11 incidence of HTLV-I myelopathy is 3 per 100,000 and the prevalence is 68 per 100,000.
Transmission Known routes of HTLV-I transmission are breast milk, sexual intercourse, butchering or eating meat from nonhuman primates, and exposure to contaminated blood products. The most common circumstances leading to contaminated blood product exposure are blood transfusion, reuse of contaminated hypodermic needles (intravenous drug use), and transplacental infection. There is no strong evidence to support oral contact as a mode of 17 infection in humans, although oral epithelial cells have been found to contain HTLV-I. The risk of transmission via breast-feeding, continued for 12 months after birth, was found to be 17 percent in a prospective study of children born to mothers infected with HTLV-I; the risk 18 A high increases threefold when the mother and child share five or more HLA class I types. 19 proviral load in breast milk increases the risk of transmission. Breast milk containing 20 HTLV-I–infected lymphocytes has been found among seropositive human mothers. The efficiency of transmission by21,22 breast milk appears to be approximately five times greater than for the transplacental route. A long-term study of married couples in Japan found that transmission by sexual contact was 22 more effective from men to women over 10 years than from women to men. The presence of HTLV-I–infected lymphocytes in semen may partially explain this difference. A more recent
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study of stable married couples in which one person is a seropositive blood donor has shown 23 lower rates of sexual transmission over a decade. Transmission of the virus by transfusion of contaminated blood products is a 11,24 A study in the United States of25the prevalence of well-documented route of infection. HTLV-I antibodies among blood donors yielded a rate of 0.02 percent. Seroconversion and spastic paraparesis have developed in patients as soon as 6 months after transfusion with 26 contaminated blood products. The median time to development of myelopathy after blood transfusion was estimated at 3.3 years among 134 patients with both a history of blood 11 transfusion and HAM. The efficiency of transmitting the infection via blood transfusion has been estimated to range from 44 to 63 percent, but there are no prospective quantitative data for estimating the risk of developing myelopathy among those who developed infection as a 27 result of transfusion. It has been speculated that a high viral load at the time of transfusion may predispose patients to more rapid development of the myelopathy. Blood banks in the United States routinely screen all donors for the presence of HTLV-I and HTLV-II antibodies. Among infected donors, HTLV-II infection is more common. Reuse of contaminated needles among intravenous drug users is another major source of HTLV-I/II infection. Khabbaz and colleagues found that the seroprevalence of HTLV-I/II antibodies increased from zero (among drug addicts younger than 19 years) to 32 percent 28 29,30 (among addicts older than 45 years). Coinfection with HIV is common in this setting. Patients seen in clinics for sexually transmitted diseases were 10 times more likely to be infected with HTLV-I/II if they were also intravenous drug users than other patients attending clinics for sexually transmitted 25 diseases. Many of the HTLV infections among intravenous drug users are due to HTLV-II. HTLV-II occasionally causes a myelopathy indistinguishable from that of HTLV-I, but the other clinical manifestations commonly associated with HTLV-I 31 infection are not clearly caused by HTLV-II infection. The frequency of HTLV-II infection in the United States among intravenous drug users is greater with increasing age, coincident 28 HIV infection, and in women, blacks, and Hispanics. A recent study in Cameroon revealed evidence of multiple HTLV-I infection subtypes in humans and cross-species transmission among hunters or butchers of nonhuman 32 primates. New HTLV human infections (HTLV-III and HTLV-IV) were found also. HTLV-IV, for example, was not identifiable in the nonhuman primate population. The sensitivity of current antibody screens for HTLV-I/II in detecting these presumably novel HTLV infections is unclear. CLINICAL AND LABORATORY FEATURES
Symptoms and Signs The most common initial symptoms in three classic series of patients, confirmed by a more 9–11,33 (Table recent clinical series from Peru, were either leg weakness or difficulty walking 47-1). Other common symptoms were painful legs, paresthesias, or back pain. There were occasional complaints of bladder dysfunction. The mean duration of symptoms at the time of data collection was 13 years in two of these series. Click here to view this table.... The most common neurological sign among these patients was a spastic paraparesis that 9,10,33 Bilateral hyperreflexia in the arms was present was asymmetric in one third of patients. in most patients, but upper-limb weakness or spasticity was uncommon. All patients who were symptomatic for greater than 7 years requiredassistance with walking, and one fourth were wheelchair bound. The usual course of the gait disorder was slow deterioration to severe disability over 2 to 10 years. Rapid progression was associated with severe spasticity, 33 diminished vibration sensation, and tremor in one recent series. Bladder dysfunction has been found in 96 percent of patients, despite the relative infrequency of subjective complaints of sphincter dysfunction. Urodynamic studies on 14 patients with HTLV-I myelopathy and urinary symptoms of urgency, frequency, or retention provided 34 evidence of a spastic bladder in 13 instances. Loss of touch and pain sensation was present (after an average duration of illness of 8 years) 9 in 40 percent of the patients in one series. Although motor and bladder dysfunction appear first, sensory involvement becomes manifest later. These patients rarely, if ever, develop a sensory level. The reported frequency of specific symptoms and signs varies between clinical studies and must be interpreted with caution. Each clinical series is a cross-sectional snapshot of a
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disease process that evolves over years. Neuromuscular presentations of HTLV-I infection have been described occasionally. Some 35–37 Proximal patients have an inflammatory myopathy indistinguishable from polymyositis. myopathic weakness, an elevated serum creatine kinase concentration, electromyographic changes of a myopathy associated with muscle membrane instability, and an endomysial lymphocytic inflammatory infiltrate on a muscle biopsy sample are present. One patient with polymyositis, but no spinal cord involvement,36had evidence on a muscle biopsy sample of direct infection of muscle fibers with HTLV-I. Transduction of muscle cells with the tax gene 38 in vitro has been shown to induce myocytotoxicity. Polyneuropathy has been mentioned uncommonly39in the literature; many reports lack complete clinical and neurophysiological information. There is a paucity of information regarding peripheral nerve pathology among these patients, but it appears that inflammation, demyelination, or axonal loss may be 40,41 present. Ophthalmological manifestations include uveitis, lymphomatous infiltration of the eye, and retinal vasculitis. Ocular findings in Caribbean and Brazilian populations have included 42,43 44 Cases of optic neuropathy have been documented. corneal pathology. In one study, the prevalence of HTLV-I infection among patients with presumed idiopathic Bell's palsy admitted to the hospital in Trinidad was greater than in the general population and 45 a hospitalized control group. These authors recommended that patients with idiopathic facial nerve palsy in endemic areas be screened for HTLV-I infection.
Systemic Manifestations The clinical importance of HTLV-I infection in producing systemic manifestations in the absence of myelopathy or leukemia/lymphoma has become increasingly recognized in recent 46 years. Abnormal pulmonary computed tomography (CT) findings were found in 30 percent of patients in one recent series. The findings included centrilobular nodules, thickening of bronchovascular bundles, ground-glass opacity, bronchiectasis, and interlobular septal thickening. Pathology in a significant minority showed lymphocytic infiltration along respiratory 47 bronchioles and bronchovascular bundles. The extent of bronchoalveolar lymphocytosis from bronchoalveolar lavage fluid correlated with the copy number of HTLV-I proviral DNA in another study, suggesting a possible role for the lymphocytosis in the pathogenesis of HTLV-I 48 pulmonary disease. Epidemiological data suggest an increased49frequency of bladder or renal infection and arthritis among persons infected with HTLV-I. Proviral load50was higher among HTLV-I patients with arthritis than infected, nonarthritic HTLV-I controls. The prevalence of Strongyloides infection has been reported to be more frequent among HTLV-I carriers than among matched individuals without HTLV-I infection, possibly related to altered 51 host immune responses. Other reported disease associations include Sjögren's52syndrome, sarcoidosis, monoclonal gammopathy, and idiopathic thrombocytopenic purpura.
Clinical Neurophysiology Lower-limb somatosensory evoked potential studies are useful to detect subclinical, unilateral, or34,53,54 bilateral sensory spinal cord involvement in patients with HTLV-I Central motor conduction times are slowed in up to 74 percent of patients myelopathy. 54,55 The recording of visual evoked potentials, brainstem auditory evoked with HAM. potentials, and upper-limb somatosensory evoked potentials is of less certain value. The frequency of abnormal findings has varied widely in different series, but abnormalities occur 43,54 The variability in frequency of evoked potential abnormalities in only a minority of patients. may be due to a disease burden that increases with disease duration, the distribution of the multifocal lesions in the CNS, and different criteria used to define electrophysiological abnormalities between laboratories. With regard to the peripheral nervous system, minor slowing of conduction velocities, prolonged minimum F-wave latencies, and mild prolongation of distal motor latencies have been reported in some series, but nerve conduction studies have been normal in other 34,39,56,57 studies.
Neuroimaging Magnetic resonance imaging (MRI) of the cervical and thoracic spinal cord is usually normal. In a minority of patients, nonspecific changes include spinal cord atrophy and multifocal 58 increased T2 signal in white matter, rarely associated with contrast enhancement.
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Brain MRI may reveal multifocal lesions of high signal intensity on T2-weighted images in 59 subcortical, deep, or periventricular white matter. A comparison of brain MRI features between patients with HTLV-I, multiple sclerosis (MS), collagen vasculitis, and other noninflammatory neurological diseases showed that patients with HAM had more small and 60 large lesions scattered throughout subcortical, periventricular, and deep white matter. There was a much higher frequency of periventricular lesions in patients with HAM than in the collagen vasculitis group, and a lower frequency of small and deep, subcortical, infratentorial, and periventricular white matter lesions than in the MS group. An additional neuroimaging study, applying MRI criteria for MS, suggested that patients with MS have at least some 61 lesions that are significantly larger than the lesions seen in patients with HAM. Brain MRI revealed more 62 than 10 white matter lesions in 8 of 22 patients with HTLV-I myelopathy in one series. Patients with multifocal white matter lesions had a longer disease duration and greater disability than patients without white matter lesions. In a follow-up study of patients treated for 2 years with corticosteroids, clinical deterioration occurred and follow-up63brain MRI showed larger and more numerous lesions regardless of corticosteroid therapy. The frequency of MRI abnormalities in different series probably reflects differences in disease severity and duration. Neuroimaging alone is not specific enough to distinguish 58 between diseases causing multifocal white matter abnormalities.
Cerebrospinal Fluid The CSF in patients with HTLV-I myelopathy reveals lymphocytic pleocytosis or elevated 10,34 The glucose concentration protein concentration in approximately 50 percent of patients. 34 is normal. Oligoclonal bands are often present in serum and CSF. Antibodies from the bands were directed against64,65 specific HTLV-I antigens among 5 patients in one series and in Intrathecal synthesis of antibodies to HTLV-I viral antigens 19 of 22 patients in another. 66 occurs most often among patients with myelopathy. An elevated immunoglobulin G (IgG) index or HTLV-I antibody index has been found in patients with HTLV-I myelopathy and 64,67,68 The presence of provides indirect evidence of synthesis of IgG antibody in the CNS. specific HTLV-I antibodies in the CSF may reflect activated B-cell clones inside and outside the CSF–CNS64compartment or selective synthesis of antibody in the CSF–CNS compartment. More recently, assays have been developed to assess proviral load directly in peripheral blood and CSF lymphocytes; these studies have revealed higher proviral69–71 loads in CSF and blood lymphocytes among patients with HAM than asymptomatic carriers.
Serology The U.S. Public Health Service first established guidelines for serological testing for HTLV-I 72 antibodies in 1988. Specimens initially positive by enzyme-linked immunosorbent assay (ELISA) are retested in duplicate. If one of the duplicate tests is positive, then reactivity is unlikely to be due to errors of technique. The serum must be further analyzed by Western blot for immunoreactivity to the gag gene product p24 and an env gene product (gp46 or 72 gp61h68) for a specimen to be considered a true seropositive. Specimens meeting these criteria73are always positive for HTLV-I or HTLV-II using the polymerase chain reaction (PCR) assay. Indeterminate specimens are those that are positive by ELISA and duplicate testing but in which Western blot immunoreactivity can be found only to either the gag or env gene product. Possible explanations for seroindeterminate status include exposure to HTLV-I without self-sustaining infection (e.g., via a blood transfusion), low level HTLV-I infection,74,75 A variety cross-reactivity with another infectious agent, or infection with a novel retrovirus. of screening tests in specific sequence have been proposed as alternatives, but none has 76 been adopted uniformly. Incidence and prevalence data regarding infection are based on serological screening with available ELISAs and Western blot techniques There are no population-based screening studies performed with PCR techniques. If there is a high clinical suspicion for HTLV-I infection and the screening ELISA is negative or the Western blot is indeterminate, then PCR analysis is necessary to detect the virus. Recent studies have strongly suggested that false-negative results are probably more common than is appreciated. For example, coinfection with HIV may result in a negative 77 HTLV-I/II ELISA. Another study found that among former injection drug users, standard serological markers missed patients with HTLV-I infection detected by PCR/Southern blot 78 analysis. The ability to measure proviral load in peripheral blood mononuclear cells has resulted in the observation that there is a sixfold increase in viral load in these cells among
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HAM patients compared with asymptomatic HTLV-I–infected controls.
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Hematology Atypical lymphocytes with convoluted nuclei (flower cells) can be found in the blood of 81 80 infected patients. These cells normally constitute 0.1 to 2 percent of the lymphocytes. Flower cells have been reported to comprise up to 10 percent of lymphocytes among patients 82 with T-cell leukemia and HTLV-I myelopathy, but this observation varies among countries. Flower cells have not been found to be predictive of the development of acute T-cell leukemia/lymphoma, but the frequency of flower cells among HTLV-I seropositive83individuals is substantially greater (6.8%) than in seronegative or HTLV-II–positive subjects. Among the 1 to 4 percent of infected individuals who develop leukemia or lymphoma, 40 percent will 27 achieve a brief remission, but the malignancy is rapidly and uniformly fatal. DIFFERENTIAL DIAGNOSIS The differential diagnosis of HTLV-I myelopathy includes disorders causing a chronic progressive spastic paraparesis. Intrinsic spinal cord lesions and extrinsic mass lesions producing spinal cord compression can be excluded with appropriate cervical and thoracic spine neuroimaging (e.g., MRI or CT myelography). Sensory disturbances almost always predominate over motor abnormalities in the myelopathies associated with vitamin B12 deficiency, nitrous oxide abuse, syphilis, and hypothyroidism. Patients with amyotrophic lateral sclerosis can present with a spastic paraparesis, but diffuse lower motor neuron signs appear with follow-up. Furthermore, persistent bladder dysfunction is prominent in HTLV-I myelopathy and absent in amyotrophic lateral sclerosis. Ingestion of raw cassava or chickpeas can precipitate a subacute myelopathy, but this will be suggested by a careful history. The number of genes responsible for hereditary spastic paraplegia continues to grow, but in cases with bladder involvement, possible vertical transmission of HTLV-I myelopathy should be considered. Manifesting female carriers for adrenoleukodystrophy may present with a motor myelopathy and normal spinal cord neuroimaging; screening for very-long-chain free fatty acids will confirm the diagnosis in 85 percent of affected patients. Unusual variants of the hereditary cerebellar ataxias can cause isolated spastic paraparesis. For example, compound heterozygotes for the frataxin gene may exhibit a phenotype of spastic 84 paraparesis alone. A predominantly spinal presentation of chronic progressive MS or a spinal dural arteriovenous fistula may be difficult to distinguish from HTLV-I myelopathy. Clinical features favoring MS include spontaneous exacerbation and remission of symptoms and signs, abnormalities of vision or extraocular movements, and conspicuous sensory findings. Features supporting a diagnosis of HTLV-I myelopathy include a predominantly motor clinical deficit, multiple oligoclonal bands in the serum, positive HTLV-I serum antibodies, and elevated HTLV-I CSF antibody index. Assessment of proviral load in peripheral blood or CSF lymphocytes may become a clinical diagnostic tool in the future. Systemic manifestations of HTLV-I infection such as lung involvement may also help to distinguish HTLV-I myelopathy from MS. A spinal dural arteriovenus fistula may be missed by spinal CT and detected only by myelography, MRI, or spinal angiography. The diagnosis is very unlikely in the presence of features supportive of HTLV-I myelopathy and the absence of subarachnoid space signal voids that indicate abnormal venous dilatation. PATHOLOGY AND PATHOGENESIS
Pathology 3,85,86
There are relatively few autopsy series describing patients with HTLV-I myelopathy. 3 The largest group consists of 10 cases described before the availability of antibody testing. The pathological similarities between those 10 cases and more recent case reports are striking. The pathological findings indicate an active chronic meningomyelitis involving predominantly 3 the thoracic spinal cord. Similar changes are frequently present to a lesser extent in the cervical spinal cord and brain, correlating with the presence of hyperreflexia in the arms, 3,6,87 abnormal white matter on brain MRI, and abnormal evoked potentials. The most conspicuous thoracic spinal cord damage is located in the lateral corticospinal 86 tracts and consists of a profound loss of myelin. Damage to the gray matter of the spinal cord is less conspicuous. The meninges are thickened and nerve roots are involved in the inflammatory process. Capillary proliferation is more evident in the white than in the gray
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matter of the spinal cord and brain. Perivascular cuffing with lymphocytes and perivascular demyelination is common and profuse in the thoracic spinal cord. HTLV-I–infected cells are located exclusively in perivascular mononuclear cell infiltrates. The brain and cervical spinal cord demonstrate milder perivascular cuffing. Severe inflammation is more common in cases of short rather than very long duration. Cases of very long duration show little active inflammation, correlating with3the clinical observation that the myelopathy may sometimes reach a plateau and stabilize. An autopsy series of seven patients revealed apoptosis of presumably infected CD4 cells in 88 the presence of cytotoxic T cells in inflammatory lesions. The quantity of HTLV-I proviral DNA correlated with the number of CD4 cells. These data suggest that the inflammation may be in response to the HTLV-I–infected CD4 cells in the spinal cord.
Pathogenesis The exact pathogenesis of HTLV-I myelopathy is unclear. The conclusion that HTLV-I infection is the cause of the myelopathy is drawn from several lines of evidence: (1) intrathecal synthesis of HTLV-I antibody has been demonstrated among affected 64,67 (2) antibodies derived from oligoclonal bands in the CSF often react with HTLV-I patients, 64,67 (3) the virus has been isolated from cultured mononuclear cells obtained viral antigens, 4,80,89 (4) HTLV-I–specific nucleic acid sequences and from the peripheral blood and CSF, 90,91 (5) infection of animal models with viral antigens have been found in the CSF, retroviruses can result in a spastic paraparesis, and (6) the virus has been demonstrated in CD4 lymphocytes undergoing apoptosis predominantly in a perivascular distribution in the 88 spinal cord. The downstream sequence of events leading to the development of the myelopathy is less clear, but there has been considerable progress in understanding the pathobiology of the virus and some cellular events that appear to be important. HTLV-I is an enveloped, double-stranded, RNA retrovirus. The provirus 1,8 contains several structural genes (gag, pol, and env) and two regulatory genes (tax, rex). The gag region encodes viral core–associated proteins p19 and p24. The pol region encodes reverse transcriptase. The env region encodes for a single precursor peptide that is glycosylated and cleaved into a transmembrane protein (gp21) and a spike protein (gp46). The envelope protein binds to the glucose transporter (Glut-1) and neuroplin-1 (NRP1) on CD4 and CD8 lymphocytes and is taken into the cell, where it integrates as a provirus into the cellular 8,92,93 Once viral proteins are transcribed, the tax gene activates the viral long chromosome. terminal repeat and host genes through several signal transduction pathways. Activation of tax can occasionally result in monoclonal proliferation of infected cells and play a role in the initial malignant transformation of lymphocytes; tax need not remain active for the full evolution of leukemia or lymphoma. In HAM patients, the proliferation of HTLV-I–infected cells is polyclonal. The pathology is not due to a direct effect of viral infection of neurons or glia but to the immune response to infected lymphocytes. The activated tax gene is known to 93 reduce immunological self-tolerance in the CD4 cells of HAM patients. There are animal models of retrovirus-related disease reminiscent of HTLV-I myelopathy. Visna, a retroviral disease of sheep, is transmitted through breast milk. Some visna-infected animals acquire a progressive paraparesis associated with CNS demyelination and 94 myelopathy and leukemia are associated perivascular inflammation. A noninflammatory 95 with murine leukemia virus infection. The routes of disease transmission and tropism for both neural and hematological tissue among these retroviral animal diseases are strikingly similar to HTLV-I infection in humans. The inability of neurons to produce interferon-gamma results in HAM in a rat model; the lack of interferon-gamma appears to be the result2,96 of failure The to upregulate the interleukin (IL)–12 receptor gene in response to IL-12 stimulation. contribution of other host and viral factors that help determine which infected individuals acquire HTLV-I myelopathy, acute T-cell leukemia or lymphoma, or no clinical disease are 97,98 The host or viral factors that explain the predilection for the thoracic still being explored. spinal cord are unknown. The genetic, structural, clinical, and epidemiological similarities between HTLV-I and HTLV-II viruses imply that HTLV-II may also be implicated in malignant, neurological, or immunological disease. Knowing the role of HTLV-II infection in the production of human disease is important because of the known high seroprevalence rate among intravenous drug users, the lack of data on the distribution and prevalence of infection among other population 28,99 HTLV-II has been isolated from subgroups, and the preventable nature of the infection. patients with hairy cell leukemia, but most patients with hairy cell leukemia do not harbor the 100 virus. The pathogenetic role of HTLV-II in the production of hairy cell leukemia remains tenuous. A comprehensive review of HTLV-II infection and neurological disease concluded that true neurological manifestations, other than an uncommon myelopathy associated with
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intrathecal synthesis of HTLV-II antibodies, were questionable. In a small number of patients, neuroimaging of the spinal cord and brain revealed104 multifocal white matter disease; spinal cord biopsy of a lesion was positive for HTLV-II RNA. More information is needed to assess the importance of HTLV-II infection in the production of human neurological disease. PREVENTION AND TREATMENT
Prevention Prevention is a significant public health problem given the large pool of asymptomatic carriers and the lifetime risks of T-cell1,2leukemia (1% to 4% of infected individuals) and HAM (0.25% to 2.0% of infected individuals). The implementation of rational prevention and screening programs reflects the local prevalence and impact of the infection as well as the available public health resources. The guidelines for prevention of HTLV-I infection, first published in 1993 by the U.S. Public 100 Health Service, are still accurate. Patients should be instructed that the virus does not cause acquired immunodeficiency syndrome but results in a lifelong infection. There should be discussion about the mode and efficiency of transmission, disease associations, and the probability for development of disease. Patients should be advised to share the information with their physicians, avoid sharing needles or syringes, avoid breast-feeding infants, use latex condoms to prevent sexual transmission, and avoid donation of blood, semen, body organs, or other tissues. Differing approaches have been taken to screening blood donors in Sweden and Japan. The prevalence of HTLV-I infection is very low in Sweden (2 per 100,000 donors); it has been estimated that the cost of testing every blood donation for the virus was 18-fold higher than 105 the cost of testing new blood donors only. Deleting the testing of prior donors was estimated to result in missing one positive donor every 7 years. As a result, only new blood donors in Sweden are screened for HTLV-I infection. In contrast, the frequency of HTLV-I infection in Japan has resulted in screening of all blood donors. The prevalence of HTLV-I carriers in the Nagasaki prefecture of Japan was reported in 1997 to be approximately 10 percent in persons older than 40 years. A prefecture-wide effort to prevent women from breast-feeding their infants106–108 was calculated to have prevented 80 percent of subsequent mother-to-child transmissions. Other issues surrounding blood donation and organ donation have been explored. A study of 35 million blood donations in the United States explored the risk of receiving blood from a donor who ultimately seroconverts. Among recipients of blood from these donors, none were 109 positive for HTLV-I or HTLV-II. Given the low frequency of HTLV-I infection among potential organ donors, the shortage of organs, and the low risk of developing disease associated with HTLV-I/II infection, the authors of one study have 110 suggested that organ transplantation from HTLV-I/II-infected donors should be allowed. Much of the developing world affected by HTLV-I infection does not routinely screen blood donations for HTLV-I/II infection. Prenatal screening of mothers in high prevalence areas would enable the education of seropositive mothers regarding the risk of transmission by 111 to a recent study from Japan, breast-feeding. The latter risk may be eliminated, according 112 if mother's milk is subjected to freeze-thaw processing. 113
There have been a number of efforts to develop an HTLV-I vaccine. The viral envelope protein has been used to immunize animal models with varying success. A recent polyvalent synthetic peptide vaccine induced partial protection against HTLV-I infection in squirrel 114 monkeys.
Immunomodulation Definitive therapy is lacking for HTLV-I myelopathy. Existing therapeutic observations are difficult to assess due to study design limitations. Available studies lack appropriate controls, adequate blinding, sufficient time to assess therapeutic benefits in the setting of an indolent disease, or adequate statistical power to assess important therapeutic questions. Available clinical studies using corticosteroids have yielded negative results. The observed initial 115 benefit of corticosteroids among Japanese patients disappeared with long-term follow-up. Another study demonstrated progression of white matter lesions on follow-up brain MRI 63 prednisolone, despite corticosteroid therapy. Uncontrolled studies of plasma exchange, 116–118 Successful pentoxifylline, and danazol have suggested neurological improvements. bone marrow transplantation or use of alemtuzumab for adult T-cell leukemia has been
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119–122
reported also. However, bone marrow transplantation has not been used for HAM. Conducting multicenter, controlled, blinded trials is likely to be logistically challenging in the developing countries in which the infection is highly endemic.
Symptomatic Treatment Symptomatic therapy is focused on the relief of spasticity and painful muscle spasms and assiduous care of the spastic bladder. Stretching programs may reduce the frequency of motion-induced spasms. Baclofen or tizanidine may be useful for the relief of painful spasms or limb spasticity. Dantrolene or benzodiazepines can occasionally be helpful. Intramuscular botulinum toxin or ethanol has been used to provide temporary (up to 3 months) relief as well. Acidification of the urine with ascorbic acid and a low threshold for performing urine cultures and treating with antibiotics is necessary given the increased risk of bacterial urinary tract infection. Ditropan (oxybutynin chloride) or related agents may help relieve the urinary urgency and frequency associated with a spastic bladder. Neuropathic pain may respond to 123 gabapentin, nortriptyline, or ketamine. The intervention of rehabilitation specialists may be helpful to preserve ambulation and other functional skills as long as possible.
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 48 Fungal Infections of the Central Nervous System GARY M. COX • DAVID T. DURACK • JOHN R. PERFECT •
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PATHOGENS HOST FACTORS CRYPTOCOCCUS NEOFORMANS COCCIDIOIDES IMMITIS HISTOPLASMA CAPSULATUM BLASTOMYCES DERMATITIDIS PARACOCCIDIOIDES BRASILIENSIS SPOROTHRIX SCHENCKII PENICILLIUM MARNEFFEI CANDIDA SPECIES ASPERGILLUS SPECIES ZYGOMYCOSIS PSEUDALLESCHERIA BOYDII PHAEOHYPHOMYCOSIS HYALOHYPHOMYCOSIS DIAGNOSIS TREATMENT Specific Antifungal Agents Amphotericin B Flucytosine Fluconazole Itraconazole Voriconazole and Posaconazole Echinocandins Combination Regimens Surgical Treatment Specific Fungal Infections of the CNS Cryptococcal Meningitis Candida Meningitis Coccidioidal Meningitis Other Fungal Infections
Fungal infections of the central nervous system (CNS) are increasing in frequency because of both the growing population of immunocompromised patients and improvements in
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diagnostic techniques. Published information on diagnosis and treatment of this diverse group of infections ranges from extensive to nonexistent. Therefore, an extensive survey of the literature, coupled with clinical experience, forms the basis of knowledge on the management of these important infections. Current understanding of fungal infections involving the CNS is summarized in this chapter. PATHOGENS Fungi that can invade the CNS and cause infection fall into two general groups. The first group consists of primary pathogens, including Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Sporothrix schenckii, Histoplasma capsulatum, Pseudallescheria boydii, and the dematiaceous fungi. CNS involvement by these fungi can occur either in patients with intact immune systems or, at higher rates, in patients with immunosuppression. The second group consists of opportunists that cause CNS infection almost exclusively in patients with defective host defenses; this group includes Candida species, Aspergillus species, and the Zygomycetes. This grouping, based on the host's immune status, is not absolute because many exceptions occur, but it is useful as a framework for further discussion. Finally, there are some fungi for which only a few case reports of CNS involvement exist; these are so rare that only direct reading of the 1–4 reports can1–4be helpful. These2,5 are mostly common environmental fungi and include 6 7 8,9 Rhodotorula, 10 Aureobasidium, Acremonium, Clavispora, Blastoschizomyces, 11 12,13 14 15 Trichosporon, Sepedonium, Schizophyllum, Paecilomyces, Pneumocystis, and 16 Ustilago. Some of the key characteristics of the more common CNS fungal infections are listed in Table 48-1. Click here to view this table.... HOST FACTORS Geographical factors are important for certain fungal infections of the CNS. Several fungi are not geographically restricted, having worldwide distribution. These include Candida albicans and other Candida species, Aspergillus species, and C. neoformans. By contrast, certain mycoses such as histoplasmosis, blastomycosis, coccidioidomycosis, penicillinosis, and paracoccidioidomycosis are largely confined to certain geographical boundaries, although with modern travel, these lines can become blurred. There are also reports of CNS infections with black molds such as Cladophialophora and Ramichloridium species, which may occur in certain areas of the world with a higher frequency. Thus, it is essential that clinicians evaluating a case of chronic meningitis acquire an accurate travel history from patients or family members. The CNS is an immunologically sequestered site, with anatomical barriers that tend to exclude not only invading microorganisms but also some components of the immune system. Host defenses normally are highly effective in excluding fungi from the CNS, but certain conditions can lead to failure of this protective function. Some patients with fungal infections of the CNS have no apparent immune defect or underlying disease, but the majority has some flaw in their defenses that allows invasion by fungi. Some of these defects are obvious, such as direct inoculation of organisms into the CNS after trauma or by indwelling catheters such as for ventriculostomies. Others are more subtle, involving defects in the cell-mediated immune system. In most cases, the fungus appears to enter via the respiratory tract and to seed the CNS hematogenously, but other extracranial origins of CNS infection have been identified; for example, abscesses, mycotic aneurysms, and meningitis can arise from septic 17 emboli associated with endocarditis. The most important risk factor for the development of CNS fungal infections is suppression of the host immune system, whether due to an underlying disease or to immunosuppressive drugs. Both the etiology of these CNS infections and their response to therapy depend somewhat on the type of immunosuppression. For instance, administration of immunosuppressive drugs such as systemic corticosteroids is a leading risk factor for the development of CNS fungal infections with C. neoformans and Aspergillus species. In addition, neutropenia due to cancer chemotherapy is associated with CNS infections caused the iron chelator deferoxamine by Aspergillus and Candida species, and treatment with 18 predisposes to rhinocerebral Zygomycetes infections. There are several underlying diseases associated with an increased incidence of CNS fungal infections. The most important of these associations is the link between acquired immune deficiency syndrome (AIDS) and cryptococcal meningitis without highly active antiretroviral therapy (HAART). From 5 to 30 percent in sub-Saharan Africa of patients with human
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immunodeficiency virus (HIV) infection will eventually develop C. neoformans infection. This is the fourth most common opportunistic infection seen in patients with AIDS in the United States and the most common CNS infection. However, the number of cases of cryptococcal infection in patients with AIDS has decreased following the introduction of HAART. Cryptococcal meningitis continues to occur early in some patients who have not received antiretroviral drugs or later as viral resistance develops to HAART. There have also been several reports of patients infected with HIV who have contracted CNS infections with 19,20 Aspergillus species. These infections have, so far, been predominantly cerebral mass lesions, although cerebral infarctions, meningitis, and spinal cord involvement have also been 21 observed. Patients with AIDS may also present with disseminated histoplasmosis, 22 23 penicillinosis, or coccidioidomycosis, with CNS involvement. Patients who undergo organ transplantation and receive concomitant immunosuppression are at significant risk of CNS fungal infection. The most common fungal pathogens in this 24 setting are C. neoformans, Aspergillus species, and Candida species. Infection with C. neoformans in organ transplant recipients is usually manifested as a chronic meningitis occurring 6 months or more after transplantation. By contrast, infections with Aspergillus and Candida species usually occur within the first 2 months after transplantation, and CNS involvement is usually manifested by brain abscesses. In fact, CNS aspergillosis may be 25 underdiagnosed in organ transplant recipients. In one series of 44 brains from liver transplant recipients examined at autopsy, 26 9 cases of cerebral aspergillosis were identified, of which only 2 were diagnosed before death. Other underlying diseases or conditions associated with CNS fungal infection include malignancies, diabetes mellitus, and prematurity. Patients with poorly controlled diabetes, with or without ketoacidosis, are at increased risk of rhinocerebral Zygomycetes infections. Premature infants are at risk of disseminated infections with Candida species, and the CNS is involved in two thirds of these cases. Infections that arise from direct inoculation of fungi into the CNS are usually seen after head trauma or neurosurgical procedures or as complications of implanted cerebrospinal fluid (CSF) shunts. In patients who have sustained open head injuries, fungi that are ubiquitous in the environment may contaminate the wounds, leading to meningitis and focal brain 27 abscesses. With CSF leaks, the initial infection may be bacterial, but during the use of broad-spectrum antibacterial drugs, a superinfection of the meninges with Candida can occur. Infection is frequently associated with the presence of a CSF-diverting shunt, but fungi are only occasionally implicated in these infections. The most common fungus associated with CSF shunt infections is C. albicans. It appears that infection occurs as a result of either contamination of the shunt apparatus during insertion or subsequent manipulation or by 28,29 Among 20 cases of CSF shunt infection with C. albicans reported hematogenous spread. in the literature, there appears to be an association with recent antibacterial therapy and that have caused CNS colonization with Candida species at other body sites. Other fungi 1 30 infection in the setting of a CSF shunt include C. neoformans, Trichosporon beigelii, 31 Candida glabrata, and Candida tropicalis. There is some controversy concerning the origin of cryptococcal shunt infections. Many of the patients with CSF shunts who were subsequently found to have infection with C. neoformans had their shunts originally placed for 32,33 idiopathic hydrocephalus or for chronic culture-negative meningitis. These patients probably had chronic CNS cryptococcal infection before their shunts were inserted, and the diagnosis was made only after the shunt was in place. Therefore, it is not clear whether the presence of a CSF shunt places a patient at higher risk of the development of CNS cryptococcal infection. However, the timing of shunt placement may be important to management strategies. If the shunt was placed before therapy, it will probably need to be removed for successful management. If the patient is on adequate therapy, shunts can be placed or replaced as needed. There are rare reports of fungal infection associated with 34–36 account for neurosurgical procedures; among these, Aspergillus and Candida species most of the cases. Some of these patients were considered to have had direct extension of the fungus from the sinuses during surgery, and some were thought to have had fungi introduced along with devices inserted during an operative procedure. Many of these patients have had additional predisposing conditions such as treatment with antibacterials or high-dose corticosteroids. Immune reconstitution syndrome (IRS) fungal infections are so critically linked to immunodeficiencies and their underlying diseases or risk groups that it is difficult to acknowledge that overstimulation of the immune system can have profound consequences. For instance, although host immunity is critical in the eradication of a CNS infection, immunological recovery can also be detrimental and contribute to worsening disease expression. This entity of overstimulation of the immune system has been called IRS or immune reconstitution inflammatory syndrome (IRIS). 37,38 This syndrome has been elegantly Upon initiation of antiretroviral described during HAART and cryptococcal meningitis.
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therapy, HIV RNA levels decrease, and there is repopulation with memory and naive CD4 lymphocytes, and within 4 to 6 weeks, there is an immunological shift from a Th2 to a Th1 response. IRS may be manifested by increase numbers of CSF cells, headaches, fever, and evidence of increased inflammation on radiographs but no evidence of viable yeasts in the CSF. High intracranial pressure in association with aseptic meningitis, inflammatory lesions within the spinal cord, and the hallmark finding of granuloma formation in the tissue represent features of IRS. Patients who started on antiretroviral therapy within 30 to 60 days of treatment for C. neoformans infection are significantly more likely to develop IRS than those 37,38 who started antiretroviral therapy at a later time. Similarly, in solid organ transplant recipients with cryptococcosis, IRS was observed in 5 percent of patients within 1 to 2 months after initiation of antifungal therapy. In transplant39recipients, IRS was more common in those receiving potent immunosuppressive regimens. Although these two risk groups are the most common risk groups for IRS after the start of antifungal therapy, the syndrome can occur in any patient in whom there is a rapid shift in immune reactivity and is even a clinical 40 management problem in apparently normal hosts with cryptococcal meningitis. Since the occurrence of IRS in patients with CNS fungal infections is most commonly construed as a failure or relapse of infection that leads to unwarranted or inappropriate changes in specific therapy, its recognition is important. It needs to be considered when treatment appears to have controlled the growth of organisms by culture or biomarkers, but new signs of inflammation driven by sophisticated imaging studies and nonspecific clinical signs and symptoms occur. There are no precise gauges for immunological recovery in the CNS, and thus IRS is a clinical diagnosis. Recognition of IRS is important to clinical management of CNS infections because excessive inflammation can be detrimental at this site. In fact, even corticosteroid therapy might need to be considered to reduce inflammation and cerebral edema when IRS is prominent during effective antifungal therapy. It should be recognized that, in the management of CNS fungal infections such as cryptococcal meningitis, a robust Th1 response with either elevated endogenous or exogenous cytokines such as interferon-gamma is associated with more 41,42 but at times, this can be too efficient killing of yeasts in the subarachnoid space, exuberant so that IRS can also lead to a negative impact on the host. CRYPTOCOCCUS NEOFORMANS 37
The encapsulated yeast C. neoformans is the most common cause of fungal meningitis. The first report of cryptococcal infection in humans was provided by Busse and Buschke in 1894/1895; this patient had bone infection. The first case of meningeal cryptococcal infection was reported 10 years later, in 1905. During the twentieth century, cryptococcosis emerged as a significant CNS infection. A review of the incidence of systemic mycoses in selected hospitals in the United States showed an increase in infections during the 1960s and 1970s. The number of human infections with C. neoformans increased dramatically in the United States and certain African countries following the onset of the AIDS epidemic. In the United States, before the introduction of HAART, cryptococcal meningitis occurred in approximately 5 to 10 percent of all patients with AIDS. In less developed countries lacking access to HAART, cryptococcal meningitis continues to occur in up to 25 percent of the patients with AIDS. This ubiquitous encapsulated saprophytic yeast occupies a wide environmental niche. It is found worldwide in bird excreta, soil, animals, and even humans. It is likely that most infections occur after inhalation of small yeast forms. The yeast has a polysaccharide capsule that ranges widely in size, from 1 to 30 μm. On inhalation of the yeasts or basidiospores, a primary pneumonia may develop, or the host may form a primary lung-lymph node complex in which the yeasts remain dormant for long periods, perhaps until host defenses become weakened. The reason this yeast has a particular tendency to spread to the CNS remains unexplained; CNS infection usually manifests as a meningitis, although mass lesions or torulomas may be seen. There are four serotypes (a, b, c, d) based on capsular polysaccharide, and these are divided into several species: C. neoformans var. grubii or neoformans (serotypes a and d), and C. gatti (serotypes b and c). All serotypes can cause meningitis, but there is some geographical variation in distribution of disease caused by these serotypes. Most patients with cryptococcal meningitis in the United States and Europe have been infected with serotype a or d strains. Infections with the b and c strains are more common in southern California, Southeast Asia, and Australia; this distribution reflects the natural distribution of certain Eucalyptus trees that are likely the environmental repository for 43 C. neoformanas var. gatti. However, a recent outbreak of C. gatti infections on Vancouver Island suggests that there are other trees containing this fungus. The complex interactions of the immune system with C. neoformans remain incompletely
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understood. However, multiple lines of evidence suggest that host factors are paramount in preventing these yeasts from seeding the subarachnoid space. Host factors are an important determinant of both the incidence and prognosis of this infection. Host resistance depends primarily on cell-mediated immunity, but the humoral immune response does play a part. Despite earlier reports that approximately 50 percent of patients with cryptococcal meningitis had no known immunodeficiency, more recent experience suggests that a much higher proportion of patients have some identifiable form of immunosuppression. In reality, probably less than 20 percent of the cases have no known underlying disease. Most cases of cryptococcal meningitis occur in those with defective cell-mediated immunity due to corticosteroid treatment, reticuloendothelial malignancy, organ transplantation, sarcoidosis, collagen vascular diseases, or AIDS. The finding that lymphocyte functions are abnormal in most patients with disseminated cryptococcosis provides further support for the contention that immunosuppression usually is necessary for meningitis to develop. Most patients with HIV infection have CD4 counts less than 100/μl. Moreover, certain immune defects may persist after infection has been eliminated by treatment. Two exogenous factors have played a major role in making cryptococcal meningitis the most common fungal CNS infection. The first factor is corticosteroid treatment, which causes multiple immune defects. Excess endogenous or exogenous corticosteroids greatly increase the patient's susceptibility to cryptococcal meningitis. The second factor is HIV infection, with resulting loss of CD4 cells. These cells, which are central to many immune responses, must be particularly important in the host response to C. neoformans. Most patients with AIDS and cryptococcosis present with a particularly high burden of organisms. India ink examinations of the CSF are positive in more than 80 percent of patients, and extraordinarily high titers of cryptococcal polysaccharide antigen in CSF and serum are common. A remarkable feature of these patients' response to infection is the paucity of CSF leukocytes. Approximately two 3 thirds of patients with AIDS and cryptococcal meningitis have fewer than 20 leukocytes/mm in the CSF on presentation. This quantitative deficiency in the inflammatory response indicates an impaired immune system and ultimately a poor prognosis despite therapy. Patients with cryptococcal meningitis may present with a spectrum of CNS findings, ranging from symptoms of acute headaches and fever to subacute dementia developing over weeks. The latex agglutination test and enzyme-linked immunosorbent assay are both sensitive (>90%) and specific (>90%) if proper controls are used. Although cases occasionally are difficult to diagnose, with the proper use of CSF culture, India ink studies, and polysaccharide antigen test, the only limiting factor is usually failure to perform a lumbar puncture because the diagnosis was not considered. COCCIDIOIDES IMMITIS C. immitis is a dimorphic fungus with a natural habitat in semiarid soil, which explains its geographical distribution in the southwestern United States and in parts of Mexico and South America. Because many tourists travel through these areas and may become infected, clinicians outside the organism's natural habitat occasionally encounter coccidioidomycosis. This fungal infection begins as a primary pulmonary infection after inhalation of the organism. Most patients remain asymp-tomatic, and less than 0.2 percent of primary infections disseminate. Occasionally, this fungus may reach the meninges, either by hematogenous spread or by direct extension from osteomyelitis of the skull or vertebrae. 44,45
There are cases in which brain Symptoms of chronic meningitis are most common. 46,47 Spinal involvement occurs without meningitis, but this presentation is unusual. arachnoiditis with obstructive hydrocephalus and cerebral vasculitis with infarcts have been 48–50 Finally, it appears that patients with coccidioidomycosis involving the facial skin reported. 51 are at higher risk of meningitis than those with skin involvement at more distant body sites. Diagnosis may be confirmed by culture of the fungus from the CSF, but in many patients in endemic areas, it is diagnosed on the basis of a CSF pleocytosis (which shows eosinophilia in up to 70% of cases) and evidence of complement-fixing antibodies (CFAs) in the CSF. CFA titers are positive in 70 percent of patients at initial diagnosis, and in almost all patients as meningitis progresses. It is likely that genetic susceptibility plays a subtle but important role as a risk factor for meningitis. Meningitis appears to develop at a greater rate in African Americans and certain Asian populations than in whites. Most patients who contract CNS infection with C. immitis have no underlying disease, but immunosuppressed patients are at increased risk. However, corticosteroid treatment has been associated with more severe manifestations of primary infection, as well as with
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reactivation of latent disease and dissemination to the CNS. There have been many cases of 52 CNS infection with C. immitis in patients with AIDS. The fact that several areas of high prevalence of HIV infection are also areas of endemicity for this fungus has tremendous implications for the health care system because it is likely that the number of CNS infections due to C. immitis will parallel the numbers of patients with AIDS. Interestingly, the natural history of coccidioidal meningitis shows that patients whose only extrapulmonary site of53 infection was the CNS lived significantly longer than patients with more diffuse disease. It has also been shown that the white cell count in the CSF decreases during the course of untreated infection. However, lifelong triazole therapy for meningitis is required because of 54 the high rate of relapse. HISTOPLASMA CAPSULATUM H. capsulatum is a dimorphic fungus endemic in certain areas in the Ohio and central Mississippi valleys and Latin America. It can be found in bird and bat guano and in soil contaminated with guano. Many outbreaks of the disease have been attributed to disturbing contaminated soil, thus allowing the conidia to become airborne. Most infections develop after inhalation of the conidial form of the fungus, and infection in endemic areas is very common. Skin test data indicate that in one endemic area, up to 69 percent of the population 55 showed evidence of previous infection with this fungus. Most of the people infected have minimal symptoms, and dissemination occurs only rarely. When dissemination does occur, it has been estimated that between one tenth and one fourth of patients have CNS involvement. Although granulomas and other brain parenchymal lesions have been described, most patients with CNS lesions present with meningitis. Although Histoplasma meningitis can occur in apparently normal hosts, it has been shown to occur in immunocompromised hosts at a higher rate. Patients with AIDS are at high risk of development of disseminated disease, usually due to reactivation of latent infection. In the era before HAART, involvement of the CNS during disseminated infection was particularly 56 common in patients with AIDS. Because CSF cultures may be positive in only 10 to 30 percent of cases, even when large volumes of CSF are incubated for weeks, it is important to check CSF serologies for both antibodies and antigen. There are occasional cross-reactions 57,58 The Histoplasma CSF with other fungi, which can cause diagnostic confusion. polysaccharide antigen has been found to be positive in 40 percent of patients with histoplasma meningitis. BLASTOMYCES DERMATITIDIS B. dermatitidis is a dimorphic fungus endemic in Africa and in certain parts of the lower Mississippi valley, North Central states, and mid-Atlantic states in the continental United States. It is presumed to be inhaled from a source in soil, but its natural location in the environment has not been defined. Most people with infection have subclinical disease, and dissemination occurs rarely. Disseminated blastomycosis is characterized by granulomatous or suppurating lesions (or both) of the lung, bone, and skin. In some series, blastomycosis has been reported to involve the brain in 6 to 33 percent of disseminated cases. Although patients with CNS blastomycosis usually present with evidence of infection at other sites, 59,60 occasionally meningitis is the initial presentation, without evidence of extraneural disease. Although CSF cultures are rarely positive, chronic neutrophilic pleocytosis is a common 61 an finding in blastomycotic meningitis. CNS involvement is not limited to meningitis; 62,63 occasional patient has a mass lesion (blastomycoma) in the brain parenchyma. Immunocompromised patients are at increased risk of infection with B. dermatitidis. A review of 24 cases of infection with B. dermatitidis in a heterogeneous population of immunocompromised patients showed 6 cases of disseminated disease, including 4 with 64 CNS involvement. PARACOCCIDIOIDES BRASILIENSIS P. brasiliensis is a dimorphic fungus endemic to subtropical areas of Mexico and Central and South America. The lung is the primary location for initial infection; a few patients have widely disseminated disease that involves the CNS, but rarely has the infection been reported to involve only the CNS. Meningitis is an 65 unusual manifestation of infection with P. brasiliensis but occurs occasionally in normal hosts. The host response against this microorganism remains poorly understood. SPOROTHRIX SCHENCKII S. schenckii is a worldwide saprophyte of vegetation, notably sphagnum moss. Sporotrichosis
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presents as a chronic infection of skin and subcutaneous lymphatics, developing after a primary inoculation such as a rose thorn puncture. Pulmonary disease from inhalation of spores is uncommon. Dissemination beyond the skin, lung, and joints is rare; only 66–68 Most of the approximately a dozen cases of Sporothrix meningitis have been reported. patients with meningitis did not have overt extraneural disease at presentation. Diagnosis of this infection can be extremely slow and difficult using traditional culture methods; to reduce delays of up to 6 to 7 months, a test for Sporothrix antibodies in the CSF should be done in any undiagnosed case of chronic meningitis. Although meningitis with S. schenckii is so uncommon that risk factors cannot be defined accurately, certain patients may be predisposed to dissemination from a local infection, including patients with myelodysplastic syndromes, ethanol abusers, or patients on 66 corticosteroids. Disseminated sporotrichosis has also been described in patients with AIDS. PENICILLIUM MARNEFFEI This dimorphic fungus is found in the geographical range of bamboo rats and has become a common cause of opportunistic infection in HIV-infected patients in parts of Southeast Asia. Pathophysiologically, the infection appears similar to histoplasmosis, but it has a unique predisposition for producing skin lesions. In one series, 3 of 20 CSF samples were positive for this fungus during disseminated disease. Remarkably, 10 percent of patients in one series 22 with disseminated penicilliosis also had concomitant cryptococcal meningitis. CANDIDA SPECIES Candida species form part of the normal human microbial flora and rarely cause invasive disease unless host defenses have been impaired. This yeast can gain access to the blood stream and then the CNS via contaminated intravenous catheters or through illicit 69 70,71 2 Neonates, neutropenic subjects, and patients recovering from intravenous drug use. 72,73 are particularly susceptible to invasive candidiasis, including CNS major surgery are the most common fungi to involvement. Based on autopsy studies, Candida species 74,75 76 77 invade the CNS. Candida may cause meningitis, ventriculitis, or parenchymal lesions such as abscesses or granulomas. C. albicans is the species implicated in most81–83 CNS 78–80 infections, but other species such as Candida tropicalis, Candida lusitaniae, and 84 Candida parapsilosis, occasionally produce CNS infection. In the normal host, Candida rarely causes deep-seated infections. However, there are multiple factors that can encourage spread of Candida from mucosal surfaces to deeper tissues, including the subarachnoid space. These factors include prematurity, broad-spectrum antibacterial therapy, hyperalimentation, malignancies, indwelling catheters, treatment with corticosteroids, neutropenia, abdominal surgery, diabetes mellitus, burns, and intravenous drug use. Candida invades brain tissue more commonly than the subarachnoid space. Candida species are susceptible to the oxidative and nonoxidative antimicrobial mechanisms of professional phagocytes, cells that are undoubtedly important for control of infections with Candida. The importance of the host response has been further emphasized by reports of Candida meningitis in both congenital and acquired immunodeficiency syndromes. Patients with chronic granulomatous disease of childhood and myeloperoxidase 85,86 may present with Candida meningitis. Several cases of Candida meningitis deficiency have been reported in patients with the global immune defects caused by severe combined 87 immunodeficiency (SCID). Therefore, a specific underlying immunodeficiency should be considered in any case of spontaneously occurring Candida meningitis, especially in children. Patients with AIDS frequently have mucocutaneous forms of candidiasis such as thrush and esophagitis, but involvement of the CNS has been reported only rarely in these patients. Although neutropenia is a risk factor for Candida infection of the CNS, most patients with candidemia with or without neutropenia do not commonly have seeding of the CNS. However, candidemia in neonates may be more likely to seed the subarachnoid space and produce a as a superinfection of the CSF in CNS infection. Candida meningitis has been described 88 patients recovering from bacterial meningitis. Candida infection can involve the brain and subarachnoid space by direct extension through trauma, ventriculostomy placement, or ventricular shunts, particularly in the presence of antibacterial use. Candida can also invade 89 from adjacent sinuses or bone. Finally, the infection can produce intracranial extension 88 through an arteritis and even lead to subarachnoid hemorrhage. The CSF in Candida meningitis can show a predominance of either mononuclear or 90 neutrophilic phagocytes. Unfortunately, only approximately half of routine CSF cultures yield the fungus, despite the fact that Candida organisms are easy to grow in the laboratory. A large CSF volume is needed to optimize culture, and better methods are needed to detect fungal products or antigens. The clinical significance of a positive culture for Candida
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organisms from CSF obtained through an indwelling device like a ventriculostomy tube is 91 are normal, another CSF unclear. If a positive culture is found and CSF parameters 91 specimen should be obtained from a lumbar puncture. In the absence of symptoms or an abnormal CSF profile, and with a negative follow-up culture, further treatment is probably 71,91 but the device should be removed and, if necessary, replaced. unnecessary, ASPERGILLUS SPECIES Aspergillus species are ubiquitous in the environment and can be found in the air of most buildings, including hospitals. Both neutrophils and macrophages provide important host defense mechanisms directed against the spores and hyphae of Aspergillus. CNS infection with Aspergillus species can develop by direct extension from the paranasal sinuses; by direct inoculation after head trauma, surgery, or lumbar puncture; or by hematogenous spread in immunocompromised hosts, particularly those with prolonged neutropenia. This 75 fungus accounts for approximately 5 percent of CNS fungal infections. A clinically important characteristic of Aspergillus infections is their predilection to invade arteries, causing thromboses. Therefore, cerebral infarction or mycotic aneurysm due to invasion along cerebral arteries is a common presentation of Aspergillus infection in the CNS. Meningitis and 92,93 meningoencephalitis19,94–97 can also occur, and rhinocerebral disease similar to mucormycosis has been described. Most intracranial infections with Aspergillus have occurred in neutropenic patients. The risk of disseminated aspergillosis with subsequent brain parenchymal involvement or meningitis 98 increases with the duration of neutropenia or high-dose corticosteroid therapy for graft-versus-host disease. Most infections manifest as parenchymal lesions, but meningitis 99 and spinal cord lesions have been seen. Occasionally, Aspergillus infection involves the vertebrae and eventually the subarachnoid space. Patients with chronic granulomatous disease of childhood are particularly susceptible to this type of infection. The pulmonary alveolar macrophage may be most important in initial control of this ubiquitous fungus in the lungs, but polymorphonuclear leukocytes are probably crucial in defense against CNS invasion. Diagnosis can be delayed because of insensitivity of cultures. Thus, both CSF polymerase 100 chain reaction and galactomannan antigen tests are being studied to help in diagnosis. ZYGOMYCOSIS Fungi of the class Zygomycetes are widespread in the environment. Infection is usually due to inhalation of spores. The genus Rhizopus is responsible for most infections caused by this group. CNS infection in compromised hosts can occur by direct extension from the paranasal sinuses through hematogenous spread such as illicit intravenous drug use or even by spread 101 species, commonly invade up nerve roots into the CNS. Zygomycetes, like Aspergillus 102,103 Zygomycetes occasionally arteries and cause thromboses with resulting infarction. invade the subarachnoid space; however, disease limited to the meninges is unusual. Patients with diabetes mellitus (with or without ketoacidosis) or malignancy or those receiving immunosuppressive or voriconazole therapy for a severe underlying disease are at risk of disseminated infection. There have been reports of disseminated zygomycosis, including 18 brain involvement, in patients on dialysis receiving desferroxamine. This iron-chelating agent may interfere with the antifungal activity of transferrin, thus allowing dissemination of Zygomycetes. PSEUDALLESCHERIA BOYDII P. boydii has worldwide distribution in soil and contaminated water. This fungus is also known as Monosporium apiospermum or Scedosporium apiospermum when it is in the asexual state. Although rare, infection can result in brain abscesses or chronic neutrophilic 104 with aspiration of contaminated water during meningitis. CNS infection is associated 104,105 Presumably, this fungus penetrates through the trauma or near-drowning in fresh water. cribriform plate during water immersion or establishes a pulmonary focus with later dissemination to the CNS, producing meningitis or brain abscesses. Other risk factors include 106 steroid immunosuppression and diabetes. PHAEOHYPHOMYCOSIS The dematiaceous fungi are a group of common environmental molds that have brown pigment in their walls; thus, diverse genera are linked by their ability to produce melanin. This group of fungi has occasionally caused CNS infection, and for certain species, it appears that there is some neurotropism. Cladosporium trichoides, also known as Xylohypha bantiana and
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renamed as Cladophialophora bantianum, is the most common isolate of this class of fungi found in CNS infections; the infection usually manifests as a brain abscess, although 107–110 Meningitis caused by other species of these “black meningitis has been described. molds” is also reported occasionally, and it111–114 has even been caused by contaminated corticosteroid injections around the spine. Most patients diagnosed with brain abscesses due to one of the dematiaceous fungi have no apparent underlying immune defect, but immunosuppressed patients can be at risk. The portal of entry for these fungi in most cases is not known, but because of a predilection for abscess formation in the frontal and parietal lobes, it can be hypothesized that at least some of these infections result from direct extension through the sinuses. HYALOHYPHOMYCOSIS These nonpigmented, hyaline filamentous molds cause occasional infections of the CNS. For 115 Acremonium and example, meningitis and cerebritis have been reported with 14 Paecilomyces species. In severely neutropenic patients, the soil saprophytes, Fusarium species, can produce CNS lesions. Because of similar histopathological features, Fusarium infection can be confused with aspergillosis unless cultures are performed. Finally, in the growing immunosuppressed population, Trichosporon infection, which usually involves only superficial skin or hair shafts, can disseminate to the brain. CNS infections with both T. 10,116,117 9 beigelii, and Blastoschizomyces capitatus (Geotrichum capitatum) have been reported. DIAGNOSIS The diagnosis of CNS fungal infections can be very difficult, even when involvement of the CNS occurs in the setting of disseminated fungal infection. This is due to many factors, including unusual clinical presentations of patients with CNS fungal infection, difficulty in culturing the organism, and the lack of sensitive serological tests for most of the fungi. In cases of cerebral mass lesions due to fungi, most patients present with nonfocal neurological complaints and physical findings. For instance, many patients present only with altered sensorium or seizures, despite having extensive focal CNS infection revealed by radiographic testing. Patients with fungal meningitis usually present with chronic signs and symptoms. Some combination of fever, headache, lethargy, confusion, nausea, vomiting, stiff neck, and neurological deficits usually is present. However, these markers of CNS infection may not always be present when the patient is first observed. In fact, the characteristic markers of CNS infection, fever and headache, both may be absent, and patients may present only with a subacute dementia. Furthermore, cases of cryptococcal, coccidioidal, and Histoplasma meningitis may be indolent, with symptoms persisting for months to years if 118–122 untreated ; thus, timing of symptoms is not always an accurate guide to diagnosis. However, patients with fungal meningitis usually present with subacute symptoms; some cases of cryptococcal meningitis present acutely after only several days of symptoms. Immunocompromised patients, especially those receiving high doses of corticosteroids or with an underlying HIV infection, can manifest symptoms or signs over just a few days. Fungal infection is a primary consideration in the differential diagnosis of any case of chronic meningitis. Ellner and Bennett have defined this group of patients as those with CNS 123 abnormalities that either progress or fail to improve during at least 4 weeks of observation. The differential diagnosis of chronic meningitis includes both infectious and noninfectious causes (Table 48-2), but fungal infection should be high in the differential diagnosis. It may be particularly difficult to distinguish infection due to fungi from that caused by certain other subacute or chronic pathogens such as mycobacteria. Click here to view this table.... The CSF findings in fungal meningitis have been well described. Most cases3have a in mononuclear pleocytosis, with counts ranging between 20 and 500 cells/mm . However, 124 some cases of fungal meningitis, there is a predominance of polymorphonuclear cells. Eosinophilic pleocytosis of the CSF has been described in cases of coccidioidal meningitis 125 and, rarely, in cases of cryptococcal meningitis. If there are eosinophils in the CSF, Coccidioides should be strongly considered because approximately 70 percent of cases have 126 3 CSF eosinophilia. Very low CSF leukocyte counts (<10/mm ) may occur if the patient is severely immunosuppressed; even a normal CSF profile has been observed in some cases. CSF protein levels usually are elevated, but if very high protein concentrations (≥1.0 g/dl) are present in CSF, a subarachnoid block is likely. CSF glucose can vary from normal to low. The causes of hypoglycorrhachia are listed in Table 48-3. The finding of low glucose concentration in the CSF favors an infectious disorder and may have prognostic significance
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in that persistent hypoglycorrhachia after treatment for cryptococcal meningitis without HIV infection raises the likelihood of relapse. It is very unusual to see fungi on direct stains prepared from CSF, except in the case of cryptococcal meningitis. India ink preparations of CSF are positive in approximately 50 percent of all patients with cryptococcal meningitis, and in 80 percent or more of patients who also have HIV infection. CSF lumbar pressure needs to be measured; elevated pressures of 250 mmH2O or higher may have prognostic and 127 therapeutic implications, particularly in cryptococcal meningitis. Click here to view this table.... The number of fungi present in CSF in cases of fungal meningitis is highly variable. In some cases of6 cryptococcal meningitis with a heavily positive India ink examination, there are at least 10 colony-forming units (CFUs)/ml of CSF, whereas the dimorphic fungi often have less than 1 CFU/ml of CSF. Approximately 75 percent of all patients with cryptococcal meningitis yield positive CSF cultures; patients with HIV infection show a higher burden of organisms, and cultures are positive in 90 percent or more of these cases. Unfortunately, in cases due to fungi other than cryptococci, CSF cultures are often negative and are only very rarely positive in patients with cerebral mass lesions due to fungi. For example, only one third to one half of patients with coccidioidal meningitis yield CSF cultures that are positive. Patients with blastomycotic meningitis rarely yield positive CSF cultures, and in proven Histoplasma cases, it is difficult to find the organisms in the subarachnoid space, even at necropsy. Because the burden of organisms in CSF is so often low, relatively large volumes of CSF (10 to 20 ml) should be obtained and sent for culture in suspected cases. The laboratory should centrifuge specimens and culture the sediment on appropriate fungal media. Candida organisms can be identified by the laboratory within a few days, and, in an occasional difficult patient, hypertonic media may be helpful for growing the organism. Cryptococcus should be identified within 3 to 10 days in most cases, but the classic dimorphic fungi (e.g., Histoplasma or Coccidioides) may require longer incubations. The lysis-centrifugation method for isolating H. capsulatum from blood and CSF has improved detection compared with routine or radiometric methods. Blood cultures may also be helpful for identifying the fungus that is causing meningitis in a particular host. Unfortunately, except for infections with Candida species or Cryptococcus, blood cultures are rarely positive in patients with fungal meningitis. CSF cultures can also be negative simply because the samples were not taken from the localized site of active infection. For instance, because fungi commonly cause a basilar meningitis, it is not surprising that cisternal128 or ventricular fluid may occasionally yield organisms when fluid from the lumbar tap is sterile. Thus, diagnosis of a difficult case of chronic meningitis may require not only repeated examination of lumbar spinal fluid but also examination of cisternal or ventricular fluid. Positive cultures are the standard for diagnosis of fungal CNS infections, but they may be difficult to obtain or may take a long time to grow. Hence, despite some limitations, serological tests are important for the diagnosis of many fungal infections in the CNS. For example, the latex agglutination test for cryptococcal polysaccharide antigen is the single best serological test for diagnosis of fungal infections. It can be used equally well on serum or CSF. The test is rapid and often is positive even when culture is negative. When samples are heated to eliminate rheumatoid factor and proper controls for nonspecific agglutination and interfering substances 129 are used, the test is more than 90 percent sensitive and specific for cryptococcal infection. If surface condensation from agar plates is added to the assay, false-positive results may occur. False-positive results can also be seen with disseminated T. beigelii infections and paravertebral bacterial infections. If there is a positive antigen test result in a patient whose clinical presentation is not consistent with cryptococcal meningitis, the laboratory should repeat the test, and if it is still positive, a repeat lumbar puncture is indicated. False-negative results occur as well and can be due to very low burdens of pathogens, a prozone phenomenon due to antigen excess, or the performance characteristics of various different proprietary antigen detection kits. The cryptococcal polysaccharide antigen test using appropriate controls is an excellent diagnostic test if it is positive, at any titer. The value of using antigen titers as diagnostic and prognostic guides is 130 well established. However, titers are less valuable for guiding therapeutic decisions and often are not helpful. Detection of the Histoplasma polysaccharide antigen in urine and serum has been proven to be a valuable adjunctive test in the diagnosis of patients with disseminated infections due to H. capsulatum. It is also useful in monitoring therapy and for the early detection of relapsing infection in patients with AIDS. In the diagnosis of patients with Histoplasma meningitis, this 131 assay detected antigen in the CSF of 5 of 12 patients. However, there may be false-positive results in patients with meningitis due to other fungi. Tests detecting CSF antibodies against Histoplasma antigens are also useful, with antibodies being detected in
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approximately 75 percent of cases of CNS infection. The antibody tests are not highly specific, and positive results can also be found in patients with other fungal infections or with bacterial meningitis. Perhaps the best way to diagnose CNS Histoplasma infections when cultures are negative is to perform both of these tests because at least one of the antigen 132 or antibody assays was positive in 13 of 14 episodes of Histoplasma meningitis in one study. In the absence of any other positive cultures or serologies, empirical treatment for Histoplasma infection should be started in patients with chronic meningitis of uncertain etiology when the Histoplasma antigen or antibody assays of the CSF are positive. In coccidioidomycosis,133 elevated serum CFA titers above 1:32 to 1:64 are the hallmark of disseminated disease. However, patients with isolated meningitis without extraneural infection may have low serum CFA titers. In patients with coccidioidal meningitis, CFA titers are present in the CSF of 70 percent initially and in almost 100 percent of patients as the infection progresses. CFA is absent from unconcentrated CSF in the presence of high serum titers due to extraneural disease, unless there is a parameningeal lesion next to the dura. The CFA titers appear to parallel the course of meningeal disease and have been used to guide treatment. The titers should decrease with successful therapy. The ability to detect specific antibodies in CSF has been used in the diagnosis of meningitis 67 caused by S. schenckii. Meningitis due to this particular organism is unusually difficult to diagnose, and delays of up to 7 months from the onset of symptoms can occur when diagnosis is based only on the results of cultures. Latex agglutination and enzyme immunoassay tests have been used successfully to detect CSF antibodies and to confirm the diagnosis of Sporothrix meningitis. When a titer of 1:8 or more was used, there was no cross-reaction with other fungal, bacterial, or viral pathogens. There is intense interest in developing serological tests for other fungal infections, especially those due to Candida and Aspergillus. Detection of unique antigens or metabolic products from these fungi in CSF has, so far, not been extensively used in the clinical setting of meningitis. It is likely that the galactomannan detection test for Aspergillus will prove useful in diagnosing this rare and difficult-to-detect infection and the β-glucan test needs validation with CSF specimens. Two other approaches for diagnosis of fungal meningitis are detection of host products and the use of molecular amplification. Although not specific 134 for fungi, CSF lactic acid concentrations usually are elevated in fungal meningitis, and, in some cases, specific fungal CSF T-cell responses can be detected. It is likely that as further experience accumulates with polymerase chain reaction–based diagnostics for meningitis, fungal sequences will be included in new diagnostic approaches using molecular amplification. Imaging studies can be extremely helpful in the diagnosis of CNS fungal infections. Localization of mass lesions or areas of meningeal inflammation by computed tomography (CT) or magnetic resonance imaging (MRI) can guide the neurosurgeon to areas for biopsy in selected cases. It appears that MRI with gadolinium enhancement is more sensitive than contrast CT scans. In cases of fungal meningitis, CT scans and MRI can be unremarkable or may show meningeal enhancement, hydrocephalus, atrophy, edema, or mass lesions. Some of these findings indicate the need for surgical intervention. In cases of meningitis refractory to conventional diagnostic approaches, meningeal biopsy for histological study and culture can be considered. However, even this invasive test can yield false-negative results. TREATMENT Experience varies in the treatment of the various forms of fungal CNS infection. Treatment for cryptococcal meningitis has been studied intensively, whereas many fungal CNS infections are so rare that only a few cases have been described. In the treatment of fungal infections of the CNS, an important adjunct to antifungal therapy is the reversal, if possible, of any immunocompromising conditions. This may include decreasing doses of corticosteroids or the use of immunomodulators to improve host immunity. A short review of available antifungal agents is followed by recommendations for specific fungal CNS infections.
Specific Antifungal Agents Amphotericin B Despite its serious toxicities, the polyene antibiotic amphotericin B has been the gold standard in the treatment of disseminated mycoses for more than three decades. Amphotericin B deoxycholate has been used successfully to treat many cases of fungal meningitis. This is remarkable inasmuch as amphotericin B levels in the CSF during
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treatment are low or even unmeasurable. The drug may accumulate in the meninges to provide direct antifungal activity. Alternatively, the known immunostimulatory properties of amphotericin B may improve the host's CNS immune response. Because amphotericin B is poorly delivered to the subarachnoid space from the blood, it has been administered by direct injection into the CSF through lumbar or ventricular catheters in difficult cases. In doses up to 0.25 or 0.50 mg daily, intrathecal amphotericin B has been used to suppress coccidioidal meningitis, to treat overwhelming cryptococcal meningitis, and to attempt to eliminate yeasts from the CSF when previous intravenous administration of the polyene has failed. However, intrathecal administration of amphotericin B carries certain major risks, including arachnoiditis, vasculitis, and secondary bacterial infection of CSF catheters. The newer lipid-associated formulations of amphotericin B are less toxic than standard amphotericin B deoxycholate. These drugs have lower rates of renal toxicity, and some formulations may have lower rates of infusional toxicities. However, it appears that higher doses of the lipid-complexed forms are necessary to achieve clinical response rates 135 comparable to those obtained with amphotericin B alone. It is now clear that the lipid-associated preparations have a role in treating systemic fungal infections because avoidance of renal toxicity is an important factor. It is not yet clear that these higher doses will affect the outcome of CNS infections, although in one study of cryptococcal meningitis, a higher dose of liposomal amphotericin B compared favorably in regard to CSF sterilization 136 lipid products for treatment of CNS infections should with standard amphotericin B. These 137,138 be used on a case-by-case basis. Flucytosine Flucytosine has been used to treat infections due to Candida and Cryptococcus and for chromoblastomycosis. It penetrates well into the subarachnoid space, with drug concentrations in the CSF approaching 75 percent of simultaneous serum levels. Despite its excellent pharmacokinetics, a problem with flucytosine when given alone in the treatment of CNS fungal infections is that fungi often acquire resistance to it, resulting in treatment failure. Therefore, this agent usually is not used alone in CNS infections but in combination with other antifungals. Flucytosine has significant toxicity for the bone marrow, liver, and gastrointestinal tract. Toxicity can manifest as diarrhea, hepatitis, or potentially life-threatening bone marrow suppression. Flucytosine toxicity, especially bone marrow suppression, is usually related to serum concentrations exceeding 100 μg/ml. With the availability of assays to determine serum concentrations of flucytosine, there should be less reluctance to use this drug in patients with decreased bone marrow reserves because toxicity can be minimized by monitoring serum drug levels during therapy. Serum flucytosine concentrations 2 hours after a dose should be maintained between 30 and 80 μg/ml, and doses of 100 mg/kg per day in patients with normal renal function usually can achieve these drug levels. Fluconazole Fluconazole is a triazole antifungal useful in the treatment of many CNS fungal infections. It has a favorable pharmacokinetic profile, and its penetration into the CSF is excellent, with levels reaching 60 to 70 percent of those of serum. Experience in treating cryptococcal meningitis with fluconazole in patients with AIDS is extensive and is reviewed later. Fluconazole has also been used successfully in cases of CNS infection due to Candida species, B. dermatitidis, C. immitis, and H. capsulatum. This drug has particular value in the long-term suppression of coccidioidal meningitis. Itraconazole Itraconazole is another triazole drug with a broad spectrum of in vitro antifungal activity. This agent has poor penetration into CSF, but in animal models and in limited numbers of human infections, itraconazole has shown efficacy in CNS infections. It is thought that this agent may bind to host cells and thus be transported to sites of infection in the CNS. One of the main differences between itraconazole and fluconazole lies in the activity of these agents against Aspergillus species. Itraconazole is much more potent against Aspergillus and has been used in limited numbers of patients for the treatment of CNS aspergillosis. Absorption of this drug is variable, and serum drug levels should therefore be measured to ensure adequate serum concentrations; for CNS infections, intravenous or oral elixir preparations should probably be used rather than tablets. Voriconazole and Posaconazole
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These are two extended-spectrum triazoles with broad antifungal activity. In particular, these compounds have potent activity against molds. Voriconazole is available in both oral and intravenous preparations, whereas posaconazole has only an oral formulation at present. Both of these two agents can penetrate the brain and CSF. Voriconazole has variable 139 penetration, but levels in CSF can range from 0.22 to 1.0 of a simultaneous serum level. It is likely that these drugs will become a cornerstone antifungal regimen in the management of mold infections of the CNS, either alone or used in combination. For instance, voriconazole has been used in more than 50 patients with cerebral aspergillosis with a success rate of 140 approximately one third. It was suggested that voriconazole and the use of neurosurgical procedures had a positive impact on outcome. Voriconazole treatment has had reasonable 141,142 and we have seen it success with Scedosporium apiospermum infections of the CNS, be successful in the management of CNS phaeohyphomycosis. There is some experience with posaconazole in the treatment of mold infections of the CNS,142 and in a small series, approximately 50 percent of patients were successfully managed. Posaconazole, unlike voriconazole, has activity against Zygomycetes infections and thus, along with lipid products of amphotericin B, might be considered in the treatment of CNS zygomycosis. Both voriconazole and posaconazole have been used in cryptococcal meningitis; their general use has primarily been in patients with refractory disease, with about a 50 percent success 143,142 This low success rate probably reflects the patient population studied, and it is rate. likely that these azoles perform similarly to fluconazole in cryptococcal meningitis. These agents are not first-line initial induction therapy for cryptococcal meningitis but can be used in clearance or suppression phases. With still so little experience, it is difficult to give precisely either the optimal dose or duration of treatment, but it seems reasonable to give the maximum tolerated dose for a prolonged period of time for CNS mold infections. Echinocandins There are three clinically available echinocandins: caspofungin, micafungin, and anidulafungin. These agents target the fungal cell wall by inhibiting the 1,3-β-glucan synthase of fungal species. They are particularly potent against Candida species and possess some activity against Aspergillus species; their clinical experience remains limited in CNS infections. It does appear 144 that echinocandins, like caspofungin, can achieve therapeutic levels of drug in the CSF, but it remains unclear how well this class of drugs penetrates and kills fungi in brain tissue. Occasional case reports have shown the success of 144,145 By contrast, a caspofungin in treating Candida meningitis from adults to neonates.146 Candida brain abscess failure with caspofungin has been reported. There is still much to be learned about the use of the echinocandins in CNS infections including dose, duration, and rate of success. It is reasonable to consider their use in Candida meningitis, although there are alternatives. The echinocandins might be considered in combination with other drugs for susceptible mold infections of the brain, although their success in brain parenchymal infections is not clear. This class of drugs should not be used in the management of cryptococcal meningitis. Combination Regimens Combinations of antifungal drugs have been studied for the treatment of CNS infections in an attempt to obtain147better clinical results, shorter courses of therapy, and reduced toxicity of increased activity against amphotericin B. Rifampin added to amphotericin B has shown 148 various yeasts compared with amphotericin B alone in vitro. There are few clinical data in humans by which to judge its effectiveness in CNS fungal infections, but rifampin does penetrate well into the subarachnoid space. There has been some interest in treating CNS 149 fungal infections with a combination of polyene and azole antifungals. There are no comparative clinical data to support such combined regimens, but animal data have shown some additive effect from using amphotericin B and an azole together in treating cryptococcal meningitis, and an open trial in cryptococcal 150 meningitis found excellent results with a regimen combining polyene, triazole, and flucytosine. However, a recent landmark study on comparing combinations in cryptococcal meningitis 151 used quantitative CSF yeast counts to study four groups, each containing 16 patients. It was shown that amphotericin B plus flucytosine led to a faster decrease in CSF yeast counts than amphotericin B, amphotericin B plus fluconazole, or even triple-drug therapy with amphotericin B, fluconazole, and flucytosine. This combination remains the standard for induction therapy of cryptococcal meningitis. With the availability of four classes of antifungal agents for invasive mycoses and the life-threatening and difficult-to-treat nature of many of these CNS mold infections such as Aspergillus, Scedosporium, and black molds, combinations of polyenes, azoles, echinocandins, and flucytosine have been used empirically
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in the clinic. Unfortunately, at present, there can be no specific guidelines about their routine use, and each individual case needs to be judged at the bedside with guidance from in vitro susceptibility and expert opinion. When amphotericin B and azoles are used in sequence, there has been no detectable clinical antagonism when azoles have followed initial polyene therapy. Because of the prolonged treatment courses that must be used in CNS fungal infections, it is desirable to have an effective oral regimen. The combination of flucytosine and fluconazole has been presented as 152 an oral regimen that may have clinical efficacy this combination in comparable with that of amphotericin B. The published experience with 153 treating systemic fungal infections is limited to cryptococcal meningitis and is generally favorable, but its utility as a primary regimen in CNS fungal infections remains to be established.
Surgical Treatment Neurosurgical procedures can play an important role in the diagnosis and treatment of some CNS fungal infections. Obtaining appropriate CSF or tissue samples for diagnosis using neurosurgical procedures may be required in some cases. The placement of CSF-diverting shunts may be needed in cases of hydrocephalus and increased intracranial pressure. Placement may be necessary even during the period of active drug treatment of infection. The placement of reservoirs to allow long-term intrathecal administration of antifungals may be required in certain CNS infections such as coccidioidal meningitis. Surgical resection of parenchymal lesions has been undertaken to reduce mass effect in some cases of Histoplasma, Cryptococcus, and Aspergillus infection, but for these fungi, the presence of parenchymal CNS lesions usually does not indicate the need for neurosurgical excision. By contrast, when black molds such as Cladophialophora or Ramichloridium species and other dematiaceous fungi cause mass lesions in the CNS, surgical resection or debulking is usually required for cure. In addition, rhinocerebral infections154due to Zygomycetes require prompt débridement of necrotic tissue in the brain. Fungal infections of CSF shunts and reservoirs are uncommon. They are most often due to Candida species. Shunt infections should be treated with removal of the shunt and systemic antifungal therapy when possible. However, there are cases in which shunt removal is not possible or in which shunt placement occurs during periods of active drug treatment of meningitis. We have been able to treat some cases of cryptococcal meningitis with amphotericin B and flucytosine in the presence of CSF-diverting shunts, but we have also seen cases in which removal of the shunt apparatus was required for cure. We recommend that in the setting of a CNS fungal infection, CSF shunts should be removed if the shunt was placed before antifungal therapy.
Specific Fungal Infections of the CNS Cryptococcal Meningitis Before the availability of amphotericin B, cryptococcal meningitis was uniformly fatal, although occasionally an untreated patient survived for several years. Early treatment trials showed that immunosuppressed patients with cryptococcal meningitis had higher treatment failure rates than immunocompetent patients. This was also true in patients with AIDS, who were found to have low response rates to initial therapy and very high relapse rates once therapy was stopped. Because of this important dichotomy in the patient populations with cryptococcal meningitis, the treatments for patients with AIDS and without AIDS are discussed separately. Amphotericin B used alone at daily doses of 0.4 to 0.8 mg/kg for 10 weeks provides effective therapy for patients without HIV infection who contract cryptococcal meningitis. The addition of flucytosine to this regimen has been studied in an effort to decrease both the duration of therapy and the total dose of amphotericin B. A collaborative trial compared amphotericin B 0.4 mg/kg per day for 10 weeks with amphotericin B 0.3 mg/kg per day plus flucytosine 150 155 mg/kg per day for 6 weeks. The final outcomes were similar in the two groups, suggesting that the addition of flucytosine to amphotericin B allows shorter courses of therapy with lower doses of amphotericin B. Since this trial, much more experience with amphotericin B plus 156 flucytosine as primary therapy in cryptococcal meningitis has accumulated. This combination usually sterilizes the CSF within 2 weeks and cures many patients within 4 to 6 weeks of treatment, with manageable amphotericin B toxicity. Patients with good prognostic features and no known immunosuppressive conditions have been successfully managed with as little as 4 weeks of combined therapy. However, this regimen requires the administration of an intravenous medication for prolonged periods, and some treatment failures (15% to
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30%) will occur. Treatment regimens using oral antifungal agents for cryptococcal meningitis would obviously 157–159 There be attractive, and therefore both itraconazole and fluconazole have been tried. are no large trials comparing azole antifungals with amphotericin B in patients without HIV infection. Personal experience and data extrapolated from trials with patients with AIDS suggest that fluconazole can be used successfully as sole therapy for patients with cryptococcal meningitis, but that it may not be as effective as the combination of amphotericin B plus flucytosine. Itraconazole has also been used successfully in treating cryptococcal 160 meningitis, but because there is more experience with fluconazole, many physicians consider this the preferred azole agent when a triazole is used in meningitis. A compromise can be reached in an effort to reduce the amount of time on intravenous therapy by using an “induction phase” of amphotericin B plus flucytosine followed by a prolonged consolidation or maintenance phase with oral fluconazole or itraconazole. This combined drug regimen is recommended in treatment guidelines published by the Infectious Diseases Society of 161 America (IDSA) and consists of amphotericin B at a dose of 0.7 to 1.0 mg/kg per day plus flucytosine at a dose of 100 mg/kg per day to keep serum levels below 100 μg/ml for 2 weeks, after which the patient is switched to fluconazole at a dose of 400 mg daily, assuming normal renal function, for a minimum of 10 weeks. A lumbar puncture should also be performed after 2 weeks; if the CSF cultures still yield C. neoformans, treatment with amphotericin B and flucytosine should be reinstituted for another 2-week course of induction 161 therapy. If the CSF is sterile after amphotericin B plus flucytosine therapy, fluconazole can be continued. The total duration of fluconazole therapy should be tailored to the individual patient, but at least 10 weeks of treatment should be administered,161 and this should be extended for patients with immunosuppression as mentioned later. Because most relapses of cryptococcal meningitis occur within 6 months to 1 year after stopping therapy, we suggest giving a suppressive dose of fluconazole 200 to 400 mg daily for 6 months to 1 year in most patients who do not have HIV infection. Additional and higher doses of fluconazole may be required in patients with brain parenchymal lesions, persistent symptoms, concomitant immunosuppressive therapy, or underlying immunosuppressing diseases. The need for intraventricular or intrathecal amphotericin B in cryptococcal meningitis remains controversial. Some investigators have used intraventricular amphotericin B with success in cases with a poor prognosis. However, our experience is that this route of administration is rarely necessary and may have complications. In high-risk patients, it may be better to switch to lipid-based amphotericin B regimens and use doses up to 5 mg/kg per day or possibly higher rather than risk the side effects of direct injection of amphotericin B into CSF. Once therapy has been started, the frequency of lumbar punctures should be determined by clinical response. A lumbar puncture done after the second week of therapy should show that the CSF is sterile if the combination of amphotericin B and flucytosine was used. Once therapy is completed, further lumbar punctures should be performed at intervals, depending on the patient's signs and symptoms. As previously mentioned, most relapses occur during the first 6 months after primary therapy. Persistently elevated polysaccharide antigen titers or positive India ink examinations indicate failure of therapy only when the CSF culture is positive or the patient demonstrates neurological deterioration. There is probably little value in following serial cryptococcal polysaccharide antigen titers to make therapeutic decisions. The management of cryptococcal meningitis in patients with AIDS presents a major therapeutic problem, although it has improved during the era of HAART. Response to initial therapy in HAART-treated cases has improved, and the relapse rate, which was very high, has been reduced by suppressive fluconazole treatment. Recurrence of symptomatic cryptococcal meningitis in patients with AIDS has been shown to be due to the same strain 162 that caused the original infection, and it is thought that the prostate or brain parenchyma can serve as a site for persistent residual infection despite sterilization of the CSF. There is a relatively substantial amount of clinical data to support recommendations for the treatment of AIDS-associated cryptococcal meningitis published by the Infectious Diseases 161 Society of America. First, induction therapy includes amphotericin B 0.7 to 1.0 mg/kg per day with or without flucytosine 100 mg/kg per day for 2 weeks. We favor the combination 163 regimen because of more rapid CSF sterilization and potentially fewer relapses. In patients who have significant renal dysfunction, the substitution of liposomal amphotericin B 136 (AmBisome) 4 mg/kg per day or amphotericin B lipid complex (ABLC) 5 mg/kg per day can be made for amphotericin B. The induction period usually lasts for 2 weeks but can vary depending on the patient's clinical response. Patients are then switched to fluconazole (400 to 800 mg daily) for 10 weeks. Fluconazole alone has been evaluated for primary therapy of 157–159 and is successful, but clinical experience suggests that it takes cryptococcal meningitis longer to sterilize CSF compared with amphotericin B. Therefore, triazoles may be more effective when the burden of yeasts in CSF is lower. Although there can be a series of
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complications in an individual patient, it is anticipated that 80 to 90 percent of patients will respond well to the initial course of therapy. The third stage of the treatment plan is the continued use of lifelong fluconazole suppression at a dose of 200 mg daily for prevention of 164,165 The high rate of relapse in these patients led to the routine institution of lifelong relapse. fluconazole suppressive161 therapy for all patients with AIDS who respond to initial treatment for cryptococcal meningitis. However, the immune restoration associated with HAART has prompted reinvestigation of lifelong suppression. Some patients who have been treated with antiretroviral therapy and had a sustained immunological response may be able to safely discontinue maintenance therapy. One prospective trial evaluated 42 patients who responded to antifungal therapy for cryptococcal meningitis and were randomized to either continue or discontinue maintenance therapy for cryptococcal meningitis once the CD4 count had increased to above 166 100 cells/μl and the HIV viral load had been below 50 copies/ml for 3 months on HAART. Over a median follow-up of 48 weeks, there were no relapses in either group. Another study was a retrospective review of 100 patients who had responded to treatment for cryptococcal meningitis and who had a CD4 count above 100 cells/μl while receiving HAART. All the patients had their long-term suppressive therapy stopped and were 166 followed closely. Prior to discontinuation of maintenance therapy, the median duration of HAART was 26 months, the median duration of maintenance therapy was 33 months, and the median time that the CD4 count had been above 100 cells/μl was 1 month. Forty-one patients had a positive serum cryptococcal antigen at the time maintenance therapy was discontinued. Over a median follow-up of 28 months, there were two relapses of cryptococcal 166 meningitis and two cases of extrameningeal cryptococcosis. The relapse in one patient occurred at a CD4 count of 46 cells/μl, but the other three patients all had negative serum cryptococcal antigen test results at the time therapy was discontinued, and at the time of CNS relapse or extrameningeal disease, patients had undetectable HIV viral loads and CD4 counts above 100 cells/μl (two above 400 cells/μl). We believe that maintenance therapy can be stopped in some carefully selected patients. Appropriate candidates for stopping maintenance therapy are those who have had at least 2 years of therapy with fluconazole, along with a CD4 count above 100 cells/μl (or more than 10% CD4 cells). These patients should be monitored closely, and fluconazole maintenance reinstituted if the CD4 count falls below 100 cells/μl (and below 10% CD4 cells). Following serum cryptococcal antigen titers does not appear to have much value. Increased intracranial pressure is a well-described acute problem in patients being treated for 127,167 Symptoms in such patients usually begin shortly after initiating cryptococcal meningitis. antifungal therapy and include systemic hypertension, increasing headaches, impaired consciousness, visual impairment, and cranial nerve palsies. These symptoms can occur suddenly, and head CT scans usually show no evidence of hydrocephalus or mass lesions. The opening pressure at lumbar puncture can be extremely high (≥250 mmH2O). The pathophysiological cause of increased intracranial pressure in this setting is uncertain, but it 167 is probably CSF outflow obstruction. Most patients with AIDS-associated cryptococcal meningoencephalitis present with increased intracranial pressure, and clinical experience shows that up to 70 percent of this patient127,157,161,168–173 population will have opening pressures of more Almost all these patients will rapidly than 200 mmH2O on the initial spinal tap. respond to the removal of large volumes of CSF, which can be accomplished with lumbar punctures. Treatment guidelines published by the Infectious Diseases Society of America recommend that sufficient CSF be removed to achieve a closing pressure of less than 200 161 mmH2O or 50 percent of the opening pressure. Some patients will require serial lumbar punctures for relief of severe symptoms and physical findings. For those patients requiring 127,169 very frequent lumbar punctures, ventricular shunts should be considered. Despite theoretical concerns about placing catheters in infected spinal fluid, experience in other patients shows that the placement of catheters during active infection does not result in difficulties of clearing the infection if antifungal drugs are already administered. Lumbar drains are another option, but the relatively frequent complication of bacterial superinfection precludes long-term use. Corticosteroids and acetazolamide to decrease increased intracranial pressure in the setting of AIDS-associated cryptococcal meningitis have been 174 to be beneficial and are not routinely recommended for used, but these do not appear 161 control of intracranial pressure. Anecdotal support for a strategy of aggressive management of intracranial pressures comes 175 from a retrospective review of 26 patients with cryptococcal meningitis, in whom only 5 were managed according to the Infectious Diseases Society of America treatment guidelines mentioned previously. Most of the deviations from the guidelines involved the management of increased intracranial pressure, and neurological complications were seen in 20 percent of the patients whose care conformed to the published guidelines and in 50 percent of patients 175 whose care had major deviations from the guidelines.
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Visual loss in cryptococcal meningitis may not respond to maneuvers aimed at decreasing intracranial pressure. Blindness is usually not due to endophthalmitis and is often bilateral 176 and permanent. Many treatments have been tried in an effort to restore vision, including repeat lumbar punctures, treatment with corticosteroids, fenestration of the optic nerve sheath, and release of perioptic nerve arachnoidal adhesions. Unfortunately, none of these has been very effective. The management of IRS in cryptococcal meningitis is uncertain. First, the diagnosis is imprecise but is considered when CSF cultures are negative and antigen is stable or decreasing on therapy and the patient has persistent or increasing evidence of inflammation by cell counts or radiograph. Second, treatment is not well studied, but clinical responses do occur to administration of corticosteroids. Therefore, it is a syndrome that can complicate treatment and needs to be considered and managed individually at the bedside. There are several major prognostic factors that determine the outcome of patients with cryptococcal meningitis. First, control of the underlying disease is essential; this is the most important factor in predicting outcome. Second, the burden of yeasts in the CSF, indicated by positive India ink examinations, high polysaccharide antigen titers, and elevated intracranial pressure, is critical. High numbers of yeasts worsen the prognosis, and these patients may need more aggressive individual clinical management. Third, the impact of the host response is important. Patients with a poor CSF inflammatory response, such as those with fewer than 3 20 leukocytes/mm , do not respond as well to current therapies as those with a stronger host response, and studies suggest that immunomodulators may be important in addressing this factor. For instance interferon-gamma at the CSF site helps determine clearance of infection 41 with recombinant interferon-gamma from this site, and one clinical study of treatment 42 tended to reduce CSF yeast counts faster. Interferon-gamma treatments may be useful in cases of cryptococcal meningitis in which it is difficult to eliminate yeasts from CSF with standard treatments. Fourth, clinical symptoms at presentation, such as a decreased 156,177 Earlier diagnosis may be sensorium, suggest advanced disease and a poor prognosis. the best means to improve prognosis. Candida Meningitis Treatment of Candida meningitis has received less attention than that of cryptococcal infection. There are reports of spontaneous cures of meningitis due to Candida species, but clinical experience suggests that treatment is indicated for all these patients. Even with treatment, mortality rates for Candida meningitis range between 10 and 20 percent. There is no consensus on the best regimen, but the combination of amphotericin B and flucytosine resulted in a high cure has synergistic activity against Candida in vitro. This combination has 178 73 rate. There is substantial experience with amphotericin B alone, which can successfully treat Candida meningitis. Also, fluconazole with high CSF penetration can be used in certain cases, although it usually does not sterilize CSF as fast as amphotericin B–containing 179 amphotericin B has been used after failure of conventional regimens. Liposomal 180 180 amphotericin B and has been combined successfully with flucytosine. The successful use of echinocandins in Candida meningitis remains imprecise, and recommendation of use in CNS infec tions is uncertain. In patients with ventriculoperitoneal shunts or ventriculostomies, it is recommended that any prosthetic material or device be replaced 181 has improved with treatment, but mortality during systemic antifungal therapy. Prognosis 90,182,183 It is essential that this infection be and neurodevelopmental disabilities persist. detected early, treated aggressively, and, if possible, prevented. Coccidioidal Meningitis In contrast to meningitis due to other fungi, the primary mode of treatment for coccidioidal meningitis is not systemic but intraventricular amphotericin B. In these infections, systemic amphotericin B in a total dose of 0.5 to 1.0 g is given mainly to treat undetected foci outside the CNS. Control of the CNS infection is then achieved by intraventricular administration of amphotericin B. Intrathecal therapy is begun with small doses of 0.01 mg/day and increased gradually, as tolerated, up to 0.5 mg/day. The drug can be administered in the lumbar, cisternal, or ventricular space; the latter is preferred. Arachnoiditis, neurotoxicity, and secondary bacterial infections of the CSF can complicate therapy. Recommendations for length of therapy are variable, and because of the poor prognosis for a complete cure, some patients have been treated indefinitely. The CSF leukocyte count has been used to follow progress and to judge the need for further therapy. Lowering of the CSF antibody titer after treatment is a good prognostic sign. The clinician must be vigilant for the development of hydrocephalus or a superimposed bacterial infection during treatment.
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There has been some clinical benefit from treatment with azoles. Miconazole and ketoconazole have been tried, but response has been only fair, and these agents are not recommended. Recent experience has focused on using fluconazole and itraconazole as therapy for coccidioidal meningitis. One article reported on the treatment of 47 patients with 184 coccidioidal meningitis with fluconazole 400 mg/day. A positive response to therapy was seen in 37 patients and appeared to be unrelated to the presence of hydrocephalus or HIV infection. Toxicity was minimal in patients treated for long periods. With these data, it is now reasonable to consider fluconazole as a first-line agent in patients with coccidioidal meningitis. Fluconazole's ease of administration and lack of toxicity compared with intrathecal amphotericin B are important considerations. However, several issues remain. The optimal dose of fluconazole is not known, and some authorities believe that 800 mg daily should be used as initial treatment. The use of induction therapy with intrathecal amphotericin B followed by long-term azole therapy has also been proposed as a possible treatment strategy in some cases. Itraconazole has also been reported to be effective in patients with relapsing coccidioidal meningitis, but it is unknown what role this drug will have in treatment. Current treatment strategies consider coccidioidal meningitis to be only suppressed, not cured, thus requiring lifelong therapy. Observational studies suggest that with current treatments, more than 70 percent of patients will relapse on discontinuation of54treatment. Therefore, lifelong suppressive therapy with an azole is usually recommended. Other Fungal Infections Meningitis due to Histoplasma, Sporothrix, or Blastomyces usually responds to prolonged courses of amphotericin B. The role of azole drugs in these infections is not clearly defined, but they generally are used after aggressive polyene treatment. P. boydii CNS infections may respond to the newer triazoles such as voriconazole. Infections of the CNS with Aspergillus species are usually fatal despite therapy. However, there are a few cases of successful therapy with high-dose amphotericin B and new triazoles. Patients with CNS aspergillosis may be considered for combination therapy with voriconazole/posaconazole plus an echinocandin and even adding a lipid amphotericin B preparation to control infection. It is also helpful to debulk an abscess with surgery. Zygomycetes infections of the CNS should be treated initially with high doses of lipid formulations of amphotericin B and, if possible, surgical débridement of infarcted tissue. Surgical debulking of fungal masses is even more important in the phaeohyphomycoses, which then may be treated with a combination of a polyene, an azole, and flucytosine. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 49 Parasitic Infections of the Central Nervous System ROBERT A. SALATA • CHARLES H. KING •
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PROTOZOAN INFECTIONS Cerebral Malaria Cerebral Toxoplasmosis African Trypanosomiasis Primary Amebic Meningoencephalitis and Granulomatous Amebic Encephalitis Cerebral Amebiasis due to Entamoeba histolytica HELMINTHIC INFECTION Cestodes Cysticercosis Echinococcosis (Hydatid Disease) and Sparganosis Nematodes Disseminated Strongyloidiasis Trichinosis Eosinophilic Meningitis: Angiostrongyliasis, Gnathostomiasis, and Visceral Larva Migrans Onchocerciasis and Loiasis Trematodes Schistosomiasis Paragonimiasis and Fascioliasis
Protozoa and helminths are unique infectious agents that contribute significantly to human morbidity and mortality. Although these agents are referred to as parasites, implying a dependent way of life, they are in this context no different from other infectious agents, such as bacteria and viruses. However, protozoa differ biologically from metazoa or helminths. Protozoa are single-celled, generally microscopic animals that characteristically undergo multiplication in the mammalian host. In contrast, helminths are multicellular, vary tremendously in size, and in general are not capable of multiplying within the mammalian or definitive host, although exceptions exist. Protozoa and helminths have complex life cycles and have adapted to exist within the hostile environment of one and sometimes several hosts. The distribution of these infectious agents parallels the poor socioeconomic conditions in the developing world. Some infections, however, are now becoming clinically significant to immunosuppressed patients worldwide. Central to the clinician's approach to the patient with central nervous system (CNS) infection with a protozoan or helminthic organism is the taking of a thorough geographical history and
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an increased index of suspicion. Once such an infection is suspected, appropriate diagnostic tests should be helpful. The following descriptions are organized to include the disease entities summarized in Table 49-1. Click here to view this table.... PROTOZOAN INFECTIONS
Cerebral Malaria During the past three decades, there has been a major resurgence of malaria, and this 1–3 mosquito-borne infection is the leading parasitic cause of death worldwide. Of the four species of Plasmodium that infect humans, Plasmodium falciparum causes the most significant morbidity and mortality. More than 80 percent of the fatal cases of P. falciparum 4–6 malaria are associated with cerebral involvement. Malaria is estimated to have a worldwide prevalence of more than 300 to 800 million cases per year and, in Africa alone, results in more than 1 million malaria-related deaths. Overall, 1–3 malaria is associated with a minimum economic cost of $12 billion annually. Infection is widely distributed (Fig. 49-1), with P. falciparum, which accounts for the majority of malaria deaths, predominating in sub-Saharan Africa, Haiti, New Guinea, Southeast Asia, South America, and Oceania. Cases of malaria in the United States are either imported or 7–12 The growing number of cases of malaria seen in the United associated with transfusion. 7–11 States is related to greater numbers of travelers to and immigrants from malarial areas.
FIGURE 49-1 Worldwide distribution of malaria.
During the twentieth century, the history of malaria was dominated by efforts directed at controlling the vector and developing antimalarial agents. In 1976, the World Health Organization (WHO) abandoned a worldwide malaria eradication program because of the development of resistance to dichlorodiphenyltrichloroethane (DDT) by the vectors and 1 resistance to chloroquine by P. falciparum. Most of the recent efforts have been directed at 12 seeking newer approaches, such as vaccines. Four species of malaria infect humans: P. falciparum, Plasmodium vivax, Plasmodium ovale, 1–3 and Plasmodium malariae. The infective sporozoites are injected by female anopheline mosquitoes into subcutaneous tissue and thereafter circulate to the liver to invade hepatocytes. Parasites multiply, and after 1 to 2 weeks, schizonts rupture and release thousands of merozoites, which then enter the blood stream to infect erythrocytes. All exoerythrocytic forms of P. falciparum rupture at about the same time, and none persist chronically in the liver. Invasion of erythrocytes by merozoites requires specific surface receptors on the parasite and erythrocyte. P. falciparum requires glycoporin, the major surface glycoprotein on 13,14 erythrocytes, for infection. P. falciparum can, in fact, develop in erythrocytes of all ages, and parasitemia can reach high levels; the magnitude of parasitemia relates to morbidity and 15 mortality. Within the erythrocyte, merozoites develop eventually into schizonts, which rupture to release
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merozoites capable of infecting new erythrocytes. Only the asexual erythrocytic stages are directly deleterious to the host, and the mechanisms involved in the development of clinical manifestations are related to fever, anemia, tissue hypoxia, and immunopathological events 1–3 (proinflammatory cytokines and both humoral and cell mediated). A number of serious complications can occur in P. falciparum malaria, including acute renal failure, pulmonary 1–6,15–17 edema, acidosis, hypoglycemia, and cerebral malaria. The exact mechanisms 15 underlying these complications are unknown, but all are associated with tissue hypoxia. Cerebral malaria occurs in 0.5 to 1 percent of P. falciparum cases, and 20 to 50 percent of 1–3, patients with cerebral malaria die. Sequestration of parasitized erythrocytes 4–6 within the capillaries of the cerebral cortex is typically observed (Fig. 49-2 and Fig. 49-3). Such sequestration may result from an interaction between vascular endothelial cells and protrusions (knobs) of the parasitized erythrocytes due to specific receptors or possibly to 18 One mediator of endothelial cell damage is tumor necrosis factor α endothelial cell damage. 19,20 In a murine model of cerebral malaria, TNF was essential for the histopathology (TNF-α). 20 and acute neurological manifestations. It has been hypothesized that in human cases, erythrocyte sequestration may result subsequent to TNF-mediated vascular2,3,20 changes. However, Increased serum TNF levels have been measured in patients with malaria. clinical studies of anti-TNF antibodies and other strategies to reduce TNF production have shown no convincing clinical benefit other than reduction in fever. There is some evidence that human cerebral malaria is related to the release of nitrous oxide and subsequent increased permeability of the blood–brain barrier, but the overall effect of nitric oxide on brain function in cerebral malaria is unclear. Few patients with cerebral malaria have cerebral 21 or increased intracranial pressure as edema on computed tomography (CT) scans 21–25 and no abnormalities in blood–brain barrier function have measured at lumbar puncture, 25 been identified.
FIGURE 49-2 Cerebral malaria: sequestration of parasitized erythrocytes in a
cerebral capillary. (Hematoxylin and eosin; original magnification 840×.)
FIGURE 49-3 Cerebral malaria: necrotic cerebral capillary containing
parasitized erythrocytes and surrounded by a ring hemorrhage. (Hematoxylin and eosin; original magnification 840×.) High fever and rigors are the hallmarks of acute malaria. A prodrome may occur, with 26 malaise, headache, myalgias, and fatigue that may mimic viral illness. Other manifestations may include backache, arthralgia, abdominal pain, nausea, vomiting, cough, tachypnea, lethargy, and frank delirium. Fever commonly rises to 105°F and may remain elevated between paroxysms of P. falciparum infection. On examination, patients are frequently found to have splenomegaly and tender hepatomegaly. Lymphadenopathy is not a feature, and its
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presence should prompt investigation of an alternative etiology.
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In cerebral malaria due to P. falciparum infection, presenting features may include seizures, disturbances of consciousness, acute delirium, meningismus, and, infrequently, focal 2,3,15,20 Other neurological abnormalities, including pyramidal signs or movement disorders. causes of CNS infection and encephalopathy must be excluded, and biochemical screening of blood and examination of cerebrospinal fluid (CSF) are mandatory. Hypoglycemia may occur as a complication of severe P. falciparum malaria or its treatment, especially in pregnant patients or in association with severe disease, and may be responsible for 27 deteriorating neurological status. The diagnosis of malaria rests primarily on the demonstration of parasites in peripheral blood 2,3,28 Although a higher degree of parasitemia is expected during paroxysms, the time smears. at which blood smears are collected is less important than the frequency of collection—smears should be collected several times daily and on several successive days. Efforts to quantify malarial forms are useful in assessing the severity of disease and the falciparum response to antimalarial therapy. A high degree of parasitemia, seen with P. 2,3 malaria, is considered to exist when 5 percent of erythrocytes are infected. Once parasites have been detected, species can be determined. Serological tests are not reliable in establishing the diagnosis of malaria. Methods with similar or greater sensitivity than blood smears are becoming available for the diagnosis of falciparum malaria. These techniques include an enzyme-linked immunosorbent assay (ELISA) for a histidine-rich P. falciparum antigen, an immunoassay for species-specific parasite lactate dehydrogenase isoenzymes, and DNA hybridization2,3and amplification of parasite DNA or mRNA using the polymerase chain reaction (PCR). The immunosorbent assays may be most applicable to the field. A variety of abnormalities in laboratory tests may be observed in cases of falciparum malaria, including a normocytic, normochromic hemolytic anemia, leukopenia, monocytosis, thrombocytopenia, minimal proteinuria, 2,3 mild azotemia, elevated liver enzymes, and lactic acidosis, disseminated intravascular coagulation. With severe P. falciparum malaria, 27 renal failure, pulmonary edema, and hypoglycemia may be observed. In cases of P. falciparum cerebral malaria, CSF examination occasionally reveals elevated 21,22,24 Hypoglycorrhachia is not a21feature. There is protein concentration or mild pleocytosis. no consistent CT pattern, and cerebral edema occurs in only a few cases. 1–6,8
Delay in the diagnosis of P. falciparum infection may prove to be fatal because patients who appear clinically stable may deteriorate rapidly if not treated. If P. falciparum infection is suspected, the patient should be hospitalized. It should be ascertained whether the patient 29–32 or whether has traveled to or resided in an area with chloroquine-resistant P. falciparum adequate prophylaxis has been taken. Patients with P. falciparum malaria that is suspected to be chloroquine resistant and who are not desperately ill and capable of taking oral medication can be treated with oral atovoquone plus proguanil (Malarone) for 3 days or oral quinine three 33 Alternate agents for oral treatment times daily plus doxycycline or clindamycin for 7 days. 34 include pyrimethamine plus sulfadoxine (unless concern for resistance), or mefloquine (unless concern for resistance if acquired in region of Southeast Asia) or oral artensonate 2,3 (not available in the United States), or amodiaquine. Oral quinine may cause cinchonism, characterized by tinnitus, headache, nausea, and visual disturbances. The special problems related to treating malaria in children and pregnant women have been reviewed 1–3,35 elsewhere. In patients with suspected chloroquine-resistant P. falciparum malaria with high parasitemia or major complications or in those unable to take oral medications, artensonate intravenously 36–38 These drugs are not yet approved or artemether intramuscularly can be used if available. 39–47 may be administered by continuous intravenous in the United States. Quinidine gluconate infusion (10 mg/kg loading dose, then 0.02 mg/kg per minute). This infusion is usually continued for 72 hours; it is discontinued sooner if parasitemia decreases to 1 percent or less. Parenteral quinidine may be cardiotoxic, and appropriate monitoring must be performed. Once the patient improves and can take oral medication, quinidine can be discontinued and a 7-day course of treatment can be completed with a combination of oral quinine and tetracycline. Quinine is the only available drug in some endemic areas for intravenous therapy for severe falciparum malaria. Quinine is much less cardiotoxic than quinidine. Intravenous preparations of quinine are not commercially available in the United States, nor can they be obtained from the Centers for Disease Control and Prevention on an emergency basis. After initiation of antimalarial therapy, patients with P. falciparum infection must be closely monitored for complications and response to treatment.
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Symptomatic and supportive therapy of cerebral malaria should include fluid restriction and efforts aimed at minimizing nosocomial complications. High doses of corticosteroids, which have been administered traditionally, should be avoided because a double-blind, prospective trial demonstrated prolonged coma and a higher incidence of complications in 22 dexamethasone-treated patients compared with those receiving placebo. In fulminant cases of P. falciparum malaria, exchange blood transfusion has been used as a lifesaving 41,48,49 adjunctive measure.
Cerebral Toxoplasmosis Infection due to Toxoplasma gondii may be acute or chronic, symptomatic or asymptomatic, 50–52 and it may affect both normal and immunocompromised hosts. Involvement of 50–53 the CNS and retina occurs primarily in immunodeficient individuals or in congenital infection. Toxoplasma infects all orders of mammals; cats appear to be associated with disease transmission. In humans, Toxoplasma antibodies increase with advancing age; seropositivity 50–53 may reach 90 percent by the fourth decade of life. The two major routes of transmission to humans are the congenital and oral routes (ingestion of undercooked meat or from contaminated soil). The more frequent route of infection is probably through ingestion of50–53 meats, vegetables, and other food products that have been contaminated with oocysts. Other routes of transmission of toxoplasmosis that 50 have been recognized include transfusion of whole blood or leukocytes self-inoculation of organisms in laboratory workers, 51 53–57 with organisms, and organ transplantation. After cysts or oocysts are ingested by cats, T. gondii invades the intestinal epithelial cells. Millions of noninfective oocysts may then be released daily, becoming infective for up to 1 year after sporulation. Upon entry into humans, the tachyzoite form of the parasite disrupts host cells and disseminates via the lymph and blood systems. Tachyzoite invasion is associated with focal necrosis and intense mononuclear cell infiltration. Both humoral and + cell-mediated immune responses (CD8 -specific helper T cells) and appropriate cytokine release (interleukin [IL]1, IL-12, and interferon-gamma [IFN-γ]) can limit tachyzoite 50–52 invasion. The lack of antibody transfer to the eye and CNS may allow more widespread proliferation in these areas. Cysts that are established in numerous tissues and organs ordinarily elicit little or no inflammatory response but persist to serve as a potential reservoir for reactivation. With congenital infection and in immunodeficient hosts, acute infection may produce severe and widespread necrosis and progress rapidly to involve the brain, lung, and 53–57 heart, often resulting in death. Infection of the CNS may be associated with focal or diffuse necrotizing meningoencephalitis, with perivascular mononuclear cell proliferation that may or may not be associated with 50,51 Infarction and hydrocephalus may result. Involvement of the eye organisms (Fig. 49-4). may result in chorioretinitis characterized by severe inflammation and with Toxoplasma 50–52 necrosis.
FIGURE 49-4 Cerebral toxoplasmosis: a resolving lesion in a brain autopsy
specimen from a patient with acquired immunodeficiency syndrome (AIDS). Mononuclear infiltrate is present, with the organism (arrow) visible at the periphery of the lesion. (Hematoxylin and eosin; original magnification 140×.) Only 10 to 20 percent of adult cases of toxoplasmosis are symptomatic.
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adenopathy is most frequently seen, but generalized adenopathy may be present. In some cases, adenopathy is accompanied by fever, night sweats, malaise, sore throat, rash, 50,51 ; toxoplasmosis accounts for less than 1 hepatosplenomegaly, and atypical lymphocytosis percent of mono-nucleosis syndromes. In the immunocompetent individual, the course of toxoplasmosis is usually benign and self-limited. A form of the disease with persistent lymphadenopathy has been reported. Rarely, normal individuals have progressive disseminated disease with CNS infection. 50–52
Toxoplasma gondii is an important cause of chorioretinitis. Most cases are the result of congenital infection, with occasional cases of reactivation disease seen in older individuals. The lesion is a focal, necrotizing retinitis with yellow-white patches. With healing, the lesions 58 pale, atrophy, and often develop black pigment (Fig. 49-5). Panuveitis may accompany chorioretinitis; papillitis is usually a sign of CNS involvement. There may be decreased visual acuity, scotoma, pain, photophobia, epiphora, and loss of central vision with macular involvement. Relapses of50chorioretinitis are frequent, but they are rarely associated with systemic manifestations.
FIGURE 49-5 Toxoplasma chorioretinitis: a pale, atrophied lesion containing
black pigment. Congenital infection results from asymptomatic infection of the mother during gestation. 52 Infection developing in the mother prior to conception is not transmitted to the fetus. Risk to 52 the fetus increases with infection acquired later in pregnancy. Signs and symptoms may be absent or may include chorioretinitis (bilateral), strabismus, blindness, epilepsy, mental retardation, anemia, jaundice, rash, petechiae, encephalitis, pneumonitis, microcephaly, 52 intracranial calcification, hydrocephalus, and hypothermia. If clinical findings are apparent in the neonate, sequelae are usually severe. Most infants are without clinical evidence of infection at birth, and symptoms that develop later in life may be mild or severe. Severe and often fatal toxoplasmosis has occurred in patients immunocompromised by treatment with corticosteroids or cytotoxic agents and in those with lymphoreticular 53–66 malignancies, organ transplantation, or acquired immunodeficiency syndrome (AIDS). The rate of reactive toxoplasmosis is not as high in immunosuppressed hosts without human immunodeficiency virus (HIV) infection as in those with AIDS. In these individuals, toxoplasmosis is usually due to reactivated disease; primary infection may be observed as well. Most immunodeficient individuals with toxoplasmosis have disease of the CNS with
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encephalitis, meningoencephalitis, or mass lesions. Pneumonitis or myocarditis may also 53–66 develop. 63
In AIDS patients with cerebral mass lesions, toxoplasmosis is the most frequent etiology. In the past, up to one third or more AIDS patients with antibodies to T. gondii had reactivated CNS toxoplasmosis. However, the widespread use of antimicrobial drugs to prevent Pneumocytosis jeroveci and of highly active antiretroviral therapy (HAART) has resulted in 65 reduction in reactivated disseminated toxoplasmosis-associated deaths in those patients. Because of the high prevalence of chronic T. gondii infection in tropical countries, reactivated toxoplasmosis is now66more frequently observed among HIV-infected immigrants from developing countries. In AIDS patients, cerebral infection develops as the result of reactivation. In3most instances, Toxoplasma encephalitis develops when the CD4 count falls below 100/mm . These patients most frequently have multifocal abscesses scattered throughout the cerebral hemispheres (Fig. 49-6) and present subacutely with focal 62,63 The incidence of fever, new headache, seizures, and alterations in neurological deficits. 58–66 Cerebral toxoplasmosis in AIDS patients is discussed mental state has been variable. further in Chapter 45.
FIGURE 49-6 Cerebral toxoplasmosis. Computed tomography (CT) scans from
a patient with AIDS demonstrate multiple, bilateral, enhancing hemispheric lesions with associated edema. The finding of T. gondii in blood or body fluids confirms acute infection. Most laboratories do not have the capacity to isolate T. gondii. The histological presence of tachyzoites also 52 establishes the diagnosis of the acute form of toxoplasmosis. The peroxidase-antiperoxidase technique has been used with63,67 success to demonstrate tissue tachyzoites, particularly in the CNS of patients with AIDS. Serological50,51 testing for specific antibody against T. gondii is the primary means of diagnosis. The Sabin–Feldman dye test, primarily measuring immunoglobulin G (IgG) 68 Low titers may persist for life, and titers do not antibodies, is both sensitive and specific. 68 correlate with severity of infection. The indirect fluorescent antibody test is easier to perform, safer, and more economical than the dye test and is the most widely used. The indirect fluorescent antibody test measures the same antibodies as the dye test, but reliable 52 developed to measure quantitative titers are difficult to obtain. Several assays have been 69–71 Negative serological IgM antibody, which appears earlier and declines faster than IgG. tests practically exclude the diagnosis of acute toxoplasmosis in immunocompetent individuals. Acute infection is documented with seroconversion or a twofold titer increase in acute and convalescent sera. Low titers of IgG antibody 50 are typically present in patients with ocular toxoplasmosis; IgM titers are usually not present. Toxoplasma chorioretinitis can generally be excluded if IgG serological test results are negative. Serological diagnosis of congenital infection depends on finding persistent or increasing titers on the dye test or 52 indirect fluorescent antibody test or a positive IgM titer. The diagnostic criteria for serological testing in toxoplasmosis also apply to immunocompromised hosts. However, serological diagnosis may be limited in these patients owing to depressed antibody responses. In AIDS cases, anti-Toxoplasma IgM or increasing 62,63,72 IgG levels are infrequently seen. Although some reports have suggested that negative serology in AIDS patients excludes toxoplasmosis from consideration, other centers have not 63 confirmed these observations and seronegative patients are also at risk of developing acute
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toxoplasmosis. It appears that Toxoplasma serology usually can neither confirm nor exclude the diagnosis of T. gondii in patients with AIDS. The diagnosis of T. gondii infection by polymerase chain reaction assay is evolving. Polymerase chain reaction assay can be performed on CSF, peripheral blood, 51 bronchoalveolar lavage fluid, or vitreous humor. The neuroradiographic features of toxoplasmosis of the CNS in AIDS patients have been 58–66,73 Neither the location, degree of enhancement, nor associated extensively reviewed. edema on CT can necessarily distinguish toxoplasmosis from CNS lymphoma, which is the 62 second most frequent etiology of intracranial mass lesions in AIDS patients. Several investigators have reported that magnetic resonance imaging (MRI) appears to be more 73,74 sensitive than CT, often showing lesions or additional foci that were undetected by CT. Pleocytosis (mononuclear), protein concentration elevation, and normal glucose levels are 62,63 ; these abnormalities are not specific, and lumbar puncture may often reported in the CSF be hazardous in patients with large mass lesions. The greatest controversy regarding cerebral toxoplasmosis in AIDS patients relates to the necessity of performing invasive brain biopsy initially for diagnosis. Brain biopsies may be 62 associated with hemorrhagic complications in AIDS patients. Most authorities suggest that in an AIDS patient with positive Toxoplasma IgG serology who has a consistent clinical and 75 radiographic presentation for cerebral toxoplasmosis,62,63 initial empirical therapy is reasonable. Most patients respond to therapy within 7 to 10 days. Biopsy should be reserved for cases that are refractory to appropriate empirical therapy, for those with single lesions on MRI with negative results on specific IgG tests, or for presentations more suggestive of lymphoma or other processes at the onset. Immunocompetent patients with lymphadenopathy are usually not treated unless there is evidence of visceral disease or symptoms have persisted or are unusually severe. Normal individuals who have acquired the disease by laboratory accidents or via transfusions should be treated as having an infectious disease. In these circumstances, infection is usually 50,51 Normal patients should be treated for 2 to 4 months and then reassessed. severe. Specific treatment of ocular toxoplasmosis has resulted in resolution of symptoms and 51 improvement in vision. Corticosteroids have been used in cases with involvement of the macula or optic nerve, and76,77 photocoagulation has been used to treat active lesions or to prevent spread of lesions. Treatment of the infected pregnant woman decreases the incidence of fetal infection but does 50,51 Results of uncontrolled human experience and animal studies not completely eliminate it. suggest that postnatal treatment of infected infants may prevent the development of 52 treatment of the pregnant patient and infected infant have been sequelae. Guidelines for 52 summarized elsewhere. Immunodeficient patients who have toxoplasmosis should always be treated if the infection is acute. Treatment is continued for 4 to 6 weeks beyond the resolution of all signs and symptoms. Most patients with AIDS and cerebral toxoplasmosis respond to specific therapy 75,76 However, the prognosis in these patients is poor, with a median survival for T. gondii. after diagnosis of 4 months. Toxicity associated with anti-Toxoplasma therapy has occurred in 60 percent, and relapse of Toxoplasma encephalitis has been reported in 50 percent of 75 cases. It appears that lifelong suppression of toxoplasmosis is necessary after acute 3 treatment in AIDS patients unless CD4 counts increase to greater than 200 cells/mm and the HIV RNA plasma level has remained low for 6 months after initiation of highly active antiretroviral therapy. 50,51
The most effective drugs for toxoplasmosis are pyrimethamine and the sulfonamides. These antifolates are active against tachyzoites and are synergistic in combination. Pyrimethamine is lipid soluble and readily absorbed from the gastrointestinal tract; 10 to 25 percent of the drug penetrates the CSF. With severe infection, this drug is given in a dose of 100 mg/day in two divided doses for 2 days and then as 25 to 50 mg daily or every other day, based on the severity of illness. The most common adverse effect associated with 50,51 which theoretically can be reduced with the pyrimethamine is bone marrow toxicity, concurrent administration of folinic acid (10 mg/day). Less-serious side effects have included headache, gastrointestinal symptoms, and rash. Sulfadiazine is administered as a loading dose of 75 mg/kg up to 4 g, followed by 100 mg/kg per day up to 6 g. Sulfamethazine and sulfamerazine have activity similar to that of sulfadiazine; all other sulfonamides have been inferior. Important adverse effects associated with the sulfonamides have included skin 50,51 hypersensitivity reactions and bone marrow toxicity. Alternative agents for Toxoplasma infection have included spiramycin, azithromycin,
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77,78
atovaquone, and clindamycin. Spiramycin is less toxic52than standard therapy and has been used to treat infected pregnant women and infants. No widespread experience of its use in immunocompromised patients or with cerebral toxoplasmosis has been reported. Clindamycin (oral or intravenous), which concentrates in the choroid, has been used successfully to treat ocular and CNS toxoplasmosis in combination with pyrimethamine. Atovaquone, which is active against the tachyzoite and tissue cyst forms, has been used as second- or third-line therapy along with pyrimethamine. The macrolide azithromycin has been used with pyrimethamine in successful therapy of toxoplasmosis. Other drugs with activity 50,51 against T. gondii include dapsone, roxithomycin, monocycline, and rifabutin.
African Trypanosomiasis Known widely as sleeping sickness, human African trypanosomiasis (HAT) infects more than 79,80 81,82 and remains a potential danger for travelers to endemic areas. 12,000 Africans yearly Two distinct forms of the disease in humans exist: western (chronic), due to infection by Trypanosoma brucei gambiense, and eastern and southern (acute), due to Trypanosoma 79,80 brucei rhodesiense. African79,80 trypanosomiasis remains a risk for approximately 45 million people in endemic The cases of African sleeping sickness seen in U.S. citizens have been due areas. 81,82 primarily to infection with T. brucei rhodesiense. Trypanosoma brucei80gambiense occurs mainly in the northern and western areas of sub-Saharan Africa. This species is transmitted by blood-sucking Glossina flies (G. palpalis and related species), better known as tsetse flies. An important factor in the epidemiology of infection related to T. brucei gambiense is the chronic nature of the illness, with few 79,80 incapacitating symptoms for many months. Flies that feed on these individuals can easily become infected, thereby perpetuating epidemics. East African trypanosomiasis is found in the eastern and southern parts of Equatorial 79,80 This form is transmitted by G. morsitans and related species. These vectors are Africa. less fastidious, so that disease can occur in places not necessarily corresponding to the classic tropical forest. Wild animals are reservoirs of infection. Disease related to T. brucei rhodesiense is more acute and progressive, so that infected individuals do not usually serve as a source of continued infection as they are removed by treatment, hospitalization, or 80–82 death. Tsetse flies become infected with trypanosomes after taking a blood meal from infected animals or humans. A complex set of developmental changes within the fly results in the 79 formation of the infective metacyclic form. When the fly bites humans, the parasites are injected into the blood stream, where they develop into slender forms that rapidly divide. As infection progresses, the long, slender forms develop into short, stubby, nondividing forms. In the mammal, trypanosomes are restricted to extracellular spaces, including the blood stream, 83 lymphatics, tissue fluids, and, later in the infection, the CSF. Antigenic variation by the long, slender forms accounts for the appearance of recurrent 84,85 This is waves of parasites after antibody-mediated killing of earlier populations. associated with changes in the major protein of the surface of blood-stream trypanosomes, 86 leads to ever-increasing the variant surface glycoprotein (VSG). This cyclical phenomenon 75,80 In addition, there is the immunoglobulin levels (mainly IgM) in the blood stream and CSF. 87 continued production of immune complexes. In African trypanosomiasis, significant lesions are demonstrable in the CNS and lymphatic 80 system. With infection due to T. brucei rhodesiense, there is less lymphatic involvement, and the findings in the heart and pericardium are often striking. In the CNS, a meningoencephalitis occurs, with perivascular inflammation with lymphocytes, plasma cells, 79,80,87–90 These and pale-staining mononuclear cells called morular or Mott cells (Fig. 49-7). 79,80 cells are believed to play an important role in the production of IgM.
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FIGURE 49-7 African trypanosomiasis: perivascular cuffing with mononuclear
cells. (Hematoxylin and eosin; original magnification 1,000×.) The earliest manifestation seen in both East and West African infections is a local, hard, painful lesion (chancre or trypanosomid) developing at the site of the insect bite. The second phase of the illness begins with widespread dissemination of the organism through the blood 84,87 stream and lymphatics, resulting in headache, fever, tachycardia, dizziness, and debility. The systemic phase of trypanosomiasis occurs in recurrent fashion, with each episode lasting 1 to 6 days, followed by an asymptomatic period of up to several weeks (Fig. 49-8). With progression of the disease, the systemic episodes decline in severity.
FIGURE 49-8 African trypanosomiasis: periodicity of parasitemias, which
correlates with systemic clinical features. In Gambian disease, a frequent finding is lymphadenopathy, typically of the posterior cervical 79,80 These nodes may be large, separated, and nontender; their consistency has been chain. compared with that of ripe plums (Winterbottom's sign). The early systemic stage of Gambian trypanosomiasis lasts from 6 months to 1 year. The initial neurological changes in Gambian trypanosomiasis are often subtle and have included an indifferent attitude, aimless gazing, inversion of the sleep cycle, tremor, and hyperesthesia. In the late stage of disease, there is progressive CNS involvement, with somnolence alternating with insomnia, alterations in thermoregulation, incoordination, hypertonia, abnormal movements83and gait, tremor, hyperreflexia, and, in the final stages, stupor and total indifference. The disease is invariably fatal, and undoubtedly malnutrition, accidents, and concurrent infections contribute to this outcome. With infection due to T. brucei rhodesiense, the onset of signs and symptoms occurs within a few days after a bite by the tsetse fly. In travelers, the disease often begins while they are 79–81 Lymphadenopathy is unusual. The clinical journeying home or soon after their return. features of Rhodesian trypanosomiasis are similar to those seen in West African disease except that they are shorter in duration and more acute in presentation. Signs of CNS invasion appear early, and neurological deterioration is very rapid. Death occurs in a matter of weeks to months after the onset of symptoms, with the most common cause of death 80 being cardiac failure. Examinations of blood, CSF, and aspirate of a lymph node for trypanosomes are essential diagnostic steps. Buffy-coat samples of blood should be examined because of high sensitivity
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in parasite detection. The CSF has an increased protein concentration, pleocytosis (with morular cells), increased IgM levels, and occasional trypanosomes in centrifuged specimens. Other nonspecific laboratory abnormalities may include anemia, monocytosis, and increased serum IgM. Several immunodiagnostic tests developed for epidemiological surveys are of limited usefulness in acute diagnosis. The drugs traditionally used in the treatment of African trypanosomiasis are suramin, 91,92 Suramin, used for Rhodesian pentamidine, and92the organic arsenicals. trypanosomiasis, is given intravenously initially as 100 to 200 mg and increased, as tolerated, to 1 g on days 1, 3, 7, 14, and 21. Transient albuminuria is often observed; heavy proteinuria, shock, febrile reactions, and desquamative rash are less common side effects. Pentamidine, used for Gambian trypanosomiasis, is given intramuscularly at 4 mg/kg per day for 10 total doses. Hypotension, fever, rash, azotemia, liver enzyme abnormalities, and 91 hypoglycemia may occur with pentamidine use. Neither suramin nor pentamidine penetrates the CNS adequately. Thus, the more toxic arsenicals must be included in the regimen if infection of the CNS is suspected. For Gambian disease, melarsoprol is given as 2.2 mg/kg per day intravenously for 10 days. For Rhodesian infection, melarsoprol is used most widely in a series of three to four daily injections, to a total 92,93 For patients with dose of 3.6 mg/kg with a maximum of 200 to 500 mg per injection. severe CNS involvement (higher CSF protein levels and pleocytosis [cerebral white blood 3 80 count >5/mm ]), up to four courses of arsenical therapy may be necessary. Toxic effects of the arsenicals include optic nerve atrophy, rash, and acute encephalopathy. Prednisone, which reduces the risk of encephalopathy by two thirds and the risk of death by 50 percent, 94 should be used in all melarsoprol-treated patients. Treatment of trypanosomiasis is fraught with the difficulties of drug toxicity and the increasing 80 emergence of trypanosomes resistant to arsenicals. Studies have indicated that difluoromethylornithine (eflornithine), an inhibitor of polyamine biosynthesis, is effective for 95–98 Clinical studies97have shown promising results in Gambian but not Rhodesian disease. patients with CNS involvement and with few side effects.
Primary Amebic Meningoencephalitis and Granulomatous Amebic Encephalitis Primary amebic meningoencephalitis is caused by the free-living amebas Naegleri 99–102 fowleri. CNS infection is acute and generally related to a necrotizing hemorrhagic 103 meningocephalitis. Since this condition was first recognized in 1965 by Fowler and Carter, a number of cases have been reported worldwide. Primary amebic meningoencephalitis has been reported from 18 countries in both tropical 99 and temperate areas. Cases of infection with Naegleria have occurred primarily in the southern United States, Australia, Great Britain, and the former Czechoslovakia. In the United States, more than 50 cases from 14 states have occurred, primarily in children and young adults during summer months. The majority of cases 104 (80%), caused by N. fowleri, are epidemiologically associated with freshwater contact. The portal of entry for Naegleria is the nose, with invasion of the olfactory neuroepithelium. Organisms gain99,100 access to the CNS by being forced through the mucosa covering the Nae-gleria infection initially involves the superficial gray matter and later cribriform plate. the deep matter and cerebellum. Prominent involvement of the frontotemporal areas, olfactory bulbs, and subarachnoid space is observed. Neutrophil invasion, extensive necrosis, and vascular invasion are typical (Fig. 49-9). Rarely, Naegleria infection disseminates from 99,100 99,100 the CNS. An acute, diffuse myocarditis has also occasionally been reported. The pathogenesis of infection with free-living 105 amebas is poorly understood 106 but may involve phagocytosis, phospholipase A2 activity, or complement resistance.
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FIGURE 49-9 Primary amebic meningoencephalitis: Naegleria trophozoites
(arrows) surround a small blood vessel in the brain. (Hematoxylin and eosin; original magnification 1,000×.) Patients with acute amebic meningoencephalitis present with severe headache, fever, lethargy, nausea, and vomiting. Olfactory involvement, manifested as nasal stuffiness or 99,100 Seizures, nuchal rigidity, confusion, and changes in smell, may be a clue to the etiology. then coma may develop within days. Focal neurological99signs occur early. The course is one of rapid deteriora- tion and death within 48 to 72 hours. Pulmonary edema and heart failure may complicate the course. Death is usually the result of brainstem herniation. Examination of the CSF in patients with the acute syndrome reveals neutrophilic pleocytosis, 99,100 In cases due to hypoglycorrhachia, high protein concentration, and99,100,107 red blood cells. Naegleria, highly motile trophozoites are identified. Cultures of the CSF may grow Naegleria. Few survivors of acute primary amebic meningoencephalitis due to Naegleria have been 99,100,107,108 reported. The most effective agent in vitro for Naegleria infection is amphotericin B (systemic and intrathecal). Intravenous doses of amphotericin B should be increased, as tolerated, to as high as 1 mg/kg per day. Supplemental intrathecal, intracisternal, or intraventricular doses should be given. The most effective total dose of amphotericin B has not been determined, but therapy should be continued for at least 10 days. Acanthamoeba causes a subacute or chronic granulomatous disease known as granulomatous amebic encephalitis in both immunosuppressed and immunocompetent 109–114 Several species of Acanthamoeba (Acanthamoeba castellani, individuals. Acanthamoeba culbortsonii, Acanthamoeba healyi, Acanthamoeba polyphaga, and Acanthamoeba rhysodes) are associated with an insidious onset of disease with a protracted course and usually fatal outcome. Granulomatous amebic encephalitis usually occurs in AIDS 99,100,112–116 Acanthamoeba can also be patients and other immunosuppressed persons. associated with disseminated99,100 disease as well as a painful, sight-threatening infection of the eye, Acanthamoeba keratitis. The epidemiology of infection related to Acanthamoeba is unknown, but because the natural habitat of this organism is soil and water, a relationship to these elements is probably important. Because the CNS infection due to Acanthamoeba occurs frequently in 110 immunocompromised individuals, it is possible that this organism, which can be found in 99,100 Acanthamoeba may also invade the CNS in the oral pharynx, invades as an opportunist. this manner but may secondarily involve the CNS after infection in other sites, including the 99,100 eyes, lungs, skin, and uterus. 99,100
Acanthamoeba may also cause multiple brain abscesses. Granuloma formation occurs, with giant cells, vasculitis, mycotic aneurysms, and few neutrophils. With multiple brain 110 abscesses, there is involvement of the midline deep structures and frontotemporal areas. 110
In cases of acute disease related to Acanthamoeba, parasites are seldom identified. With subacute or chronic presentations of Acanthamoeba, a moderate mononuclear pleocytosis is 99 present, along with increased protein and normal glucose concentrations ; amoebas are
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usually not present in the CSF. CT may confirm the presence of multiple abscesses in deep 99 midline areas. Serological tests may be of value, given the prolonged99course. Histopathology or culture of brain biopsy may also yield the diagnosis. As most cases of granulomatous amebic encephalitis due to Acanthamoeba are established postmortem, experience with specific treatment is extremely limited and recommendations are primarily based on in vitro susceptibility testing. In a small number of cases diagnosed early in the course, successful therapy with a combination of pentamidine isethionate, sulfadiazone, 5′-flucytosine, fluconazole, itraconazole, and trimethoprim-sulfamethoxozole 99–101 has been reported. Azithromycin has activity in vitro.
Cerebral Amebiasis due to Entamoeba histolytica In recent years, two morphologically indistinguishable but genetically distinct species of Entamoeba histolytica have been delineated. Entamoeba dispar, the more prevalent species, is associated only with an asymptomatic carrier state and has been identified frequently in homosexual men. E. histolytica is the cause of colitis, liver abscess, and extraintestinal 117,118 infection. Of the various extraintestinal manifestations of infection due to E. histolytica, brain abscess is 119–122 a rare but generally fatal complication. Although a number of cases of amebic brain abscess have been reported, less than one third have been confirmed by identification of the parasites. Entamoeba histolytica, the causative agent of amebiasis, has been reported to infect 10 percent of the world's population, accounting for 50 million symptomatic cases and 100,000 123 areas include Africa, South and Central America, Mexico, India, deaths per year. Endemic 123 In the United States, amebiasis, with a prevalence of 2 to 6 and Southeast Asia. 117,118,124 is seen most commonly in chronically institutionalized individuals, percent, 117,118 homosexual men, and lower socioeconomic groups in the southeast. 117,118
Humans are the primary reservoir of infection. Infection is transmitted by ingestion of cysts in contaminated food or water or unusually through fecal-oral contact. Excystation occurs in the small intestine, producing trophozoites. In the colon, where the parasite resides, encystation may occur with cysts passed in the stool. In a few cases, trophozoites invade the 117,118 Invasion of tissues leads to significant necrosis colonic mucosa, 125 and symptoms result. of these tissues. Invasive disease117,118 most frequently presents as inflammatory colitis, with the potential sequela Other extraintestinal complications, oc curring less frequently, most of liver abscess. often result from contiguous spread of infection from liver abscess into the pleural, pericardial, and peritoneal spaces. Hematogenous spread of infection has been recognized 119–122 and may result in cerebral infection. In reported series, 0.6 to 8.1 percent of cases of fatal amebiasis have been complicated by 119–122 Lombardo and associates noted 17 cases of cerebral involvement in brain abscess. 120 210 autopsy cases of amebiasis from Mexico City. Patients presented with focal neurological signs, seizures, and mental status changes. The areas of the brain most frequently involved included the basal ganglia and frontal lobes. In the few cases in which lumbar puncture was performed, a mild pleocytosis and increased protein concentration (as 119–122 with pyogenic brain abscess) was observed. Most cases of cerebral amebiasis have occurred in the setting of hepatic abscess. Diagnostically, 90 to 95 percent of cases of liver abscess are associated with positive 117,118 Attempts to confirm the diagnosis of cerebral amebiasis by examination of serology. CSF or stool for cysts and trophozoites have been largely unsuccessful. Thus, diagnosis of cerebral amebiasis depends primarily on documenting extraintestinal sites of involvement, especially the liver, and on serological confirmation. 117
Most cases of cerebral amebiasis have119–122 been fatal or found at autopsy. Fatal outcome has The early administration of metronidazole, an been due, in part, to delay in diagnosis. imidazole with exceptional tissue amebicidal activity and penetration of the CSF, provides the best chance of a successful outcome. A role for surgical drainage has not been established. HELMINTHIC INFECTION Because of their size (50 μm to 15 cm), multicellular (metazoan) parasites pose a distinct 126 problem for host immunity. The helminthic species that cause CNS disease are diverse; each parasite has a complex life cycle that involves human as well as nonhuman animal
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hosts in different stages of its development. To facilitate presentation of this section, the parasites under discussion have been grouped according to class (i.e., as cestodes [tapeworms], nematodes [roundworms], or trematodes [flukes]) for the reason that parasites of the same class share common features of development and often produce similar pathology in the CNS. As a reference, Table 49-2 summarizes the class distribution of the helminthic species discussed. Myiasis and pentastomiasis (not included in this chapter), which represent infestation with arthropods (insect larvae), may also involve invasion and 128 encystment in CNS tissues and may also cause secondary bacterial infection of the CNS. Click here to view this table....
Cestodes Cysticercosis 129
Cysticercosis is perhaps the most common CNS helminthic infection in the United States, and its manifestations are typical of many other metazoan parasite infections. The syndrome represents human infection with the immature or larval form of the tapeworm Taenia 130 solium. Because pigs are the usual intermediate host for T. solium, cysticercosis has a worldwide distribution in pork-producing countries. Although rare in the United States, Canada, and Western Europe, neurocysticercosis is common in Mexico, areas of Central and South America, Africa, the Cape Verde Islands, India, China, Thailand, Korea, the 130 Most U.S. cases result from patient emigration from or travel to Philippines, and Indonesia. 129,131–133 Transmission within the United States has been documented these endemic areas. 134 among household contacts of tapeworm-infected immigrants from endemic areas. Therefore, a careful exposure and travel history is essential in evaluating the potential for neurocysticercosis in symptomatic patients. Typically, infection results from the accidental ingestion of tapeworm eggs via fecal contamination of foods. After ingestion, tapeworm eggs hatch within the gastrointestinal tract and penetrate the bowel wall. The organisms then migrate into host tissues, favoring muscle and subcutaneous tissue. Over the next 60 to 70 days, 130 the early larval forms (oncospheres) mature to cysticerci measuring 0.5 to 3 cm in diameter. Neurocysticercosis, discussed here, results from infection of the CNS or eye. Cysts may be130 found, however, in any body tissue, including the heart, liver, lungs, and peritoneal cavity. After provoking an initial immune response by inflammatory white cells (neutrophils, larvae promote eosinophils, and lymphocytes) within infected tissues, encysting T. solium 130,135 fibroblast proliferation and become surrounded by a thick fibrous capsule. This encapsulation is associated with a waning of host inflammatory response. Later, when the parasite dies, the cysts begin to break down and may start to swell. In addition, local inflammation may recur or increase, owing to parasite decomposition and the associated release of parasite antigens. It is frequently at this point that patients experience the onset of neurological symptoms. The reported onset of symptomatic neurocysticercosis ranges from 1 136 to 35 years after exposure, although the average life span of encysted cysticerci is estimated to be 4 to 5 years. The clinical symptoms of neurocysticercosis are produced by mass effect, by obstruction of ventricular outflow with hydrocephalus, or by chronic inflammation in the subarachnoid space, which mimics chronic meningitis and may lead to communicating hydrocephalus. As occurs with tuberculous meningitis, parasite-induced chronic inflammation at the base of the brain 137 may entrap cerebral vessels, leading to angiitis, acute vascular compromise, and stroke. This presentation is particularly common in the “racemose” form of neurocysticercosis, in 138 which multilobulated vesicles proliferate on the surface of the brain. Both acute hydrocephalus and 139,140 stroke may be associated with sudden death in the patient with neurocysticercosis. With neurocysticercosis, the most common clinical presentation is epilepsy (30% to 92% of patients). Seizures may be focal or generalized and may vary in frequency. The onset of epilepsy may be associated with focal deficits corresponding to the location of the symptomatic cyst; if intracranial hypertension is present, papilledema may be noted. Hydrocephalus usually presents with headache, which may be accompanied by nausea, vomiting, ataxia, visual disturbances, and confusion. Impairment of intellectual function may be significant; 132,133 reported symptoms include amnesia, apathy, emotional lability, and With acute heavy infections, a syndrome of cysticercotic encephalitis hallucinations. may develop, particularly in young women. Severe diffuse brain edema may ensue, leading to 141 coma and death. Spinal cord cysticercosis may lead to a compressive myelopathy or a
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The specific diagnosis of neurocysticercosis may prove difficult, as the history, clinical 129 findings, and results of laboratory studies may be nonspecific. A history of exposure to the helminth or residence in endemic areas adds weight to the diagnosis. Furthermore, a careful physical and radiographic search should be made for systemic cysticerci, on which a biopsy can be performed to confirm parasitic infection. The CSF findings are suggestive of chronic meningitis, with most patients having a lymphocytic pleocytosis, hypoglycorrhachia, and 132,133 Eosinophilic pleocytosis is less common (10% to 30% of elevated opening pressure. 143 patients) and is not specific to neurocysticercosis. Imaging studies, such as CT scanning or MRI, 131,144 have proved to be the most useful tests for Multiple cysts up to 5 cm in diameter are supporting the diagnosis of neurocysticercosis. frequently noted in the cortex and meninges as well as in the cerebral white matter. Most cases have 10 or fewer cysts evident. The parasites' appearance may vary, depending on their stage of development and viability. Early lesions may appear solid, whereas older 130 lesions appear cystic. With time, cysts may eventually calcify and regress into scars. The appearance may be modified by surrounding inflammation, with some lesions becoming evident only on contrast-enhanced scans. The appearance of cysts may alter with therapy, 145,146 with some cysts showing more marked contrast enhancement after drug treatment. Ordinary CT scans may not demonstrate intraventricular or subarachnoid cysts well. In such 144,145,147 Experience with MRI cases, contrast cisternography or MRI may prove more useful. suggests that this modality may provide a more sensitive and specific diagnosis of neurocysticercosis, particularly in cases in which ventricular or subarachnoid cysts are involved. Not only can degenerate and viable cysts be discriminated by T1- and T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI, but it is frequently possible to discern the protoscolex of the viable tapeworm cyst. Serological testing for cysticercosis is available from the Centers for Disease Control and Prevention, Atlanta, Georgia, and from commercial laboratories. In large series, however, testing of serum and CSF by complement fixation, indirect hemagglutination, or 148 enzyme-linked immunosorbent assay has proved of variable sensitivity and specificity. Indirect hemagglutination or enzyme-linked immunosorbent assay testing appears to provide the greatest sensitivity (60% to 90%), but false-positive reactions may occur in patients with echinococcosis, schistosomiasis, or other tapeworm infections. Most current diagnostic tests are based on specific detection of glycoprotein parasite antigens using Western blot 149 (enzyme-linked immunoelectrotransfer blot [EITB]). The constellation of suggestive CT scan or MRI, positive serology, and evidence of systemic (extra-CNS) cysticercosis strongly favors the diagnosis of neurocysticercosis. In the presence of a negative serology or with an ill-defined solitary cyst, the diagnosis is more tenuous; the differential diagnosis must include glioma or other CNS tumors, brain abscess, vasculitis, tuberculosis, cryptococcosis, 144 echinococcosis (hydatidosis), or other parasitic infection. In some cases, stereotactic biopsy may be necessary to establish the diagnosis. Specific antiparasitic therapy is not required in all cases of neurocysticercosis. In a series of CT-diagnosed disease, 90 percent of patients with hemispheric lesions and 92 percent of 133 patients without hydrocephalus had benign outcomes without specific antiparasitic therapy. Nonspecific therapy, including anticonvulsants for control of seizures, ventricular shunting for control of hydrocephalus, and corticosteroids for reduction of pericystic inflammation, successfully controlled CNS symptoms in these patients. Nevertheless, the overall case fatality rate for neurocysticercosis is 10 percent, indicating that certain groups of patients with more aggressive or advanced disease may require specific antiparasitic treatment to control 150 their disease. The antihelminthics praziquantel and albendazole have become accepted129,150 as specific antiparasitic treatment for treatment of some types of neurocysticercosis. 150 However, the general utility of drug therapy for neurocysticercosis remains controversial. Initial recommendations for specific antiparasitic therapy were based on a number of nonrandomized case series (each involving small numbers of treated patients who were compared with historical control subjects) that suggested that both praziquantel and 151,152 Since albendazole hastened the clearance of cysticercal lesions seen on CT or MRI. these initial reports, subsequent concurrently controlled, randomized trials have indicated that antihelminthic therapy given with corticosteroids is not superior to corticosteroid therapy alone in terms of long-term control of seizures or resolution of intraparenchymal CNS 150,153 cysticerci. Other reports have indicated that antihelminthic therapy may exacerbate obstruction of CSF flow, enhance eye inflammation in ocular disease, and increase the risk of 154,155 Thus, the risk/benefit ratio for treating pericystic vasculitis, with increased risk of stroke. disease limited to the CNS parenchyma appears marginally unfavorable. Still, randomized,
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well-controlled trials have not yet been done for the treatment of other forms of neurocysticercosis (i.e., intraventricular, basilar, and spinal cysticercosis), and the true value of drug treatment of these forms of the disease is not known. Because antiparasitic drug treatment of intraventricular cysts may prove efficacious and because of the higher risk of disease progression and mortality in this setting,130,150 therapy for this form of the disease is However, when possible, surgical currently recommended by experienced groups. resection remains the treatment of choice for intraventricular cysts. If, based on review of the latest literature, the decision is made to medically treat an individual patient with complicated neurocysticercosis, treatment should generally be given with high 130,146,152,156 or albendazole doses of either praziquantel (50 mg/kg per day for 15 to 30 days) 151 (10 to 15 mg/kg per day for 8 days) with the goal of achieving drug levels sufficient to kill remaining living cysts. As noted earlier, cyst death is often accompanied by increased local inflammation, leading to an increase in patient symptoms. Before, during, and after drug therapy, seizures should be controlled with appropriate antiepileptic medications, and 157 symptomatic hydrocephalus should be relieved by shunting. Shunt complications due to blockage and bacterial infection are common in patients with neurocysticercosis. Patients 146 with basilar disease or arachnoiditis may not respond well to antiparasitic therapy. CNS inflammation can be reduced by concurrent administration of pharmacological doses of corticosteroids (dexamethasone); however, corticosteroids do not necessarily eliminate the 154,158 159 and intracranial pressure elevation. risk of serious complications, such as infarction Limited pharmacological evidence suggests that concurrent corticosteroid and antiseizure 160,161 In contrast, corticosteroid therapy may therapy may lower serum praziquantel levels. (variably) increase circulating levels of albendazole and its active metabolites in some patients. On this basis, some experts favor the use of albendazole for medical treatment of 151,159 Overall, in view of the significant variation between patients in cyst neurocysticercosis. number, location, and activity, the decision to use surgery or antiparasitic agents for 150 treatment of neurocysticercosis must be individualized for each patient. Echinococcosis (Hydatid Disease) and Sparganosis Other cestodes (tapeworms) that can cause human CNS tissue injury include the canine multilocularis and the tapeworms Echinococcus granulosus and Echinococcus 162 diphyllobothroid tapeworms of the Spirometra genus. As in cysticercosis, humans serve as the unwilling intermediate hosts in the tapeworm life cycle. Echinococcosis is common in the Middle East, the Mediterranean basin, regions of Africa, Australia, and the Arctic regions of 162 Asia and North America. With echinococcosis, migrating oncospheres rarely encyst in the CNS. However, echinococcal cysts that reach the CNS may produce symptoms by local inflammation, by mechanical obstruction of CSF flow (hydrocephalus), or by cortical irritation 163 bone, (with associated seizures). In addition, when hydatid cysts form within vertebral 164 compression or spinal dislocation may lead to secondary spinal cord damage. When found, CNS hydatid cysts are most frequently associated with cysts elsewhere in the body (Fig. 49-10). Eosinophilia or eosinophilic meningitis is an inconstant finding, but serological testing (indirect hemagglutination or enzyme-linked immunosorbent assay combined with immunoelectrophoresis) has proved fairly sensitive and specific for the diagnosis of 162,165 Serological response tends to be less sensitive, however, in echinococcosis. 166 extrahepatic hydatid disease, and aspiration or excisional surgical biopsy, with precautions for preventing spread of the cyst, may be necessary to establish the diagnosis in the CNS. For symptomatic cysts, the approach to treatment involves chemotherapy with albendazole or 162,167–169 combined with standard surgical resection or gamma-knife mebendazole, 170 radiosurgery when practical. Chemotherapy of vertebral bone hydatid cysts has not proved very successful, and, when possible, surgical excision remains the treatment of choice for symptomatic CNS cysts.
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FIGURE 49-10 Pulmonary echinococcosis: a large calcified cyst of the lung.
Sparganosis, caused by Spirometra larvae, is rare. Humans acquire infection by ingesting procercoids in copepods (water fleas) found in pond water or by ingestion of, or cutaneous 171 exposure to, meat from plerocercoid-infected animals. Symptoms and signs arise from mass effects from cysts found172,173 in the CNS or may result from cyst invasion in and around the Surgery is 174 the treatment of choice, although mebendazole eye, with secondary infection. and praziquantel therapy has been attempted.
Nematodes Disseminated Strongyloidiasis Strongyloides stercoralis is a gastrointestinal nematode parasite of humans that is endemic to many tropical and subtropical regions of the world as well as to areas of the southern 175 United States. Travel to or migration of patients from these areas accounts for most of the disease seen in temperate regions. It is of note that, after exposure, infection may persist for 175 decades. A second distinctive feature of Strongyloides (that contrasts it with the other enteric nematodes) is its release of living progeny instead of eggs within the gastrointestinal tract. Normally, these immature larvae are not infective for humans until they pass outside the body and spend days to weeks undergoing transformation into infectious filariform larvae. In individuals who are chronically ill (protein-calorie malnutrition, burns, tuberculosis, syphilis) or immunosuppressed (lymphoma, renal transplantation, AIDS, corticosteroid therapy, irradiation, or chemotherapy), however, this transformation may occur within the176patient's own gastrointestinal tract, leading to overwhelming autoinfection with Strongyloides. In many cases, the underlying parasitic infection may have been completely asymptomatic prior to the onset of disseminated strongyloidiasis. Presenting symptoms of disseminated strongyloidiasis include severe generalized abdominal 175,176 Invasion of the lungs may produce pain, distention, jaundice, and signs of sepsis. asthma-like symptoms, with cough, wheezing, and eosinophilia. Parasites migrating from the gut often carry enteric bacteria into various tissues around 176 the body, resulting in the appearance of polymicrobial bacteremia and septic shock. CNS involvement often results in acute mental status deterioration associated with signs of pyogenic meningitis, with
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progression to coma (Fig. 49-11). Alternatively, the process may be subacute, resulting in a picture of cerebritis or chronic meningoencephalitis, which may be mistaken for CNS 177 vasculitis. Diagnosis of CNS strongyloidiasis is usually clinical, based on the results of stool examinations for larvae and the presenting systemic symptoms. Therapy is primarily supportive, addressed to the symptoms induced by inflammation and bacterial superinfection. It is important to bear in mind, however, that corticosteroids may exacerbate the process of 176 Strongyloides autoinfection. Concomitant thiabendazole or ivermectin therapy should be 175,176 initiated to eliminate or suppress parasitic infection within the gut. In immunosuppressed individuals, it may not be possible to eradicate infection, but if immunosuppression can be suspended or176 reduced during antiparasitic therapy, the effectiveness of antihelminthics may Otherwise, suppressive doses of ivermectin should be given on a periodic be improved. 175 basis. Disseminated strongyloidiasis can be prevented in some cases by screening the stool of patients at risk prior to the initiation of immunosuppressive therapy. In AIDS-endemic areas, it would be prudent to screen and treat all HIV-infected individuals for Strongyloides infection at their first visit (i.e., prior to any progression to advanced immunosuppression and clinical AIDS).
FIGURE 49-11 Strongyloides stercoralis in the meninges, with acute hyperemia
and inflammatory cell infiltration. Trichinosis Trichinella spiralis infection is found worldwide and is acquired by ingestion of contaminated pork or other meat (e.g., bear meat). Infectious cysts within striated muscle tissue are178 digested, releasing maturing adult forms of Trichinella within the gastrointestinal tract. Days to weeks later, these adult forms release living infective larvae in the gut. These immature forms penetrate the bowel wall, enter the circulation, and initiate the clinical syndrome of trichinosis by invading various body tissues. Trichinosis is characterized by fevers, headache, myalgias, eosinophilia, and periorbital edema and may be complicated 178,179 by carditis or respiratory failure through direct involvement of Neurological disease occurs as a consequence of cardiac and respiratory muscles. larval invasion of the CNS and can be associated with seizures, meningoencephalitis, focal 180–184 Progression of infarction may infarction or hemorrhage, or cranial vessel thrombosis.184 lead to severe cerebral edema, herniation, and death. Muscle biopsy for the demonstration of Trichinella larvae (Fig. 49-12) is the diagnostic procedure of choice in that serological response may lag several weeks behind the onset of 178 infection. In some cases, larvae may be demonstrated in sediments of centrifuged CSF. CT scan and MRI may reveal multiple infarcts or hemorrhagic185lesions, either in areas findings, corresponding to focal motor deficits or throughout the brain. In some cases, CT 183 angiography, and electroencephalography (EEG) may be entirely nondiagnostic.
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FIGURE 49-12 Trichinella spiralis: larva encysted in human striated muscle.
The optimal treatment of trichinosis has not been established. Corticosteroid therapy is frequently used to control the signs and symptoms of trichinosis, although, as with strongyloidiasis, it has the potential to enhance larval dissemination. Thiabendazole, albendazole, and mebendazole have been used to eliminate the source of invading larvae (i.e., adult worms within the gut). Thiabendazole and mebendazole therapy may be of value in 186 the patient suffering from severe muscle involvement. Eosinophilic Meningitis: Angiostrongyliasis, Gnathostomiasis, and Visceral Larva Migrans When humans are187,188 exposed to parasites of domestic or wild animals, an acute or subacute Because humans are not successful or “patent” hosts for these illness may result. parasites, adult parasites do not develop within the body. Nevertheless, immature larvae may migrate for weeks within host tissues before dying. In the unnatural human host, the inflammatory response to tissue invasion by these parasites may be much more severe than the response noted in the normal patent animal host. Human CNS disease is common following infection by the rat lungworm Angiostrongylus cantonensis, which is transmitted by ingestion of snails, slugs, or undercooked prawns or 189 crab. Neurological disorders are also common with infection caused by Gnathostoma parasites of dogs and cats, which are transmitted by ingestion of undercooked freshwater fish 127,187,190 Angiostrongyliasis is found in Southeast Asia, or of frog, bird, or snake meat. Indonesia, Japan, the189 Philippines, Taiwan, southern areas of the Pacific, Egypt, Cuba, Jamaica, and Hawaii and may potentially be transmitted by snails in North America. Gnathostomiasis has been reported in Japan, China, Malaysia, Indonesia, India, Bangladesh, 188 Central and South America, and Israel. With both parasites, symptoms occur 1 to 3 weeks after exposure and may be associated with creeping143,189,190 skin eruptions, abdominal and pleural symptoms, fever, and CNS invasion is marked by headache, meningismus, cranial nerve eosinophilia. 127,187,191 Spinal cord palsies, and paresthesias, which may be protracted and severe. involvement may present as radiculomyeloen-cephalitis. The CSF examination is remarkable for intense eosinophilic pleocytosis (up to 143 90%), with mildly elevated CSF protein and normal or low-normal glucose concentrations. The CSF cytology occasionally reveals parasite larvae, but the specific diagnosis is more frequently based on clinical presentation, exposure history, and serological evidence. Optimal therapy 189,190 for these parasites is not established. 192 Mebendazole and corticosteroids have been used ; albendazole and corticosteroids have been used to treat symptoms of angiostrongyliasis 193 although no controlled studies are available to assess to treat systemic gnathostomiasis, 189 the efficacy of such treatment. Both infections are self-limited in nature, although neurological deficits may persist for months to years. Visceral larva migrans is a common U.S. parasitic infection that must be included in the differential diagnosis of eosinophilic meningitis. It is caused by inadvertent ingestion of the 194 eggs of animal roundworms, most frequently Toxocara canis and Toxocara cati. Infection is frequently seen in children with pica who ingest contaminated soil. Developing larvae hatch
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194
within the gut and may migrate into the CNS or eyes. Neurological symptoms are rare but may include absence attacks, generalized convulsions, focal sensorimotor deficits, and 143,188,194 Focal retinal inflammation may be paraplegia, depending on the species of parasite. 194 mistaken for retinoblastoma, leading to unnecessary enucleation of the eye. Systemically, infection may be characterized by fever, hepatomegaly, eosinophilia, and symptoms of pulmonary infection. Diagnosis is established by a history of animal exposure and by serological studies, although by itself, ocular disease may yield only low or nonspecific 195 194 anti-Toxocara titers in the serum. A CSF eosinophilic pleocytosis may also be noted. Treatment with corticosteroids is frequently used to alleviate inflammatory symptoms. Specific antiparasitic therapy with diethylcarbamazine, albendazole, or thiabendazole has 194 been associated with improvement of symptoms in some cases. Such therapy is not recommended in all cases because the outcome of most infections is generally benign. Onchocerciasis and Loiasis The filarial nematode parasites Onchocerca volvulus and Loa loa are transmitted from human to 196,197 human by biting flies, with an obligate developmental stage in the intermediate Onchocerciasis is found in Central and West Africa, Central and South vector fly. 196 197 America, and Yemen. Loiasis is localized to the western portion of Central Africa. In both diseases, developing filarial adults release their offspring as living microfilariae within the body, and it is the host reaction to these widely distributed larval forms that causes CNS disease. Onchocerciasis is the fourth leading cause of blindness in the world. Microfilarial invasion of the eye tissues results in conjunctivitis, keratitis, anterior uveitis, significant chorioretinitis, and 196 occasionally optic atrophy. In some areas, retinal findings may be the predominant presenting sign (Fig. 49-13). Individuals from areas with endemic HIV infection should be evaluated by an experienced ophthalmologist to exclude opportunistic cytomegalovirus infection and toxoplasmosis.
FIGURE 49-13 Onchocercal chorioretinitis. Composite photograph of the retina
of a patient from West Africa. 196
The diagnosis of onchocerciasis is made by examination of skin snips for microfilariae. Curative therapy is problematic in that the drugs198,199 diethylcarbamazine and suramin are Repeated annual administration of the associated with enhanced ocular inflammation. 196 drug ivermectin controls microfilarial load without exacerbation of eye symptoms. Caution must be used to exclude concurrent loiasis before ivermectin therapy is first administered (see later). Loa loa infection is usually associated with angioedematous skin reactions called calabar 197 swellings. Rare patients may develop nephropathy, cardiomyopathy, and encephalopathy associated with heavy infection and circulation of microfilariae in the blood stream. In many cases, CNS symptoms are exacerbated or brought on by attempted antimicrofilarial 200 depression and therapy. The encephalopathic state is marked by insomnia, headache, and 197 may be followed by coma and death in patients with severe microfilaremia. Some patients manifest microfilaria in the CSF. Postmortem examination reveals both diffuse acute cerebral edema and a granulomatous reaction surrounding degenerating larvae. Optimal therapy for this CNS syndrome has not been established, although, where available, plasmapheresis can be used to lower high worm burdens197 (>2,500/ml) before drug treatment in order to limit the risk of complications during therapy.
Trematodes
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Schistosomiasis Schistosoma organisms are trematode parasites transmitted to humans in contact with fresh water. The infectious larvae (cercariae) are released by parasitized snails, which serve as 201 intermediate hosts. There are three major species: Schistosoma mansoni is common to Africa and Brazil; Schistosoma haematobium is found in Egypt, in the Middle East, and throughout tropical Africa; and Schistosoma japonicum is found in Asia, Indonesia, and the Philippines. After cercariae penetrate the skin, developing worms migrate to the mesenteric blood vessels (S. mansoni and S. japonicum) or to the venous system surrounding the ureters and bladder (S. haematobium). Host morbidity results from release of parasite eggs into surrounding host tissues, with resultant granulomatous inflammation and scar formation. CNS disease is relatively rare in schistosomiasis and appears to result from aberrant deposition of eggs within nervous tissues, either by migration of adults into the CNS or by transport of eggs into the CNS circulation via collateral veins. The syndrome of cerebral schistosomiasis is most common in S. japonicum infection, 201 affecting up to 2 to 4 percent of patients. It is characterized by focal motor and sensory deficits, seizures (jacksonian or generalized) with electroencephalographic abnormalities, focal abnormalities on MRI, and hyperdense, multinodular enhancing lesions on CT scans, 202–204 In uncontrolled trials, treatment with praziquantel (60 mg/kg) with surrounding edema. has been associated with improvement or cure of seizures and resolution of CT 203 abnormalities. By contrast, cerebral schistosomiasis is rarely seen with infections due to other schistosome 201 species. With S. mansoni infection, cerebral involvement often appears with acute infection, manifesting as a febrile meningoencephalitic reaction that may be associated with a 205 206 Chronic CNS disease may show evidence of vasculitis or cutaneous allergic reaction. 207 mass lesions. Spinal cord syndromes 208–212 appear to be more common in patients with S. mansoni or S. Presentation may be acute or subacute and may be associated haematobium infection. 213,214 with cutaneous deposition of eggs at the level of spinal cord involvement. Presenting 208–212 syndromes include low back pain, paraparesis, sensory loss, and bladder dysfunction. 212 Acute vascular compromise may result in myelonecrosis, or expanding granulomatous inflammation may lead to cord compression with evidence of CSF blockage 212 on MRI, 208 deterioration to one of myelography, or CT. The course may vary from one of rapid 207,215 gradual improvement and resolution after antiparasitic therapy. 201
Diagnosis should include parasitological or serological evidence of schistosome exposure 216 and must exclude other causes of myelitis found in areas endemic for schistosomiasis. Because developing areas also pose significant hazards in terms of chemical and venomous toxins as well as endemic polio and coxsackievirus infection, it may not be possible to determine 216 with certainty the etiology of a patient's CNS disease without biopsy or autopsy diagnosis. Therapy 201 with praziquantel will provide eradication of infection in more than 80 percent of or both, patients. Symptomatic treatment with corticosteroids or surgical decompression, 207,215 may be necessary to control acute CNS symptoms and prevent tissue injury. Paragonimiasis and Fascioliasis Tissue trematodes (flukes) infect217 humans who consume larval metacercariae in undercooked Paragonimus species are endemic in areas of Asia and crustaceans or raw water plants. 217,218 but paragonimiasis has also been transmitted within the South and Central America, 219 United States. Fascioliasis is cosmopolitan in its distribution and is common to many sheep- and cattle-raising areas. Disease occurs as maturing larvae migrate through host tissues from the gastrointestinal tract to the lungs (paragonimiasis) or liver (fascioliasis). CNS disease is frequent in paragonimiasis but rare in fascioliasis, occurring when ectopic parasite 217,218 Presenting CNS syndromes may localization takes place within the brain or spinal cord. include acute and chronic meningitis, mass lesions, hemorrhage, infarction, or ocular abnormalities (papilledema, hemianopia, nystagmus,217and optic atrophy). Frequent symptoms include seizures, headache, and visual disturbance. Intellectual deterioration and vomiting may also be noted. Diagnosis depends on a positive exposure history, along with parasitological, serological, or 217 biopsy evidence of infection. Sputum examination for ova is appropriate for identification of
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the lung fluke Paragonimus westermani, the most common cause of paragonimiasis in Asia, whereas stool examination for ova is appropriate for identification of the liver fluke Fasciola hepatica. Radiographic examination of the lungs may show typical lesions of concurrent Paragonimus infection; retrograde cholangiography and bile duct aspiration may confirm exposure to or infection with liver flukes. Skull radiographs may show localized punctate or 220 nodular calcification. Neuroimaging studies may reveal ventricular dilatation and multiple lesions within brain tissues. In the CSF, examination often shows lymphocytic pleocytosis and elevated protein concentration, but eosinophils are found in less than 10 percent of CSF 221 samples examined. Effective therapies for CNS paragonimiasis or CNS fascioliasis are not established. A combination of 218,221 surgical removal of the parasite and praziquantel therapy has been Symptomatic therapy with corticosteroids, anticonvulsants, or ventricular recommended. shunting may be necessary. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 50 Neurological Complications of Vaccination ALEX C. TSELIS •
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Previous HISTORY OF VACCINES TYPES OF VACCINES COMPLICATIONS OF VACCINATION DETECTION OF VACCINE ADVERSE EVENTS Smallpox Measles, Mumps, and Rubella Measles Mumps Rubella Diphtheria, Pertussis, and Tetanus Diphtheria Pertussis Tetanus Influenza Hepatitis B Poliomyelitis
Yet it was with those who had recovered from the disease that the sick and the dying found most compassion. These knew what it was from experience, and had now no fear for themselves; for the same man was never attacked twice—never at least fatally. Thucydides, The Peloponnesian War: Plague of Athens, 430 bc Moreover, I have known certain persons who were regularly immune, though surrounded by the plague-stricken, and I shall have something to say about this in its place, and shall inquire whether it is impossible for us to immunize ourselves against pestilential fevers. Fracastoro, On Contagion, 1546 Infectious diseases have historically been the major cause of human morbidity and mortality. Vaccinations have added immeasurably to human health by preventing such diseases. The benefits of vaccinations have not come without some costs, however, and rare adverse
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effects of vaccines occur. Many important adverse events are neurological, and these are discussed in this chapter. In addition, the U.S. Centers for Disease Control and Prevention 1 (CDC) regularly update and publish useful summaries of vaccine recommendations. Table 50-1 shows a schedule for the routine immunization of healthy children and adolescents. Click here to view this table.... HISTORY OF VACCINES The idea of vaccination came from the observation that a survivor of “the plague” was unlikely to fall ill from that disease again. It had long been known that matter from smallpox lesions, when inoculated into the skin of a naive recipient, often caused a mild form of the disease and protected against the full disease. Lady Mary Wortley Montague, the wife of the British ambassador to Turkey, introduced this method, called variolation, to Europe in 1721. Variolation was not always safe and occasionally resulted in fully virulent smallpox. In 1798, Jenner used cowpox inoculation to protect against smallpox, which eliminated the possibility of transmitting fully virulent smallpox with variolation. The basic strategy of vaccination further developed with Louis Pasteur's first successful rabies vaccine, Max Theiler's yellow fever vaccine, and Jonas Salk's and Albert Sabin's polio vaccines. Other important vaccines include those against influenza, whooping cough (pertussis), diphtheria, tetanus, hepatitis B, measles, mumps, rubella, Haemophilus influenzae B, meningococcus, and varicella-zoster. Vaccines are available in Asia to prevent Japanese encephalitis and in Central Europe to prevent tick-borne encephalitis. TYPES OF VACCINES Vaccines are made up of relevant antigens presented to the immune system in a way that generates protective immunity against the fully virulent pathogen without causing disease. There are several types of vaccines with different mechanisms of action. These include inactivated, attenuated, subunit, recombinant, component, DNA, and vector vaccines. Inactivated vaccines consist of pathogens that have been treated by chemical or physical methods so that they are nonviable. These treatments generally modify viral proteins essential to some critical function, such as attachment of the virus to the cell. Nevertheless, in successful vaccines, these inactivated organisms have sufficient antigenicity that protective immunity is achieved. Examples of inactivated vaccines include influenza vaccine, the Salk polio vaccine, rabies vaccine, and the whole-cell pertussis vaccine. Attenuated vaccines use a virus (or other pathogen) that has been adapted to replicating in a different host system, such as tissue culture, or in chicken eggs. This is achieved by serially passaging the virulent (or wild-type) pathogen in an alternative host system. The pathogen is now “adapted” to the alternative host system and humans are an “unnatural host.” The agent is unable to express its full virulence and so causes a mild infection but still stimulates full immunity. An example of an attenuated vaccine is the combined measles, mumps, and rubella (MMR) vaccine. Subunit vaccines are composed of subunits of a pathogen that are both nontoxic and immunogenic. Hepatitis B vaccine is an example, as is acellular pertussis vaccine. Hepatitis B vaccine consists of hepatitis B surface antigen (HBsAg) that was originally purified from the plasma of hepatitis B carriers. Because of concerns about using human-derived material, the gene for hepatitis B surface antigen was introduced into yeast that then synthesized pure hepatitis B surface antigen. This is the first human recombinant vaccine. Component vaccines usually consist of the capsular material of common bacterial pathogens. Antibodies to the capsules allow opsonization of the organism. Examples of component vaccines are those to pneumococcus, meningococcus, and Haemophilus influenzae B. These vaccines are often not sufficiently immunogenic in very young infants and have to be specially formulated by conjugation to peptides, which enhance their antigenicity. Toxoid vaccines are bacterial toxins (diphtheria, tetanus) that have been rendered nontoxic, but not nonimmunogenic, by chemical treatment. DNA vaccines are DNA sequences of the gene for an immunogenic antigen and are injected into muscle where they direct the synthesis of the antigenic peptide. This is then presented to the immune system by the “infected” muscle cell, which mimics a natural infection. However, DNA vaccines have proved to be poorly immunogenic in humans and none are available for human use. Vector vaccines consist of a nonpathogenic virus, which has one of its genes replaced by a
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gene for an antigen of interest. Such vaccines are being investigated but are not yet available for human use. COMPLICATIONS OF VACCINATION As mentioned earlier, the benefits of vaccination come with a price. There are several ways that vaccinations can cause adverse effects. Most often, they induce a nonspecific inflammatory reaction with headache, malaise, mild fever, and pain at the injection site. This reaction is self-limited and needs no treatment beyond mild analgesics. More serious adverse effects include contamination of the vaccine with fully virulent virus, reversion of attenuated virus to a fully virulent form, contamination of the vaccine with previously unrecognized agents, the use of inappropriate antigens causing an aberrant immune response with injurious effects, and induction of an immune response with autoimmune character. Some adverse effects are of unknown mechanisms. Some vaccines have inadvertently contained fully virulent virus. In the so-called Cutter incident, inadequate inactivation of the virulent virus during manufacture of the vaccine occurred shortly after the introduction of the Salk inactivated poliovirus vaccine. Procedures for inactivation of the virus by treatment with formalin were not followed precisely. Some of the virus that went into the vaccine was fully virulent, causing cases of paralytic poliomyelitis. Reversion to virulent form occurs rarely with the use of the Sabin vaccine, which is an attenuated poliovirus vaccine. During replication of the virus, mutations that restore pathogenicity can occur rarely and result in vaccine-associated paralytic poliomyelitis. In some cases, the virulent vaccine virus spreads to the vaccinated person's contacts, and small outbreaks of polio can result. Contamination with previously unrecognized agents is an ever-present danger. There are numerous examples. In World War II, U.S. military personnel serving in the tropics contracted hepatitis after being vaccinated for yellow fever. The yellow fever vaccine, an attenuated vaccine, had human serum added to it for stabilization of the attenuated virus. Some of this serum had been obtained from carriers of hepatitis B. Another contaminant of yellow fever vaccine was avian leukosis virus, present silently in chicken eggs, which were used for growing virus for vaccine manufacture. The Salk polio vaccine virus was grown in monkey kidney tissue culture, which contained the SV40 virus in latent form, and the vaccine was thus contaminated with this agent. A more ominous example is that of the contamination of louping-ill vaccine, the virus of which was grown in the brains of sheep and given to animals in Britain. At least one of these sheep had scrapie and the vaccine was contaminated with scrapie prions. This resulted in an outbreak of scrapie in the vaccinated animals. As a consequence, the U.S. Food and Drug Administration (FDA) requires that any animal protein products used in the manufacture of vaccines is from countries certified to be free of bovine spongiform encephalopathy (BSE), which is known to be transmissible to humans. Inactivation of some viruses may render certain important antigens nonantigenic. For example, formalin-inactivated measles vaccine used in the 1960s provided short-term protection but in some cases resulted in “atypical measles,” an unusually severe form of measles often complicated by pneumonia. These patients were found not to have antibodies to the F (fusion) protein of the measles virus, so that the virus was able to spread by cell-to-cell fusion. It is thought that formalin renders the F protein nonimmunogenic, so that the spread of wild virulent virus infection is unchecked. Inappropriate immune responses are well recognized to occur after vaccinations, especially with vaccines made of viruses grown in neural tissue. The classic example is that of the old neurally derived rabies virus, which often resulted in “neuroparalytic accidents.” These were illnesses causing acute demyelination in either the central or peripheral nervous system. Thus, acute disseminated encephalomyelitis (ADEM) and Guillain–Barré syndrome (GBS), involving central and peripheral demyelination, respectively, have both been observed after the use of the older rabies vaccines. Other vaccines have also been thought to have a causal 2 connection to demyelination, but this is rare. Restricted forms of central demyelination, such as optic neuritis and transverse myelitis, have also been described but are rare enough that a causal connection is in doubt. Restricted peripheral forms of demyelination, such as brachial plexopathy, have also been reported. One of the mechanisms of demyelination by vaccines is that of molecular mimicry, in which antigenic epitopes in the vaccine resemble those in myelin. Although this mechanism of mimicry has not clearly been shown to act in central demyelination (except possibly for measles, as discussed later), neurally derived vaccines contain myelin antigens (rather than mimics) and can trigger such disease. It should be noted that peripheral demyelination is known to occur by this mechanism.
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An instructive example of demyelination triggered by a neurally based vaccine is that of rabies vaccine. The idea of using modified infectious material to protect from viral disease was adopted by Pasteur, who used attenuated rabies virus from infected rabbit spinal cord to protect dogs from rabies. His strategy was to take infected rabbit spinal cord and allow it to dry, which attenuated the virus present in the cord. The longer the desiccation, the more attenuated the virus became. Eventually, the virus was sufficiently attenuated that it was innocuous but sufficiently immunogenic that it could prevent infection by fully virulent virus. The vaccine was originally administered as a series of injections of ever less attenuated virus, the idea being to stimulate the immune system with more virulent and therefore antigenic virus. The original Pasteur vaccine was thus rather cumbersome to administer, with multiple painful injections, and frequently gave rise to “neuroparalytic accidents.” This phenomenon inspired experiments by Thomas Rivers, who showed that a similar central demyelination could be induced in monkeys by serial injections of sterile white matter; this was the origin of experimental allergic encephalomyelitis, a model now used to study multiple sclerosis. In order to minimize this complication of neurally based vaccines, vaccines were made from virus that was grown in myelin-free environments. Fuenzalida first produced a myelin-free vaccine in 1956 by propagating virus in neonatal mouse brains, which still contained neural antigens. The first non-neural tissue-based vaccine was the duck embryo vaccine (DEV), in which vaccine virus was propagated in duck eggs. Human cells were used to develop rabies vaccines free of animal proteins, and the human diploid cell vaccine (HDVC), the contemporary standard, was first developed in the early 1960s. Very few “neuroparalytic accidents” have occurred with the current neural antigen-free vaccines. Thus, the more free the vaccines were of neural tissue, the lower was the risk of a “neuroparalytic accident.” In some parts of the world, however, the cheaper neural-based vaccines are still used. Some adverse events are of unknown mechanism. For example, rare episodes of intussusception were reported several years ago after administration of rotavirus vaccine, with 15 cases occurring with administration of 1.5 million doses, leading to that vaccine's 3 withdrawal. DETECTION OF VACCINE ADVERSE EVENTS Detection of vaccine adverse events can be difficult as they are uncommon and often manifest as illnesses that are known to occur in the unvaccinated. Many of these illnesses are not reportable to health departments. However, health officials will take note of an unusually high incidence of disease and launch an investigation. Surveillance for any unusual disease activity can be active or passive. Active surveillance is when cases are actively sought by sending questionnaires to physicians' offices and hospitals or systematically examining records at hospital records rooms. Passive surveillance occurs when physicians or the public send unsolicited information about cases to health department officials. Passive surveillance provides very limited epidemiological information, as it does not indicate the proportion of those with the complication who were actually reported (no numerator information) and how many were actually exposed to the vaccine (no denominator information); furthermore, the clinical details are often insufficient to make a secure diagnosis. Case reports and case series of illnesses following a vaccination may be published, but it is difficult to establish causality on this basis and, in fact, such reports may be misleading. The older literature is replete with case reports of some illness following a vaccination, but a causal connection is never made, and these cases remain curiosities. Certain reports have generated considerable controversies that have led to a decrease in vaccine coverage and to outbreaks of disease. This points to the necessity of performing controlled studies that can address the issue of causality. Analytical population-based studies, comparing vaccinated and nonvaccinated subjects, can, with proper statistical analysis, be quite conclusive about etiological links between a vaccination and an illness. An example would be the analysis of data from patients with Guillain–Barré syndrome that was linked to the influenza vaccine used in 1976. This is discussed later. Randomized, double-blind, placebo-controlled trials of vaccines are required as part of the U.S. Food and Drug Administration approval process and are very reliable, but only common adverse events can be found by this method. The Vaccine Adverse Event Reporting System (VAERS) is a passive surveillance system in which a complication is reported to the U.S. Food and Drug Administration by sending in a completed hard copy form or submitting the information on a Web site form. Another passive surveillance system consists of the National Vaccine Injury Compensation Program (NVICP), which compensates individuals who have
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had a serious and permanent adverse effect from a vaccine and who meet other criteria. The establishment of extensive databases provides a new resource for vaccine safety studies. The U.S. Centers for Disease Control and Prevention is operating a Vaccine Safety Datalink (VSD) project, which links to the databases of eight health maintenance organizations that together have 6 million individuals as members. This database4 has been used for a number of population-based studies, including vaccine safety studies. General information on vaccinations is available from various Web sites (Table 50-2). Click here to view this table....
Smallpox Smallpox (or variola) is a highly contagious disease caused by a double-stranded DNA virus 5 that is airborne. Smallpox is mostly of historical significance at this time, but its potential as a weapon of biowarfare has drawn public health interest in smallpox vaccination issues. The illness begins abruptly with headache, fever, and back pain followed by a characteristic rash. The rash begins on the face, followed by the arms and legs, and finally spreads to the torso. The rash begins with scattered macules and evolves into papules, vesicles, and finally pustules that then dry and crust over. The patient ceases to be contagious after the crusts fall off. There are two broad forms of the disease: the severe form, variola major, which had a mortality rate of about 30 percent, and a milder form, variola minor (alastrim), with a mortality rate of approximately 1 to 5 percent. There are several types of variola major, with the hemorrhagic smallpox form of the disease having a mortality of nearly 100 percent. The original smallpox vaccination (variolation) involved the transfer of material from smallpox pustules or crusts into a scratch in the skin of the subject to be vaccinated. This often resulted in a milder form of the disease, presumably because the preparation of the material from the smallpox lesions attenuated the smallpox virus contained therein. Variolation thus is the first example of an attenuated vaccine. However, the attenuation was often inadequate and some recipients developed full-blown smallpox. Jennerian vaccination uses an animal poxvirus to induce cross-protective immunity against smallpox. However, the actual modern vaccine virus is not cowpox but vaccinia, a related virus. At what point cowpox was replaced by vaccinia or whether the original “cowpox” was some mixture of cowpox and vaccinia viruses is unknown. 6
Vaccinia is quite reactogenic and has a spectrum of systemic complications. These include nonspecific malaise and fever, as well as a number of skin reactions including urticaria, erythema multiforme, bacterial infection of the injection site, and progressive vaccinia infection, which occurs in the immunosuppressed and can be fatal. A few cases of mild myopericarditis have been reported in civilian and military vaccinees, with resolution and return to active duty in 7 to 10 days. Neurological complications are uncommon, but well reported. An idea of the neurological complications of smallpox vaccination with vaccinia can be gained by a report from South Wales in which a large population was vaccinated against smallpox as a result of an epidemic in 1962. More than 800,000 individuals were vaccinated with 7 1,300,000 vials of vaccine, and 39 cases of neurological illness ensued. There were 30 cases of central nervous system (CNS) disease: postvaccinal encephalomyelitis (11 cases), postvaccinal encephalopathy (3 cases), meningism/aseptic meningitis (7 cases), epilepsy (3 cases), and focal lesions of the brain and spinal cord (6 cases). There were 9 cases involving the peripheral nervous system: polyneuritis (5 cases), brachial neuritis (2 cases), and myasthenia gravis (consisting of a relapse in preexisting illness (2 cases). The incidence of neurological complications was thus on the order of 5 per 100,000 subjects vaccinated, and the risk of encephalitis-encephalopathy roughly 2 per 100,000 vaccinations. More recent series suggest that postvaccinal encephalitis is less common. In a literature review of the complications of smallpox vaccination, Fulginiti and associates found postvaccinial encephalomyelitis occurring in 2 to 6 per million primary vaccinees, depending 6 on age. They noted that the risk in Europe was much higher, as high as 1 in 4,000, presumably because a different strain of vaccinia virus was used there. There have been rare reports of isolation of vaccinia virus in the cerebrospinal fluid (CSF) in cases of encephalitis following vaccination. The overall death rate from all causes following smallpox vaccination was 0.5 to 5 per million vaccinees.
Measles, Mumps, and Rubella Measles, mumps, and rubella were once common childhood illnesses in the developed world,
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but they became rare after the introduction of vaccines that prevent them. These vaccines are commonly given together in combination as MMR vaccine. This minimizes the number of injections to which small children are subjected. Formulations containing only some of these have been used in the past: measles (M) vaccine and measles plus rubella (MR) vaccine. Measles Measles is a viral exanthem caused by an enveloped single-stranded RNA virus that is transmitted through the air and initially infects the respiratory epithelium, where it replicates. This gives rise to a primary viremia that implants virus in lymphoid tissues. A secondary viremia follows, and the virus is disseminated throughout the body. During measles, a significant distortion of the immune system occurs, with paradoxical features. There is a nonspecific systemic immune activation, along with immunosuppression, causing susceptibility to bacterial and viral superinfections. The latter are the main causes of morbidity and mortality and are enhanced by malnutrition, making measles a major cause of death in developing countries. The main complication of measles is pneumonia, which is usually due to bacterial superinfection in children and to direct measles virus infection of the lungs in adults. Pneumonia occurs in roughly 10 percent of patients and causes more than 60 percent of the mortality resulting from the disease. Other complications include otitis media and laryngotracheobronchitis. The main neurological complication of measles is ADEM, in which there is acute multifocal inflammatory demyelination, occurring in roughly 1 per 1,000 cases. This may actually be due to molecular mimicry, since T cells from measles-associated ADEM patients proliferate on exposure to myelin basic protein, whereas cells from patients with uncomplicated measles do not. The mortality rate of ADEM is between 10 and 30 percent, and sequelae are common 2 and severe. Measles virus was first isolated and propagated in tissue culture by Enders and Peebles in 1954, and efforts at making measles vaccine followed shortly thereafter. The first vaccines were made from the Edmonston B strain. It is instructive to review the process by which the virulent virus is attenuated. The Edmonston B strain, the actual strain used in the vaccine, was obtained from the original Edmonston isolate (named after the individual from whom it was first obtained) by serial passage in primary kidney cells (24 passages), primary human amnion cells (28 passages), chicken embryos (6 passages), and then in chicken embryo cells. This vaccine was first introduced in 1963, but the high rate of fever and rash prompted its discontinuation. Other vaccine strains were available and less reactogenic. One of these, the Moraten strain, introduced in 1968, was derived from the Edmonston B strain by a further 40 passages in chicken embryo cells. Another strain, the Schwarz strain, was obtained from the Edmonston B strain by a further 85 passages in chicken embryo cells and was used from 1965 to 1976. The Moraten vaccine is the only one used in the United States today. Other vaccine strains are used elsewhere in the world. The effectiveness of vaccination may be gauged from the fact that before vaccination, 4 million cases of measles occurred annually in the United States, whereas there were only 309 cases in 1995. Neurological complications of measles vaccination have been reported but are uncommon. Case reports of encephalopathies are not uncommon, but do not, by themselves, provide evidence of causation. In order to better understand the risk of adverse events to measles vaccine, Weibel and co-workers analyzed data from claims of measles vaccine-induced 8 encephalopathy submitted to the National Vaccine Injury Compensation Program. In the years 1970 to 1993, 403 claims of postvaccination encephalopathy were made and reviewed in their study. The inclusion criteria included an acute encephalopathy 2 to 15 days after vaccination (M, MR, MMR) leading to permanent brain damage or death, with no other known cause that would explain the illness. Of these cases, 48 met the criteria. The mean age of the cases was 17.5 months (range, 10 to 49 months). There were three main groups of complications, with ataxia in 6, behavioral changes in 8, and seizures in 34. Fever preceded the encephalopathy in most, and one quarter of the cases had a measles-like rash that occurred 1 or 2 weeks after vaccination. Cerebrospinal fluid was analyzed in most children and was abnormal in 40 percent: pleocytosis was present in 70 percent (range, 7 to 246 cells/ml), and protein was elevated protein in more than one third (range, 117 to 172 mg/dl). No other viruses were present. When the number of patients with encephalopathy was plotted against the day of onset, a typical epidemic curve was obtained, with a peak at 8 to 9 days, suggesting a causal (rather than merely temporal) connection between the vaccination and the neurological illness. A mere temporal, noncausal relationship would show no such peak since cases would occur at random after the vaccination.
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The final outcomes in these groups were as follows. In the group with acute ataxia, mental retardation occurred in three, a seizure disorder in one, chronic ataxia in four, and sensorineural hearing loss in one. In the patients with initial behavioral change, the outlook was rather more negative, and all rapidly progressed to coma, with two deaths. In the seizure group, there were two immediate deaths, and all survivors had chronic encephalopathy; there were three delayed deaths occurring 3 months to 4 years later. In one case, the autopsy showed cerebral edema with uncal herniation, and in the other, a “viral encephalitis” with hemorrhagic infarctions of the thalamus and pons. The risk of neurological illness can be estimated from the fact that from 1970 to 1993, approximately 75 million children had measles vaccine by age 4 years, based on a 90 percent immunization rate and 83 million births. The limits of risk are, based on 48 claimants meeting criteria and on all 403 claimants, 0.64 to 5.37 cases per million vaccinees. In a study of 1.8 million Finnish MMR vaccinees, actively surveyed from 1982 to 1996, adverse events were tabulated and analyzed. Of 173 potentially serious reactions reported, 77 were neurological and consisted mostly of febrile seizures, with good recovery. One patient later developed Lennox–Gastaut syndrome. Four cases of encephalitis were reported, one of which was due to herpes simplex. The others were uncharacterized. Various other neurological complications were due to other known causes (such as bacterial meningitis). Miscellaneous other cases of Guillain–Barré syndrome (two patients with eventual recovery), transient confusion, and transient ataxia were noted. Interestingly, no cases of autism were 9 found. Recently, measles vaccine has been proposed as a cause of autism, a complex (and probably heterogeneous) neurobehavioral syndrome. Much discussion has been stimulated by a report of 12 children who developed cognitive problems as well as inflammatory bowel 10 disease a few days to a few months after receiving MMR vaccine. However, the ages at which MMR vaccine is given are also the ages when autism manifests clinically, although 11 there is evidence that the beginnings of the disease occur well before birth. Furthermore, there was no population-based study with controls to estimate the relative risk of autism 12 following vaccination. A report from the Institute of Medicine reviewed published and unpublished reports concerning the issue of MMR vaccine13and concluded that there is no clear causal connection between the vaccine and autism. Certainly, autism and inflammatory bowel disease existed well before MMR vaccine was developed, so the vaccine cannot be the sole cause of these disorders. Another hypothesis is that autism was caused in especially susceptible subjects by thimerosal, a mercury-containing preservative that was used in vaccines. The review of the literature cited previously also showed no clear causal connection between thimerosal and autism, and, in any case, thimerosal is no longer used in childhood vaccines. Mumps Mumps is an acute febrile illness caused by rubulavirus, in the paramyxovirus group. The clinical illness in children usually is self-limited, with fever, malaise, headache, and often an acute painful parotitis. The disease can occasionally be complicated by meningitis and rarely by meningoencephalitis, with residual deficits. Sensorineural deafness is an uncommon sequela but can be a major cause of deafness in children during epidemics. In adults, mumps has a higher rate of systemic complications such as orchitis in men and oophoritis and mastitis in women as well as pancreatitis and myocarditis. The main original vaccine virus strains were named the Jeryl Lynn and Urabe strains, after the hosts from which the original unattenuated viruses were isolated. The Jeryl Lynn strain vaccine was tested in two clinical trials, one in Philadelphia nursery school and kindergarten children in 1965 to 1967 and one in schoolchildren from Forsyth County, North Carolina, in 1966 to 1967. Mumps vaccine was first licensed for use in 1967. The number of cases of mumps in the United States was 152,209 in 1968 and decreased to 2,982 in 1985. The number of cases increased briefly after vaccination rates declined but decreased again after mumps vaccination was required for school entry to 751 cases in 1996. Aseptic viral meningitis is the main neurological complication of mumps vaccination and is probably because natural mumps is frequently accompanied by meningitis. The Urabe strain vaccine was discontinued in the United States after it was linked to aseptic meningitis occurring in141 case in 900 vaccinees in one Japanese series to 1 case in 200,000 vaccinees. For the Jeryl Lynn vaccine, the incidence is 1 case in 1.8 million vaccinees. By 14 comparison, aseptic meningitis occurs in approximately 1 in 400 cases of natural mumps. The aseptic meningitis is self-limited.
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Rubella Rubella is a self-limited viral infection in children, with a fever and rash, caused by a single-stranded RNA virus. The virus causes most of its damage by prenatal infection. The congenital rubella syndrome is well described, and the triad of neurological, eye, and cardiac defects is characteristic. The disease also includes a spectrum of disease, including thrombocytopenic purpura, hepatitis, bone lesions, interstitial pneumonitis, diabetes mellitus, 15 and thyroid problems. The vaccine has very few complications in children, with rare mild rash and fever. In adults, the most common side effect is polyarthralgias. A few scattered reports of peripheral mononeuropathies and radiculopathy following rubella vaccination have 16 been published, but a review of these could not establish a causal relationship.
Diphtheria, Pertussis, and Tetanus Diphtheria Diphtheria is a disease caused by strains of Corynebacterium diphtheriae, which make diphtheria toxin, a binary toxin consisting of two molecular components: fragments A and B. Fragment B binds to the target cell and allows access of fragment A to the cytoplasm. Fragment A inactivates elongation factor-2 (EF-2), inhibiting protein synthesis in the cell, causing necrosis. Usually diphtheria infects pharyngeal epithelium, where the superficial layers of the mucosa become necrotic and provide an excellent culture medium for the bacteria. These areas of tissue necrosis with exudation form the so-called diphtheritic “membranes.” Systemic absorption of diphtheria toxin from the pharynx causes cardiac and neurological effects. Patients with diphtheritic myocarditis may develop congestive heart failure, with abnormal electrocardiograms showing heart block. Pathological examination shows interstitial inflammation and hyaline degeneration of fibers. Diphtheritic “neuritis” includes several entities, including an isolated paralysis of soft palate, ocular motor palsies, paralysis of the diaphragm, and a disorder resembling the Guillain–Barré syndrome. The pathogenesis of these various disorders is not understood. In the 1920s, before diphtheria toxoid was introduced, there were approximately 100,000 cases in the United States annually. In the past few decades, no more than a handful of cases has occurred each year. The importance of vaccination is illustrated by the fact that when vaccine coverage decreases, large epidemics of the disease follow, as happened in Russia in the 1990s, when the public health infrastructure could no longer cover the population adequately. The mortality rate of the untreated disease is very high: 30 to 50 percent of cases. After the introduction of antitoxin therapy, the mortality rate declined to 10 to 20 percent of cases; modern intensive care has reduced this to 5 to 10 percent. Originally, vaccination against diphtheria was undertaken by injecting mixtures of toxin and antitoxin. In the early 1920s, it was found that treatment of diphtheria toxin with formalin resulted in a nontoxic immunogenic toxoid. This was incorporated with tetanus toxoid and inactivated whole-pertussis cells, and diphtheria-pertussis-tetanus (DPT) vaccine was marketed to the public in the mid-1940s. There have been remarkably few neurological complications from diphtheria toxoid, although they may be difficult to discern, as the toxoid is usually given in combination with pertussis and tetanus vaccines. Local injection-site reactions can be painful as they are intramuscular; infants may react with prolonged crying, irritability, drowsiness, loss of appetite, and vomiting, and limitation of abduction of the injected arm may occur regardless of age. Pertussis Pertussis, or whooping cough, is caused by Bordetella pertussis, a commonly circulating bacterium that has multiple antigenic components. The disease begins with a seemingly minor upper respiratory infection, with minimal fever and an intermittent cough that becomes severe and progresses to paroxysms in which coughing becomes very vigorous, interfering with breathing and increasing intracranial pressure by a continual Valsalva maneuver. The paroxysmal stage lasts between 2 and 6 weeks before resolving. The disease was commonly lethal in the past. At the beginning of the 1900s, approximately 5 of every 1,000 liveborn infants died of pertussis before 5 years of age. Today, there are fewer than 10 deaths per year in the United States. When vaccine coverage declines, the disease reemerges because pertussis vaccine protects against bacterial toxins but does not necessarily eliminate the pathogen from the population (unlike smallpox, for example). Indeed, decreases in vaccine coverage of a population are commonly followed by outbreaks
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of the disease. The pathogenesis of the disease is not completely known, but is likely due to a toxic effect on respiratory epithelium with denudation of respiratory passages. An important complication of pertussis is pertussis encephalopathy. This is a vaguely described syndrome of encephalopathy and seizures occurring in 0.08 to 0.8 per 1,000 cases, with the youngest infants at highest risk. In the years 1997 to 2000, pertussis 17,18 encephalopathy and seizures occurred in 0.1 and 0.8 percent of cases, respectively. There appear to be two clinical forms, one with an abrupt onset of seizures and coma and the other with the gradual onset of somnolence progressing to coma. The prognosis appears to be rather poor,19with death, permanent cognitive deficits, and recovery each occurring in one third of cases. The pathological changes are characterized by congestion and brain petechiae, but the pathogenesis is unclear and may involve the effects of anoxia and increased venous pressure in the brain from the Valsalva maneuver caused by the severe cough. A toxic element may relate to bacterial toxins or cytokines, although intravenous injection of toxin does not appear to cause neurological complications. Pertussis vaccine has dramatically decreased the burden of disease in vaccinated populations; it declined from about 200,000 cases in the United States in the mid-1930s to a nadir of 1,010 cases in 1976, with a subsequent increase to about 8,000 cases occurring in 2000 for unclear reasons. The original vaccine consisted of inactivated whole bacterial cells. Whole-cell vaccine is reactogenic, causing painful local injection-site reactions and fever. The latter can lead to febrile seizures in children, who are an especially susceptible population. This triggered reports of severe neurological illnesses following pertussis vaccination. To ascertain the risk of neurological illness attributable to pertussis vaccine, an active survey of encephalopathic illnesses was performed in all British children from July 1976 to June 20 1979 in the National Childhood Encephalopathy Study (NCES). A comparison was made of rates of vaccination in those who had or did not have an encephalopathy. The first 1,000 cases of encephalopathy were tabulated and were compared with two matched controls per case. Of the 1,000 cases, 35 had pertussis vaccine, whereas of the 2,000 controls, 34 had pertussis vaccine within 7 days. Thus, within 7 days, encephalopathy occurred in 3.5 percent (35 of 1,000) of cases, whereas the background rate of having been vaccinated in the previous 7 days was 1.7 percent (34 of 2,000) of controls, giving a risk ratio (RR) of 2.4 (P < 0.001). Within 72 hours of vaccination, encephalopathy occurred in 2 percent (20 of 1,000) of cases, with a background vaccination rate of 0.9 percent (18 controls) (RR = 2.6; P < 0.01). All vaccines with a pertussis component, for example, pure pertussis vaccination, DPT vaccination, and diphtheria-pertussis (DT) vaccination, were counted as pertussis vaccination. The 35 cases of encephalopathy following pertussis vaccination were divided into three groups: group A consisted of those who were normal before and at 15 days after vaccination, group B consisted of those normal before but abnormal 15 days after vaccination, and group C were those abnormal before and after vaccination. There were 20 cases in group A, with convulsions in 12, encephalopathy in 4, infantile spasms in 3, and acute infantile hemiplegia in 1. In group B, there were 12 cases, with prolonged convulsions in 2, encephalopathy in 6, infantile spasms in 3, and Reye's syndrome in 1. In group C, there were three cases, all with prolonged convulsions. The ultimate outcomes at 1 year of these cases differed in the three groups. In group A, 18 cases were normal, and one each had a minor or major delay. In group B, four had minor delay, five had major delay, and two died. Thus, the risk of neurological adverse events after pertussis vaccination was small, and the prognosis was dictated by the patient's condition at 15 days. Patients who were normal at 15 days would likely be normal at 1 year, whereas an abnormality at 15 days implied a negative outcome at 1 year. The estimated attributable risk of a serious neurological disorder at 7 days after DPT vaccination is 1:110,000 injections, with a 95 percent confidence interval (CI) of 1:360,000 to 1:44,000. A new acellular vaccine consisting only of a subset of antigenic components of the bacterial 21 cell was introduced in 1996 and appears to be much less reactogenic. Tetanus Tetanus is a neurological disease caused by Clostridium tetani, which is present ubiquitously in soil. The organism has two toxins carried on a plasmid, namely, tetanospasmin, the neurotoxic component, and tetanolysin, which is a hemolysin. Tetanospasmin is elaborated locally and transported to the CNS by both blood and local axonal transport. It interferes with release of the presynaptic inhibitory neurotransmitters glycine and γ-aminobutyric acid (GABA), causing inappropriate disinhibition of spinal cord reflex arcs, with greatly increased tone in the muscles and intermittent painful spasms. Respiratory compromise may lead to a
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fatal outcome. The toxin is very potent: the lethal dose is 2.5 ng/kg. The case fatality ratio of the untreated disease is 25 to 70 percent overall and 100 percent at the extremes of age. With intensive care, the mortality rate decreases to 10 to 20 percent. Tetanus toxoid consists of formalin-treated tetanospasmin, which induces an immune response that provides good protection lasting 10 years. Adverse events are rare and are 22 mostly anecdotal. Brachial plexopathy occurs in 1:100,000 vaccinees within 1 month of vaccination, and there may be a slightly increased risk of Guillain–Barré syndrome (0.4 per million doses). One person had an illness resembling Guillain–Barré syndrome on each of three vaccinations with tetanus toxoid. There is some tantalizing evidence that tetanus toxoid 23 decreases the risk of multiple sclerosis.
Influenza Influenza is an acute, febrile, debilitating viral infection of the upper respiratory tract that causes significant work and school absences each year. It can be complicated by pneumonia and, rarely, by ADEM. In children, the complications of influenza or its treatment include encephalopathies such as Reye's syndrome as well as a toxic encephalopathy of unclear nature, possibly related to cytokine production in the course of disease. The virus was first isolated in 1933 by Smith, Andrewes, and Laidlaw. In 1935, neutralizing antibodies were detected in subjects given subcutaneous injections of influenza virus. The first trial of an influenza vaccine demonstrated some degree of protection in 1936. The virus was grown in a suspension of mouse lung and injected into children. Further studies of influenza vaccination using inactivated influenza virus were carried out by the military in the early 1940s and the benefit of the vaccine was clear-cut. This led to the licensing of influenza vaccines in the United States in 1945. In 1947, a dramatic failure of the vaccine during an influenza epidemic led to the discovery that the vaccine produced immunity to the vaccine virus but not to the epidemic strain. This was the result of antigenic change in influenza virus. Such change can be of two types: (1) antigenic drift, in which the accumulation of mutations in the genes coding for the surface antigens of the virus renders it sufficiently different from the previous strains so that it can cause disease despite exposure to the previous virus and (2) antigenic shift, in which there is reassortment of genes coding for the surface proteins from viruses circulating between birds and pigs. This experience led to the establishment of worldwide sentinel centers by the World Health Organization, which monitor for new strains of influenza virus every year, so that the new strains can be incorporated into the updated vaccine. This is an important activity because new pandemics are expected to occur in the future. The recent circulation of the H5N1 strain in Southeast Asia is of great concern because of the highly lethal nature of the disease and its potential for human-to-human transmission. Current vaccines use two strains of influenza A and one influenza B virus, all grown in embryonated chicken eggs and inactivated with betapropiolactone. In 1975, a fatal case of swine flu in a military recruit prompted the institution of a national swine flu vaccination program in 1976 to 1977 because of the fear that this would resemble the 1918 influenza epidemic that caused such widespread mortality. The vaccine was produced and 45 million doses were administered by mid-December 1976. In late November and early December 1976, cases of Guillain–Barré syndrome were reported to local health departments and prompted an investigation of the relationship to the flu vaccine. Langmuir and co-workers investigated the results of an active surveillance of all such cases reported during the period of vaccination, prompted by reports of a possible causal connection and requested by a court in which a lawsuit had been filed. The study uncovered 1,300 possible 24 cases, of which 944 could be evaluated. There were 504 cases in vaccinees and 440 cases in nonvaccinees. Although the data were insufficient to diagnose Guillain–Barré syndrome definitively, the cases could be classified as to the extent of involvement into “extensive” and “limited” paresis. When the distribution of cases was plotted as a function of time since vaccination, the “extensive” cases followed a typical log-normal epidemic curve, whereas cases of limited paresis showed no such curve. This implies a causal relationship between vaccination and Guillain–Barré syndrome in a small number of cases. The effect of the vaccine lasted 6 to 8 weeks. The actual risk of Guillain–Barré syndrome attributable to vaccine was 4.8 to 5.9 per million vaccinees. Interestingly, no such increased risk was found in England and25,26 the Netherlands, as well as in 1.7 million U.S. military personnel who received Furthermore, there was no increased risk27of Guillain–Barré syndrome a double dose. to 1980 and 1980 to following influenza vaccination in the 1978 to 1979 seasons, the 1979 28 29 1981 seasons, and the 1992 to 1993 and 1993 to 1994 seasons. Despite a theoretical concern for the safety of influenza vaccines in patients with multiple sclerosis and central demyelination, it appears to be quite safe. There was no increase in the onset or relapses of multiple sclerosis in a retrospective study after swine flu vaccine, which
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is known to be associated with peripheral demyelination (albeit weakly). There were no 31 increases in relapse rate in a double-blind trial involving 66 patients with multiple sclerosis. Non–swine influenza vaccines are safe to use in multiple sclerosis. A case-control study of influenza vaccine done by the Vaccine Safety Datalink study group showed that influenza 32 vaccination was not associated with either multiple sclerosis or optic neuritis. In fact, the study showed no association between vaccination against hepatitis B, tetanus, measles, or rubella and either multiple sclerosis or optic neuritis. After a review of controlled studies looking at the risk of relapse of multiple sclerosis after influenza vaccination, the Immunization Safety Review Committee of the Institute of Medicine concluded that there was sufficient evidence to reject any causal relationship between such relapses and influenza 26 vaccination.
Hepatitis B Hepatitis B is caused by a hepadnavirus, a partially double-stranded DNA virus, which is endemic worldwide, especially in sub-Saharan Africa and Southeast Asia. The virus is present in blood and semen and can thus be transmitted sexually and through inadequately processed blood products. The disease is usually self-limited in adults, with a clinical spectrum of asymptomatic infection to severe disease, followed by resolution and clearance of virus. However, in infants and children (80% to 90% of those infected before 1 year) as well as in some adults (approximately 5% of those infected), the acute infection is often asymptomatic but evolves into a chronic active hepatitis, with progression to cirrhosis and hepatic carcinoma. In highly endemic areas such as sub-Saharan Africa and Southeast Asia, this is one of the most common cancers, leading to significant mortality. In 1991, two cases 33 of central demyelination were reported after receipt of recombinant hepatitis B vaccine, one being in a patient with preexisting multiple sclerosis. A report of eight patients with disseminated central demyelination with persisting activity on imaging 34 studies was published in 1999. This report occasioned much controversy in France, and other cases were subsequently reported, but calculations of the expected number of new cases of multiple sclerosis (1 to 3 per 100,000 annually) showed that the disease incidence in the vaccinees (0.65 per 100,000 annually) was actually less than would have been expected, 35 so that the risk of multiple sclerosis following vaccination is unlikely to be increased. More detailed comparisons were done in several studies. A population-based retrospective cohort study of 134,698 members of several health maintenance organizations compared the rate of CNS demyelination in hepatitis B vaccinees with that in nonvaccinees and found no 36 difference between them. In a case-control study from British Columbia, the rates of development of multiple sclerosis in adolescents vaccinated against hepatitis B in the years 1992 to 1998, after universal hepatitis B vaccination became available, were compared with those not vaccinated (in the years 1986 to 1992, before the vaccine was available). There 37 was no statistically significant difference between the two groups. A multicenter hospital-based study in France enrolled 402 cases of central demyelination and 722 controls. The odds ratio of a first CNS demyelinating event within 2 months of vaccination was 1.8 (95% CI: 0.7 to 4.6). For confirmed multiple sclerosis, the odds ratio was 2.0 (95% CI: 0.8 to 5.4). It was concluded that there was no evidence of a strong association between central 38 demyelination and receipt of hepatitis B vaccine. There is thus little evidence of causality between hepatitis B vaccination and multiple sclerosis. Other studies showed no evidence 39 that hepatitis B vaccine triggered relapses in patients with established multiple sclerosis.
Poliomyelitis Poliomyelitis caused by poliovirus type 1, 2, or 3 usually is asymptomatic or consists of a mild febrile illness in early childhood. In older children, adolescents, or adults, the febrile illness may be accompanied by damage to the anterior horn cells in the spinal cord. The disease is spread by fecal-oral contact and caused considerable morbidity before the Salk vaccine. Early attempts at vaccination in the 1930s were disastrous: inadequate attenuation of the virulent virus led to polio in recipients (there was no test for attenuation of viruses), different serotypes were unknown and therefore not protected against, and there were no safety precautions against injecting neurally derived material. In the Cutter incident that was associated with Salk inactivated vaccine, 260 vaccinees and contacts contracted polio. These cases were thought to be related to the vaccine because they occurred in just a few Western states, all were injected by vaccine supplied by a single manufacturer (Cutter Laboratories), the injected extremities were disproportionately affected, and the cases were traced to lots that were found to be inadequately attenuated.
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The Sabin oral vaccine consists of attenuated virus that replicates in the gut and induces immunity in both the vaccinee and contacts (because the vaccinee sheds vaccine virus). Rarely, however, the virus reverts to a virulent form and may cause vaccine-associated paralytic poliomyelitis (VAPP) in 1 per 1 million doses in vaccinees or their contacts. Because the only polio seen in North America was vaccine associated, the Sabin vaccine was withdrawn from use in 1994. It is still in use in other parts of the world and has occasionally caused small epidemics of paralytic disease, with a recently reported outbreak occurring in 40 China in 2004. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 51 Sarcoidosis of the Nervous System ALLAN KRUMHOLZ • BARNEY J. STERN •
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SARCOIDOSIS PATHOPHYSIOLOGY EPIDEMIOLOGY NEUROLOGICAL MANIFESTATIONS Cranial Neuropathy Meningeal Disease Hydrocephalus Parenchymal Disease Endocrine Disorders Mass Lesions Encephalopathy-Vasculopathy Seizures Myelopathy Peripheral Neuropathy Myopathy NEUROPATHOLOGY DIFFERENTIAL DIAGNOSIS Presence of Systemic Sarcoidosis Diagnosis of Neurosarcoidosis TREATMENT Cranial Neuropathy Peripheral Facial Palsy Other Cranial Nerve Palsies Aseptic Meningitis Hydrocephalus Parenchymal Disease Peripheral Neuropathy and Myopathy GENERAL SUPPORTIVE CARE ALTERNATIVE TREATMENTS PROGNOSIS
Sarcoidosis was first described in 1877 by Sir Jonathan Hutchinson as a disease of the 1,2 skin. At the turn of the century, Caesar Boeck termed the disease multiple benign sarkoid, because of its histological similarity to sarcoma, and from this is derived the modern term
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sarcoidosis. Boeck also demonstrated the unifying feature of sarcoidosis as epithelioid cell granulomas that could involve different organs, a view that remains the basis of current thinking. Sarcoidosis is today recognized as a multisystem granulomatous disorder of unknown etiology. Typical presentations include bilateral hilar adenopathy, pulmonary 4 infiltration, and skin and eye lesions. Neurological involvement in sarcoidosis was first reported in the early 1900s by Heerfordt, 5 who described patients with cranial nerve palsies. Neurological manifestations—or neurosarcoidosis—are now recognized to occur in about 5 percent of patients with sarcoidosis and are varied. In addition, neurological manifestations are the presenting feature 6,7 of sarcoidosis for approximately 50 percent of these patients. Neurosarcoidosis manifests in diverse ways, including with cranial neuropathies, aseptic meningitis, mass lesions, encephalopathy-vasculopathy, seizures, hypothalamic-pituitary disorders, hydrocephalus, 8–11 Because its neurological myelopathy, peripheral neuropathy, and myopathy. manifestations are so diverse, its etiology is unknown, and confirmative laboratory tests are lacking, neurosarcoidosis poses major clinical challenges. The diagnosis of neurosarcoidosis is usually based on the identification of a characteristic neurological presentation in an individual with systemic sarcoidosis, as suggested by clinical and imaging findings and confirmed by examination of appropriate pathological specimens. Treatment of neurosarcoidosis is frequently a challenge. Although corticosteroids are regarded as the keystone of treatment, they are not always successful and have serious side effects. Moreover, some patients with neurosarcoidosis are refractory to conventional 6,7,12,13 Optimal management of patients with therapy, and approximately 5 to 10 percent die. neurosarcoidosis requires an understanding of the broad clinical spectrum of systemic sarcoidosis and neurosarcoidosis, appreciation of the best ways of confirming the diagnosis, and awareness of the full range of treatment options. SARCOIDOSIS The first internationally accepted definition of sarcoidosis was proposed in 1975 and remains of value today. It states: “Sarcoidosis is a multisystem granulomatous disorder of unknown etiology, most commonly affecting young adults and presenting most frequently with bilateral hilar adenopathy, pulmonary infiltration, skin or eye lesions. The diagnosis is established most securely when clinical and radiographic findings are supported by histologic14evidence of widespread noncaseating epithelioid-cell granulomas in more than one organ.…” Sarcoidosis usually presents between the ages of 20 to 40 years. However, it also occurs in 15 children and older populations. It appears to have similar clinical manifestations in all age groups. Intrathoracic structures are most commonly affected (87% of patients), followed by lymph node, skin, and ocular disease in 15 to 28 percent of patients (Table 51-1). Although it is generally understood that a diagnosis of sarcoidosis is most secure when it is based on histological confirmation, on average 30 percent of the patients described lack histological 16 confirmation, and the diagnosis is often based solely on clinical and radiological findings. Click here to view this table.... Involvement of any organ by sarcoidosis is possible and may occur with or without major symptoms. Sarcoidosis may be asymptomatic, or it can present with constitutional symptoms and pulmonary or extrapulmonary manifestations. Anatomical presence of the disease in an organ often occurs without overt clinical evidence of dysfunction. It is estimated that 20 to 40percent of patients are asymptomatic at presentation, their disease being discovered by 16 routine chest radiography. In fewer than 10 percent 17,18 of patients with sarcoidosis, the onset of symptoms is neither Neurological manifestations of sarcoidosis are in this category. systemic nor pulmonary. Other forms of extrapulmonary sarcoidosis include skin lesions, lymphadenopathy, parotid gland masses, liver or spleen enlargement, and ocular and cardiac involvement. Many laboratory abnormalities have been described in sarcoidosis, but no specific or highly sensitive diagnostic test is yet available. For example, patients may demonstrate anemia, leukopenia, thrombocytopenia, hypergammaglobulinemia, hypercalcemia, and hepatic or renal dysfunction. Active sarcoidosis may cause an elevation in serum angiotensin-converting 3 enzyme (ACE), which can then serve as a marker of the disease. Serum ACE is thought to be produced by alveolar macrophages and epithelioid giant cells and, in effect, reflects the “granulomatous load” of a patient. Serum ACE, however, is neither highly sensitive, with just 50 to 60 percent of patients with active sarcoidosis showing abnormalities, nor very specific because it is also often elevated in patients with other conditions, such as liver disease, diabetes mellitus, hyperthyroidism, systemic infection, malignancy, and Gaucher's disease (Table 51-2). Nevertheless, although much controversy exists as to the proper place of the
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serum ACE assay in the diagnosis of sarcoidosis, most investigators accept that it is a useful 3 marker of systemic disease activity. Click here to view this table.... Most patients with systemic sarcoidosis have a good prognosis. For approximately two thirds, the disease resolves spontaneously without major difficulties. This benign course is most common in asymptomatic patients with only hilar adenopathy on chest radiographs; they have 19 a 70 to 80 percent likelihood of spontaneous remission. However, for one third of patients, symptoms persist or the disease progressively worsens. Pulmonary dysfunction is the major issue for most patients with a persistent or progressive clinical course; 15 to 20 percent of 3,19,20 such patients have some permanent loss of lung function. Mortality in systemic sarcoidosis is reported as below 5 percent. Deaths are most often due to respiratory failure and sometimes are associated with cardiac problems, such as cor pulmonale and heart failure. However, death due to extrathoracic sarcoidosis17–21 affecting organ systems such as the kidneys and the nervous system is also well described. 4
The basis of therapy for all forms of sarcoidosis is corticosteroids. However, debate as to the precise indications for treatment persists. Indications for treatment are controversial because many patients with sarcoidosis are asymptomatic at the time of presentation and the rate of spontaneous resolution of sarcoidosis is high. In addition, the clinical presentations and course are so varied that treatment studies, particularly large, well-controlled studies, are not available. However, based on experience, there is little disagreement that corticosteroids have proved effective in rapidly suppressing some of the acute manifestations of sarcoidosis. Moreover, chronic therapy is widely considered to be necessary to limit recurrence or progression of disease. However, the value of corticosteroids in the long-term treatment of sarcoidosis remains scientifically unsubstantiated, and corticosteroids are recognized not to be curative treatment for all patients with sarcoidosis. Corticosteroid treatment seems most clearly indicated for patients with significant functional impairment in any organ system, particularly with major pulmonary, cardiac, ocular, or central nervous system (CNS) 19,20–23 Alternative immunosuppressive therapies for refractory sarcoidosis have also damage. 4,7,22 been studied and proposed. PATHOPHYSIOLOGY Although the precise etiology of sarcoidosis remains unknown, major strides have been made in understanding its pathogenesis. For example, there is strong evidence that23–27 This sarcoidosis is caused by heightened immune processes at sites of disease activity. contrasts sharply with 3,28 earlier concepts that had related sarcoidosis to impaired immunity and to generalized anergy. Current understanding of the immunopathology of sarcoidosis derives largely from studies of pulmonary sarcoidosis. The initial lesion in pulmonary sarcoidosis is an alveolitis, an inflammation of the alveolar structures of the lung (Fig. 51-1 and Fig. 51-2). This inflammation provides the appropriate environment for granuloma formation. Evidence indicates that these granulomas contain activated mononuclear cells thatprimarily have a secretory, rather than phagocytic, role. There is activation of T lymphocytes that congregate at sites of disease activity and secrete various cytokines,24,25,27 including interleukin-2, interleukin-1, These immunopathological interferon-gamma, and tumor necrosis factor (Fig. 51-2). mechanisms are certainly not limited to pulmonary sarcoidosis. Undoubtedly, processes similar to those in the lung underlie the pathogenesis of other forms of sarcoidosis, including neurosarcoidosis (Fig. 51-3).
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FIGURE 51-1 Postulated mechanisms of pulmonary damage in sarcoidosis.
FIGURE 51-2 Immunological mechanisms active in the pathogenesis of
pulmonary sarcoidosis.
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FIGURE 51-3 Immunopathogenic mechanisms postulated as responsible for
development of the granulomatous inflammation of neurosarcoidosis. Sarcoidosis can be28–30 thought of as an inflammatory response to an as yet unidentified foreign There has long been a suspicion that sarcoidosis is an inflammatory antigen (Fig. 51-1). disorder; fever, malaise, weight loss, cutaneous anergy, and polyclonal hyperglobulinemia all are consistent with this hypothesis. The central pathological hallmark of sarcoidosis, the granuloma, consists of macrophages, macrophage-derived epithelioid cells, and 31 central multinucleated giant cells that secrete cytokines (Fig. 51-2 and Fig. 51-3). About this 29,32 The core exist CD4 and CD8 lymphocytes, B lymphocytes, plasma cells, and fibroblasts. lymphocytes are thought27to be stimulated by antigen presentation by activated macrophages at sites of inflammation. Unfortunately, the inciting antigen or antigens remain unknown. Among the suspected causes have been infectious agents, organic agents such as pine pollen, and inorganic 18,33,34 Of the various possible infectious causes, mycobacterial infections have substances. 35–38 More recently, Propionibacterium species have also been received the most attention. 39 implicated. In reaction to an antigen, monocytes and macrophages form granulomas, and ultimately irreversible obliterative fibrosis can develop (Fig. 51-1). Furthermore, small foci of ischemic necrosis can be found, probably as a consequence of in situ thrombosis owing to perivascular inflammation. Importantly, granulomas are not specific for sarcoidosis, and indistinguishable or nearly identical lesions occur in a variety of other conditions that must be 32 excluded before a diagnosis of sarcoidosis can be made with certainty. EPIDEMIOLOGY The prevalence of sarcoidosis is estimated to be on the order of 60 per 100,000 population, while the annual incidence is approximately 11 per 100,000 population. However, the exact prevalence and incidence of sarcoidosis are difficult to validate because there is no single diagnostic test for sarcoidosis. Differences in case-finding methods also undoubtedly account for some discrepancies in reported frequencies for sarcoidosis and make difficult any comparisons of its rate of occurrence in different populations. For instance, studies that include only symptomatic patients actually underestimate the true prevalence of sarcoidosis because 20 to 40 percent of persons shown to have sarcoidosis are completely symptom-free at the time of initial diagnosis and are discovered by routine or screening chest 16 radiographs. Reports of disease frequency that rely on the findings of chest radiographic surveys probably give the best indication of the frequency of sarcoidosis because pulmonary inflammation and intrathoracic lymphadenopathy are by far the most common manifestation of sarcoidosis. However, some autopsy series suggest that the true prevalence of sarcoidosis
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16
Population differences for sarcoidosis have been described. For instance, in the United States there is a reported increased incidence of sarcoidosis in blacks compared with whites; 14,16 Certain areas of the world, such as the disease also seems to be more severe in blacks. Sweden, also seem to have a higher incidence of sarcoidosis, whereas it appears to be quite 18 rare in other areas, such as China or Southeast Asia. These studies also raise the possibility of a genetic predisposition to the development of sarcoidosis. Indeed, sarcoidosis 40 does seem to occur with greater likelihood in some families, but as yet no well-defined genetic pattern has been recognized and no consistent mode of inheritance has been 14,16 discovered. Sarcoidosis can occur at any age. Although the likelihood of sarcoidosis is greatest in the 15,16 The exact third and fourth decades, the youngest reported patient is a 28-month-old child. frequency in children is difficult to assess because most countries understandably limit the use of routine screening chest radiography in children. Clinically, when sarcoidosis affects children, the distribution of organ involvement appears similar 15 to that reported for adult cases, and the patterns of neurosarcoidosis seem analogous as well. An increasing number of studies address candidate genes that may predispose to the development of sarcoidosis. To date, there is no consensus as to a robust genotype that 40 predisposes to sarcoidosis. There is a familial clustering of sarcoidosis. In a multivariate model, the familial adjusted relative risk was 4.7 (95% CI = 2.3–9.7). White patients demonstrated a higher familial relative risk compared with African American patients (18.0 vs. 2.8; P = 0.098). NEUROLOGICAL MANIFESTATIONS Neurological symptoms6,7are the presenting feature of sarcoidosis in one half of individuals with neurosarcoidosis. Some three quarters of patients destined to develop neurological disease do so within 2 years of becoming afflicted with sarcoidosis. The approximate frequency of the various neurological complications is presented in Table 51-3. Only rarely do patients with neurosarcoidosis have no evidence of disease in other organ systems, such as 6,8–10,12,41–43 However, systemic disease may not always be evident early in the lungs. apatient's clinical course and, in some instances, is difficult to find. One third to one half of patients with neurosarcoidosis develop more than one neurological manifestation of their disease. Click here to view this table.... Involvement of the CNS in sarcoidosis is best conceptualized as an inflammatory process affecting primarily the leptomeninges (Fig. 51-4), with sarcoidosis spreading along the Virchow–Robin perivascular spaces to invade the brain, spinal cord, or localized cranial nerves.
FIGURE 51-4 Central nervous system (CNS) sarcoidosis: clinicopathological
relationships.
Cranial Neuropathy 6
The most frequent neurological complication of sarcoidosis is cranial neuropathy. This occurs in approximately three quarters of patients with neurosarcoidosis. Any cranial nerve 6 can be affected, and more than one half of patients have multiple cranial nerve lesions. By far the most commonly affected cranial nerve is the facial, or seventh, nerve.
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Olfactory nerve dysfunction can occur secondary to meningeal sarcoidosis involving the subfrontal region. However, anosmia or hyposmia may also result from local nasal granulomatous invasion by sarcoidosis. Accordingly, in a patient with olfactory complaints, an otolaryngological evaluation is necessary before impaired olfaction can be attributed to CNS disease. Optic nerve involvement is much less frequent than other ocular manifestations of sarcoidosis, such as uveitis. Optic neuropathy can present with visual loss that is acute, 44 subacute, or chronic and can be painful or painless. The visual loss may be due to bulbar or retrobulbar invasion of the optic nerve by granulomas, compression of the optic nerve by a granulomatous mass, or optic atrophy. Optic disc edema may be secondary to papilledema due to sarcoidosis-induced increased intracranial pressure 45 or a direct local invasive effect of sarcoidosis. A chiasmal syndrome also has been reported. Disorders of ocular motility may follow involvement of cranial nerves III, IV, or VI in the 6 granulomatous process. Typically, these nerves are damaged in their extra-axial course in the subarachnoid space as they traverse the meninges. However, they may also be involved in local orbital disease, and rarely brainstem intra-axial pathways can be affected by 45 disordered ocular motility is due to sarcoidosis involving the sarcoidosis. Uncommonly, 46 Occasionally, pupillary dysfunction is caused by extraocular muscles. 45,47–49 For instance, Horner's syndrome due to disruption of the cervical neurosarcoidosis. 48 sympathetic nerves has been reported. 6
Trigeminal nerve disease may present as facial numbness or, rarely, trigeminal neuralgia. Headache may also represent trigeminal nerve dysfunction intracranially. Involvement of the muscles of mastication is unusual. Of the cranial nerve syndromes, peripheral facial nerve palsy is the most common, and it is also the single most frequent neurological manifestation of sarcoidosis. It develops in 25 to 50 percent of all patients with neurosarcoidosis. Although the condition is usually unilateral, bilateral facial palsy can occur, presenting with either simultaneous or sequential paralysis. More than half of all patients with facial palsy also have other forms of nervous system involvement. In patients with an isolated facial palsy, spinal fluid examination typically is normal, but when other manifestations of neurosarcoidosis are present, the spinal fluid examination is abnormal in 80 percent of patients. The specific cause of facial nerve palsy in sarcoidosis is variable. Rarely, the facial palsy is caused by parotid inflammation. More likely, the nerve is compromised as it traverses the meninges and subarachnoid space, or, as 42 suggested by Oksanen, facial paresis is due to intra-axial inflammation involving the facial nerve. In general, the prognosis for the facial palsy is good, with 6,12 more than 80 percent of patients having a good outcome in terms of recovery of function. Eighth cranial nerve involvement is the second most common cranial neuropathy occurring in 50 sarcoidosis. Inflammation may involve the auditory or vestibular portions of the nerve. When either loss of hearing or 51,52 vestibular dysfunction occurs, it may be sudden or insidious If hearing loss occurs, it is typically of the sensorineural and often fluctuates over time. type. As with facial nerve palsy, bilateral eighth nerve disease may occur. In fact, either 6,8 bilateral seventh or eighth nerve dysfunction is suggestive of neurosarcoidosis. Glossopharyngeal and vagus nerve involvement by sarcoidosis causes dysphagia and dysphonia. Hoarseness is more commonly due to laryngeal nerve dysfunction from 53 intrathoracic disease than CNS inflammation involving the vagus nerve. Eleventh and twelfth cranial nerve disease can occur but seems to be rare.
Meningeal Disease Meningeal disease occurs in approximately 10 to 20 percent of patients with neurosarcoidosis and can present as aseptic meningitis or, less commonly, as a meningeal or dural mass lesion. Aseptic meningitis is characterized by headache, meningismus, and a sterile cerebrospinal fluid (CSF) with a predominantly mononuclear pleocytosis, and it may be 54 a recurrent problem in some patients with neurosarcoidosis. Hypoglycorrhachia, or low CSF glucose concentration, is occasionally found, and there is often an elevation of the CSF protein concentration. Since meningeal involvement in sarcoidosis is a common pathological finding, it is surprising that aseptic meningitis is not more common. However, it is not at all uncommon for there to be asymptomatic chronic meningitis within the context of other CNS manifestations of sarcoidosis. When meningeal sarcoid mass lesions occur, they may mimic 55,56 intracranial tumors, such as meningiomas (Fig. 51-5).
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FIGURE 51-5 Cranial magnetic resonance imaging (MRI), coronal section,
T1-weighted image with gadolinium enhancement, demonstrating a convexity sarcoid mass lesion that was initially mistaken for a meningioma.
Hydrocephalus Hydrocephalus is noted in about 10 percent of neurosarcoidosis patients and may have fatal consequences. Patients with acute hydrocephalus may die suddenly of increased intracranial pressure, and even patients with chronic hydrocephalus have the potential to decompensate acutely. Patients with acute hydrocephalus characteristically present with headache, altered mentation or consciousness, and impaired gait. On examination, papilledema or other signs of raised intracranial pressure may be found. Acute decompensating hydrocephalus is a medical emergency that necessitates prompt diagnosis and treatment. Once clinically suspected, the diagnosis of hydrocephalus is best substantiated with imaging studies, such as cranial computed tomography (CT) or magnetic resonance imaging (MRI). A diagnostic lumbar puncture57has been associated with sudden neurological deterioration in patients with hydrocephalus. The hydrocephalus may be of either the communicating or noncommunicating type. Chronic basilar meningitis with obliteration of subarachnoid CSF flow is a major cause of communicating hydrocephalus. In addition, infiltration of the ventricular system by granulomas, granulomatous compression of the aqueduct, or outlet obstruction of the fourth 58 ventricle by granulomas may cause noncommunicating hydrocephalus.
Parenchymal Disease Parenchymal brain disease is reported in about 50 percent of patients with neurosarcoidosis and can present in several forms. Hypothalamic dysfunction is the most common manifestation of CNS parenchymatous disease. When hypothalamic dysfunction occurs, it usually involves the neuroendocrine system or “vegetative functions,” such as thirst, temperature regulation, appetite, sleep, and libido. However, neuroendocrinological disease may also occur secondary 6to pituitary disease. Any of the neuroendocrinological systems can be affected by sarcoidosis.
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Endocrine Disorders Endocrinological dysfunction in sarcoidosis is due to either a hypothalamic59–63 or a pituitary Given the granulomatous mass (Fig. 51-6) or a more diffuse “local” encephalopathy. the relative frequency of such predilection of sarcoidosis for the basal meninges (Fig. 51-4), 63 endocrinological disturbances is not surprising. Potential endocrinological manifestations include thyroid disorders, disorders of cortisol metabolism, and sexual dysfunction. An elevated serum prolactin level, found in 3 to 32 percent of patients with sarcoidosis, may be an indication of hypothalamic dysfunction. In fact, because neuroendocrinological involvement is relatively common in individuals with CNS neurosarcoidosis, patients with more than just an isolated facial palsy probably merit a thorough evaluation with specific attention to hypothalamic hypothyroidism, hypocortisolism, and hypogonadism.
FIGURE 51-6 Cranial MRI, sagittal section, T1-weighted image with gadolinium
enhancement, showing hypothalamic and pituitary involvement by sarcoidosis. Hypothalamic disorders vary in their effect on vegetative functions. A disorder of thirst is the most common hypothalamic disorder related to neurosarcoidosis and is attributed to a 59 of inappropriate change in the hypothalamic “osmostat.” More rarely, the syndrome 7,59 Neurosarcoidosis-induced secretion of antidiuretic hormone or diabetes insipidus occurs. disruptions of hypothalamic function have also been described as59,64,65 causing disorders of appetite, libido, temperature control, weight regulation, and sleep. Mass Lesions An intraparenchymal lesion due to sarcoidosis may present as an isolated mass (Fig. 51-7) or masses in any cerebral area or as multiple cerebral nodules. Such nodules may actually represent an inflammatory reaction in the Virchow–Robin spaces. Subdural plaque-like masses may also occur and are discussed in a later section. Calcifications may be seen. Although intraparenchymal mass lesions were historically considered rare, CT and MRI have shown parenchymatous disease to be more frequent than was previously thought. The symptoms and signs in individual cases depend on the location of the lesion.
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FIGURE 51-7 Cranial MRI, axial section, T1-weighted image with gadolinium
enhancement, demonstrating a frontal intracerebral mass that was proved by biopsy to be neurosarcoidosis. Encephalopathy-Vasculopathy The diffuse encephalopathy and vasculopathy associated with neurosarcoidosis are not well understood. Moreover, it is often difficult, both clinically and pathologically, to differentiate clearly between these entities. In fact, these two manifestations of neurosarcoidosis frequently coexist. For these reasons, we find it best to consider them as a single overlapping 5 entity, while recognizing that in individual patients one form or the other may predominate. The diffuse encephalopathy-vasculopathy found in neurosarcoidosis can involve the cerebral hemispheres or basilar regions. Patients may have a delirium, personality change, or isolated 66–68 memory disturbance as a result of focal or diffuse parenchymal inflammation (Fig. 51-8). Clinical findings correlate with the extent of enhancement on imaging studies and increased signal intensity on T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI.
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FIGURE 51-8 Cranial MRI, axial section, T2-weighted image, showing a large
area of abnormality in the temporal lobe that was proved by biopsy to be sarcoidosis manifesting with a focal encephalopathy-vasculopathy. Encephalopathic patients may have perivascular inflammation or granulomas infiltrating both arteries and veins and extending into brain parenchyma. Several investigators have observed 69,70 Large arteries granulomatous small-vessel arteritis in patients with neurosarcoidosis. have also been involved in the granulomatous process (Fig. 51-9). Microscopic pathology demonstrates arteritis with perivascular inflammation. Typically, the vascular adventitia shows infiltration with granulomas and inflammatory changes, but the media, elastica, and intima of 70–73 Veins can also be involved in sarcoidosis, producing arteries can70,71,73 also be affected. Although disease is rarely evident on angiography, angiographic changes infarctions. suggestive of71,72 vasculitis as well as an ill-defined occlusive process have been documented.
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FIGURE 51-9 Cranial MRI, coronal view, T1-weighted image with gadolinium
enhancement, showing gyral enhancement in the distribution of a posterior cerebral artery branch stroke. Transient56,71–73 ischemic attacks and ischemic stroke due to neurosarcoidosis have been Ischemic stroke usually is the consequence of inflammation and thrombosis reported. involving large or small arteries, but other causes include compressive perivascular mass lesions and emboli from sarcoidosis-associated cardiomyopathy or cardiac arrhythmias. Caplan and co-workers emphasized the arterial and venous involvement of the meninges and parenchyma in the angiitic 73 form of sarcoidosis and related this to observable perivascular causing intracranial hypertension lesions in the optic fundus. Also, dural sinus obstruction 64,74 has been related to inflammation from sarcoidosis. Seizures Seizures are another important manifestation of CNS parenchymal disease due to neurosarcoidosis. They may be75focal or generalized and have been correlated with a poor prognosis in neurosarcoidosis. This is because they reflect the presence of severe CNS parenchymal disease or hydrocephalus, and these manifestations have a higher risk of 13,75 Importantly, seizures in patients with progressive or recurrent disease or death. neurosarcoidosis are relatively easy to control if the underlying CNS inflammatory process is 13 effectively treated. Myelopathy Spinal cord involvement is another form of CNS parenchymal sarcoidosis. Spinal cord sarcoidosis may manifest as intramedullary, intradural but extramedullary, or extradural 76,77 Intramedullary spinal cord disease can also present with a granulomatous masses. myelitis that is analogous to the cerebral encephalopathy-vasculopathy of sarcoidosis. Intraspinal mass lesions due to sarcoidosis present with a nonspecific imaging appearance (Fig. 51-10). Also, spinal arachnoiditis may occur. In addition, sarcoidosis may present as a radiculopathy, polyradiculopathy, or cauda equina syndrome. Finally, spinal cord sarcoidosis may appear, typically in the late stages of spinal cord disease, as focal spinal cord 76,77 atrophy.
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FIGURE 51-10 Spinal MRI. A, Axial view. B, Sagittal view, with gadolinium
enhancement, demonstrating an intraspinal mass due to sarcoidosis.
Peripheral Neuropathy Although sarcoidosis commonly affects cranial nerves, peripheral neuropathy is less frequently described. Still, a variety of peripheral neuropathies are reported in sarcoidosis, including chronic sensorimotor, pure motor, or pure sensory polyneuropathies, mononeuritis 78 The most common form is a chronic multiplex, and an acute demyelinating polyneuropathy. 78 sensorimotor polyneuropathy of the axonal type. Sarcoid neuropathy typically begins months to years following an initial diagnosis of sarcoidosis, but in some instances, symptoms of neuropathy precede the discovery of systemic disease. The neuropathy is usually mild and classically manifests with distal paresthesias, decreased vibration and 78 proprioception sensation, and reduced ankle reflexes. Neuropathy has been attributed to epineurial and perineurial granulomas and an associated granulomatous vasculitis, producing axonal degeneration with associated demyelination. Endoneurial granulomas may also occur and are associated with primary segmental demyelination in patients with sensorimotor 79 neuropathy. Nerve damage may be due to granulomatous vasculitis, the compressive effects of granulomas, or local effects of inflammation. Over the past several years, a80sarcoidosis-associated small-fiber sensory neuropathy has increasingly been recognized. Patients have uncomfortable paresthesias distally in their extremities, with impaired pain and temperature appreciation. Initially patients can experience 81 multiple painful sensory mononeuropathies. These patients typically have normal nerve conduction velocities but have a decreased number of small fibers in cutaneous nerves documented on skin biopsy of the extremities. The pathophysiology of this process is poorly understood. Granulomas are not found on skin biopsy. It is possible that the neuropathy is a response to inflammatory mediators.
Myopathy Sarcoidosis may directly involve muscles and present with myopathy of various types. Manifestations of sarcoid myopathy include acute, subacute, or chronic weakness; fatigue; muscle pain; and palpable muscle nodules. Severe muscle disease can result in fibrosis and contractures. Sarcoidosis may also manifest with myositis, muscle atrophy, or occasional pseudohypertrophy. Muscle involvement by noncaseating granulomas can be demonstrated with muscle biopsy. However, incidental non-caseating granulomas have been found in muscle biopsy specimens in as many as 50 percent of patients with sarcoidosis but no clinical evidence of muscle disease. Differentiating between sarcoid myopathy, polymyositis or dermatomyositis, and granulomatous myopathy may be difficult, 82–84 and it is important to evaluate other organ systems carefully for evidence of sarcoidosis. NEUROPATHOLOGY Noncaseating granulomas and the accompanying diffuse mononuclear cell infiltrates that are characteristic of sarcoidosis can be found in any part of the neuraxis, including peripheral
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nerve or muscle (Fig. 51-11). The most common site of inflammation is the meninges, 9,85 Sarcoid granulomas especially in the basal region of the brain (Fig. 51-4 and Fig. 51-12). may be widely distributed or concentrated in one or more areas43to form a mass. Although sarcoidosis is not usually considered to be a primary vasculitis, arteriolar and venous 9,73,86–88 The granulomatous inflammation infiltration does occur and may lead to infarction. found pathologically may correlate directly with clinical deficits or may be subclinical and 85,89 unexpressed.
FIGURE 51-11 A, Photomicrograph of an intraparenchymal noncaseating
sarcoid granuloma of the brain (200×). B, Photomicrograph of a sarcoid granuloma in the brain, demonstrating a multinucleated giant cell (400×).
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FIGURE 51-12 Coronal midfrontal section of the brain of a patient with
neurosarcoidosis, showing thickening and inflammatory changes of the basal meninges and optic chiasmal region. As previously mentioned, CNS involvement can be conceptualized as an inflammatory process affecting primarily the leptomeninges (Fig. 51-4). Inflammation may spread along the Virchow–Robin perivascular spaces to invade the brain or spinal cord, or it may remain more 85,88,90 Presumably, much of the active inflammation localized and involve the cranial nerves. is reversible at an early stage. Ultimately, as the disease progresses, irreversible fibrosis or ischemic necrosis develops, leading to permanent neurological damage and persisting deficits. Inflammation can also extend to the CSF pathways, leading to hydrocephalus. Brain or spinal cord disease can take the appearance of discrete granulomatous mass lesions or a diffuse encephalopathy-vasculopathy. The hypothalamic region is the most common site of parenchymal disease. Granulomas are apparent in the epineurium and perineurium of peripheral nerve in symptomatic patients. The endoneurium may contain a mononuclear cell infiltrate. Perivascular and vascular inflammation may be seen in the epineurial and perineurial vessels. All nerve fiber sizes can be affected. There seems to be a predominantly axonal neuropathy with only minor segmental demyelination. The exact mechanism of peripheral nerve damage varies, but it includes injury resulting from vascular compromise, direct compression from granulomas, and immunological factors that may affect the peripheral 91 axons or Schwann cells. Muscle pathology is common in sarcoidosis. Muscle biopsy of symptomatic patients reveals typical noncaseating granulomas, and more diffuse inflammation also occurs, with muscle 83,92 Moreover, asymptomatic noncaseating fiber degeneration and regeneration and fibrosis. granulomas have been found in as many as one half of all patients with sarcoidosis having a 83 muscle biopsy. DIFFERENTIAL DIAGNOSIS Diagnostically, two common clinical situations occur in which patients with neurosarcoidosis are encountered: (1) A patient without established sarcoidosis has a clinical picture suggestive of neurosarcoidosis. In this situation, the major goal is to establish the presence of systemic sarcoidosis. (2) A patient with already established systemic sarcoidosis develops neurological symptoms. The focus is then on confirming that the neurological problem is due to neurosarcoidosis rather than to another cause.
Presence of Systemic Sarcoidosis When a patient without documented systemic sarcoidosis develops a clinical syndrome
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suggestive of neurosarcoidosis, evidence of sarcoidosis should be sought in other organ systems. Such systemic disease can best be documented when a thorough, systematic evaluation based on the known natural history of sarcoidosis is undertaken (Table 51-1). In particular, sarcoidosis most frequently affects intrathoracic structures (87% of patients), followed by lymph node, skin, and ocular involvement (15% to 28% of patients). Histological support for a diagnosis of sarcoidosis should be pursued, based on the clinical evaluation and these statistics. Since corticosteroid therapy may mask signs of systemic disease, treatment should be postponed, if possible, while a search for systemic disease is initiated. Pulmonary involvement is so common in sarcoidosis that this possibility should be considered first when one attempts to establish the presence of systemic sarcoidosis. Indeed, nearly 90 percent of patients with sarcoidosis are reported to show radiographic evidence of pulmonary 93 involvement. Still, although an abnormal chest radiograph is often seen in sarcoidosis and can be supportive evidence of that diagnosis, such findings are not necessarily specific or pathognomonic for sarcoidosis. Additional evidence to support pulmonary involvement can be obtained from chest CT and pulmonary function testing, including diffusion capacity. Moreover, when chest imaging or pulmonary function studies suggest pulmonary or intrathoracic lymph node involvement, a diagnosis of sarcoidosis is confirmed by obtaining histological evidence by transbronchial or mediastinal biopsy. Apart from the lungs, other organ systems merit consideration. Because of ease of access, early consideration should be given to a skin or lymph node biopsy of suspicious sites. Clinical information should also guide the evaluation of other organ systems for evidence of systemic sarcoidosis. For instance, nasal mucosal, conjunctival, lacrimal gland, liver, and muscle biopsies can be considered on the basis of individual clinical assessments. A thorough ocular examination is indicated to search for uveitis, retinal periphlebitis, or superficial lesions for conjunctival biopsy. Ocular findings in sarcoidosis include lacrimal gland inflammation, conjunctival nodules, iritis, uveitis, retinal lesions (vascular sheathing, granulomas, vascular occlusions, and 1,94 chorioretinitis), and optic disc pathology (edema, granulomatous nodules, and atrophy). The Kveim–Siltzbach test is not widely available and is no longer much used. However, historically it was yet another means for diagnosing systemic sarcoidosis. Kveim–Siltzbach reagent is a suspension derived from the spleen of a patient with sarcoidosis. This suspension is injected intracutaneously and, when positive, produces a cutaneous nodule that, on biopsy, reveals noncaseating granulomas. Although this represents a specific and sensitive test, it requires a period of 4 to 6 weeks before biopsy can be performed, making this unsatisfactory for patients with acute severe neurosarcoidosis who may require prompt 95 test, a role has corticosteroid treatment. Recently, as an alternative to the Kveim–Siltzbach 41 been proposed for diagnostic biopsy of Mantoux skin test sites. Gallium-67 scanning has been promoted as a valuable imaging method for initial detection of 63 systemic sarcoidosis, but it has limited utility95for longitudinal clinical follow-up because of its expense and the potential radiation exposure. Detection of inflammation in the lacrimal, 96 minor salivary, and parotid glands on a gallium scan is especially suggestive of sarcoidosis. More recently, fluorodeoxyglucose positron emission tomography (PET) scanning has been97 recognized as a sensitive technique for highlighting regions of increased metabolic activity. Although increased activity on PET scans can represent neoplasia or infection as well as granulomatous inflammation, when used in the proper context PET scans can be a valuable tool for documenting systemic disease and targeting a biopsy. Various laboratory measures have been described as abnormal in sarcoidosis. Although none is highly specific for sarcoidosis, they can be of some value. These abnormalities include increased serum ACE; increased serum gamma globulins; hematological disorders, such as anemia, leukopenia, and thrombocytopenia; and metabolic derangements, such as hypercalcemia, hypercalciuria, and hepatic and renal dysfunction. The most specific laboratory test associated with sarcoidosis is determination of the serum ACE level. However, its sensitivity is not high, with just 50 to 60 percent of patients with active sarcoidosis showing abnormalities. In addition, serum ACE is not very specific because it is abnormal in other 98 conditions, as discussed earlier (Table 51-2).
Diagnosis of Neurosarcoidosis Patients with well-documented systemic sarcoidosis who develop neurological disease suspected to be due to neurosarcoidosis merit careful appraisal to exclude causes other than sarcoidosis for their neurological problems. Neurosarcoidosis can be confused with many other neurological diseases, and because it is often not possible or judicious to biopsy
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affected tissue from the nervous system, good clinical judgment becomes critical. Consideration must be given to disease entities that may mimic neurosarcoidosis, particularly infection and neoplasia. Once such disorders have been excluded, treatment for neurosarcoidosis can be instituted. When the response to treatment is disappointing, the diagnosis of neurosarcoidosis should be reconsidered and a more extensive evaluation, including a biopsy, considered to exclude other causes of symptoms. Although not specifically diagnostic, certain tests can support a presumptive diagnosis of neurosarcoidosis. Brain imaging studies can be particularly helpful in confirming the presence, classifying the nature, and monitoring the treatment of neurosarcoidosis. The 99 preferred imaging technique is now MRI with contrast enhancement. T1-weighted images provide less useful information than T2-weighted and FLAIR inversion recovery studies. With T2-weighted and FLAIR imaging, areas of increased signal intensity can be better appreciated, especially in a periventricular distribution. Administration of contrast medium helps by demonstrating leptomeningeal enhancement (Fig. 51-13) as well as parenchymal abnormalities (Fig. 51-5 and Fig. 51-6). Enhancement presumably reflects a breakdown of the blood–brain barrier and implies active inflammation. Spinal MRI may reveal intramedullary disease, which appears as an enhancing fusiform enlargement, focal or diffuse 76,77 Enhancing nodules or thickened or matted nerve enhancement, or atrophy (Fig. 51-10). roots may also be appreciated in MR images of the cauda equina.
FIGURE 51-13 Cranial MRI, axial view, T1-weighted image, with gadolinium
enhancement, demonstrating marked dural enhancement due to sarcoidosis. CSF analysis may be helpful. More than 50 percent of patients with CNS sarcoidosis have 6,49 Reported abnormalities include an elevated CSF pressure, a high some CSF abnormality. protein level, hypoglycorrhachia, and a predominantly mononuclear pleocytosis, with up to 3 several hundred cells per mm . In addition, some patients have oligoclonal bands in the CSF or an elevated immunoglobulin100 G (IgG) index. However, none of these abnormalities is specific for neurosar-coidosis. Newer CSF assays may prove more specific for CNS sarcoidosis. The CSF level of ACE activity tends101–103 to be raised in some 50 percent of untreated patients with CNS although abnormalities are also seen in the presence of infection and sarcoidosis,
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malignancy. The CSF ACE level may be abnormal even with corticosteroid therapy, but less consistently than in untreated patients. The degree of elevation of CSF ACE level may 101–103 CSF ACE is thought to be produced by CNS granulomas, parallel the clinical course. especially those near the meninges. A normal CSF ACE assay, however, does not exclude the diagnosis of neurosarcoidosis, and assay methodology and normative values have not been well standardized; a recent study suggests a cut point of 8 nmol/ml/min (sensitivity 55%, 104 105 specificity 94%), although the overall utility of the assay has been questioned. Evoked potentials are useful in evaluating some patients with neurosarcoidosis. Visual evoked potentials (VEPs) can reveal abnormalities of the anterior visual pathways. They are often abnormal in patients with symptomatic optic nerve disease and may be abnormal in some patients with CNS sarcoidosis but no clinical evidence of optic nerve 6,106,107 Streletz and colleagues reported VEP abnormalities in a high proportion dysfunction. of patients with neurosarcoidosis. Even some patients with sarcoidosis, but without ocular or 106 neurological disease, were found to have abnormal responses. Their study suggests that subclinical neurosar-coidosis may be more common than previously realized, but not all 6 investigators confirm a high incidence of VEP abnormalities in asymptomatic patients. Some investigators suggest, instead, that VEP abnormalities in particular, and evoked potential disturbances in general, are useful in symptomatic neurosarcoidosis, as they demonstrate 6 relevant abnormalities that may be used to monitor the clinical course of the disease. Similarly, brainstem auditory evoked potentials (BAEPs) are often abnormal in neurosarcoidosis in patients with brainstem or eighth nerve symptoms and may be abnormal 107 in neurologically ill patients without overt disease in these areas. However, they are rarely, if ever, abnormal in patients without clinically evident CNS sarcoidosis. Somatosensory evoked potentials have not been comprehensively studied in the assessment of patients with sarcoidosis. Preliminary evidence suggests that their clinical utility is similar to that of VEPs and brainstem auditory evoked potentials in confirming the involvement of a specific sensory 108 system that may be clinically affected. Nerve conduction studies in patients with sarcoidosis-associated neuropathy usually reveal changes compatible with an axonal neuropathy, although slowing is sometimes more 91,109 Electromyography may be pronounced and suggestive of demyelinating disease. indicative of denervation in patients with a neuropathy or radiculopathy and reveal myopathic 84 MRI may reveal a characteristic changes in patients with a symptomatic myopathy. 110 “star-shaped” pattern for muscle nodules. Muscle or nerve biopsy is informative if the diagnosis of neuromuscular disease is in doubt. Muscle biopsy can be targeted to areas of MRI enhancement. Neurosarcoidosis, because of its varied manifestations, is in the differential diagnosis of many unexplained neurological syndromes. Recent data on the clinical presentation of neuromyelitis optica suggest that this disorder may emerge as an important differential 111 diagnostic consideration in patients with optic neuropathies and spinal cord syndromes. The diagnosis of sarcoidosis is most secure when it is based on pathology and when more than one organ system is involved. However, since tissue from the nervous system is difficult to secure for pathological analysis and other tests are not diagnostic of neurosarcoidosis, the diagnosis of neurosarcoidosis, despite all efforts, must sometimes remain tentative. It is 43 We have useful when one considers a diagnosis of neurosarcoidosis to grade its likelihood. 43 found the following categories useful, as adapted from Zajicek and co-workers : Possible neurosarcoidosis: The clinical syndrome and diagnostic evaluation suggest neurosarcoidosis. Infection and malignancy are not excluded or there is no pathological confirmation of systemic sarcoidosis. Probable neurosarcoidosis: The clinical syndrome and diagnostic evaluation suggest neurosarcoidosis. Alternative diagnoses are excluded. There is pathological confirmation of systemic sarcoidosis. Definite neurosarcoidosis: The clinical presentation is suggestive of neurosarcoidosis, other diagnoses are excluded, and there is supportive nervous system pathology or the criteria for “probable” neurosarcoidosis are met and the patient has had a beneficial response to immunotherapy over a 1-year observation period. TREATMENT No rigorous studies compare various treatments for neurosarcoidosis. Corticosteroid therapy is the mainstay of treatment and is indicated for any patient without a specific contraindication to it. Decisions about issues such as the optimal therapeutic dose and duration of therapy are
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made on an individual basis. A treatment paradigm is given in Figure 51-14.
FIGURE 51-14 Treatment paradigm for patients with neurosarcoidosis.
Treatment with corticosteroids is widely accepted and recommended for all forms of neurosarcoidosis. In support of this, many individual case reports and series provide evidence that on a short-term basis it can produce impressive responses and alleviate symptoms. Still, it is not fully established that treatment changes the natural history and long-term course of neurosarcoidosis. A major theoretical goal for long-term treatment with corticosteroids is to diminish the irreversible fibrosis that can develop and to minimize the tissue ischemia that might result from perivascular inflammation. Once treatment with corticosteroids or other immunomodulating or immunosuppressive agents is begun, it need not continue indefinitely, particularly at extremely high doses. The inflammatory process can recede, allowing therapy to be withdrawn gradually. Recommended treatment regimens for the various manifestations of neurosarcoidosis are detailed.
Cranial Neuropathy Peripheral Facial Palsy Facial weakness may improve without any specific treatment. A controlled trial of treatment has not been done, and the long-term prognosis for patients seems favorable. Nevertheless, it seems reasonable to give a short course (2 weeks) of prednisone. For the first week, the recommended prednisone dose is in the range of 0.5 to 1.0 mg/kg daily, or 40 to 60 mg daily. This is followed by a gradual reduction leading to discontinuation of prednisone over the second week, although tapering is probably unnecessary. General supportive care, as for any patient with a peripheral facial palsy, should be provided. Other Cranial Nerve Palsies Patients with other cranial neuropathies may be managed with a corticosteroid protocol similar to that described for peripheral facial palsy. However, often more than 2 weeks of therapy is needed. In particular, patients with optic neuropathy or dysfunction of the eighth cranial nerve may need more prolonged, aggressive therapy, which may not prevent irreversible optic and eighth nerve damage.
Aseptic Meningitis Acute aseptic meningitis may respond to a short (2-week) course of prednisone, 0.5 to 1.0 mg/kg per day. The goal of therapy for chronic aseptic meningitis should not be complete clearing of an asymptomatic CSF pleocytosis. Attempts to completely normalize the spinal fluid may needlessly expose patients to the adverse side effects of corticosteroids or other
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therapeutic agents. There is no evidence that clearing the CSF of an abnormal cellular response necessarily corresponds to clinical well-being in patients with chronic aseptic meningitis who are otherwise asymptomatic.
Hydrocephalus Asymptomatic ventricular enlargement usually does not require therapy. Mild, symptomatic hydrocephalus may respond to corticosteroid treatment, and prolonged therapy is often appropriate. Life-threatening or corticosteroid-resistant hydrocephalus requires ventricular shunting or a ventricular drain. Unfortunately, mild hydrocephalus may evolve to severe, life-threatening disease quite rapidly. Therefore, patients and care-providers should be well educated as to the symptoms of acute progressive hydrocephalus and know how to obtain prompt emergency care. At times, high-dose intravenous corticosteroid therapy (methylprednisolone 20 mg/kg per day for 3 days) can stabilize a patient with life-threatening hydrocephalus, although usually prompt surgical intervention with a ventricular drain or ventriculoperitoneal shunt is necessary. Shunt placement is not without risk in this patient population, which is why “prophylactic” shunting in asymptomatic patients with hydrocephalus is not readily advocated. Shunt obstruction is common, and placement of a foreign object in the CNS of an immunosuppressed host predisposes to infection. To further complicate management, there are case reports of patients with relatively modest hydrocephalus who, following a diagnostic lumbar puncture, develop marked neurological deterioration, 59 sometimes with a fatal outcome.
Parenchymal Disease Corticosteroid therapy may improve the status of patients with a diffuse encephalopathy-vasculopathy or CNS mass lesion. Only rarely, however, does immunosuppressive treatment improve neuroendocrine dysfunction or vegetative symptoms. Corticosteroid treatment of CNS parenchymal disease and other severe neurological manifestations of sarcoidosis usually starts with prednisone, 1.0 to 1.5 mg/kg daily. Critically 112 ill patients may require high-dose intravenous corticosteroid therapy. A short course of methylprednisolone, 20 mg/kg daily intravenously for 3 days, followed by prednisone, 1.0 to 1.5 mg/kg per day for 2 to 4 weeks, is occasionally warranted. The higher doses are used in patients with particularly severe disease. Such patients often require more prolonged therapy, and prednisone should thus be tapered very slowly. The prednisone dose can be tapered by 5-mg decrements every 2 weeks as the clinical course is monitored. Neurosarcoidosis may worsen at a low prednisone dose (approximately 0.1 mg/kg or 10 mg or less daily). Some patients exhibit an individual therapeutic lower limit, or dosage below which worsening can almost be predicted. Once a daily prednisone dose of approximately 10 mg is achieved, the patient should be evaluated for evidence of worsening disease. Clinical disease can be monitored by symptoms, but subclinical disease can also be monitored. For patients with CNS disease, enhanced MRI is useful. Intense enhancement, in the meninges, for example, suggests that neurosarcoidosis is active, and further decreases in the corticosteroid dose may lead to a clinical exacerbation. Other manifestations of neurosarcoidosis can be evaluated for subclinical deterioration on an individualized basis (e.g., by evaluating nerve conduction studies or serum creatine kinase level), but persistent mild CSF abnormalities are usually not an indication for continuing or escalating high-dose corticosteroid therapy. Efforts to “normalize” the CSF often require powerful immunosuppression, with its attendant adverse effects. If the sarcoidosis appears quiescent, a low daily prednisone dose of about 10 mg can be tapered further by 1 mg every 2 to 4 weeks. If a patient has a clinical relapse, the dose of prednisone should be doubled (unless the dose is very modest, in which case a prednisone dose of 10 to 20 mg daily can be prescribed). The patient should then be observed for approximately 4 weeks before another taper is contemplated. Patients may require multiple cycles of higher and lower corticosteroid dosing during attempts to taper medications. Nevertheless, the disease may become quiescent and, without attempts at withdrawing medication, patients may be needlessly exposed to the harmful side effects of long-term, high-dose corticosteroids. Seizures, when they occur, are generally not a major limiting problem and can usually be well controlled with antiepileptic medication if the underlying CNS inflammatory reaction is effectively treated. However, seizures are an indication of or marker for the presence of parenchymatous involvement of the brain, which, in itself, is a serious manifestation of
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neurosarcoidosis.
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12,13
In patients with a CNS mass lesion that is unresponsive to high-dose corticosteroids, surgical resection may be considered, especially in life-threatening situations.
Peripheral Neuropathy and Myopathy Patients with a peripheral neuropathy or myopathy may respond to a several-week course of corticosteroids, usually beginning with prednisone, 1 mg/kg per day (or approximately 60 mg/day). Here, too, prolonged treatment may be indicated. Corticosteroids should be tapered slowly, as discussed earlier. GENERAL SUPPORTIVE CARE Patients with neurosarcoidosis, and particularly those receiving treatment with immunosuppressive agents, require close attention to their general medical well-being. Potential adverse effects of treatment should be carefully sought. For example, formal, prescribed exercise and dietary programs are often beneficial in helping the patient avoid the weight gain associated with high-dose and long-term corticosteroid treatment. Rehabilitation services should be utilized as appropriate. Depression is not uncommon, and treatment is often helpful. Sleep disorders, especially sleep apnea syndrome, should be considered as a cause of fatigue or cognitive decline. Therapy for endocrinological disturbances is important. In particular, hypothyroidism, especially hypothalamic hypothyroidism, and hypogonadism are major problems in neurosarcoidosis and should be treated. Patients receiving protracted, low-dose corticosteroid regimens require supplemental doses of corticosteroids during periods of intercurrent illness or stress. Hyperglycemia is a potential side effect of long-term, high-dose corticosteroid treatment but usually is not associated with ketoacidosis. Exercise and dietary programs are useful in managing hyperglycemia, but oral hypoglycemic agents or insulin 113 therapy may occasionally be needed. Patients with sarcoidosis are at risk for osteoporosis, especially from corticosteroid therapy. The treatment of osteoporosis in this context is a challenge because sarcoidosis may cause hypercalcemia and hypercalciuria. Management requires reduction of corticosteroid dosage when possible, cautious use of supplements of calcium and vitamin D, hormonal treatment, 114 and use of other bone-building agents. Screening and serial measurements of bone density may be particularly useful in judging an individual patient's progress. Patients with refractory neurosarcoidosis are at risk from both the sarcoidosis-associated inflammatory process and the complications of treatment. If a patient is not doing well, not only should the original diagnosis of sarcoidosis be questioned but the patient should also be evaluated for intercurrent complications such as infection, malignancy, and epidural lipomatosis. Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin's lymphoma, although a recent survey in Scandinavia failed to 115 find such an association for sarcoidosis. ALTERNATIVE TREATMENTS Treatment alternatives to corticosteroids must sometimes be considered for patients with neurosarcoidosis. Experience in this area is limited, and no alternative treatment to corticosteroids has been studied rigorously. Indications for the use of such treatments include contraindications to corticosteroids as initial therapy, serious adverse chronic corticosteroid effects, and progressive disease activity despite aggressive corticosteroid therapy. Medication alternatives to corticosteroids that have been used to treat sarcoidosis include mycophenolate mesylate, azathioprine, methotrexate, cyclophosphamide, cyclosporine, chlorambucil, hydroxychloroquine, pentoxifylline, thalidomide, and infliximab (and related 7,22,116–119 Radiation tumor necrosis factor alpha antagonists etanercept and adalimumab). therapy has also been reported to have limited success. These various approaches have not been studied in a scientifically controlled manner against placebos or comparable treatments. Such trials are difficult because neurosarcoidosis is a rare disorder with varied clinical presentations. Practically, consideration should be given to introducing alternative therapy whenever a patient shows signs of serious corticosteroid side effects or requires frequent large increases in corticosteroid dosage to control symptoms. Alternative treatment with an immunosuppressive agent or irradiation is a logical adjunctive therapy for refractory neurosarcoidosis based on current concepts of the immunopathogenic mechanisms of the disease. Alternative therapy may allow a gradual decrease in corticosteroid dosage to prevent
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or minimize corticosteroid complications, often without deterioration in the patient's clinical status. Rarely, however, can corticosteroids be eliminated completely. Some patients may continue to deteriorate despite combination therapy, and6,7,12,13 the reported mortality in neurosarcoidosis remains a substantial 5 to 10 percent. The potential adverse effects of the therapy and extent of systemic disease should determine the choice of alternative treatment. It is wise to choose an agent whose adverse effects spare an organ or organ system that may already be compromised. For example, cyclosporine usually should be avoided in patients with significant hypertension or renal disease, and azathioprine may not be the best choice for patients with 120,121 liver or hematological problems or Methotrexate, with its who have a deficiency of thiopurine S-methyltransferase. associated liver and pulmonary toxicity, poses problems for patients with impaired liver or lung function. However, in general, the side effects of these alternative medications are limited and predictable and respond to withdrawal of the offending agent. It is even possible to restart the medication in some cases, without recurrent side effects. Recent series describe promising results with methotrexate for patients with122,123 refractory Good 124 sarcoidosis or who are unable to tolerate the side effects of corticosteroids. results in treating neurosarcoidosis patients with methotrexate have also been reported. Patients in whom methotrexate treatment failed were then treated with intravenous 109 cyclophosphamide. Although these findings are promising and deserve consideration, they are based on nonrandomized and uncontrolled trials. 108
Cyclosporine has had demonstrated efficacy in some patients with neurosarcoidosis. The blood level for cyclosporine should be measured and maintained at a level similar to that used for renal transplantation patients. For some of the other alternative therapies, including azathioprine, chlorambucil, and cyclophosphamide, dosing should be targeted to achieve hematological endpoints, such as lowering the total white blood cell count to approximately 3 3 3,500/mm or the lymphocyte count to 1,000/mm . A major advantage of alternative immunosuppressant medications is that they may enable a gradual reduction of corticosteroids to108 about 15 to 30 percent of the stabilizing dose and thus offer a “corticosteroid-sparing” effect. Even with the use of alternative medication, symptoms may recur when corticosteroids are decreased below 10 mg/day. Attempts to withdraw corticosteroid therapy totally may result in worsening symptoms, suggesting that alternative immunosuppressant medication is best used as an adjunct to corticosteroids. Some patients do quite well on corticosteroid therapy alone after alternative medication has been withdrawn, and others can be maintained on the alternative agent alone. Another viable option for some patients with refractory CNS sarcoidosis is radiation therapy. The small number of reported patients treated in this way precludes definitive conclusions about efficacy. Some case reports suggest a beneficial response, especially if total nodal and craniospinal irradiation is done. A total dose of 19.5 Gy with daily fractionation of 1.5 Gy has 125 been suggested. Total nodal irradiation has also been administered in refractory patients. It appears that although radiation therapy can sometimes be of benefit, continued immunosuppressive therapy is usually necessary. Although it is not possible to predict with absolute certainty which patients with neurosarcoidosis will have disease refractory to conventional corticosteroid treatment, certain patients may have a particularly high-risk clinical profile. For instance, patients with an optic neuropathy or CNS parenchymatous disease (e.g., mass lesions or extensive encephalopathy-vasculopathy) are at especially high risk. Such patients might benefit from the prompt use of adjunctive alternative treatment should they become refractory to corticosteroids or develop intolerable side effects. Patient response to a particular alternative therapy can be determined only by trial: a good clinical response cannot be predicted and patients may show a good response to one agent after an initial failure to respond to another. If a patient is stable for several months on low-dose prednisone and an alternative treatment, slow tapering of the alternative treatment can be pursued while the clinical course is monitored. PROGNOSIS The clinical course and prognosis for neurosarcoidosis varies but is somewhat predictable. For example, some two thirds of patients have a monophasic neurological illness; the remainder have a chronically progressive or remitting-relapsing course. Those with a monophasic illness typically have an isolated cranial neuropathy, most often involving the facial nerve, or an episode of aseptic meningitis. Those with a chronic course usually have CNS parenchymal disease, hydrocephalus, multiple cranial neuropathies (especially involving 12 cranial nerves II and VIII), peripheral neuropathy, or myopathy. Patients with CNS
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parenchymal disease or hydrocephalus are at highest risk for death, from either the inflammatory process itself or complications of therapy. Mortality with neurosarcoidosis is 6,7,12,13 approximately 5 to 10 percent. Because most patients with neurosarcoidosis are treated with immunosuppressive agents, it 6,7 is impossible to determine the natural history of the untreated disorder. Although therapy can certainly improve patients in126 the short term, it is not clear that the ultimate outcome of the disease is necessarily changed. Even in severely ill or impaired patients, the inflammatory process may spontaneously subside over time. Other patients with remitting-relapsing or progressive disease can become severely incapacitated even with aggressive treatment. In monitoring the response to treatment, a target measure, such as a specific clinical sign, symptom, functional assessment, or neurodiagnostic test, should be sought. For instance, a timed walk can be used for clinical assessment in some patients; in patients with an intracranial mass, MRI is a helpful neurodiagnostic measure. This type of approach can be used to judge a response over a relatively short period of time. Despite limitations in our understanding of the natural history of sarcoidosis, treatment with corticosteroids seems to benefit many patients with neurosarcoidosis. Even more importantly, patients benefit most from a comprehensive approach to care based on an understanding of the full clinical spectrum of neurosarcoidosis, an appreciation of the whole range of treatment options, and the anticipation of complications, such as those relating to corticosteroid treatment.
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 52 Neurological Complications in Critically Ill Patients CHARLES F. BOLTON • G. BRYAN YOUNG •
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SEPTIC (SEPSIS-ASSOCIATED) ENCEPHALOPATHY Clinical Features Laboratory Features Autopsy Findings Pathogenesis NEUROMUSCULAR PROBLEMS IN THE CRITICAL CARE UNIT Critical Illness Polyneuropathy Motor Neuropathy and Neuromuscular Blocking Agents Chronic Polyneuropathies Neuromuscular Transmission Disorders and Myopathies Transient Neuromuscular Blockade Critical Illness Myopathy Critical Illness Polyneuropathy and Myopathy ELECTROPHYSIOLOGICAL STUDIES OF THE RESPIRATORY SYSTEM MONONEUROPATHIES
The term critical illness has been widely used for many years to describe the condition of any patient with illness severe enough to be considered at risk for death. In modern general medical and surgical intensive care units (ICUs), where at least 25 percent of patients may 1 have this condition, it has become synonymous with the syndrome of sepsis and multiple organ failure. This syndrome has probably always been a component of preterminal illness, but before the advent of modern methods of treatment, the syndrome evolved so quickly that the nature of the preterminal events was not considered. However, with the use of intravenous transfusions, antibiotics, activated protein C, and improvements in assisted ventilation, patients are now kept alive for days, weeks,1,2and even months in intensive or critical care units, and as many as 40 percent recover. Thus, it is now possible to study the syndrome in detail, and its effects on the various major organ systems, including the central and peripheral nervous systems. In the past, sepsis was defined as the systemic response to dividing and invading microorganisms of all types. However, in many instances the offending organism cannot be cultured. For example, blood cultures are negative in half of the patients suspected of being septic. Moreover, the criteria for diagnosing sepsis based on systemic responses are still unsettled. The term systemic inflammatory response syndrome (SIRS) should now be applied
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to a severe clinical insult that arises not only as the result of infection but also as the result of 3 noninfectious processes such as trauma, burns, and pancreatitis. The chief clinical features of this syndrome are two or more of the following: (1) temperature exceeding 38°C or less than 36°C, (2) heart rate greater than 90 beats/min, (3) respiratory rate greater than 20 breaths/min or arterial partial pressure of carbon dioxide (Paco2) less than 32 torr (4.3 kPa), 3 and (4) white blood cell count (WBC) more than 12,000 cells/mm or with more than 10 3 percent immature (band) forms. SIRS may be accompanied by hypotension (blood pressure less than 90 mmHg or a reduction of more than 40 mmHg from baseline in the absence of 4 other causes of hypotension). 2,5
In SIRS, cellular and humoral responses are activated to produce changes in the microcirculation throughout the body (Fig. 52-1). The cellular response involves epithelial and endothelial cells, macrophages, and neutrophils. These induce the humoral response; proinflammatory mediators are activated locally and include interleukins-1, -2, and -6, tumor necrosis factor (TNF)–α, arachidonic acid, coagulation factors, free oxygen radicals, and proteases. These cellular and humoral factors interact with themselves and with adhesion 6 molecules, which are increased in the blood of septic patients. Adhesion molecules adhere to leukocytes, platelets, and endothelial cells; they also induce “rolling neutrophils” and fibrin platelet aggregates that obstruct capillary flow. Endothelial damage increases capillary 2 permeability, which induces local tissue edema. Levels of protein C are reduced in sepsis. Endothelial damage impairs the endothelium-dependent activation of protein C, thus shifting 7,8 the balance to thrombosis. Activation of nitric oxide, now known to be the endovascular relaxing factor, causes arteriolar dilation, which may further slow capillary flow. Thus, essential nutrients fail to reach the organ parenchyma. For example, despite adequate oxygenation via mechanical ventilation, there is5a severe oxygen debt at the parenchymal level contributing to multiple organ dysfunction. Considering the profound disturbances of the microcirculation and the impaired delivery of substrates, especially oxygen and glucose, upon which the nervous system depends, it is not surprising that the nervous system is affected. There is no known specific treatment, but it is known that if the underlying sepsis can be brought under control by either medical or surgical means, the various manifestations of the syndrome disappear and full recovery is possible.
FIGURE 52-1 Schematic, theoretical presentation of disturbances in the
microcirculation to various organs, including brain, peripheral nerve, and muscle, in systemic inflammatory response syndrome (SIRS). The result is impaired perfusion due to excessive vasodilatation through overproduction of nitric oxide, and aggregation of cellular elements through activation of adhesion molecules and deactivation of protein C. Increased capillary permeability causes edema and the potential for entry of toxic substances. (Adapted with permission from Bolton CF: Neuromuscular manifestations of critical illness. Muscle Nerve 32:140, 2005.) The patients who are most susceptible are those suffering from multiple injuries or severe medical illness or who have just had major surgery, particularly if they are elderly or have serious underlying disease that may affect their resistance to infection. Early intubation and transfer to the critical care unit is usually necessary. In the course of time, various intravascular lines are inserted, either for treatment or to monitor vital function. There is little
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doubt that these invasive procedures induce the state of sepsis if it was not already present. Thus, it is generally recognized that patients who have been in the unit for more than 5 days almost invariably become septic and, if that is not controlled, soon develop the syndrome of multiple organ failure. Either the central or peripheral nervous systems may be affected in 70 percent of patients 9 with sepsis and multiple organ failure. Within hours of the onset of sepsis, a mild 9 encephalopathy develops, termed septic or sepsis-associated encephalopathy. When deterioration to a state of multiple organ failure occurs, this encephalopathy becomes severe, but it soon subsides if the sepsis is successfully treated. However, the clinician may then note that it is difficult to wean the patient from the mechanical ventilator. If lung and heart disease are excluded, critical illness polyneuropathy, critical illness myopathy, or a combination of 10 both (critical illness neuromyopathy) is almost always the cause of this circumstance. However, as with encephalopathy, the polyneuropathy or myopathy eventually disappears if the sepsis does not recur and the patient survives. SEPTIC (SEPSIS-ASSOCIATED) ENCEPHALOPATHY The term septic encephalopathy refers to altered brain function related to the presence of microorganisms or their toxins in the blood. This condition has been recognized by surgeons and internists as a component of multiple organ failure, but it has received little systematic study.
Clinical Features The clinical diagnosis of septic encephalopathy is one of exclusion. Altered brain function in the febrile patient can be due to a number of conditions other than the sepsis itself (Table 52-1). Space does not allow a complete discussion of the differential diagnosis, butother entities can usually be ruled out by the history, physical examination, and laboratory tests. It is often necessary to perform a lumbar puncture to exclude bacterial meningitis. Click here to view this table.... 11
We carried out a retrospective study on 12 autopsied patients and a separate clinical, prospective study involving 69 patients, each with fever and12either a positive blood culture or a localized bacterial or fungal infection as inclusion criteria. Patients with a fever and either a positive blood culture or a localized bacterial or fungal infection were included for both studies. We excluded patients younger than 16 years and those with central nervous system (CNS) disorders unrelated to the febrile illness, preexisting metabolic disorders, and conditions that affect the brain other than by a septic mechanism. In the prospective study, we also excluded patients receiving heavy sedation or analgesics and those receiving skeletal muscle relaxants. For this study, using an arbitrary set of bedside criteria, we classified patients as nonencephalopathic, mildly encephalopathic, and severely encephalopathic. In our classification, nonencephalopathic patients cooperated with testing and passed a series of tests of attention, concentration, orientation, and short-term memory. The mildly encephalopathic patients completed testing but failed to “pass,” and the severely encephalopathic patients were too obtunded to test. The clinical picture is similar to that of diffuse or multifocal encephalopathy in general. The level of consciousness varies from clouding of consciousness to coma. Delirium occurs infrequently, preceding stupor or coma. Mildly encephalopathic patients often show considerable fluctuation in their clinical state, and older individuals become especially confused at night. Attention, concentration, and memory are impaired. Writing disturbances occur, as in other acute confusional states. Paratonic rigidity, or gegenhalten (a rate-dependent resistance to passive movement), is almost universal in encephalopathic patients. Tremor, asterixis, and multifocal myoclonus occur in 10 to 25 percent of noncomatose encephalopathic patients. Alterations of pupillary size or reaction, abnormalities of individual cranial nerves, focal neurological signs, or convulsive seizures typically do not occur. Hemiparesis or gaze palsy was found in 6 and focal or generalized convulsive seizures occurred in 5 of the 12 patients in our retrospective (autopsy) series, but were rare in our prospective study. The difference may be accounted for, in part, by the duration of sepsis in the autopsy group and the pathological findings (discussed later). As expected, the mortality rate in our prospective study was12significantly greater among the severely encephalopathic patients than in the other groups. Nearly half of the severely encephalopathic patients but none of the nonencephalopathic patients died. About 25 percent of the nonencephalopathic patients had clinical and electrophysiological evidence of mild peripheral neuropathy. Among the moderately and severely encephalopathic patients, 50
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percent and 75 percent, respectively, had critical illness polyneuropathy; among the patients 12 in the latter group, the polyneuropathy was usually severe. The time courses of the encephalopathy and the polyneuropathy often differed. The encephalopathy peaked earlier and cleared long before the polyneuropathy in the course of the septic illness. Some severely encephalopathic patients were obtunded for a month or more, but CNS function improved soon after the infection and systemic metabolic problems were controlled or resolved. There was a strong association of adult respiratory distress syndrome with severe encephalopathy. Transient hypotension was more common at the onset of sepsis in the severely encephalopathic patients, although there was no difference in blood pressure among the three groups at their initial neurological assessment. The degree of prior hypotension was not sufficient to account for the neurological findings. Interestingly, none of the following correlated with the severity of encephalopathy: age (a trend for correlation of age and degree of encephalopathy did not achieve statistical significance), gender, temperature, or type of organism (no difference between gram-positive and gram-negative organisms, but patients with Candida, although few in number, were more severely affected).
Laboratory Features The electroencephalogram (EEG) is a sensitive monitor of septic encephalopathy. We found it to be more sensitive than our arbitrary clinical assessment of mental status, in that some nonencephalopathic patients had mild EEG abnormalities that resolved on subsequent recordings. The mildest EEG change consisted of mild, generalized slowing (theta activity). More severe EEG abnormalities, which correlated with more profound depression of consciousness, consisted of greater slowing (delta activity), triphasic waves, or a 13 burst-suppression pattern (Fig. 52-2). Using computational nonlinear analysis techniques, Straver and colleagues showed that EEG features correlated with the severity of illness and that the EEG became disorganized with greater severity of illness, suggesting a shift in the 14 processing ability of the brain. Although there is a direct relationship between the degree of EEG abnormality and mortality, some patients with even the most severe categories of abnormality recover. Thus, the EEG cannot be used to predict a hopeless prognosis in septic 13,14 encephalopathy.
FIGURE 52-2 Electroencephalograms (EEGs) from patients with septic encephalopathy.
A, Patient with mild encephalopathy. The EEG shows a mild excess of low-voltage 6to 7-Hz theta rhythms in both left (odd-numbered electrode placements) and right (even-numbered placements) hemispheres. B to D, Severely encephalopathic patients.
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B, Bilateral intermittent rhythmic delta (<3 Hz) waves on a background of mild slowing. C, Triphasic waves. D, Burst-suppression pattern. Serum levels of creatinine and bilirubin showed a direct, linear correlation with the severity of 13 the encephalopathy. Although hyperventilation is a feature of sepsis, there were no significant differences in blood pH, bicarbonate, or Pco2 among the three groups. In our retrospective study, a drop in platelet count was associated with the development of brain purpura and neurological signs. We did not find any abnormalities in the cerebrospinal fluid (CSF) or on unenhanced computed tomography (CT) 13 brain scans in any of our patients, including those who showed microabscesses at autopsy. Using transcranial Doppler studies, Straver and colleagues have shown an increase in cerebral mean and end-diastolic flow velocities in the brains of patients with septic 15 encephalopathy. The severity of the systemic sepsis correlated with the increased flow velocity. This finding implies that patients with severe septic encephalopathy are at risk for ischemic cerebral damage. As a corollary, care should be taken to avoid hyperventilation in such patients. The drop in Paco2 could lead to a further decrease in cerebral perfusion.
Autopsy Findings In our autopsy series, 8 of the 12 patients had disseminated microabscesses in the brain, chiefly in the cerebral cortex and subcortical white matter. Because there was some reaction in the brain around the microabscesses, these lesions did not appear to be just agonal phenomena. Four patients had increased protoplasmic astrocytes in the cerebral cortex. They were unrelated to the microabscesses and probably reflected a metabolic encephalopathy. Three patients had central pontine myelinolysis, a condition that has been related to overcorrection of hyponatremia, as discussed in Chapter 19. Vascular lesions were found in six patients: five had multiple cerebral infarcts (one terminal), and one who had thrombocytopenia before death had brain purpura. We have had only two autopsies in our prospective series, and neither showed abnormalities in the brain. The significance of the aforementioned pathological findings is not clear, mainly because these patients had been septic for weeks. There is no way of knowing with certainty when the lesions found at autopsy actually developed. It is possible that focal signs and seizures could have been produced by the lesions, but the microabscesses and vascular lesions were small and multifocal. Furthermore, occasionally focal signs and focal seizures can occur in metabolic encephalopathies. In a literature search, we could not find a study of encephalopathy in septic humans comparable to ours. As we reported in this chapter in the third edition of this book, “watershed” cerebral infarctions have been described in patients who died of septic shock, but without clinical correlations. Such watershed infarcts are ischemic lesions at or near the terminal portions of the anterior, middle, and posterior cerebral arteries, and they are typically associated clinically with bibrachial paralysis, which we have never encountered in our patients. Other authors have chosen cases with microabscesses at postmortem examination, rather than starting with clinically septic patients. There is one report of a patient dying of sepsis due to a breast abscess who showed sagittal sinus thrombosis and thrombophlebitis of cerebral cortical veins.
Pathogenesis The pathogenesis of septic encephalopathy remains uncertain; however, there are a number of possible mechanisms that are not mutually exclusive. Since mild cases resolve without sequelae, it is likely that reversible, metabolic factors are operative. The cases with neurological deficits may have one or more of the structural lesions we have found at postmortem; for example, multifocal, microscopic ischemic lesions and microabscess of the brain. The principal chemical mediators of the sepsis syndrome are cytokines, chemical messengers released from lymphocytes and macrophages. These play a key role in the alteration of the microcirculation of the brain (Fig. 52-1), increased blood–brain barrier, altered metabolism of the body, and derangements of the brain's extracellular milieu and neurotransmitter balance.
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Multifocal brain ischemia may relate to activation of “adhesion molecules,” the selectin and integrin group, causing leukocyte 5adherence or “rolling leukocytes,” which may be an early cause of endothelial cell damage. This affects nitric oxide synthesis by the endothelium. Nitric oxide is the “vascular relaxing factor”; its synthesis is increased by endotoxin and cytokines in sepsis, leading to reduced peripheral vascular resistance and hypotension. Although this seems counterproductive, such multifocal vasodilatation helps ensure adequate organ perfusion in sepsis; inhibition of nitric oxide production can lead to decreased organ 16 important role in perfusion and a fall in oxygen extraction by tissues. Nitric oxide plays an 17 regulating brain circulation and the permeability of the blood–brain barrier. Endothelial damage in sepsis may then compromise regional cerebral blood-flow and account for the multifocal, dynamic increases in blood–brain (and possibly blood–nerve) permeability mentioned earlier. Uncommonly, brain lesions relate to focal brain or disseminated intravascular coagulation. An increase in blood–brain barrier permeability in SIRS can produce multifocal vasogenic edema and alter the composition of the brain's extracellular fluid. Tumor necrosis factor–alpha and interferon-gamma increase the permeability of cerebral endothelial 18,19 It has also been shown that the perivascular end-feet of astrocytes are disrupted in cells. 20 pigs with fecal peritonitis injected with endotoxin. Alterations in the adrenergic system may also play a role: the β2-adenoreceptor agonist dopexamine inhibits brain edema in animal models of sepsis, while the α1-adenoreceptor blocker methoxamine prevents it. The combined effect increases tissue edema and alters the chemical milieu of the interstitial fluid of the brain. Cytokines themselves may directly affect brain function. Again, their access to the brain may be facilitated by alterations in blood–brain barrier function. When directly injected into the brain or ventricles of animals, interleukin-1 and interleukin-2 alter behavior 21 and EEG frequencies. Interleukin-1 facilitates sleep and induces fever by its effects on the hypothalamus. Some of these effects relate to activation of opiate receptors in the brain; the possibility of effects on other peptide systems in the brain remains to be explored. Proinflammatory cytokines may also activate STAT 3, a transcription molecule, in 22 astrocytes. The significance of this is not clear, but astrocytes play a key role in maintaining a homeostatic environment for CNS neurons. Lipopolysaccharides and proinflammatory cytokines, including interferon-gamma, upregulate inducible nitric oxide synthase (i-NOS) in 23 astrocytes. This leads to the production of reactive oxygen species such as nitric oxide and superoxide, causing oxidative stress for astrocytes and neurons of the brain. Transport of amino acids across the blood–brain barrier is altered in sepsis; that is, there is an alteration in transcapillary transport systems. This could alter the chemical milieu of the brain cells; substances normally excluded from the brain may gain access to neuronal receptors. These include drugs as well as the relative amounts of certain endogenous substances. The latter include higher ratios of aromatic to branched-chain amino acids (increased in the plasma because of altered metabolism in liver and muscle) and increased exposure to other peptides and hormones. Such changes play a role in the documented alteration of certain putative neurotransmitters in sepsis, such as serotonin, norepinephrine, and dopamine. Additional neurotransmitter alterations include increased serotonin turnover 24 and decreased noradrenergic transmission in the brain in sepsis. A similar derangement in neurotransmitter balance occurs in hepatic and uremic encephalopathy. Astrocytic dysfunction, mentioned earlier, contributes to increases in extracellular glutamate, an excitotoxic neurotransmitter that can cause neuronal death or seizures through activation of 25 N-methyl-d-aspartate (NMDA) receptors. The brain may also be affected indirectly because of the failure or altered metabolism of other organ systems. Within 5 hours from the onset of sepsis, the liver shows impaired ability to clear indocyanine green. We have found an elevated serum bilirubin12concentration in Endogenous sepsis, with a direct relationship to the severity of the encephalopathy. 26 benzodiazepine-like substance is also increased in hepatic failure. Although this has not been explored in sepsis, we have found that some patients with septic encephalopathy may improve with flumazenil, a γ-aminobutyric acid–A antagonist, even in the absence of exogenous benzodiazepines (unpublished observations). In advanced sepsis, the failure of other organs (e.g., kidneys, heart) may, in turn, affect brain function and lead to an encephalopathy. In intensive care, iatrogenic factors should always be considered. Sedative drugs, particularly opiates and benzodiazepines, are commonly used to ease the use of assisted ventilation. If renal impairment occurs, opiate clearance is reduced, and this may lead to prolonged obtundation. Brain function of critically ill patients, as reflected by the27EEG, is highly sensitive to midazolam; the same probably applies to other benzodiazepines. On a clinical basis it is difficult to determine whether encephalopathy is due to sepsis, sedative drugs, or both. Daily
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interruption of sedative drugs may partially overcome this difficulty. monitoring may also be helpful.
Continuous EEG
Total parenteral nutrition is sometimes associated with hypophosphatemia or hyperosmolality, both of which may cause coma. High serum levels of penicillin, usually in association29with renal impairment, may cause seizures, as may the newer antibiotic imipenem. Central pontine myelinolysis may complicate the sudden increases of plasma osmolality in critically ill patients. In summary, there are multiple, non–mutually exclusive mechanisms to explain septic encephalopathy. Many of these are reversible, but some mechanisms may lead to neuronal death, for example, oxidative stress, excitotoxicity, microinfarctions or osmotic demyelination. These are summarized in Figure 52-3.
FIGURE 52-3 This graphic represents the three principal cell types relevant to
septic encephalopathy: the endothelial cell in brain capillaries, the astrocyte, and the neuron. Conceptually the encephalopathy can be divided into dysfunction that is reversible or irreversible, with structural changes in the brain. Further discussion is provided in the text. AA, amino acid; ARAS, ascending reticular activating system; BBB, blood–brain barrier; fx, function; rCBF, regional cerebral blood-flow. (From Wilson JX, Young GB: Progress in Neurosciences: Sepsis-associated encephalopathy—evolving concepts. Can J Neurol Sci 2003;30:98, with permission.) NEUROMUSCULAR PROBLEMS IN THE CRITICAL CARE UNIT The list of conditions that can affect the neuromuscular system in patients in the critical care unit is remarkably long and potentially involves dysfunction of the entire nervous system (Table 52-2). To pinpoint the site of dysfunction may be extremely difficult, especially in the setting of the critical care unit. History taking is often impossible, as an endotracheal tube prevents speech, and the often associated encephalopathy prevents reliable communication of any type. The limbs are not easily assessed, owing to the presence of intravenous lines, splints, bandages, and so forth. Thus, although a neurological examination tailored to the comatose patient may provide some assessment of the nervous system, we have found that the presence and severity of either brain or peripheral nervous system dysfunction is often difficult to document by purely clinical methods. Click here to view this table.... De Jonghe and co-workers in France tested muscle strength in critically ill patients when they 30 in became alert enough to voluntarily activate the muscles. However, they found weakness 10 only 25 percent, less than half of those identified by electrophysiological methods. Thus, we routinely use electrophysiology to assess such patients. Using electrophysiological tests, we have found that both septic encephalopathy and critical illness polyneuropathy are almost invariable manifestations of the sepsis and multiple organ failure syndrome, and the other conditions listed in the table are only rarely involved. In fact, these other conditions are usually evident before the patient has been admitted to the critical care unit and are the obvious reason for neuromuscular respiratory failure. Myasthenia gravis and Guillain–Barré syndrome are good examples, although in some instances it is necessary to exclude these
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conditions systematically. Repetitive nerve stimulation may be required to investigate for a defect in neuromuscular transmission. Such studies have revealed the presence of 31,32 myasthenia gravis or the Lambert–Eaton myasthenic syndrome not previously suspected. 33 Electrophysiological studies may disclose motor neuron disease for the first time. Muscle biopsy may be necessary to exclude primary myopathies such as polymyositis or a metabolic disturbance such as acid maltase deficiency. Except for critical illness polyneuropathy, the Guillain–Barré syndrome is, in our experience, the most common neuromuscular problem seen in the unit. It can almost invariably be recognized by clinical features occurring prior to admission to the critical care unit, by the pattern of abnormalities on electromyography (EMG) and nerve conduction studies, and by CSF examinations. The following sections focus on the major neuromuscular conditions to be considered in critically ill patients being managed in critical care units.
Critical Illness Polyneuropathy Critical illness polyneuropathy (Table 52-3) is a predominantly motor, axonal polyneuropathy occurring as a complication of the systemic inflammatory response (septic) syndrome in 50 to 34–38 Since as many as 50 percent of patients in 70 percent of patients with that syndrome. major medical and surgical critical care units have the syndrome, critical illness polyneuropathy must now be regarded as a particularly common neuromuscular disorder. Critical illness myopathy may be common in units that frequently use neuromuscular blocking 39 agents and steroids. Click here to view this table.... The first, and often the only, clinical sign of critical illness polyneuropathy is respiratory muscle weakness, manifested as a difficulty in weaning from the mechanical ventilator. Other neuromuscular causes of difficulty in weaning may be trauma to the phrenic nerve, neuromuscular transmission defect, primary myopathy, and disorders of central drive due to 31 an associated encephalopathy. In severe critical illness polyneuropathy there are weak or absent movements of the limbs, even when the limbs are stimulated distally by pressure over the nail beds. Tendon reflexes that were previously present cannot be elicited. By contrast, head, face, and jaw movements are relatively preserved. In two of our patients, this absence of movement in the extremities but preservation of movement of the head had erroneously been diagnosed as resulting from high cervical spinal cord disease. Patients with lesser degrees of polyneuropathy show more equivocal signs, with variably weak muscles, particularly distally, and reduced or absent tendon reflexes, notably at the ankles. However, many patients have no clinical signs of neuromuscular disease. The polyneuropathy tends to be more severe the longer that the patient is in the unit. Electrophysiological studies clearly establish the presence of a peripheral neuropathy and 38 document its severity. Upper- and lower-limb motor and sensory conduction studies initially reveal only a reduction in the amplitude of compound muscle and sensory nerve action potentials, with no change in latency or conduction velocity. The duration of the compound muscle action potential (CMAP) may be prolonged, suggesting primary dysfunction of the 10 muscle fiber membrane in addition to denervation (Fig. 52-4). Then, within a matter of 2 weeks, fibrillation potentials and positive sharp waves appear in muscle, and sensory and compound muscle action potentials are further reduced. Even in the more advanced stages of critical illness polyneuropathy, conduction velocity and distal latencies remain relatively normal, emphasizing the purely axonal, degenerative nature of the neuropathy.
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FIGURE 52-4 Measurement of compound thenar muscle action potentials at the
onset of sepsis (A) and 3 weeks later (B). Note the marked decline in amplitude and increase in duration, without change in latency, on stimulation of the median nerve at the wrist and elbow. These changes suggest primary dysfunction of the muscle fiber membrane in addition to denervation. (From Bolton CF: Evidence of neuromuscular dysfunction in the early stages of the systemic inflammatory response syndrome. Intensive Care Med 19:1179, 2000, with permission.) Comprehensive examination of the entire nervous system at autopsy, plus nerve and muscle biopsy, has revealed that there is a primary axonal degeneration36,40 of motor and sensory fibers, There is a resulting particularly involving distal nerve fibers (Fig. 52-5 and Fig. 52-6). denervation atrophy of muscle; histopathological examination during the acute phase reveals scattered, angulated fibers and later shows grouped atrophy (Fig. 52-7). Neither the nerve nor the muscle shows any inflammatory change. Aside from chromatolysis of the anterior horn cells secondary to the peripheral axonal injury, the CNS is spared. Axonal degeneration of intercostal and phrenic nerves and denervation atrophy of respiratory muscles explain the respiratory insufficiency. Latronico and associates found that some patients have abnormal electrophysiological but normal biopsy findings of 40 nerve and muscle, suggesting that functional changes precede structural alterations.
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FIGURE 52-5 Transverse section of the superficial peroneal nerve showing
severe axonal degeneration and loss of myelinated fibers. (Toluidine blue; original magnification 773×.) (From Zochodne DW, Bolton CF, Wells GA, et al: Critical illness polyneuropathy: a complication of sepsis and multiple organ failure. Brain 110:819, 1987, with permission.)
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FIGURE 52-6 Longitudinal section of the deep peroneal nerve demonstrating
axonal degeneration and loss of myelinated fibers. (Toluidine blue; original magnification 778×.) (From Zochodne DW, Bolton CF, Wells GA, et al: Critical illness polyneuropathy: a complication of sepsis and multiple organ failure. Brain 110:819, 1987, with permission.)
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FIGURE 52-7 Transverse section of iliopsoas muscle showing scattered and
grouped atrophic fibers consistent with denervation atrophy. (Hematoxylin and eosin; original magnification 195×.) (From Zochodne DW, Bolton CF, Wells GA, et al: Critical illness polyneuropathy: a complication of sepsis and multiple organ failure. Brain 110:819, 1987, with permission.) The mechanism of the polyneuropathy is not known. However, our investigations have excluded potential causes of polyneuropathy, including Guillain–Barré syndrome, various 41 toxins, drugs (particularly antibiotics), and nutritional deficiency. It is our belief that the polyneuropathy is probably caused by the same fundamental defect that affects all organ systems in the critical illness syndrome through involvement of the microcirculation (Fig. 41 52-1). We speculate that the primary axonal damage may be due to involvement of axonal transport systems, which are known to be energy-dependent; this fact may explain why predominantly distal nerve segments are involved. Moreover, it is known that the blood–nerve barrier, in contrast to the blood–brain barrier, shows increased permeability to histamine and serotonin. Several mediators of the septic syndrome are known to have histamine-like action. Circulating “toxins” could potentially gain access to the endoneurial space and directly damage the axon. It is also possible that disturbance of the microcirculation, as has been postulated to occur in sepsis and multiple organ failure, is the mechanism by which these events in peripheral nerve are initiated. Our studies provide no evidence that the use of antibiotics causes the polyneuropathy. Indeed, because successful treatment of the sepsis results in improvement in the polyneuropathy, we advise that all medical and surgical means of improving the sepsis and multiple organ failure be instituted. Moreover, all critical care units should use whatever methods are necessary to avoid sepsis (e.g., use of sterile techniques and avoidance of invasive procedures unless absolutely necessary). Although we have no evidence that the polyneuropathy is due to nutritional deficiency, it seems prudent to administer total parenteral or enteral nutrition from the start of critical illness. Those individuals responsible for physical therapy and rehabilitation should be aware of the nature and severity 42 of the polyneuropathy, so that they will take it into account as the patient gradually recovers. Intravenous immune globulin has been widely used to treat sepsis but appears to have little
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43,44
effect on critical illness polyneuropathy. Interventions to interrupt the septic cascade utilizing monoclonal and polyclonal antibodies directed against bacterial endotoxin, oxygen radical scavengers, platelet activating factor receptor antagonists, and hemofiltration 10 techniques and plasma exchange have had little effect on the septic syndrome. Administration of recombinant activator protein 1 to reduce intravascular 2thrombosis improved morbidity and mortality, but polyneuropathy was not evaluated. The most interesting recent development was the well-designed study by van den Berghe and associates showing that better control of blood glucose levels utilizing insulin not only improves morbidity and mortality but also reduces the incidence of critical illness 45 polyneuropathy.
Motor Neuropathy and Neuromuscular Blocking Agents Polyneuropathy may develop in patients who have been in the critical care unit for several days, or possibly weeks, and received competitive neuromuscular blocking agents, such10as pancuronium bromide or the shorter-acting vecuronium, to ease mechanical ventilation. These agents will have been used for longer than 48 hours, occasionally for days or weeks. When these agents are discontinued, difficulty in weaning the patient from the ventilator and limb paralysis are noted. The serum creatine kinase (CK) level is mildly or moderately elevated. Electrophysiological testing sometimes reveals a defect in neuromuscular transmission. If present, it will be demonstrated on slower rates of stimulation, as expected with a postsynaptic defect. There is evidence of severe primary axonal degeneration of predominantly motor fibers on nerve conduction and needle EMG studies. Muscle biopsy shows varying degrees of denervation atrophy and muscle necrosis. Although the mechanism of this neuropathy is unknown, we believe that sepsis38is an important underlying factor in the condition of most, if not all, of these patients. Thus, if the various systemic complications can be treated successfully, the neuromuscular condition itself36,38 improves spontaneously and good recovery may occur, sometimes quite rapidly. 37,40,46 and others have failed to implicate neuromuscular blocking agents as a cause We of critical illness polyneuropathy. However, the neuromuscular blocking agent probably has an additional toxic effect on nerve and muscle, and its use should be avoided, if possible.
Chronic Polyneuropathies Occasionally, chronic polyneuropathies will evolve as rapidly developing respiratory insufficiency. Although rare, this may occur in chronic inflammatory demyelinating polyneuropathy and diabetic polyneuropathy. It is generally worthwhile to undertake phrenic nerve conduction studies and needle EMG of the diaphragm to show clearly that the respiratory insufficiency is due to the neuropathy. Such studies complement the conventional electrodiagnostic studies that document the presence of a polyneuropathy.
Neuromuscular Transmission Disorders and Myopathies As noted previously, neuromuscular transmission disorders and myopathies are more varied and complex and may be difficult to distinguish from critical illness polyneuropathy and especially from the motor axonal neuropathy or critical illness myopathy that may be associated with the SIRS and the use of competitive neuromuscular blocking agents and steroids. Electrophysiological studies, measurements of blood CK level, and at times muscle biopsy will usually further define the nature of the muscular weakness (Table 52-3). Transient Neuromuscular Blockade Competitive neuromuscular blocking agents, often used to ease mechanical ventilation, are metabolized or cleared by the liver and kidney. Hence, in the presence of failure of these organs, the effect of the neuromuscular blocking agent may be prolonged for a number of 47 days after it has been discontinued. Repetitive stimulation studies will correctly identify the defect in neuromuscular transmission. However, by the time of testing, many of these patients will already have developed an underlying critical illness polyneuropathy in addition to a neuromuscular transmission defect, each disclosed by electrophysiological studies. Recovery may be prolonged for several weeks or even months in severe cases. Critical Illness Myopathy 48
An acute myopathy often affects critically ill patients. Whereas acute quadriplegic myopathy
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has been the most common designation, others include critical care myopathy, acute necrotizing myopathy of intensive care, thick filament myopathy, critical illness myopathy, acute corticosteroid myopathy, acute hydrocortisone myopathy, acute myopathy in severe asthma, and acute corticosteroid and pancuronium–associated myopathy. The term critical 49 illness myopathy is now considered the most appropriate description for this syndrome. By definition, patients are or were critically ill, and weakness should have started after the onset of critical illness. Critical illness myopathy may occur independently of, or in association with, critical illness polyneuropathy. De Letter and co-workers showed a relationship between the early onset and severity of critical illness polyneuropathy and myopathy and Apache III scores, which 50 myopathy develops in at measure the severity of critical illness and sepsis. Critical illness 51 of patients after least one third of ICU patients52treated for status asthmaticus, in 7 percent 53 orthoptic liver transplantation, and in patients after heart transplant. It may occur in the severe acute respiratory syndrome (SARS), even though there is no evidence of virus on 54 55 culture and electron microscopy. In a prospective study by Trojaborg and colleagues, all 22 critically ill patients showed clinical, electrophysiological, and muscle biopsy evidence of a primary myopathy. The major feature is flaccid weakness, which tends to be diffuse, involving all limb muscles and the neck flexors and often the facial muscles and diaphragm. Thus, most patients are 56 difficult to wean from mechanical ventilation. Ophthalmoplegia may be present. Tendon reflexes are often depressed, but normal reflexes do not exclude the diagnosis. Myalgias are uncommon. Although the myopathy develops acutely, the time of onset is usually difficult to determine because of the commonly associated encephalopathy and administration of neuromuscular blocking agents. Nerve conduction studies reveal low-amplitude CMAPs, some of which may be of long observed this prolongation in every muscle tested duration (Fig. 52-4). Park and co-workers 57 in patients with critical illness myopathy. The sensory nerve action potentials (SNAPS) should be normal but may be reduced in amplitude owing to tissue edema. Near-nerve recordings overcome this difficulty. Examination of motor unit potentials may be impaired by the attendant septic encephalopathy and sedation. This difficulty may be partially overcome by recording from the tibialis anterior muscle and activating motor units by plantar stimulation. Fibrillation potentials and positive sharp waves will be present in both critical illness myopathy and neuropathy. In critical illness myopathy, motor unit potentials are of low amplitude and short duration, with high-frequency components. Quantitative studies of motor unit potentials 55 confirm that their duration is decreased. However, such units are also seen in critical illness polyneuropathy with predominantly distal motor axonopathy, as demonstrated in single-fiber 58 of the muscle membrane can be demonstrated by direct studies. Electrical inexcitability 59 patients with severe critical illness myopathy and needle stimulation of the muscle in 60 markedly reduced or absent CMAPs. In critical illness polyneuropathy, there is a response to direct muscle stimulation but not to stimulation of the nerve supplying the muscle. Direct 61,62 muscle stimulation may therefore be helpful in the differentiation of these two disorders. However, the results of direct muscle stimulation are only semiquantitative, and this, coupled with the coexistence of critical illness neuropathy and myopathy, may make interpretation difficult. Trojaborg has proposed an electrophysiological approach using the methods noted, 63 plus motor unit estimate techniques. A more consistent and easily measured response is the duration of the CMAP, which is increased in duration in a manner consistent with a primary myopathy (Fig. 52-4). Determination of serum CK level may be helpful in differential diagnosis (Table 52-3). 64,65 whereas in other types of Markedly elevated levels suggest a necrotizing myopathy, critical illness myopathy the serum CK elevations66are not so severe and may be delayed for serum CK levels in critical 10 days or more after administration of steroids. By contrast, 36 illness polyneuropathy are normal or only mildly elevated. Phrenic nerve conduction studies and needle EMG of the diaphragm and chest wall muscles 67 are valuable in assessing patients with suspected critical illness myopathy. Phrenic nerve conduction studies typically show normal latencies but diaphragm CMAP amplitudes may be reduced, with a return toward normal as recovery occurs. Needle EMG may reveal positive sharp waves and fibrillation potentials in respiratory muscles. Motor unit potentials may be difficult to interpret in the diaphragm because they normally have a “myopathic” appearance. Identification of the subtypes 10 of critical illness myopathy, as described here, may aid in prognostication (Table 52-3). Thick-Filament Myosin Loss
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This syndrome, frequently termed acute quadriplegic myopathy, occurs in the setting of sudden, severe asthma or in post-transplant patients requiring tracheal intubation and placement on a ventilator in combination with high-dose corticosteroids and neuromuscular blocking agents. It68is a rare complication in critically ill children, post-transplant children being especially at risk. Serum CK levels may be elevated only mildly. Muscle biopsy shows destruction of the thick myosin filaments, often seen on light microscopy but found more definitively on electron69microscopy. The typical histopathological features are shown in Figure 52-8 and Figure 52-9. There is no specific treatment. The best approach is to avoid neuromuscular blocking agents and, especially, steroids, or to use these medications as sparingly as possible.
FIGURE 52-8 Both histochemical type 1 and type 2 fibers show extensive
central pallor. Myofibrillar ATPase (pH 9.4; 50×). (From Danon MJ, Carpenter S: Myopathy and thick filament [myosin] loss following prolonged paralysis with vecuronium during steroid treatment. Muscle Nerve 14:1131, 1991, with permission.)
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FIGURE 52-9 At high magnification, central, sharply bounded A-band loss
contrasts with its peripheral preservation. (Epoxy resin section, paraphenylene diamine, phase optics 1380×.) (From Danon MJ, Carpenter S: Myopathy and thick filament [myosin] loss following prolonged paralysis with vecuronium during steroid treatment. Muscle Nerve 14:1131, 1991, with permission.) Rhabdomyolysis
Rhabdomyolysis occurs in the setting of critical illness and the use of neuromuscular blocking 70 agents and corticosteroids. It may be due to a variety of causes and presents with weakness, myalgia, and swelling in the affected muscles. Massive muscle necrosis results in the release of potassium and initially sequesters calcium. The resultant hyperkalemia and hypocalcemia may produce life-threatening cardiac arrhythmias and renal failure. Serum CK level is elevated, often to greater than 10,000 IU/L. Myoglobinuria occurs frequently. The electrophysiological findings are those of an acute myopathy. Motor and sensory nerve conduction studies are usually normal. On needle EMG, fibrillation potentials are usually 71 sparse and transient and motor unit potentials often normal. Muscle biopsy may be normal or show varying degrees of myofiber necrosis without inflammation, myosin loss, or other specific features. Thus, despite considerable weakness and elevated serum levels of CK, EMG and muscle biopsy are often unimpressive, consistent with rapid and complete recovery. During bacteremia, microabscesses may be deposited throughout skeletal muscle and present the clinical picture of acute rhabdomyolysis. Blood culture will identify the offending organism, and muscle biopsy will identify the microabscesses. This is a variant of pyomyositis 10 typically seen in tropical countries or in children. Acute Necrotizing Myopathy 64,65
Acute necrotizing myopathy of intensive care may be simply an extension of acute rhabdomyolysis and is induced by the same variety of infective, chemical, and other insults.
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Serum CK levels are markedly elevated, myoglobulinuria is present, electrophysiological examinations suggest a severe myopathy, and pathological studies show widespread 65 necrosis of muscle fibers. Recovery of muscle strength may not occur in severe cases. Cachectic Myopathy
Muscle weakness and wasting commonly occur in starvation and malnutrition, as in anorexia 72,73 and are termed cachectic nervosa or following gastric bypass surgery for morbid obesity myopathy or disuse atrophy. It is likely a common complication of critical illness and accounts for significant wasting and weakness of muscle. Electrophysiological findings and serum CK levels are normal. Muscle biopsy is normal or reveals type II fiber atrophy. The diagnosis of cachectic myopathy is made by exclusion of other neuromuscular complications of critical illness. Management of Critical Illness Myopathy
Whether a clinician should routinely pursue a muscle biopsy in order to distinguish critical illness myopathy from other myopathies or from critical illness polyneuropathy is questionable. Muscle biopsy should be considered if another myopathic process, such as an inflammatory myopathy, is suspected or if the histological findings may affect management. For example, a firm diagnosis of critical illness myopathy may lead to avoidance of intravenous corticosteroids or neuromuscular blocking agents. As indicated in Table 52-3, the various types of critical illness myopathy can be distinguished by clinical, electrophysiological, 10 Severe critical illness and histological features. This is important for prognosis. 64 polyneuropathy and necrotizing myopathy of intensive care may have a poor prognosis for recovery of strength, but the prognosis is much better for rhabdomyolysis, cachectic myopathy, and thick filament myosin loss. Critical Illness Polyneuropathy and Myopathy The predominance of either critical illness polyneuropathy or myopathy in individual patients probably varies depending on the use of neuromuscular blocking agents and corticosteroids. Thus, in an ICU where these medications were used in post-transplant patients, the incidence 39 of critical illness myopathy was high ; by contrast, in another ICU where there were no post-transplant patients and neuromuscular blocking agents and steroids were rarely used, 38 the incidence of myopathy was low. Sepsis is likely the predominant underlying factor, with the additional factors of neuromuscular blocking agents and corticosteroids combining to account for the pathophysiology (Fig. 52-10).
FIGURE 52-10 A simplified depiction of theoretical mechanisms of dysfunction
in critical illness polyneuropathy and myopathy. Sepsis with disturbance of microcirculation is a common underlying factor, neuromuscular (N-M) blocking agents enhance denervation, and corticosteroids subsequently induce a myopathy with thick-filament myosin loss. Varying pathological changes in muscle may result. In the early stages of sepsis, there may be a purely functional loss, with no structural change in nerve or muscle. (From Bolton CF: Neuromuscular complications of sepsis. Intensive Care Med 19:S58, 1993, with permission.) The range of severity of combined critical illness polyneuropathy and myopathy may be quite 10 marked. Despite severe respiratory and limb weakness with electrophysiological evidence of predominant involvement of muscle and marked elevations of serum CK, the patient may
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make a rapid recovery if the muscle biopsy is normal. Conversely, recovery may not occur in patients with clinical and electrophysiological evidence of severe involvement of both nerve and muscle, high levels of serum CK, myoglobin in the urine, and necrosis of muscle on morphological study. Latronico and associates reported that 74 of 263 patients (28%) with combined critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) were left 74 with severe disability. ELECTROPHYSIOLOGICAL STUDIES OF THE RESPIRATORY SYSTEM The techniques of phrenic nerve conduction and needle EMG of the diaphragm have proved of great value in establishing that respiratory insufficiency is due to a neuromuscular disorder. The techniques can indicate impairment of “central drive” as a disturbance of the voluntary or automatic centers of respiration, or impairment of phrenic nerves, neuromuscular junction, or muscle. For example, in patients with Guillain–Barré syndrome, the degree of involvement of the phrenic nerves can be determined and will supplement measurements, including of vital 75 capacity, in determining the need for respiratory assistance. Documenting the degree of axonal degeneration or demyelination of phrenic nerves aids in long-term prognostication. In a study of 40 patients who had difficulty in weaning from the ventilator76when a neuromuscular cause was suspected, 38 were shown to have such a of both disorder. In an earlier study, Spitzer and associates also found a high incidence 77 polyneuropathy and myopathy as causes of prolonged difficulty in weaning. Most had critical illness polyneuropathy, but there were varying combinations of unilateral phrenic nerve damage, neuromuscular transmission defects, and primary myopathies. Combined electrophysiological studies of limbs and the respiratory system are therefore of assistance in identifying these conditions and rendering a prognosis. MONONEUROPATHIES A variety of mononeuropathies may occur in patients being treated in the critical care unit. Lumbosacral or brachial plexopathies may be secondary to direct trauma, usually from motor vehicle accidents or surgery. Insertion of catheters into the iliac arteries or aorta may dislodge thrombi, and the resulting emboli impair vascular supply to nerves and, in this manner, induce focal ischemic plexopathy. Direct surgical trauma to vessels may also induce vascular insufficiency. Motorcycle accidents commonly injure the brachial plexus. Proximal lesions are suggested by Horner's syndrome, winging of the scapula, and diaphragm paralysis. Electrophysiological studies, ideally performed after 3 weeks, further help to localize the lesion. Myelography, CT myelography, or magnetic resonance imaging (MRI) may provide more positive evidence of root avulsion, which would preclude attempts at operative nerve repair. Fractures of the pelvis may cause varying patterns of damage to the lumbosacral plexus. Observations of focal weakness on reflex-induced voluntary movement, plus abnormalities of the tendon reflexes, may provide an initial clue to the presence of such damage. Thus, weakness of hip adduction and flexion and of knee extension and an absent patellar reflex suggest damage to the L2–L4 roots of the lumbosacral plexus. Electrophysiological studies should successfully demonstrate abnormalities on motor and sensory nerve conduction studies and, in particular, needle EMG should localize the lesion to the brachial or lumbosacral plexus. There are several types of mononeuropathies. If the patient's primary reason for admission to the unit was the postoperative state, the initial surgery may have induced a mononeuropathy when operating room equipment, or perhaps the surgery itself, directly damaged peripheral nerves, since a variety of limb nerves may be damaged by trauma. For example, weakness of dorsiflexion of the wrist and digits and an absent brachioradialis reflex suggest radial nerve damage in the spiral groove of the humerus by fracture or direct compression. Phrenic nerves may be damaged, either bilaterally or unilaterally, at the time of surgery by direct trauma or by the application of cold, as occurs with the hypothermia associated with cardiac surgery. More distal nerves may be damaged as the result of impairment of nutrient blood supply through distal embolization. Thus, following cardiac or vascular surgery, patients may have varying combinations of involvement of femoral or sciatic nerves. Electrophysiological studies show a relatively pure axonal degeneration of motor and sensory fibers. Patients who are being anticoagulated run the risk of hemorrhage. The sudden rise in tissue pressure produces a “compartment syndrome,” the severe compression resulting in ischemia
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to nerve, as well as muscle. The compartments most commonly involved are the iliopsoas and gluteal, producing acute femoral or sciatic neuropathies. Fractures and soft tissue trauma may also induce compartment syndromes. An immediate CT scan should be ordered, which will show the location of the hemorrhage. Then, surgical decompression may successfully decompress the nerve. The situation is so acute and urgent that electrophysiological studies are of little value. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 53 Neurological Complications of Imaging Procedures WILLIAM P. DILLON • CHRISTOPHER F. DOWD •
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COMPLICATIONS OF INTRAVENOUS INJECTION OF CONTRAST MATERIAL Iodinated Contrast Media Contrast Media for Magnetic Resonance Imaging Miscellaneous Complications of Contrast Media NONINVASIVE IMAGING PROCEDURES Computed Tomography Magnetic Resonance Imaging SPINAL PROCEDURES Myelography and Intrathecal Injections of Contrast Media Terminology Technique Complications of Intrathecal Puncture Complications of C1–C2 Puncture Complications Related to Contrast Agent Discography Epidural and Transforaminal Anesthetic Neural Block ANGIOGRAPHY Cerebral and Aortic Angiography Spinal Angiography Peripheral Angiography EMBOLIZATION AND STENTING PROCEDURES
Neurological complications of imaging procedures are varied and largely related to either local complications of an invasive procedure or complications arising from the systemic use of intravenous contrast agents. This chapter provides a summary of neurological complications related to those imaging procedures that are commonly performed in modern radiological practices. Some historical perspective is presented as well, and the reader must be aware that changes in the practice of radiological procedures affect the kinds of complications and their incidence over time. COMPLICATIONS OF INTRAVENOUS INJECTION OF CONTRAST MATERIAL Radiographic contrast agents have been in use for over 70 years and are employed in approximately 10 million radiographic procedures annually in the United States. They find
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wide use in the evaluation of disease processes both within the central nervous system (CNS) and throughout the body. Contrast material helps define normal vascular anatomy as well as pinpoint patterns of abnormal contrast enhancement indicative of pathological processes. Most patients tolerate radiographic contrast with few or no side effects.
Iodinated Contrast Media Iodinated contrast medium is currently available in ionic and nonionic, water-soluble formulations. Ionic contrast media are less expensive but are associated with a higher incidence of adverse reactions than nonionic contrast agents; approximately 4 to 12 percent of patients receiving ionic media experience some hypersensitivity reaction within minutes or after several hours compared with 1 to 3 percent of patients receiving nonionic contrast 1 media. Nonionic contrast agents have largely replaced ionic contrast media for intravascular use throughout the body and should be used exclusively in children younger than 2 years, patients at risk for allergic reactions, and those with renal failure, diabetes, cardiopulmonary disease, or serious illnesses. Another advantage of nonionic agents is their isotonicity, which 1 markedly reduces the sensation of heat and flushing. The toxicity of ionic contrast media is well documented and is related to the tonicity, ionic2 charge, and chemical toxicity of the agents, as well as allergic/anaphylactic phenomena. Idiosyncratic allergic reactions may occur on first or subsequent contrast administration and range from hives to more severe reactions such as pulmonary or cerebral edema, laryngospasm, bronchospasm, and cardiovascular collapse. Dose-related effects of tonicity and chemical toxicity mainly affect the heart, lungs, and kidneys and include cardiovascular depression and renal failure. Secondary neurological symptoms and signs may result when significant cardiorenal dysfunction occurs. Life-threatening reactions occur on the order of 0.05 to 0.16 percent of ionic contrast media injections and 0.03 percent with nonionic contrast materials; the death rate, however, is similar1,3with both types of agents, occurring in approximately 1 to 3 per 100,000 injections. The most common major neurological complication ascribed to ionic contrast2,4,5 media is a Seizures and seizure, which occurs primarily in patients with primary or metastatic tumors. parkinsonian symptoms as well as cortical blindness have also been reported after the use of 6–8 ionic media during cardiac or vertebral angiographic procedures. The latter syndrome is usually transient and has been associated with abnormal retention of contrast medium within the occipital cortex. It has been postulated that a time- and dose-related breakdown of the blood–brain barrier leads to subsequent direct neuronal toxicity. Aggravation of myasthenia 9 gravis is a potential risk of intravenous ionic contrast administration but appears to be somewhat less frequent with the nonionic formulations. These complications are now rarely seen because low osmolality, non-ionic contrast media have largely replaced ionic media for intravascular use. Regardless of the type of contrast medium used, extravasation into the soft tissues of the arm at the time of injection may lead to local tissue injury, including skin necrosis. The risk of severe soft-tissue injury is greatest with extravasation of ionic contrast agents that have been 10 injected by power injectors. Swelling, which attends severe extravasation injuries, can also lead to compartment syndromes and therefore to injury of the peripheral nervous system. Automated power injectors, which are used in daily practice, may result in the extravasation of large volumes of contrast material, leading to severe tissue damage. Infants, young children, and unconscious and debilitated patients (diabetics, chemotherapy patients) are 11 particularly at risk of extravasation.
Contrast Media for Magnetic Resonance Imaging Contrast media for magnetic resonance imaging (MRI) have a lower toxicity profile and much higher patient tolerance than iodinated contrast media. Most magnetic resonance contrast agents are variations of chelates of gadolinium, a lanthanide metal. Gadolinium is toxic in its free form, but through chelation with DTPA or other moieties is safely distributed and then eliminated from the body by renal clearance. Both ionic and nonionic formulations of gadolinium are available. Gadolinium-based contrast media are safe and well tolerated by the 12,13 Minor vast majority of patients; the incidence of complications is less than 0.5 percent. side effects, including headache, nausea, and vomiting, are sometimes noted,14but the risk of anaphylaxis is extremely low, on the order of 1 per several 100,000 injections. Nonetheless, 15 severe reactions and death secondary to gadolinium administration have been reported. Li and associates showed that among 45 patients who developed reactions to gadolinium, only 3 (6.7%) had prior adverse reactions to iodinated contrast, 3 had prior reactions to a different 12 gadolinium-based compound, and 10 had prior food or drug allergies (9) or asthma (1).
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Gadolinium agents cross the placenta, with undetermined effects on developing fetuses, and are seen in small amounts in the breast milk of lactating mothers; therefore, they are not 16 recommended for use in pregnant or lactating women unless absolutely necessary. To our knowledge, there have been no reports of gadolinium-based contrast agents causing seizures. Recent reports of systemic nephrogenic fibrosis, characterized by fibrosis of skin and other organs, following gadolinium administration in patients with renal failure have raised concern about the use of gadolinium contrast in this setting. Dialysis immediately following gadolinium administration is recommended to minimize this possible 17,18 complication. Other novel MRI contrast agents are also now available for limited clinical applications. The superparamagnetic iron chelates recently have been approved. These work on the basis of reducing signal within normal tissues such as19–21 lymph nodes and liver and thus providing Chelates of manganese are also approved contrast for nonenhancing abnormal tissues. for liver imaging. Free manganese has a theoretical risk of parkinsonian complications, but 22 the chelated compound caused no serious side effects during phase 2 clinical trials. Intravascular contrast agents are being evaluated and promise to improve magnetic resonance angiography and perfusion of brain tumors.
Miscellaneous Complications of Contrast Media Reflux of ionic x-ray contrast medium has been reported into the abdominal port of a ventriculoperitoneal shunt after bladder rupture sustained during voiding cystourethrography. This extravasated contrast medium then tracked up the ventriculoperitoneal shunt, causing 23 seizures and ventriculitis. Venous air embolism has been documented during infusion of contrast medium, due to either 24,25 scalp vein malposition or inadvertent trapping of air within power injectors or tubing. Venous air embolism can cause stroke, especially in infants with patent cardiac foramen ovale or other right-to-left shunts. The presence of iatrogenic air in the venous sinuses is important to recognize and distinguish from infectious causes. Acetazolamide, a vasodilator of the cerebral circulation, is now occasionally administered before perfusion MR and computed tomography (CT) studies. Comparison of studies before and after acetazolamide allows determination of the cerebral vascular reserve. Acetazolamide, although well tolerated, has minor side effects such as nausea and headache. It is a diuretic, so adequate hydration and satisfactory serum potassium levels must be ensured, particularly in those already receiving diuretics for medical reasons. Acetazolamide is probably not indicated in the setting of acute stroke because its diuretic effect may reduce cerebral perfusion. NONINVASIVE IMAGING PROCEDURES
Computed Tomography Direct and acute neurological effects from CT itself have not been reported. Neurological complications of x-ray CT are usually related to complications of sedation, contrast administration, or other mishaps that incidentally attend the procedure. There is a theoretical risk of irradiation-induced cataracts or tumors following multiple CT studies. This concern has increased with recent technological advances: helical-mode scanners are now used routinely in CT angiography and CT perfusion studies to scan rapidly large regions of the body. Multiple scans during infusions of contrast material may result in additional irradiation exposure. For this reason, MRI may be a better method of following patients who require repeated imaging procedures, if they are able to tolerate this examination.
Magnetic Resonance Imaging MRI has rapidly gained wide acceptance in the imaging of the CNS as well as for musculoskeletal and many cardiac and general body applications. Images are produced by placing a patient in an extremely strong applied static magnetic field (on the order of 15,000 to 30,000 times the earth's magnetic field) and then probing the magnetic relaxation properties of water protons in the body using radiofrequency pulses; computer mathematical manipulation allows the production of images. Because of the need for a very strong continuous magnetic field, the presence of metal objects in or around the imaging environment can be hazardous, since they can accelerate as missiles, harming patients and staff. Patients, staff, and others coming into proximity of
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the magnet are therefore routinely screened for ferromagnetic objects. The major contraindications to MRI examinations include the prior placement of ferromagnetic aneurysm clips or cardiac pacemakers, intraocular metallic foreign bodies, certain types of prosthetic cardiac valves, electronic or magnetically activated medical devices, and any other 26,27 The hazard of aneurysm clips deserves large, potentially ferromagnetic foreign body. special attention. Most currently manufactured aneurysm clips have little if any ferromagnetic 28 properties, as judged by lack of deflection within a magnetic field when tested in vitro. At least one instance of fatal clip movement in a patient has, however, been reported, in this 29 case due to inaccurate information supplied during the screening process. The performance of MRI in patients with aneurysm clips is therefore a matter of30–32 controversy; The potential newer nonferromagnetic clips appear to be safe, but discretion is advised. information to be gained from the procedure must be carefully balanced against the potential danger of clip movement. Although the metal from the clip may cause significant artifact on the examination, useful information can often still be gleaned by appropriately tailoring the examination. The potential risks of metallic stents and endovascular detachable coils also merit consideration. Although they do not pose a serious risk in the magnetic environment, a large experience has not yet accumulated. These devices produce ferromagnetic artifact, and thus 33–35 MRI is safe for patients who have recently had the local anatomy is distorted on MRI. 36 placement of a coronary stent. Some monitoring devices are potentially dangerous because looped metallic wires may acquire induced currents, resulting in burns to the skin attachment sites. For this reason, all physiological monitoring equipment and37–39 other devices must be carefully screened and approved specifically for use during MRI. 40Extensive testing and safety information about specific devices is available from Shellock. Screening of patients referred for MRI is primarily through a questionnaire regarding the potential contraindications. When in doubt, the specific medical device must be documented precisely and in writing before entry of the patient into the magnet. This information can be checked against the known magnetic deflection properties of the device, as appropriate. In patients with a history of possible metallic ocular foreign body, plain radiography of the orbit 41–45 or orbital CT can be used to exclude the presence of significant metal fragments. Another potential hazard related to the static magnetic field required for MRI is that of missile injury, mentioned earlier. The missile effect is perhaps the most serious potential hazard because many clinicians entering the MR environment are not aware that the magnet is always “on.” Paper clips, scissors, vacuum cleaners, oxygen tanks, and other ferromagnetic metallic items have been rapidly pulled into the bore of a magnet when inappropriately 44,46 Proper introduction to safety precautions brought close to it, sometimes with fatal results. for visitors is important. The rapid switching of the gradient coils used in MRI causes a loud vibration or banging noise. This has been estimated at between 65 and 95 DB. Hyperacusis is reported very commonly after MRI. Both temporary and permanent instances of hearing loss have also been reported; for these reasons, the use of earplugs is mandatory during MR examination. These are especially recommended in cases requiring very rapid switching of gradients coils, as with most magnetic resonance angiography sequences and ultrafast techniques such as 47 fast spin-echo and echo-planar techniques. Tissue heating is also a potential but to date insignificant complication of MRI. The U.S. Food and Drug Administration (FDA) limits radiofrequency energy deposition to 0.4 W/kg. In animal studies, levels at 10 times this rate over a 75-minute period raise the skin and eye temperature of a sheep by only 1.5°C, with no observed side effects. SPINAL PROCEDURES
Myelography and Intrathecal Injections of Contrast Media The number of myelographic procedures has dramatically diminished since the introduction of MRI and CT. In our own institution, the rapid acceptance of MRI resulted in a 48 percent decrease in the number of myelograms between 1981 and 1986 and a further 75 percent reduction from 1986 through 1988. This trend is substantial for all regions of the spine, but especially for cervical and lumbar myelography. CT and MRI have largely replaced myelography in the evaluation of the spinal cord and lumbar spine. MRI has clearly been 48,49 discitis, established as superior to myelography in the evaluation of lumbar disc disease, 50 51,52 Compared with and vertebral osteomyelitis and extradural and intradural spinal lesions. CT and MRI, myelography is limited as a single investigation of lumbar disc disease because of its insensitivity to extraforaminal, paraspinous, and lateral disc disease. In such a setting, if
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CT is used as the modality of first choice, the number of myelograms is decreased by over 60 53 percent. Low-dose CT myelography is preferred to plain-film myelography for evaluating the thecal sac in those patients who cannot tolerate MRI because of severe claustrophobia or the presence of a pacemaker or implanted metallic device such as aneurysm clips or dorsal column stimulators. In addition, some patients with severe spondylitic disease of the spine or postoperative changes with prominent osteophytes are best studied by low-dose CT myelography. In such instances, a lumbar puncture is performed and a low-dose injection (5 to 8 ml) of contrast is instilled before CT scanning. There are few indications left for traditional plain-film (high-dose) myelography. Suspected cerebrospinal fluid (CSF) loculations, arachnoid cysts, or arachnoiditis may still require study by myelography because the septations separating these CSF-filled structures can be difficult to detect on MRI. In addition, myelography in combination with CT is required occasionally to locate precisely the site of a spinal CSF leak and is complementary to MRI in verifying the presence of dural arteriovenous fistula. Myelography is also indicated for the evaluation of patients with back pain after orthopedic instrumentation because CT and MRI are compromised by metallic artifact. The reduction in numbers of myelograms performed at major institutions has reduced the exposure of trainees in radiology to this procedure. As with any procedure, the incidence of complications associated with a procedure relates to the experience of the practitioner. In the case of myelography, it is our impression that the rate of complications is on the rise because of the decrease in experience of recent trainees. It is therefore appropriate to review the neurological complications of myelography and intrathecal injections of contrast material despite their decline in use. Terminology Myelography consists of plain films after intrathecal instillation of contrast media through either a lumbar puncture or a cervical puncture at the C1–C2 level, posterior to the spinal cord. Water-soluble, nonionic contrast agents are currently used. Using a tilt-table and fluoroscopy, the contrast is positioned by gravity into the area of interest. Cervical, thoracic, and lumbar myelography as well as “total” intrathecal opacification can be accomplished through a single needle puncture. Before MRI, the choice of a lumbar or C1–C2 puncture was largely determined on the basis of clinical symptomatology. In recent years, low-dose (lower than routinely administered for plain-film myelography) injections before CT scanning, so-called CT myelography, has gained in popularity and in many institutions has replaced formal plain-film myelography. Current helical high-speed CT scanners that are capable of high-resolution, less than 1-mm contiguous scans through the entire cervical region in less than 1 minute produce superb tomographic reformations following intrathecal injection. Occasionally contrast must be positioned intracranially to opacify the CSF cisterns. MRI has now largely replaced CT cisternography, but it is still used occasionally to evaluate for CSF leak and intracranial arachnoid cyst. Technique There are several approaches for performing intrathecal injections. Usually, a 22-gauge or smaller spinal needle is positioned with fluoroscopic guidance in the lumbar or cervical subarachnoid space. This requires topical and subcutaneous anesthesia and is contraindicated in those with bleeding disorders. If required, a C1–C2 puncture is most safely performed using lateral fluoroscopy so that the needle can be placed without patient movement and the contrast location can be monitored. The needle enters the lateral neck just below the mastoid tip and is fluoroscopically positioned in the posterior aspect of the cervical subarachnoid space, which is usually rather capacious, behind the cervical spinal cord. As discussed later, C1–C2 puncture carries a risk of cervical cord puncture, and efforts must be taken to avoid this by proper positioning of the patient and careful technique. If CT is required, a low-dose injection of contrast medium is usually performed from the lumbar route, which is associated with fewer potential complications than the cervical route. CT is performed immediately after instillation of contrast medium. Delayed CT has been used in the past to evaluate syringomyelia, but MRI now best evaluates this condition. Cisternal puncture in the suboccipital region is rarely if ever performed. The authors have never performed this procedure themselves and see little indication for its use in the current era of MRI.
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Complications of Intrathecal Puncture The neurological complications of myelography and intrathecal injections can be separated according to those related to intrathecal needle puncture itself and those related to instillation of intrathecal contrast material. Vasovagal Response
Vasovagal syncope occurs infrequently during lumbar puncture. Its occurrence can be anticipated by communication with the patient and by noting the initial appearance of diaphoresis. This usually occurs during head elevation and can be countered by prompt lowering of the patient's head. Headache
Headache and associated nausea and vomiting are the most frequent complications of 54–59 The incidence of headache after myelography has lumbar puncture and myelography. decreased with the development of nonionic, water-soluble contrast agents. The etiology of headache is often obscure and may be related to a variety of complications. These include neurotoxic effects of the contrast agent, persistent CSF leak at the puncture site with postural low-pressure headache syndrome, intracranial hematomas, and psychological factors. Post–lumbar puncture headache is usually due to persistent CSF leakage from the puncture 60,61 site, and its incidence is related to the size of the needle. In a study by Skalpe and Nakstad, 1,000 myelograms performed56with a nonionic, water-soluble agent (iohexol) were reviewed for adverse effects. Headache occurred in 38 percent of patients and was most frequent after cervical myelography with a lumbar puncture technique and with the patient placed horizontally after the examination. The lowest frequency of headache occurred after cervical myelography with the C1–C2 puncture technique, with the patient placed in bed and the head elevated 20 degrees. The frequency of headache during lumbar myelography performed on an outpatient basis was 49 percent; however, no serious complications were encountered in this group. Many authors believe that the occurrence of headache, nausea, and vomiting is probably more related to spinal puncture and persistent leakage of CSF than to the toxicity of myelographic contrast media. After myelography, it is current practice to keep patients in62,63 a supine position, with the head Oral hydration is encouraged. elevated approximately 25 to 45 degrees for 4 to 6 hours. Autologous epidural blood patch and intravenous hydration is indicated in those patients with 64 severe postural headache persisting for longer than 48 hours after myelography. 60
Psychological factors may also play a role in the etiology of headache. Lee and colleagues studied the psychological aspects 65 of headache after lumbar puncture in 100 consecutive patients undergoing myelography. Headache was found to be strongly associated with a normal examination and showed an association with hospital anxiety-depression score. Sex and age have also been studied with regard to the incidence of adverse reactions to myelography. Maly studied a prospective group of over 1,700 patients undergoing 66 myelogra-phy. Regardless of the type of contrast medium or type of myelography, adverse reactions were 1.4 to 3.0 times as frequent in women as in men. Headache was more frequent in both women and men aged 26 to 50 years compared with older patients. The reason for this difference is unclear. Hearing Loss
Hearing loss has been described as an adverse reaction after lumbar puncture as well as myelography. Michel and Brusis reported67–69 nine cases of hearing loss after myelography, In six of the nine patients, bilateral impairment lumbar puncture, and spinal anesthesia. was present; recovery of normal hearing occurred in six patients. They speculated that this complication relates to alteration in the pressure equilibrium between CSF and perilymph, resulting in the release of perilymphatic fluid into the subarachnoid space. Alternatively, a direct toxic effect of contrast material on the inner ear may be a factor in hearing loss. They recommended the use of fine-gauge needles to reduce the leakage of CSF through the dural puncture. The use of nonionic myelographic agents is now standard, and these agents have been clearly shown to be safer than ionic formulations. Epidermoid Tumors
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Iatrogenic70,71 intraspinal epidermoid tumors have been reported as sequelae of lumbar It is believed that implantation of epithelial cells from the skin into the thecal sac puncture. or epidural space during lumbar puncture may allow this benign tumor to grow gradually. The incidence of iatrogenic epidermoid tumors is exceedingly rare, probably owing to improved needle design for lumbar punctures. Epidermoid tumors appear on MRI as masses with signal characteristics similar to CSF. Both myelography and CT scans demonstrate epidermoids as a CSF-density mass filling the thecal sac. The presence of this rare tumor should arouse suspicion of possible iatrogenic causes, and a history of prior lumbar puncture should be sought. Hemorrhage 72–75
Intracranial hemorrhages secondary to myelography have been well documented. In all likelihood, most of the hemorrhagic complications of myelography relate to persistent CSF leakage and low intracranial CSF pressure, which then result in the production of subdural hematomas. Subdural hematomas occur in response to low CSF pressure as a result of tearing of bridging veins or possibly as a response to accommodate the loss of intracranial volume. Subdural hematomas have also been recognized as a complication of spontaneous 76–78 The possibility of subdural hematoma should be considered in patients CSF leakage. who complain of prolonged headache or who manifest neurological signs after lumbar puncture or myelography, especially if large quantities of CSF have been removed. Acute epidural hematoma complicating myelography in a normotensive patient with normal blood 79 and Van de Kelft and coagulability is rare but has been reported by Stevens and colleagues, 72 associates have reported bilateral intraparenchymal hemorrhages in a 38-year-old woman 7 days after lumbar myelography. The etiology of these hematomas remains obscure. Spinal punctures should not be performed in the setting of abnormal coagulation factors. In patients receiving systemic anticoagulants, there is an increased risk of paraparesis. This 80 complication is usually related to epidural hematoma at the site of puncture. Puncture of the Conus Medullaris
Although uncommon, puncture of the spinal cord and conus medullaris has been 81,82 This complication can be avoided by restricting lumbar punctures to below the described. L3 level. Low-lying conus and tethered cord may increase the risk of conus puncture, but MRI can delineate these anatomical abnormalities. Complications of C1–C2 Puncture The frequency and approach to cervical myelography has been revolutionized with the wide acceptance of MRI. Cervical myelography through the C1–C2 level approach was routine for many years and was thought in experienced hands to be a safe alternative to the lumbar approach for cervical myelography. However, complications related to the C1–C2 approach have been well documented in the literature and include those associated with direct puncture of the spinal cord, laceration of epidural and vertebral venous and arterial structures, and complications related to neck hyperextension during the procedure. The indications for C1–C2 puncture are now quite infrequent. In those patients who cannot undergo MRI but who require cervical myelography, low-dose CT myelography through a lumbar puncture often suffices. This route of administration has been associated with a slightly higher incidence of headache, nausea, and vomiting than with the C1–C2 puncture; however, the use of low-dose, nonionic, water-soluble agents has reduced these complications to an acceptable level. Therefore, in our view, there are few if any indications for the C1–C2 approach in current neuroradiological practice. The complications of C1–C2 puncture are nevertheless worthy of discussion. Katoh and co-workers documented the complications of lateral C1–C2 puncture myelography in 112 83 patients. Spinal cord and blood vessel punctures were the most serious encountered. The authors pointed out that these complications principally depended on incorrect positioning of the patient's neck and83–85 misdirection of the x-ray beam. Spinal cord puncture is the most The injection of contrast material into the spinal cord may be serious complication. associated with hemorrhagic necrosis of the gray matter and acute neurological decline. Acute and permanent trigeminal dysesthesias and quadriparesis may also occur as a complication of C1–C2 puncture. The important factor in avoiding this complication is proper patient positioning. A free flow of CSF should be documented before contrast injection. The patient should experience no pain during the instillation of contrast media. If there is pain, the procedure 83 should be terminated immediately and the cause of the pain assessed. Katoh and associates also documented three cases of epidural injection during a C1–C2 puncture, a
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complication we have also seen in our practice. Injection into the epidural venous plexus and intra-arterial injection into an aberrant vertebral artery have been documented. In approximately 2 percent of patients, the vertebral artery swings inferiorly into the posterior 86 C1–C2 interspace ; in such cases, an approach by lateral C1–C2 puncture may then inadvertently lacerate or puncture it. Rogers reported the death of a patient after C1–C2 myelography due to acute subdural hemorrhage as a consequence of laceration of an 87 anomalous intraspinal vertebral artery. 88,89
Robertson and Smith documented 68 major complications of cervical myelography. Two thirds of the complications were attributed to cervical spine hyperextension during the procedure and one third to lateral C1–C2 puncture. The narrow sagittal diameter of the spinal canal and severe cervical spondylosis were frequent contributing factors to hyperextension injury of the cervical spinal cord. These authors recommend that MRI be performed first in patients with suspected spinal canal stenosis, severe spondylosis, or myelopathy of any cause. Should cervical CT myelography then be required, it is our view that a low-dose lumbar injection followed by thin-section CT is a safer alternative than C1–C2 puncture. Complications Related to Contrast Agent Neurological complications related to the intrathecal administration of contrast agents range from aseptic meningitis to encephalopathy and seizures. Other reported complications include hyperthermia, hallucinations, depression and anxiety states, and headache. The development of nonionic, water-soluble contrast agents has reduced these neurotoxic side effects significantly. Meningitis 90–97
Both aseptic and bacterial meningitis are reported complications of myelography. Bacterial meningitis, which is characterized by the abrupt onset of fever, usually within 24 hours after the intrathecal instillation of contrast, must always be excluded when it is a clinical possibility. Use of face masks by physicians performing lumbar puncture has been advocated 94,98,99 In aseptic meningitis, transient CSF to reduce the possibility of oral contamination. pleocytosis (neutrophils and lymphocytes) and elevated protein concentrations accompany symptoms and signs that are similar to those of bacterial meningitis. Once a bacterial infection has been excluded, the use of corticosteroids may be helpful in relieving symptoms of aseptic meningitis. Persistent leakage of CSF at the puncture site must also be considered in patients with postural headache and pleocytosis, since the clinical picture may be confused with aseptic meningitis. Seizures
Intrathecal contrast material may cause other, less frequent but potentially serious complications. Encephalopathy, seizures, and focal neurological deficits have all been reported after myelography, presumably owing to reflux of contrast material into the 100–103 The risk of seizures is on the order of 0.1 to 0.3 percent with the nonionic, brain. 100 water-soluble contrast agent iopamidol. Increased risk of seizures is present when the total dose of iodine is greater than 4,500 mg, there is a preexisting seizure disorder, a cervical route of injection is chosen, or the patient is concurrently taking a drug known to lower the seizure threshold. Inadvertent administration of the ionic contrast media used for urography or angiography during myelography causes convulsions that probably arise within the spinal cord itself as 104,105 These water-soluble, ionic contrast agents are visually well as the brain. indistinguishable from the nonionic contrasts used for myelography; therefore, great care must be taken in identifying the specific brand and subtype chosen for myelography. Because of these serious complications, the U.S. Food and Drug Administration has published guidelines that require specific warning labels to be attached to water-soluble, ionic contrast agents. Arachnoiditis
Arachnoiditis, or inflammation of 106–108 the leptomeninges, has also been ascribed to the use of Iophendylate, an oil-soluble contrast agent no longer contrast agents for myelography. used in clinical practice, was first noted to cause arachnoiditis, especially when accompanied by subarachnoid blood (i.e., after a traumatic tap). Water-soluble contrast agents reduced the incidence of arachnoiditis and were proven safe in the setting of subarachnoid
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109,110
hemorrhage. In many cases it is difficult to ascribe this syndrome with confidence to the contrast agent because confounding variables such as trauma, surgery, infection, or bleeding may have occurred within the111 spinal subarachnoid space and these have also been the observation that associated with arachnoiditis. The issue is further complicated by112 arachnoiditis can be induced by intrathecal corticosteroid injections. Contrast-related arachnoiditis may appear months or years after the instillation of the compound. Clinically, patients usually have symptoms of constant low back pain aggravated by movement. Evidence of multifocal radiculopathy is found on examination. On repeat myelography or MRI, the nerve roots of the cauda equina appear thickened, clumped, and adherent to the periphery of the thecal sac. The incidence of arachnoiditis with the newer water-soluble, nonionic contrast agents is much lower than with iophendylate or with ionic, water-soluble agents (e.g., metrizamide). The pathogenesis of postmyelographic arachnoiditis is unclear. One group found that after 8 days, progressively more severe arachnoid fibrosis developed in animals undergoing 113 metrizamide myelography. However, no iodine was found in the arachnoid 24 hours after myelography. Therefore, the chronic effects of water-soluble media on the arachnoid are apparently not mediated by contrast media persisting in the arachnoid or by immunocomplexes. Clinical reports have suggested that myelography and laminectomy may produce more arachnoiditis than myelography alone; however, others have disputed this 114,115 We have witnessed at least two cases of acute, severe arachnoiditis after point. myelography and laminectomy. In these instances, MRI demonstrated prominent enhancement of intrathecal nerve roots. Clinically, patients responded to corticosteroids and conservative therapy.
Discography Discography is a procedure that involves the placement of a needle in the nucleus pulposus of a lumbar or cervical disc and the injection therein of water-soluble contrast agents. CT can be performed after discography for added spatial resolution. However, the value of discography is primarily as a provocative test. An attempt is made to recreate the patient's pain syndrome and to isolate a symptomatic disc that may not be abnormal on MRI or CT. Its 116,117 but discography is performed quite frequently in the United usefulness is controversial, States. Horton and Daftari found that although MRI and discography correlated in many 118 instances, MRI could not reliably predict which disc was the cause of a patient's pain. Complications with discography are rare and are mainly related to the introduction of infection into the disc space through nonsterile technique. Disc space infections after discography 119,120 Many groups add have been clearly documented, although their incidence is low. antibiotic to the 121 contrast media used for discography, but evidence of benefit for routine use is controversial. Care must be taken to prevent intrathecal instillation of antibiotic-contrast solutions. Both septic and aseptic discitis are potential side effects. The incidence of discitis may be related to the length of the procedure, the use of a single needle technique, and breaks in sterile technique. Johnson found no evidence that diagnostic discography injured 122 have demonstrated exacerbation of preexisting normal discs, but at least two reports123,124 herniated disc material by discography.
Epidural and Transforaminal Anesthetic Neural Block Patients with back or neck pain often benefit from local anesthetic blockade either to confirm the location of the pain generator or to reduce pain, or both. Diagnostic and therapeutic nerve root blocks involve the local injection of anesthetics such as 0.75 percent bupivacaine with or without steroid compounds into the epidural space of patients suffering from local or radicular back or neck pain. Anesthesiologists also use spinal or epidural anesthesia for intra- and postoperative pain control. Injections are administered via a 22-gauge or smaller needle placed into the area of interest using fluoroscopic or CT guidance. Direct injections are made into the epidural compartment of the spine or facet joints or focally around an exiting nerve in the neural foramen. Complications of these procedures relate primarily to intravascular injection into arteries supplying the spinal cord, complications of needle placement, inadvertent injection into the spinal cord or nerve root itself, and rare allergic or other side effects related to the injected agents. Botwin and co-workers reviewed the incidence of complications of fluoroscopically guided lumbar epidural injections in 207 patients and found a 9.6 percent incidence of minor complications ranging from transient headache, back pain, leg pain, facial flushing, vasovagal reaction, and increased blood sugar levels, most likely 125 induced by systemic absorption of corticosteroid. Serious complications such as epidural hematoma, intraspinal injection, and paraplegia or quadriplegia secondary to inadvertent injection into the spinal artery have been reported following transforaminal epidural nerve 126,127 block.
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ANGIOGRAPHY Angiography is essential in the diagnostic evaluation of many patients with vascular disease, but it carries the greatest risk of morbidity among diagnostic imaging procedures. This risk is generated by the necessity of inserting a catheter into a blood vessel, directing the catheter to the required location, injecting contrast material to visualize the vessel, and removing the catheter while maintaining hemostasis. Skill, experience, and judgment are elements that help reduce the risk of this invasive procedure, but risk cannot be eliminated completely. Moreover, therapeutic transcatheter procedures (embolizations) have become important definitive and adjunctive therapies in patients with cerebrovascular, visceral, and peripheral vascular disease. The decision to undertake a diagnostic or therapeutic angiographic procedure requires sober assessment of the goals of the investigation and its risks. Neurological complications of angiography or embolization are the most feared because of the relative permanence of the deficit, which can profoundly impair the patient. Neurological sequelae are encountered most often in angiographic procedures undertaken to evaluate or treat the vessels of the brain and spinal cord, but they can result from procedures undertaken to evaluate vascular disease elsewhere.
Cerebral and Aortic Angiography Most aortic arch, carotid, and vertebral arteriograms are carried out by transfemoral arterial access. A common femoral arterial puncture provides retrograde access through the aorta to the aortic arch and great vessels. Arch aortography can be performed using a pigtail catheter, and selective catheterization of the carotid or vertebral arteries can be accomplished with a wide variety of catheter–guide wire combinations. The most feared complication of cerebral angiography is stroke. Thrombus can form on or inside the tip of the catheter, especially if the catheter is not flushed properly with heparinized saline at regular intervals. Atherosclerotic intimal plaque may be present along the arterial wall, especially at the common carotid bifurcation. This thrombus or plaque can embolize distally into the cerebral circulation by force of injection or from dislodgment of plaque by the catheter or guide wire. The duration and extent of the resulting ischemic neurological deficit depend on the size and length of the embolus, its composition (fresh thrombus is thought to fragment more readily), its location, and the available collateral circulation. Identified risk factors for ischemic complications include lack of experience on the part of the 128 cardiac output, decreased oxygen-carrying angiographer, atherosclerosis, vasospasm, low 129 The risk of a neurological complication has capacity, advanced age, and possibly migraine. 128–136 Hankey and colleagues reviewed been estimated by many authors and is variable. eight prospective and seven retrospective studies involving over 8,000 patients with known cerebrovascular ischemic disease and estimated the risk of cerebral angiography at 4 percent for transient ischemic attack and stroke, 1 percent for permanent deficit, and very low 134 (<0.1%) for death. 137
Bendszus and associates assessed the incidence of clinically silent embolism. Diffusion-weighted scans were performed before and after 100 consecutive cerebral angiograms in 91 patients. Diffusion MRI showed 42 high signal areas in 23 patients, with patterns consistent with embolic events. The frequency of lesions was significantly higher in patients with a history of vasculopathy or with vessels difficult to probe. The fluoroscopy time, amount of contrast medium used, and use of additional catheters were also correlated with the appearance of lesions. Ischemic complications can also result from intimal dissection of the carotid or vertebral artery by direct trauma from the tip of the catheter or guide wire. If the thin intimal lining is torn, a pocket of blood can form beneath it, resulting in extension of the intimal dissection, narrowing or occlusion of the arterial lumen, and production of thromboemboli in the stagnant trapped pool of blood between the intima and media. Catheter-induced spasm of an artery also raises the potential for neurological complication. Although usually temporary, this phenomenon can result in a transient deficit if the spasm prevents adequate blood flow distally. The clinician must identify the presence of spasm before the injection of contrast agent because such an injection into the stenotic spastic segment can result in dissection and possibly in permanent deficit. Intravascular contrast material injected into the cerebral vasculature may have a toxic effect on the brain. In particular, patients with dolichoectasia of the basilar artery may sustain reversible brainstem dysfunction and acute short-term memory loss after multiple contrast injections into the vertebrobasilar system. It is postulated that the contrast bathes the perforating arteries of the brainstem on the dependent dorsal aspect of the basilar artery
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because of its irregular dolichoectatic configuration. Limiting contrast injections into the vertebrobasilar system reduces the occurrence of this phenomenon. Rarely, an intracranial aneurysm ruptures during an angiographic contrast injection, causing 138 subarachnoid hemorrhage. This is reported to result from the force of the injection, although this theory is not accepted universally. Before catheter insertion into the common femoral artery, the local soft tissues must be infiltrated with an anesthetic agent, usually lidocaine. If the anesthetic agent is inadvertently injected into the femoral nerve, this may cause transient dysesthesias along the course of the nerve, which lies medial to the common femoral artery in the inguinal space. This rare phenomenon is usually self-limited. In decades past, common practice dictated the use of a direct carotid artery puncture for the performance of cerebral angiography. Although this technique is now outmoded, rare circumstances might require its use. Administration of local anesthesia for such a procedure may result in direct intracarotid injection of lidocaine, which can cause generalized seizures. Moreover, intimal damage may occur at the puncture site from the puncture needle or from subintimal contrast or saline injection, the most common cause of a neurological deficit 129 occurring during direct carotid angiography. Poor hemostatic control of the carotid puncture site may cause an expanding hematoma, which can deviate the trachea. Axillary or brachial artery approaches are also used for cerebral angiography when the transfemoral route is not possible. These access routes are discussed later.
Spinal Angiography Spinal angiography may be indicated to evaluate vascular malformations and tumors and to identify the artery of Adamkiewicz before aortic aneurysm repair. Although the procedure requires the use of relatively large volumes of contrast and is tedious and lengthy compared with most other angiographic procedures, the incidence of complications is low. Forbes and colleagues evaluated 134 consecutive spinal angiograms prospectively and found neurological complications 139 in only 3 patients (2.2%), 2 of whom recovered fully within 24 hours and 1 within 1 week. The adverse events included paraparesis, subjective visual blurring, and speech changes. Formerly, contrast material was implicated in the production of spasms during injection, but this phenomenon seems to occur rarely with newer, nonionic contrast agents.
Peripheral Angiography Peripheral (noncerebral-noncardiac) angiography also uses a transfemoral approach where possible. Although the cerebral vasculature is not examined per se, there is a risk of producing a cerebral embolic event if the subclavian or axillary arteries require examination because of the adjacent origins of the vertebral and carotid arteries. Catheter manipulations are sometimes performed in the descending aortic arch to form special loops in the catheter's distal segment, and this may produce a neurological deficit by dislodging plaque from great vessels or by thrombus forming on the catheter tip. Many patients undergo peripheral angiography to evaluate atherosclerotic disease of the abdominal aorta and iliofemoral system, which itself may preclude the use of a femoral artery puncture. If transfemoral access is not possible because of severe atherosclerosis, the 140–143 An axillary axillary or brachial routes may be used. Each has its own set of risks. puncture is performed with the arm abducted. The axillary artery is palpated, and the puncture is made as deep into the axilla as possible. The left axilla is chosen for most examinations of the descending aorta and its branches; the right axilla is preferred for studies of the carotid and vertebral arteries. For peripheral angiography, an axillary approach carries 144 145 a twofold to fourfold greater risk of neurological complications than a transfemoral approach. Stroke can result from dislodgment of atherosclerotic plaque at the origin of the vertebral artery during catheter passage to the aorta. Hemostasis at the puncture site is a much more crucial issue than with a femoral puncture: the axillary artery is more difficult to compress after removal of the catheter, and an expanding hematoma may injure the brachial plexus. Brachial artery access requires the use of a smaller diameter catheter because of the smaller size of the artery. Puncture is made in the antecubital fossa, and the catheter is navigated retrogradely through the brachial, axillary, and subclavian arteries to the aorta. Risks of cerebral thromboemboli exist 129 as with the transaxillary route. The median nerve can be damaged by needle puncture or by compression from a developing hematoma.
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EMBOLIZATION AND STENTING PROCEDURES The development of new materials and techniques has advanced the relatively young and small field of interventional neuroradiology, providing new therapeutic options for patients with difficult neurovascular problems. A variety of procedures is available, including detachable coil or balloon therapy for aneurysms, particulate or liquid adhesive embolization of arteriovenous malformations (AVMs), balloon angioplasty or stenting of stenosis or vasospasm, transarterial or transvenous embolization of dural arteriovenous fistulas, balloon occlusion of carotid-cavernous and vertebral fistulas, endovascular treatment of vein of Galen malformations, preoperative embolization of tumors, and thrombolysis of acute arterial or venous thrombosis. Many of these diseases place the patient at high risk for cerebral hemorrhage, stroke, or death. These endovascular treatments have their own risks, and therapy should be tailored to the disease risk of individual patients. The highest complication rates are found predictably with therapies geared to treating the highest risk diseases. Among potential complications of endovascular aneurysm therapy are aneurysmal rupture, stroke from thromboemboli or from migration of the balloon or coil, and death. In a large series of surgically difficult intracranial aneurysms treated with detachable balloons, Higashida146,147 and colleagues reported a 7.4 percent incidence of stroke and a 9.8 These figures must be considered in light of the high morbidity and percent death rate. mortality among patients with untreated and surgically unapproachable aneurysms,148,149 a patient has population posing very high risks. The advent of the electrolytically detachable coil reduced these rates. Pruvo and co-workers reported morbidity and mortality rates of 4 and 1.5 percent, respectively, in the first 200 patients whom they treated with Guglielmi 150 detachable coils for ruptured intracranial aneurysms. This mirrors our personal experience in coil embolization of more than 1,000 aneurysms. Endovascular treatment of AVMs is frequently used as a preoperative adjunct to surgical resection or stereotactic radiosurgery. Embolic materials include liquid adhesives, polyvinyl alcohol particles, and fibered coils. Therapeutic risks include AVM rupture with intracerebral hemorrhage; inadvertent embolization of normal arteries, causing stroke; and gluing of the 151 catheter into the embolized artery. In separate studies using different embolic agents (liquid adhesives and polyvinyl alcohol particles) for AVM embolization, the permanent 152,153 neurological complication rate was 8 percent in each. Endovascular therapy is also applicable to vascular problems involving the spinal cord. In the treatment of intramedullary AVMs, which often present with hemorrhage, embolization may provide definitive, palliative, or adjunctive therapy. The major risk is occlusion of a normal portion of the anterior or posterolateral spinal arteries with the embolic material. Casasco and colleagues have estimated the risk of a permanent therapy-related neurological deficit at 5.7 154 percent. This risk is similar in the treatment of perimedullary spinal arteriovenous fistulas. The spinal dural arteriovenous fistula represents a shunt between a dural artery on the nerve root sleeve and an adjacent radicular vein that drains toward the spinal cord, resulting in a venous engorgement syndrome. The risk involved in endovascular treatment of this dural process is lower because spinal arteries are not involved directly. Endovascularly deployed stents are being used increasingly in the treatment of diseases of the supra-aortic vessels. This technique often follows angiography and can be complicated by transient or permanent neurological deficits secondary to emboli, dissection, or occlusion of the vessel. The risk of neurological deficits has decreased as experience has accumulated and newer stents have been developed, but it is nevertheless in the range of 10 to 15 155 percent. Lovblad and associates prospectively studied 19 patients referred for investigation of carotid156 artery disease by echo-planar diffusion-weighted MRI before and within 24 hours of stenting. They found that three patients had presumed small embolic infarcts; two patients were asymptomatic and one had weakness of the hand that corresponded anatomically to the location of the diffusion abnormality. Other complications of carotid artery stenting include 157,158 transient bradycardia, hypotension, and those related to femoral artery catheterization. Although advances in imaging capabilities, catheters, and embolic materials will advance endovascular capabilities, the knowledge, judgment, and experience of the angiographer will have the greatest effect in diminishing the risks of endovascular therapy.
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 54 Neurological Complications of Anesthesia DAVID L. BROWN • ANGELA T. TRUONG •
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PERIOPERATIVE MENTAL STATUS CHANGES Intraoperative Awareness Postoperative Confusion Delayed or Absent Awakening POSTOPERATIVE NEUROLOGICAL DEFICITS Central Nervous System Injury Related to General Anesthesia Regional Anesthesia and Injury to the Neuraxis Delayed Neurological Symptoms Following Spinal and Epidural Anesthesia Epidural Abscess Peripheral Nerve Injury Cardiovascular Monitoring PERIOPERATIVE SEIZURES General Anesthetics Regional Anesthetics PERIOPERATIVE HEADACHE PERIOPERATIVE VISUAL CHANGES PERIOPERATIVE AUDITORY CHANGES EVALUATION OF PERIOPERATIVE NEUROLOGICAL COMPLICATIONS
Neurological complications related to anesthesia often evoke powerful images, such as the vegetative patient who has sustained intraoperative cerebral hypoxia or the paraplegic patient whose neurological deficit is thought to be the result of spinal or epidural anesthesia. Most neurological complications of anesthesia are neither as sensational nor as clear in causation. The remarkable safety of modern anesthetic practice, due to both more sophisticated monitoring of hypoxemia and improvements in drugs and techniques, necessarily requires us to focus on many less severe complications, perhaps better termed side effects, rather than on the dramatic central nervous system (CNS) injuries that may occur. In an effort to facilitate the coverage of neurological complications of anesthesia, rather than simply providing a list of different complications, this chapter is arranged by symptom complexes that physicians are asked to deliberate upon. The conditions that are covered include (1) mental status changes associated with anesthesia; (2) perioperative sensorimotor neurological deficits; (3) perioperative neurological excitation, including seizures and myoclonus; (4) perioperative headache; (5) perioperative visual changes; and (6) perioperative auditory changes.
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PERIOPERATIVE MENTAL STATUS CHANGES The administration of anesthesia is designed to produce an altered mental status for a circumscribed length of time. When mental status changes persist beyond the immediate perioperative period, it is necessary to verify that there are no reversible causes. To better understand the most typical alterations of mental status that may be identified perioperatively, three such changes are discussed: (1) intraoperative awareness, (2) postoperative confusion, and (3) delayed or absent awakening (postoperative coma).
Intraoperative Awareness One of patients' primary clinical fears as they approach surgery is that they may “be awake” during the surgical procedure. Prior to the introduction of clinically useful muscle relaxants (curare) in 1942, patient movement with surgical stimulation often alerted the anesthesiologist to an inadequate depth of anesthesia. The introduction of neuromuscular blocking drugs allows many high-risk patients to undergo surgical procedures safely and successfully. However, since patient movement does not occur in such circumstances, the 1 anesthesiologist may be unaware of an inadequate depth of anesthesia. Intraoperative awareness under2–5general anesthesia is a rare occurrence, with a reported incidence of 0.1 to 0.2 percent. Severely traumatized patients, whose anesthetics may be minimized, have a higher incidence of recall than healthy patients undergoing elective 7 6 surgery. Obstetrical patients are another group who report awareness more frequently. In these cases, owing to hemodynamic instability or to urgency of inducing anesthesia in a mother and fetus in distress, anesthetics may be minimized and thus lead to a higher incidence of recall. The American Society of Anesthesiologists (ASA) Task Force on Intraoperative Awareness identified several patient characteristics that may place a patient at risk for awareness. These include a history of substance use or abuse, a limited hemodynamic reserve, and an American Society of Anesthesiologists physical8 status of 4 or 5, indicating the presence of serious medical illnesses or moribund condition. Four features have been identified that may alert physicians to the postoperative syndrome of intraoperative awareness: (1) anxiety and irritability, (2) repetitive nightmares, (3) a preoccupation with death, and (4) a reluctance by patients to discuss their symptoms lest they be thought 9 insane. Significant psychological sequelae such as post-traumatic stress disorder may occur after an episode of intraoperative awareness and render patients disabled for an extended period of time. Treatment is aimed at obtaining a detailed account of the patient's experience by a structured interview as well as discussion with the patient about the possible reasons for occurrence of recall. Counseling or psychological support should be offered. In recent years, a number of processed electroencephalographic (EEG) devices have been introduced and promoted as monitors to aid in reducing the possibility of patients experiencing awareness under general anesthesia and as anesthesia-depth monitors. Although the concept is intriguing, the general clinical applicability of anesthesia-depth 10 monitors in the prevention of intraoperative awareness remains to be established. The general consensus is that the decision to use a brain function monitor such as the bispectral index (BIS) should be made on a case-by-case basis for selected patients.
Postoperative Confusion Many investigations of postoperative confusion have concentrated on elderly patients in whom prolonged mental status changes are thought to be more frequent following anesthesia. Although advances in surgical techniques and new anesthetic drugs and modalities have offered improved outcomes, a significant number of patients continue to report postoperative cognitive impairment. Table 54-1 highlights11the factors that need to be considered when a patient develops confusion postoperatively. The most immediate concern is to exclude cerebral hypoxia, although this etiology has become an infrequent cause of postoperative confusion since the advent of perioperative pulse oximetry. Many studies comparing general and regional anesthetic techniques for elderly patients have been performed12–15 in an effort to clarify the relationship between anesthetic choice and postoperative Although many believe that regional anesthetic techniques decrease the risk confusion. of mental status deterioration, there are no definitive randomized studies to support the 16 conclusion. Click here to view this table.... Two separate entities of postoperative cognitive impairment have been described: postoperative delirium and postoperative cognitive dysfunction. Postoperative delirium involves an acute change in cognitive function that develops over a brief period of time, with a
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fluctuating course. It usually lasts for several days to a few weeks. The etiology of delirium is multifactorial. Drugs and their side effects, drug toxicity, adverse drug interactions, metabolic abnormalities, hypoxia, hypercarbia, infection, pain, and organic brain disease have all been implicated. Minimizing the use of drugs such as benzodiazepines, anticholinergics, and 17 and hematocrit antihistamines; maintaining oxygen saturation greater than 95 percent 18 greater than 30 percent ; and allowing for early patient mobilization and exposure to familial interaction in appropriate environmental circumstances have all been suggested to decrease the incidence of postoperative delirium in the elderly. Postoperative cognitive dysfunction is a disorder involving a deterioration of intellectual function presenting as impaired memory or cognitive impairment. Features may range from mild forgetfulness to severe permanent cognitive disturbance resulting in withdrawal from society and loss of independence. The reported incidence of19postoperative cognitive dysfunction is 26 percent at 1 week and 10 percent at 3 20 months. Postoperative cognitive dysfunction may persist in 1 percent of cases after 1 year. Its etiology is likely multifactorial and includes the preoperative status of the patient, factors related to anesthesia, factors related to surgery, and factors related to the immediate postoperative period. Some of the difficulty in analyzing postoperative confusion relates to the various analgesic techniques prescribed following the anesthetic. It is probable that development of perioperative confusion will be further clarified once the interaction between intraoperative anesthetic and postoperative analgesia techniques is better understood.
Delayed or Absent Awakening Failure of the patient to awaken promptly after general anesthesia has been attributed by Denlinger to three principal causes: 21 (1) prolonged drug action, (2) metabolic encephalopathy, and (3) cerebral injury (Table 54-2). Once again, the approach to managing the patient who fails to awaken from anesthesia is to exclude important and easily reversible causes such as hypoxia, hypercarbia, hypoglycemia, and electrolyte abnormalities. One of the most common causes of delayed awakening is prolonged anesthetic effect. The passage of time is the only practical method of evaluating this etiology, although pharmacological antagonists such as naloxone, flumazenil, and physostigmine are often administered in an effort to hasten awakening. For a nonanesthesiologist, it is important to determine what type of anesthetic was administered to the patient who is failing to regain consciousness. By understanding the pharmacological profiles of specific anesthetic drugs given, the anticipated duration of drug effects can be better assessed. Many of the more recently introduced anesthetics currently in widespread use are much shorter acting than their older counterparts. For example, intravenous propofol, synthetic opioids such as sufentanil and remifentanil, and inhalational agents such as sevoflurane and desflurane are much shorter acting than barbiturates such as thiopental, opioids such as morphine, and older volatile agents such as enflurane and isoflurane, respectively. Click here to view this table.... POSTOPERATIVE NEUROLOGICAL DEFICITS There are few physicians other than anesthesiologists who fully understand modern anesthetic techniques. When sensorimotor neurological deficits appear perioperatively, it is intuitively appealing for many to relate the deficit to some aspect of anesthetic or surgical care. A case report highlighting a healthy 47-year-old woman who developed complete transverse myelitis after receiving an uncomplicated general anesthetic for a total abdominal hysterectomy and bilateral salpingo-oophorectomy is an excellent example to consider in contemplating the linkage between a perioperative neurological deficit and the anesthetic or 22 surgical procedure. As the authors of this report highlight, had this neurological injury developed after regional anesthesia (i.e., the administration of a local anesthetic to produce nerve block centrally or in the peripheral nervous system), the causal relationship would seem to have been established simply because a needle had been inserted near the neuraxis. In considering the CNS injuries that may result from anesthetic and surgical procedures, one practical way of categorizing the injuries is related to anesthetic type (i.e., whether general or regional anesthesia was used).
Central Nervous System Injury Related to General Anesthesia The administration of general anesthesia23is rarely accompanied by development of an There are specific higher risk surgical procedures, unexpected CNS deficit postoperatively. 24 25,26 or cardiovascular procedures requiring cardiopulmonary such as27,28 aortic, spinal cord, that are the most frequent causes of the injuries associated with general bypass, anesthesia.
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Patients who undergo surgical procedures with a significant incidence of spinal cord injury often have somatosensory evoked potentials (SSEPs) utilized for intraoperative monitoring of spinal cord function. Function of the anterior spinal cord is difficult to evaluate intraoperatively, however, because somatosensory evoked potentials focus primarily on posterior column function. In addition to specific procedure-associated CNS injuries, both intracerebral and cervical spinal cord injuries have been produced during attempts at tracheal intubation. These injuries occur most often in severely injured patients who require urgent tracheal intubation, but patients undergoing elective surgery (e.g., patients with rheumatoid arthritis or Down's 29 syndrome) may also develop cord injury following tracheal intubation. It seems clear from work by Magnaes that pressure on the spinal cord may increase by approximately 15-fold 30 during routine tracheal intubation in patients with cervical spondylosis. Intracranial injuries related to nasal intubation have occurred in patients with basilar skull fractures who were 31,32 In undergoing nasogastric, and presumably nasotracheal, intubation in a “blind” fashion. such patients, the tracheal tube may be unintentionally passed into the cranium via the basilar skull fracture. This injury is rare, and thus prospective data are not available, but with the introduction of easy-to-use fiberoptic laryngoscopes, it is likely that the incidence of this rare complication is decreasing. The occurrence of a perioperative stroke may be detected by failure of the patient to awaken promptly following a general anesthetic or by the development of typical unilateral sensorimotor deficits. In general surgical patients (i.e., adults undergoing surgery not involving the heart or carotid arteries), the incidence of strokes in the perioperative period is approximately 2 per 1,000. In this study by Larsen and co-workers, 6 strokes developed in 2,463 patients, and they all appeared late in the postoperative period (i.e., 5 to 26 days 33 postoperatively). Thus, none of these strokes seemed directly related to the anesthetic or surgical procedure. Strokes were more frequent after emergency surgery than after elective operation. Patients with previous cerebrovascular disease, atrial fibrillation, hypertension, 34 advanced age, and atherosclerosis have an increased risk for stroke. Another group of patients who are at higher risk for stroke than other adults are pregnant patients, who appear to be approximately 13 times more likely than nonpregnant women of the same age to develop a perioperative stroke.
Regional Anesthesia and Injury to the Neuraxis A central deficit following spinal or epidural anesthesia does occur but less frequently than many physicians believe and much less frequently than most patients' level of anxiety justifies. Nevertheless, the development of sensorimotor deficits following an epidural or a spinal anesthetic requires prompt evaluation and treatment in the hope of preventing permanent deficits. It seems probable to many that if a needle catheter is inserted near the neuraxis and weakness or sensory change is found postoperatively, the most probable cause of the 35 neurological deficit is the anesthetic. When the incidence of permanent and profound neurological deficit following spinal and epidural anesthesia is surveyed, it appears that in 36 large series the figure ranges from 1 in 16,000 to 1 in 65,000 patients. If milder neurological deficits are the focus, such as symptoms of cauda equina dysfunction, a Swedish survey from 1980 to 1984 suggests that the incidence is approximately 1 in 12,820 patients 37 undergoing spinal, epidural, or caudal anesthesia. Table 54-3 highlights the different complications in this Swedish series. A French questionnaire series suggests that neurological change following spinal anesthesia may be as high as 5 to 7 patients per 38 10,000. Click here to view this table.... Schreiner and colleagues reported three cases of major paralysis following general anesthesia in an effort39to highlight the lack of connection between neurological deficit and anesthetic technique. The differential diagnosis of perioperative paralysis is outlined in Table 54-4; although regional anesthesia is not listed as a specific cause, the table shows the circumstances in whichit may be of etiological importance. Patients must be evaluated with urgency. Space-occupying lesions, such as epidural hematomas, demand immediate decompression if permanent neurological injury is to be minimized. In a literature review of 40 epidural abscesses, the time of recognition of the lesion ranged from 72 hours to 5 months after presentation. In this group of 16 patients, approximately half had complete neurological recovery. Most patients with epidural hematomas have complete return of neurological function if decompression is carried out within 4 to 8 hours; evaluation must therefore be rapid and imaging studies performed promptly.
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Click here to view this table.... Too often, non anesthesiologists seem to believe that spinal and epidural anesthesia are quite similar and that it matters little which drug or technique is used. When involved in consultation in an urgent situation, it is incumbent upon the evaluating physician to contact the patient's anesthesiologist to determine which type of drug or vasoconstrictor was used and the anesthesiologist's expectation for the length of motor and sensory block. In a particular subgroup of patients, the physician needs to maintain a heightened awareness of the possibility of development of neuraxial bleeding. These are patients who have received or are receiving low-molecular-weight heparin (LMWH) in combination with neuraxial 41 anesthesia. The most practical way of assessing the risk is to review the consensus statements on this topic published by the American Society of Regional Anesthesia (Table 54-5). Click here to view this table.... In patients at highest risk for developing epidural hematomas, it may be prudent to use the shortest acting agent possible in order to avoid confounding the postoperative diagnosis of lower-extremity weakness. Most anecdotal reports of epidural hematomas suggest that back pain is prominent during their development. If a local anesthetic is utilized and the sensory level is more cephalad than the level of the hematoma, however, any back pain produced by the hematoma may be masked.
Delayed Neurological Symptoms Following Spinal and Epidural Anesthesia In the etiology of neurological changes that occur at some time (i.e., days to weeks) after spinal and epidural anesthesia, the clinical conditions that must be considered include cauda equina syndrome, aseptic meningitis, adhesive arachnoiditis, and epidural abscess (Table 54-6). Click here to view this table.... Cauda equina syndrome has received considerable notoriety with a report by Rigler and colleagues, who described 42 its development following continuous spinal anesthesia techniques in four patients. There was a 1- to 2-week delay in diagnosis in all these patients. The authors speculated that a maldistribution of local anesthetic was responsible for the development of a neurotoxic reaction to the subarachnoid injection of drug. The cauda equina syndrome may develop after either single-shot spinal, continuous spinal, or epidural anesthesia. Regarding spinal techniques in which hyperbaric anesthetic drugs are utilized, it has been postulated that the transient neurological change that 43 some patients report as S1 root pain may be due to the anatomical location of the S1 roots. These roots are located most posteriorly when the patient assumes the supine position, and the hyperbaric drug may concentrate in their vicinity, causing mild, transient S1 irritation. There is evidence, both 44 clinical and from bench work, that a number of the commonly used local anesthetics, if given in high enough concentration (i.e., four to eight times the usual concentration), may be neurotoxic. If some situation develops that prevents the free flow of the local anesthetic in the cerebrospinal fluid (CSF), a higher than usual concentration may be present near neural structures.
Epidural Abscess Epidural abscesses may develop following instrumentation of the epidural space. With surgical epidural anesthesia, epidural abscess formation is exceedingly unusual. For example, in a review of 43 cases of bacterial spinal epidural abscesses noted from 1981 to 1991 in four Houston teaching hospitals, there were no cases directly related to spinal or 45 epidural anesthesia for surgical care. About one third of these cases did develop after instrumentation of the neuraxis (i.e., after laminectomy, discography, or epidural steroid injection for chronic pain therapy). Table 54-7 highlights predisposing factors that were found in these 43 patients. Click here to view this table.... With regard to anesthesia-related epidural abscesses, Ngan Kee and colleagues in New Zealand reported a case of epidural abscess developing 40 in an obstetrical patient 5 days after anesthesia, and they reviewed 15 other published cases. They noted that most of these epidural abscesses involved catheters that were in place for less than 5 days, and they
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believed that thoracic catheters may have been associated with higher rates of abscess development than those found at lumbar sites. Symptoms progressed from (1) backache, to (2) radicular pain, to (3) weakness, and finally to (4) paralysis. Positive blood cultures46 correlate with the organisms found in the epidural abscess in 25 percent of patients. The imaging study most useful for the diagnosis of epidural abscess is magnetic resonance 47 surgical drainage combined with antibiotics remains the imaging (MRI). Immediate 48 treatment of choice.
Peripheral Nerve Injury It has long been emphasized that peripheral49nerve injuries are related primarily to “malpositioning” of patients intraoperatively. When the American Society of Anesthesiologists reviewed closed malpractice claims, approximately 16 percent of 50 anesthesia-related malpractice claims involved neural injury. As shown in Table 54-8, most peripheral nerve injuries involved upper-extremity nerves, especially the ulnar nerve. In many cases, the exact mechanism of specific nerve injuries could not be identified, and very often the standard of care for protection of 51,52 upper-extremity sites had been met in patients developing perioperative neuropathy. Click here to view this table.... In a community hospital practice, more than 6,500 patients undergoing operation were followed prospectively, and 17 patients developed ulnar nerve palsy (0.26% incidence). Of these patients, 50 percent were undergoing orthopedic surgery, and 33 percent were 53 undergoing coronary bypass grafting. The cubital tunnel (Fig. 54-1 and Fig. 54-2), through which the ulnar nerve passes on its way from the arm to the forearm, is the region at which most perioperative ulnar neuropathies develop, and either accentuated extension or flexion 54 may be involved in compression injury at this site. A predominance of ulnar nerve injury in males suggests that there is an anatomical predisposition associated with the male body 54 include very obese habitus. Other identified risk factors for perioperative ulnar neuropathy 55 or very thin body habitus and prolonged hospitalization (>14 days).
FIGURE 54-1 Anatomical disposition of cubital tunnel and its content (right
elbow flexed): 1, ulnar nerve; 2, ulnar collateral artery; 3, triangular arcuate ligament; 4, medial epicondylar groove; 5, medial lip of trochlea; 6, medial ligament of elbow. (From Perreault L, Drolet P, Farny J: Ulnar nerve palsy at the elbow after general anaesthesia. Can J Anaesth 39:499, 1992, with permission.)
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FIGURE 54-2 Cubital tunnel in extension (A) and 90-degree flexion (B): 1, slack arcuate ligament; 2, flexor carpi ulnaris; 3, taut arcuate ligament. (From Perreault L, Drolet P, Farny J: Ulnar nerve palsy at the elbow after general anaesthesia. Can J Anaesth 39:499, 1992, with permission.)
When patients undergoing coronary artery bypass graft (CABG) procedures are monitored with somatosensory evoked potentials perioperatively,almost 70 percent of patients may show evoked-potential changes during the procedure when surgical retractors are in 56 use and up to 6 percent of patients have evidence of nerve deficits at 1 week postoperatively. There is evidence that group A nerve fibers rely on aerobic metabolism to a greater extent than do C fibers, consistent with the clinical observation that motor function and tactile sensations are lost long before pain sensation is lost in perioperative neuropathies related to nerve ischemia 57 from stretch or positioning. When a tourniquet is used during surgical procedures, arbitrary decisions are often made about the length of time it can be in place as well as the level of pressure chosen to occlude blood flow to the limb. Many suggest that after 2 hours of tourniquet inflation the blood flow be reestablished for 10 to 15 minutes to minimize perioperative neuropathy, although there is little evidence that the 2-hour limit has any physiological basis. Data 58 suggest that 3 hours is a “reasonable” upper limit for safe application of automatic tourniquet. In any event, tourniquet time should be individualized, and decisions should be based on patient as well as surgical factors. When peripheral nerve blocks are utilized during surgical procedures and a neural deficit develops, the regional anesthetic is often suspected to be the cause. In a prospective survey involving more than 100,000 regional anesthetics, the frequency of neurological complications after peripheral blockade was found to be less that that associated with 59 neuraxial anesthesia. Of 34 neurological complications, 21 were associated with paresthesias during needle placement or pain during injection of local anesthetic, suggesting 59 nerve trauma or intraneural injection. It is important to realize that many factors distinct from the regional anesthetic may contribute to postoperative neurological injury. These include pressure injury from improper patient positioning, tightly applied surgical casts or dressings, and trauma from surgery itself. Patient factors such as body habitus or a preexisting 60 neurological deficit may also play a role.
Cardiovascular Monitoring Anesthesiologists are often involved in insertion of central venous catheters for cardiovascular monitoring perioperatively. There are numerous reports of neural injury related
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61–64
to central venous cannulation. As shown in Figure 54-3, numerous neural structures can be injured during cardiovascular cannulation. It may be that significant injury is more likely with cannulation in patients who are already anesthetized because they are unable to describe pain or paresthesias during the insertion.
FIGURE 54-3 Left oblique view of nerves in the neck and supraclavicular fossa
that may be injected during both internal jugular and subclavian central venous techniques. (With permission of the Mayo Foundation.) PERIOPERATIVE SEIZURES There are numerous reasons for patients to exhibit changes in mental status as well as abnormal motor activity in the perioperative period. These include simple “faints” during intravenous cannulation and seizures induced by inhalational agents or related to systemic toxicity of local anesthetics. Simple faints or symptoms compatible with vagal reactions during intravenous cannulation may occur in up to 17 percent of ambulatory patients younger than 65 40 years. It can sometimes be difficult to determine whether an idiopathic seizure has occurred preoperatively or whether the patient has experienced a simple faint. It does seem clear that younger patients are more likely to experience these perioperative events and that the greater the 65 number of attempts to place the intravenous cannula, the higher the incidence 66 of such events. Perioperative seizures may also be psychogenic in origin. Although psychogenic seizures are exceedingly rare in this setting, there are patients for whom this diagnosis needs to be considered.
General Anesthetics As shown in Table 54-9, a number of anesthetic drugs are proconvulsants, with a significant number of these also identified as anticonvulsants, depending on the dose and rate and route 67 of administration. In considering inhalational anesthetic agents, the drug that has been linked to seizure activity most often is enflurane. In the clinical setting, enflurane is known to be potentially epileptogenic. During enflurane anesthesia with hyperventilation, the resultant hypocapnia potentiates seizure-type discharges. This electroencephalographic-activating
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property of enflurane has been used intraoperatively to activate and identify seizure foci in need of surgical resection. In this situation, spike activity not present preoperatively has been 68 observed to persist following surgery. Click here to view this table.... Intravenous anesthetic agents have also been implicated in perioperative seizures. Meperidine neurotoxicity, manifesting clinically as shakiness, tremors, 69 myoclonus, and seizures, is the most frequent cause of opioid-induced seizure activity. The accentuation of abnormal motor movements is attributed to its N-demethylated metabolite normeperidine. Previously identified risk factors for the development of meperidine-related seizures include renal failure, 70 high meperidine dosages, and co-administration of hepatic enzyme-inducing in this setting, and both resolve with medications. Myoclonus generally precedes seizures 71,72 the discontinuation of meperidine administration. An anesthetic drug, ketamine, which frequently is used in trauma patients undergoing surgery, has been linked to the activation of epileptogenic foci in patients with known seizure 73 disorders. It appears that doses larger than 2 mg/kg of intravenous ketamine are needed to influence the incidence of seizures in these patients. In addition to frank seizure activity, some general anesthetics may produce abnormal neurological findings persisting for up to 60 minutes after cessation of the anesthetic. In a prospective study, it was found that neurological abnormalities such as quadriceps hyperreflexia, extensor plantar responses (Babinski's sign), and intense muscle spasticity can be found for up to nearly 1 hour in patients receiving enflurane–nitrous74oxide anesthesia, as well as at a lesser frequency with isoflurane–nitrous oxide anesthesia. The incidence of these neurological findings declined as patients became more alert. In one healthy 38-year-old woman undergoing arthroscopy of the knee, myoclonic jerks involving multiple muscle groups (except those innervated by cranial nerves) occurred75over the first 48 hours postoperatively; neurological findings after this period were normal.
Regional Anesthetics A variety of CNS effects may occur when local anesthetics are used for regional block. The initial symptoms of local anesthetic-induced CNS toxicity include lightheadedness, dizziness, 76 and visual and auditory disturbances such as difficulty in focusing and tinnitus. Objective signs of CNS toxicity are excitatory in nature and include muscular twitching, shivering, and tremors of facial muscles and distal extremities. Ultimately, generalized tonic-clonic seizures occur. Other signs that may precede the occurrence of such seizures include euphoria, dysarthria,77sweating, vomiting, pugnaciousness, loquaciousness, and an inability to respond to reason. Stimulation of the CNS with local anesthetics may occur from unintended intravascular injection or rapid systemic uptake from the regional block site. The initial phase of CNS excitation may be due to a selective inhibition of inhibitory pathways in the cerebral cortex, thus allowing facilitatory neurons to discharge in an unopposed fashion. The net stimulation of glutamate release, an excitatory amino acid neurotransmitter, may also play a role. With an increase in the dose of local anesthetic, activity of both inhibitory and excitatory 78 pathways is inhibited, leading to a generalized state of CNS depression. A number of investigators have published on the incidence of seizures secondary to the clinical use of local anesthetics, and the centers most experienced in the use of regional block report a 77 figure of approximately 0.1 to 0.33 percent. There is a predictable pattern of peak serum levels, depending on the site of regional block, but most systemic toxic reactions result from direct intravascular injection of local anesthetic rather than from rapid systemic uptake. If signs of CNS toxicity or frank convulsions occur, a number of steps must be followed to minimize adverse outcomes. With seizures induced by local anesthetics, hypoxemia, hypercapnia, and acidosis rapidly develop, and symptomatic treatment of the toxicity must involve treatment of these factors. Oxygen should be given via a bag and mask; tracheal intubation is indicated only in cases of ineffective ventilation. The next step in therapy remains controversial, involving administration of either succinylcholine or anticonvulsant drugs. Succinylcholine is often recommended because seizures are usually short-lived, and pharmacologically induced muscle relaxation facilitates ventilation and decreases the magnitude of metabolic acidosis. Nevertheless, it does not prevent seizures or decrease cerebral metabolism. In addition to the toxic CNS effects, cardiovascular collapse and arrhythmias may also result from a systemic reaction to local anesthetics. It was originally postulated that toxicity (both CNS and cardiovascular) of local anesthetics parallels anesthetic potency; current information suggests that the long-acting agents bupivacaine and 79–81 etidocaine are proportionately more cardiotoxic than their anesthetic potency predicts. This relative increase in cardiotoxicity appears to result from more potent effects on sodium
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channels by long-acting drugs. Thus, if a seizure and cardiovascular collapse occur owing to a local anesthetic, resuscitation may require 1 to 2 hours because it may take an extended period of time to “wash out” the long-acting local anesthetic from the myocardium during the low-flow states that are produced with cardiopulmonary resuscitation. PERIOPERATIVE HEADACHE Chronic headaches occur in 10 percent of the general population. Since approximately 25 million people undergo surgery in the United States each year, a considerable number of these patients will have chronic headaches. When headaches occur perioperatively, it is important to determine whether they correspond to prior headache patterns or represent an entirely new symptom complex. Table 54-10 lists some causes of perioperative headache. The perioperative period is stressful, and tension and stress-related headaches may be exacerbated during this time. A significant percentage of the population consumes caffeine-containing drinks on a regular basis, and the perioperative period often limits caffeine intake. One review of 287 patients undergoing minor elective procedures with general anesthesia suggests that headaches related to caffeine withdrawal may begin 24 hours after cessation of caffeine intake and may 82,83 The use of nitrous oxide in patients with inflamed sinuses or last for up to 5 or 6 days. air-containing middle-ear spaces may result in sinus or ear block and thus headache. The etiology is related to increases in pressure from nitrous oxide equilibrating with the air contained in these structures; the diagnosis is often made by exclusion. General anesthesia may be accomplished by the use of face masks that produce pressure on terminal trigeminal nerve branches, such as the supraorbital or infraorbital nerve; long-standing headaches may 84 then result from compression neuropathy. Other causes of headache are intracranial mass lesions that may occur in patients at any time; these need to be distinguished from benign causes of new-onset headache in the perioperative period. The complicating feature is that spinal anesthesia (with dural puncture) may be associated with headaches in from 1 to 5 percent of patients, depending on gender, age, and type of needle utilized for the anesthetic. The headache related to spinal puncture (decreased intracranial pressure) is possibly related to traction on trigeminal, glossopha-ryngeal, or vagal fibers, though85,86 there is increasing evidence that cerebrovascular vasodilatation may also be involved Click here to view this table.... Post–spinal puncture headaches are more common in women than in men and in the young than in the elderly; they are also more common when a large needle is used for dural puncture, especially when the bevel of the needle results in dural fibers being cut 87,88 It should be emphasized that an arbitrary period of recumbency after spinal transversely. 89 anesthesia has not been found to decrease the incidence of such headache, and some data indicate that early ambulation may actually decrease the incidence of post–spinal 90,91 Approximately 50 percent of these headaches do not interfere with puncture headache. daily activities, whereas 35 percent92are severe enough that daily activities are affected and the patient must rest intermittently. It is important that patients with post–spinal puncture headaches be referred for definitive treatment with an epidural blood patch when appropriate. The safety and efficacy of this approach (>90% efficacy in relieving headache per epidural 93–95 If an epidural blood patch is unsuccessful in relieving patch) have been well documented. headaches ascribed to dural puncture, further questioning should ascertain whether the headaches have the “postural hallmark” of being dramatically relieved in the supine position. In selected patients, it may be clinically appropriate to administer a second epidural blood patch without further diagnostic evaluation, but if a headache does not respond to this second patch, further consultation should be undertaken to exclude underlying structural lesions. PERIOPERATIVE VISUAL CHANGES Visual changes can occur after both general and regional anesthesia. While the patient is anesthetized, pressure transmitted to the globe of the eye can occlude retinal artery flow, resulting in postoperative blindness. A specific subgroup of patients who are at increased risk for visual loss following surgery are patients undergoing complex spine surgery during which general anesthesia is administered. Visual loss following spine surgery is an uncommon occurrence, with ophthalmic complications reported to occur in less than 0.2 percent of spine 96–98 Investigations suggest that the visual 99 loss is due to ischemic optic neuropathy, surgeries. central retinal artery occlusion, or cerebral ischemia. The American Society of Anesthesiologists Task Force on Perioperative Blindness identified high-risk patients as those who undergo spine procedures while positioned prone, those who have prolonged 100 procedures, and those experiencing substantial blood loss. The practice advisory suggested measures to be taken when providing anesthesia care to patients at risk for
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postoperative visual loss. Intraoperatively, high-risk patients should be positioned with the head maintained in a neutral position, level with or higher than the heart. Avoidance of direct pressure on the eyes is imperative. Colloids in addition to crystalloids should be used to maintain intravascular volume. Finally, consideration should be given to the staging of 101 procedures that are anticipated to be lengthy and associated with substantial blood loss. Spinal puncture may be followed by cranial nerve palsies, the most frequent involving the 102,103 The most commonly proposed abducens nerve (bilaterally on rare occasion). explanation for the predominance of sixth cranial nerve changes following development of low cerebrospinal fluid pressure is that the nerve's relatively long intracranial course renders it susceptible to both pressure and stretch. Others promote the concept that the abducens palsy is due to increased venous pressure in the cavernous sinus, since the nerve courses through this site. Venous dilatation occurs in the cranium in compensation for a decrease in cerebrospinal fluid pressure, which may occur following spinal anesthesia. It is clear that the needle size is crucial for both post–spinal puncture headache and abducens nerve palsy. At one neurology clinic in a large university in Germany, 800 patients underwent diagnostic lumbar puncture yearly with 22-gauge needles and in less than 5 percent of cases, with 20-gauge needles. Over a 14½ -year period, 2 patients experienced abducens palsy, 104 translating to a risk of less than 1 in 5,800 spinal punctures. Pupillary changes may follow epidural and spinal anesthesia. There are numerous case reports of the development of 105–107 These are related to local anesthetic effects Horner's syndrome after epidural block. upon sympathetic nerves, but the level of the central block surprisingly does not correlate with 108 the development of Horner's syndrome, at least in the parturient. Among 150 parturient patients undergoing epidural anesthesia for cesarean section or labor, the frequency of Horner's syndrome was 1.3 percent for labor analgesia and 4 percent when the epidural 108 block was used for cesarean section. Horner's syndrome occurs only for the duration of local anesthetic block and, accordingly, should not confound postoperative pupillary assessment except in rare circumstances. Horner's syndrome has also been noted with other regional techniques, and continuous brachial catheter local anesthetic infusions have also 109 been associated with its development. Thus, if postoperative pupillary changes complicate neurological diagnosis, attempts should be made to determine whether a regional block technique might have produced Horner's syndrome. Trigeminal nerve changes have also 109 been found following epidural anesthesia and analgesia. Once again, this is an unpredictable accompaniment of the epidural local anesthetic, and time will clarify its relationship to the regional block. One final ocular alteration that may confuse neurological diagnosis in the immediate perioperative period is the pupillary dilatation that follows “total” spinal anesthesia. This occurs most frequently when an intended epidural anesthetic injection is unintentionally administered into the subarachnoid space. This produces unconsciousness as well as markedly dilated pupils. Symptomatic support of the circulation and ventilation is necessary, and time (1½ to 4 hours) will help clarify the patient's clinical course. It is important to understand that these pupillary changes are a predictable accompaniment of unintentional “total spinal” anesthesia, and diagnosticians should not be misled by the unusual appearance of the widely dilated pupils. PERIOPERATIVE AUDITORY CHANGES Similar to visual changes following anesthesia, auditory changes can accompany either general or regional anesthetic techniques. Auditory changes following general anesthesia are most commonly related to “ear block” that develops110 following the use of nitrous oxide in patients susceptible to eustachian tube obstruction. The ear block is similar to that found after ear blocks associated with air travel. Symptoms resolve with time, although nasopharyngeal decongestants may also help reduce mucosal edema to the point that the ear block can be cleared. Patients who have undergone spinal anesthesia and who are not experiencing headaches from spinal puncture may show a decrease in the ability to hear if sensitive testing is used. Wang and colleagues studied 28 patients receiving spinal anesthesia for transurethral resection of the prostate and found that as larger needles were111utilized, more marked (perhaps subclinical) changes in auditory function were found. None of their patients had headaches; thus, decreased hearing may occur in isolation. The decrease in hearing may relate to a decrease in cerebrospinal fluid volume that reduces the perilymphatic pressure; as the endolymphatic pressure equilibrates slowly compared with the perilymphatic pressure, endolymphatic hydrops results. Thus, a decrease in intralabyrinthine pressure probably causes the transient hearing loss. Hyperacusis may also develop following spinal 112 anesthesia.
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EVALUATION OF PERIOPERATIVE NEUROLOGICAL COMPLICATIONS When neurological changes occur postoperatively, many physicians and nurses assume that “something” must have gone wrong intraoperatively. As the American Society of Anesthesiologists closed-claims analysis of perioperative injury indicates, many perioperative neuropathies have no ready explanation, and our inability to define the etiology of such nerve injuries probably reflects an incomplete understanding of perioperative nerve function. The first step in managing a perioperative neurological change is to obtain a comprehensive evaluation by a skilled neurologist. It is also important to minimize speculation in the medical record and simply document facts. Time is often helpful in identifying the etiology of neurological changes, and early electrodiagnostic studies should also be considered, when appropriate, since preexisting nerve damage may evidence itself in the perioperative 113,114 This is important because abnormal spontaneous activity is unlikely to appear in period. affected muscles until 2½ to 3 weeks following nerve injury; the presence of such activity in the immediate postoperative period suggests that the nerve lesion existed before operation. Time is of the essence if a major injury of the neuraxis is being evaluated. If concern is present about an epidural hematoma following either epidural or spinal anesthesia, imaging studies should be obtained immediately, since recovery of neural function is related to the duration of neural compression by the hematoma. Finally, if perioperative neural changes are present, both the surgeons and the anesthesiologists involved in the patient's care should be included in consultation. Contemporary surgical and anesthetic care has become complex, and these individuals may offer unique insights into predictable perioperative changes that other physicians would find difficult to uncover.
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 55 Neurological Complications of Thermal and Electrical Burns MARC D. WINKELMAN •
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THERMAL BURNS Central Nervous System Complications Metabolic Encephalopathies Central Nervous System Infections Cerebrovascular Disease Blindness Peripheral Nervous System Complications Mononeuropathies Polyneuropathy ELECTRICITY AND LIGHTNING Effect on the Nervous System Clinical Syndromes Transient Loss of Consciousness Transient Paralysis Injury of Peripheral and Cranial Nerves Spinal Cord Injury Brain Injury
Fires and burns are the fifth leading cause of accidental death in the United States. Each year, 1.2 million people seek medical attention for a burn; 50,000 are hospitalized, and 3,900 1 complications can follow a burn has been known since the die. That serious neurological 2 nineteenth century. The complications of thermal burns differ considerably from those of electrical burns and therefore are considered separately. Electricity is encountered in two forms: lightning and man-made current. The neurological effects of these two forms are much the same, and they are considered together. THERMAL BURNS The term thermal burn refers to a burn caused by contact with flames, hot metal, or hot water, or by the flash of radiant heat from an explosion. The extent of a burn is expressed as the percentage of the total body surface area involved. The depth is gauged as full thickness when the dermal appendages are destroyed and partial thickness when they are spared. Patients with extensive, full-thickness burns are more likely to die or to sustain neurological complications than those with less severe burns. They are the ones who require the intensive
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care of a burn unit and with whom this chapter is concerned. Neurological diagnosis is difficult because extensively burned patients are difficult to examine. Their burned eyelids are swollen shut; their faces are swollen and move poorly. It is hard for the patient to move swollen and bandaged limbs and for the doctor to assess their tone and reflexes. Under these circumstances, a full neurological examination cannot be performed; hence, focal signs may escape detection. Peripheral neuropathies may go unnoticed, and symptoms of focal, structural cerebral lesions may be attributed to metabolic or toxic encephalopathies. The limitations of the neurological examination must be appreciated, and cerebral imaging, examination of the cerebrospinal fluid (CSF), and nerve conduction studies may be required more often than for other types of patient.
Central Nervous System Complications Because the brain and spinal cord lie deep in the body, they are not injured by the heat of flash or flame. Most victims are neurologically normal immediately after their burn. Those who are not have usually sustained head trauma or anoxic encephalopathy caused by carbon 3,4 monoxide poisoning or cardiopulmonary arrest due to smoke inhalation. Most disorders of the central nervous system (CNS) arise later, during hospitalization, not as a direct consequence of the burn but as a result of some other complication: a systemic infection, 4 disseminated intravascular coagulation (DIC), hypotension, or metabolic abnormalities. Most of them bear a characteristic temporal relationship to the burn, which may provide a valuable clue to diagnosis. The overall frequency of CNS complications was 5, 6.6, and 14 percent in reports of three 2,5,6 Metabolic encephalopathies, cerebrovascular large clinical series of patients with burns. lesions, and CNS infections are the major types of complications and occur in that order of 2,4,6 4 Adults and children are equally affected. Many patients have more than one frequency. 4 CNS complication, for several reasons. First, a systemic infection can affect the brain by direct invasion, by an intermediary mechanism of disease (e.g., DIC or septic shock), and by leading to systemic metabolic abnormalities. A patient may thus be affected in more than one way. Second, patients may have several independent CNS complications: infectious and noninfectious, metabolic and structural. Third, elderly patients may have coexisting cerebral diseases in addition to complications of their burn. Often a single diagnosis is an adequate but incomplete explanation for a cerebral symptom. For example, a patient with an atherosclerotic cerebral infarct or a metabolic encephalopathy may also have a CNS infection. Therefore, diagnostic evaluations must be extensive, and the response to treatment may be difficult to interpret. Metabolic Encephalopathies Burned patients are liable to a variety of metabolic derangements, many of which cause encephalopathy. Anoxemia, hyponatremia, serum hyperosmolality, and uremia, treated in 2,7 detail in the following sections, are the major ones, but there are others. Hypernatremia, due to insensible water loss through the burn wound, is the most common electrolyte abnormality. A burn causes a marked increase in metabolic rate. There is increased production of glucose, and this may lead to hyperglycemia. Insulin resistance and intravenous hyperalimentation are other causes of hyperglycemia in this setting. Hypoglycemia is usually associated with overwhelming systemic infection. Sequestration of calcium in burned skin may cause hypocalcemia, which in turn can lead to seizures and confusion. Hypomagnesemia, with muscle cramps or hallucinations, occurs occasionally. Anoxic Encephalopathy
A severe burn is attended by the rapid and massive accumulation of edema in the burned 7 and unburned skin (“burn edema”). Intravascular volume depletion and hypotension follow, leading to ischemic tissue damage. This state is called burn shock. Anoxic encephalopathy is the most common neurological complication of a burn, and burn shock is its most common 4,6 After the first week, septic shock becomes the cause in the first few days after a burn. 4 major cause. Hyponatremic Encephalopathy
Fluid resuscitation for burn shock can result in dilutional hyponatremia, the most common 5,6,8 cause of early confusion and seizures in burned patients, especially children. 7 Later in the hospital course, hyponatremia is most often associated with systemic infection.
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Uremic and Hepatic Encephalopathy
Uremic encephalopathy is most often due to acute renal failure, which in turn is caused by 4 acute tubular necrosis or DIC. The causes of acute tubular necrosis are much the same as those of anoxic encephalopathy. In patients with chronic liver disease, hepatic 4 encephalopathy can develop during convalescence from a burn. Precipitating causes include a systemic infection, narcotic analgesics, hypovolemia, and bleeding from a Curling ulcer of 7 the stomach. Central Pontine Myelinolysis
Burned patients, like people with alcoholism, are especially susceptible to central pontine myelinolysis (p. 350). In a retrospective autopsy study, 9this disorder was found 25 times more often in burned patients than in the general population. It was associated with a prolonged period (≥3 days) of extreme serum hyperosmolality (≥360 mOsm/kg) but not with hyponatremia or the correction of hyponatremia. Infection was a major factor in the genesis of the hypernatremia, azotemia, and hyperglycemia that contributed to hyperosmolality. Central pontine myelinolysis was a late complication; it began after the second hospital week in most cases and never in the first week. The lesions were often small and asymptomatic. Even when the lesion is large, diagnosis is difficult. Metabolic coma may hide the motor signs of central pontine myelinolysis, or they may be missed as a result of the difficulties of neurological examination described earlier. Late development of quadriplegia, pseudobulbar palsy, the locked-in syndrome, or coma unresponsive to correction of serum hyperosmolality suggests the diagnosis. Magnetic resonance imaging (MRI) can confirm it. Central Nervous System Infections Infection is the most common cause of morbidity and mortality in burned patients, because they are immunocompromised in several ways. The burn destroys the skin barrier to microorganisms, and the devitalized eschar of the burn wound makes an ideal culture medium. Inhalation of smoke injures the local defense mechanisms of the tracheobronchial tree. Intravenous and urethral catheters and endotracheal tubes promote intraluminal ingress of organisms.10In addition, both the cellular and the humoral immune systems sustain complex impairments. CNS infection is the 4result of hematogenous spread of microorganisms from a source outside the nervous system. Burn wound infection, pneumonia, suppurative thrombophlebitis, and infective endocarditis are the most common sources. Candida species, Pseudomonas 4 aeruginosa, and Staphylococcus aureus are the most common pathogens. Most CNS infections arise in the second and third weeks after the burn; they occur only rarely in the first 4,6 week and never in the first few days. This delay occurs because the CNS is a secondary rather than a primary target of invading microorganisms. Serious infections, including those of the CNS, do not follow minor burns but extensive, deep7 burns, that is, full-thickness burns that involve at least 30 percent of total body surface area. The foregoing facts may help in neurological diagnosis. A week or more after receiving extensive burns, a patient with a systemic infection is at high risk for development of a CNS infection. In contrast, patients without a known site of infection, positive blood cultures, or systemic signs of infection and those in the first week after their burn are unlikely to have an 4 infection of the CNS. Similarly, a patient with a burn involving less than 30 percent 4of total body surface is unlikely to have a CNS infection, even if there is a systemic source. Such patients have less suppression of systemic immune function than those with a major burn 10 and are better able to contain a local infection. Pseudomonas aeruginosa 4,6
Bacterial meningitis develops in 1 to 4 percent of extensively burned patients. P. 4,6 aeruginosa infection is the most common etiology. Moreover, in one autopsy series, meningitis developed in 15 percent of burned patients who had a systemic Pseudomonas 4 infection. A burn wound infection was the most common source. Blood cultures were positive. This is the only CNS infection that has been reported to begin in the first week after 4,6 a burn. Other gram-negative enteric organisms, such as Escherichia coli, but no 4 gram-positive bacteria or fungi have been reported to cause meningitis in burned patients. Gram-negative rods have not caused other types of intracranial infection, such as brain 4,6 abscess. The diagnosis of meningitis may be difficult because the burn surgeon will probably have
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initiated treatment of the primary (source) infection by the time of neurological consultation. This may eliminate the headache and stiff neck of meningitis without eradicating the infection. In some patients, only confusion, stupor, or coma is found. Hence, a metabolic or septic encephalopathy may be diagnosed. However, a gram-negative infection outside the CNS, especially one due to P. aeruginosa, occurring in the setting of an extensive burn that is more than 1 week old, should prompt lumbar puncture. Evidence of meningitis, perhaps partially treated, may be found. If cultures and smears of CSF are negative, antibiotics effective against P. aeruginosa meningitis should be prescribed because that is the likeliest pathogen. 4 Many burned patients have more than one systemic infection. Adequate coverage should also be provided for meningitis due to all other microorganisms grown in systemic culture. If the skin of the back is burned, it may be impossible to do a lumbar or cervical puncture. This is the case in the most extensively burned patients; unfortunately, they are the ones most likely to develop meningitis. If such a patient has a systemic infection due to a gram-negative rod, particularly P. aeruginosa, an antibiotic with good CSF penetration should be prescribed so that meningitis, although impossible to document, should not go untreated. Candida Species
The frequency of Candida infections is increasing among burned patients—a result of the use of broad-spectrum antibiotics for bacterial infections, longer survival of older and more extensively burned4,10 patients, and the use of central intravenous catheters and intravenous Half the patients with invasive candidiasis have cerebral involvement at hyperalimentation. 4,11 This most often takes the form of disseminated microabscesses; large autopsy. 4,11–13 Patients abscesses, meningitis, and mycotic aneurysms are much less common. Candida have almost always had at least one previous, treated bacterial infected with 4 infection. This is reflected in the relatively late onset of cerebral candidiasis—usually late in 4 the second hospital week, and never in the first week. 14
The antemortem diagnosis of disseminated cerebral microabscesses is difficult. They typically produce drowsiness, confusion, stupor, or coma. Fixed, focal cerebral signs and focal seizures are unusual. The CSF remains normal. Often less than 3 mm in diameter, the abscesses are too small to be detected by computed tomography (CT) scanning, but they do appear as small, bright foci on T2-weighted and fluid-attenuated inversion recovery (FLAIR)–sequence MRI, and they probably enhance with contrast. Thus, it may require MRI to distinguish multiple cerebral microabscesses from a metabolic or septic encephalopathy. The diagnosis of cerebral candidiasis may be difficult because the CSF is usually normal, and the diagnosis therefore requires the demonstration of infection outside the CNS. The primary site of infection may not be apparent, and metastatic foci of infection may be hidden as 11 microabscesses in the myocardium or kidney. Pneumonia, evidence of which can be seen on a chest radiograph, is not common. Positive urine, sputum, fecal, and wound cultures can mean colonization rather than infection. Blood cultures are often negative. Without 4 candidemia, the diagnosis is usually made only after death. There is currently no single test that identifies every case of invasive candidiasis. The diagnosis begins with a high index of suspicion in patients with unexplained systemic signs of infection; deep, extensive burns; and a prior bacterial infection. Blood cultures, biopsy of the burn wound (the most frequent site of infection), serological tests, and repeated clinical evaluation for involvement of the skin and eye may help with diagnosis. In an autopsy study, almost half the burned patients with 4 candidemia had cerebral involvement. Therefore, a positive blood culture should prompt systemic antifungal therapy. Staphylococcus aureus 4
S. aureus spreads to the brain by way of endocarditis in burned patients. Intracranial spread 15 from other sites has been reported only once in this group of patients. The sequence of events is burn wound infection, bacteremia, infection of a heart valve, and embolism of infected material to the brain, with infarction or microabscess formation. Other cerebral complications of endocarditis, such as meningitis and mycotic aneurysm, presumably occur in burned patients but have not been reported. Intracranial staphylococcal infections begin relatively late—in most cases more than 10 days after the burn—presumably because the brain is infected after the burn wound and endocardium. The frequency of CNS infection with this organism has declined since the mid-1970s because better antibiotic treatment of burn wound infections prevents the development of endocarditis. The diagnosis of staphylococcal cerebral microabscesses is as hard as that of microabscesses due to Candida, but the identification of S. aureus as the cause is easier because blood cultures are positive. The diagnosis of a staphylococcal CNS infection should prompt a search for endocarditis.
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Cerebral infarction and S. aureus infections are discussed later. Cerebrovascular Disease Cerebrovascular lesions typically present as a stroke (i.e., the sudden onset of a focal neurological deficit), but in burned patients this often is not the case, for three reasons. First, there is the difficulty of neurological examination, described earlier. Second, multiple cerebral complications, the general debility of patients, and the use of narcotic analgesics may obscure the acute onset of cerebrovascular accidents. And third, cerebral infarcts and 4 hemorrhages are often multiple and bilateral in patients with burns, turning an asymmetric neurological picture into one of relative symmetry. Thus, an infarct or hemorrhage may present not as a stroke but in the guise of a metabolic encephalopathy; therefore, any unexplained cerebral symptom or sign should lead to brain imaging. Septic Infarction
Cerebral infarction is due more often to complications of the burn than4 to atherosclerosis, atrial fibrillation, and other premorbid conditions unrelated to the burn. Each major infection discussed earlier can cause septic occlusion of cerebral blood vessels, with infarction of brain. Meningeal infection can extend into the walls of arteries and veins that run through the subarachnoid space, leading to inflammation and occlusion of affected vessels. This is a common4 complication of P. aeruginosa meningitis and can occur in the first week of disease. Embolism of infected material with occlusion of cerebral arteries is a classic complication of infective endocarditis. Only one burned patient with cerebral aspergillosis has been reported, but Aspergillus is a common cause of systemic infection in patients with 4,10 burns.11,12 Aspergillus and Candida species invade and occlude blood vessels at their portal of entry. The fungi then spread through the blood stream, causing inflammation and 12 In the brain, infarction is the major thrombosis of blood vessels in distant organs. 16 Aspergillus. Candida causes mainly microabscesses; infarcts are pathological effect of 4,13 fewer. Radiological features do not distinguish septic infarcts from those caused by premorbid 4 vascular disease, but certain clinical points are helpful. Septic infarction may affect patients of any age and does not occur during the first week after a burn. Patients have extensive burns and systemic signs of sepsis. Focal neurological deficits do not improve. In contrast, infarction caused by premorbid conditions may occur at any time during the hospital course and regardless of the severity of the burn or the presence of systemic infection. Patients are usually elderly, have conventional risk factors for cerebral infarction, and may have had previous cerebral infarcts or coronary or peripheral vascular disease. When a burned patient has a cerebral infarct and a septic cause seems likely, it is important to determine the mechanism involved—meningitis, endocarditis, or fungal invasion of a vessel—and the responsible micro-organism. If the patient was neurologically normal before cerebral infarction, meningitis is unlikely. Physical signs of meningitis, infective endocarditis, or disseminated candidiasis may be found. The mechanism and etiology of septic infarcts correlate with one another. Cerebral infarction in a patient with S. aureus bacteremia suggests the presence of endocarditis. A systemic P. aeruginosa infection suggests that meningitis due to that organism underlies the infarct. If meningitis is found, it is the likely mechanism of infarction, and P. aeruginosa is the probable cause. Thus, examination of the CSF should always be considered. If evidence for neither meningitis nor endocarditis is found, fungal invasion of cerebral blood vessels should be suspected. Cerebral infarction in a patient with invasive candidiasis or aspergillosis suggests that the infection has spread to the brain. A cerebral infarct in a patient with systemic signs of sepsis but negative cultures suggests the possibility of infection with Candida or Aspergillus. Disseminated Intravascular Coagulation 17
DIC is a well-known complication of burns. Bacteremia or fungemia with or without 4,17 Fibrin thrombi occlude capillaries and small arteries and veins hypotension is the cause. throughout4,18 the body. In the brain, disseminated hemorrhagic infarcts and microinfarcts are 18,19 They may or may not produce focal cerebral signs. DIC, like disseminated the result. microabscesses, may simulate a metabolic or toxic encephalopathy. CT scanning detects the larger infarcts. Microin-farcts may appear as small, bright foci on T2-weighted and FLAIR-sequence MRI. DIC is unlikely to be the cause of early neurological symptoms; it 4,17 usually begins later than the first week after a burn, and never before the fourth day. The diagnosis of DIC can be difficult in a patient with burns. A bleeding diathesis may be
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absent. None of the elements of the typical coagulation profile is specific for DIC. Consumption of platelets and clotting factors in 17 the burn wound itself may result in thrombocytopenia and prolonged clotting times. Bacteremia itself and certain drugs may cause thrombocytopenia. Nutritional deficiency and antibiotic-induced alteration of the flora of the gut may deplete the body of vitamin K and consequently of vitamin K–dependent clotting factors. Moreover, titers of fibrin degradation products are elevated early in all patients with 17 burns. Helpful findings in the diagnosis of DIC are a sudden decline in the platelet count or the plasma concentration of fibrinogen (sometimes from an elevated level into the normal 17,18 Heparin has not been proved helpful in range) and a positive biopsy of unburned skin. treating DIC in patients with burns. Treatment of the infection and hypotension underlying DIC and replacement of depleted platelets and clotting factors are the recommended 20 approaches. Border Zone Infarction
Cerebral infarction in the arterial border zone may occur4early in the hospital course as a complication of burn shock and, later, with septic shock. The location of the infarct on brain imaging and the clinical setting point to the diagnosis. Venous Infarction
Cerebral infarction caused by occlusion of dural sinuses and large and small cerebral veins 21 has been reported in burned patients. Meningitis was not associated. DIC or intravascular volume depletion may have been responsible. Magnetic resonance venography or simple MRI can detect occlusion of large venous channels. Nonbacterial thrombotic endocarditis and deep venous thrombosis with paradoxical embolism are possible but unreported causes of cerebral infarction in burned patients. Intracranial Hemorrhage 4
Intracranial hemorrhage occurs much less often than cerebral infarction. Lobar hemorrhage, subarachnoid hemorrhage, and widespread parenchymal petechiae (“brain purpura”) have 4,22 A bleeding diathesis related to DIC or thrombocytopenia, resulting, in turn, been reported. 4 from bacteremia, 4is the cause. Cerebral hematomas and infarcts may both be present in patients with DIC. Blindness 23–30
Several patients with binocular blindness after a thermal burn have been reported. The cases are heterogeneous, and no syndrome of blindness emerges that is specifically related to burn injury. Cortical blindness appeared suddenly and resolved substantially in three 24,26,27 Bilateral occipital lobe infarction was patients during their convalescence from a burn. the likely cause. Various optic neuropathies caused blindness in the other patients. The 25 24 bacterial meningitis, dural sinus underlying causes included nutritional deficiency, 24 23,29,30 24 and neuromyelitis optica. In some patients, blindness and thrombosis, hypotension, signs of optic neuropathy were part of an acute, widespread cerebral disease that probably 23,24 Recently, Unsold and caused increased intracranial pressure but went undiagnosed. colleagues, reporting two cases of burn-associated optic neuropathy and reviewing the literature, speculated that28demyelination caused by a circulating toxin released from burned skin could be the cause.
Peripheral Nervous System Complications Mononeuropathies In a prospective study, 26 percent of patients hospitalized with burns developed a 31 mononeuropathy. The figure would be more meaningful and useful if electrical burns had been distinguished from thermal burns. Heat may cause coagulation necrosis of nerve trunks 32 involved in a thermal burn. Superficial nerves, such as the ulnar nerve at the elbow and the sensory branch of the radial nerve in the hand, are more liable than deep nerves to thermal damage. Such injuries cannot be treated surgically. Many limbs burned deeply enough to involve nerves require amputation. Blunt trauma from a fall is another cause of nerve injury in burned patients and may affect nerves in unburned or burned limbs. Reference was made earlier to burn edema, the massive swelling that follows a serious burn.
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When the indistensible eschar of a burn surrounds a limb, the hydrostatic pressure within may be sufficient to shut off the flow of blood. Thus, in a circumferential burn, a tourniquet 32 effect may lead to ischemic necrosis of distal muscle and nerve. This is the major nerve injury that presents in the first day or so after a burn. Loss of peripheral pulses or Doppler-audible flow in the distal vascular arches and digital arteries of a limb is an indication 32 for immediate escharotomy. In very deep burns, edema develops below the skin and 33 subcutaneous fat, inside the osteofascial compartments that envelop muscle and nerve. Blood flow may be obstructed to such an extent that ischemic necrosis of tissue results, but the deep fascia, not the burn eschar, is responsible, and fasciotomy, not escharotomy, is the appropriate treatment. These compartment syndromes are rare in thermal burns but common in electrical burns. 32,34
Nerves can be lacerated during Most nerve injuries occur as complications of treatment. escharotomy. The ulnar nerve at the elbow, the peroneal nerve as it winds around the head of the fibula, and the sensory branch of the radial nerve are especially vulnerable because they are superficial. The same nerves are liable to compression by tight dressings or malpositioning. 32
Heterotopic bone formation can cause a mononeuropathy late in the hospital course. The ossification is usually periarticular. The elbow is the joint affected most often, and the ulnar nerve may be compressed. Treatment consists of decompression and transposition of the nerve. The cause of heterotopic bone formation is unknown, and recurrence is common. Marquez and associates described several patients with multiple mononeuropathies in burned and unburned35limbs that could not be attributed to the mechanisms of injury discussed previously. They speculated that thrombosis of the vasa nervorum or a circulating neurotoxin derived from burned tissue was responsible but had no supportive evidence. Polyneuropathy Helm and co-workers studied 57 patients with thermal burns in whom neuromuscular 34 symptoms developed during hospitalization. Thirty-one of them (54%) were found to have a polyneuropathy. Weakness in the distal muscles of the extremities was the major neurological sign; sensation was normal in most patients. Most patients recovered after their burns had healed. Three prospective studies have addressed the frequency of 31,36,37 Polyneuropathy was reported to develop in polyneuropathy in severely burned patients. 15, 29, and 41 percent of patients treated in a burns intensive care unit. There are several possible reasons for the discrepancy among these figures: inclusion of patients with electrical burns, lack of distinction between the syndromes of polyneuropathy and multiple 31,36 different levels of burn severity among the study populations, and small mononeuropathy, 31,37 numbers of patients. The cause of burn-associated polyneuropathy has not been determined. Critical illness 35,38,39 A polyneuropathy (discussed in Chapter 52) has been reported in four burned patients. fifth patient, with pneumonia, gram-negative bacteremia, adult respiratory distress syndrome, 40 and acute renal failure, is probably another example. Perhaps burn-associated polyneuropathy is critical illness polyneuropathy that develops in the burn unit. That the occurrence of polyneuropathy correlates with measures of severe illness, such as the depth and extent of the burn and the length of stay in the intensive-care unit, is in keeping with that 31,34,36,41 Margherita and associates suggest, in contrast, that burn-associated idea. polyneuropathy is37a direct specific result of thermal injury, but they do not offer a precise idea of pathogenesis. ELECTRICITY AND LIGHTNING Serious electrical injuries are much less common than serious thermal burns. They account 1,42–44 Electricity causes three types of for only 3 to 7 percent of admissions to burn units. burn. High-voltage current often jumps a gap between its source and a victim. This “arc” can attain a temperature of 4,000°C and cause a severe burn, identical to a flash burn. Ignition of a victim's clothing may cause a flame burn. These thermal burns make the victim of electrical trauma liable to the neurological complications discussed earlier. The third type of burn is produced only when the victim becomes part of an electrical circuit, and current flows through the body on its way to ground. Burns mark the points of entry and exit. These “contact burns” are much deeper than flash and flame burns and often involve nerves. Structures between the entry and the exit wounds, including nerves, spinal cord, and brain, conduct the current and sustain its direct effects. Also of importance are two indirect mechanisms of neurological damage: cardiac arrest and trauma. Passage of an electrical current through the heart
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causes asystole or ventricular fibrillation, with syncope or anoxic encephalopathy occurring as a result. An electrical shock often causes the victim to fall, and this may result in head injury. Moreover, emanating from the axis of a45,46 lightning channel is a cylindrical shock wave of Like the force of an explosion, it may cause expanded, displaced, and returning air. trauma directly or by throwing the victim to the ground.
Effect on the Nervous System Man-made electricity or lightning can injure any structure in the peripheral or CNS through 43,47,48 A which it passes. The degree of damage is directly related to the amount of current. small current produces only a derangement of function, and clinical manifestations are transient. Larger currents cause structural damage that may be reversible or irreversible; neurological deficits may be permanent or may resolve with time. The quantity of current varies directly with its voltage and the duration of its passage and inversely with the resistance of the skin, which it must breach before it reaches neural 49 structures. An arbitrary division is made at 1,000 V between high-tension and low-tension electrical current. Household current is 110 or 220 V; high-tension wires carry current of several thousand volts. Alternating current causes muscle tetany, which may prolong an electrical shock by causing the victim's hand to grip the contact. Thus, alternating current is more dangerous than direct current. A high-tension circuit is often completed by arcing before contact is made. A massive contraction of axial and limb musculature ensues, and this can throw the victim to safety. Thus, low-tension alternating current may cause more damage to the nervous system than high-tension current. 50
Electricity takes the shortest pathway through the body to ground. Identifying the entry and exit wounds is important, because the current injures only structures between them. When current travels from hand to hand, the nerves and muscles in the arms, the brachial plexus, and the cervical spinal cord lie in its pathway, but the brain does not. A current pathway from head50to feet includes the brain, the entire spinal cord, and the nerves and muscles in the legs. A bolt of lightning can exceed 200 million V, which is far larger than the voltage of the highest-tension electrical wire. A direct strike need not, however, be fatal, for two reasons. 51 First, the duration of the electrical discharge is short, approximately 149millisecond. Second, most of the current flows over the surface of the body, not through it. Lightning, considerably attenuated after striking a tree, can “splash” or “spray” onto a nearby person. Moreover, once lightning has struck the ground, the weakened current can run up one leg and down the other leg of a bystander (stride potential). Such phenomena probably explain 52 how one bolt of lightning can injure many people gathered together. In addition to entrance and exit burns, lightning figures may be present on the skin. They are arborescent red lines 53,54 As they fade, they may that indicate the path of lightning over the surface of the body. leave pigmentary changes in their place. Their presence on a victim's back may help account for myelopathy after a stroke of lightning. As current flows through the resistance of tissue, electrical energy is turned into heat (Joule effect). This is the cause of many electrical lesions of the nervous system, but some may be due to nonthermal effects. Three arguments support this idea. First, the peripheral nerve and brain of animals can43,48,55 be damaged experimentally by electrical current without an appreciable Second, some victims43,53 of electrical trauma are left with a rise in temperature. Third, neurological symptoms may begin neuropathy or myelopathy but no electrical burn. a considerable time after an electrical shock. Lee has suggested electrical breakdown of cell 56 membranes—electroporation—as a nonthermal mechanism of tissue injury. Perforations in the plasma membrane large enough to alter the electrochemical balance between the intracellular and extracellular compartments would result in a cellular metabolic disorder that might cause the eventual death rather than the immediate death of a cell.
Clinical Syndromes Transient Loss of Consciousness Lightning or man-made electrical current passing through the head causes immediate loss of consciousness. Patients awaken in minutes to hours. Agitation, confusion, retrograde amnesia, headache, and even a convulsive seizure often follow, but complete recovery is to 43,52,53,57 Some patients may have sustained cerebral concussion caused by a be expected. fall or the cylindrical pressure wave of the lightning bolt, but electrically induced seizure activity or inhibition of cerebral function is the likely pathophysiological mechanism in most
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cases. Brief loss of consciousness often follows passage of lightning or high-tension current outside the head. Transient cardiac asystole, ventilatory failure caused by tetanic contraction or paralysis of the thoracic musculature, acute intracranial 43,53,55,58 hypertension, and loops of current Loss of consciousness is that find their way into the head are possible mechanisms. sometimes delayed rather than immediate, or it may occur immediately and then again 53,58,59 A similar phenomenon can follow mild head trauma and probably somewhat later. represents vasodepressor syncope. Pa tients who lose consciousness for more than a few hours or have focal cerebral signs do not fall into this category; anoxic encephalopathy or a serious head injury should be suspected. Transient Paralysis Immediate and transitory sensorimotor paralysis is the neurological syndrome that typically results from lightning stroke. Charcot coined the term keraunoparalysis (“lightning paralysis”). Symptoms and signs correspond to the sites in the peripheral nervous system, spinal cord, and occasionally the brain through which lightning has passed. Paraplegia is most common, but quadriplegia, monoplegia, bibrachial paralysis, hemiplegia, ventilatory paralysis, cranial 53,60 Signs of involvement of the autonomic neuropathies, and aphasia have been reported. nervous system are common and include pupillary abnormalities and61,62 loss of peripheral Prolonged pulses, as well as coldness and pallor or cyanosis of the weak limbs. ventilatory paralysis and binocular mydriasis can simulate death. This accounts for the clinical dictum that some patients who “die” after lightning stroke can “live again” if given 63 to hours and cardiopulmonary resuscitation long enough. Lightning paralysis lasts minutes 52,59,64 seldom more than a day, although minor paresthesias may linger for weeks. High-tension electrical current can occasionally produce the same syndrome, and one case 43,44,58,65,66 The pathophysiological basis of following a low-voltage shock has been reported. the syndrome is unknown. Injury of Peripheral and Cranial Nerves High-Tension Current
A focal peripheral or cranial neuropathy is the44most common serious neurological complication of a high-tension electrical burn. In three large series of patients, the frequency 42,44,67 The lesion is usually located in the midst of a contact burn was 13, 22, and 34 percent. 43,68 It consists of coagulation necrosis but may be elsewhere 69 in the pathway of the current. parallels that of thermal damage to surrounding muscle, and is caused by heat. Its severity 43 If the nerve sheath and blood vessels, and tendons. Symptoms begin immediately. 44 damage to peripheral nerves vasculature are intact, some function may return. Permanent 43 does not extend beyond the area of local tissue damage. 70
High-tension electrical current, including lightning, causes coagulation necrosis of muscle in its path-way. Swelling begins within hours. Massively swollen muscles, encased in compartments of fascia and bone, may compress adjacent blood vessels. The result is ischemic necrosis of tissue, including muscle and nerve. The diagnosis of this compartment syndrome can be difficult. Unburned skin may cover a vast extent of burned muscle (“hidden muscle damage”). The swollen muscle is confined by fascia, over which the skin may be loose, not taut. Distal pulses may be present. Myoglobinuria and acute renal failure are clues to the diagnosis. More than one peripheral nerve may be affected: the median, musculocutaneous, and radial nerves in the anterior arm and the median and ulnar nerves in the anterior forearm. Wick catheters (to measure the pressure inside a muscle compartment) and nerve conduction studies may help in diagnosis, but most surgeons perform emergency fasciotomy on clinical indication. Swelling of burned tissue can cause acute entrapment of nerves that pass through tight anatomical canals. The median nerve may be affected in the carpal tunnel or between the heads of the pronator teres muscle (pronator syndrome), the ulnar nerve in Guyon's canal or the cubital tunnel, and the posterior interosseous nerve in the arcade of Frohse. The most common clinical problem is a deep burn of the anterior wrist associated with a median or ulnar neuropathy. Many surgeons routinely open the carpal tunnel and Guyon's canal in such 32,71 Patients who respond presumably have a compressive neuropathy; those circumstances. who do not may have a primary electrical neuropathy. Scar tissue in healing electrical burns may grow around or within a peripheral nerve, thereby impeding regeneration or causing a new mononeuropathy late in the hospital course. This 43 happens most often with deep burns of the wrist. The responsible scar is usually apparent on the surface of the body.
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Low-Tension Current
Peripheral nerve injury by low-tension current is uncommon but can occur when the 63,72,73 Electrical resistance of the skin is lowered by water or when contact is prolonged. burns, if present, are minor, and the neural lesion lies far from where current entered the body. For example, current flow from hand to hand may cause a brachial plexopathy or an axillary or radial neuropathy, and from hand to foot, an ipsilateral long thoracic 72–74 Usually only one nerve is involved. Pain in the limb begins with the shock, neuropathy. and muscle weakness appears instantly or after a delay of hours to days; in one case, there 65 was a delay of 2 weeks. Symptoms may worsen over several hours. Full or almost full spontaneous 61,75,76 recovery is the rule, although reflex sympathetic dystrophy may ensue as a complication. A nonthermal mechanism of injury is probably responsible. Experimental studies illustrate the probable physiological and anatomical changes that occur. When low-tension electrical current was applied to the sciatic nerve of the cat, limb paralysis and nerve conduction abnormalities increased in duration from minutes to weeks and then became permanent, as 43,48 No morphological change was found after very brief the quantity of current increased. periods of paralysis. Demyelination of axons was associated with paralysis that lasted for 2 to 3 weeks; recovery of strength was probably due to remyelination. In animals with permanent paralysis, there was destruction of axons as well as myelin. Heavily myelinated fibers were 77 more vulnerable than lightly myelinated and unmyelinated ones. Other authors hold that focal neuropathies long delayed in onset or progressive in course are due to heat-induced 78,79 perineural fibrosis or damage to vasa nervorum. Lightning
Limb neuropathies have been reported more often than cranial neuropathies with man-made electricity, but with lightning the reverse is true. This is probably because lightning often involves the head. These cranial neuropathies resemble low-tension rather than high-tension electrical neuropathies in two important respects. First, they are usually reversible, 49 probably because most of the current flows over the80victim, and burns tend to be superficial. Second, their onset may be delayed for a few days. Optic neuropathy, ocular palsies, Horner's syndrome, internal ophthalmoplegia, and lesions of the facial, vagus, and glossopharyngeal 51,62,80–83 45 Deafness is83especially common. In one case, autopsy nerves have been recorded. showed loss of hair cells from the organ of Corti, but most victims have conductive 45,48,84 deafness caused by thermal injury or rupture of the tympanic membrane or middle ear. Three cases of acute paraplegia or tetraplegia after a lightning strike or electrical shock were 85–88 attributed to polyneuropathy, but the evidence was unconvincing. Spinal Cord Injury Delayed Electrical Myelopathy
This is the most characteristic neurological effect of electricity. Estimates of its frequency 44,89–92 The following analysis is based range from less than 1 percent to 9 percent of victims. 83,89–96 High-tension current (usually >5,000 V) or lightning, a on a review of 25 patients. current pathway crossing or running the length of the spinal cord, and at least some deep electrical burns are typical. If the victim's skin is wet, enough household current can flow to 96 damage the spinal cord. Neurological symptoms may appear immediately, but a delay of 1 day to 6 weeks—1 week on the average—is typical. Neurological signs worsen for 2 to 14 days, usually for approximately 5 days. One third of patients recover fully, one third make a partial recovery, and one third do not recover at all. Those with signs of a complete spinal cord lesion or with prolonged progression of signs do not recover completely. Almost all patients have pyramidal signs (paraparesis or quadriparesis with spasticity, hyperreflexia, and Babinski signs). A few show atrophy of muscle innervated by segments of the spinal cord through which the current flowed. Sensory signs are less prominent than motor and may be transitory. Joint position sense and vibratory sense are affected more than pain and temperature. Sphincter paralysis is uncommon. In one patient, only Lhermitte's sign 65 MRI showed hyperintense signal within a developed. In another patient, T2-weighted 97 three-segment span of the spinal cord. 83,91,94,95,98
Five patients have had postmortem examinations. The abnormal portion of the spinal cord corresponded to the pathway of the current. The white matter was more affected than the gray matter, and the lateral and posterior columns were affected most. They showed demyelination with relative preservation of axons. Central chromatolysis, necrosis, and mild loss of anterior horn cells were also found. In three patients, some segments of the cord were
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necrotic. There were no vascular changes. The preponderance of long-tract signs over muscle atrophy correlates with that of damage to white matter over gray matter. Spinal cord compression due to intervertebral disc herniation or fracture of99the spine—usually the thoracic spine—is the major consideration in the differential diagnosis. It can result from a fall or from tetanic contraction of the paraspinal muscles during electrical shock. The absence of pain in electrical myelopathy is a useful diagnostic point. Spinal Atrophic Paralysis
Panse coined the term spinal atrophic paralysis for a syndrome of focal muscular atrophy 53 occurring after a shock from man-made electricity. No figure of its frequency is available, but it must be quite rare, since no new case has been published since Panse's original review 53 in 1955. Low-tension current, a pathway from hand to hand (across the cervical spinal cord), and either minor or no burns typify the context in which the syndrome occurs, but it may also follow lightning stroke. Pain or paresthesia in the arm through which current entered begins at once but disappears within days or weeks. Weakness begins immediately or after a few days' or weeks' delay. Muscle wasting becomes evident weeks to months later. The muscles of the shoulder girdle or the hand are affected (those supplied by the middle or lower cervical segments). Involvement is usually unilateral. Some but not all patients have weakness and spasticity in the legs. Sensory signs may be present in the arms or legs. Horner's syndrome, cyanosis and coolness in the hand, and trophic changes in the fingernails are occasionally present, as is sphincter incontinence. The weakness and muscle atrophy worsen for a few months but then stabilize or improve. If the current flows from hand to foot or from foot to foot, the muscles of the leg may atrophy. 53
Panse contrasted the syndrome to that of delayed electrical myelopathy. In the latter disorder, high-tension current injures mainly the white matter of the spinal cord by means of heat; the gray matter is relatively spared. In spinal atrophic paralysis, low-tension current injures mainly the gray matter of the cord—specifically, the anterior horn cells—by a nonthermal mechanism, and the white matter is relatively spared. There are no postmortem studies of the disorder, but Langworthy found experimentally that the anterior horn cells of the 47 spinal cord are especially vulnerable to electrical current. Amyotrophic Lateral Sclerosis
Delayed electrical myelopathy and spinal atrophic paralysis resemble amyotrophic lateral sclerosis (ALS) in some respects: there are upper and lower motor neuron signs, whereas sensory and sphincter functions are often spared. Reports of patients with progressive rather than self-limited disease have advanced the idea of an association between electrical shock 53,100,101 In these patients, signs developed pointing to parts of the brain and spinal and ALS. cord outside the pathway of electrical current. Hence, a direct effect of current could not have 100 caused them. Patten speculated that an autoimmune mechanism might be the cause. Epidemiological studies have found electrical shock and lightning stroke, like other types of 102 trauma, to be more frequent in ALS than in control patients. The meaning of this finding is unclear because all these retrospective analyses depend on adequate memory of events by subjects and on valid selection of the control population. Brain Injury Electrical Burns of the Skull
The skull's resistance to electrical current protects the brain from electrical injury. Only high-voltage current passes through the skull. The heat generated by this passage causes coagulation of the blood in the underlying dural sinuses and coagulation necrosis of the 43,53,103 Distant cerebral structures in the pathway of the current may also be underlying brain. affected. For example, a man with an electrical burn of the occipital bone is reported to have had thrombosis of the torcular herophili and necrosis of the cerebellum as well as necrosis of 104 Skull burns with open dura are conducive to the development of the optic nerves. 42,67 meningitis,43,53 and necrotic skull bones (not yet sequestered) to epidural abscess formation. Lightning Strike to the Head 53
This is fatal in most victims. Most survivors sustain no cerebral damage, but several cases 53,105,106 In animals, cerebellar Purkinje cells seem to of cerebellar ataxia have been reported.
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be particularly vulnerable to electrical current. That may be the pathological basis of the clinical syndrome in humans. Parkinsonian signs and hemiplegia have also been reported, 53,57,60 Some of these patients may but no pathological or neuroimaging data are available. have had the syndrome of delayed parkinsonism after cardiac arrest. Cerebrovascular Complications
A small number of reported patients have had cerebral infarction, subarachnoid hemorrhage, 53,65,107–115 The precise or intracerebral hemorrhage after electrical shock or lightning stroke. cause of these complications is unclear; however, intense constriction of the lumen for 1 to 55,116 Structural 10 minutes follows the experimental passage of current through an artery. changes also occur. Heat causes coagulation necrosis of the endothelium and muscular 116,117 Deprived of the support of the intima and coat, but the adventitia is little changed. media, the artery becomes dilated, and a fusiform aneurysm may develop. Complications include thrombosis, the formation and embolism of mural thrombi, and rupture with 118 or cerebral infarction soon or long hemorrhage. These may lead to intracranial hemorrhage 53,65 Dural sinus thrombosis may also after an electrical current has passed119 through the head. cause venous infarction of the brain. Other mechanisms may also lead to cerebrovascular complications. For example, an electrical shock can induce acute hypertension (with blood 53,120 and such effects on the blood pressure may pressures up to 400 mmHg) in animals, 107 lead to cerebral hemorrhage. Trauma caused by a fall or the cylindrical shock wave of a lightning bolt may also lead to intracerebral or subarachnoid bleeding or to arterial dissection 46,108–111 Cardiac arrest may cause cerebral infarction in the arterial with cerebral111 infarction. a patient may have a stroke soon after—but unrelated to—an border zone. Finally, 112 electrical shock. Dystonia 121–126
Nine patients with dystonia after electrical shock have been reported since 2002. Low-tension current (eight patients) and lightning (one patient) were involved and caused minor burns, if any. In five patients, a fixed dystonic posture developed in the upper limb through which current had entered; two patients had cervical dystonia, and two had dystonia of the tongue. The onset of dystonia was delayed by a few days to weeks in all but122 two patients. Reflex sympathetic dystrophy developed in the same limb in one patient. No other neurological signs, electrophysiological evidence of peripheral nerve injury, or brain imaging abnormality was present in any of the patients. Seven patients were treated with botulinum toxin and three responded; one patient improved spontaneously. Dystonia has been reported 127 123 after other types of limb trauma. It is psychogenic in some patients but not in others. Why it might occur is unknown, but speculation centers on a “central resetting” of basal 123 ganglia outflow after disruption of sensory input. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 56 Abnormalities of Thermal Regulation and the Nervous System DOUGLAS J. GELB •
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THERMOREGULATORY SYSTEM NEUROLOGICAL CAUSES OF ABNORMAL THERMOREGULATION Hypothalamic Lesions Lesions of Effector Pathways Miscellaneous Lesions Thermoregulatory System Overload Malignant Hyperthermia Neuroleptic Malignant Syndrome NEUROLOGICAL CONSEQUENCES OF ABNORMAL THERMOREGULATION HYPERTHERMIA Non-neurological Causes Neurological Manifestations Systemic Manifestations Patient Management HYPOTHERMIA Non-neurological Causes Neurological Manifestations Systemic Manifestations Patient Management Therapeutic Hypothermia
The human thermoregulatory system serves to maintain the body temperature near 37°C (98.6°F). Both the central nervous system (CNS) and the peripheral nervous system are important for thermoregulation, so a variety of neurological disorders may produce thermoregulatory abnormalities. At the same time, the nervous system is highly sensitive to the effects of body temperature, so thermoregulatory disorders may produce a variety of neurological problems. This chapter covers both the neurological conditions that produce thermoregulatory disorders and the neurological conditions that may result from abnormal temperature regulation. THERMOREGULATORY SYSTEM A thermoregulatory “center” in the preoptic and anterior hypothalamus is believed to integrate thermal inputs and to produce an output that adjusts body temperature to match a
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set-point. Thermoregulatory disorders may be produced either by malfunction of this thermoregulatory system or by conditions that overwhelm the capacity of the system. Thermoregulatory disorders should be distinguished from other causes of abnormal body temperature, in which the thermoregulatory system functions properly but the set-point is shifted. The most common condition of this type is fever, which is thought to be produced by 8–12 Shifts in the set-point may also be responsible an abnormal upward shift of the set-point. for variations1,13 of body temperature with the menstrual cycle and for diurnal temperature fluctuations. The afferent limb of the thermoregulatory system is concerned primarily with the core body temperature. In particular, neurons in the preoptic and anterior hypothalamic areas are sensitive to the temperature conditions existing in the thermoregulatory center itself. There are also thermosensitive neurons in the brainstem and spinal cord and, possibly, in the 6,14,15 The specific cold and warm thermoreceptors in the skin contribute abdominal viscera. relatively little to thermal equilibrium (although rapid, transient thermoregulatory responses may follow rapid changes in skin temperature before any significant change in brain 1 temperature occurs). The efferent limb of the system serves to generate or dissipate heat, as necessary. Basal metabolic activity produces heat, and within a narrow range of ambient temperatures called the thermoneutral zone, the core temperature can be maintained primarily by adjusting 16,17 Outside this range, heat generation is achieved primarily by metabolic1,18,19 rate. Brown adipose tissue contributes to heat production in neonates exposed to shivering. 16,17,20 Heat dissipation is achieved by evaporation (sweating) cold, but not in older individuals. 19,21 Evaporative and by nonevaporative heat loss (conduction, convection, and radiation). 1,19 heat loss is the most important of these mechanisms in most clinical situations. Nonevaporative heat loss can occur only when the ambient temperature is lower than the skin temperature. When that is the case, the amount of heat dissipated is a function of vasomotor activity: increased skin blood-flow promotes heat dissipation, whereas reduced skin blood-flow minimizes heat dissipation. These thermoregulatory vasomotor effects are controlled by both the hypothalamus and local reflexes. The local vasomotor reflexes can override the hypothalamic regulation when there are sufficiently extreme local temperature 14,21,22 conditions. NEUROLOGICAL CAUSES OF ABNORMAL THERMOREGULATION In principle, thermoregulatory disorders could be produced by abnormal function of the thermoregulatory center or by interruption of its afferent or efferent connections. Because the major afferent input comes from neurons that are themselves located in the hypothalamus, afferent disruption is not a significant concern. Consequently, the main neurological causes of abnormal thermoregulation are diseases of the hypothalamus and its autonomic outflow. In addition, a few neurological disorders result in excessive heat production that overwhelms the thermoregulatory system. Table 56-1 and Table 56-2 summarize the main causes of hyperthermia and hypothermia, respectively. Click here to view this table.... Click here to view this table....
Hypothalamic Lesions Hypothalamic lesions may produce either hyperthermia or hypothermia, although 23–25 Hyperthermia has been described with hypothalamic hypothermia is more common. 26–28 29 27,29,30 stroke, and encephalitis. Head trauma and brain surgery involving the tumors, 26,31 Hypothermia has been reported with hypothalamus may also produce hyperthermia. 27,29,32 33 34,35 33,36 strokes, subarachnoid hemorrhage, sarcoidosis, and hypothalamic tumors, 37 It is common in Wernicke's encephalopathy and may be the presenting idiopathic gliosis. 38–40 Its occurrence in Wernicke's encephalopathy has been attributed to lesions in feature. 39 the posterolateral hypothalamus and in the floor of the fourth ventricle. In contrast, although fever is also common in Wernicke's encephalopathy (occurring in about 12% of patients), an 39 Accidental hypothermia has been seen in infection is almost always found to account for it. 41 ; again, thishas been attributed to hypothalamic two patients with Parkinson's disease 41,42 Prominent abnormalities of sweating (anhidrosis or hypohidrosis) have abnormalities. 43–45 and been described both in primary autonomic failure and in multisystem atrophy, hyperthermia may be of major concern when patients with these disorders live in hot climates without air conditioning.
Lesions of Effector Pathways
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Interruption of the autonomic outflow from the hypothalamus may produce either hyperthermia or hypothermia by impairing the effector mechanisms necessary for heat 23,46,47 Lesions of the spinal cord above the high dissipation or production, respectively. thoracic level may interrupt descending pathways that influence the intermediolateral cell 48,49 Spinal cord column, producing both vasomotor abnormalities and disorders of sweating. lesions also interrupt descending input48,50 to anterior horn cells, impairing or eliminating Any neuromuscular disease that is severe enough shivering below the level of the lesion. to cause profound weakness may produce the same result. Finally, both acquired and hereditary polyneuropathies may51–53 involve autonomic fibers and produce abnormalities of Either hypothermia or hyperthermia may result. vasomotor activity and sweating. 54 Hypothermia is more common in diabetic patients 52,55 than in normal subjects, for example, In contrast, some diabetics manifest a probably because of impaired vasomotor reflexes. syndrome of heat intolerance that is attributed to anhidrosis. Because the autonomic nerve involvement in diabetes is usually predominantly distal, these patients sometimes51,56 exhibit profuse sweating over the head and upper trunk (“compensatory hyperhidrosis”).
Miscellaneous Lesions Disorders that produce widespread damage to the CNS can impair thermoregulation, but the 57 causes precise mechanism is often difficult to establish. Intracranial hemorrhage often 25,57–59 elevation of body temperature that is not explained by hypothalamic damage. 60–62 Degenerative diseases can be associated with hypothermia. Hypothermia has been seen 40,63–65 ; postmortem examination of the hypothalamus in patients with multiple sclerosis 65 64 revealed plaques of demyelination in one patient but not in another. One patient has been reported in whom a syndrome like Wernicke's encephalopathy (with hypothermia and eye movement abnormalities) was attributed to a hematoma at the mesencephalic-diencephalic 66 junction. Agenesis or dysplasia of the corpus callosum may be associated with episodic hyperhidrosis 67–69 There may also be associated abnormalities in and hypothermia (Shapiro's syndrome). the septal region, cingulate gyrus, and posterior hypothalamus. A similar syndrome 68,70–75 has occasionally been seen without any associated abnormality of the corpus callosum. The periods of sweating may last from minutes to hours, and the hypothermia may last from 30 minutes up to several weeks. Episodes may be separated by intervals of months to years. There is often ataxia and impaired cognition during the hypothermic episodes. Some of these patients have been found to have abnormalities in the anterior hypothalamus or infundibular nuclei. Recurrent hypothermia has also been attributed to “diencephalic epilepsy,” but 68 Episodic hypothermia without electrographic seizures have not been demonstrated. 76 hyperhidrosis has also been described. Cases of periodic hyperthermia associated77,78 with agenesis of the corpus callosum (“reverse Episodic hyperthermia or hypothermia Shapiro's syndrome”) have been reported. associated with other manifestations of autonomic dysfunction have also been described 79,80 81 and in a patient with aneurysmal subarachnoid hemorrhage. after head trauma 26
Hyperthermia has been reported after operations in the posterior fossa and in patients with 82 acute hydrocephalus. It is difficult to make inferences about localization from such patients, however, because of the presence of mass effect. Hyperthermia associated with ischemic lesions in the posterior fossa has also been reported, but the details provided were 83 insufficient to judge the extent of pathological involvement. As a general rule, even when a patient has CNS disease, hyperthermia should not be attributed to “neurogenic factors” unless there is clear involvement of the hypothalamus or effector pathways.
Thermoregulatory System Overload Several neurological diseases produce thermoregulatory disorders by creating conditions that overwhelm the capacity of the thermoregulatory system. Just as paralysis may eliminate effective shivering and result in hypothermia, muscle hyperactivity may result in hyperthermia. 84 Elevated body temperatures are common after generalized seizures,85 for example, and are tetanus, of prognostic relevance in patients in generalized status epilepticus. Generalized 9 delirium tremens, and catatonia are also associated with hyperthermia. Two noteworthy examples of hyperthermia associated with increased muscle activity are malignant hyperthermia and neuroleptic malignant syndrome. Malignant Hyperthermia Malignant hyperthermia is characterized by vigorous muscle contractions and an abrupt
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increase in temperature on exposure to certain drugs, notably inhalational anesthetics and 86–92 The hyperthermia is probably a direct result of the heat produced by succinylcholine. sustained muscle activity, which, in turn, is likely to be due to defective regulation of intracellular free calcium. Malignant hyperthermia is inherited as an autosomal-dominant trait with variable penetrance, and about 50 percent of cases are linked to mutations in the gene for the ryanodine receptor, a protein that provides the primary channel for release of calcium 93–97 Patients with primary muscle disorders, notably stored in the sarcoplasmic reticulum. central core disease and Duchenne muscular dystrophy, have an increased incidence of malignant hyperthermia. In fact, central core disease also results from mutation in the gene for the ryanodine receptor, although the specific mutations and the clinical manifestations are 93–96,98 Although patients with different in central core disease and malignant hyperthermia. myotonic dystrophy may also have adverse effects from anesthesia (contractures after administration of succinylcholine, and increased susceptibility to respiratory depression after receiving barbiturates or opiates), they do not appear to have an increased risk of malignant 88 hyperthermia. Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome is also characterized by hyperthermia and muscle rigidity, 99–102 although altered consciousness and cardiovascular lability are cardinal features as well, 99,100,102,103 and the hyperthermia may be mild or delayed. Although the elevated body temperatures are at least partly due to the muscle activity, there may also be an elevation of the hypothalamic temperature set-point. This condition is typically triggered by exposure to neuroleptic agents, but it has also been described in patients being treated for presumed Parkinson's disease after sudden withdrawal of dopaminergic agents or changes in their medication regimen. When associated with neuroleptics, the condition typically arises within 2 weeks of starting therapy or increasing the dose, but at times it may begin within hours or after a delay of months. The pathophysiology of neuroleptic malignant syndrome is not fully understood. A sudden and profound reduction in dopaminergic activity is considered the principal abnormality, 104 although dysregulated sympathoadrenal hyperactivity has also been proposed. NEUROLOGICAL CONSEQUENCES OF ABNORMAL THERMOREGULATION Most cases of abnormal thermoregulation occur in individuals without a primary neurological disease. These individuals are exposed to external temperature conditions (or, less commonly, to internal metabolic derangements) that overwhelm the thermoregulatory system. Regardless of the underlying cause of the hyperthermia or hypothermia, neurological manifestations are prominent. Neuronal function is significantly affected by even moderate changes in temperature. Basic electrical parameters, such as membrane capacitance, axoplasmic resistance, maximal sodium and potassium conductances, and ion channel rate constants, vary systematically with temperature. Consequently, the amplitude, duration, maximal rate of rise, net ionic 105 movements, and conduction velocity of the action potential all are affected by temperature. 106 These parameters, in turn, determine the likelihood of propagation107,108 or conduction block. Such considerations apply to both central and peripheral neurons. With respect to the peripheral nervous system, these effects have long been recognized because of their impact 109–112 For example, the maximal motor conduction on clinical electrophysiological tests. 110 velocity of human ulnar nerve falls by 2.4 m/sec for every 1°C decline in temperature. 109,111,112 Compound action potential amplitudes increase with falling temperatures. The duration of motor unit action potentials increases and mean amplitude112 declines as temperature drops, and polyphasic potentials become more frequent. Short-term and sustained hypothermia also113 prolong the latencies of visual, somatosensory, and brainstem auditory evoked potentials. Although these alterations in function can have significant clinical consequences, they do not represent actual injury to the nervous system. At extreme temperatures, however, such injury does occur. Direct thermal injury to the brain and spinal cord results in the production of a variety of cytokines and altered expression of heat-shock proteins, leading to endo thelial cell injury and diffuse microvascular thrombosis, and ultimately to cell death, edema, and 114,115 Cerebellar Purkinje cells are particularly vulnerable. There is an increase hemorrhage. in the cerebral metabolic rate116at temperatures between 38°C and 42°C, but at 43°C cerebral with rising metabolic rate is decreased. Cerebral oxygen metabolism also increases 116,117 temperatures up to 42°C, but it declines as temperatures rise further. With extreme reductions in temperature, there is a roughly exponential decline in metabolic
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rate, with a reduction of approximately 50 percent in the rate of chemical reactions for every 118 cerebral oxygen consumption by about 50 10°C. There is a corresponding reduction in119–121 This reduction in metabolic rate is percent for119–127 every 10°C decline in temperature. but neural damage still occurs. In experimental studies using hippocampal protective, slices, the critical survival time for complete recovery of neural activity after oxygen and 118 glucose deprivation was 10 minutes at 37°C, 15 minutes at 28°C, and 45 minutes at 21°C. In patients who died of hypothermia, autopsy has revealed perivascular hemorrhages in the 128 region of the third ventricle, with chromatolysis of ganglion cells. It is difficult to know to what extent these metabolic and pathological abnormalities result from direct damage to neural elements and to what extent they reflect systemic effects (including cardiovascular collapse) that secondarily injure the nervous system. It is clear, however, that they are associated with symptomatic manifestations that often dominate the clinical course of both hyperthermia and hypothermia. HYPERTHERMIA The neurological causes of hyperthermia were considered earlier.
Non-neurological Causes Conditions in which the thermoregulatory system is overwhelmed by extremely high external 9,23,129–132 The most severe form of heat stress temperatures are called heat stress disorders. disorder is heat stroke, which is defined as a core body temperature above 41°C associated with CNS dysfunction such as delirium, seizures, or 114,130–134 coma. Heat stroke is also characterized Heat exhaustion is a milder by hot, dry skin, but this is not a diagnostic criterion. form of heat stress disorder, characterized by progressive lethargy, headache, vomiting, tachycardia, and hypotension; the main distinguishing feature is that the level of 23 consciousness is depressed in heat stroke but not in heat exhaustion. These two conditions form a continuum: if untreated, heat exhaustion may progress to heat stroke. The term classic heat stroke refers to the disorder that results from prolonged exposure to high environmental temperatures while the individual undertakes normal activities; the term 9,19,23,114,130–132,135–138 exertional heat stroke applies in situations of physical exertion. Exertional heat stroke typically occurs in healthy young individuals, often athletes and military personnel. Inadequate cardiovascular conditioning, poor acclimatization, dehydration, heavy clothing, low work efficiency, and reduced ratio of skin area to body mass all 139,140 are risk factors. Classic Congenital or acquired abnormalities of sweat gland function may contribute. heat stroke, in contrast, is typically seen in the elderly, especially those with chronic diseases (e.g., alcoholism, malnutrition, diabetes, cardiovascular dysfunction, obesity). Anticholinergic and diuretic medications are predisposing factors. People in lower socioeconomic groups are at particular risk, especially those living in urban areas, because they are exposed to a 9,19,23,141 greater thermal load and often live in apartments with inadequate ventilation. The most common cause of hyperthermia is simple dehydration because it results 9,131,134 in vasoconstriction and decreased sweating, thereby interfering with heat dissipation. 142 143 Heat dissipation may also be impaired9 in advanced scleroderma or in miliaria, or by 144 extensive use of occlusive dressings. Both thyrotoxicosis (mainly during thyroid storm) 145 and pheochromocytoma can cause hyperthermia on the basis of hypermetabolism. Drug exposure can produce hyperthermia in several ways, including increased metabolic rate, 9,23,133,135,146–153 hyperactivity, and impaired heat dissipation (Table 56-3). Click here to view this table....
Neurological Manifestations The earliest neurological manifestations of hyperthermia include thirst, weakness, and 23 fatigue. Skeletal muscle cramps may occur in the exertional heat stress disorders and are probably due to hyponatremia. Patients with heat exhaustion are frequently agitated and may develop delirium and incoordination. Tetany or paresthesias sometimes occur from hyperventilation. In general, hyperthermia that is severe enough to cause stupor or coma occurs only with heat 154 stroke. Heat stroke may present with the sudden onset of stupor or coma, or patients may pass through a prodromal period that can include headache, drowsiness,156confusion, 155 of patients. Examination agitation, and delirium. Seizures occur in 60 to 70 percent 155,156 Caloric responses are intact 155 reveals pupils that154 are usually small and often pinpoint. except terminally. Diffuse hypertonia is common, but flaccidity has also been described.
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Hemiplegia, cerebellar deficits, and papil-ledema may also occur. Cerebrospinal fluid (CSF) from patients with heat stroke is usually normal but may show an135,155 increased protein Slowing of the concentration, xanthochromia, and mild lymphocytic pleocytosis. electroencephalogram (EEG) occurs at temperatures above 42°C. Most patients who recover from heat stroke have no157–159 permanent neurological sequelae, but and a157 few cases of persistent some develop a syndrome of ataxia and dysarthria, hemiparesis, myelopathy, or quadriparesis have been reported. There are reports of persistent polyneuropathy after whole-body hyperthermia160for cancer, and localized of severe heat stroke neuropathies after hyperthermic isolated limb perfusion. Survivors 161 may also develop premature cataracts, attributed to dehydration.
Systemic Manifestations The mildest manifestations of heat stress disorders are mild dependent edema and syncope. Possible explanations for the edema include salt supplementation, heat-induced vasodilatation with consequent oliguria, and increased aldosterone production. Syncope has been attributed to vasodilatation, postural pooling of blood, diminished venous return to the heart, reduced cardiac output, and a global reduction in cerebral perfusion. Skeletal muscle cramps also occur in mild heat stress disorder, as noted earlier. 19,130,135,137,156,162,163
Heat stroke is associated with diffuse systemic derangements. Respiratory alkalosis is almost always present, and tetany may occur. Hypoxia, metabolic acidosis, hypokalemia, hyperkalemia, hypernatremia, hypophosphatemia, hypomagnesemia, and hypoglycemia may each be seen. Peripheral leukocytosis in the range of 20,000 to 3 30,000 cells/mm is common. Cardiovascular manifestations include low cardiac output and low diastolic pressure. Subendocardial hemorrhages may occur. Minor electrocardiographic changes (transient 164 conduction abnormalities and inverted or flattened T waves) are sometimes found. Apart from the respiratory alkalosis, pulmonary manifestations may include pulmonary edema and adult respiratory distress syndrome in the presence of disseminated intravascular coagulation (DIC). Rhabdomyolysis is almost universal in exertional heat stroke but is uncommon in classic heat stroke. Elevated serum creatine kinase levels occur in both conditions. Elevated serum levels 162 of lactate dehydrogenase correlate with a poor prognosis. Acute renal failure occurs in about 25 percent of patients with exertional heat stroke but is uncommon in classic heat stroke. Elevated serum amylase levels are common. Serum concentrations of liver enzymes are often elevated also, and cholestasis and patchy hepatic necrosis have been described. Diarrhea and vomiting are common; hematemesis and melena may occur in severe cases. Clinically significant coagulopathies are common. Contributing factors include abnormal hepatic function with resultant impairment in clotting factor synthesis, thermal activation of either clotting factors or platelets, thrombocytopenia, and fibrinolysis. In severe heat shock, disseminated intravascular coagulation is almost always present.
Patient Management There are three components to the management of the hyperthermic patient: treatment of the underlying cause (when possible), cooling, and treatment or prevention of common 19,114,130–133,135,137,156,163 complications. Most of the hypothalamic causes of hyperthermia are not amenable to acute treatment, although dexamethasone administration is appropriate when there is vasogenic edema. Certain spinal cord lesions associated with hyperthermia (e.g., epidural hematoma or abscess) may require immediate treatment, but no acute treatment is possible for other lesions. Hyperthermia caused by excessive muscle activity is treated by reducing or eliminating the muscle activity. Patients in status epilepticus may require neuromuscular blockade (in addition to continuing measures for controlling their seizures) if temperatures 165 exceed 40°C for a prolonged period. Patients with malignant hyperthermia are treated by stopping the responsible anesthesia, instituting hyperoxygenation, and intravenously 86–90,92,135,166 Dantrolene is a skeletal muscle relaxant that administering dantrolene. uncouples excitation and contraction by preventing the release of calcium from the 87,89,91,166 It has also been used successfully to treat neuroleptic sarcoplasmic reticulum. 90,92,99–101,166 Because of the apparent role of dopaminergic systems in malignant syndrome. neuroleptic malignant syndrome, bromocriptine and amantadine have also been tried 92,99–102 Electroconvulsive therapy therapeutically, and favorable results have been reported.
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99–102
may be useful in severe, refractory cases.
Non-neurological causes of hyperthermia may also be amenable to specific treatment. Thyrotoxic crisis is treated with β-adrenergic antagonists, glucocorticoids (because of increased requirement and reduced adrenal reserve), and large doses of an antithyroid agent such as propylthiouracil. Patients with pheochromocytoma are treated with α-adrenergic antagonists. Dehydrated patients are rehydrated as necessary. For hyperthermic patients in whom a precipitating drug can be identified, treatment is directed at minimizing the drug's toxicity. Patients in delirium tremens require large doses of benzodiazepines. For the hyperthermia of heat stress disorders, treatment of the underlying cause simply consists of removing the patient from the hot environment. Cooling may be achieved by either evaporative or direct external 23,114,130–133,135,146,156,167–169 Evaporative methods involve wetting the skin with tepid methods. water and directing bedside fans at the patient. Direct external cooling involves immersion of the patient in ice water, use of a hypothermic mattress, or packing the patient in ice. These direct external cooling techniques produce vasoconstriction, which impedes removal of heat from the core. To counteract this response, these cooling methods are applied (either simultaneously or in alternation) with vigorous skin massage, tepid (40°C) water spray, or exposure to hot moving air (45°C). Cooling is more rapid and more effective with direct external methods than with evaporative methods, but evaporative techniques are often adequate and permit more convenient patient management and monitoring. In rare instances, neither method is sufficient; more aggressive options include peritoneal lavage with iced saline, gastric lavage or enemas with ice water, and hemodialysis or 9,132,135,168–169 cardiopulmonary bypass with external cooling of blood. Regardless of the cooling method used, shivering often occurs as the body temperature falls. It can be treated with phenothiazines, benzodiazepines, or nondepolarizing muscle relaxants. As the patient's core temperature reaches 38°C or 39°C, cooling is stopped to avoid overshoot hypothermia. Centrally acting antipyretic medications exert their effect by lowering the temperature set-point. They are therefore appropriate for use in fever, where the set-point is abnormally high. In thermoregulatory disorders, however, the problem lies not in the set-point itself but in the system's inability to attain it. It follows that manipulation of the set-point has no effect on body temperature, so central antipyretic medications are of no help in this situation. The most important complication of hyperthermia is hypotension, which should be treated 131,135,167 131 Vasopressors may be used if necessary. Dopaminergic with fluid administration. and α-adrenergic agonists should be avoided because of their tendency to produce vasoconstriction. Patients should receive 100 percent oxygen until adequate oxygenation is documented. Serum electrolyte and glucose concentrations should be assessed frequently, and abnormalities treated as necessary. To promote urine output, patients are given an initial 132,135,156 If disseminated dose of mannitol and subsequent doses of diuretics as necessary. intravascular coagulation occurs, it should be treated in the same way as in any other setting. 156 When seizures occur, they are usually treated with benzodiazepines. The prognosis for patients with hyperthermia depends on the peak temperature reached and the duration of 156 Mortality rates as high as 70 percent have been symptoms before initiation of treatment. 146 most recent series suggest a mortality rate of 5 to 10 percent with reported in the past, but9,155,156 appropriate management. HYPOTHERMIA Neurological causes of hypothermia were discussed earlier.
Non-neurological Causes As with hyperthermia, hypothermia is usually due to conditions that overwhelm the thermoregulatory system, rather than to a primary malfunction in the system. Accidental hypothermia is defined as an unintentional decline in the core temperature below 35°. It is most commonly seen in neonates, the19,170–174 elderly, and those who are unconscious or immobile, In the United States, hypothermia is seen most especially because of drug exposure. 171,175–177 Alcohol is a vasodilator, a CNS depressant, an anesthetic, frequently in alcoholics. and a risk factor for trauma and environmental exposure, all of which increase the risk of hypothermia. Other drugs predispose to hypothermia in various ways, including depression of the hypothalamic center, inhibition of shivering by neuromuscular blockade, and 23,171–173,175–180 vasodilatation (Table 56-4).
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Click here to view this table.... Patients with severe burns, exfoliative dermatitis, or other dermatological conditions may develop hypothermia because of increases in both evaporative and nonevaporative heat loss 181,182 Hypothermia and the inability to regulate these processes through vasoconstriction. may also occur 128,144,175,177,183 in the setting of several endocrine disorders that impair178 metabolism, including 178 hypoadrenalism, and hypopituitarism. Hypoglycemia, hypothyroidism, 175,177 diabetic ketoacidosis, and hyperosmolar coma are also associated with hypothermia, but it is not clear whether this is because of a hypometabolic state or a direct effect on the hypothalamic thermoregulatory center. Malnutrition may be complicated by fatal hypothermia, presumably on the basis of hypometabolism, hypoglycemia, and loss of subcutaneous 178 and hypothermia that tissue. One reported patient with thymoma had hyperhidrosis 184 resolved after treatment with intravenous gamma globulin.
Neurological Manifestations The neurological manifestations of hypothermia progress in a relatively predictable 171,174,176,177,185 Thought processes may be normal with rectal temperatures as low as manner. 34°C, but below this temperature most patients exhibit psychomotor retardation, speech perseveration, lethargy, or confusion. A few patients have been described as alert with rectal temperatures as low as 31°C, but this is uncommon. Dysarthria develops at temperatures below 33.5°C, and below 28°C most patients only grunt in response to questions, although some patients remain verbally responsive at temperatures as low as 23.5°C. Most patients still make purposeful responses to noxious stimuli even with temperatures approaching 20°C. Pupillary size is not affected by hypothermia in a consistent way, but pupillary reaction to light becomes progressively more sluggish as temperatures decline below about 32°C. Eye 177 movement abnormalities were frequent in one series but did not correlate with temperature; they may have reflected the presence of Wernicke's encephalopathy, since they occurred mainly in alcoholic patients. Deep tendon reflexes are typically normal or even increased at temperatures as low as 29.5°C, but they become progressively diminished at lower temperatures. Extensor plantar responses are rare at any temperature. Increased muscle tone is frequent even in mild hypothermia, and it is universal at temperatures below 29.5°C. Myotonia is common. Focal dystonias and dyskinesias are rare, but patients may exhibit a characteristic posture consisting of flexion in all four limbs, with the limbs held close to the torso. Even in hypothermic patients who have a stiff neck, examination of the cerebrospinal fluid 177 produces a fall in cerebrospinal fluid pressure fails to reveal pleocytosis. Hypothermia 186 has also been shown experimentally because of reduced cerebral blood-flow ; hypothermia 187 changes to reduce cerebrospinal fluid secretion in animals. The EEG frequency spectrum188,189 with hypothermia, with increased beta and theta activity and reduced alpha activity. 190 Triphasic waves have been reported in a patient whose rectal temperature was 34°C. At temperatures below 28°C, there is progressive slowing in the recording. As the temperature falls further, a burst-suppression pattern appears, and the EEG becomes isoelectric below 10°C to 20°C. Brainstem auditory evoked potentials (BAEPs) show increasing latencies of 113,191 Visual evoked potential (VEP) latencies waves I, III, and V as temperature decreases. 113,188 The changes that occur in also increase progressively as temperature declines. electromyographic (EMG) and nerve conduction studies were discussed earlier. Patients who recover from hypothermia usually have no long-term neurological problems.
Systemic Manifestations During the shivering phase (typically between 35°C and 30°C), there is an initial rise in metabolic rate and oxygen consumption, but at temperatures below about 30°C19,172–174,176,178 shivering ceases and there is a rapid decline in metabolic rate and oxygen consumption. As shivering abates, respiration slows and becomes shallow. This is primarily a reflection of 176 reduced respiratory requirements rather than pathologically depressed respiratory drive. Similarly, the heart rate slows and cardiac output declines with decreasing temperatures, but it is sufficient to meet systemic metabolic requirements. Clinically significant hypotension 19,176 The principal cardiac does not occur until temperatures of 25°C and below are reached. concern is the risk of arrhythmia. Arrhythmia is preceded by characteristic J-point elevation 171–173,176,178,192 The J wave (or “Osborn wave”) becomes that appears at about 33°C. increasingly prominent as the temperature falls and is consistently present below 25°C. Atrial 176,192 Prolongation of PR and QT intervals occurs, with fibrillation is common below 33°C. progressively more advanced degrees of heart block or bradycardia as the temperature
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continues to fall. Below 28°C the 171–173,176,178,192 myocardium becomes extremely irritable, and ventricular fibrillation or asystole may occur. Mild hypothermia induces diuresis because peripheral vasoconstriction redistributes blood to internal organs, including the kidneys, and also because of a blunted response to antidiuretic 171–173,176 As hypothermia progresses and cardiac output falls, renal blood-flow and hormone. 172,173 Because glomerular filtration rate decline also, ultimately resulting in acute renal failure. of hemoconcentration, the hematocrit rises by about 2 percent for every 1°C drop in core 176,178 Platelet count is reduced and function is impaired, producing temperature. 172,173,176,193 The intrinsic and extrinsic clotting pathways are both affected coagulopathy. 172 176,193 also. Granulocytopenia may occur with temperatures below 28°C. 172,173,176
Moderate elevations in serum glucose concentration are sometimes seen.172,176 Endocrine and functions generally remain normal. Ileus frequently occurs in hypothermia, asymptomatic pancreatitis is common (diagnosed on the basis of elevated serum amylase 128,172,194 Hepatic detoxification and conjugation functions are levels and on autopsy findings). 172 impaired, resulting in prolonged drug half-lives. Because the depressed level of consciousness blunts protective airway reflexes, there is a high incidence of pneumonia.
Patient Management The management of hypothermia is analogous to the management of hyperthermia. The three principal components are treatment of the underlying cause (when possible), rewarming, and treatment or prevention of common complications. The comments made previously regarding treatment of hypothalamic and spinal cord pathology causing hyperthermia also apply to hypothermia from these causes. In addition, thiamine should be given routinely to hypothermic patients unless Wernicke's encephalopathy can be excluded with confidence. The spells of some patients with episodic hyperhidrosis and hypothermia have reportedly responded to cyproheptadine, clonidine, anticonvulsants, dopamine agonists, or peripheral muscarinic blockade with oxybutynin or 68,69,71,73,78,195,196 glyco-pyrrolate. With regard to non-neurological causes of hypothermia, naloxone should be routinely administered to hypothermic patients in coma because of the high incidence of drug exposure in this setting and the lack of evidence for any harmful effect of naloxone in hypothermia. Any metabolic derangement predisposing to hypothermia should be144,171,176,183 corrected. ; In particular, exogenous thyroxine is usually required in treating myxedema coma when it is not given, the mortality rate is high. For patients with dermatological conditions and those without any predisposition to hypothermia other than environmental exposure, treatment of the underlying cause consists of simply drying them and removing them from the cold environment. There are three rewarming methods: passive external rewarming, active external rewarming, 128,163,170,171,173–176,178,197–199 Passive external rewarming is the and active central rewarming. slowest and least invasive of these techniques. Patients are placed in a warm environment and covered with blankets or aluminized body covers, and intravenous fluids are warmed to a temperature of 36°C to 39°C. This technique is usually adequate for patients with a core temperature of 32°C or above as long as the external hypothermic stresses are removed. Caution is necessary in patients who must avoid the cardiovascular stress of shivering, however. Active rewarming may be indicated in such patients; alternatively, shivering can be suppressed by giving meperidine, or it can be eliminated by inducing neuromuscular blockade (in patients who are already sedated and receiving mechanical ventilation). Active external rewarming consists of heating the skin with heating pads, heated blankets, hot water bottles, a forced air heating system, or radiant heat from a light source, or by immersion in warm water. Concern has been raised about these methods, however, because warming the skin before the core may result in peripheral vasodilatation and consequent hypotension. It may also cause an abrupt return of blood to the core from relatively hypoperfused regions, resulting in acidosis. Active central rewarming techniques include the administration of heated oxygen by face mask or endotracheal tube, warm gastric or bladder irrigation, peritoneal lavage, pleural lavage, and hemodialysis or cardiopulmonary bypass with extracorporeal blood rewarming. The most effective of these methods are peritoneal lavage, pleural lavage, and extracorporeal blood rewarming, but these are also the most invasive procedures. In general, they should be reserved for patients with temperatures below 30°C, although decisions in individual cases will be influenced by cardiopulmonary status and underlying disease.
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Because aspiration and pneumonia are common complications of hypothermia, all patients with a depressed level of consciousness should be intubated. Patients should receive 100 percent oxygen until adequate oxygenation has been documented. Blood gas interpretation is complicated in these patients, because blood pH increases by 0.015 for each 1°C decline in temperature, and the partial pressure of carbon dioxide (Pco2) declines by 4.4 percent and Po2 by 7.2 percent. Thus, if blood is warmed to 37°C before analysis, the measured Pco2 and Po2 values will be higher than those that actually exist in the patient. Even so, the pH and 172–174,176 Pco2 do not need to be corrected for the patient's body temperature. Human acid-base regulation changes with falling body temperature to produce an alkaline shift by relative hyperventilation. This adaptation helps preserve protein and enzyme function as temperatures drop. In effect, the “normal” values of pH and Pco2 change with falling body temperature in such a way as to cancel the changes that occur in anaerobically warmed blood. However, Po2 must be corrected for body temperature, or the value will be overestimated. Hypotension in hypothermic patients is generally due to dehydration, which, in turn, results from increased urine output. Fluid resuscitation is usually adequate. When it is not, more aggressive rewarming may be necessary, since dobutamine and dopamine have reduced efficacy in this situation and they are arrhythmogenic. Similarly, cardiac arrhythmias in hypothermic patients are resistant to many pharmacological agents, pacing efforts, and defibrillation. Aggressive rewarming techniques may provide the only hope for effective treatment. In particular, electrical defibrillation is usually ineffective at temperatures below 30°C. Lidocaine and procainamide have been of little benefit in this situation, although 171,176 bretylium may be effective. Electrolyte concentrations in the blood must be monitored closely, and abnormalities managed as necessary. Potassium levels vary greatly during treatment. Treatment may also produce hypophosphatemia. Patients should be assessed for coagulopathy, including disseminated intravascular coagulation, and treated as necessary. A nasogastric tube should be inserted and serum amylase level checked because of the risk of pancreatitis and ileus. The prognosis in hypothermia is influenced more by the patient's age and underlying disease 172,175,176,178 Some patients have been than by the magnitude of the temperature drop. successfully resuscitated after 2 hours of apparent arrest, and others have survived temperatures below 20°C. This has prompted some to advocate warming all patients to normal temperatures before concluding that resuscitation is futile (“nobody is dead unless they are warm and dead”). Although this recommendation puts appropriate emphasis on the marked protective effects of hypothermia, it is probably best to judge each case based on the specific clinical situation.
Therapeutic Hypothermia Efforts to exploit the protective effects of hypothermia date back at least to the 1940s, but serious complications prevented the widespread adoption of therapeutic hypothermia. Interest has recently been revived, and both internal and external cooling techniques have been studied in a variety of acute neurological contexts, including head trauma, spinal cord trauma, cardiopulmonary arrest, ischemic stroke, subarachnoid hemorrhage, hepatic 123–127 The results encephalopathy, infantile viral encephalopathy, and perinatal asphyxia. have been mixed, with the most convincing evidence of benefit in patients resuscitated after cardiac arrest. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 57 The Neurology of Aging RICHARD K. OLNEY • MICHAEL J. AMINOFF •
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AGE-RELATED CHANGES IN THE NERVOUS SYSTEM Decline in Cognitive Function Changes in Cranial Nerve Function Changes in the Motor System Alterations in Station and Gait Changes in Tendon Reflexes and the Sensory System Reappearance of Release Signs Pathological Reflexes Postural Tremor NEUROLOGICAL DISEASES THAT ARE COMMON WITH AGING Alzheimer's Disease, Frontotemporal Dementia, and Vascular Dementia Metabolic Encephalopathy Parkinsonism Nonparkinsonian Gait Disorders Peripheral Neuropathy Orthostatic Hypotension Falls Hypothermia and Hyperthermia Sleep Disorders OTHER NEUROLOGICAL DISEASES
The diagnosis of neurological disease requires the recognition of symptoms and signs that are not present in normal individuals of comparable age. The clinician's diagnostic acumen is especially challenged when he or she is confronted with a patient older than 75 years because the clinical manifestations of normal age-related changes that occur in the nervous system differ more quantitatively than qualitatively from the early signs of common neurodegenerative diseases of older individuals. The normal age-related changes that occur in the findings on neurological examination are reviewed in this chapter, as are certain common neurological diseases that are associated with aging, with emphasis on their distinguishing features. AGE-RELATED CHANGES IN THE NERVOUS SYSTEM Normal age-related changes are defined as progressive and irreversible changes in the
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findings on neurological examination that develop with advancing age in most individuals without overt disease. These changes are observed with variable frequency and severity depending on the study design and the rigor with which associated diseases are excluded. With regard to study design, cross-sectional studies tend to magnify the frequency and severity of age-related changes, in part because it is difficult to exclude the increasingly common effects of associated diseases and differences in social, educational, and environmental factors. Longitudinal studies minimize age-related effects, partly because long-term follow-up is more readily attained in those individuals who maintain normal function and because subjects who develop overt disease are later excluded. Thus, although they are described with variable magnitude and frequency, there are1,2 a number of important changes in the normal neurological examination with advancing age.
Decline in Cognitive Function The normal age-related decline in cognitive function has been characterized with increasing accuracy and precision over the past four decades. Since the late nineteenth century, measures of intelligence have been identified that reach a peak in young adulthood and then 3 decline throughout the remainder of life. In the 1950s, intelligence quotients (IQs) derived from the Wechsler Adult Intelligence Scale (WAIS) were interpreted to support this belief because performance IQs declined more than 40 percent and verbal IQs decreased half as much with increasing age from the late twenties to the early seventies. Subsequently, the effect of slower motor responses on timed performance tasks and the confounding influence of cohort differences were recognized as factors that cause an overestimation of the 3 measured age-related decline in intelligence in cross-sectional studies. Longitudinal studies have generally demonstrated stability rather than decline in verbal intelligence before the age 4 of 60 years. Verbal intelligence often declines thereafter by an average of less than 5 4 percent through the seventh decade and by less than 10 percent through the eighth decade. 5 Cognitive function is even relatively stable in most individuals during the ninth decade. With regard to specific aspects of cognitive function that decline with aging, the influence of 1 speed on successful completion of the task is an important consideration. Apart from slowness of movements (discussed later), the speed of central processing is reduced with advancing age. This can be demonstrated neuropsychologically as slowness of perceptual processing and neurophysiologically as a delay in event-related evoked potentials. Experiments with visual word identification have shown that slowness of processing does not develop abruptly in old6 age but occurs continuously with aging from the third through the eighth decades of life. Other experimental studies demonstrate similar degrees of slowing for processing of language and information and longer retrieval time for information from 7–9 short- and long-term memory. Reduction in the speed of central processing with advancing age can also be demonstrated neurophysiologically. An event-related evoked potential is the electrocerebral activity that occurs in response to the information content of a specified signal or event. These potentials are often recorded as the response evoked by an infrequent auditory signal that is inserted at random into a sequence of more frequent auditory signals of a different pitch. The event-related evoked response occurs between 200 and 500 msec after the infrequent auditory signal, and attention is usually directed at the peak of the positive waveform at approximately 300 msec (the P300). The mean latency for this component is approximately 300 msec in the third decade of life. Thereafter, as reflected in several studies, the latency increases by 9 to 17 msec per decade with aging, so that the mean latency is 350 to 380 10 msec by the age of 70 years. Thus, both neurophysiological and neuropsychological investigations support the general concept that the speed of central processing is reduced with advancing age. Mild memory impairment is another specific aspect of cognitive function that declines with advancing age. Although slowness of central processing underlies many aspects of the measured age-related decline in cognitive function, the deficit in recent memory and learning can be demonstrated apart from processing speed with untimed supraspan learning tasks. A supraspan is an amount of information just beyond that which can be recalled immediately from the working memory. An example of a supraspan memory test is serial digit learning, in which a subject is given 12 trials to learn and recall eight or nine digits in a standardized but untimed protocol. Published normative data for this test reflect mild impairment in recent memory and learning in older individuals, with subjects aged 65 to 74 years generally scoring 11 10 percent lower than younger subjects with similar educational backgrounds. In a longitudinal study of 212 community-based healthy persons, the acquisition and early retrieval of new information declined over the 3-year study, but not memory retention, language, 12 visuospatial ability, or abstract reasoning.
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The terms benign senescent forgetfulness and age-associated memory impairment were coined in recognition that the mild impairment in memory with normal aging is distinct from early dementia. This is manifested clinically as difficulty in retrieving the name of a vague acquaintance, remembering to buy every needed item at the grocery store without a list, or recalling where an object was placed, rather than as difficulty in remembering significant personal events. Such common complaints of the elderly are due more to decreased learning than to increased forgetfulness. In evaluating the memory function of 161 community-dwelling, cognitively normal individuals ranging in age from 62 to 100 years, learning or acquisition of memory for pictures and words declined uniformly with advancing age; however, delayed recall or forgetfulness was similar at all ages if adjusted for number of 13 initially learned objects. This reinforces the observation that preservation of delayed recall discriminates normal older individuals from those with mild dementia better than other 14,15 cognitive attributes among a large battery of neuropsychological tests. Thus, it is generally agreed that there is an age-related decline in the speed of central processing, performance on timed tasks, and recent memory and learning, whereas verbal 1 intelligence is well preserved at least through the seventies. Several short, standardized tests are available that are clinically useful for distinguishing these normal age-related changes in cognitive function from mild dementia. Two of the more commonly used tests are the Mini-Mental State and the six-item Orientation-Memory-Concentration Test; their utility 16–18 and limitations are discussed else-where.
Changes in Cranial Nerve Function Changes in the cranial nerve examination relate primarily to an age-related decline in sensory 19–23 With regard to vision, contrast sensitivity and functions, especially for vision and hearing. 20 visual acuity decline with advancing age. The pupils become progressively smaller with age and are less reactive to light and accommodation, reducing the amount of light that reaches 19,20 Increasing opacity of the lens and vitreous further decreases the visual input, the retina. 20 and increasing rigidity of the lens reduces its accommodative ability. These preretinal and retinal factors are the major causes of presbyopia. A restriction in the range of eye movements, especially vertically, develops with advancing 19–21 Whereas young adults normally have 35 to 45 degrees of upgaze, 15 to 20 degrees age. of upgaze is normal in those in their eighth decade. When limited upgaze and diminished visual acuity are combined with decreased mobility of the neck, vision above the horizontal may be functionally impaired (e.g., with loss of ability to read signs mounted high on the walls or hung from the ceiling). Approximately 10 percent of the population has a hearing loss sufficient to impair 22 communication; among those older than 65 years, 40 percent are so affected. Hearing worsens with age, but the severity of auditory impairment at any given age is quite variable. Presbycusis, usually described as a progressive elevation of the auditory threshold (especially for higher frequencies), has distinct peripheral and central components. The peripheral component relates to loss of hair cells in the cochlea, degeneration of cells in the spiral ganglion, atrophy of the stria vascularis, and thickening of the basement 22,23 The central component22,23 relates to changes in the auditory pathways and membrane. structures in the brainstem and cortex.23 The peripheral component primarily accounts for the elevation of the auditory threshold, whereas the central component affects speech perception (“age-related auditory processing disorder”), leading to poorer comprehension of 22,23 speech in noise or with rapid or indistinct speech. 24
Risk factors for presbycusis include noise exposure; cigarette smoking ; medication use; 23 hypertension; and family history. The use of aminoglycoside antibiotics, cisplatin, loop diuretics, or anti-inflammatory agents may contribute to hearing loss.
Changes in the Motor System A progressive decline in muscle mass (“sarcopenia”) and strength and in the speed and coordination of movement has long been recognized as an accompaniment of aging. The muscle wasting occurs diffusely but is most notable in intrinsic hand and foot muscles. In cross-sectional studies, strength consistently and progressively declines with increasing 25–27 In one comprehensive cross-sectional study of 61 normal men ranging in age from age. 20 to 80 years, the maximal force that could be exerted by various arm and leg muscles decreased across the age range by 21 to 45 percent, with hip extension28,29 showing the greatest 25 Diminished decline. The decline in strength is more marked in the legs than arms. 26 strength with advancing age is less prominent in longitudinal studies but still quite apparent.
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Grip strength did not decline in only 15 percent of subjects over the age of 60 years during a 26 9-year longitudinal study. Declining strength and progressive loss of muscle mass accompany each other with advancing age, but the loss of muscle bulk is insufficient to 26,27 explain the degree of decreased strength. The pathophysiology of this mild generalized weakness is multifactorial, and the sedentary life-style and decreased caloric and protein intake of many elderly30,31 subjects may be Electromyographic contributory; however, a neurogenic basis is of prime importance. studies have consistently shown features of chronic partial denervation with reinnervation as the usual accompaniment of advancing age. The results of neuropathological studies on muscle biopsies of normal elderly subjects are consistently but mildly abnormal. Features of neurogenic change (fiber type grouping and grouped atrophy) are far more prominent in most studies than other features, such as those of disuse, fibrosis, and myopathic change (type II atrophy, increased numbers of central nuclei, and other nonspecific features of myopathy). The mild but widespread neurogenic component of these generalized changes in muscle is 32 largely due to a mild amount of anterior horn cell degeneration. Motor unit number estimates for the tibialis anterior muscle are less in old (61 to 69 years) than in young men (23 to 32 years) and even less in very old men (80 years or older), but strength is not reduced until beyond 80 years, suggesting that age-related motor unit loss, at least in this muscle, 33 does not limit function until a critical threshold is reached. Furthermore, the stiffer muscle34 structure and prolonged myosin cross-bridge cycles of aged muscles may be contributory. In addition to strength, the speed and coordination of movements decline with advancing 31 age. Thus, the speed of simple tasks (e.g., hand and foot tapping) slows by 20 to 24 percent from ages 20 to 80 years, and coordination for the manipulation of small objects and 25 for tracking decreases by 14 to 27 percent. Activities of daily living (e.g., putting on a shirt, zipping a garment, and rising from a chair) required 31 to 40 percent more time in older 25 individuals. On the routine neurological examination, these changes are manifested as mild bradykinesia with all motor tasks and as mild incoordination without dysmetria on the finger-to-nose and heel-to-shin tests.
Alterations in Station and Gait 25,35
The station and gait show conspicuous changes with advancing age. Both depend on adequate sensory input, efficient integration of this input with motor control programming, and an adequate motor response. In two comprehensive cross-sectional studies of the normal changes that occur in neurological function with aging, the single 25,36 greatest change among Whereas most young many tests occurred in the ability to maintain balance on one leg. adults could maintain station on one leg with the eyes closed for the full test time 25 of 30 seconds, few older subjects could perform the task for more than a few seconds. In a study that compared optimally healthy elderly subjects, the 17 young old, aged 65 to 74 years, could stand on one leg with eyes closed for 3 to 4 seconds on average, whereas the 34 36 oldest old, aged 84 to 100 years, were unable to do so usually for even 1 second. In this study, the age-related change in balance was more obvious for one-leg standing time with the eyes open, with the younger group having a mean of 20 seconds and the older group a mean of 3 25,37,38 seconds. Although increased postural sway is virtually universal with advanced postural righting reflexes are preserved in most people during the seventh and age, 36 eighth decades. Increased postural sway relates more consistently to diminished sensation for vibration and joint position in the lower limbs than to visual or vestibular changes with 37,38 In addition to increased postural sway, dynamic posturography demonstrates a age. 39 the elderly diminished capacity to process conflicting sensory input with aging. Furthermore, 40 have a reduced ability to use visual information to improve control of balance. 35
Changes in gait among the elderly are well recognized. Qualitatively, the normal gait of an octogenarian is usually described with the same adjectives as are used to describe a parkinsonian gait. Thus, the gait is slightly broadened and the steps mildly shortened, with a modest diminution in the arm swing and a slightly stooped posture. In one study of optimally healthy elderly subjects, the group of oldest old took more steps and more time36to walk 30 feet than the group of young old, but both groups had a similar step cycle rate.
Changes in Tendon Reflexes and the Sensory System The most prominent age-related change in the findings on sensory examination is a decrease 25,36,41,42 Although in the sensitivity of vibratory perception, especially distally in the legs. vibratory threshold is elevated by 52 to 58 percent at 80 years compared with 20 years at the clavicle, shoulder, and elbow, the change is 64 to 67 percent at the tibia and wrist, 86 percent 25 at the ankle, and 97 percent at the toe. A less prominent distal diminution in the perception
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of painful and tactile stimuli is described in some but not other cross-sectional studies. Quantitative sensory testing has demonstrated an obvious effect of age on vibratory and cooling detection thresholds in a population-based sample of control subjects of normal 43 health ranging in age from 20 to 74 years. Changes in the deep tendon reflexes are similar to those described for vibration, with a mild generalized reflex depression and a more marked depression or absence of the Achilles 42 tendon reflex. During the seventh decade, the Achilles tendon reflex was absent in only 3 percent of healthy control subjects in a randomly selected, population-based study, although 43 at least 7 percent had a depressed or absent Achilles tendon reflex. The frequency of absent ankle 36,43 reflexes is 8 to 29 percent in the eighth decade and over 50 percent after 85 The knee and upper-limb reflexes are absent in 0 to 6 percent of subjects in years of age. 36,43 the seventh and eighth decades. This distal depression of deep tendon reflexes and sensory function is primarily due to distal degeneration of sensory axons. Age is inversely correlated with the amplitudes of both 44 sensory and motor responses on nerve conduction studies, but especially with the amplitude of sensory nerve action potentials, which correlates with 44 a loss of sensory axons. Conduction velocity also declines in both motor and sensory fibers, although the correlation between conduction velocity and age has varied widely in different studies and is not always evident. Neuropathologically, degeneration of both myelinated and, to a lesser extent, 45 unmyelinated peripheral sensory fibers has been identified with advancing age (Fig. 57-1). Similar axonal degeneration has been described in mixed sensorimotor nerves. Studies of 46 intra-epidermal nerve fibers has shown a length-dependent loss of fibers with aging, and45 selective loss of sensory receptors has also been documented, as is reviewed elsewhere.
FIGURE 57-1 Fiber density of large and small myelinated axons in human sural
nerve at different ages. (Data derived from Tohgi H, Tsukagoshi H, Toyokura Y: Quantitative changes with age in normal sural nerves. Acta Neuropathol [Berl] 38:213, 1977.)
Reappearance of Release Signs Although the reappearance of release signs may support the concept that a loss of cortical suppression has occurred, the prevalence of these signs in normal individuals is important36,47 to recognize. The palmomental reflex is present in 0 to 947,48 percent of normal elderly subjects. The suck reflex has been observed in 1 to 8 percent. The glabellar reflex is present in 0 to 6 percent of young old (aged 65 to 74 years) and old old (aged 75 to 84 years) but has a 36,47,48 The snout reflex is more frequency of 21 percent in the oldest old (over 84 years). common, being present in 7 to 29 percent of the young old and old old and 44 percent of the 36,47,48 However, the grasp reflex is rare in normal healthy elderly subjects up to 100 oldest old. 36,47,48 Bilateral grasp reflexes may occur with degenerative or diffuse vascular years of age.
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disease involving the frontal lobes, but more precise localization of responsible lesions may not be possible; lesions in the49–51 supplementary motor cortex or cingulate gyrus have been Thus, a positive palmomental, glabellar, snout, or suck implicated in some instances. reflex should be interpreted with caution, because these reflexes may be observed in normal elderly individuals. Only the reappearance of the grasp reflex is a reliable sign that more cortical suppression has been lost than is normal for age. Although a bilateral palmomental response may be regarded as physiological, a unilateral response is sometimes taken to suggest a localized contralateral lesion. However, no significant association between the side of the reflex and that of a hemispheric lesion was found by Gotkine and associates, indicating that a unilateral response should not be 52 accorded localizing value.
Pathological Reflexes An extensor plantar response is not usually accepted as a normal age-related change in the neurological examination but is assumed to reflect some underlying pathological process. However, an extensor plantar response was observed in 6 percent of the young old (aged 65 to 74 years) and in 12 percent of the36oldest old (over 84 years) in a study of optimally healthy, functionally independent individuals.
Postural Tremor A patient with essential tremor typically comes to medical attention during middle age. A similar postural tremor that develops with advanced age is frequently labeled a senile 53 tremor. In addition to a postural upper-limb tremor, the head, voice, or lower limbs may be affected. The prevalence of postural tremor increases with advancing age. In a population-based study of community-living people 65 years or older, postural tremor was identified on examination in 16.5 percent of those aged 65 to 74 years, in 20.7 percent of 54 those aged 75 to 84 years, and in 25.6 percent of those 85 years or older. Furthermore, a parkinsonian rest tremor was observed in 5 to 6 percent in each age group, with only half having the diagnosis of Parkinson's disease. In that study, the overall prevalence of parkinsonism (defined by a combination of bradykinesia, gait disturbance, rigidity, and tremor, with two or more being required for diagnostic purposes) was 14.9 percent for people aged 65 to 54 74 years, 29.5 percent for those aged 75 to 84, and 52.4 percent for those aged 85 and older. The prevalence of tremor was approximately 15 percent in another study of men and women aged between 50 and 89 years, with the tremor being due to parkinsonism in 2.75 percent and reflecting an exaggerated physiological or essential tremor in 12.5 percent; In subjects aged between 80 and 55 89 years, the prevalence of parkinsonism was 33 percent in men and 22 percent in women. NEUROLOGICAL DISEASES THAT ARE COMMON WITH AGING
Alzheimer's Disease, Frontotemporal Dementia, and Vascular Dementia Alzheimer's disease is a dementia with insidious onset and progression that usually occurs in middle or late life. The diagnosis can be definitively confirmed only by histopathological examination of the brain. The disease was initially described in a 51-year-old woman by Alzheimer in 1907 and was considered a presenile dementia for the first half of the twentieth 56 century. However, a broader definition that is independent of age has become accepted. Based on clinical or pathological criteria, or both, the incidence of Alzheimer's disease is 123 per 100,000 per year in adults over the57age of 29 years, with the incidence of dementia of all types being 187 per 100,000 per year. However, the incidence of Alzheimer's disease increases exponentially with advancing age, at least through the ninth decade, so that the 57 incidence at 80 years of age is 100 times greater than at 50 years. The prevalence of Alzheimer's disease increases from 1 to 15 percent from 65 to5885 years of age, and more than half of the residents of nursing homes have this disease. Clinical criteria for the diagnosis of probable Alzheimer's disease were proposed by the Work Group on the Diagnosis of Alzheimer's Disease, established by the National Institute of Neurological and Communicative Disorders and Stroke59(NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA). Dementia of any type is diagnosed clinically by behavioral changes that include a decline in memory and other cognitive functions. The clinical diagnosis of dementia cannot be made while an alteration in the level of consciousness is present because drowsiness and agitation interfere with the assessment of cognitive function. If the patient is alert, possible decline in cognitive function is determined by comparing the present and previous levels of performance as well as by neurological and
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neuropsychological examinations. Specifically, deficits in two or more areas of cognition must be established, and progressive worsening of memory and other cognitive functions must be documented. Impaired recall of recently learned material is usually the first sign of an early 13–15 Neuropsychological examinations are important to document objectively that dementia. two or more areas of function are impaired quantitatively to a greater extent than normal for age and that these cognitive deficits are progressive over time. The Mini-Mental State and the Blessed Dementia Scale are two16–18 specifically recommended tests that may be used The Blessed Dementia Scale or a shorter derived clinically to aid in this determination. form of it, the six-item Orientation-Memory-Concentration Test, are particularly useful in 16 identifying a mildly demented patient. The estimate of severity of dementia based on either of the Blessed tests also correlates with the number of neuritic plaques documented 16 neuropathologically, so either of these tests has utility in staging the severity of dementia. The Mini-Mental State examination is particularly useful in staging the severity of dementia because it assesses language and praxis in addition to memory, and its scores correlate well 60–62 with the neuropathological estimates of synaptic density in the frontal lobes. More extensive neuropsychological testing is important for documentation of the range and severity of cognitive impairment in the clinical setting of an early or uncertain diagnosis and in research studies. Impairment of delayed recall is the most sensitive measure to distinguish early dementia from normal aging, but measures of learning and memory are not useful in 63 staging the severity of dementia. Combined measurements of fluency, praxis,63and recognition memory best differentiate mild from moderate or severe dementia. Once the presence of dementia is documented, other criteria for the clinical diagnosis of probable Alzheimer's disease include an insidious onset between the ages of 40 and 90 years and the absence of systemic disorders or other brain diseases that by themselves 56,59 The diagnosis is could account for the progressive deficits in memory and cognition. further supported by documentation of impairment in activities of daily living and alteration in behavioral patterns. A positive family history is obtained in approximately 5 percent of cases. Laboratory tests are important to confirm other specific causes for dementia. Normal cerebrospinal fluid, an electroencephalogram that is either normal or shows nonspecific abnormalities, and evidence for cerebral atrophy with computed tomographic scanning or magnetic resonance imaging are supportive of probable Alzheimer's disease. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are likely to become increasingly important with the development of radioligands for the detection of 64–66 Various biomarkers in the the pathology of Alzheimer's disease or the brain amyloid load. cerebrospinal fluid (such as concentrations of total tau, phosphorylated forms of tau, and beta amyloid) may be important in suggesting the likely development of Alzheimer's disease in patients with mild cognitive impairment or in helping support a clinical diagnosis of 67,68 Alzheimer's disease, but they are not routinely determined. Neuropathologically, neuronal cell loss is present 69 in the brains of patients with Alzheimer's is primarily seen in the large disease relative to age-matched control subjects, and this loss 2 62 neurons that have cross-sectional areas of more than 90 μm . Furthermore, this neuronal cell loss is particularly seen in the cholinergic cells of the nucleus basalis and the 62 serotonergic cells of the raphe. Synaptic loss has also been described and correlates well 70 with cognitive decline; synaptic dysfunction undoubtedly precedes synaptic or neuronal loss. Nevertheless, measurement of neuritic plaques and neurofibrillary tangles of phosphorylated tau protein remains the routine basis for pathological confirmation of Alzheimer's disease. The diagnosis of definite Alzheimer's disease requires confirmation of the characteristic neuropathological features, which primarily consist of an abnormal number of neuritic plaques (Fig. 57-2) and neurofibrillary tangles (Fig. 57-3). Although often present in small numbers in normal elderly subjects, numerous neuritic plaques and neurofibrillary tangles are present in 71,72 (Fig. 57-4). The necessary brain sites in which the pathognomonic Alzheimer's disease neuritic plaques and71,72 neurofibrillary tangles must exist to confirm the diagnosis are less Whereas some neuropathologists require only lesions in the uniformly accepted. hippocampus, others demand involvement of the neocortex with or without hippocampal lesions. The frequency of pathological confirmation of the clinical diagnosis of probable Alzheimer's disease, based on the NINCDS-ADRDA criteria, has been studied. In 57 cases, an increased concentration of plaques and tangles was found more often in the hippocampus than in the neocortex of patients with probable Alzheimer's disease; an increased number of lesions was never found in the neocortex without a concomitant increase in the 72 hippocampus. The clinical diagnostic criteria proposed by the NINCDS-ADRDA Work Group resulted in 71,72 pathological confirmation in 84 to 100 percent of cases with examination of the hippocampus.
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FIGURE 57-2 Neuritic plaque with central core of amyloid protein (Bielschowsky
silver stain, original 250×).
FIGURE 57-3 Neurofibrillary tangle (Bielschowsky silver stain, original 250×).
FIGURE 57-4 Numerous neuritic plaques and neurofibrillary tangles in
advanced Alzheimer's disease (Bielschowsky silver stain, original 100×). Whereas pure Alzheimer's disease accounts for 50 to 60 percent of cases, frontotemporal dementia is less common and is important to distinguish from Alzheimer's disease. Three major anatomic subtypes are described, in all of which the frontotemporal regions of the brain are selectively affected while more posterior regions are spared. These subtypes consist of frontal variant (behavioral variety), temporal variant (semanticdementia), and a left
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frontal-predominant subtype called progressive nonfluent aphasia. The disorder, which is often familial, is characterized by marked changes in personality and social behavior, typically 73 commencing in middle or later life, with survival for several years. The disorder may masquerade as a major depression. It progresses more rapidly than Alzheimer disease; 74 progression is especially fast in the frontal variant or with coexisting motor neuron disease. Multi-infarct dementia is the second most frequent56cause of dementia and is the primary pathological process in5610 to 20 percent of cases. The two disorders co-exist in another 10 to include to 20 percent of cases. The concept of multi-infarct dementia has been expanded 75,76 a broader array of vascular disease that is capable of producing vascular dementia. Although the cumulative risk is higher for women than men to develop Alzheimer's disease from 65 to 95 years of 77 age, the cumulative risk for development of vascular dementia is similar for both sexes. The criteria for vascular dementia that were proposed at an International Workshop sponsored by the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l'Enseignement en 76 Neurosciences (AIREN) are listed in Table 57-1. Clinical criteria for probable vascular dementia are the presence of dementia, the presence of cerebrovascular disease, and a temporal relationship between the two. Dementia is diagnosed in a manner similar to that for Alzheimer's disease. Diagnosis of cerebrovascular disease requires the presence of focal neurological signs and abnormal brain imaging that supports vascular disease. The findings on brain imaging may consist of multiple large-vessel infarcts, a single strategically placed infarct (e.g., involving the angular gyrus, thalamus, or basal forebrain), multiple lacunae, extensive periventricular white matter lesions, or combinations of these. The temporal relationship may consist of onset of dementia within 3 months after a recognized stroke or of a course that is not insidiously progressive. The criteria for definite vascular dementia include the preceding probable clinical criteria and pathological confirmation of vascular and no other disease. Click here to view this table.... The relationship between dementia and white matter lesions that are seen on computed tomography (CT) scans or magnetic resonance imaging (MRI) has been clarified. Such white matter lesions do correlate with cognitive impairment if they are large or confluent, but are not 76,78–80 Furthermore, the prevalence of small relevant to dementia if they are less extensive. white matter lesions in patients with Alzheimer's disease is not significantly different from that in age-matched healthy control subjects if both groups are screened equally to exclude 81 cerebrovascular disease risk factors. Not surprisingly, then, in a neuropathological study, the exclusion of only those cases with vascular lesions larger than 50 ml from pure Alzheimer's disease produced the highest agreement with the clinical72 diagnosis of probable Alzheimer's disease by the NINCDS-ADRDA criteria (88% accuracy). The pathophysiology of dementia of the Alzheimer's type remains uncertain, but Alzheimer's disease may represent a syndrome in which the cumulative effects of one or more different 62,82 In some pathophysiological processes converge to produce a consistent clinical picture. individuals, the predominant pathophysiological process may involve a molecular genetic abnormality, such as a point mutation in the amyloid precursor protein. In others, abnormalities of tau protein or mitochondrial function may be more relevant to loss of synaptic density on cholinergic cells of the nucleus basalis or serotonergic cells of the raphe. Certain patients may have a genetic risk factor, such as the presence of the apolipoprotein E 82 ε-4 allele, but additional factors must also be present for the disease to develop. Protective factors have been identified also, such as the presence of the apolipoprotein E ε-2 allele. Women have an increased risk for Alzheimer's disease, but the risk of gender may be 77,82 The mechanisms for protection afforded by mitigated by estrogen replacement therapy. higher education and the use of nonsteroidal anti-inflammatory drugs may offer other treatment opportunities. Studies of treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) for hypercholesterolemia have suggested83that the risk of Alzheimer's disease is reduced in patients receiving these agents in midlife. Treatment strategies may have to be multifactorial and individualized for each patient. The beneficial effect of treatment with acetylcholinesterase inhibitors on some patients supports 84,85 although the scientific basis for use of these the cholinergic hypothesis to 86 some extent, agents has been questioned. Memantine is beneficial when assessed by functional and global87measures, but its effect on cognitive scores and behavior and mood outcomes is less effects on cognition but may improve clear. Testosterone replacement therapy has minimal 88 quality of life in patients with Alzheimer's disease. More effective treatments that prevent or alter the course of the disease are being sought. In regard to management, physicians are often asked to provide information about the driving ability of patients with early Alzheimer's disease, and in some states physicians are required to report all patients with cognitive impairment to public health authorities. In one study, an experienced neurologist's
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assessment of driving competence seemed to be a valid predictor of driving performance in patients with early disease, although a professional driving instructor was the most stringent 89 rater of driving performance. In patients with advanced Alzheimer's disease, attention to end-of-life measures is important, as discussed in Chapter 63.
Metabolic Encephalopathy Metabolic encephalopathy is a diffuse but potentially reversible disorder of cerebral function that often impairs the state of arousal and cognitive function and is due to a metabolic or toxic cause. When such a metabolic disturbance develops acutely, an alteration in arousal with either drowsiness or agitation is common. This state alerts the clinician that evaluation of metabolic factors may be etiologically important and at the same time precludes the diagnosis of dementia. However, when the metabolic disturbance develops insidiously over weeks or months, arousal is often not affected. Metabolic encephalopathy may then be difficult to distinguish from dementia. Furthermore, the two disorders commonly coexist in the elderly. When they are coexistent, chronic metabolic encephalopathy is the remediable aspect of cognitive impairment in an insidiously developing dementia. The incidence of metabolic encephalopathy in 200 elderly outpatients with suspected 90 dementia has been studied prospectively with follow-up of outcome. The patients had a mean age of 76 years, with a range from 60 to 94 years; more than 89 percent lived in the community, either alone or with a relative. Whereas Alzheimer's disease was diagnosed clinically in 75 percent, a total of 248 medical diagnoses were made in 124 of the 200 patients, and more than 30 percent had more than one condition contributing to their dementia-like presentation. Metabolic encephalopathy was the primary reason for cognitive impairment in 18 patients. It resulted from adverse drug reactions (10 patients), hypothyroidism (3), hyperparathyroidism (2), hyponatremia (2), and hypoglycemia (1). Even after excluding depression, 45 of the 200 patients experienced cognitive 90 improvement for 1 month or longer because of treatment of the identified medical condition. Adverse drug reactions as91the cause of cognitive impairment were the focus of a subsequent report by the same group. Of 308 elderly patients, 35 were identified who had cognitive impairment for over 3 months without alteration in the level of arousal and who improved with discontinuation of the causal drug. The most common offending drugs were benzodiazepines (13 patients), other sedative or tranquilizing drugs (9), antihypertensives (5), and cimetidine (3). The patients with these adverse drug reactions took an average of twice the number of prescription drugs as the others (an average of four vs. two). However, reductions in the dosage or discontinuation of antihypertensives may be associated with long-term detriment. Untreated high blood pressure is associated with an increased risk of cognitive decline, which 92 is reduced with antihypertensive therapy.
Parkinsonism Certain movement disorders, particularly tremor, restless legs syndrome, and parkinsonism, have a high prevalence with increasing age55in the general community but are underrecognized and treated inadequately. In some instances, movement disorders are iatrogenic. For example, drug-induced parkinsonism occurs in about 1 percent of men and 2 55 to 3 percent of women aged between 50 and 89 years. This section reviews those aspects of Parkinson's disease that deserve special consideration in the elderly; it is not intended to be a comprehensive review. The average annual incidence of Parkinson's disease is93,94 approximately 20 per 100,000, or In contrast to the incidence of approximately one sixth of that for Alzheimer's disease. 57 Alzheimer's disease, which increases throughout life, the incidence of Parkinson's disease 93,94 increases with advancing age until it reaches a peak at approximately 75 years of age. Although93,94 the incidence of Parkinson's disease is lower during the ninth than during the eighth the prevalence continues to increase through the ninth decade because decade, 93,94 The overall prevalence of parkinsonism was reportedly 33 long-term survival is common. 55 or 52 percent for percent in men and 22 percent in women aged between 80 and 89 years 54 many instances the diagnosis was unrecognized or patients the group aged 85 and older. In 55 were not receiving standard care. With current treatment strategies, the life expectancy is normal in Parkinson's disease if the adverse effects of significant coexisting disorders are 95 dementia is a coexisting disorder that becomes increasingly common considered. However, 96 higher in community-dwelling parkinsonian with advancing age. The risk of death is twofold 54 individuals than in those without parkinsonism, probably because of associated dementia and other diseases.
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Although a considerable number of elderly subjects have a slow, shuffling gait with a stooped posture, these parkinsonian features are not considered adequate by many clinicians to 97,98 A rest tremor, rigidity, and an establish the diagnosis of Parkinson's disease in the elderly. exaggerated glabellar reflex or a definite beneficial response97,98 to levodopa, or both, are usually An asymmetrical onset is necessary to diagnose Parkinson's disease with confidence. likely. Older patients with Parkinson's disease more often have difficulty in walking than do 99 impairment may relate to the combined younger patients. The severity of gait and postural 100 effect of the disease and the aging process. Otherwise, the features of Parkinson's disease are similar in the elderly and the middle-aged adult. The treatment of Parkinson's disease requires special consideration in the elderly, primarily 99 because of the greater sensitivity of elderly patients to adverse drug reactions. Confusion is a major side effect of anticholinergic medications, especially in the elderly with preexisting minor cognitive impairment. Constipation in both sexes and urinary retention in men are two other frequent side effects of anticholinergic medications. Hallucinations, delusions, and chorea are often dose-limiting side effects of dopaminergic medications, especially in the elderly, whether levodopa or dopamine agonists are prescribed. In contrast to the anticholinergic medications, the dosage of dopaminergic treatment can usually be adjusted to provide functional improvement with fewer adverse effects. Thus, treatment of Parkinson's disease in the elderly often requires the slow introduction and careful adjustment of levodopa/carbidopa therapy and avoidance of anticholinergic drugs.
Nonparkinsonian Gait Disorders 35,101
Over 20 percent of people use mechanical aids for35,101 walking by the age of 80 years. Various gait disorders are seen in elderly patients. One102general pattern is associated with decreased arm swing and other signs of bradykinesia. Some patients with this general pattern of gait disorder also have the specific, previously discussed, diagnostic features of Parkinson's disease or Alzheimer's disease. However, a large number of elderly patients with this gait disturbance lack these specific diagnostic features, leaving101 a nonspecific bradykinetic senile gait as the presumptive diagnosis by exclusion. The distinction between this nonspecific gait and a mildly parkinsonian-appearing “normal” gait is largely based on clinical experience and judgment. 35
A second type of disorder is the cautious gait. In some series, this is the most common 35 pattern. Patients with a cautious gait do not hesitate to initiate walking, but do so slowly, with a short stride and a normal or slightly broadened base. Although turns are en bloc, the normal cadence and quick initiation of walking distinguish this from the previous pattern. 35,101
A third pattern is a gait with ataxia or dysequilibrium. This gait may be associated with other signs of cerebellar, posterior column, or peripheral nerve disease. However, elderly patients often have falls and an ataxic gait that is associated with decreased proprioception and vibratory perception but not with other signs of a specific neurological disease. Hence, classification of an abnormal senile gait may be difficult even in a patient with frequent falls.
Peripheral Neuropathy The distinction of polyneuropathy, especially distal axonal polyneuropathy, from normal age-related changes that occur in the peripheral nervous system is often a quantitative 103 one. Normal changes with aging do not produce positive symptoms (e.g., paresthesias or dysesthesias) or significant negative symptoms (e.g., weakness that interferes with activities of daily living). Although distal sensory impairment for vibration and depressed or absent Achilles tendon reflexes are often found in normal elderly subjects, the development of a painless pressure sore on a foot or bilateral partial footdrop indicates a severity of distal axonal degeneration that is far greater than normal for age. Diabetes mellitus is the most common cause104 of distal axonal polyneuropathy in the elderly, as it is in middle-aged and and nutritional deficiency polyneuropathies are also common younger adults. Alcoholic 104 causes in the elderly. In this age group, a mild sensory neuropathy may be a more common presentation of cobalamin deficiency than subacute combined degeneration of the 105 spinal cord.
Orthostatic Hypotension Orthostatic hypotension is present in 10 to 30 percent of subjects older than 65 years if defined as a decline of more than 20 mmHg in systolic pressure or of more than 10 mmHg in diastolic pressure for more than 1 minute. The presence of orthostatic hypotension is a risk factor for increased mortality over 4 years that is independent of other associated diseases,
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such as diabetes mellitus, hypertension, cerebrovascular disease, and coronary artery 106 disease. Orthostatic hypotension most commonly has a non-neurogenic cause; medication such as antihypertensives and tricyclic antidepressants are often responsible. A significant factor underlying the increasing frequency of orthostatic hypotension with age may be 107 diminution in baroreceptor sensitivity with advancing107 age. The elderly have not only less reduction in heart rate in response to pressor drugs but also a blunted increase in heart rate with standing even in the absence of hypotension. In addition to blunting of the autonomic response as a predisposing factor to orthostatic hypotension, compensatory mechanisms that restrict volume depletion are also impaired in the elderly. Syncope becomes more common with advancing age, and orthostatic hypotension is a 108 common cause. However, this diagnosis is accepted only when postural changes in blood pressure can be demonstrated by examination. Management of symptomatic orthostatic hypotension is initially with nonpharmacological methods; patients are encouraged to make slow position changes, to increase their fluid and salt intake, to use compression garments, and to elevate the head of the bed. Pharmacological treatment is typically with fludrocortisone or midodrine. Further discussion of autonomic function in the elderly is provided in Chapter 8.
Falls Injuries are a common reason for death in subjects over the age of 75 years, with falls accounting for most of these injuries. When a fall at home causes a hip fracture, placement in a nursing home at discharge from the hospital is commonly a permanent move. People who have had a hip fracture have markedly reduced quadriceps strength and increased body 109 sway compared with age- and sex-matched control subjects. Thus, falls in the elderly have a special significance as a cause of morbidity and mortality and as a sign of impending loss of independence. The potential causes of falls include a large number of differential diagnostic possibilities. Approximately half of falls are related to tripping. Individuals who walk faster and take longer strides have a higher risk of tripping but are more likely to recover their balance after tripping. Because the incidence of falls is determined more by the frequency of tripping than the ability 110 to recover, the likelihood of falling can be reduced by not hurrying while walking. Syncope due to orthostatic hypotension is another identifiable cause for falling. Additional111–113 risk factors for falls include cognitive impairment, loss of vision, and peripheral neuropathy.
Hypothermia and Hyperthermia The ability to maintain thermal homeostasis diminishes as age increases, with hypothermia 108 recognized as a cause of death more commonly than hyperthermia. Hypothermia is defined as a core body temperature below10835°C. The annual mortality rate from hypothermia is 17 per million over the age of 74 years. In the elderly, both heat production and heat 108,114 The basal metabolic rate and the ability to produce heat conservation are impaired. 114 through shivering and other muscular activity become lower with advancing age. Likewise, the ability to 115 conserve heat is diminished through a decreased ability to vasoconstrict peripherally. Hyperthermia is defined as a core temperature above 41.1°C, or above 40.7°C with anhidrosis or altered mental status. Impairment of heat loss in a warm environment is the 116 Reduced peripheral vasodilatation is more important than cause of hyperthermia. 115,116 Further discussion of this topic is provided in Chapter 56. diminished sweating.
Sleep Disorders 108,117
The pattern of daily sleep normally changes with advancing age. Typically, elderly subjects report a shorter nocturnal sleep duration with more frequent arousals during the night and earlier awakening in the morning, but they also nap more frequently in the daytime. Polysomnography indicates that normal elderly subjects have a marked decrease in stage IV sleep time, a moderate reduction in total sleep and rapid eye movement (REM) sleep times, and more frequent nocturnal awakenings. Non-REM and REM sleep cycles are similar to those of young adults except for a shorter first cycle due to the reduction in stage IV sleep. Therefore, normal sleep in the elderly may be described as having a weaker monophasic circadian rhythm. 108,117
Because these disorders do not differ in Disorders of sleep are common in the elderly. elderly and younger subjects, the reader is referred to Chapter 32 for a review of sleep disorders in general. Two aspects, however, warrant particular consideration in the elderly.
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First, the possible effect of an enforced cycle must be considered in evaluating a complaint of insomnia or excessive daytime drowsiness in the institutionalized elderly patient. Nursing home environments typically require all patients to retire and awaken on a predetermined schedule. Although this strong environmental pattern successfully induces synchronized circadian rhythms in most of the population, such synchronization may be difficult for some individuals, resulting in complaints of disordered sleep. Second, although the sleep apnea syndrome is among the most common causes for excessive daytime somnolence, sleep-disordered breathing is common in normal elderly subjects, and different criteria need to be defined for the diagnosis of sleep apnea in older patients. The sleep apnea syndrome may be diagnosed in young adults when five or more apneic or hypopneic episodes occur during one night. However, 27 percent of healthy, asymptomatic subjects118 older than 60 years have five or more such episodes of sleep-disordered breathing per night. Furthermore, elderly subjects with and without118 sleep-disordered breathing are similar in terms of daytime alertness and cognitive function. OTHER NEUROLOGICAL DISEASES The epidemiology of many neurological diseases changes with advancing age. Cerebrovascular disease becomes particularly common with advancing age. New-onset epilepsy is also common; seizures are often symptomatic partial seizures that are readily controlled, and tolerability and safety of medication are important considerations in selecting an antiepileptic agent. Sedating agents such as phenobarbital are best avoided in the elderly, as also are enzyme-inducing agents such as phenytoin and carbamazepine because of their potential for drug interactions. Gabapentin and levetiracetam have good safety and cognitive profiles and do not interact with other drugs; several of the other newer agents are also 119 worthwhile in this regard. Patients older than 63 years have a different pattern of risk patients, suggesting that factors for the development of carpal tunnel syndrome than younger 120 different underlying pathogenetic mechanisms are operative. Because discussion of these disorders is provided in standard neurological textbooks, they are not considered here. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 58 Seizures and General Medical Disorders JACK M. PARENT • MICHAEL J. AMINOFF •
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RENAL FAILURE HEPATIC DISEASE CARDIAC DISEASE SEIZURES IN CRITICALLY ILL PATIENTS General Considerations Nonconvulsive Status Epilepticus Seizures Caused by Anoxic-Ischemic Encephalopathy CONNECTIVE TISSUE DISEASES HEPATIC PORPHYRIAS SEIZURES IN TRANSPLANT RECIPIENTS HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND SEIZURES SEIZURES ASSOCIATED WITH SYSTEMIC CANCER PULMONARY DISEASE ENDOCRINE OR METABOLIC DISORDERS Disorders of Glucose Metabolism Thyroid Disease Disorders of Sodium Homeostasis Calcium and Magnesium Imbalance SEIZURES RELATED TO ALCOHOL AND DRUGS OF ABUSE POST-TRAUMATIC EPILEPSY
Seizures commonly arise as a symptom of neurological dysfunction in various general medical disorders. The occurrence of epileptic seizures in medically ill patients often carries significant implications regarding the treatment and prognosis of the primary disease. In addition, the treatment of epilepsy due to primary disturbances of central nervous system (CNS) function, or of seizures caused by general medical disorders, may be complicated or influenced by factors associated with systemic disease. The occurrence and management of seizures in common medical conditions that may either produce acute or recurrent seizures, or exacerbate an existing epilepsy syndrome, are discussed in this chapter. Attention is also directed at certain uncommon medical diseases in which seizures are a relatively frequent complication, and at the treatment of preexisting epilepsy in patients with medical conditions that might complicate management. The general topic of drug-induced seizures1,2 arising during the treatment of various medical diseases has been reviewed elsewhere and is not addressed. Specific therapeutic agents that may cause seizures are discussed in the context
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of the relevant disorders. RENAL FAILURE Seizures are a common manifestation of uremic encephalopathy. In acute uremia, generalized tonic-clonic seizures occur and may appear in flurries; they typically develop 3,4 between 7 and 10 days after the onset of renal failure, while the patient is anuric or oliguric. Focal seizures or even epilepsia partialis continua may also occur but should prompt investigations to exclude an underlying structural cerebral lesion. Uremic convulsions usually appear with advanced chronic renal4 failure, especially if a significant encephalopathy is present or at a preterminal stage. Seizures occur in less than 3 10 percent of cases of chronic renal insufficiency. This represents a decline in recent years, perhaps because of more aggressive treatment of renal failure and related seizure risk factors such as hypertensive encephalopathy, metabolic disturbances, and altered renal 3 clearance of proconvulsant medications such as penicillin. Generalized tonic-clonic seizures are the seizure type most frequently encountered in uremic patients, although partial and 4 myoclonic seizures occur as well. Treatment requires the correction of metabolic abnormalities and renal failure, although often no specific cause of the convulsions can be identified and anticonvulsant treatment is necessary. Phenytoin, phenobarbital, and valproic 4,5 acid are effective. Status epilepticus occurs rarely in the context of chronic renal failure and is managed as is status epilepticus due to other causes. The dialysis dysequilibrium syndrome may be accompanied by generalized convulsions, which occur most commonly during the late stages or several hours after a hemodialysis session. Fluid shifts may be responsible, leading to cerebral edema from increased brain 6 osmolality6,7in the uremic state. Improved dialysis techniques have reduced the incidence of seizures. Dialysis encephalopathy is a syndrome associated with chronic hemodialysis. Distinctive speech abnormality, psychiatric disturbances, cognitive changes, asterixis, myoclonus, gait ataxia, and seizures are typical. The electroencephalogram (EEG) is abnormal, with bursts of frontally predominant high-voltage delta or spike-wave activity as 8 discussed in Chapter 18. The syndrome has been attributed to increased aluminum levels in the brain. The aluminum may derive from the water used in the dialysate, and 6–8 the disorder has declined in frequency with treatment of the dialysate to remove aluminum. Seizures occur most commonly during or immediately after dialysis and are usually generalized 4 convulsions, although myoclonic and simple or complex partial seizures are also seen. With 4,8 disease progression, seizures become increasingly resistant to pharmacological therapy. In patients with preexisting renal disease, anticonvulsant use may be complex because of altered protein binding and renal excretion; dialysis may also lead to removal of anticonvulsant agents. Phenytoin, for example, is normally 90 percent bound to plasma proteins, primarily albumin. In severe renal failure, the free (unbound) fraction commonly increases from 10 to 20 percent, which leads to5,9a greater volume of distribution and lower total (bound + unbound) serum concentrations. The concentration of pharmacologically active (unbound) phenytoin is unchanged, however, so that the benefit of a given dose is maintained. The therapeutic range of total phenytoin concentrations decreases from the 9 usual 10 to 20 μg/ml to approximately 5 to 10 μg/ml in severe renal disease. Free phenytoin levels may be used to monitor treatment in uremic patients, with a therapeutic range of 1 to 2 μg/ml in both normal and altered protein-binding states. Phenytoin accumulation is unlikely if hepatic function is preserved, so the total daily dose need not be lowered. However, it is probably best given in divided doses rather6 than as a single daily dose because the half-life may be decreased with renal insufficiency. Supplemental doses are9 not required after dialysis because phenytoin is not removed to any significant extent. Myoclonic and generalized tonic-clonic seizures may respond particularly to valproic acid in 5 uremic patients. Valproate undergoes pharmacokinetic changes similar to phenytoin in renal insufficiency. Plasma protein binding decreases, but the free concentration remains 9 constant. Thus, the therapeutic range of valproic acid may be decreased. Supplemental doses are not required because of dialysis. Plasma levels of phenobarbital are unchanged in uremia, but lower maintenance doses should be used when phenobarbital is given chronically to patients with severe renal 5,9 insufficiency. Phenobarbital, which is 40 to 60 percent protein bound, may be partially 9 removed by hemodialysis; additional doses may be needed in some patients after dialysis. 5 Primidone, like phenobarbital, may accumulate and lead to clinical toxicity in uremic patients, 9 whereas serum levels of carbamazepine are unchanged in uremia. Ethosuximide levels 9 decline with hemodialysis, and supplementation is necessary. Experience is more limited with the newer antiepileptic agents, but many have reduced
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clearance in11the setting of12impaired renal function; included among them are felbamate, 13 14 15 gabapentin, topiramate, levetiracetam, vigabatrin, pregabalin, and oxcarbazepine 16 and its active metabolite monohydroxycarbazepine. Gabapentin and pregabalin should be used cautiously in patients with renal impairment, given their extensive renal 11,15,17–19 Gabapentin dosage should be reduced in proportion to the reduction in clearance. creatinine clearance or, in the setting of hemodialysis, it should be given as a single dose 20 after each session. Hemodialysis19also reduces pregabalin concentrations such that additional doses may be required. Topiramate elimination occurs mainly through urinary excretion, although to a lesser extent when hepatic enzyme-inducing medications are 12,21 Doses of topiramate should be lowered when renal insufficiency is coadministered. 22 and supplemental doses may be present, as is the case with gabapentin and pregabalin, 12 in hemodialysis patients, necessary after hemodialysis. The same is true of levetiracetam 13 with doses of 250 to 500 mg typically given after dialysis sessions. Zonisamide is up21,23 to 50 percent protein bound and undergoes both hepatic metabolism and With moderate or severe renal failure, doses may need to be reduced. renal clearance. Zonisamide protein binding may be decreased in patients with severely impaired renal function undergoing hemodialysis. Because of the low clearance with end-stage renal failure, supplemental zonisamide often is unnecessary if a single daily dose is given after each 24 by moderate or dialysis session. Tiagabine pharmacokinetics apparently are not altered 25 This also appears to be severe renal insufficiency, and dosage adjustment is unnecessary. 26 renal impairment may prolong its half-life and it is the case for lamotrigine, although severe 27 cleared extensively with hemodialysis. HEPATIC DISEASE Despite early reports that convulsions are common in patients with acute hepatic encephalopathy, Plum and Posner28found a relatively low incidence when seizures related to Either focal or generalized seizures may occur, usually in alcohol withdrawal were excluded. 29 stage 3 hepatic encephalopathy. Treatment involves management of the hepatic dysfunction and hepatic encephalopathy. Anticonvulsant therapy often is not required except when an underlying cause of epilepsy (e.g., prior cerebral trauma) is present. 30
Chronic liver disease does not usually cause convulsions. The occurrence of seizures in alcoholics with hepatic cirrhosis is usually related to prior trauma, intracranial hemorrhage, or 31 and rarely in Wilson's alcohol withdrawal. Seizures occur commonly in Reye's syndrome 29 disease. Convulsions in patients with acute hepatic necrosis are frequently associated with severe hypoglycemia. Unless hepatic dysfunction is severe, liver disease usually does not have a major effect on anticonvulsant pharmacokinetics. Decreased protein binding of phenytoin and valproic acid 5,9 correlates well with levels of serum albumin and bilirubin. However, clearance is usually unchanged. Dosages of these medications may need to be decreased if liver disease is severe but usually not otherwise; serum drug concentrations should be determined frequently. Valproic acid is potentially hepatotoxic and thus should be used with care in 5 patients with established liver disease. Barbiturates, benzodiazepines, and other sedatives or CNS depressant drugs can provoke 31 hepatic encephalopathy in patients with preexisting but compensated liver disease. They are therefore best avoided in this context. Carbamazepine exhibits slightly decreased protein binding in patients with hepatic disease, but this does not affect serum carbamazepine 5 concentrations. The clearance of many of the newer antiepileptic agents is altered by hepatic disease. Lamotrigine metabolism is reduced in patients with significant liver disease, necessitating a 32 decrease in dosage. Dosage reduction is required also in patients with unconjugated hyperbilirubinemia (Gilbert's syndrome) because lamotrigine clearance is only about two 33 thirds of normal in this setting. Tiagabine is metabolized extensively by the liver. Reduced elimination with hepatic dysfunction 13 therefore requires12lowering of the dose or an increase in 34 the dosing interval. Levetiracetam and topiramate clearances are reduced only modestly with liver impairment, and no dosage adjustments are necessary unless kidney function also is compromised. Gabapentin and pregabalin are not metabolized to any15,20 significant extent by Felbamate should the liver, and therefore their use is not complicated by hepatic disease. not be used in patients with liver dysfunction because of the probable increased risk of 20 felbamate-induced hepatic failure. CARDIAC DISEASE Cardiac disease may lead to seizures as a result of focal cerebral ischemia from cardiogenic
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embolism or of global cerebral ischemia after cardiac arrest. Convulsive or myoclonic seizures are common after cardiac arrest, and status epilepticus occurs occasionally (see p. 35 1081). Seizures may also infrequently complicate coronary bypass surgery. Heart disease and epilepsy often coexist, especially in the elderly. This may complicate the treatment of acute seizures and status epilepticus because of the increased risk of adverse effects from anticonvulsant drugs. Although intravenous benzodiazepines and phenytoin are important for controlling convulsions and status epilepticus, they may cause hypotension and cardiac arrhythmias, especially in patients of advanced age or with underlying cardiac disease. These adverse effects relate to the rate of drug delivery; the toxicity of the phenytoin diluent, propylene glycol, may be responsible, although direct cardiac effects of phenytoin also contribute. In patients with preexisting cardiac disease, intravenous phenytoin should be administered at 25 rather than 50 mg/min with continuous electrocardiographic monitoring and frequent blood pressure measurements. If hypotension or arrhythmias do occur, they usually respond to temporary cessation of the infusion, but the rate may have to be decreased to 10 mg/min or less when it is restarted. Fosphenytoin, a water-soluble prodrug of phenytoin that does not require propylene glycol as a diluent, may have a lower risk of 36 hypotensive and arrhythmogenic events than parenteral phenytoin. However, the advantages of this more expensive therapy remain to be firmly established. Chronic administration of anticonvulsant drugs has rarely been associated with significant cardiovascular complications. Symptomatic arrhythmias have been reported in patients receiving carbamazepine in therapeutic dosages, but underlying cardiac abnormalities usually 37,38 Routine electrocardiograms should probably be obtained in patients have been present. with preexisting cardiac disease who receive either carbamazepine or phenytoin on a long-term basis. In such circumstances, events associated with loss of consciousness may relate to either arrhythmia or seizures, and thus complicate patient evaluation. Anticonvulsant agents may also interact with certain cardiac medications. The concomitant 39 use of phenytoin and quinidine may increase ectopy in patients with ventricular arrhythmias. The metabolism of quinidine, digoxin, lidocaine, and mexiletine may be increased by 39 phenytoin and phenobarbital because of40induction of hepatic microsomal enzymes. Amiodarone increases phenytoin levels, and calcium-channel blocking agents, such as verapamil, can increase serum carbamazepine concentrations. Thus, in epileptic patients with cardiac dysfunction, serum levels of anticonvulsant drugs may have to be monitored at frequent intervals, and cardiovascular function followed closely when either antiepileptic or cardiac medications are introduced or altered. SEIZURES IN CRITICALLY ILL PATIENTS
General Considerations Seizures are among the most common neurological complications of severe medical 41 illnesses treated in the intensive care setting. In a study by Bleck and colleagues, neurological complications occurred in 217 (12.3%) of a total of 1,758 patients admitted to an intensive care unit with a non-neurological primary diagnosis. Seizures occurred in 61 cases (28.1%) and were the most frequent neurological complication after metabolic encephalopathy. Seizures most commonly resulted from vascular lesions, but infection, metabolic derangement, mass lesion, hypoxia, and a variety of other causes were found. Approximately two thirds of patients experienced focal-onset seizures, and the remainder had seizures of presumed generalized onset. Status epilepticus occurred in six cases, two of which were refractory to standard treatment and required management by pentobarbital-induced coma. Neurological complications in this study were associated with increased mortality rates and longer lengths of stay in the intensive care unit and in the hospital. The evaluation of seizures in patients with severe medical illness involves first distinguishing between a primary neurological disturbance and a systemic etiology. Suspicion of a brain lesion should be particularly high in patients experiencing seizures of focal onset, although it is important to keep in mind that generalized tonic-clonic seizures may be either focal or generalized in onset, and that certain metabolic disturbances may cause focal seizures. A thorough clinical evaluation and metabolic screening is necessary in all cases. Medications should be carefully scrutinized, bearing in mind the possibility of drug-induced seizures. Because the physical examination is often complicated and vascular and infectious causes of 41 seizures are common in the critically ill, neuroimaging and cerebrospinal fluid (CSF) evaluation are often required. The EEG may provide evidence for a focal cerebral disturbance and is the only means for determining the presence of ongoing nonconvulsive seizures.
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Several important considerations arise with regard to the treatment of seizures in the critically ill patient. More aggressive antiepileptic drug therapy of discrete seizures is often warranted given the increased risk of seizure-related complications in patients who are already compromised by severe illness such as multiorgan system failure. However, anticonvulsants are ineffective in controlling seizures caused by various metabolic derangements such as severe hypoglycemia or hyperglycemia, hyponatremia, and hypocalcemia. In these instances, therapy should be directed at correcting the underlying abnormality. When antiepileptic drug treatment is necessary, the increased potential for complex drug interactions in patients receiving numerous other medications, altered pharmacokinetics due to factors such as renal or hepatic impairment, and adverse systemic effects must be considered. For example, in the hypoalbuminemic patient, it may be necessary to monitor free anticonvulsant drug levels when using an antiepileptic drug, such as phenytoin, that exhibits significant serum protein binding. Treatment may also be further complicated by the requirement for parenteral administration in patients with gastrointestinal dysfunction. For discussion regarding specific treatment issues in cases of severe organ system disease, the reader is referred to the individual disease sections in this chapter. Experience is limited in the use of newer anticonvulsant agents in this setting, especially given the lack of parenteral formulations.
Nonconvulsive Status Epilepticus Nonconvulsive seizures and nonconvulsive (absence or complex partial) status epilepticus 42 may occur in critically ill patients. Although its incidence is not known, nonconvulsive status epilepticus is probably under-recognized based on studies of patients in neurological 43,44 This condition should be intensive care units using continuous EEG monitoring. suspected in any critically ill patient with altered mental status of unknown cause. Subtle motor activity, such as rhythmic twitching of fingers or eye movements, should raise suspicion of seizure activity in this setting. Prompt recognition and treatment is essential because delay in44diagnosis and longer duration of seizure activity have been associated with a poor outcome.
Seizures Caused by Anoxic-Ischemic Encephalopathy Seizures resulting from global anoxic-ischemic cerebral damage occur acutely after 45–48 They typically resuscitation from cardiopulmonary arrest in 15 to 44 percent of survivors. commence within 24 hours of cardiopulmonary arrest and may consist of generalized tonic-clonic,46,49 tonic, myoclonic, or partial seizures, as well as tonic-clonic or myoclonus status Electrographic status epilepticus with restricted clinical manifestations epilepticus. (usually limited solely to extraocular or facial muscles) is 50 also well described after cardiopulmonary arrest, but may be difficult to recognize. The occurrence of seizures or even generalized tonic-clonic status epilepticus does not 46,47,49 However, influence the eventual clinical outcome of patients in postanoxic coma. myoclonus status epilepticus, that is, continuous myoclonus for at least 30 minutes with or 46,51,52 does suggest a poor prognosis after global cerebral without other seizure types, 46,48,51,53 It may begin at any49,52,53 time within approximately 5 days after hypoxic-ischemic insult. Generalized myoclonus may be52,53 cardiopulmonary arrest, most often within 24 hours. synchronous or asynchronous, but sometimes involves the facial muscles predominantly. The EEG typically reveals generalized spike-wave or polyspike-wave bursts on an abnormal background or a burst-suppression pattern; a diffuse alpha-frequency pattern is sometimes 48,52,53 Neuropathological examination shows diffuse anoxic-ischemic damage involving found. cerebral cortex, hippocampus, cerebellar Purkinje cells, thalamus, basal ganglia, and to a 48,52,53 lesser extent, the brainstem and spinal cord. 48,52,53
Myoclonus status epilepticus is poorly responsive to anticonvulsant therapy and may48 well represent a marker of severe anoxic-ischemic brain injury that rarely permits survival. Some instances of pure anoxic cerebral injury, such as isolated pulmonary failure, may have a somewhat better prognosis. Treatment decisions in these settings should be individualized using data from the clinical examination and neurophysiological studies. CONNECTIVE TISSUE DISEASES The connective tissue diseases are discussed in detail in Chapter 29. Cerebral vasculitis or vasculopathy may cause seizures in a variety of these diseases. In Sjögren's or Behçet's syndromes, convulsions may be associated with a flare of disease activity. Seizures rarely result from cerebral involvement in rheumatoid arthritis, scleroderma, or mixed connective 54 tissue disease. Systemic or isolated CNS vasculitides may also lead to seizures. Seizures may arise in certain of these disorders as a consequence of the involvement of other organs,
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such as the kidneys, or from complications of treatment, especially with immunosuppressive agents. Systemic lupus erythematosus (SLE) probably has the highest incidence of seizures and other neurological or psychiatric manifestations. The incidence of seizures in SLE ranges 55–58 Generalized convulsions occur most commonly, but simple between 10 and 54 percent. 55 or complex partial, absence, and akinetic seizures also occur; status epilepticus is rare. Occasionally, seizures or other neurological abnormalities59are the initial features of SLE, and systemic manifestations may not develop for many years. In patients with SLE and seizures, cerebral microinfarcts and, less often, subarachnoid and intracerebral hemorrhages are found on 60 pathological examination and may relate to an immunologically mediated vasculopathy. Convulsions may also arise from infections related to immunosuppressive therapy, lupus nephritis with associated uremia, or hypertensive 56,57 Evaluation therefore requires brain imaging, CSF encephalopathy, or as a terminal event. examination, metabolic studies, and assessment of systemic disease activity. The treatment of seizures in SLE depends on their cause. Convulsions resulting from a flare of cerebral lupus may not require anticonvulsant therapy because they are frequently solitary and self-limited. However, if several seizures occur over 24 to 48 hours or more, anticonvulsant medications can be prescribed for a limited time (e.g., 3 months) while the underlying SLE is treated. In severe cerebral lupus associated with recurrent seizures, immunosuppression with corticosteroids or other 55 immunosuppressive agents, such as cyclophosphamide and azathioprine, is indicated. Neuropsychiatric manifestations imply a poorer prognosis for SLE than otherwise, but the presence of seizures or psychosis without 55 other neurological features or significant renal disease does not reduce survival. Anticonvulsant drug therapy in SLE is complicated because many anticonvulsants may cause 61,62 Drug-induced drug-induced lupus (e.g., hydantoins, trimethadione, and ethosuximide). 63,64 65 61 valproic acid, primidone, and lupus also has been reported with carbamazepine, 66 lamotrigine. Drug-induced SLE typically occurs months after anticonvulsant therapy is initiated and usually remits days, weeks, or months after discontinuation of the offending agent. Laboratory findings are unlike those of idiopathic SLE because complement levels are 61 usually normal and antibodies to native DNA are typically not found. 67
There is no evidence that antiepileptic medications exacerbate idiopathic SLE, and anticonvulsant treatment should not be withheld from patients with SLE when it is required for seizure control. HEPATIC PORPHYRIAS Acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria are the three autosomal-dominant forms of hepatic porphyria that produce neurological manifestations. In acute intermittent porphyria, partial deficiency of porphobilinogen deaminase causes accumulation of δ-aminolevulinic acid and porphobilinogen, which are excreted by the kidneys. Partial deficiencies of coproporphyrinogen oxidase and protoporphyrinogen oxidase lead to hereditary coproporphyria and variegate porphyria, respectively. The acute hepatic porphyrias may cause peripheral neuropathy, autonomic dysfunction, and neuropsychiatric disturbances. Between 5 and 20 percent of patients with acute intermittent 68,69 They may be porphyria have seizures, which occasionally are the presenting feature. 70,71 71,72 and sometimes occur in flurries or even as status epilepticus. partial or generalized Their etiology is unknown but may relate to γ-aminobutyric acid (GABA) receptor binding by 73,74 68 which causes seizures when infused directly into rat brain. In δ-aminolevulinic acid, addition, defects in hepatic heme synthesis can alter brain levels of neurotransmitter 68 substrates, such as tryptophan, which may be important. During acute porphyric attacks, seizures may also relate to fluid and electrolyte disturbances, such as from excessive vomiting and inappropriate antidiuretic hormone secretion. 75–78
Thus, Porphyria sometimes coexists with idiopathic or symptomatic epilepsy. anticonvulsant treatment may be needed on both a short-term and a long-term basis in patients with hepatic porphyria. Almost all of the older antiepileptic agents, including phenobarbital, phenytoin and other hydantoins, primidone, carbamazepine, valproic acid, succinimides, oxazolidines, and 70,71,75–81 are held to exacerbate hepatic porphyria by stimulating hepatic benzodiazepines, δ-aminolevulinic acid synthase activity. With regard to the newer antiepileptic agents, experimental studies suggest that lamotrigine, felbamate, topiramate, or tiagabine use will 82,83 These studies are supported clinically in the case of exacerbate hepatic porphyrias.
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lamotrigine, which was suspected to have induced a porphyric attack and resultant 84 have not been incriminated in multiorgan system failure. Bromides and magnesium sulfate70,78,79 Gabapentin, pregabalin this way and have been used safely in patients with porphyria. and levetiracetam do not lead to significant hepatic microsomal enzyme induction and are therefore also probably safe to use, although experience is limited. Treatment of seizures during acute porphyric attacks includes intravenous carbohydrate, usually as a 10 percent dextrose solution, infusions of hematin or heme-arginate, and correction of associated metabolic abnormalities such as hyponatremia. If seizures persist or status epilepticus supervenes, magnesium sulfate may be infused intravenously to keep 71,72 The acute use of serum magnesium concentrations between 2.5 and 7.5 mmol/L. 79 paraldehyde or intravenous benzodiazepines may be safe but remains controversial. Successful treatment of patients with hepatic porphyria and acute seizures or status 85–87 88,89 or levetiracetam. epilepticus has been described with gabapentin Long-term pharmacotherapy of recurrent seizures in patients with hepatic porphyria 70,76,79 is difficult. Bromides are often used despite their toxicity and narrow therapeutic index. Serum bromide concentrations should not exceed 90 mg/dl. In addition, despite evidence that 70,79 low-dose clonazepam may be safe in the chronic clonazepam is porphyrinogenic, 75,76,78 treatment of patients with hepatic porphyria. 85–89 The treatment of choice, however, is Although one report described the probably either gabapentin or levetiracetam. 90 successful use of oxcarbazepine in a case of porphyria cutanea tarda, its use in hepatic porphyrias is questionable given the hepatic enzyme–inducing properties of oxcarbazepine. In all cases, urinary δ-aminolevulinic acid and porphobilinogen levels must be monitored closely during therapy. If seizures continue, empirical therapy with other anticonvulsants may have to be instituted. SEIZURES IN TRANSPLANT RECIPIENTS The neurological complications of organ transplantation are summarized in Chapter 46. Transplant recipients are at risk for seizures that may relate to their underlying illness, prior treatments (e.g., irradiation or chemotherapy), and perioperative metabolic abnormalities or complications such as cerebral ischemia. After surgery, the effects of immunosuppression, therapeutic agents, and rejection are also important causes.91–96 Children in general appear to be at greater risk than adults for post-transplantation seizures. Immunosuppressive agents, especially cyclosporine, have been associated with seizures. Seizures due to cyclosporine have been reported in 1.5 percent of renal transplant recipients 97 but higher incidences have also been noted, and 5.5 percent of bone marrow recipients, 98,99 92,93 and in children. Such seizures may occur with especially after liver transplantation serum levels of cyclosporine within or exceeding the therapeutic range. They may relate to a 100 cyclosporine metabolite, but various metabolic and systemic abnormalities, as well as other therapeutic agents, have been reported to potentiate them. These factors91,99,104 include con 101,102 103 hypertension, hypomagnesemia, comitant methylprednisolone therapy, 98 105,106 hypocholesterolemia, microangiopathic hemolytic anemia, and (after renal 107 transplantation) aluminum overload. Other immunosuppressive agents may also cause post-transplantation seizures. FK506 (tacrolimus) has 108–110 neurological complications similar to cyclosporine, including seizures and and the antirejection agent OKT3 can cause seizures as part of a encephalopathy, 111 cytokine encephalopathy. Sirolimus (rapamycin), one of the newer immunosuppressive agents, did not cause seizures or other neurotoxicity in at least one series consisting of 112 busulfan, either alone or kidney and liver transplant recipients. In bone marrow recipients, 113,114 in combination with cyclophosphamide, may cause seizures. Seizures may also result from CNS infections or relate to noninfectious structural and metabolic abnormalities that require specific treatment. Cerebral ischemia or hemorrhage, hyponatremia with central pontine myelinolysis, hyperosmolar states, hypoglycemia, delayed 93 malignancy related to prior treatment, or multiorgan system failure may be responsible. Finally, transplant rejection may lead to an encephalopathic syndrome that includes 92,115 116 sometimes as the first manifestation of rejection. seizures, 91,99
The approximate percentage incidence of seizures is 17 to 25 for liver transplantation, 3.7 96,117 105,118 3 to 11.5 after marrow replacement, and 1.5 to 5 in to 22 after lung transplantation, 97,107 Seizures occur in approximately 15 percent of heart renal allograft recipients. 119 transplantation cases. In bone marrow recipients, prior irradiation, intrathecal or systemic chemotherapy, systemic complications (e.g., thrombocytopenia), or relapse of disorders such as leukemia may be responsible. Renal transplant recipients may have seizures as a result of
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uremia or other metabolic abnormalities, or from post-transplantation cerebral 93 reticuloendothelial tumors. Heart and liver recipients are likely to have early postoperative seizures from focal or global cerebral ischemia. The occurrence of seizures necessitates a thorough evaluation to determine the specific cause. Biochemical screening tests, determination of blood levels of immunosuppressive agents, CSF examination, and neurophysiological and brain magnetic resonance imaging (MRI) studies may be necessary. The treatment of seizures in transplant recipients may be difficult. When seizures are self-limited and caused by correctable abnormalities that are not recurrent, anticonvulsant therapy is probably not required. Prolonged seizures or those placing the patient at high risk of complications should be controlled with benzodiazepines. Long-term anticonvulsant therapy is required for recurrent seizures. An anticonvulsant agent is selected, bearing in mind the type of transplantation procedure undergone by the patient and the immunosuppressive drugs in use. Valproic acid is best avoided in liver recipients because of its potential hepatotoxicity; low-dose levetiracetam (500 mg twice daily) is a reasonable 120,121 Carbamazepine should not be used in bone alternative, although experience is limited. marrow recipients because it may cause myelosuppression. Bone marrow engraftment occurs 2 to 6 weeks after transplantation, and phenytoin and valproic acid are best avoided 93 over this period in favor of phenobarbital or a newer agent. The enzyme-inducing anticonvulsants may affect immunosuppressive agents metabolized by the liver. Thus, the clearance of cyclosporine and corticosteroids is increased by 93,122–124 necessitating increased dosages of phenobarbital, phenytoin, and carbamazepine, corticosteroids by 25 to 30 percent and of cyclosporine depending on serum 122,125 cyclosporine 104 levels. The use of valproic acid avoids such pharmacokinetic interactions. Oxcarbazepine add-on therapy led to decreased serum cyclosporine and sodium concentrations in a single report involving a renal transplant patient, but the abnormalities 126 reversed with reduction in the dose of oxcarbazepine. Levetiracetam does not appear to influence immunosuppressive drug levels, has been used successfully in liver transplant recipients, and therefore may be a good initial choice for antiepileptic drug therapy in the overall transplant population. The lack of hepatic enzyme–inducing activity of pregabalin and gabapentin suggests that they also may be useful in this context. HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND SEIZURES 127
Seizures are common in adults (but not in children 128) infected with human immunodeficiency virus (HIV), may occur at any stage of HIV disease, and are sometimes the presenting 129 in symptom of HIV infection. Generalized tonic-clonic seizures occur most commonly 128,129 but simple patients with HIV infection or acquired immunodeficiency syndrome (AIDS), and complex partial seizures may also occur. Convulsive status epilepticus is reported 128,129 to have occurred at presentation in 8 to 10 percent of HIV-infected patients with seizures, 128 and nonconvulsive status epilepticus has also been described. Unlike the finding of persistent lateralizing clinical signs, the occurrence of partial seizures does not necessarily relate to an opportunistic CNS infection or intracerebral mass lesion. For almost half of the patients with HIV infection or AIDS evaluated for seizures, no cause other than the HIV infection can be found. Evidence of HIV encephalopathy may be present 128 clinically or at autopsy. Other CNS disorders associated with AIDS also cause seizures, such as cerebral toxoplasmosis, primary CNS lymphoma, cryptococcal meningitis, or cerebrovascular events. A detailed diagnostic evaluation is therefore required when HIV-infected patients experience a new onset of seizures, and may include biochemical screening tests, cerebral MRI, CSF examination (including cytology), and determination of cryptococcal antibody titers in serum and CSF. Further details are provided in Chapter 45. Patients with HIV-infection or AIDS presenting in status epilepticus should be treated urgently with the usual protocols. Because of the relatively high risk of recurrent seizures or status epilepticus in HIV-infected persons, chronic anticonvulsant treatment should be instituted 128,129 Most of the older antiepileptic agents are best avoided in patients after an initial seizure. with HIV infection or AIDS. For example, phenytoin interacts with protease inhibitors, is associated with a high incidence of hypersensitivity and other adverse reactions, and has caused intoxication in patients treated concurrently with fluconazole, an antifungal agent used 130–132 The high incidence of cognitive adverse effects with commonly in AIDS patients. phenobarbital makes its use undesirable in the AIDS population. Carbamazepine should be avoided because of the risk of bone marrow suppression in patients who may be predisposed to this complication because of concurrent medications. Thus, monotherapy with one of the newer antiepileptic agents that do not significantly induce hepatic microsomal enzymes, such
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as levetiracetam, pregabalin or gabapentin, is preferable as first-line therapy. SEIZURES ASSOCIATED WITH SYSTEMIC CANCER Seizures may arise as a complication of systemic cancer or its treatment. In a prospective study of 851 (mainly adult) patients with systemic cancer referred for neurological 133 consultation, seizures prompted the referral in 5.4 percent. Intracranial metastasis was identified in one half, metabolic factors were deemed causative in one third, and the remainder had cerebral hemorrhage, preexisting epilepsy, or an uncertain etiology of their seizures. Seizures are a more common neurological complication of systemic cancer in children. Thus, Antunes and De Angelis reported that seizures were the second most 134 common reason for neurological referral in a series of 157 children with systemic cancer. Of the 29 cases (18% of total referrals), a cerebral structural abnormality was identified in approximately one third. Seizure types are partial with or without generalization, or primarily generalized tonic-clonic, depending on the etiology. In addition, nonconvulsive status 135 epilepticus may lead to an altered mental status in patients with systemic cancer. A number of potential etiologies must be considered when convulsions occur in the patient with cancer (Table 58-1). Direct effects of cancer include parenchymal metastasis, which is particularly common with melanoma, lung, breast, renal cell, gastrointestinal, and germ cell 136 tumors, as well as leptomeningeal and dural metastatic disease. Partial or secondarily generalized tonic-clonic seizures arise in these circumstances. Seizures may also result from cerebrovascular events due to hypercoagulable states or nonbacterial thrombotic endocarditis associated with cancer. CNS infections, including fungal or parasitic abscesses, may result from immunosuppression after chemotherapy and produce seizures. Convulsions are an uncommon complication of chemotherapy, but may be seen with etoposide, l-asparaginase, alkylating agents such as chlorambucil or busulfan, immunotherapies, 136 methotrexate, and cytosine arabinoside. Other causes include cancer-induced metabolic disturbances, paraneoplastic encephalitis, and drugs used to treat cancer complications, such as pain medications or antibiotics. Click here to view this table.... A cerebral structural abnormality must be sought in any patient with systemic cancer presenting with seizures of unknown etiology. Cerebral MRI is the study of choice. In the absence of a brain lesion, CSF evaluation with cytological analysis is necessary to assess for infection or meningeal tumor involvement. Coagulation studies and biochemical screening are also warranted, and imaging studies of the cerebral venous system should be performed if clinical suspicion exists for venous sinus thrombosis. EEG evaluation may be needed if the type of seizure and etiology remain uncer tain. Finally, any medications used that predispose to seizures should be identified. Antiepileptic drug treatment is necessary unless the seizure is symptomatic of a reversible cause. Certain situations may, however, complicate the selection of the appropriate anticonvulsant agent. Phenytoin should not be used in patients receiving137 whole-brain cranial irradiation because of an increased risk of Stevens–Johnson syndrome. Carbamazepine, which often causes a mild leukopenia, is best avoided in those at risk for bone marrow suppression. Another potential complication of anticonvulsant therapy involves interactions with chemotherapeutic agents used to treat cancers. Similarly to most anticonvulsants, many chemotherapeutics undergo hepatic metabolism or influence hepatic microsomal enzymes. Thus, coadministration of drugs in these two classes may lower the effectiveness of cancer 138 chemotherapy, interfere with seizure control, or induce anticonvulsant toxicity. Because of these potential interactions, the use of antiepileptic agents with limited hepatic metabolism and enzyme induction, such as levetiracetam or pregabalin, should be considered in individuals undergoing cancer chemotherapy. PULMONARY DISEASE Asthma and epilepsy are both relatively common, and the two disorders may coexist in the same patient. Epilepsy may rarely result from recurrent severe hypoxic episodes during asthmatic attacks, and hypoxia-induced seizures occur infrequently during acute asthma ex-acerbations. Seizures may result from certain antiasthmatic medications and especially as a complication of theophyl-line use. This complication is most likely due to the inhibition of 1 may phosphodiesterase, which may reduce adenosine-mediated CNS inhibition. Seizures 139 occur with serum levels in the therapeutic range or that are only mildly elevated. Partial or generalized seizures, or status epilepticus, occur with acute overdose; status epilepticus140 may be unresponsive to anticonvulsants and require hemodialysis or hemoperfusion therapy.
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Theophylline is best avoided in epileptics because of the risk of seizure exacerbation and 141,142 potential pharmacokinetic interactions with anticonvulsant drugs. Isoniazid, an antituberculosis agent, 1may also cause seizures in therapeutic doses, but more generalized convulsions and status frequently does so with overdosage. Repeated 143 epilepticus are common after an overdose. Convulsions probably relate to a lowering of brain γ-aminobutyric acid levels through the antagonism of a pyridoxine-dependent cofactor involved in its synthesis. Prolonged seizures may respond to intravenous pyridoxine and 1 benzodiazepines. ENDOCRINE OR METABOLIC DISORDERS
Disorders of Glucose Metabolism In a prospective study of 125 patient visits to an urban emergency department 144 for symptomatic hypoglycemia, documented seizures were observed in 7 percent. Both focal motor and generalized seizures were characteristic; however, seizure flurries or convulsive status epilepticus also occurred. Other neurological abnormalities included depressed level of consciousness, behavioral changes, tremor, and hemiparesis. These deficits correlated poorly with level of hypoglycemia, although in symptomatic patients levels were usually below 54 40 mg/dl. Hypoglycemia must be considered in any patient with seizures; it is treated by intravenous administration of dextrose and correction of any other metabolic abnormalities. Patients usually do well with prompt therapy but are best hospitalized for54observation because hypoglycemia may recur hours after adequate initial treatment. 145
Seizures are relatively common in nonketotic hyperglycemia. Partial motor seizures or 146,147 occurring in 19 percent of epilepsia partialis continua may be the presenting feature, 145 occur in nonketotic hyperglycemia, including cases. Virtually any type of seizure may 146,148,149 Patients are typically middle-aged or older, movement- or posture-induced seizures. may have no history of diabetes, and have recurrent partial motor seizures. A mildly altered level of consciousness and focal neurological deficits may also be present, as discussed in Chapter 21. The range of glucose elevation is broad and may be associated with only mild 146 elevation of serum osmolarity. Seizures are refractory to anticonvulsant medication but respond to correction of hyperglycemia with insulin and intravenous fluid replacement. 146 Associated focal neurological abnormalities are usually transient, and recovery is typically complete if treatment is initiated before coma occurs. Underlying focal cerebral structural abnormalities are uncommon, but it is nevertheless prudent to obtain neuro-imaging studies when seizures first occur in association with nonketotic hyperglycemia and in patients with persistent neurological deficits. Anticonvulsant therapy is not required for seizures related to nonketotic hyperglycemia. Convulsions may recur despite anticonvulsant drugs if control of 147 specifically be avoided because it can blood glucose is not maintained, and phenytoin must150 exacerbate hyperglycemia by inhibiting insulin release. The pathogenesis of seizures in nonketotic hyperglycemia may involve localized cerebral ischemia, cortical deformation from brain dehydration, or54,149 increased γ-aminobutyric acid metabolism through the succinic semialdehyde pathway. Depressed brain γ-aminobutyric acid levels presumably lower the seizure threshold by decreasing cortical inhibition.
Thyroid Disease Seizures are not uncommon in hypothyroidism, and if myxedema coma ensues, the 151 frequency approaches152,153 20 percent. They are usually generalized and remit with treatment Anticonvulsant drugs, such as phenytoin and carbamazepine, of the hypothyroidism. may reduce serum thyroxine and triiodothyronine measurements because of competition for serum binding proteins; however, patients remain clinically euthyroid because free thyroxine 154,155 and triiodothyronine fractions are increased. 152
Seizures are uncommon in thyrotoxicosis, but hyperthyroidism or excess thyroxine may occasionally cause seizures or exacerbate preexisting epilepsy. Thus, thyroxine reduces the seizure threshold in certain animal models of156 epilepsy, whereas thyroidectomy protects Both partial and generalized seizures may against pharmacologically induced seizures. 157,158 157,159 and in those receiving thyroxine for hypothyroidism. occur in hyperthyroid patients In addition, worsening of both partial and generalized epilepsies may occur with increased 160,161 When seizures occur in the setting of thyrotoxicosis, the hyperthyroid thyroxine levels. state should be corrected; anticonvulsants usually are not required except occasionally in the acute setting.
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Disorders of Sodium Homeostasis Hyponatremic encephalopathy relates to an osmotic imbalance between the extracellular fluid 162 and brain cells, and to the effects of a compensatory loss of intracellular cations. Symptoms reflect the rate of development of hyponatremia rather than absolute serum 163 138 sodium levels, and chronic hyponatremia is surprisingly well tolerated. A full account of the neurological manifestations is provided in Chapter 19. Both partial and generalized seizures occur with hyponatremia and may be the first sign of symptomatic water intoxication. Hyponatremic convulsions are especially common in infants 164 and young children. They require aggressive treatment in the form of intravenously administered hypertonic saline. This should be given at a controlled rate so that the serum sodium concentration increases by no more than 1 mmol/L per hour, until the patient is either asymptomatic or the sodium concentration has increased by a maximum of 12 mmol/L over 162,165 More rapid correction of the first 24 hours and 25 mmol/L in the initial 48 hours. 165–167 ; hypertonic162saline is hyponatremia may cause pontine and extrapontine myelinolysis best avoided once the plasma sodium concentration reaches 125 to 135 mEq/L. The causes and features of hypernatremia are discussed54in Chapter 19. Generalized or partial seizures may occur, especially during rehydration. Cautious correction of hypernatremia with half-isotonic saline may lower the risk of convulsions during treatment.
Calcium and Magnesium Imbalance The causes and clinical features of hypocalcemia are discussed in163 Chapter 19. Altered sensorium and seizures are common neurological manifestations. Hypocalcemic seizures are usually generalized, but partial seizures occur in 20 percent of patients and may include motor or sensory phenomenology. Between 30 and 70 percent of patients with hypoparathyroidism experience seizures, often accompanied by an altered sensorium and 54 tetany, although tetany is occasionally absent. Treatment of hypocalcemic seizures involves correction of serum calcium levels and treatment of any underlying cause. 168
especially Multifocal and generalized seizures may also be provoked by hypomagnesemia, 163 Convulsions in when the serum magnesium concentration decreases below 0.8 mEq/L. 163,168 administered such circumstances are treated with parenteral magnesium salt solutions by slow intravenous bolus after the adequacy of renal function has been determined; calcium 163 gluconate should be available to counteract transient hypermagnesemia. SEIZURES RELATED TO ALCOHOL AND DRUGS OF ABUSE Seizures are a common consequence of alcohol (see Chapter 37) and recreational drug abuse (Chapter 38). Alcohol-related seizures are usually self-limited convulsions that occur within 48 hours after cessation of alcohol use, often accompanied by other169signs and symptoms of alcohol withdrawal. They may be isolated or occur in flurries and are usually attributed to brief abstinence or acutely declining ethanol levels in long-standing heavy drinkers. Seizures sometimes have focal features, often because of prior cerebral trauma. However, alcoholics are at high risk for head injury, CNS infection, cerebrovascular disease, and metabolic derangements, and detailed clinical and laboratory evaluation is therefore necessary whenever seizures occur. Hematological, bio chemical, and toxicological testing is indicated, and brain computed tomography (CT) or MRI studies should be obtained when a 169 focal cerebral lesion is suspected or for a first convulsion. CSF examination is necessary when meningitis or encephalitis is a consideration, and the EEG is useful if the seizure type or etiology is uncertain. Because alcohol-related seizures are self-limited and alcoholics are poorly compliant, long-term anticonvulsant therapy is rarely indicated. Phenytoin is of limited utility for treating 170 but benzodiazepines may control seizures in the setting of acute alcohol withdrawal, 171 seizures and other symptoms of ethanol withdrawal. This is supported by a randomized, double-blind trial of lorazepam for the prevention of alcohol-related seizures, which demonstrated that lorazepam decreased the risk of recurrent convulsions over a 6-hour 172 observation period compared with placebo. Furthermore, significantly fewer patients in the treatment group were admitted to the hospital or returned to an emergency department with seizure recurrence after173 the observation period. Convulsive status epilepticus may also result from alcohol withdrawal and should be treated with intravenous benzodiazepines and phenytoin according to standard protocols.
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Patients with seizures solely in the setting of alcohol or drug abuse do not, by definition, have epilepsy. However, approximately 2 to 4 percent of patients with alcohol-related seizures 169 Heavy ethanol intake may exacerbate seizures in epileptic have preexisting epilepsy. 174 patients, and patients should be advised against chronic or heavy alcohol intake and isolated drinking binges that are often associated with lack of sleep. Seizures may be induced by acute intoxication with illicit drugs or, less frequently, may appear as a withdrawal phenomenon. Such seizures are typically isolated convulsions that are self-limited and do not require acute or chronic treatment with antiepileptic medications; therapy should be focused instead on the problem of substance abuse. Prolonged seizures and status epilepticus resulting from illicit drugs do, however, necessitate urgent treatment. 175 The drug of abuse most commonly implicated as a cause of convulsions is cocaine. 169 Seizures resulting from cocaine abuse are increasing in frequency. Cocaine-induced convulsions may result from direct CNS stimulant effects through blockage of neurotransmitter reuptake at dopaminergic and noradrenergic nerve terminals, a possible kindling effect with chronic administration, cerebrovascular or systemic effects, and as a 1,169 Between 2 and 8 percent of patients terminal event in massive cocaine overdose. presenting to the emergency department with cocaine toxicity exhibit seizures, usually single, 176 generalized tonic-clonic convulsions. Anticonvulsant therapy is not warranted except for prolonged seizures or status epilepticus. Focal-onset seizures or those associated with abnormal neurological findings in cocaine users should raise concerns about an acute intracranial process and lead to evaluation by CT and possibly MRI or cerebral 176 Neuroimaging should also be performed in patients with new-onset angiography. 169 seizures. Seizures are infrequent in intoxication with other recreational drugs. Amphetamine is an uncommon cause of generalized convulsions, which occur more commonly after intravenous 175 use and administration of high doses. Focal features or abnormal findings on examination 169 should raise concerns for the presence of an underlying cerebral structural abnormality. Seizures are also uncommon with phencyclidine (PCP). Generalized convulsions occurred in only 3.1 percent of 1,000 patients coming to an emergency department with177phencyclidine intoxication, although 16 percent of seizure patients had status epilepticus. Heroin use has been associated with convulsions, although this may relate to175,178 anoxia and chemical Complications of adulterants rather than to a convulsant effect of heroin itself. intravenous drug abuse that may cause seizures, including infectious endocarditis and HIV infection, should be sought in patients with convulsions associated with the use of heroin or other intravenous drugs. Marijuana is often used concurrently with heroin and 178 other recreational drugs but seems independently to lower the risk of a first seizure. Finally, an abstinence syndrome that includes withdrawal seizures similar to those observed in 1 alcoholics may relate to chronic sedative administration. Seizures caused by barbiturate and benzodiazepine withdrawal have become less common, although they are more likely to 1 occur with short-acting agents and should be treated with parenteral benzodiazepines. POST-TRAUMATIC EPILEPSY Head injuries are a significant cause of recurrent seizures in the general population. Post-traumatic epilepsy occurs most frequently when the dura is breached. Most seizures appear179,180 within the first year after head injury, but an increased risk is present for at least 5 years. Seizures occurring after head injury can be divided into early and late categories. Early seizures occur within 7 days of injury, are more common in young children, have an incidence 179 convulsions or partial seizures without of 2 to 6 percent, and typically consist of generalized 181 generalization; complex partial seizures are rare. The occurrence of early seizures does not necessarily imply that recurrence will occur, but seizures developing more than 1 hour 179,182 Other risk factors for the after injury suggest an increased risk of late seizures. occurrence of late seizures include focal lesions (hematoma, contusion) or neurological 181,183 With penetrating injuries, the signs, dural penetration, and prolonged coma or amnesia. risk of seizures relates to the volume of brain tissue destroyed 180,184 and is increased with lesions Regardless of whether located centroparietally or when metal fragments are retained. early seizures occur, these late seizures consist of either generalized convulsions (sometimes with a focal onset) or, less commonly, partial seizures with either simple or 181 complex symptomatology. The EEG is disappointing as a predictor of the risk for development of post-traumatic epilepsy. In one study, EEGs recorded at 1 month were normal in 8.3 percent of patients with 183 partial seizures and in 27.3 percent of those with generalized seizures after head injury.
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There is controversy about the role of prophylactic anticonvulsant treatment of patients with head trauma. The ideal therapy would block the formation of an epileptogenic focus and thereby prevent the development of epilepsy. Certain early reports suggested a decreased incidence of seizures after head injury in patients treated prophylactically with one or two anticonvulsants (usually phenytoin, sometimes combined with phenobarbital). However, these studies are difficult to interpret on methodological grounds. More recent prospective 185–187 but despite more trials show no effect of such prophylactic antiepileptic medications, 188 rigorous designs, these studies have also been criticized methodologically. A more definitive study by Temkin and colleagues showed that phenytoin prevented seizures for the first week after cerebral injury but was no better than placebo in exerting a protective 189 effect during the remainder of the study period. It was therefore concluded that phenytoin should be given to patients at risk for post-traumatic seizures but discontinued after the first week following injury unless further seizures occurred. Additional randomized or quasi-randomized monotherapy studies have shown no benefit of prophylaxis with other antiepileptic drugs, including phenobarbital, carbamazepine, and valproic acid, on the 190,191 ). Glucocorticoids also development of late post-traumatic seizures (reviewed elsewhere appear192to have no benefit in preventing the development of seizures after traumatic brain injury. Studies using some of the newer anticonvulsant agents are ongoing, but novel antiepileptogenic strategies clearly are needed. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 59 Movement Disorders Associated With General Medical Diseases CHADWICK W. CHRISTINE • MICHAEL J. AMINOFF •
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CHOREA AND DYSTONIA Hypoxic-Ischemic Disorders Toxins Drug-Induced Dystonia and Chorea Infectious Disorders Bacterial Infections Viral Infections Fungal and Parasitic Infections Autoimmune, Inflammatory, and Paraneoplastic Disorders Metabolic Disorders Approach to Diagnosis Treatment MYOCLONUS Hypoxia-Ischemia Metabolic Disorders Autoimmune and Inflammatory Disorders Drug- and Toxin-Induced Myoclonus Paraneoplastic Disorders Infections Injury by Physical Agents Approach to Diagnosis Treatment TREMOR Stroke Medications Toxins and Recreational Agents Metabolic Disorders Infections Immune Disorders Other Causes of Tremor Approach to Diagnosis Treatment PARKINSONISM Vascular Causes
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Medications and Bone Marrow Transplantation Toxins Metabolic Disorders Infections Autoimmune and Paraneoplastic Disorders Trauma Other Causes of Parkinsonism Approach to Diagnosis Treatment
CHOREA AND DYSTONIA Dystonia or chorea occurs in a wide variety of medical disorders. Although chorea is typically a more fluid, “dance-like” undulation of a limb, and dystonia is a slower movement or a sustained abnormal posture of a limb or the trunk, it is sometimes difficult to distinguish between them. Approximately 25 percent of dystonias and most choreas are symptomatic or secondary to a neurodegenerative disorder, hereditary metabolic defect, or systemic medical disorder. Responsible neurodegenerative or inherited metabolic disorders are reviewed 1,2 elsewhere. In a series of 51 cases of chorea from Italy, vascular causes were identified in 40 percent, drug-induced causes in 14 percent, acquired immunodeficiency syndrome (AIDS)–related causes in 10 percent, Huntington's disease in 10 percent, hyperglycemia in 4 percent, and hyponatremia in 4 percent; single cases (2 percent each) of borreliosis (Lyme disease), 3 Sydenham's chorea, and acanthocytosis were also identified. The epidemiology will differ in regions where AIDS or other infectious conditions are more prevalent. Chorea is usually associated with dysfunction of the thalamus or basal ganglia. In most cases, the physiological effect of the disorder reduces inhibitory input from the globus pallidus interna to the motor 2 thalamus, resulting in excessive thalamocortical motor facilitation. Dystonia is characterized by impaired inhibition at multiple levels of the central nervous system, and altered levels of several neurotransmitters have been reported in various diencephalic nuclei, as well as the putamen, globus pallidus, red nucleus, and4 subthalamic nucleus. Nonetheless, the generation of dystonia remains poorly understood.
Hypoxic-Ischemic Disorders Chorea and dystonia due to hypoxia-ischemia may result from global or focal cerebral hypoperfusion as well as cellular hypoxia, such as in mitochondrial toxicity. Hypoxia-ischemia 5 induces numerous metabolic changes in striatal function. A decrease in the levels of inhibitory neurotransmitters occurs, with hypoxic-ischemic necrosis of medium-sized γ-aminobutyric acid (GABA)–ergic striatal spiny neurons and enkephalinergic putamenal projections to the external pallidum. In contrast, the striatal cholinergic system becomes upregulated after hypoxia-ischemia, and it is therefore interesting that anticholinergic agents often reduce dystonic movements. Onset of a movement disorder is often delayed after hypoxic injury. This may reflect the time required for remyelination, inflammatory changes, ephaptic transmission, oxidation reactions, maturational or aberrant synaptic reorganization, 6 trans-synaptic neuronal degeneration, or denervation supersensitivity to occur. Stroke may cause a variety of movement disorders depending on the location of the lesion and age of the patient. In a series of 1,500 patients with stroke, Alarcon and colleagues found that movement disorders occurred in about 4 percent of these patients; chorea occurred in 36 percent, whereas dystonia, tremor, and parkinsonism were less common, occurring in 28, 25, 7 and 10 percent, respectively. The average age at onset of chorea was 75 years, whereas that for dystonia was 48. Hemichorea occurred most commonly with contralateral thalamic strokes but also occurred with other lesions of the basal ganglia (putamen and subthalamic nucleus), white matter tracts (corona radiata, internal and external capsule), and pons. Putamenal strokes caused dystonia most frequently, although lesions of the pons or globus pallidus and larger strokes of the frontal lobe were also sometimes responsible. The time to onset of the movement disorder was shorter for chorea—usually within 1 week of the stroke—whereas dystonia and tremor developed 2 to 3 weeks after stroke. Focal ischemia or stroke to the contralateral basal ganglia is the most common cause of acquired 8 Most patients who develop chorea or dystonia after a stroke improve over hemidystonia. 7 time. The prognosis of chorea and9 dystonia resulting from global hypoxic-ischemic injury differs in infants, children, and adults. In infants and children, the interval before the movement 10 disorder develops is longer and abnormal movements are more likely to generalize. In
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adults, chorea or dystonia becomes manifest as any hemiparesis resolves and it usually remains localized. Only in young children with postpump chorea and adults with post-thalamotomy syndrome does the movement disorder commonly begin within a week of injury. Such differences may relate to differences in neuroplasticity or variability in the 9 metabolic response of the brain to injury. What determines whether global cerebral hypoxia-ischemia causes dystonia or parkinsonism? Marsden and colleagues have noted that at the time of anoxia the mean age of patients developing the akinetic-rigid syndrome was 41 years, whereas for those developing pure dystonia it was 13.5 years, suggesting that there is an age-dependent difference in the effect of cerebral hypoxia. Moreover, injury to the putamen is more likely to cause a dystonic picture, whereas lesions of the globus pallidus are usually associated with 10 parkinsonism. Perinatal hypoxic-ischemic injury may lead to any pattern of dystonia, often after a long interval. At onset the dystonia is focal or, rarely, segmental, and commonly spreads over a period of6,86 months to 28 years, resulting in segmental dystonia, hemidystonia, or generalized dystonia. The longer the latency to onset or the period of progression, the less certain it is that hypoxia is responsible. Thus, complete evaluation for other causes is always important. The most frequently observed pathological finding is a marble-like appearance of the striatum due to altered myelination (“status marmoratus”). Postpump chorea consists of chorea or ballismus, episodic eye deviations, and hypotonia. It occurs in infants or children within 12 days of cardiac surgery involving hypothermia, cardiopulmonary bypass, and often complete circulatory arrest, and may be severe. Although this surgical complication was previously common, occurring in up to 20 percent of children, 11 current techniques have drastically reduced its incidence to well under 1 percent. Infants younger than 6 weeks are less susceptible; in older infants, the chorea is often mild and reversible. The pathophysiology is poorly understood, although it seems likely that hypoxic-ischemic mechanisms secondary to surgical technique (including deep hypothermia) 12 play a role. Previously normal children and young adults sustaining acute hypoxic injury usually have focal or unilateral findings clinically and on imaging studies, despite the global insult. Dystonia 10 may develop after 1 week to 3 years and typically generalizes over the following months (up to 5 to 10 years); imaging shows abnormalities especially in the putamen. Polycythemic chorea occurs for uncertain reasons. Polycythemia rubra vera has a male predominance, but polycythemic chorea is more common in women. Neurological manifestations of polycythemia are common, occurring in 50 to 80 percent of patients and include headache, vertigo, stroke, visual symptoms, tinnitus, and paresthesias. Chorea is a 13 rare complication, occurring in 0.5 to 5 percent of patients. Examination may also show a plethoric complexion and splenomegaly. The chorea may begin suddenly or gradually, is sometimes episodic, and typically becomes generalized but affects particularly the facial, lingual, and brachial muscles. The limbs are hypotonic, with pendular patellar tendon reflexes. The chorea may persist for up to several years, with spontaneous remissions and recurrences. Treatment is of the underlying polycythemia, but the relationship between red blood cell counts and chorea is often weak.
Toxins Exposure to certain gases and heavy metals is a rare cause of encephalopathy, parkinsonism, and dystonia, probably as a result of cellular hypoxia from mitochondrial dysfunction or the generation of free radicals. Carbon monoxide toxicity appears to result from a combination of tissue hypoxia and direct cellular toxicity. Carbon monoxide binds to 14 hemoglobin and cytochromes, thereby inhibiting the electron transport chain. After initial recovery, about 10 percent of survivors will develop parkinsonism several weeks to months 15 later; approximately 80 percent recover within 6 months. Imaging often reveals focal injury particularly to the pallidum and diffuse white matter changes, and magnetic resonance 16 Treatment with spectroscopy of white matter lesions are consistent with demyelination. 15 levodopa and anticholinergic agents is not helpful. 17
Cyanide poisoning usually results in death but may cause parkinsonism and dystonia. The movement abnormalities may initially improve, only to worsen days to months later, followed by stabilization and gradual but incomplete recovery. Cyanide reacts with cytochrome c oxidase, causing cellular hypoxia. Imaging studies show lesions in the caudate and lentiform nuclei, precentral cortex, and cerebellum. Functional imaging shows reduced dopamine 18 transporter uptake suggestive of nigral neuronal loss. Ingestion of methanol results in the production of formaldehyde by the liver; the liver and
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erythrocytes synthesize formic acid, which inhibits cytochrome oxidase and, thus, mitochondrial electron transport and tissue adenosine triphosphate production. Metabolic acidosis injures the retina and optic nerves and leads to necrosis of the putamen, subcortical white matter, cerebellum, brainstem, and spinal cord, resulting in parkinsonism, bradykinetic 19,20 Initial treatment relies on correction of the metabolic dystonia, tremor, and blindness. acidosis with ethanol and elimination of methanol with hemodialysis. Gradual improvement may occur with time, and treatment with amantadine and dopaminergic medications 19 sometimes helps. Manganese toxicity may occur as an occupational exposure (e.g., in miners of the ore or with chronic exposure to metal alloys, batteries, paint, varnish, enamel, or colored glass) or as a consequence of liver failure. Manganese increases free radical formation, inhibits antioxidant function, may reduce mitochondrial energy production, and perhaps increases glutamate neurotoxicity. It leads to apathy, restlessness, and bradykinesia, and eventually to rigidity, dystonia, hyperreflexia, Babinski signs, gait instability, and rest or postural tremor. Remission may occur in mild cases if further exposure is prevented, but the course21is otherwise progressive, although there are reports of improvement after chelation. Pathological examination reveals damage to the globus pallidus and substantia nigra pars reticulata (which are downstream from the nigrostriatal dopaminergic pathway), consistent with the 22 failure to respond to levodopa. Magnetic resonance imaging (MRI) may show hyperintensity of the putamen on T1-weighted images. Organic mercury poisoning, as seen formerly with the ingestion of certain fungicides and shellfish (Minamata disease), causes visual loss, ataxia, paresthesias, and cognitive dysfunction. Choreoathetosis, parkinsonism, and tremor also occur, and dystonic posturing is occasionally seen. Inorganic mercury poisoning, seen in glass blowers, hatters, and battery 23 workers, produces a psychotic encephalopathy and tremor. Dystonia secondary to copper accumulation occurs in Wilson's disease. If hepatic damage is mild, significant improvement follows chelation therapy with penicillamine or trientine. Liver transplantation may be required for nonresponders and patients with severe liver 24 dysfunction. This movement disorder may respond to trihexyphenidyl, levodopa, bromocriptine, or amantadine. Cellular and global hypoxia-ischemia have been implicated in disulfiram overdose in adults 25,26 and children. In one such case, psychomotor slowing and parkinsonism were evident several days after awakening from coma, and over 10 years progressed to include dystonia of a lower limb and speech, and blepharospasm. Brain computed tomography (CT) shows hypodense lesions, and MRI shows hyperintense lesions in the pallidum and inferior 25 putamen.
Drug-Induced Dystonia and Chorea Medications may cause dystonia (Chapter 36) and chorea (Table 59-1). Acute iatrogenic dystonic reactions are idiopathic, reversible, and common. They may occur almost immediately (minutes to hours) after the first dose of a medication, or days to weeks later. For dystonia, the most common offenders include antipsychotics (both typical and atypical), benzodiazepines, anticonvulsants, dopamine agonists, and tricyclic antidepressants. Reactions have been encountered less often with calcium-channel blockers, propranolol, 27 histamine blocking drugs (cimetidine, ranitidine, cetirizine), 28 substituted benzamides (metoclopramide, sulpiride, clebopride, and domperidone). Selective serotonin-reuptake inhibitors (including fluoxetine, paroxetine, fluvoxamine, and sertraline) have been associated 29 with dystonia. Patients with AIDS dementia complex are particularly sensitive to neuroleptic-related acute dystonic reactions because of underlying dopaminergic 30 dysfunction. Click here to view this table.... Treatment involves a gradual reduction and discontinuation of the offending medicine and, if necessary, administration of an anticholinergic or a benzodiazepine. Diphenhydramine, benztropine mesylate, chlorpheniramine, diazepam, or lorazepam may be given orally or intravenously; treatment for several days is sometimes necessary, especially if the causal agent was taken regularly or in depot form. Chorea has been reported secondary to a variety of medications including anticonvulsants (phenytoin, carbamazepine, valproate, and gabapentin), stimulants (amphetamine, cocaine, methylphenidate, pemoline), benzodiazepines, estrogens, lithium, levodopa (with or without catechol-O-methyltransferase [COMT] inhibitors), dopamine agonists, tricyclic
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antidepressants, and antihistamines, as well as other agents such as baclofen, cimetidine, 2,31 thyroxine, cyclosporine, and aminophylline. 32Azar and colleagues reported chorea and encephalopathy associated with ciprofloxacin. Disulfiram overdose or poisoning (discussed earlier) may present clinically with encephalopathy, ketotic hyperglycemia, and dystonia. Tardive dyskinesias typically involve repetitive orolingual facial movements or repetitive movements of the head, trunk, and extremities. The dyskinesia may take the form of dystonia, chorea, akathisia, tremor, or myoclonus. It is not clear what determines the type of movement disorder that develops; there is no correlation with type or number of neuroleptic agents taken or duration of their use. Orofacial dyskinesias typically develop after 1 to 2 years of antipsychotic use but may occur after only months. Older patients seem more susceptible than young persons. The antipsychotic should be discontinued if feasible; this may initially exacerbate the dyskinesia, but the movement disorder ultimately decreases or disappears in up to 50 percent of patients, persisting unchanged in the remainder. Other dopamine-blocking drugs, including certain calcium-channel blockers (especially cinnarizine and flunarizine) and rarely serotonin reuptake inhibitors, have been associated with the development of tardive dyskinesias. Dopamine-depleting agents (reserpine, tetrabenazine) are the most useful adjunctive treatments, followed by benzodiazepines and by dopamine and γ-aminobutyric acid agonists; 33 anticholinergic drugs may exacerbate the syndrome. Tardive dystonia may be indistinguishable from idiopathic dystonia and may respond to sensory tricks. It may be focal, segmental, or generalized; however, the head and neck region are most commonly affected, resulting in torticollis, blepharospasm, or oromandibular 33 dystonia. Orobuccal-lingual dyskinesia or other tardive movements may occur in tardive dystonia, unlike in idiopathic dystonia. The onset is insidious, typically after several years of antipsychotic use, but may occur with exposures shorter than 1 year. Tapering the antipsychotic occasionally produces gradual or partial remission of tardive dystonia, often after an initial worsening. An increase in dose of the antipsychotic or its continuation may lead to temporary benefit, but probably worsens the long-term outlook. If treatment with an antipsychotic is necessary, replacement of the original neuroleptic with clozapine or sometimes quetiapine has been helpful. Approximately 50 percent of patients benefit from dopamine-depleting or -blocking agents (e.g., reserpine or tetrabenazine) and anticholinergic 33 treatment. For patients with focal or segmental dystonia, botulinum toxin injections are beneficial. Stereotactic surgery, including pallidotomy and pallidal deep brain stimulation, has 34 been successful for severe tardive dystonia. Among the medications known to cause dyskinesias, antipsychotic agents—especially haloperidol—remain the most common offenders and cause dystonia by blocking dopamine receptors in the basal ganglia. The “atypical” antipsychotic agents appear to be less frequently associated with the development of tardive dyskinesias, although they still occur. A recent study on injectable risperidone found a 1-year rate for developing dyskinesia of 1.2 35 percent. However, aside from the well-recognized antipsychotics, other less well recognized dopamine-blocking agents such as antiemetics and gastrointestinal agents such as prochlorperazine, promethazine, and metoclopramide can cause tardive syndromes. Some medications appear to cause chorea in the setting of preexisting basal ganglia injury. For example, dose-related 36 dyskinesias develop in a large proportion of parkinsonian patients taking carbidopa/levodopa. Similarly, many patients who develop chorea while taking oral contraceptives have had striatal abnormalities on imaging studies or a past history of37 Sydenham's chorea, chorea gravidarum, or chorea with Henoch–Schönlein purpura. Other medications do not require a preexisting basal ganglia abnormality: for example, dopamine agonists and anticonvulsants (particularly when more than one is taken) may cause dyskinesias or frank chorea. Rarely, children treated with theophylline for an asthma attack have developed transient orobuccal-lingual dyskinesias or generalized chorea; hypoxia, other possible metabolic abnormalities, and the concomitant use of other 38,39 medications make the precipitating factor unclear. Among illicit drugs, cocaine and amphetamines (Chapter 38) have been most frequently associated with dyskinesias. Both influence central dopaminergic mechanisms, and cocaine also decreases serotonin turnover and degradation. Both may lead to choreoathetoid movements of the extremities, less often the head or trunk, or buccolingual dyskinesias within 24 hours of use, which typically resolve without treatment in 2 to 6 days. However, in chronic users, chorea persisting for more than 1 year after discontinuation of these stimulants has 40,41 been described.
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Infectious Disorders Infections may cause the full spectrum of movement disorders (Table 59-2). Movement abnormalities usually develop during the acute illness and are transient, but abnormal movements sometimes begin or persist after the infection has cleared. One mechanism is vasculitic ischemia of the basal ganglia, although direct neuronal injury by the organism or a toxin, and autoimmune cross-reactivity with basal ganglia epitopes are also postulated to play a role. Click here to view this table.... Bacterial Infections Sydenham's chorea is a transient chorea associated with rheumatic fever and preceding infection with group A beta-hemolytic streptococci, usually occurring in childhood between 42 ages 7 and 12, with a range of 3 to 17 years. After 10 years of age, it is more common in girls. The chorea42is usually generalized (80% of cases), and may be the presenting feature of and associates found rheumatic fever. An encephalopathy occurs in 10 percent. Cardoso 42 that rheumatic fever presented with chorea in 9 of their 13 patients. Behavioral abnormalities are common; a recent study found obsessive-compulsive disorder and 43 attention deficit and hyperactivity in about 25 percent of patients. The pathogenesis of Sydenham's chorea may be related to the development of anti–basal ganglia antibodies, 44 which have been found in patients with this disorder. Although the condition is usually self-limited over months, symptomatic treatment with valproic acid or carbamazepine can be considered in those with severe chorea. Dopamine-receptor blocking drugs are reserved for 2,31 Recurrences frequently occur, usually those who do not respond to these anticonvulsants. within 2 years of the initial episode. Secondary prophylaxis with penicillin should be considered to avert further rheumatological injury. Neuroimaging studies may be normal or 45 show contralateral or bilateral striatal abnormalities that resolve as the chorea settles. 46 Positron emission tomography (PET) scanning shows reversible striatal hypermetabolism. Tuberculous meningitis may cause dystonia or chorea. Brain imaging may be normal or may show ischemic or hemorrhagic infarcts as well as hydrocephalus. Direct infection or infarction of the basal ganglia may account for the development of the movement disorder. Treatment 47 is with antituberculous therapy. Most patients improve over several weeks. Mycoplasma pneumoniae causes pneumonia but also affects the central nervous system 48 (CNS) in approximately 5 percent of patients requiring hospitalization. Aseptic meningitis, cranial neuritis, transverse myelitis, or encephalitis may occur, and neurological symptoms may precede pulmonary ones. Generalized choreoathetosis and dystonia have been 48,49 Cerebral imaging may be unremarkable or show abnormalities in the caudate, described. putamen, and globus pallidus. The cerebrospinal fluid (CSF) is normal or exhibits a mild lymphocytosis with elevated protein concentration. The diagnosis is made by respiratory cultures and tests for serum and CSF complement-fixing and cold agglutinin antibodies. In legionnaires' disease (Legionella pneumophila), high fevers and pulmonary involvement may be 50 accompanied in approximately 20 percent of cases by headache and, rarely, by chorea. The CSF and head CT scan are normal, and the diagnosis is made by serological studies. The chorea may persist for up to 2 years. 3
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Chorea has also been reported in rare patients with Lyme encephalitis or neurosyphilis and in one infant each with52Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis infection. Viral Infections Viral encephalitis may be accompanied by movement disorders, particularly in children. Japanese encephalitis, endemic to much of Asia, causes dystonia53or parkinsonism several weeks after infection. Brain MRI typically shows thalamic lesions. Varicella has been associated with transient chorea and dystonia or, less often, with hemichorea or generalized 54 early feature of herpes simplex encephalitis in infants but more chorea. Chorea can be an 55 frequently signals a relapse. In adults, human immunodeficiency virus (HIV) infection may present with hemichorea-hemiballism or with generalized chorea, usually in the presence of 56 to dementia. Most AIDS-related cases are secondary to toxoplasmosis but may also relate 30 HIV encephalitis, cryptococcal infection, or progressive multifocal leukoencephalopathy. Fungal and Parasitic Infections
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In HIV-seropositive patients, cerebral toxoplasmosis is the most common cause of dyskinesia. Toxoplasma abscesses in various diencephalic structures have been associated 57,58 with contralateral limb ballism, choreoathetosis, and dystonia. Treatment of the infection is usually successful, but improvement in the dyskinesia is seen in only57 approximately 25 percent of instances, suggesting irreversible injury to the basal ganglia. Improvement of the dyskinesia may occur with dopamine-blocking agents or dopamine depleters such as 30 only rarely in tetrabenazine. Hemichorea and hemiballismus have been reported 59 cryptococcal meningitis and may respond to antifungal treatment.
Autoimmune, Inflammatory, and Paraneoplastic Disorders Three possible mechanisms may explain the occasional occurrence of dystonia or chorea in autoimmune and connective tissue diseases. An antibody-generated cerebral vasculitis may cause transient or permanent ischemic injury to the basal ganglia. Alternatively, antibodies with stimulatory, inhibitory, or cytotoxic activities60may recognize basal ganglia epitopes, resulting in dysfunction of the neuronal circuitry. Finally, nonimmune systemic metabolic disturbances in these disorders may also play a role. In systemic lupus erythematosus (SLE), choreoathetosis develops in 1 to 2 percent of 61 the chorea occurs before the patients and may be the presenting feature. In most patients, 62 age of 30 years and tends to manifest during a lupus flare. It may be generalized or lateralized and is usually transient, lasting for a few days up to 3 years; recurrence occurs in approximately 25 percent of cases. Rarely, the chorea is permanent. The chorea may be self-limited or respond to steroid or symptomatic treatment. Imaging studies may be 62 abnormal, but the location of any lesions does not always explain the chorea. Patients with SLE and chorea may possess antiphospholipid antibodies (lupus anticoagulant or anticardiolipin antibody) that predispose to endovascular thrombosis and cerebral 62 infarction. Approximately 30 percent of patients with SLE with these antibodies have thrombotic events. Laboratory studies reveal that whole-blood clotting time is prolonged, and the prothrombin time and the Russell's viper venom time may be abnormal. The antibodies inhibit protein C activation and prostacyclin and antithrombin III activity, and may affect platelet membranes. Chorea in several patients with SLE and antiphospholipid antibodies has improved within days on warfarin or aspirin therapy, consistent with a vascular mechanism. Thus, chorea in SLE may result from autoimmune vasculitic62cerebral microthrombosis or direct antibody-mediated basal ganglia dysfunction, or both. In patients without SLE, the primary antiphospholipid syndrome is a hypercoagulable 61 state in which antiphospholipid antibodies are associated with venous or arterial thromboses. The pathology of the disorder remains unknown although most of the manifestations are believed to be thrombotic in origin. In addition to lupus anticoagulant and an immunoglobulin (IgG) anticardiolipin antibody, many patients have a low titer of antinuclear antibody, 30 percent have a false-positive Venereal Disease Research Laboratory (VDRL) test, and some have antithyroid antibodies. Chorea (either lateralized or generalized) has been the most frequently reported movement disorder62in 1 to 4 percent of patients with primary or secondary antiphospholipid syndrome, although tics, dystonia, myoclonus, and corticobasal syndrome 62,63 Brain MRI shows lesions more often than CT does, but the lesions do not may occur. 64 always explain the chorea, and some patients have normal imaging studies. This variability has led to speculation about a direct effect of the antibodies on the basal ganglia. The most effective treatment for symptomatic patients with antiphospholipid antibodies, with or without a diagnosis of SLE, is anticoagulation with warfarin to an international normalized ratio (INR) of 2 to 3, with or without 75 mg of aspirin daily. Anticoagulation reduces the risk of recurrent venous thrombosis by 80 to 90 percent and may prevent recurrent arterial 65 thrombosis. Chorea is a rare complication of polyarteritis nodosa and isolated angiitis of the CNS. 66 Patients with Behçet's67syndrome may present with chorea, jaw-opening dystonia, or paroxysmal dystonia. Typically, these patients have had an increased68CSF protein concentration and lymphocytosis, and respond to pimozide or steroids. Early reports also exist of chorea occurring in Churg–Strauss syndrome. In Hashimoto's thyroiditis, five major thyroid-related autoantibodies can lead to thyroid dysfunction and cause an encephalopathy 69,70 The CSF protein concentration is usually that may be accompanied by choreoathetosis. elevated, and some samples have oligoclonal bands or a mononuclear pleocytosis. Characteristically, the electroencephalogram (EEG) shows epileptiform activity, and transient or permanent areas of increased T2 signal are seen on brain MRI, particularly in the frontal and temporal lobes. Patients respond to prednisone, 40 to 80 mg daily, with a slow taper once improvement is stable. Complete remissions can be anticipated, although relapses
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sometimes occur or a deficit remains. Spontaneous remissions are rare. Dystonia and tremor 71 may be part of a movement disorder associated with celiac disease. Paraneoplastic chorea has been described in a series of 16 patients; most had limited 72 small-cell carcinoma of the lung, 1 had renal cell carcinoma, and 1 had lymphoma. Serological testing revealed that all had collapsing response-mediator protein (CRMP)–5 antibodies; 6 also had ANNA-1 (anti-Hu) antibodies. In most of these patients, chorea was the initial symptom. Brain imaging showed basal ganglia abnormalities, and autopsy showed perivascular inflammation and microglial activation. Four patients improved with 72 chemotherapy, and two improved with intravenous methylprednisolone. Laryngospasm, jaw-opening dystonia, and cervical dystonia have been described in paraneoplastic syndromes 73 associated with antineuronal antibody type 2 (ANNA-2, also known as anti-Ri antibodies).
Metabolic Disorders The association between thyrotoxicosis and choreoathetosis or dystonic posturing was recognized by Gowers in 1893, particularly in young women, but patients of either sex may be 74 affected. The course of the dyskinesia usually parallels that of the hyperthyroidism. Choreoathetoid movements typically involve the limbs, sometimes unilaterally, and are most conspicuous distally; the neck and face may also be affected. Paroxysmal (rather than more continuous) choreoathetosis may occur in rare instances, and paroxysmal74,75 and kinesigenic No cerebral choreoathetosis has also been reported with exogenous hyperthyroidism. lesions have been noted on MRI or at autopsy. The chorea responds to dopamine receptor blockers or propranolol even before hyperthyroidism has resolved. Altered dopamine turnover or increased dopamine receptor sensitivity may be responsible for the dyskinesia. Since chorea may occur in both hyperthyroidism secondary to Graves' disease and iatrogenic thyrotoxicosis, it is hypothesized that the disorder results from a direct effect of thyroxine on 75 the basal ganglia, perhaps by increasing dopamine receptor sensitivity. Hypocalcemia from idiopathic hypoparathyroidism may rarely cause dystonia or 76 choreoathetosis. The abnormal movements may be the presenting complaint, may be asymmetric, are usually paroxysmal, and rarely are kinesigenic. Patients are usually younger than 30 years, with calcium levels of 4 to 6 mg/dl, elevated serum phosphorus levels (5 to 12 mg/dl), and low serum magnesium. Brain imaging sometimes reveals basal ganglia calcification that persists after treatment of hypocalcemia and resolution of chorea or dystonia. Generalized chorea or hemiballism-hemichorea may occur in nonketotic hyperosmolar 77 hyperglycemia. Brain CT may show high-density lesions, and MRI often shows high T1 signal and hypoperfusion in the caudate or putamen contralateral to the side involved clinically. These imaging findings are considered to be a consequence of hyperviscosity and 78 cytotoxic edema, not petechial hemorrhage. The chorea may resolve with correction of hyperglycemia; however, dopamine-depleting agents or dopamine-blocking agents may be useful treatments until the condition resolves. Severe hypoglycemia may be accompanied by 79 either generalized chorea or hemichorea that resolves as euglycemia is reestablished. Dystonia or chorea80has rarely been noted in hypernatremic dehydration, hyponatremia, and 81,82 An encephalopathy hypomagnesemia and also after central pontine myelinolysis. associated with choreoathetosis has been reported in a patient with a splenorenal shunt83 without cirrhosis; improvement followed treatment with a low-protein diet and lactulose.
Approach to Diagnosis The evaluation of patients with involuntary movements or postures requires a detailed history, including an account of perinatal events, ethnicity, parental consanguinity, psychiatric disorders, past medications, exposure to infectious agents, immunological status, substance abuse, and exposures to toxins. The age of onset and pattern of progression further direct the evaluation. The examination of patients with dyskinesias should exclude non-neurological etiologies for the abnormal postures or movements. The disorder may also be more widespread than the location of the chief complaint. Characterization of the movement disorder and its distribution, together with findings such as organomegaly, skin lesions, retinal or optic nerve disease, or neurological deficits narrows the differential diagnosis. The relaxed patient must be observed carefully while lying, sitting, standing, and walking to determine whether any abnormality is exacerbated by movement or rest. The patient should perform tasks that are particularly impaired because certain movement disorders are solely task specific.
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The age of onset and the pattern of involvement and progression vary with the etiology. Focal or task-specific dystonias, often associated with a dystonic or essential-type tremor, onset in adulthood, a benign history, and no other abnormalities on examination, are usually idiopathic. Limb dystonia beginning as action dystonia is usually idiopathic, whereas dystonia beginning at rest is sometimes symptomatic. Dystonia with onset in the legs is usually idiopathic in children but symptomatic in adults. Chorea or dystonia of acute or subacute onset or having a rapidly progressive course is more likely to be symptomatic. Hemidystonia at any age suggests a secondary etiology, and approximately 75 percent of patients have contralateral basal ganglia abnormalities on imaging, a history of hemiparesis, or both. One third of hemidystonic patients have infarction or hemorrhage of the contralateral basal ganglia, especially the putamen. Generalized dystonia beginning at an early age may be idiopathic or symptomatic, but it is more often symptomatic when onset is in adulthood. Childhood-onset dystonias tend to become generalized, whereas those commencing in adulthood often remain focal or segmental. Similarly, tardive dystonia may be generalized in children, but it usually remains focal or multifocal in adults. Thus, dystonia of sudden onset, rapid progression, onset in infancy, cranial onset in children, lower-extremity onset in adults, or hemidystonia at any age is more likely symptomatic and requires full evaluation. A large number of factors contribute to decision making in the evaluation of chorea and dystonia. Brain MRI has a high yield, and basic laboratory studies include a complete blood count and blood electrolytes, calcium, phosphorus, uric acid, and liver and thyroid function tests. Any patient with chorea or dystonia younger than 40 years must be evaluated for Wilson's disease. Evaluation for vascular disease, a hypercoagulable state, connective tissue disorders, and antiphospholipid antibodies may be required. Serum antistreptolysin O or antihyaluronidase titers and an electrocardiogram are useful when Sydenham's chorea is suspected. Neurodegenerative and hereditary metabolic disorders require a separate battery 2,4 of studies, which are described elsewhere.
Treatment The treatment of secondary dystonia or chorea is difficult. In symptomatic cases, the underlying pathological process should be treated first, as discussed earlier. General therapeutic measures may provide symptomatic benefit when specific treatments of the underlying lesion have failed to temper the movement disorder satisfactorily. Anticholinergics, dopaminergics, antidopaminergics, benzodiazepines, anticonvulsants, and certain other medications (discussed later) are used, based on patient age, tolerance, coexisting medical illnesses, and interactions with other medications taken concomitantly. All of these medications are disappointingly variable in their efficacy. Unfortunately, there is a paucity of adequate trials demonstrating therapeutic benefit or comparative efficacy because patient numbers are small, common side effects make double-blinding difficult, and nonspecific effects such as sedation can diminish abnormal movements. Moreover, spontaneous remissions, partial or complete, and transient or permanent, may occur unpredictably. Anticholinergic medication, of which trihexyphenidyl is the best studied, is more effective in mild dystonia and in younger patients. Approximately one third of patients with secondary 84 dystonia benefit, and up to 50 percent of those with perinatal hypoxic injury improve. The selected agent is started at a low dose, which is increased slowly, depending on response and tolerance. (A particular daily dose may take several weeks to produce maximal benefit.) Side effects can be dose-limiting, particularly with advancing age. Tricyclic antidepressants and diphenhydramine are also sometimes used for their anticholinergic effects. The useful antidopaminergic medications include dopamine depleters (reserpine, tetrabenazine) or dopamine receptor antagonists (phenothiazines, haloperidol, pimozide). Tetrabenazine (not yet approved by the U.S. Food and Drug Administration) has been the most useful single agent, particularly in tardive dyskinesia, tardive dystonia, Huntington's chorea, and idiopathic generalized dystonia; patients with focal or hemidystonia or 85,86 The dose-related side effects of antidopaminergics blepharospasm do not respond. include parkinsonism, sedation, depression, and drooling, and sometimes other movement disorders, depending on the agent used; they occasionally necessitate a reduction in dosage. Dopaminergic supplementation using levodopa is singularly effective in patients with dopamine-responsive dystonia, which may be present in 5 to 10 percent of patients with childhood-onset hereditary dystonia beginning in the legs, with or without diurnal fluctuations. It is less useful in treating symptomatic dystonias. Nevertheless, amantadine or dopamine agonists are worthy of a trial in symptomatic dystonia. Anticonvulsants have been tried, usually with disappointing results. Carbamazepine is used most frequently, but in a study of 67 patients with dystonia, only 11 percent obtained
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84
moderate or greater benefit from the drug. Baclofen, a presynaptic γ-aminobutyric acid agonist, is also frequently tried and occasionally is effective. Intrathecal baclofen, delivered by an implanted pump, has been beneficial especially in those with spasticity and painful 87 spasms. Other medications that have been tried alone or in combination, with the same variability in benefit, include benzodiazepines, particularly clonazepam (27% with secondary 84 dystonia may benefit ), muscle relaxants, cyproheptadine, and lithium. Adult-onset cranial dystonias 88 are best treated with intramuscular botulinum toxin, which also benefits focal limb dystonias. Finally, surgical approaches may sometimes be warranted. Deep brain stimulation of the globus pallidus has been introduced for medically refractory dystonia, and a prospective study 89 for has found benefit in primary torsion dystonia. Deep brain stimulation has also been used 34,90 cervical dystonia and tardive dystonia, but experience with these conditions88,91 is limited. Selective peripheral denervation has been successful for cervical dystonia. The use of 92 deep brain stimulation for chorea is being explored. MYOCLONUS Myoclonus is an acute, brief, involuntary jerk caused by a sudden muscle contraction (positive myoclonus) or relaxation (negative myoclonus). It can be classified by distribution, the location of the generator, or the underlying etiology. It may recur in the same muscle groups (focal or segmental myoclonus) or asynchronously and asymmetrically in different muscle groups (multifocal or generalized myoclonus), and it may occur at rest (spontaneous), on movement (action or intentional myoclonus), or in response to specific stimuli (reflex myoclonus). Myoclonus occurs in healthy individuals (hiccups, hypnic jerks) or as a movement disorder with an idiopathic (essential), epileptic, or symptomatic etiology. Symptomatic myoclonus is the most common variety and may be due to primary neurological causes, but93it is more commonly seen in a general medical setting, to which this section is devoted. Myoclonus may be generated from spinal, subcortical, or cortical circuits and involves the somatotopically organized dorsal column/lemniscal and corticospinal systems superimposed 93 on the spinoreticular and reticulospinal circuits.
Hypoxia-Ischemia In 1963, Lance and Adams described posthypoxic action myoclonus in survivors of 94 cardiopulmonary arrest. Two forms of myoclonus are recognized in this context: acute posthypoxic myoclonus, which develops soon after hypoxia and is characterized by generalized myoclonus, and chronic posthypoxic myoclonus, which begins after a delay and 95 is characterized by action myoclonus. Multifocal myoclonus begins as the patient regains consciousness and is aggravated by voluntary motor activity. Cerebellar ataxia and cognitive impairment are often associated. Typically these signs improve with time, although some positive myoclonus and gait difficulty due to negative myoclonus may persist, resulting in falls. Acute posthypoxic myoclonus is characterized by severe, generalized myoclonus in 95 comatose patients. The jerk-like movements develop within the first day after hypoxia and are characterized by violent flexion movements. If myoclonus persists for more than 30 minutes or for most of the resuscitation day, it is often called myoclonus status epilepticus, despite the lack of evidence that the myoclonus is epileptic in nature. Wijdicks and associates found that in over 95 percent of patients with myoclonus, an EEG performed on the first hospital day demonstrated a burst-suppression pattern, alpha-pattern coma, or 96 polyspike-wave activity. Myoclonus status epilepticus occurs in 30 to 40 percent of comatose adult survivors of cardiopulmonary resuscitation, is difficult to control, and has a poor prognosis. A meta-analysis of 134 patients with myoclonus status epilepticus found that 89 percent died, 8 percent remained in persistent vegetative state, and 3 percent survived (2 97 patients are described as having had a good outcome). Chronic posthypoxic myoclonus, also known as the Lance–Adams syndrome, occurs within days to weeks after hypoxic injury, usually while the patient is still in coma. The myoclonus predominantly involves the limbs and is precipitated by active or passive movement; it 9 occasionally spreads to other portions of the body. It may95be stimulus sensitive, and negative myoclonus may also occur, predisposing patients to falls. The physiology of posthypoxic myoclonus is unclear. Analysis of CSF from affected patients has shown low levels of 5-hydroxyindole amino acid, a serotonin metabolite. Animal models also provide support for a role of the serotonergic system, showing reduced striatal serotonin 98 and cortical 5-hydroxyindole amino acid. Treatment with the serotonin precursor
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5-hydroxytryptophan has been effective in some patients and animal models. PET imaging with fluorodeoxyglucose in patients with posthypoxic myoclonus has99shown increased metabolism in several regions, including the ventrolateral thalamus. Treatment of chronic posthypoxic myoclonus is not satisfactory. However, clonazepam, valproate, and piracetam are often helpful. Treatment with 5-hydroxytryptophan (often with 9,100 Other carbidopa to limit nausea), levetiracetam, and sodium oxybate may also be helpful. 95 agents such as baclofen, diazepam, ethanol, and methysergide are sometimes helpful.
Metabolic Disorders Metabolic disorders are commonly associated with mental status changes and negative myoclonus (asterixis), which is usually of brainstem reticular origin. Renal failure and its treatment may both be associated with neurological dysfunction. Generalized and multifocal positive and negative myoclonus occur in uremic encephalopathy (Chapter 18). It may occur at rest, on movement, or in response to a stimulus. Myoclonus also occurs in patients with dialysis dementia (Chapter 18). The myoclonus is exacerbated during and after dialysis and is most prominent in the face and upper limbs. In hepatic insufficiency, asterixis or negative myoclonus is typical, but multifocal positive myoclonus also occurs. Any cause of hepatic insufficiency may result in myoclonus. Treatment requires addressing the underlying disorder. In rare instances, Wilson's disease 24 may present with progressive myoclonus. Hyperglycemia is the most common metabolic disturbance causing focal motor phenomena. In nonketotic hyperglycemia, severe hyperglycemia, hyperosmolality, and dehydration are accompanied by segmental or generalized myoclonic seizures in up to 20 percent of 101 102 patients. Asterixis or negative myoclonus is also seen. The EEG shows diffuse slowing, sometimes with a spike-wave pattern. The glucose level is typically over 600 mg/dl and osmolality above 300 mOsm/kg H2O, with mild or absent ketoacidosis. The myoclonus resolves with treatment of the hyperosmolality, and not with anticonvulsants, but therapy should be gradual, repleting approximately half the fluid deficit in the first 12 hours and the remainder over the next 24 hours because faster rates may precipitate CNS hyperglycemia and cerebral edema. 103
Vitamin B12 deficiency and its replacement may cause myoclonus in children and 104,105 adults. The myoclonus resolves after treatment with vitamin B12. In the infantile presentation, typically, the mother is vegetarian and the infant has received only breast milk. Initially, development is normal but, between 5 and 10 months of age, irritability and apathy are noted, with regression of milestones, followed by pallor, hypotonia, hyperreflexia, and a combination of tremor and myoclonus, which are most pronounced in the tongue and face but also involve the limbs and trunk. The myoclonus described in adult patients is generalized 104 or spinal and responds to vitamin B12 repletion. Alcohol-related pellagra (niacin deficiency) is characterized by the triad of myoclonus, altered 106 mental status, and generalized hypertonicity; a dermatitis is sometimes present. In 107 one case, only myoclonus and ataxia occurred, so a high index of suspicion is necessary. Typically, the myoclonus involves predominantly the face and limbs and is aggravated by startle, but not by movement or posture. Early replacement of niacin is required. Hypernatremic dehydration has also been associated with transient myoclonus and chorea in 80 chronic alcoholism.
Autoimmune and Inflammatory Disorders 108
Myoclonus occurs in autoimmune thyroiditis causing Hashimoto's encephalopathy. Any combination of cognitive impairment, encephalopathy, psychosis, transient neurological deficits, myoclonus or tremor, seizures, somnolence, or coma develops and fluctuates over weeks to months. The myoclonus may be generalized or multifocal and spontaneous or 109 reflex-evoked, and is without EEG correlates. Patients are clinically euthyroid, with elevated antithyroid antibodies, the levels of which correlate poorly with the clinical state. Further clinical and laboratory details are provided in Chapter 20. 63
Myoclonus has been described in the antiphospholipid syndrome.
Nonvasculitic autoimmune inflammatory meningoencephalitis may present with the rapid onset of dementia, parkinsonism, and myoclonus. In a single case, the EEG pattern consisted of persistent periodic sharp waves suggestive of Creutzfeldt–Jakob disease; 110 dramatic clinical improvement occurred with corticosteroids.
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A myoclonic syndrome often accompanied by ataxia may occur in celiac disease, despite 111 normal vitamin B12 and E levels. Typically, patients have a gastrointestinal syndrome that may include chronic diarrhea and abdominal pain, although gastrointestinal complaints may 112 be subtle (only nausea and vomiting episodes during infection in one report). Action or reflex myoclonus may occur in patients with established celiac disease, but whether this relates to inadequate dietary restriction or poor compliance is uncertain. The myoclonus may initially be focal but usually becomes multifocal; generalized convulsions may develop. The jerks are usually preceded by a time-locked polyspike EEG discharge, supporting a cortical origin. In some cases improvement occurs after a gluten-free diet is instituted. Anticonvulsant or benzodiazepine therapy is commonly required but is incompletely effective. Opsoclonus-myoclonus has also been described in a child with celiac disease and responded 113 to a gluten-free diet. Multifocal myoclonus has been reported in patients approximately 50 days after bone marrow 114 transplantation. The myoclonus may be spontaneous or triggered and is associated with parkinsonism and encephalopathy. Corticosteroid therapy is usually curative.
Drug- and Toxin-Induced Myoclonus Neuroleptic malignant syndrome may complicate neuroleptic treatment but also occurs with dopamine-depleting agents and on withdrawal of dopaminergic treatments. It is primarily due to functional dopamine deficiency, which leads to disinhibition of cortical and subcortical 115 excitatory pathways; norepinephrine and serotonin may also be involved. Its incidence is between 0.2 and 1.4 percent of patients exposed to neuroleptic agents. Most cases occur within a month of starting the neuroleptic agent. Fever, rigidity, and serum creatine kinase (CK) elevation (the major criteria) and tachycardia, labile blood pressure, tachypnea, diaphoresis (autonomic instability), altered mental status, and leukocytosis (the minor criteria) develop over 24 to 72 hours. Altered mental status and rigidity are often the first signs and are each present in over 95 percent of instances. The presence of all three major or two major and four minor criteria is highly predictive of the syndrome. The movement disorder is primarily an axial rigidity with tremor, choreoathetosis, dystonia, or myoclonus in the limbs. Rhabdomyolysis, renal insufficiency, respiratory failure, adult respiratory distress syndrome, disseminated intravascular coagulation, myocardial infarction, pulmonary embolism, and coma may complicate the picture. Treatment involves discontinuing the offending drug (or reinstituting dopaminergic medication) and supportive therapy; it may require administering the muscular excitation–contraction uncoupler dantrolene sodium at 2 to 8 mg/kg four times daily (maximum 10 mg/kg per dose) and the dopamine agonist bromocriptine at 5 mg four times daily (up to 50 mg/day) or subcutaneous apomorphine. Levodopa/carbidopa and amantadine 115 may also be used. With earlier recognition, the mortality rate had decreased from 75 to 11 percent by the late 1980s; rhabdomyolysis and renal failure continue to be the greatest predictors of poor outcome. Survivors almost always achieve complete recovery. The serotonin syndrome is a potential complication of treatment with antidepressants and related medications that increase cerebral serotonin neurotransmission. It is characterized by 116 mental status changes, autonomic hyperactivity and neuromuscular abnormalities. The prerequisite is a recent increase in the dosage of a serotonergic agent or the addition of a new one. Cognitive and behavioral changes include confusion, hypomania, and agitation, and myoclonus, ataxia, hyperreflexia, or tremor may also be present. Autonomic disturbances include nausea, vomiting, diarrhea, labile blood pressure, fever, shivering, and diaphoresis. The symptoms may begin as early as 2 hours after the medication is taken and usually resolve within 24 hours on discontinuation of the offending agent. When severe, serotonin syndrome may be indistinguishable from neuroleptic malignant syndrome and has a similar risk of multiple organ failure and death. Treatment requires discontinuation of precipitating drugs, supportive care, treatment for hyperthermia using benzodiazepines or neuromuscular paralysis, and administration of a 5-HT2A antagonist such as cyproheptadine (4 to 8 mg, followed by 4 mg116 six times daily to a total of 0.5 mg/kg daily) or chlorpromazine (50 to 100 mg intramuscularly). Of the non-neuroleptic psychiatric medications capable of causing myoclonus, lithium toxicity is well described. A variety of presentations occur including action, spontaneous, or stimulus-sensitive myoclonus, sometimes with opsoclonus.117 The myoclonus is of cortical origin but is not associated with epileptiform abnormalities. Vomiting and a decreased level of consciousness may also be present; in rare instances the presence of cognitive changes and characteristic EEG findings suggests the erroneous diagnosis of Creutzfeldt–Jakob disease. Full recovery is usual. Overdose with tricyclic antidepressants may result in
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myoclonus because of their ability to inhibit reuptake of serotonin and norepinephrine. 119 Myoclonus may occur with levodopa treatment. Patients usually also have dyskinesias, and the myoclonus occurs in the “on” phase, at rest, during drowsiness, and commonly during sleep. Usually there is a single, bilateral jerk of the legs or arms, although unilateral myoclonus, short repetitive jerks, and multifocal myoclonus have also been reported. Reducing the levodopa dosage may diminish the myoclonus. Tardive myoclonus due to neuroleptic medications is the least common of the tardive syndromes. It usually affects the face, neck, or upper limbs and responds to withdrawal of the neuroleptic treatment, but the movements may take several months to resolve. 33 Benzodiazepines are sometimes useful. A number of other medications and120 toxins have occasionally been associated with myoclonus and are summarized in Table 59-3. Click here to view this table.... In the eosinophilia-myalgia syndrome (a condition that was associated to contaminated l-tryptophan supplement), in addition to myoclonus, characteristic findings include a low-grade fever, myalgia, arthralgia, pulmonary symptoms,121 stiffness, skin rash, edema and induration of the limbs, peripheral neuropathy, and tremor. The eosinophil count is prominently elevated, the serum CK remains normal, and rarely there is a mild elevation in the CSF protein concentration. The myoclonus is multifocal and spontaneous or action induced, without EEG accompaniments. Unfortunately, symptoms and signs may not resolve with discontinuation of the supplement. Among illicit drugs, cocaine most commonly causes movement disorders. Myoclonus can be seen in the122setting of a cocaine-induced disorder resembling neuroleptic malignant or as multifocal rest and action myoclonus together with opsoclonus and syndrome 123 ataxia. Lead intoxication occasionally develops in one-time or chronic gasoline-sniffers, with encephalopathic symptoms developing at a serum lead level of 80 μg/dl and including myoclonus, which may be segmental or generalized and occurs spontaneously, with 124 movement, or in response to an external stimulus. The condition may respond to chelation treatment with dimercaprol and calcium disodium edetate, although repeated exposures may result in a permanent encephalopathy. Bismuth encephalopathy was initially recognized in the 1970s with the use of bismuth salts for treatment of a variety of gastrointestinal symptoms including gastric ulcers. High serum levels of bismuth result in confusion followed by severe myoclonus, truncal ataxia, dysarthria, tremor, and sometimes generalized convulsions and 125,126 The syndrome can evolve slowly over months or acutely over days and has coma. sometimes been confused with Creutzfeldt–Jakob disease or rapid-onset Alzheimer's disease. The myoclonus may be multifocal or a massive generalized movement, and may occur spontaneously, on action, and in response to stimuli. Recovery over 3 to 12 weeks is the rule when the bismuth intake is discontinued early; chelation with dimercaprol may 125 enhance renal clearance but has been associated with clinical deterioration in one patient. Diazepam, clonazepam, or valproic acid may reduce myoclonus.
Paraneoplastic Disorders Multifocal myoclonus with opsoclonus is most commonly seen as a paraneoplastic syndrome in approximately 2 to 3 percent of children with neuroblastoma. It may respond to corticosteroids, adrenocorticotropic hormone, or corticosteroids together with intravenous immunoglobulin (IVIg). In adults, it is usually associated with small-cell lung cancer or breast cancer and rarely with other tumors. The CSF protein may be mildly elevated, with a lymphocytic pleocytosis, oligoclonal bands, and elevated immunoglobulin index. Specific antibodies associated with paraneoplastic myoclonus include the anti-Hu (also called antineuronal nuclear autoantibodies or ANNA-1) and anti-Ri (ANNA-2) antibodies. PET with CT may be useful if initial radiological screening is negative and early detection and treatment 127 of the tumor appears to be useful. Occasionally the myoclonus improves with treatment of the underlying malignancy or prednisone, rarely with plasmapheresis, intravenous immunoglobulin, cyclophosphamide, or immunoadsorption therapy with a protein A column. 127 Myoclonus may respond to antiepileptic drugs. Action and 128 postural myoclonus has also been reported 129 in the setting of carcinomatous meningitis, in a child with a cerebellar ganglioglioma, and with other rare tumors. Axial myoclonus, fasciculations, and dementia have occurred with angiotropic lymphoma 130 (malignant angioendotheliomatosis).
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Infections Viral encephalopathies are the most common infectious cause of myoclonus (Table 59-2). In subacute sclerosing panencephalitis, myoclonus is time-locked to generalized bursts of high-voltage sharp waves (periodic complexes) occurring approximately every 5 to 15 seconds on EEG. The movements may be sufficiently severe to precipitate drop attacks and may persist during sleep. The myoclonus is relatively resistant to treatment, but sodium valproate, phenobarbital, carbamazepine, and clonazepam may be tried. Herpes simplex virus encephalitis and postviral acute demyelinating encephalomyelopathy may also cause myoclonus. Segmental spinal myoclonus has occurred as a late complication of herpes 131 myelitis. Progressive rubella panencephalitis may present with dementia, spasticity, and visual and cerebellar pathway involvement, together with asymmetric myoclonus; the course 132 usually is progressive. Myoclonus occurs rarely with HIV infection. In a study of 2,460 inpatients with HIV infection, 133 only 4 had myoclonus (2 with spinal myoclonus and 2 with generalized myoclonus. The myoclonus tends to be most prominent in the face, trunk, and proximal limbs and may be spontaneous or stimulated. Rarely, the myoclonus occurs with seroconversion, but usually the affected patients are significantly ill, often taking multiple medications and contending with and being susceptible to other medical problems, which must be evaluated as potential causes of the movement disorder before it can be attributed solely to HIV encephalopathy. Treatment depends on the underlying cause; in some cases, myoclonus has134,135 resolved with antimicrobial treatment for opportunistic infections or with retroviral therapy. Benign myoclonus occurs rarely with mumps. Multifocal myoclonus of the face, neck, and trunk develops within days of the infection and is associated with opsoclonus, tremor, and 136 cerebellar ataxia. The CSF may show a pleocytosis, the EEG may reflect only opsoclonus-related eye movements, and the syndrome is self-limiting in approximately 2 weeks. Viral infections associated with spinal myoclonus include human T-lymphotropic virus III 137 and myelopathy causing self-limited abdominal myoclonus and transient segmental 134 brachial myoclonus preceding or occurring during a herpes zoster outbreak. Multifocal myoclonus has been reported after an uncomplicated episode of chickenpox and 138 influenza-like illness, with spontaneous resolution over several months. Other viruses and viral infections causing encephalitis and myoclonus, sometimes with opsoclonus, include parainfluenza virus type 3, coxsackievirus B3, poliovirus, St. Louis encephalitis, JC virus causing progressive multifocal leukoencephalitis, and encephalitis lethargica. 139 Opsoclonus-myoclonus may also be the presenting symptom of West Nile virus infection. Bacterial infections associated with myoclonus are less common than viral infections.140,141 Spinal myoclonus and opsoclonus-myoclonus have been reported in Lyme neuroborreliosis 142 and in typhoid (enteric fever) due to Salmonella typhi. Opsoclonus-myoclonus has also been described as a sequela of group A β-hemolytic streptococcal infection. Initially, there is a febrile illness with pharyngitis, which is followed by the development of opsoclonus, myoclonus, and ataxia as well as behavioral changes. Laboratory investigation shows an elevated antistreptolysin titer (as well126 as antineuroleukin antibodies). The clinical syndrome responds to corticosteroid treatment. Myoclonus is seen in approximately 20 to 25 percent of patients with Whipple's disease due to the gram-positive bacillus Tropheryma whippelii, 143 although oculofacial myorrhythmia is the most characteristic movement disorder described. Further discussion of this disease is provided in Chapter 15. Multifocal myoclonus has been described as part of the postmalaria neurological syndrome, which also includes encephalopathy, tremor, and ataxia, beginning days to weeks after 144 and oculopalatal treatment of malaria, and responds rapidly to steroids. Multifocal 145 146 tuberculosis meningitis. myoclonus have also been reported in neurocysticercosis and 147 Cryptococcal encephalitis has caused generalized myoclonus.
Injury by Physical Agents 148
Spinal myoclonus may develop as a late complication of spine irradiation for cancer. The high-pressure neurological syndrome, which occurs on diving beyond a depth of 100 meters, 149 consists of cognitive impairment and hyperkinesis. Myoclonus is seen at a depth of 300 to 500 meters or 50 to 60 atmospheres. Segmental myoclonus has been reported in the setting 131 of electrical injury.
Approach to Diagnosis
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The clinical approach to evaluation of myoclonus requires a detailed history including the mode of onset, history of drug or toxin exposure, and full neurological and general medical examination. If the myoclonus is considered pathological and no offending drug or toxin is appreciated, screening blood studies may include a complete blood count and erythrocyte sedimentation rate; determination of electrolyte and glucose levels; thyroid, renal and hepatic function tests; and drug and toxin testing. An EEG to exclude an epileptic basis, and brain and spine MRI to exclude structural causes, are important. Paraneoplastic antibody testing may also be helpful.
Treatment When possible, myoclonus should be treated by addressing the underlying medical disorder. Thereafter, the location of the generator of the myoclonus can guide treatment. Cortical myoclonus responds best to anticonvulsants, particularly sodium valproate (0.6 to 3 g daily), primidone (50 to 1,000 mg daily), clonazepam (0.5 to 12 mg daily), levetiracetam (1,000 to 150 3,000 mg daily), and piracetam (2 to 20 g daily). Reticular reflex myoclonus and spinal myoclonus may respond to clonazepam, but there is no specific treatment for negative myoclonus. Other medications that have been anecdotally useful include anticholinergic agents, baclofen, tetrabenazine, acetazolamide, and opiates; γ-aminobutyric acid receptor agonists may also be effective. Combinations of two or three medications may be more 150 effective than monotherapy. TREMOR Tremor is the most common of all involuntary movements and is defined as an involuntary, rhythmic oscillation of a body part. It can be physiological (normal) or pathological, and is characterized by its frequency, amplitude, and distribution, and the position in which it occurs. Tremor is most easily classified as rest or action tremor. Some forms of tremor are generated primarily by a central oscillator, as in151 essential tremor, and others, such as physiological tremor, are mainly mechanical in origin. Central tremor is generated in the cerebellothalamocortical and dentatorubro-olivary pathways, with a poorly understood contribution from basal ganglia circuits. Rest tremor is characteristic of parkinsonism, which itself may occur secondary to a variety of causes. Such rest tremor is often accompanied by rigidity, bradykinesia, or postural instability, but may occur in isolation. Mechanical tremors decrease in amplitude and151 frequency with a load, whereas centrally generated tremors decrease only in amplitude.
Stroke Tremor may occur as a consequence of stroke. The most common lesions involve the thalamus, mesencephalon, rubro-olivary tract, and cerebellar tracts. Limb tremor may occur 47 with lesions of the cerebral cortex.
Medications Medications can cause the full spectrum of tremor subtypes (rest, postural, or kinetic), 152 although postural tremor is most common (Table 59-4). Intention tremor refers to the subtype of kinetic tremor that becomes more prominent as the limb approaches the target. Commonly used medications such as adrenergic agonists, including all β-agonists, lithium, caffeine, corticosteroids, tricyclic antidepressants, cyclosporine, and thyroid excess, usually cause postural tremor. Dopaminergic and anticonvulsant medications also cause an enhanced physiological tremor. Lithium- or valproic acid–induced tremor is present at rest and enhanced with posture or action. The antiarrhythmic amiodarone may cause a postural and terminal movement tremor in 20 to 30 percent of patients. Central cholinergic agonists such as nicotine, anticholinesterases, and aminopropanols are also tremorgenic. Click here to view this table.... Central monoaminergic stimulation by neuroleptics, phenylethylamines, and indoles may result in a parkinsonian rest tremor and a postural tremor. Specifically, tremor is seen in neuroleptic malignant syndrome and serotonin syndrome (see pp. 1105–1106). Dopamine receptor–blocking drugs and dopamine-depleting agents such as tetrabenazine and reserpine may also trigger a rest tremor.
Toxins and Recreational Agents
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A variety of toxins cause tremor directly or as part of a withdrawal syndrome (Table 59-4). Tremor may occur with acute cocaine intoxication, and persists in abstinent cocaine-, alcohol-, and opiate-dependent subjects for months after 153 the last use; rest tremor is reportedly more common in those with prior cocaine use. Alcohol and other drug withdrawal states enhance, sometimes asymmetrically, postural physiological tremor, which decreases with time but can be treated with propranolol or benzodiazepines. The intention tremor of chronic alcohol abuse, however, is the result of cerebellar injury by alcohol. With cannabis use, withdrawal symptoms may occur after as little as 7 days of use and include 154 tremor, irritability, restlessness, anorexia, fever, and other sympathetic effects. Intoxication with heavy metals and organic compounds may produce a rest or action tremor, and improvement after withdrawal of the toxin depends on the severity and duration of exposure.
Metabolic Disorders Almost any metabolic derangement may be associated with tremor. Thyrotoxicosis is the most common, producing an enhanced physiological tremor. It affects any age group and responds to treatment of the underlying disorder, but it can also be ameliorated by propranolol. Tremor is one of the first and most prevalent signs of hypoglycemia and may be seen in nonketotic hyperglycemia along with myoclonus, chorea, and dystonia. In renal insufficiency, a postural and action tremor is often evident before asterixis develops, and may foreshadow encephalopathy. The tremor in Wilson's disease may be postural, kinetic, or at 24 rest. A coarser movement of the upper limb (“wing beating” tremor) also occurs. It is present in the proximal arms and occasionally the head in the flexion-extension plane, and is due to thalamocapsular and cerebellar system pathological processes. Chelation therapy and liver transplantation can reverse the neuropathological process, but there is no effective symptomatic treatment. Hemochromatosis is associated with tremor, parkinsonism, and dementia due to iron deposits in the155 basal ganglia; progression may be forestalled by phlebotomy or liver transplantation. Variegate porphyria and the hyperadrenergic state associated with pheochromocytoma may also cause tremor, as can striatal injury in the 156 setting of hypoxic-ischemic encephalopathy. Hypomagnesemia and hypocalcemia may lead to tremor, muscle twitching, and irritability, and a severe, movement-associated, distal157 flapping tremor has been reported in hypercalcemia due158to hyperparathyroidism. Tremor has been reported with hyponatremia and its correction. Severe vitamin E deficiency (levels <5 μg/ml) may cause tremor in addition to spinocerebellar findings and peripheral neuropathy, and tremors may respond to 159 vitamin E supplementation. In infants, vitamin B12 deficiency can produce a generalized tremor syndrome and mental retardation, which are partially reversible with supplementation, although the abnormal movements may transiently increase with treatment before 103 resolving. In neonatal polycythemia-hyperviscosity syndrome, infants show diffuse tremulousness, lethargy, and hypotonia, which are somewhat responsive to plasma 160 exchange transfusion.
Infections Viral encephalitides are probably the most common infections to cause tremor (Table 59-2). Generalized tremors have also been described with poliovirus infection, St. Louis encephalitis, and the rhombencephalitis that sometimes complicates hand-foot-and-mouth 161 136 disease (due to enterovirus 71). Respiratory syncytial virus encephalitis and mumps, with a predilection for the cerebellum, manifest as intention tremor and ataxia. Echovirus 21 162 163 encephalitis and Japanese encephalitis result in tremor through basal ganglia and cerebellar involvement. Herpes zoster–related vasculitis164 affecting the midbrain may result in Congenital cytomegalovirus an ipsilateral cerebellar syndrome with intention tremor. 165 166 infection and rubella and adult tick-borne meningoencephalitis result in long-lasting neurological dysfunction, including tremor. The encephalopathy sometimes present with 167 Lassa fever may be accompanied by tremor, seizures, and coma. Meningoencephalitic involvement with flaviviruses may cause tremor in addition to the typical dengue hemorrhagic 168 fever caused by Machupo virus fever. A similar picture is seen in Bolivian hemorrhagic 169 (family Arenaviridae), which responds to ribavirin. Tremor disorders occur rarely in early HIV infection but occur in 5 to 44 percent of those with HIV-associated dementia. Tremor may be part of a parkinsonian syndrome or may occur in isolation. Typically, there is a symmetric postural tremor but there may be a rest component; kinetic components are rare. Holmes's (rubral) tremor, in which rest, postural, and kinetic components are present, has been reported in AIDS and often results from opportunistic
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infections such as tuberculosis or toxoplasmosis. In addition to drug-induced tremor from dopamine-blocking drugs such as neuroleptics and antiemetics, AIDS patients may develop a 170 reversible rest or postural tremor from trimethoprim-sulfamethoxazole. Treatment of tremor in HIV infection depends on etiology; drug-induced tremor and tremor secondary to 30 opportunistic infection may be reversible. Tremor occurs in up to 17 percent of those with tuberculous meningitis and is usually of the 146 postural variety. It may respond to antituberculous therapy over several weeks; if not, symptomatic treatment may be considered. Recovery from Plasmodium falciparum malaria is occasionally followed by a corticosteroid-responsive encephalopathy with postural tremor, cerebellar ataxia, myoclonus, 144 seizures, and motor aphasia. 47 In neurocysticercosis, tremor and parkinsonism are the most frequent movement disorders. Tremor is also seen in typhoid, together with altered bowel 171 Holmes's tremor have been reported with thalamic habits. Unilateral postural, kinetic, and 172,173 toxoplasmosis in HIV-positive patients.
Immune Disorders CNS lupus may include tremor among its many features. Waldenström's macroglobulinemia 174 has been associated with an asymmetric tremor and peripheral neuropathy. Basal ganglia and brainstem involvement in Behçet's syndrome may result in postural tremor and pyramidal 175 71 and extrapyramidal findings. Tremor may occur as a complication of celiac disease. In Hashimoto's encephalopathy, in which myoclonus and seizures are common, 80 percent of 108 older than 50 years with cerebellar degeneration, patients have postural tremor. In patients 176 the etiology is paraneoplastic in half. Intention tremor, ataxia, and dysarthria are particularly associated with anti-Yo antibodies in gynecological cancers and anti-Hu antibodies in small-cell lung cancers. Some immune-mediated polyneuropathies, particularly those associated with IgM monoclonal gammopathy and anti–myelin-associated glycoprotein antibody, are accompanied by a distally predominant action and postural tremor that sometimes responds to 177 immunosuppressive therapy or propranolol. An intention tremor has also been described in patients recovering from Guillain–Barré syndrome and in those with chronic inflammatory 178 demyelinating polyneuropathy. (It is debated whether tremor associated with peripheral neuropathies is generated by deranged sensory input, impaired stretch reflexes, muscle weakness, an associated CNS disorder, or some combination of these factors.)
Other Causes of Tremor Cerebral radiation therapy for brain tumors may be associated with generalized brain atrophy, 179 mental status changes, and movement disorders, including postural tremor. Pathologically, demyelination is found and tumor recurrence is absent. A postural and intention tremor may develop during compression during dives to depths greater than 100 meters as part of the 149 high-pressure neurological syndrome. It usually remits on decompression but occasionally persists for several months.
Approach to Diagnosis Evaluation of tremor requires a detailed history including the mode of onset, history of drug or toxin exposure, and an examination that evaluates the type of tremor and is directed at identifying any associated neurological or general medical disorders. Rapid onset (over days to months) of tremor is atypical for essential tremor but may occur when drug induced or related to an underlying medical disorder. If no offending drug or toxin is recognized, screening blood studies should include determination of electrolyte and glucose concentrations as well as thyroid, renal, and hepatic function tests. Testing for serum cortisol, parathyroid hormone, and ceruloplasmin; 24-hour urinary copper excretion; and toxicological assays may also be necessary in individual instances. Brain MRI may be required to exclude structural causes, particularly when there are other neurological findings or the tremor is asymmetric.
Treatment In all cases of tremor, an underlying disorder should be sought and treated while symptomatic treatment is contemplated. Action tremor, and particularly aggravated physiological tremor, usually responds to adrenergic blockade or primidone. β-Adrenergic
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blockers diminish tremor by their effect on peripheral β2-adrenergic receptors located on muscle fibers and spindles as well as a possible central action. Propranolol is most useful because of its effective membrane stabilization and CNS penetration, with metoprolol, nadolol, and pindolol as second choices; atenolol is the least effective. Other agents including topiramate, benzodiazepines, gabapentin, levetiracetam, and zonisamide are sometimes 180 tremor is treated by anticholinergic agents, amantadine, and dopaminergic useful. Rest 181 nucleus may be medications ; deep brain stimulation of the globus pallidus or subthalamic 182 used in patients with severe tremor that is refractory to medications. Cerebellar tremor is the most difficult to treat and only occasionally improves with 151 ondansetron, physostigmine, choline, baclofen, isoniazid, or l-5-hydroxytryptophan. The benzodiazepines and other sedatives may reduce tremor, but this effect is proportional to the degree of sedation achieved and not to a specific tremorlytic effect. Limb-loading typically reduces enhanced physiological tremor, and local cooling of a limb may temporarily reduce 151 tremor amplitude but is usually impractical. Botulinum toxin injection is sometimes partially helpful, but the utility of this treatment is often compromised by the weakness incurred. Stereotactic thalamotomy (ventral intermediate nucleus; Vim) by radiofrequency ablation or 182 thalamic (Vim) stimulation is an option if medications fail. PARKINSONISM Parkinson's disease is the most common cause of parkinsonism, but there are a number of other causes that relate to systemic disease and therefore merit discussion here.
Vascular Causes An akinetic-rigid syndrome may occur acutely or may develop in a delayed manner, months to years after focal, multifocal, or global ischemic events. It is usually symmetric, with limb 9 and axial rigidity, bradykinesia, rest or postural tremor, and postural instability. Lesions are especially conspicuous in the globus pallidus on imaging. Other vascular events such as a midbrain hemorrhage, subdural hematoma,183cortical venous thrombosis, and giant cerebral artery aneurysm may cause parkinsonism.
Medications and Bone Marrow Transplantation Drug-induced parkinsonism is common; one population-based study found that parkinsonism 184 was likely drug-induced in 20 percent of cases. Drug-induced parkinsonism differs from Parkinson's disease in that symptom onset may be rapid, often over weeks, bradykinesia is more symmetric, and tremor and postural instability are less common. However, individual cases may be clinically indistinguishable from Parkinson's disease. Drug-induced parkinsonism occurs most often in patients treated with dopamine receptor blockers (e.g., antipsychotics and metoclopramide), monoamine depleters (reserpine or tetrabenazine), and certain calcium-channel blockers (especially cinnarizine and flunarizine) (Table 59-4). Other frequently prescribed medications, such as selective serotonin reuptake inhibitors, lithium, valproate, antiarrhythmics, and diazepam, have caused parkinsonism in rare 185 instances. The parkinsonism is usually reversible over several weeks or months if the offending agent is withdrawn, but abrupt discontinuation of dopamine-blocking medications should be avoided. The protease inhibitor ritonavir was associated with reversible 186 parkinsonism in one patient taking high-dose buspirone. Parkinsonism has developed as a result of disulfiram treatment or overdose. Acute and subacute presentations (depending on the dose) have been described. Encephalopathy, hyperglycemia, ketosis, bradykinesia, and rest tremor may develop. The condition may improve after disulfiram is discontinued and with supportive therapy. CT may show hypodensity and MRI shows increased T2 signal in the 25,187 putamen and globus pallidus. A syndrome of rigidity, bradykinesia, spasticity, and often myoclonus and dementia developed acutely in five patients who had undergone successful engraftment of bone marrow 114 transplants for the treatment of various hematological diseases. MRI showed white-matter changes, and brain biopsy disclosed mild demyelination associated with active phagocytosis of myelin. Full recovery occurred in those treated with high-dose methylprednisolone. In 188 several patients, parkinsonism has been attributed to treatment with cyclosporine.
Toxins Since the recognition that 189 1-methyl-4-phenyl-1,2,3,6-tetrahydropryidine (MPTP) caused rapid-onset parkinsonism, a great deal of research has shown that factors adversely
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affecting energy metabolism and disposal of damaged proteins in dopaminergic neurons may 190 pesticides cause parkinsonism. In most epidemiological studies, prolonged exposure to 191,192 (particularly insecticides and herbicides) is a risk factor for Parkinson's disease. Other toxins that have been associated with parkinsonism include carbon monoxide poisoning, cyanide, carbon disulfide, hydrocarbons, hydrogen sulfide, lacquer thinner, mercury, methanol, organophosphates, petroleum products, and prior amphetamine 183,193 Carbon monoxide toxicity appears to result from a combination of tissue hypoxia use. and direct cellular toxicity. After initial recovery, about 10 percent of survivors will develop 15 ; approximately 80 percent recover within 6 parkinsonism several weeks to months later 15 months. Methanol poisoning may cause an acute parkinsonian state but has also been associated 19,194 Acute intoxication may with the development of parkinsonism with chronic exposure. cause coma. Upon recovery, visual impairment, hypophonia, rigidity, and bradykinesia develop that may respond to dopaminergic agents. Brain imaging shows hypointensity of the 19 putamen on CT scan and hyperintense lesions of the putamen on T2-weighted MRI. Manganese secondary to occupational exposure, such as welding, alone or in combination with liver failure, may cause parkinsonism. Brain MRI often shows increased signal in the 195 globus pallidus on21T1-weighted images. In some cases there is improvement after This form of parkinsonism is poorly responsive to dopaminergic chelation therapy. 196 treatment.
Metabolic Disorders Several metabolic conditions may mimic Parkinson's disease including folate deficiency, 155 hypothyroidism, extrapontine myelinolysis, chronic liver failure, hemochromatosis, and Wilson's disease. In Wilson's disease rigidity, bradykinesia, hypophonic speech, and tremor 24 as well as autonomic disturbances may occur. Parkinsonism has been described in liver failure from other causes. In a prospective study, 21 percent of patients with liver failure being 197 considered for liver transplantation had parkinsonism. Clinical features included rapid progression over months, symmetric akinetic-rigid syndrome, postural but not rest tremor, and early gait impairment. Serum and CSF manganese levels were elevated, and MRI showed hyperintensities involving the globus pallidus and substantia nigra resembling that seen in patients with occupational manganese exposure (Fig. 59-1). Some of these patients 197 responded to levodopa.
FIGURE 59-1 Sagittal T1-weighted magnetic resonance imaging (MRI) showing
increased signal in the globus pallidus in a 39-year-old man with advanced liver disease due to hepatitis with a 1-year history of a gait disturbance and intermittent tremulousness. Examination showed subtle tremulousness and slowing of rapid repetitive movements in all limbs. His laboratory evaluation revealed elevated serum manganese. Hypoparathyroid parkinsonism sometimes occurs as a late complication of thyroidectomy. It may occur rarely in idiopathic hypoparathyroidism; in addition to bradykinesia or rest tremor, other findings may include Babinski signs, generalized seizures, and mild chorea. The condition may respond to treatment with calcium, parathyroid hormone, and levodopa,
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although treatment with vitamin D has been required in some patients. In rare instances, parkinsonism has developed in patients with hyperparathyroidism and resolved after surgery. Parkinsonism has been described in patients with diabetes and uremia requiring dialysis. Cognitive impairment, dysarthria, bradykinesia, and rigidity develop over days to weeks. Laboratory evaluation may show a mildly elevated glucose and uremia (ranging from 37 to 122 mg/dl). Brain CT shows hypodense lenticular nuclei, and MRI shows T1 hypointense and 199 (Fig. 59-2); PET imaging T2 hyperintense lesions in the putamen and globus pallidus 200 shows reduced glucose metabolism. The condition and imaging abnormalities may resolve with hemodialysis.
FIGURE 59-2 This axial fluid-attenuated inversion recovery (FLAIR)–weighted
MRI was obtained from a 41-year-old woman with a long history of diabetes and dialysis-dependent renal failure with rapid-onset encephalopathy, dysarthria, tremor, rigidity, and bradykinesia. It shows increased signal in the putamen and globus pallidus bilaterally. Her condition improved with dialysis.
Infections Various infections may cause parkinsonism acutely or as a long-term complication (Table 59-2). Viral infections that have been associated with this phenotype include herpes simplex, HIV, Japanese encephalitis, Coxsackie B, influenza A, measles, mumps, polio, western equine encephalitis, St. Louis encephalitis, and subacute sclerosing panencephalitis. Japanese encephalitis, prevalent in most Southeast Asian countries, is estimated to be the most common viral cause of parkinsonism. Parkinsonism or other movement disorders develop 1 to 4 weeks after the acute phase and may persist for months to years. MRI has 53 shown hyperintensity of the substantia nigra on T2-weighted images. HIV infection may cause parkinsonism by direct injury to the basal ganglia or as a consequence of immunodeficiency. AIDS-associated parkinsonism is characterized by symmetric bradykinesia, rigidity, postural instability and gait impairment; tremor is often 30 absent. Mirsattari and colleagues found a 5 percent incidence of parkinsonism in a cohort of 115 HIV-infected patients, all of whom had severe immunosuppression with a mean CD4 3 201 count of 14 cells/mm . Postural and gait instability may occur early. The parkinsonism may be secondary to opportunistic infection, drug induced, or related more directly to the HIV infection. Even in the early stages of HIV infection when there is no clinically evident CNS deficit, sensitive tests may detect subtle impairments of motor function. There is evidence of early
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involvement of the basal ganglia in HIV infection: anatomical neuroimaging reveals selective basal ganglia atrophy, and functional imaging shows relative hypermetabolism in the basal ganglia and thalamus. Neuropathology frequently shows evidence of HIV infection with microglial nodule encephalitis affecting the putamen and caudate nuclei. Both lymphoma and 30 opportunistic infections with Toxoplasma and Cryptococcus show an affinity for the basal ganglia. Progressive multifocal leukoencephalopathy caused by JC virus in 202 immunosuppressed individuals may also cause parkinsonism. Perhaps because of the early involvement of the basal ganglia, HIV-infected patients develop drug-induced 203 parkinsonism at lower doses of antipsychotic treatments. One patient has been described who developed parkinsonism while being treated with a protease inhibitor (ritonavir) and 186 buspirone. When evaluating patients with HIV-related parkinsonism, opportunistic infection and drug-induced causes require exclusion. Treatment with antiretroviral medications has 204 reversed parkinsonism in a patient with HIV-associated dementia. In 1916, Von Economo described encephalitis lethargica, a disorder presenting with pharyngitis, ocular movement abnormalities, and encephalitis, with parkinsonism and other movement disorders seen as residua in many of 205,206 the survivors. Since the epidemic of 1916 to CSF shows a lymphocytic pleocytosis 1927, only sporadic cases have been described. and oligoclonal bands, but bacterial and viral cultures are unrevealing. Brain imaging may show inflammatory changes in the basal ganglia or brainstem. Dale and colleagues found elevated basal ganglia antibodies in 20 patients who developed parkinsonism, a sleep disorder, dyskinesia, and neuropsychiatric symptoms that were attributed to encephalitis lethargica. In 65 percent, antistreptolysin-O titers were elevated and 95 percent had basal ganglia antibodies, raising the possibility that encephalitis lethargica is an autoimmune 206 condition possibly triggered by bacterial infection such as in Sydenham's chorea. Some authors report improvement of this condition with methylprednisolone with or without 205,207 intravenous immunoglobulin. 146
Tuberculous meningitis is a rare cause of parkinsonism. Infection with Mycoplasma pneumoniae is another rare cause of parkinsonism. The condition begins with a flu-like illness, and bradykinesia follows; T2-weighted MRI shows increased signal of the basal 208 Reversible ganglia, which resolves several months after treatment of the infection. 209 parkinsonism has been reported in Lyme disease. Other infections associated with parkinsonism, generally in 183 association with other neurological abnormalities, include prion disease and neurosyphilis. Malaria and neurocysticercosis (both parasitic conditions) may cause parkinsonism and tremor. In neurocysticercosis, improvement may occur with albendazole and, when 47 hydrocephalus is present, placement of a CSF shunt.
Autoimmune and Paraneoplastic Disorders In addition to the common findings of recurrent oral ulcerations, bilateral posterior uveitis and retinal vasculitis, skin papules, parkinsonism, and postural tremor have been observed in 175 less common complication than Behçet's syndrome. In SLE, parkinsonism is a much 210,211 ; if not, antiparkinsonian medication chorea and may respond simply to steroid treatment may be required. Nonvasculitic autoimmune inflammatory meningoencephalitis may present with rapidly progressive myoclonus, dementia, and parkinsonism that improves with high-dose corticosteroids. The110 EEG may show persistent periodic sharp waves reminiscent of Creutzfeldt–Jakob disease. Parkinsonism (with bradykinesia, rigidity, and tremor) has been described in patients with anti-Ma2 antibodies, which are often associated with paraneoplastic limbic or brainstem 212 encephalitis. Eye movement abnormalities were notable in 90 percent with brainstem dysfunction. The most common underlying tumors were testicular and lung cancer.
Trauma Development of parkinsonism after a single head injury is exceedingly rare; when it has occurred, it has been after severe injury with loss of consciousness. Symptoms may develop over several months after injury. Neuroimaging usually demonstrates a lesion to the globus 213 also been several reports of parkinsonism pallidus or substantia nigra. There have214 secondary to chronic subdural hematoma, typically developing within weeks of the causal injury. Complete or near-complete remission of parkinsonism often follows drainage of the hematoma.
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The occurrence of parkinsonism after repeated head injury, as in boxing, has been described. The severity correlates with the length of the boxing career and the number of 215 bouts. Pathological examination has revealed atrophy of the fornix and mammillary bodies, scarring of the folia of the cerebellar tonsils, depigmentation of the substantia nigra, and an absence of Lewy bodies. Histological examination reveals neurofibrillary tangles that differ from those216 seen in Alzheimer's disease by their distribution in the superficial layers of the neocortex. A variable spectrum of signs and symptoms can be present including behavioral changes,217 dementia, and corticospinal and cerebellar symptoms; dysarthria is especially common. These patients often respond to dopaminergic treatment. Remote head injury causing loss of consciousness also appears to be a risk factor for 218 developing parkinsonism. A study of twins, which helped control for environmental and genetic characteristics, found that head injury with amnesia or loss of consciousness is a risk factor for Parkinson's disease; moreover, in twins concordant for Parkinson's disease, the 219 twin with younger-onset disease was more likely to have sustained a head injury.
Other Causes of Parkinsonism Some aspects of parkinsonism may be simulated by communicating or noncommunicating 220 hydrocephalus. In normal-pressure hydrocephalus, gait abnormalities predominate. Mass lesions are rare causes of parkinsonism. Parkinsonism resulting from focal irradiation of the brain or brainstem may respond to dopaminergic treatment and is sometimes partially 221 reversible.
Approach to Diagnosis Evaluation of parkinsonism requires a detailed history including its mode of onset, a history of drug or toxin exposure, and both general and neurological examination. Rapid onset of parkinsonism over days to months is atypical of Parkinson's disease but occurs when drug induced, after infection, or secondary to an underlying medical condition. If no offending drug or toxin can be identified, screening blood tests should be performed (blood electrolyte and glucose levels, erythrocyte sedimentation rate, and antinuclear antibody, as well as thyroid, renal, and hepatic function tests). Testing for 24-hour urinary copper excretion and serum ceruloplasmin determination should be considered in patients younger than 40 years. Toxicological screening tests may be necessary in individuals for whom no cause is found. Brain imaging, particularly MRI, may be helpful.
Treatment The management of secondary parkinsonism depends on the cause but generally includes symptomatic measures. The most common cause is medication related. When possible, the offending medication should be tapered to prevent worsening of any underlying psychiatric disorder for which it may have been prescribed and also to reduce the risk of precipitating a tardive movement disorder. When a behavioral disorder requires a dopamine-blocking agent, it is sometimes possible to switch to a dopamine antagonist with less affinity for the D2 receptor, such as clozapine or quetiapine. It may take weeks to many months for the full effect of a dopamine-blocking drug such as haloperidol to resolve. In other cases of secondary parkinsonism, management of the underlying medical disorder may take precedence. In many cases, however, treatment of the primary disorder is inadequate and symptomatic therapy is appropriate. In general, treatment of the parkinsonism with levodopa, dopamine agonists, or both may improve bradykinesia, rigidity, or tremor. The effectiveness of dopaminergic treatment varies considerably between conditions. Other agents that may be particularly useful for tremor include amantadine and 181 anticholinergic agents. Deep brain stimulation of the globus pallidus or subthalamic 182 nucleus may be used in selected patients who are refractory to medications. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 60 Neuromuscular Complications of General Medical Disorders JEFFREY W. RALPH • MICHAEL J. AMINOFF •
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DISORDERS OF THE MOTOR NEURON RADICULOPATHY DISORDERS OF DORSAL ROOT GANGLIA PLEXOPATHY PERIPHERAL NEUROPATHY Focal Neuropathy Multifocal Neuropathy Vasculitic Neuropathy Idiopathic Immune-Mediated Multifocal Neuropathy Sarcoidosis Infectious Neuropathy Polyneuropathy Endocrine Neuropathy Infectious Neuropathy Immune-Mediated Neuropathy Critical Illness Polyneuropathy Uremic Neuropathy Neoplastic and Paraneoplastic Neuropathies Nutritional Neuropathy Toxic Neuropathy Hereditary Neuropathy NEUROMUSCULAR JUNCTION DISORDERS Botulism Lambert–Eaton Myasthenic Syndrome Myasthenia Gravis Medications Causing Abnormalities of Neuromuscular Transmission Toxins MYOPATHY Endocrine-Related Myopathy Acromegaly Corticosteroid Myopathy Hyperparathyroidism and Osteomalacia Hyperthyroidism or Hypothyroidism Infectious Myopathies
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Human Immunodeficiency Virus Infection Viral Myositis Other Infections Idiopathic Inflammatory Myopathies Dermatomyositis and Polymyositis Inclusion-Body Myositis Sarcoidosis Polymyalgia Rheumatica Critical Illness Myopathy Metabolic and Toxic Myopathies Alcohol Hyperkalemia or Hypokalemia Uremia Medication-Induced Myopathy RHABDOMYOLYSIS AND MYOGLOBINURIA
The neuromuscular system involves neurons (dorsal root ganglion or anterior horn cells), spinal roots, plexuses, peripheral nerves, specialized sensory nerve endings, neuromuscular junctions, and muscles. The daunting task of approaching a disease of this system can be lessened by a few basic insights. The first is knowledge that diseases of the anterior horn cells, neuromuscular junctions, or muscles produce only motor signs, whereas most neuropathies are associated with both sensory and motor deficits. The second is recognizing 1 that neuromuscular diseases present with one of five basic patterns (Table 60-1). If the basic presentation pattern can be recognized, a short list of likely diagnoses can be generated. Weakness is usually a more prominent feature of demyelinating than axonal neuropathies. In general, electromyography (EMG) and nerve conduction studies (NCSs) are essential for confirming the anatomical localization, differentiating axonal from demyelinating neuropathies, and making prognostic statements. Decisions concerning the need for muscle or nerve biopsies should be deferred until electrodiagnostic testing is completed. Click here to view this table.... DISORDERS OF THE MOTOR NEURON When flaccid weakness and atrophy occur in muscles that share innervation by the same segment of the spinal cord or brainstem, without associated pain or sensory disturbances, a disease of the anterior horn cells (lower motor neurons) should be suspected. In the most common motor neuron disease, amyotrophic lateral sclerosis (ALS), degeneration of upper motor neurons occurs simultaneously with anterior horn cell degeneration, producing spasticity and hyperreflexia in wasted limbs. Most cases of ALS are sporadic, but approximately 10 percent of cases are inherited in autosomal-dominant or -recessive patterns. The pathogenesis of ALS is not known, but it is possible that multiple pathogenic mechanisms are at play, including impaired cellular handling of oxidative stress, neuroinflammation, neurotrophic factor deficiency, glutamate-induced excitotoxicity, and defects in protein metabolism. There is no cure for ALS, although a U.S. Food and Drug Administration (FDA)–approved inhibitor of glutamatergic neurotransmission, riluzole, slows 2 monitoring the progression of disease modestly. Noninvasive ventilation, careful nutritional 3 and supplementation, and multidisciplinary care can improve the quality of life. A sporadic clinical variant characterized by solely lower motor neuron involvement (progressive muscular atrophy) is managed similarly. Hereditary anterior horn cell diseases include spinal muscular atrophy, Kennedy's syndrome, and hexosaminidase A deficiency. Spinal muscular atrophy is an autosomal-recessive disease that may present with flaccid weakness from birth to adulthood. Mutations of the survival motor neuron (SMN1) gene cause the disease. Kennedy's disease (spinal and bulbar muscular atrophy) is an X-linked disease characterized by proximal muscle weakness, muscle atrophy, and fasciculations. Perioral fasciculations are a peculiar feature of this disease. Affected individuals often have gynecomastia and testicular atrophy with 4reduced fertility. Expansion of a CAG repeat in the androgen receptor gene is responsible. Motor neuron disorders may be difficult to distinguish from motor neuropathies because of their similar symptoms, signs, and muscle biopsy findings. EMG and nerve conduction studies are crucial in determining the diagnosis. Compression of the spinal cord may result in segmental loss of anterior horn cells, presumably from compression of the dural veins and resulting venous congestion and spinal 5,6 cord hypoxia. In cervical spondylosis, combined injury to both the anterior horn cells and descending corticospinal tracts may occur, leading to atrophy and weakness in the hands combined with spastic paraparesis; such a presentation mimics that of ALS.
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Many viruses have central nervous system (CNS) tropism, but only a few strains cause acute and selective loss of anterior horn cells. The prototypical and most severe of these infections is poliomyelitis. Poliovirus is an enterovirus spread via a fecal-hand-oral route. During an epidemic, paralytic disease accounts for 0.1 to 2.0 percent of all poliovirus infections. Most cases are either asymptomatic or develop only mild constitutional symptoms such as pharyngitis or gastroenteritis. More severe signs and symptoms, such as fever, malaise, headache, myalgia, pharyngitis, anorexia, and nausea and vomiting, occur with nonparalytic poliomyelitis, and the cerebrospinal fluid (CSF) findings are indicative of aseptic meningitis. Individuals developing acute paralytic poliomyelitis experience the same constitutional symptoms but also develop rapidly progressive weakness over the course of one to a few days. The weakness is often focal and asymmetric in the limbs or bulbar muscles, but may be symmetric or generalized. It frequently improves over several weeks to months. Rarely, 7 the live-attenuated oral poliovirus vaccine can cause paralytic poliomyelitis. Postpolio syndrome consists of new or worsened weakness, together with fatigue or pain in the muscle or joint, typically occurring 30 to 40 years after acute paralytic poliomyelitis. It is estimated to occur in 20 to 40 percent of individuals with a history of paralytic poliomyelitis. New weakness may occur in strong muscles that recovered from weakness during the acute event. The pathogenesis may involve late denervation of previously reinnervated muscle 8,9 fibers or musculoskeletal abnormalities. Progression of symptoms is usually slow. Viruses other than poliovirus, such as West Nile virus (WNV), echovirus, coxsackievirus, 10–13 Since the herpes zoster virus, and Epstein–Barr virus may cause loss of motor neurons. first North American outbreak of WNV infection14occurred in 1999, increased attention has been placed on its neurological manifestations. Only about 20 percent of WNV infections are symptomatic, usually manifesting as a febrile illness. A maculopapular rash appears in approximately one half of patients. About 1 percent of infected individuals develop 15 neurological symptoms that may include meningoencephalitis, flaccid paralysis, or both. As in poliomyelitis, the weakness is often proximal and asymmetric with no significant sensory 3 abnormalities. The CSF shows a lymphocytic pleocytosis (30 to 100 cells/ml ) and high protein content. CSF and serum should be screened for IgM antibodies to WNV using an enzyme-linked immunoabsorbent assay (ELISA). Any positive ELISA results need to be confirmed with more specific immunological tests. Treatment is supportive, although the benefit is under study of immunomodulatory therapies, including intravenous immunoglobulins (IVIg) and interferon-alpha (IFN-α) therapy. Rarely, WNV may present with 16 other neuromuscular disorders, including brachial plexopathy, rhabdomyolysis, 17 and a predominantly demyelinating polyneuropathy similar to Guillain–Barré syndrome. Paraneoplastic lower motor neuron involvement has been reported in association with lymphoproliferative disorders, thymoma, small-cell lung cancer, ovarian cancer, renal cancer, 18–21 Although the association of motor neuron disease and cancer is and prostate cancer. usually coincidental, a paraneoplastic effect should be considered in cases with pure lower motor neuron findings, prominent sensory findings, or evidence of widespread CNS involvement. Patients may have anti-Hu (ANNA-1) and anti-Yo (PCA-1) antibodies, CSF protein is often elevated, and there is a variable CSF pleocytosis. The weakness may improve after treatment of the cancer. RADICULOPATHY Pain or numbness in a dermatomal pattern accompanied by weakness in a segmental pattern suggests a radiculopathy. External compression is the most frequent cause of nerve root injury, either by intervertebral disc herniation or spondylosis. Radiculopathy resulting from degenerative spine disease is discussed further in Chapter 24. Other causes of radiculopathy may include gouty spine disease, Paget's disease, Tarlov cysts, and methylacrylate extrusion during spine surgery. Extradural tumors such as schwannomas, neurofibromas, and meningiomas may also produce a radiculopathy. A radiculopathy may result from epidural or spinal anesthesia; the injury may result from direct trauma to the nerve or from chemical injury related to the injected substance. Diabetic thoracoabdominal radiculopathy (diabetic truncal neuropathy) is a common cause of noncompressive radiculopathy. Patients present with pain and hyperalgesia in a region along the chest or abdomen. The pattern of involvement may be clearly dermatomal, but often the changes span more than one segment. Segmental weakness may manifest as an outpouching of the abdominal wall. The pathophysiology is unclear, but an inflammatory vasculopathy may be responsible. Compression of multiple lumbosacral nerve roots produces the cauda equine syndrome, which may lead to permanent urinary and fecal incontinence and lower extremity weakness
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and numbness and thus constitutes a neurosurgical emergency. The usual cause is a large, midline disc herniation. Chronic cauda equina syndrome may be caused by a developmental anomaly, such as a tethered spinal cord. Spondylosis is the most common cause of polyradiculopathy, although metastatic spinal disease should be considered when patients present with symptoms and signs attributable to injury of multiple roots. Breast cancer, lung cancer, multiple myeloma, prostate cancer, and renal cell carcinoma are the most frequent tumors that metastasize to the spine. Polyradiculopathy results from direct tumor compression or from leptomeningeal infiltration of the roots by tumor cells (carcinomatous meningitis). Treatment of spinal bony metastases often involves external beam irradiation although decompressive surgery may be necessary in radiation-resistant tumors. Carcinomatous meningitis often affects the caudal roots first. Cranial neuropathies, meningeal signs and symptoms, and a myelopathy may be associated features. CSF analysis typically shows a pleocystosis, hypoglycorrhachia, elevated protein level, and malignant cells on cytological analysis. The yield of positive cytology for malignant cells is increased 22 significantly by repeating the lumbar puncture. Treatment is usually palliative and includes radiation therapy and intrathecal chemotherapy. The median survival of patients with leptomeningeal metastases is 4 months. Infectious causes of polyradiculopathy include cytomegalovirus (CMV), Borrelia burgdorferi (Lyme disease), Epstein–Barr virus, herpes simplex virus, My-cobacterium tuberculosis, and Treponema pallidum. CMV polyradiculopathy usually presents as a late complication of acquired immunodeficiency syndrome (AIDS), but it can be a presenting manifestation of 23 human immunodeficiency virus (HIV) infection. The onset of flaccid paraparesis, 24,25 A lower-extremity numbness, and urinary retention may be acute or subacute. neutrophilic pleocytosis on CSF analysis is a clue to the diagnosis; the diagnosis is confirmed by a culture or CMV DNA polymerase chain reaction (PCR) assay on CSF. Treatment includes ganciclovir, foscarnet, or both. Lyme disease may also present as a polyradiculopathy, particularly in Europe, and may be associated with cranial neuropathies. Arachnoiditis is a nonspecific term for inflammation of the spinal leptomeninges. Historically, arachnoiditis has been associated with tuberculous and syphilitic meningitis and with obsolete oil-based contrast agents for myelography. Currently, the term often refers to the appearance of thickened meninges and clumping of the nerve roots on magnetic resonance imaging (MRI) of the spine, usually in patients who have undergone lumbar spine surgery. There is26 controversy about the association of the imaging findings, clinical findings, and symptoms. 27 Arachnoiditis28has also been described in association with toxoplasmosis and subarachnoid hemorrhage ; sometimes the cause is not known. DISORDERS OF DORSAL ROOT GANGLIA Diffuse or regional impairment of tactile sensation or gait ataxia without weakness suggests degeneration of dorsal root ganglia cells (sensory neuronopathy). Patients may also have facial numbness and autonomic involvement, manifesting as gastroparesis, orthostatic hypotension, sexual impairment, and Adie's pupils. EMG and nerve conduction studies differentiate sensory neuronopathies from more common distal sensory axonal 29 polyneuropathies. Sensory neuronopathies may be acquired (Table 60-2) or hereditary. Click here to view this table.... Paraneoplastic sensory neuronopathy is commonly associated with small-cell lung cancer but has also been described with breast cancer, ovarian cancer, Hodgkin's lymphoma, 30–32 Symptom onset is usually subacute. Antibodies to neuroendocrine tumors, and sarcoma. the Hu antigen (ANNA-1) are usually present, but their absence does not exclude the possibility of paraneoplastic sensory neuronopathy. Current evidence supports the belief that injury is T-cell mediated; the anti-Hu antibodies probably have an indirect role in the pathogenesis. Antibodies to the collapsin response-mediator protein-5 (CRMP-5) have also been described in some patients with small-cell lung cancer presenting with a paraneoplastic 33 syndrome thatincludes a sensory neuronopathy. Sensory neuronopathy may occur with other manifestations of paraneoplastic syndromes, including neuropathy, limbic encephalitis, encephalomyelitis, and gastroparesis. For these patients, the focus should be on the diagnosis and treatment of the underlying cancer. Treatment of the paraneoplastic condition 34 with IVIg, plasmapheresis, or other immunosuppressive therapies is often disappointing. Autoimmune or inflammatory conditions associated with sensory neuronopathy include 35 Sjögren's syndrome and autoimmune hepatitis. Sensory and autonomic neuronopathies may prompt the initial physician encounter regarding Sjögren's syndrome. Most of the
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patients described by Griffin and colleagues also had sicca symptoms, positive serological tests for connective tissue disease, and positive Schirmer's tests at the time of presentation 36 infiltrated by T to the neurology clinic. The dorsal root ganglia of these patients are 37,38 lymphocytes. IVIg and plasmapheresis have benefited some patients. An acute sensory neuronopathy syndrome characterized by the acute onset of widespread sensory symptoms, areflexia, impaired vibratory sensation, and gait ataxia has developed 4 39 to 12 days after initial antibiotic treatment for a febrile illness. The underlying pathogenesis in such cases may be infectious, postinfectious, or toxic (related to antibiotic use). Infectious causes of sensory neuronopathy are shown in Table 60-2. HIV infection may cause a sensory neuronopathy. T-cell infiltration of dorsal root ganglia has been found in patients with end-stage AIDS. Many of these patients also had pallor of the cervical portion of the gracile tract 40 at autopsy, suggesting that a “dying-back” axonopathy occurs along with sensory neuron loss. Latent infection of the dorsal root ganglia occurs following primary varicella-zoster virus infection. When cell-mediated immunity is compromised, reactivation of viral replication causes the clinical syndrome of herpes zoster. The elderly, transplant recipients, and HIV-positive patients are particularly vulnerable. The prodromal stage of herpes zoster includes fevers, dysesthesias, and malaise. Several days later, a vesicular eruption appears in a dermatomal distribution. Pathologically, there is intense inflammation of the dorsal root ganglia. Once the lesions become encrusted, they are no longer infectious. Approximately 3 41,42 Spread of the virus from the dorsal root43 percent of patients develop segmental paresis. ganglion to the anterior horn cells is the suggested explanation for the onset of weakness. Although41muscle atrophy may occur in the affected region, most patients recover muscle strength. Treatment during the early stages of infection includes valacyclovir or acyclovir. Postherpetic neuralgia may occur, particularly in the elderly. Tricyclic drugs or anticonvulsants are effective treatments, as discussed in Chapter 44. A number of toxins and vitamin deficiencies cause sensory neuronopathy. Because many of these also cause an axonopathy, they are discussed later (pp. 1137–1138). Hereditary sensory neuronopathy (hereditary sensory and autonomic neuropathy [HSAN]) is both genetically and phenotypically heterogeneous; some forms present with predominantly small-fiber involvement, whereas others have mixed small- and large-fiber involvement. There is variable involvement of the autonomic nervous system. Commercial genetic testing is available for some types. PLEXOPATHY Trauma and compression cause most plexus injuries; other causes include tumor infiltration, postirradiation injury, and infection. An autoimmune monophasic neuritis, often idiopathic but sometimes associated with diabetes mellitus, may involve portions of either the brachial or lumbosacral plexus. Brachial plexus lesions are a long-recognized complication of childbirth. Extreme lateral flexion of the head during delivery produces tension on the upper trunk and C5/C6 roots. If these forces damage the nerves, the child is left with Erb's palsy. The clinical picture includes adduction and medial rotation of the shoulder, extension and supination of the elbow, flexion of the wrist and extension of the fingers, often labeled as the waiter's tip posture. Less commonly, middle- and pan-plexus injuries also occur. Recognition of childhood plexus injuries is important because proper rehabilitation may prevent contractures. Another neuromuscular complication of childbirth is obstetrical lumbosacral plexopathy, which is discussed in Chapter 35. Although the clinical presentation varies, most patients develop footdrop and numbness of the anterolateral lower leg and dorsal foot. Sports, motorcycle, and industrial accidents cause traction injury to the brachial plexus. If the arm is located at the side of the patient at the time of impact or is distracted away from the torso, the upper roots and plexus are preferentially injured. If the arm is elevated above the head, the lower trunks and roots are most vulnerable. Compression injury of the brachial or lumbosacral plexus may occur during surgery or coma or from mass lesions such as a hematoma or tumor. Immune brachial plexopathy (brachial plexus neuritis, neuralgic amyotrophy, Parsonage–Turner syndrome) is an acute monophasic neuropathy that presents with severe shoulder pain accompanied by muscle weakness and atrophy. Both sporadic and hereditary forms exist. Proximal muscle groups are more commonly affected than distal ones; involvement may be either unilateral or bilateral. Sensory loss is mild. Ipsilateral
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diaphragmatic weakness sometimes occurs from phrenic nerve involvement. Nerve biopsy 44 specimens have revealed perineurial thickening and perivascular inflammatory infiltrates. Corticosteroids, IVIg, and plasmapheresis have been used in treatment with anecdotally reported success, but controlled studies are needed. Aggressive treatment to control pain is important. The prognosis is excellent, with4560 percent of patients recovering completely within 1 year and 80 percent within a few years. Nondiabetic lumbosacral radiculoplexus neuropathy refers to a similar disorder that affects the lower extremities. As with immune brachial plexus neuropathy, pain is often the initial symptom. It may occur in the back, buttock, thigh, or leg. Proximal weakness is more common than distal weakness. In time, however, the weakness often becomes more diffuse in the limb and bilateral involvement is common. Clinically, sensory deficits (despite the pain) tend to be relatively mild. Nerve biopsies have shown evidence of ischemic injury and 46 epineurial perivascular inflammatory collections. Some improvement in strength occurs with time but long-standing motor deficits are common. Case reports suggest a potential benefit of corticosteroids or IVIg therapy, but the results of controlled trials are pending. Diabetic lumbosacral radiculoplexopathy (proximal diabetic neuropathy; diabetic amyotrophy) is discussed in Chapter 21. Breast and lung cancers are the two most common secondary neoplasms to infiltrate the brachial plexus. Gastrointestinal and genitourinary cancers, melanomas, and lymphomas may also spread by metastasis to the brachial plexus. Colorectal cancer is the most common neoplasm to infiltrate the lumbosacral plexus, but uterine, prostate, and ovarian cancer may 47 also do so; other neoplasms may spread to the lumbosacral plexus metastatically. Radiation therapy that includes the plexus in the field (as for breast cancer) may produce delayed weakness, dysesthesias, and numbness in the affected limb (Chapter 28). Irradiation causes48marked fibrosis of the nerve fibers, loss of myelin, and destruction of the vascular treatment and onset of symptoms ranges from a supply. The period between the radiation 49 few weeks to more than 30 years. Paresthesias in the median-innervated digits is a common initial symptom. Subsequently, weakness of the intrinsic hand muscles develops. Prominent limb pain and a Horner's syndrome suggests tumor involvement rather than radiation-induced injury, whereas the presence of fasciculation potentials and myokymia on 48 needle EMG suggests radiation injury. Distinction of these two disorders is aided by computed tomography (CT) and MRI. Patients with radiation-induced lumbosacral plexopathy have generally been treated for lymphoreticular, testicular, uterine, or ovarian cancer. Patients usually present with slowly progressive distal weakness; numbness or paresthesia is less common.50Mild pain occurs in 50 percent of patients. The CSF protein concentration may be elevated. As with radiation-induced brachial plexopathy, the condition may stabilize, but patients are often disabled. Finally, a lower motor neuron syndrome affecting the legs may also occur following irradiation 51,52 of the distal spinal cord and cauda equina. Patients generally received more than 40 Gy. Fasciculations and wasting of the leg muscles occur with relatively intact sensation. Nerve conduction studies usually reveal intact sensory responses, which imply that the injury is proximal to the dorsal root ganglion. Needle EMG of affected muscles shows signs of chronic denervation. Examination of the cauda equina shows a vasculopathy of the proximal nerve roots. Although the condition eventually stabilizes, patients are usually left with significant disabilities. Neurogenic thoracic outlet syndrome occurs when an anomalous fibrous band between the first thoracic rib and a cervical rib or elongated transverse process on the seventh vertebral body exerts pressure on the first thoracic nerve root or the lower trunk of the brachial plexus. What results is a predominantly motor syndrome with wasting and atrophy of the hand muscles, particularly of the thenar eminence, and intermittent pain and paresthesias of the inner arm and medial hand, including the fourth and fifth digits. Electrodiagnostic studies confirm the diagnosis. A chest x-ray may show the cervical rib or an elongated transverse process; the fibrous band shows up as a radiolucency. Treatment is surgical. PERIPHERAL NEUROPATHY The distribution of findings may suggest either a focal, multifocal, or generalized/symmetric pattern of nerve involvement. For the multifocal and generalized neuropathies in particular, identifying the relative involvement of motor and sensory fibers (Table 60-3, Table 60-4, and Table 60-5) narrows the differential diagnosis. Sensory neuropathies may be further subdivided according to whether predominantly large- or small-diameter fibers are affected (Table 60-4 and Table 60-5). Knowing whether the pathogenesis is predominantly axonal or
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demyelinating (Table 60-6 and Table 60-7) also refines the diagnostic search. Generally, patients with axonal neuropathies present with predominantly sensory signs and symptoms, whereas patients with demyelinating neuropathies have more significant weakness. Given the exceptions to this rule, however, nerve conduction studies must be performed to distinguish between these two possibilities. Finally, the time course of symptom onset has important implications for pathogenesis (Table 60-8). Discussion here focuses on those peripheral neuropathies associated with systemic diseases. Click here to view this table.... Click here to view this table.... Click here to view this table.... Click here to view this table.... Click here to view this table.... Click here to view this table....
Focal Neuropathy A focal neuropathy may occur wherever ischemia, trauma, compression, injection, infection, or tumor infiltration affects the nerve. Focal ischemic neuropathies are uncommon following brief acute arterial occlusion. An exception to this rule is acute ischemic peroneal neuropathy after thrombosis or embolism of the superficial femoral or popliteal arteries. The patient presents with a cool, pulseless distal lower extremity, sudden pain in the calf or foot, and footdrop. The nerve's susceptibility is related to the common occurrence of a single arterial feeder at the lateral aspect of the knee. Once circulation is restored, recovery may take weeks but is often good. Arterial insufficiency may lead to chronic ischemic neuropathies. Brachial artery to cephalic vein shunts placed for hemodialysis have been associated with median, ulnar, and radial neuropathies. A vascular steal syndrome seems to be a major mechanism of nerve injury, but direct compression of nerves and distal limb edema may also play a role. Benign tumors of nerves (schwannomas and meningiomas) usually present as sporadic, solitary tumors with or without neurological signs or symptoms. In a patient with multiple such lesions, however, neurofibromatosis should be suspected. An enlarging lesion or the development or progression of neurological signs should raise suspicion of malignant transformation. The common entrapment neuropathies—median neuropathy at the wrist, ulnar neuropathy at the elbow, and peroneal neuropathy at the fibular head—share anatomical factors that increase the susceptibility of the nerve to injury; these factors include superficial nerve location, adjacent bony structures, and enclosure by nonelastic connective tissues. External compression of nerves generally causes focal demyelination before significant axonal loss. Various medical conditions contribute to carpal tunnel syndrome (CTS; median nerve entrapment at the wrist), the most common compressive neuropathy. Diabetes mellitus is a major risk factor, with a recent study showing a morbidity ratio of 2.5 for diabetic men and 2.3 53 for diabetic women. The pathogenesis of CTS in this context may relate to chronic endoneurial hypoxia and changes in the connective tissues of the nerve sheath or transverse 54 carpal ligament. Hypothyroidism and acromegaly are also associated with CTS. In acromegaly, edema of synovial tissues may cause nerve compression. In pregnancy (Chapter 35), edema and weight gain contribute to increased pressure in the carpal tunnel. In one prospective study of pregnant women near delivery, 62 percent had clinical evidence of 55 CTS and 43 percent had abnormal nerve conduction studies. Rheumatoid arthritis is the most important inflammatory condition associated with CTS. Rheumatoid nodules, wrist deformity, and tenosynovitis are all contributory factors. When CTS accompanies a distal symmetric polyneuropathy in a nondiabetic patient, amyloidosis should be considered. If such patients undergo carpal tunnel surgery, fat and ligament tissue should be sent to pathology for analysis of possible amyloid deposition. Other causes of CTS include ganglion cysts, lipomas, nonspecific tenosynovitis, gout, sarcoidosis, multiple myeloma, temporal arteritis, polymyalgia, and hereditary neuropathy with liability to pressure palsies. Repetitive hand motions in certain occupations may also contribute to CTS. Conservative management of CTS includes the nocturnal use of wrist splints to prevent wrist flexion or extension (which reduces pressure within the carpal tunnel) or oral or injected corticosteroids. For severe neuropathies or for those in whom conservative measures have failed, surgical release of the carpal tunnel is effective.
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The evaluation and management of the other common entrapment neuropathies are discussed in standard neurological texts.
Multifocal Neuropathy Most multifocal neuropathies are immune mediated or infectious (Table 60-9). The immune-mediated forms may be idiopathic, triggered by an infection or toxin/medication, or associated with diabetes mellitus. Themost severe presentation is the acute and catastrophic appearance of multiple mononeuropathies (mononeuritis multiplex) caused by systemic vasculitis. Click here to view this table.... Vasculitic Neuropathy Vasculitic neuropathy is an ischemic neuropathy caused by obliteration of the nerve's nutrient blood vessels by inflammatory infiltrates. It usually presents as a subacutely evolving, asymmetric, painful sensory or sensorimotor neuropathy. Often, the deficits are in the distribution of multiple individual nerves (mononeuropathy multiplex). Nerves in the lower extremities are often affected first, but any nerve may be affected. Over time in untreated patients, as additional nerves become injured, motor and sensory deficits may become confluent, thereby mimicking a polyneuropathy. Sometimes, as in the case of cryoglobulinemic vasculitic neuropathy, the initial presentation of a vasculitic neuropathy is symmetric. Neuropathy may occur with primary vasculitis, in which the underlying cause is not known, or secondary vasculitis, in which the causative factor is identified. The primary systemic vasculitides are classified according to size of the damaged blood vessels, organs involved, and the suspected immunopathological mechanisms at play. Polyarteritis nodosa, microscopic polyangiitis, Wegener's granulomatosis, and Churg–Strauss syndrome are56,57 the primary systemic vasculitides most commonly associated with vasculitic neuropathies. The most common vasculitic neuropathy is an idiopathic form similar to polyarteritis nodosa and microscopic polyangiitis but without overt systemic involvement called nonsystemic 58,59 Because these patients do not have a defined connective tissue or vasculitic neuropathy. other systemic disease, the diagnosis is established by nerve biopsy. Most of these patients have an elevated erythrocyte sedimentation rate, and a minority are anemic with peripheral leukocytosis and thrombocytosis. Secondary vasculitis may be associated with connective tissue diseases, infections, neoplasms, medications, or toxins. A number of different immune mechanisms are implicated in pathogenesis. Immune complex formation and deposition occur with hypersensitivity vasculitis associated with infections, drugs, and malignancies as well as hepatitis B–and C–associated vasculitic neuropathy. Antineutrophilic cytoplasmic antibodies play significant roles in the pathogenesis of Wegener's granulomatosis, microscopic polyangiitis, and Churg–Strauss syndrome. Finally, pathogenic T-cell responses and granuloma formation play important roles in the pathogenesis of Wegener's granulomatosis and Churg–Strauss syndrome. Given the broad differential diagnosis of vasculitic neuropathy, the laboratory evaluation is extensive and often includes a complete blood count and erythrocyte sedimentation rate; examination for antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies, complement levels, and hepatitis B and C serologies; urinalysis with microscopic analysis; and renal and hepatic function tests. The work-up may also include an HIV antibody test, chest x-ray, and Lyme antibodies. An electrodiagnostic study is essential to document the multifocal nature of the axon loss. A nerve biopsy is often necessary for diagnosis. For the systemic vasculitides, the diagnostic yield is increased if biopsy is performed on both the 60,61 nerve and muscle. The systemic vasculitides are often fatal if untreated, so aggressive immunosuppression with combined corticosteroids and cyclophosphamide is usually indicated. When vasculitis is caused by drugs, removal of the offending agent often leads to benefit. For vasculitis associated with chronic viral infections, treatment often includes antiviral therapy or removal of viral antigens by plasmapheresis. Hepatitis B
Approximately one third of cases of polyarteritis nodosa are associated with hepatitis B 62 infection. It usually occurs in the first year following infection. These patients often have mild
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hepatitis. More than6280 percent of patients with hepatitis B–associated polyarteritis nodosa have a neuropathy. Although the clinical features may be indistinguishable from classic polyarteritis nodosa, the disease manifestations of hepatitis B–associated vasculitis may be 63 more severe. Immune complex deposition is thought to be the main immunopathological mechanism. Treatment of hepatitis B–related vasculitic neuropathy is specialized. Although immunosuppressive therapies lead to increased viral replication, two retrospective studies 64,65 Following the corticosteroid suggest that a short course of corticosteroids is beneficial. therapy, either IFN-α or lamivudine may be used for at least 6 months. Plasma exchanges are usually given concurrently over a 10-week period to clear the immune complexes. Relapses are uncommon. Hepatitis C
A minority of patients with hepatitis C virus (HCV) infection develop a peripheral neuropathy. The neuropathy is sometimes associated with cryoglobulinemia. As cryoglobulinemia can cause a vasculitic neuropathy with more severe neurological deficits, it is the focus of the following discussion. HCV is the most common cause of essential mixed cryoglobulinemia, which occurs in about one third66,67 of patients with HCV; a cryoglobulinemic neuropathy only occurs in 2 to 3 percent of Other manifestations of cryoglobulinemia include edema, palpable purpura, and patients. membranoproliferative glomerulonephritis. The cryoglobulinemia results from an oligoclonal 68 expansion of B lymphocytes. How HCV produces this expansion is not fully understood. Cyroglobulinemia may cause vasculitic neuropathy by vaso-occlusion from immunoglobulin 69 precipitation or immune complex deposition with complement-mediated inflammation. T 70 cell–mediated injury to epineurial blood vessels may also occur. Most cryoglobulinemic neuropathies are distal, axonal, and symmetric with predominantly sensory deficits. Mononeuropathies, either single or multiple, may also occur. Rarely, patients with cryoglobulinemia may develop demyelinating polyneuropathies associated with IgM 71 binding to myelin. The best treatment strategy for HCV-associated cryoglobulinemic neuropathy is not known, but mild neuropathies are often treated with pegylated IFN-α2b plus ribavirin. The INF-α may 72 occasionally exacerbate a vasculitic neuropathy or produce a new multifocal neuropathy. For severe neuropathies refractory to IFN-α, immunosuppression with corticosteroids combined with cyclophosphamide or plasmapheresis should be considered. Another treatment option for patients refractory to IFN-α is administration of monoclonal anti-CD20 73 antibodies (rituximab). Other Infections
Any organism can produce a vasculitis if it elicits either circulating or in situ immune 74 the only two infections known to infect endothelial complexes. CMV and herpes zoster are 75,76 cells of peripheral nerve blood vessels. 77
HIV infection (Chapter 45) may rarely cause a systemic vasculitis. It usually occurs in the early symptomatic stage of the disease. Multiple patterns of nerve involvement have been described, including mononeuropathy, mononeuritis multiplex, cranial neuropathies, distal symmetric polyneuropathy, and asymmetric polyneuropathy. The possibility of CMV vasculitis must be excluded in this patient population. In CMV-negative cases, nerve biopsy samples show a necrotizing vasculitis that may involve the endoneurial vessels in addition to the epineurial vessels. Other causes of multifocal neuropathies in HIV patients include 78 neurolymphomatosis and diffuse infiltrative lymphocytosis syndrome. Idiopathic Immune-Mediated Multifocal Neuropathy Immune-mediated multifocal neuropathies exist in which the target of the immunological attack is the myelin or axon rather than the blood vessels. These entities include multifocal motor neuropathy (MMN), Lewis–Sumner syndrome (or multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]), sensory perineuritis, and migratory sensory neuropathy of Wartenberg. In some cases, there is overlap between these neuropathies and Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Because GBS and CIDP are usually associated with generalized weakness, however, they are discussed separately in a later section.
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Multifocal motor neuropathy is important for the generalist to recognize because it can 79 superficially mimic motor neuron disease, and attention here is focused on this disorder. Patients typically present with painless wasting and weakness of the distal upper-extremity 80 muscle groups, although any muscle group may be affected, even the tongue. Careful examination reveals that weakness occurs in a peripheral nerve rather than segmental pattern. Upper motor neuron signs are not present. Fasciculations may be seen in weak muscles. Patients may complain of mild sensory symptoms such as numbness or paresthesia, but the sensory examination is typically normal. Reflexes tend to be depressed only in regions of weakness. Proximal limb muscles and cranial nerves are usually spared. Nerve conduction studies usually reveal conduction block in motor nerves along with normal 81,82 Many patients have elevated titers to GM1 sensory nerve conduction responses. 83 ganglioside. IVIg is the most effective therapy for multifocal motor neuropathy, with approximately 80 percent of patients responding to it. Its efficacy has been confirmed by four randomized, 84–87 Other agents that may improve or stabilize the disease include placebo-controlled trials. 88,89 90,91 azathioprine, rituximab, and interferon-beta. Although a few cyclophosphamide, patients have been reported to92respond to prednisone, it is usually ineffective or may cause an exacerbation of weakness. Plasmapheresis is usually not effective. Sarcoidosis Neurosarcoidosis is discussed in Chapter 51, to which the reader is referred. Infectious Neuropathy Lyme disease and leprosy are important causes of multifocal neuropathy and are discussed separately in Chapters 41 and 43.
Polyneuropathy The medical disorders discussed in this section cause generalized and symmetric neuropathies. Often, the sensory and motor deficits are length dependent such that the deficits are most severe in the feet. With long-term disease, a classic stocking-glove neuropathy occurs with or without autonomic nervous system involvement. In demyelinating polyneuropathies, however, the weakness may involve proximal and distal muscle groups more equally. Endocrine Neuropathy Diabetic Polyneuropathy
As discussed in Chapter 21, diabetes mellitus may be associated with both generalized and focal neuropathies. The focal neuropathies include lumbosacral radiculoplexus neuropathy (diabetic amyotrophy, proximal diabetic neuropathy), thoracolumbar neuropathy, entrapment neuropathies, and cranial neuropathies. The generalized neuropathies include distal symmetric sensorimotor polyneuropathy, acute painful neuropathy, autonomic neuropathy, and acute motor neuropathy. Distal symmetric sensorimotor is the most common neuropathy 93 associated with diabetes mellitus with approximately 50 percent of diabetics developing it. Risk factors for polyneuropathy include degree of hyperglycemia, duration of diabetes, age, hypertension, and smoking. There is mounting evidence that impaired glucose tolerance, as defined by a serum glucose level of 140 to 199 mg/dl94,95 on a 2-hour oral glucose tolerance test, also may be associated with a distal polyneuropathy. Early symptoms include distal numbness. Burning dysesthesias and allodynia in the feet or toes are common. Although discomfort is present throughout the day, patients often report that it peaks at night or with rest. Cramps are common in the calves and foot muscles. Footdrop is uncommon in mild diabetic polyneuropathy. Treatment consists of tight glycemic96 control, which has been shown to help prevent and slow the progression of polyneuropathy. Many therapies aimed at preventing or reversing diabetic polyneuropathy have been investigated. Although preliminary studies of aldose reductase inhibitors and nerve97,98 growth Some factor were promising, large-scale, controlled trials produced disappointing results. studies have suggested a benefit with γ-linolenic acid, but the results of a large controlled trial have not been published. Controlled trials of intravenous preparations of the antioxidant 99,100 α-lipoic acid have demonstrated its benefit on neuropathy signs and pain. Studies reporting on the efficacy of oral formulations of α-lipoic acid have not yet been published.
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Other Neuropathies
Hypothyroidism is a common cause of median neuropathy at the wrist (CTS). Myxedematous tissue beneath the flexor retinaculum is thought to cause median nerve compression. Hypothyroidism may also cause a polyneuropathy that presents with distal dysesthesias and stocking-and-glove sensory loss. Reflexes may be diminished with a delayed relaxation phase. Electrodiagnostic and pathological studies have shown mixed axonal and demyelinating features. Considerable improvement may occur in both CTS and hypothyroid polyneuropathy following replacement therapy. Acromegaly may 101 cause entrapment neuropathies due to connective tissue hyperplasia and bony overgrowth. A sensorimotor polyneuropathy may also occur associated with hypertrophic, sometimes palpable, nerves. Infectious Neuropathy HIV Neuropathy
As discussed in Chapter 45, HIV infection is associated with both acute and chronic, multifocal or generalized polyneuropathies. These include mononeuritis multiplex from vasculitic neuropathy, GBS, CIDP, and distal sensory polyneuropathy. Of all these neuropathies, distal sensory polyneuropathy is by far the most common neuropathy associated with HIV, with at least 50 percent of patients with advanced HIV infection having 102 + it. In the era before highly active antiretroviral therapy (HAART), reduced CD4 lymphocyte cell counts and increased HIV viral loads increased the risk and severity of HIV 103,104 Dideoxynucleoside antiretrovrials also increase the risk of neuropathy, polyneuropathy. possibly because of toxicity to mitochondria. A polyneuropathy (usually symmetric) may also 105 occur as part of the diffuse infiltrative lymphomatosis syndrome. Patients typically present with burning dysesthesia in feet and ankles, often with prominent allodynia. On examination, small-fiber sensory modalities are affected predominantly. Weakness related to the neuropathy is uncommon, even in advanced cases. There is no specific treatment for the underlying pathology, although a number of treatments for neuropathic pain, including gabapentin, amitriptyline, tramadol, and lamotrigine, are effective. Other Neuropathies
HCV infection and leprosy may cause generalized and symmetric peripheral nerve involvement, as is discussed earlier in this chapter and elsewhere in this volume. Immune-Mediated Neuropathy Guillain–Barré Syndrome
Once used interchangeably with the label acute inflammatory demyelinating polyneuropathy, GBS now encompasses any acute, idiopathic inflammatory polyneuropathy producing progressive muscle weakness and areflexia, regardless of whether the underlying neuropathy is demyelinating or axonal. In the majority of cases, a respiratory or gastrointestinal illness precedes the onset of neurological symptoms by 1 to 3 weeks. Often paresthesia in the distal limbs heralds the onset of the106 neuropathy. A patient may also describe pain that is similar to sciatica, myalgia, or a cramp. Rapidly progressive, symmetric weakness soon follows. Typically the weakness starts in the legs, but it may begin in the arms or face. Symptoms may progress acutely over just a few days or subacutely over as long as 4 weeks. The degree of weakness at the nadir of the progressive phase is highly variable, from mild weakness to quadriplegia with neurogenic respiratory failure. Maximum deficits occur within 1 month, followed by a plateau lasting for days to weeks and rarely months. Gradual improvement occurs after the plateau phase. Prognosis is good, with a 5 percent mortality rate. Permanent disabilities remain in 5 to 10 percent of patients, mild deficits in 65 to 75 percent, and no deficit in 15 percent. The annual incidence is 1 to 2 cases per 100,000 population. The initial assessment of GBS patients should include measurements of respiratory capacity and inspiratory force. Patients with a vital capacity of less than 20 ml/kg or a maximum 107 inspiratory pressure less than 30 cmH2O are likely to require mechanical ventilation. These measurements are much more sensitive than arterial blood gas analysis for predicting incipient neuromuscular respiratory failure. An admission to the intensive care unit (ICU) is
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also warranted for any patient with rapidly progressive disease, significant bulbar or facial weakness, or autonomic dysfunction. On the neurological examination, motor findings typically outweigh sensory deficits. One third of patients may develop facial diplegia. Stretch reflexes are hypoactive or absent. Blood tests and a lumbar puncture should be undertaken to evaluate for other causes of acute polyneuropathy or polyradiculopathy. In 50 percent of patients, an initial CSF sample will reveal an elevated protein concentration; with subsequent analysis, 90 percent of samples show increased protein, with values ranging from 55 to 250 mg/dl. The CSF is 3 usually acellular with normal pressure. If more than 10 white cells/mm are present, alternative diagnoses should be considered. Nerve conduction studies almost always show evidence of a polyneuropathy: 69 percent of patients demonstrate a demyelinating polyneuropathy, 3 percent an axonal degeneration, 3 percent inexcitable nerves, 2 percent normal findings,108 and 23 percent equivocal findings consistent with either a demyelinating or axonal process. In Western societies, GBS is usually a demyelinating polyneuropathy or polyradiculopathy. A number of infections may trigger GBS, including CMV, Epstein–Barr virus, herpesvirus, Campylobacter jejuni, Mycoplasma pneumoniae, and HIV. Rabies and swine vaccinations, recent surgery, and pregnancy have also been implicated as triggers for GBS. Both humoral immune responses and T-cell activation are thought to play roles in the pathogenesis. Pathologically, there is the early appearance of lymphocytes surrounding nerve vessels. This is followed by demyelination, which may proceed in at least two ways. First, in 109 normal-appearing nerves, macrophage processes may strip myelin from axons. Another mechanism of demyelination involves vesicular myelin breakdown (mediated by immunoglobulin deposition and complement activation products) followed by removal of 110 debris by macrophages. Secondary “bystander” axonal degeneration may also occur. In northern China, the most common GBS sub-type is an acute motor axonal neuropathy (AMAN) associated with C. jejuni infection. The association of C. jejuni infection and GBS is also discussed in Chapter 15. These patients often have antibodies to gangliosides, including GM1, GD1a, and GD1b. The strains of C. jejuni associated with AMAN have GM1-like 111 epitopes in their lipopolysaccharide membranes that contain a Gal(b1–3)GalNac moiety. Terminal motor axon branches and the internode axonolemma also contain a high concentration of this moiety. Because of molecular mimicry between these bacterial and axon antigens, those portions of the motor axons appear to be the initial targets in the autoimmune attack. 112,113
The most common, the Miller Fisher There are several other variants of GBS. syndrome, accounts for about 5 percent of all cases of GBS. Patients develop the triad of ophthalmoplegia, ataxia, and areflexia, with varying degrees of limb weakness. Almost all 114 cases of Miller Fisher syndrome are associated with IgG antibodies to GQ1b. Other variants include weakness without paresthesias or sensory loss, pharyngeal-cervical-brachial weakness, paraparesis, facial paresis with distal paresthesias, pure ataxia, acute pandysautonomia, and acute motor-sensory axonal neuropathy (AMSAN). All variants have in common absent or diminished stretch reflexes, elevated CSF protein concentrations, and electrodiagnostic abnormalities. For severe cases, treatment includes support in the ICU and immune-modulatory therapy. Since 1984, four clinical trials have unequivocally demonstrated that plasmapheresis is 115–118 In addition, two large effective in improving short- and long-term neurological function. randomized clinical trials comparing IVIg and plasmapheresis demonstrated that they are 119,120 The cost of plasmapheresis and IVIg are similar, and the relapse equivalent in efficacy. rate for IVIg is no different from that for plasmapheresis. Compared with plasmapheresis, IVIg is associated with fewer complications (e.g., hemodynamic fluctuations), is easier to administer, and is usually available in community hospitals where plasmapheresis may not be accessible. A combination of 120 plasmapheresis followed immediately by IVIg does not lead to significantly better outcomes. 121,122
Corticosteroids are not beneficial. been sufficiently tested.
Other immunosuppressant medications have not
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
CIDP is a chronic neuropathy characterized by symmetric weakness, sensory loss, and 123–125 Weakness usually affects both proximal and distal muscle depressed stretch reflexes. groups. 126 The cranial nerves are rarely involved, but cranial neuropathies may be a presenting feature. A small percentage of patients have papilledema. The weakness must progresses
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beyond 2 months in order to meet an arbitrary criterion for the diagnosis of CIDP. The clinical course may be relapsing, progressive, or stepwise. There are a number of clinical variants of CIDP manifesting with either pure motor or sensory involvement or with evidence of only distal demyelination. CIDP may occur with certain medical disorders, including monoclonal gammopathies, inflammatory bowel disease, thyroid disease, HIV infection, diabetes mellitus, Charcot–Marie–Tooth neuropathies, and CNS demyelination. The electrodiagnostic and pathological features are similar to those of GBS. Lumbar puncture typically reveals an acellular CSF with an elevated protein level, but other laboratory tests are unremarkable. Nerve conduction studies confirm impaired nerve conduction velocities or the presence of conduction block caused by demyelination. Nerve biopsy is occasionally performed, and the findings include endoneurial perivascular inflammation with demyelination, remyelination (onion bulb formations), and secondary axonal degeneration. Randomized, controlled trials have demonstrated the benefit of corticosteroids, 127–131 A crossover study demonstrated that plasmapheresis and plasmapheresis, and IVIg. 132 The efficacy of IVIg for CIDP has also 134 been confirmed by IVIg are about equally effective. 133 a recent Cochrane review. Azathioprine, cyclosporine, mycophenolate, and cyclophosphamide are reported to be beneficial but have not been tested in controlled clinical trials. Overall, most patients respond to treatment, but relapses are common. Only a minority 135 of patients achieve a complete remission. Aggressive and early treatment is warranted because unchecked disease may eventually lead to axon loss and muscle atrophy for which there is no specific treatment. Polyneuropathy Associated With Monoclonal Gammopathy of Undetermined Significance
A monoclonal gammopathy of undetermined significance (MGUS) may present as a symmetric sensorimotor polyneuropathy with variable proportions of axonal or myelin injury. The prevalence of MGUS is 1 to 3 percent in people older than 50 years. Only a minority of those with MGUS ever develop a clinically significant neuropathy. In one series of MGUS patients, 2 of13634 patients with IgG, 2 of 14 with IgA, and 8 of 26 with IgM had evidence of a neuropathy. Other studies have suggested a stronger correlation between IgM MGUS and peripheral neuropathy. For example, Baldini and colleagues found a peripheral neuropathy in 137 14 of 31 IgM MGUS patients. Compared with neuropathy patients having IgA and IgG MGUS, patients with IgM MGUS have more sensory ataxia and more evidence of demyelination on electrodiagnostic studies. Specific antibodies can sometimes be found to myelin-specific proteins. For example, approximately 50 percent of patients with IgM 138 monoclonal gammopathies have antibodies to myelin-associated glycoprotein (MAG). The CSF is acellular but the protein concentration is often elevated. Generally, neuropathies associated with MGUS respond less well to immunosuppressive or immunomodulatory therapy than idiopathic CIDP. IgG and IgA MGUS neuropathies respond better than IgM MGUS neuropathies to plasmapheresis. Improvement has also been 139 documented with rituximab, fludarabine, and alkylating agents. Some patients have responded to IFN-α and IVIg. Critical Illness Polyneuropathy More than 50 percent of critically ill patients with sepsis and multiorgan disease fail to wean from ventilatory support. Examination in moderately advanced cases reveals flaccid, symmetric weakness, depressed or absent tendon reflexes, and impaired distal sensation. Other causes of weakness in the ICU setting include prolonged neuromuscular blockade from drugs, critical illness myopathy, and cervical myelopathy. CSF protein level is normal or only mildly elevated. Electrodiagnostic studies confirm the presence of a sensorimotor polyneuropathy. Treatment is supportive. The prognosis is variable, depending on the degree of axon loss. A more complete account of this disorder is provided in Chapter 52. Uremic Neuropathy Uremic polyneuropathy presents as restless legs, weakness, cramps, and distal paresthesias and dysesthesias in patients with end-stage renal disease (serum creatinine levels of 5 mg/dl or higher). The prevalence among patients undergoing hemodialysis treatment is 50 to 60 percent. Electrodiagnostic studies typically show evidence of distal axon loss with some evidence of demyelination. Usually the neuropathy is slowly progressive, but rapidly 141 progressive uremic neuropathy with prominent demyelinating features has been described. Renal transplantation is the best treatment for uremic polyneuropathy. Further details are provided in Chapter 18.
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Neoplastic and Paraneoplastic Neuropathies Monoclonal Gammopathy
Multiple myeloma, Waldenström's macroglobulinemia, osteosclerotic myeloma (POEMS syndrome of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes), lymphoma, and leukemia are associated with a monoclonal gammopathy. Generally, symptoms and signs are similar to those of polyneuropathy related to an MGUS. Frequently, these neuropathies are associated with significant distal weakness and some demyelinating 142 features on nerve conduction studies. Amyloidosis
Amyloidosis causes a slowly progressive distal sensorimotor polyneuropathy. Distal lower-extremity pain and paresthesias are common presenting symptoms. On examination, there is usually greater impairment of small-than large-fiber sensory function. Autonomic neuropathy frequently occurs, leading to orthostatic lightheadedness, diarrhea, bladder dysfunction, and impotence. CTS is also common in this patient population. In primary amyloidosis, the amyloid fibrils consist of portions of monoclonal immunoglobulin light chains (Bence Jones protein). In almost all these patients, a monoclonal protein may be detected in either the serum or urine. Diagnosis depends on identifying amyloid deposition in tissues. An abdominal fat aspirate is probably the best initial step for establishing the 143 diagnosis; the diagnostic yield is more than 70 percent. If this is negative, a rectal or nerve biopsy may be considered. By suppressing monoclonal light chain production, alkylating agents extend survival in patients with primary amyloidosis. Autologous peripheral blood stem-cell transplantation is also available, but high morbidity and mortality are associated with this procedure in primary amyloidosis, probably because of multiple organ disease. In familial amyloidosis, the fibrils are usually composed of mutant transthyretin. Molecular genetic testing for transthyretin mutations is a more sensitive diagnostic test than analysis of tissues for amyloid deposition. Orthotopic liver transplantation is an effective treatment for familial amyloidosis. Paraneoplastic Neuropathy
Patients with anti-Hu (ANNA-1) antibodies usually present with a sensory neuropathy, but 144–146 about 25 percent of patients present with a subacute sensorimotor polyneuropathy. Rarely, the associated neuropathy is acute, thereby mimicking GBS. Most of these patients have small-cell lung carcinoma. Peripheral neuropathy occurs as a feature of anti-CV2-antibody-associated paraneoplastic 147 syndromes in about 50 percent of cases. Usually it is a mixed axonal and demyelinating sensorimotor polyneuropathy, but a pure sensory neuropathy may also occur. Rarely, sensorimotor neuropathies have been described with anti-Ri (ANNA-2) and anti-Yo (PCA-1) antibodies. Nutritional Neuropathy Vitamin B1 (Thiamine) Deficiency
Thiamine deficiency is uncommon in industrialized countries. Inadequate consumption may occur in the context of chronic alcohol abuse, total parenteral nutrition, prolonged vomiting, and bariatric surgery. Initial neuropathic symptoms (dry beriberi) include burning dysesthesias in the feet with mild sensory loss. Fatigue, muscle aches, and cramps in the lower extremities are common. Although progression is usually subacute to chronic, the neuropathy sometimes develops over a few days. In severe cases, there may be significant weakness of ankle dorsiflexion and finger and wrist extension in addition to stocking-glove sensory deficits. The recurrent laryngeal nerve may become involved, causing hoarseness. With thiamine supplementation, the neuropathy typically improves, albeit modestly. Further details are provided in Chapter 17. Vitamin B6 (Pyridoxine) Deficiency
Deficiency of vitamin B6 (pyridoxine) causes a distal axonal sensorimotor polyneuropathy. It is a known complication of taking the prescription medications isoniazid and hydralazine. If
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these medications are prescribed, oral supplementation of vitamin B6 at daily doses of 50 to 100 mg is advised. Vitamin B6 deficiency may also occur with chronic peritoneal dialysis or 148 alcoholism. Overdosing with vitamin B6 may cause an ataxic sensory neuronopathy associated with degeneration of dorsal root ganglia neurons. Stretch reflexes are hypoactive or globally absent. Most patients have numbness, paresthesia, and gait ataxia. Daily ingestion of as little 149 as 200 mg per day has been associated with the development of a peripheral neuropathy. Vitamin B12 (Cobalamin) Deficiency
The classic neurological presentation of vitamin B12 deficiency is combined degeneration of the dorsal and lateral columns of the spinal cord. Patients present with distal numbness, paresthesias, and, occasionally, dysesthesias. Compared with patients with idiopathic distal polyneuropathy, patients with vitamin B12 deficiency are more likely to have concomitant involvement of the upper and lower extremities, initial symptom onset in the hands, and a 150 sudden onset of symptoms. In more advanced cases, paraparesis occurs with extensor plantar responses. Malabsorption is the cause of most cases; it may be due to pernicious anemia, gastric or bowel surgery, or inflammatory bowel disease. Neurological manifestations 151 of vitamin B12 deficiency may occur without anemia or elevated mean corpuscular volume. Testing for elevations of serum homocysteine and methylmalonic acid is helpful when the vitamin B12 level is borderline low. With early treatment, the paresthesias may improve, but loss of large-fiber sensory axons is often permanent. Traditionally, vitamin B12 is supplemented with weekly to monthly intramuscular injections. Because individuals with pernicious anemia still absorb small amounts of vitamin B12, oral supplementation at a dose 152 of 2,000 mg per day may be equally effective. Vitamin E Deficiency
Vitamin E deficiency presents as a spinocerebellar ataxia with polyneuropathy. It usually results from lipid malabsorption; errors of vitamin E absorption or transport are less common 153 causes. Pathologically, there is degeneration of sensory axons, dorsal root ganglia, posterior columns, and spinocerebellar tracts. The diagnosis is made by measuring serum α-tocopherol levels. Proper supplementation depends on the underlying cause of the 154 deficiency. Copper Deficiency
Recently, copper deficiency has been associated with155–157 a myeloneuropathy characterized Patients have deficits of clinically by limb paresthesia and spastic paraparesis. large-fiber sensation, and many have extensor plantar responses. Often patients have microcytic anemia and neutropenia. Many of the patients described have had prior gastric surgery. Other cases have been linked to excessive zinc levels, which are known to cause copper deficiency. Following copper supplementation, some patients showed neurological improvement. Toxic Neuropathy Alcoholic Neuropathy
A distal axonal polyneuropathy is a common complication of chronic alcoholism, occurring in approximately 10 to 50 percent of patients, depending on the study and diagnostic 158,159 Superficial sensation is predominantly impaired and dysesthesias are common. criteria. Pathologically, there is predominantly small-fiber sensory loss. The pathophysiology is not fully understood but may involve direct toxicity of alcohol on peripheral nerves; vitamin deficiencies, including thiamine deficiency, are probable contributing factors. Treatment involves abstinence and vitamin supplementation. Prognosis is good for mild to moderate neuropathy after 3 to 5 years of abstinence. Further details are provided in Chapter 37. Neuropathies Associated With Heavy Metal Exposure
Severe lead poisoning produces a subacute, asymmetric, predominantly motor neuropathy that preferentially affects the wrist and finger extensors. Footdrop is another common manifestation. Prognosis for recovery is good if the lead exposure is eliminated. Abdominal pain, anemia, encephalopathy, and mild sensory deficits may also occur.
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Arsenic ingestion typically causes acute abdominal pain followed in 5 to 10 days by dysesthesias in the hands and feet. This is followed by an axonal polyneuropathy presenting as symmetric ascending weakness. The weakness may progress over several weeks. Recovery depends on the degree of axonal loss. Additional details about the neurological complications of heavy metal exposure are given in Chapter 39. Medications and Other Chemicals
Medications and chemicals generally cause a subacutely progressive symmetric, distal, and 160 length-dependent neuropathy, with sensory and motor axonal degeneration. A careful review of occupational exposures to toxins as well as exposures related to hobbies usually leads to candidate toxins. If the exposure is terminated, the neuropathy may continue to worsen for days to weeks (“coasting”) before its course is arrested. The toxins more frequently associated with peripheral neuropathies include acrylamide, allyl chloride, arsenic, carbamates, carbon disulfide, ethylene oxide, hexacarbons, lead, methylbromide, mercury, organophosphates, platinum, polychlorinated biphenyls, and thallium, as discussed in Chapter 39. Hereditary Neuropathy Hereditary neuropathy typically presents with slowly progressive distal weakness and numbness. Examination of the feet may reveal pes cavus and hammertoes, features reflecting long-standing atrophy and weakness of the intrinsic foot muscles. Only those hereditary neuropathies with prominent systemic manifestations are discussed here. Adrenomyeloneuropathy
Adrenomyeloneuropathy is a milder phenotype of adrenoleukodystrophy, the X-linked disease associated with degeneration of white matter and the adrenal cortex caused by mutations of the ABCD1 gene. Adrenomyeloneuropathy may present from childhood to middle age, usually in men, but occasionally in women. Patients present with a spastic paraparesis, sphincter abnormalities, and sexual dysfunction with or without symptomatic adrenal insufficiency or cognitive problems. The neuropathy is responsible for weakness and depressed ankle reflexes in affected individuals. Nerve conduction studies typically have 161,162 Testing for very-long-chain shown a mixed axonal and demyelinating polyneuropathy. fatty acids is the initial diagnostic test for both males and females. Bone marrow transplantation is an effective treatment for those with MRI evidence of brain involvement and minimal neuropsychological findings. Reduction of hexacosanoic acid by Lorenzo's oil is an investigational therapeutic approach for adrenoleukodystrophy. Other investigational 163–165 treatments include lovastatin and 4-phenylbutyrate. Fabry's Disease
Fabry's disease is an X-linked recessive disorder of the gene encoding α-galactosidase A (αGal A). Deficiency of this lysosomal enzyme causes widespread accumulation of globotriaosylceramide (GL-3) in cells throughout the body. Males present in adolescence with crises of severe pain in the extremities (acroparesthesias), vascular cutaneous lesions (angiokeratomas), hypohidrosis, corneal and lenticular opacities, and proteinuria. Renal function gradually deteriorates over time, leading to end-stage renal disease. In middle age, cardiovascular and cerebrovascular disease is another cause of significant morbidity and mortality. Patients have a distal small-fiber polyneuropathy with normal nerve conduction 166 The acroparesthesias may respond to phenytoin, carbamazepine, or velocities. 167 gabapentin. The diagnosis is usually made by demonstration of deficient α-Gal A activity in plasma, leukocytes, or cultured cells. Hemodialysis or renal transplantation is often necessary. A number of trials have shown that enzyme replacement therapy benefits the acroparesthesias and renal disease, and an expert panel has recommended that enzyme 168 replacement therapy be initiated as early as possible for all males with Fabry's disease. Porphyria
Inherited defects in the hepatic enzymes responsible for heme synthesis—the hepatic porphyrias—may be associated with acute episodes of CNS and peripheral nervous system dysfunction. These disorders include acute intermittent porphyria, hereditary coporphyria, and variegate porphyria. The erythropoietic porphyrias are associated with photosensitivity but not
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neurological disease. Between attacks, patients with hepatic porphyrias are normal. An attack is typically triggered by a drug that activates the hepatic cytochrome P-450 system, although hypoglycemia and hormonal factors may also contribute. The offending medications are thought to cause an attack by at least two mechanisms. First, the defect in the heme synthetic pathway may become a bottleneck in times of stress such that not enough heme is produced to satisfy the demands of oxygen transport, electron transport, and the cytochrome P-450 system. Cellular injury may result from adenosine triphosphate (ATP) deficiency by this mechanism. Second, the metabolites of heme synthesis may be directly neurotoxic. Clinically, patients present with acute, severe colicky abdominal pain accompanied by psychiatric disturbances. Often, medications used to treat pain and anxiety only exacerbate the attack by inducing certain hepatic enzymes. A painful, often asymmetric axonal neuropathy typically appears 2 to 3 days after the onset of abdominal pain. The weakness frequently begins in the upper extremities. Proximal or distal muscle groups may be involved. Reflexes are usually lost in proportion to weakness, unlike the early areflexia typically seen in GBS. Despite the pain, sensory deficits are usually mild and patchy. The combination of abdominal pain and neuropathy makes the clinical presentation similar to heavy metal intoxication. Screening for the hepatic porphyrias involves an analysis of the heme precursors in urine. The results of the urinalysis may be normal in asymptomatic carriers. Treatment includes stopping all medications that could potentially exacerbate the attack and infusing heme. Although recovery from the psychiatric disturbances is typically rapid, recovery of the peripheral nerves depends on the severity and extent of the axon loss; ultimate recovery of the peripheral nervous system is generally good. Refsum's Disease
Refsum's disease is an autosomal-recessive disorder characterized by anosmia, retinitis pigmentosa, deafness, ataxia, ichthyosis, and neuropathy. Symptoms may begin at any age. More than 90 percent of 169 cases are associated with mutations of the phytanoyl–coenzyme A (CoA) hydroxylase gene ; less than 10 percent are associated with mutations of the PEX7 gene. The consequence of these mutations is a build-up of phytanic acid in various tissues. The presence of high levels of serum phytanic acid (>200 mmol/L) establishes the diagnosis. Phytanic acid deposition in Schwann cells and the endoneurial space leads to a distal, symmetric sensorimotor neuropathy. Reduction of phytanic acid concentrations by dietary restriction, plasmapheresis, or lipid apheresis improves ichthyosis, sensory170neuropathy, and ataxia but may not affect the retinitis pigmentosa, anosmia, and deafness. Tangier Disease
Tangier disease is a rare autosomal-recessive disorder caused by mutations in both alleles of the adenosine triphosphate–binding cassette A1 gene (ABCA1). The protein deficiency causes decreased lipid removal from cells, widespread tissue accumulation of cholesteryl 171 esters, and the absence of plasma high-density lipoproteins (HDLs). Absent high-density lipoproteins with normal triglyceride level and the presence of enlarged orange tonsils differentiates Tangier disease from other lipoprotein disorders. Patients may develop corneal opacities or hypersplenism. Despite the high-density lipoprotein deficiency, atherosclerosis does not develop earlier than normal. Polyneuropathy may take one of three forms: asymmetric, relapsing-remitting sensorimotor mononeuropathies, usually associated with normal conduction velocities; symmetric, slowly progressive distal polyneuropathy; and a slowly progressive neuropathy affecting the face and upper limbs with distal hand weakness and facial diplegia and accompanied by dissociative sensory loss that may mimic the presentation of a syrinx. There is currently no specific treatment for Tangier disease. NEUROMUSCULAR JUNCTION DISORDERS In disorders of the neuromuscular junction (Table 60-10), patients present with weakness but not numbness. The congenital myasthenic syndromes are discussed elsewhere. Click here to view this table....
Botulism Botulism is an acute paralytic illness caused by a toxin produced by Clostridium bacteria. Botulism results from (1) ingestion of the preformed toxin with absorption through the intestines, accounting for the vast majority of cases of adult food-borne botulism; (2)
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ingestion of clostridial spores that colonize the intestines and produce the toxin, accounting for virtually all forms of infant botulism and occurring rarely in adults with altered intestinal flora; or (3)172–176 infection of a wound with local production and absorption of the toxin (“wound Improperly preserved food is the most common cause of food-borne botulism”). botulism. In California,wound botulism has become a recognized complication of intravenous 177 among patients treated with “black tar” heroin use. Botulism may occur in rare instances 178 botulinum toxin for dystonia or other movement disorders. Adult food-borne botulism is characterized by rapidly progressive cranial nerve palsies, 173,176 The most common symptoms and descending weakness, and autonomic dysfunction. signs include dysphagia, hypoactive gag reflex, dry mouth, diplopia, ptosis, extraocular movement abnormalities, fixed or dilated pupils, bulbar or limb weakness (especially proximally), constipation, nausea, and vomiting. Stretch reflexes are usually hypoactive or absent but may be normal. Mental status, sensation, and CSF are usually normal. There is usually no response to edrophonium chloride (Tensilon). Atypical symptoms, signs, and 173 ancillary test results are not uncommon and do not exclude the diagnosis. The symptoms and signs in infant botulism are similar to those in adults, with the additional features of 174 hypotonia, poor suck, and failure to thrive. Symptoms usually begin 18 to 36 hours after ingestion of the spores and progress rapidly over 2 to 4 days; recovery begins within a few 172 weeks. Eight toxin types have been described (A, B, C1, C2, D, E, F, and G), but human botulism is associated only with types A, B, and E and, rarely, with F and G. Clostridium botulinum produces the type A, B, and E toxins. Clostridium butyricum can also produce the type E toxin, and Clostridium barati produces the type F toxin. In all forms of botulism, the toxin initially becomes disseminated via the systemic circulation before uptake by the terminals of peripheral cholinergic axons. Once the toxin is inside the nerve terminals, essential proteins for acetylcholine release are cleaved. Subsequently, both muscarinic and nicotinic nerve terminals degenerate. Recovery from botulism, therefore, requires regrowth of axon terminals and restoration of the neuromuscular junction. The diagnosis of botulism is usually confirmed by the detection of the toxin in the serum, stool, or wound. In addition, the wound and stool specimens are cultured to identify the offending organism. Electrodiagnostic studies are also helpful. The presence of post-tetanic facilitation of the compound muscle action potential amplitude and increasing amplitude with 20- to 50-Hz repetitive nerve stimulation is often seen, although the increase is less dramatic than in Lambert–Eaton myasthenic syndrome (LEMS). Needle EMG reveals small, short-duration, polyphasic motor unit potentials in weak muscles and may show fibrillation potentials if the test is performed several days after symptom onset. Treatment of botulism consists of early antitoxin administration and supportive care. For adults, an equine trivalent antitoxin is effective against the type A, B, and E toxins. Recently, an effective human antitoxin (BabyBIG) has become available specifically for infants that has 179 a much lower risk of anaphylaxis than the equine product. In the United States, state health departments release the equine antitoxin to providers. In order to obtain BabyBIG, the physician must contact the Infant Botulism Treatment and Prevention Program by telephone or electronically. Wound débridement and antibiotics are indicated for wound botulism but should probably be delayed until the antitoxin is given. Prognosis is usually excellent with proper supportive and respiratory care. Recovery may take several weeks to months, depending on the degree of nerve end-terminal destruction.
Lambert–Eaton Myasthenic Syndrome LEMS is an autoimmune disorder in which antibodies directed against presynaptic voltage-gated calcium channels cause proximal limb and trunk weakness. Significant ptosis and bulbar weakness are uncommon. A striking clinical feature of LEMS is that strength often improves following brief exertion. Autonomic symptoms such as a dry mouth, constipation, and urinary retention are frequent. Tendon reflexes are usually hypoactive or absent but may improve after brief exercise. Approximately 50 to 60 percent of patients with LEMS have an associated small-cell lung 180 carcinoma. Approximately 3 percent of patients with small-cell lung cancer develop LEMS. Nonparaneoplastic LEMS also occurs, particularly in younger individuals. Marked post-tetanic facilitation of the compound muscle action potential establishes the diagnosis. Detecting the presence of calcium-channel antibodies also confirms the diagnosis. Survival in paraneoplastic LEMS depends on the treatment of the underlying neoplasm.
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Anticholinesterase drugs alone may modestly benefit strength. More effective is the orphan drug 3,4-diaminopyridine, which blocks potassium channels and thereby prolongs the activation of voltage-gated calcium channels. The increased concentrations of calcium in the axon terminals facilitate acetylcholine release presynaptically. The benefit of this drug was 181 demonstrated in a double-blind, placebo-controlled, crossover study. Because it is not an FDA-approved medication, it is available only at select centers in the United States. Other treatments that may be effective include plasmapheresis, IVIg, prednisone, and azathioprine.
Myasthenia Gravis Myasthenia gravis is an autoimmune disorder in which antibodies directed against nicotinic acetylcholine receptors cause fluctuating muscle weakness due to defective neuromuscular transmission. There are two clinical forms of myasthenia gravis: ocular and generalized. In the ocular form, weakness is restricted to the eyelids and extraocular muscles. Individuals with generalized myasthenia frequently also have weakness of those muscles plus variable weakness of bulbar, respiratory, or limb muscles. About 50 percent of patients present with ptosis or diplopia. Of these, about half will progress to generalized myasthenia gravis. A number of autoimmune diseases may be associated, including autoimmune thyroid disease and, more rarely, rheumatoid arthritis and systemic lupus erythematosus (SLE). Approximately 75 percent of myasthenics have thymic abnormalities. Thymic hyperplasia is the most common abnormality; about 15 percent of patients have a thymoma, usually a noninvasive cortical182thymoma. Approximately one third of patients with a thymoma develop myasthenia gravis. Because of the risks of thymoma, MRI or CT of the mediastinum is necessary for all newly diagnosed myasthenic patients. Thymectomy is generally recommended for all patients with thymomatous myasthenia gravis. In rare instances, myasthenia gravis has been associated with small-cell lung cancer and Hodgkin's disease. Rarely, a medication such as d-penicillamine can induce the onset of autoimmune myasthenia gravis, possibly through antigenic mimicry. The diagnosis is made by the history, examination, presence of acetylcholine receptor antibodies (present in up to 90% of cases of generalized disease), edrophonium chloride test, and electrophysiological studies. Approximately 35 to 50 percent of patients testing negative for acetylcholine183receptor antibodies have antibodies to the muscle-specific receptor tyrosine kinase (MuSK). It is rare for patients to have antibodies both to the acetylcholine receptor and to MuSK. Most patients with MuSK antibodies are women, and many have prominent 184,185 Standard electrodiagnostic tests for bulbar, neck, and respiratory weakness. myasthenia gravis may be normal or only mildly abnormal in patients with MuSK-seropositive myasthenia. Recently, however, Oh and colleagues have shown 186 that repetitive stimulation of the facial nerve may be a useful diagnostic test in these patients. Treatment of myasthenia gravis consists of anticholinesterases, immunomodulation, thymectomy, or some combination of these approaches. The first major prospective, multicenter trial on the benefit of thymectomy for seropositive, nonthymomatous generalized myasthenia gravis is planned 187 to enroll subjects in the near future.
Medications Causing Abnormalities of Neuromuscular Transmission A number of medications impair neuromuscular transmission. Corticosteroids, adrenocorticotropic hormone (ACTH), calcium-channel blockers, citrate, intravenous radiographic contrast medium, and intravenous gadolinium impair acetylcholine 188–192 Anticholinesterase drugs may cause depolarizing blockade. The tetracyclines, release. polymyxins, phenothiazines, fluoroquinolones, and trimethaphan cause weakness by blocking acetylcholine receptors. Aminoglycosides, lincosa-mides, procainamide, quinidine, lidocaine, β-adrenergic blockers, chloroquine, phenytoin, trimethadione, lithium, thyroid hormone, and 193,194 quinine have both pre- and postsynaptic effects.
Toxins A number of industrial and animal toxins affect neuromuscular transmission. Organophosphate and carbamate insecticides inactivate acetylcholinesterase at neuromuscular, autonomic, and central cholinergic synapses, leading to depolarizing 195 blockade. Symptoms include diarrhea, increased salivation, miosis, bradycardia, hypotension, and confusion.
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Venom from snakes may either block196 acetylcho-line receptors or decrease the release of acetylcho-line from the end-terminal. Venom from the black widow spider and scorpion 197,198 venom deplete acetylcholine stores through increased release of the neurotransmitter. Tick paralysis occurs 199 through a neurotoxin that appears to cause weakness by impairing acetylcholine release. MYOPATHY Myopathies usually present with symmetric, proximal weakness. Involvement of the neck flexors and extensors and the facial muscles is not uncommon, but weakness of the extraocular muscles is rare. Muscle atrophy and depressed reflexes occur in advanced cases. The common causes of myopathy are listed in Table 60-11. The congenital and genetic myopathies are beyond the scope of this discussion and are covered in general neurology textbooks. Although myalgia may occur with certain myopathies, most myopathies (including the inflammatory myopathies) are painless. Exercise intolerance and exercise-induced muscle cramps are clues to one of the metabolic myopathies. Click here to view this table.... The evaluation for a suspected myopathy begins with measurement of serum creatine kinase (CK) activity. Increased serum CK levels usually imply sarcolemmal injury. Normal serum CK levels may occur with disuseatrophy, corticosteroid myopathy, mitochondrial myopathies, and critical illness myopathy associated with thick-filament loss. Many of the metabolic myopathies are associated with normal serum CK levels between attacks. Mild to moderate serum elevations of CK are generally seen with the inflammatory myopathies, toxic myopathies, and adult-onset muscular dystrophies. High serum CK levels are associated with severe toxic/necrotizing myopathies (related to medications or severe electrolyte disturbances) and muscular dystrophy presenting in childhood. Needle EMG supports the clinical diagnosis and excludes the possibil- ity of a neuropathy. The electromyographer may also advise the best target for a muscle biopsy, which is often required for a definitive diagnosis.
Endocrine-Related Myopathy Acromegaly Slowly progressive proximal weakness not associated with muscle atrophy occurs in about half of acromegalic patients. Many patients have decreased exercise tolerance. Serum CK levels may be mildly elevated. When growth hormone levels normalize, the myopathy usually resolves. Corticosteroid Myopathy Corticosteroid myopathy may occur with either excessive exogenous or endogenous corticosteroids and is characterized by the insidious onset of proximal limb weakness. Patients who develop weakness usually have other stigmata of long-term corticosteroid use, including a moon facies, suprascapular fat pad, and fragile skin. Old age and cancer are risk 200 factors for corticosteroid myopathy. Myalgias may occur. Serum CK levels are typically normal. The dose and duration of corticosteroid treatment associated with the development of a myopathy vary widely, but most patients have received therapy for at least 4 weeks. With high-dose corticosteroids, however, the weakness may occur within 2 weeks of starting therapy. The fluorinated corticosteroids, including triamcinolone, betamethasone, and dexamethasone, are particularly likely to cause myopathy. Pathologically, there is selective atrophy of the type 2, glycolytic muscle fibers without muscle degeneration or inflammation. The pathogenesis probably relates to impairment of muscle protein and carbohydrate metabolism. The goal of treatment is to lower the corticosteroid dose to as low a level as possible. Recovery may take weeks to months but is usually excellent. A severe, acute necrotizing myopathy can result from large doses of intravenous corticosteroids combined with a neuromuscular blocking agent, usually in the setting of 201–203 There is probably overlap between this condition and treatment for status asthmaticus. critical illness myopathy, as discussed in Chapter 52. Hyperparathyroidism and Osteomalacia
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Proximal muscle weakness may be associated with primary and secondary hyperparathyroidism, vitamin D deficiency, and other disorders of vitamin D metabolism. Patients with primary hyperparathyroidism often complain of weakness and fatigue, but objective loss of muscle power is uncommon. Proximal weakness may be associated with discomfort on movement. Muscle stretch reflexes tend to be brisk. Serum CK levels are normal. Pathologically, atrophy of type II muscle fibers is a consistent feature. Secondary parathyroidism usually occurs in the setting of renal failure. The myopathy associated with uremia is discussed later. Osteomalacia presents with proximal weakness and bone pain. Nutritional deficiency of vitamin D is the leading cause of osteomalacia worldwide, but gastrectomy and celiac sprue are responsible for most of the cases in the United States. Renal tubular acidosis and anticonvulsant therapy may also cause osteomalacia by interfering with vitamin D metabolic pathways. Vitamin D deficiency may lead to secondary hyperparathyroidism; it may then be difficult to determine which factor is more important in the pathogenesis of the weakness. When vitamin D–deficient patients are supplemented with vitamin D, the response is variable and any improvement occurs over many weeks. Hyperthyroidism or Hypothyroidism Approximately 50 percent of thyrotoxic patients develop weakness. The pattern of weakness is typically proximal; patients frequently complain of fatigue and breathlessness. Myalgia is common. Usually the onset is insidious, although the onset may be more rapid in severe hyperthyroidism. In fact, rhabdomyolysis with myoglobinuric renal failure may occur in the setting of a thyroid storm. In general, however, severe generalized weakness in thyrotoxic patients should raise the suspicion of concomitant myasthenia gravis. Serum CK levels are usually normal. The EMG reveals small, short, polyphasic motor units without abnormal spontaneous activity. In addition to nonspecific myopathic findings, muscle biopsies may reveal a lower proportion of type I fibers. Following treatment, the proportion of type I fibers increases. Prognosis for recovery is excellent once a euthyroid state is achieved. Thyrotoxic periodic paralysis is characterized by recurrent attacks of generalized weakness lasting for minutes to days. The weakness may be provoked by a carbohydrate meal, cold, or rest after exercise. It is usually seen in young Asian or Native American adults. The paralytic attacks are not related to the duration or severity of the thyrotoxicosis. Treatment of acute paralytic attacks includes potassium supplements. The paralytic attacks disappear once the patient is maintained in a euthyroid state. Hypothyroidism causes a myopathy characterized by proximal weakness, fatigue, slowed 204 movements and reflexes, cramps, stiffness, myoedema, and muscle enlargement. The serum CK level is elevated even in asymptomatic hypothyroid patients and is frequently elevated more than 10 times the upper limit of normal in symptomatic patients. The EMG findings may be normal. Nonspecific myopathic findings are seen on muscle biopsy. After thyroid supplementation, recovery is excellent.
Infectious Myopathies Human Immunodeficiency Virus Infection As discussed in Chapter 45, several different types of myopathy have been associated with HIV infection. First, an inflammatory myopathy resembling polymyositis (PM) both clinically 205 and pathologically may occur. Although it may present at any stage of HIV infection, it is usually a complication of AIDS. Patients present with slowly progressive proximal arm and leg weakness. Serum CK levels are elevated, often more than 10 times the upper limit of normal. Pathologically, the findings are similar to idiopathic PM. Viral particles have not been identified in muscle cells. Most cases respond to corticosteroid therapy. Second, 206,207 a nemaline Third, rod myopathy may occur with or without associated inflammation in HIV patients. inclusion-body myositis (IBM) has been described in HIV patients. It is clinically and pathologically indistinguishable from sporadic IBM, except that the age at onset is earlier. Fourth, muscle atrophy and weakness occur in the HIV wasting syndrome. Pathologically, there is atrophy of the type II muscle fibers. Tumor necrosis factor α (TNF-α) is implicated in the pathogenesis of this syndrome. Fifth, myoglobinuria (sometimes recurrent) may occur at 208 any stage of HIV infection. Multiple factors, including concomitant medication use, probably contribute to its pathogenesis. Sixth, a pyomyositis manifesting as localized pain and swelling 209 in a limb may occur. It is usually associated with Staphylococcus aureus infection. Seventh, a proximal myopathy associated with myalgias in the thighs and calves may occur
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with high-dose zidovudine (AZT) treatment. Serum CK levels may be normal or mildly elevated. Pathologically, many fibers reveal “ragged red” features consistent with mitochondrial toxicity. Discontinuation of the medication usually results in improvement but sometimes not full recovery. Viral Myositis Viruses implicated with causing a myopathy include adenovirus, coxsackievirus A and B, echovirus, influenza A and B, Epstein–Barr virus, adenovirus, echovirus, parvovirus, parainfluenza virus, paramyxovirus, CMV, hepatitis211,212 B, herpes simplex virus, herpes zoster, Myalgia is the most common human T-lymphotropic virus 1 (HTLV-1), and HIV. neuromuscular symptom associated with viral illness. After the viral illness, swollen muscles and sometimes rhabdomyolysis with myoglobinuria occur. For many of the virus strains mentioned here, there is no clear evidence that the virus actually infects or replicates within human muscle tissue. In such cases, the pathogenesis of the muscle injury is uncertain. Other Infections The three most common parasitic infections of muscle are toxoplasmosis, cysticercosis, and trichinosis. Toxoplasmosis is the most common protozoan infection to cause a myositis, the others being sarcocystis, trypanosomiasis, microsporidiosis, and malaria. Toxoplasma gondii is transmitted to humans by ingestion of undercooked meats and by contact with cat feces. Patients present with a fever accompanied by any one of multiple possible systemic features, including lymphadenopathy, pericarditis, hepatosplenomegaly, meningoencephalitis, and myositis. The myositis associated with toxoplasmosis resembles idiopathic PM and dermatomyositis (DM). Pathologically, cysts containing bradyzoites may be seen in muscle fibers or near inflammatory infiltrates. Prognosis for a full recovery is excellent following treatment. Cestode (tapeworm) infections resulting in myopathy include cysticercosis, echinococcosis, coenurosis, and sparganosis. Cysticercosis caused by Taenia solium infection may result from eating uncooked infected meat (particularly pork) and by the fecal-oral route. Patients may present with enlarged yet weak muscles (pseudohypertrophy). Myalgia and muscle 176 tenderness are common. Nematode (roundworm) infections associated with a myopathy include trichinosis, toxocariasis, cutaneous larva migrans, and dracontiasis. Trichinosis occurs after ingestion of inadequately cooked meat. Following a prodrome of abdominal cramps and diarrhea, patients develop generalized weakness that may be accompanied by the classic cutaneous stigmata 213 of DM. Serum CK levels are elevated and eosinophilia is present.
Idiopathic Inflammatory Myopathies DM, PM, and IBM present with subacute to chronic, symmetric proximal limb weakness with sparing of the ocular muscles. All share evidence of lymphocytic infiltration of the muscle, but important differences exist among these diseases, particularly in mechanisms of pathogenesis and response to214 treatment. Many cases previously labeled as PM may have had IBM or another myopathy. Dermatomyositis and Polymyositis The annual incidence of DM and PM in the general population is 0.1 to 1 per 100,000. Women are affected more often than men. Most patients present with a several month history of subacute proximal weakness, usually without significant muscle atrophy. Typically, the onset of the weakness cannot be precisely recalled. Other symptoms may include dysphagia, nasal regurgitation, or aspiration from weakness of oropharyngeal muscles or the 215 upper esophagus. Myalgias and muscle tenderness occur in 25 to 50 percent of cases but tend to be mild. Muscle pain is more prominent in viral or bacterial myositis, the inherited metabolic myopathies, polymyalgia rheumatica, and fibromyalgia. In DM, various cutaneous manifestations may precede or accompany the onset of weakness. These include Gottron's sign (scaly, erythematous rash over the extensor surfaces of the metacarpophalangeal and interphalangeal joints; a similar rash may occur over the extensor surfaces of the elbows and knees), diffuse flat erythema in the anterior neck and chest and other sun-exposed areas, swelling and reddish violaceous discoloration of the upper eyelids
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(heliotrope rash), periungual erythema, dilated nail-bed capillary loops, and rough, cracked skin at the fingertips (so-called mechanic's hands). Of note, patients with DM and SLE often share the same 308A polymorphism of the tumor necrosis factor-α promoter region, which suggests that ultraviolet light–induced production of tumor necrosis factor-α may contribute to 216 light sensitivity in both diseases. Interstitial lung disease is an important complication of PM and DM. Particularly for PM, the presence of interstitial lung disease is 217 associated with antibodies to the histidyl-transfer RNA precede the myopathy or (histidyl-tRNA) synthetase (anti–Jo-1). The lung disease may 218 accompany it in 5 to 40 percent of patients with DM and PM and may present acutely with a nonproductive cough, dyspnea, hypoxemia, and lung infiltrates or chronically with dyspnea. 219 Sometimes it is discovered in asymptomatic patients on screening chest radiographs.220 The presence of interstitial lung disease is a poor prognostic factor for long-term survival. Patients with DM and PM may have cardiac involvement, which may manifest as 217 supraventricular arrhythmias, atrioventricular conduction blocks, and bundle branch block. Congestive heart failure has also been described. An associated malignancy, in particular ovarian, pancreatic, stomach, and colorectal cancers and non-Hodgkin's lymphoma, is seen 221,222 in 6 to 45 percent of DM patients and in 0 to 28 percent of PM patients. PM and DM may overlap with a number of connective tissue diseases, including scleroderma, SLE, and, rarely, rheumatoid arthritis and Sjögren's syndrome. In scleroderma, a bland myopathy with mild to absent elevations of serum CK levels is common. In a small percentage of patients, severe proximal muscle weakness occurs with significant serum CK 223 elevations. Overall, the incidence of myositis in scleroderma ranges from 5 to 17 percent. In North American patients, the anti–PM-Scl antibody is a marker for scleroderma-myositis. PM and DM also occur in association with SLE. The presence of autoantibodies against nuclear components helps distinguish a PM-SLE overlap syndrome from idiopathic PM. In a 224 cohort of 330 patients with SLE, 10 had a myositis. Serum CK levels are usually elevated in PM and DM and generally reflect the disease activity; levels are generally higher in PM than DM and may even be normal in active DM. Serum antibody tests to nuclear and cytoplasmic components help support the clinical diagnosis of PM or DM, assist the diagnosis of overlap syndromes, and categorize subgroups of inflammatory myopathies. Muscle-specific antibodies have specific associations with HLA haplotypes and certain disease manifestations. These include antibodies to aminoacyl transfer RNA synthetases, components of the signal recognition particle (SRP), and nuclear helicase/adenosine triphosphatase Mi-2. About 50 to 75 percent of those with antibodies to 225 cytoplasmic transfer RNA synthetases (including anti–Jo-1) have interstitial lung disease. Patients with anti-SRP antibodies often have acute-onset severe myositis without an associated rash or lung disease. Patients with anti–Mi-2 antibodies usually have a florid rash 226 and an abrupt onset of weakness. MRI shows evidence of inflammation in muscles and subcutaneous fat, fibrosis, and 227 calcification. Because MRI is noninvasive, it can be performed serially to assess disease progression and monitor response to treatment; it may also be used to identify a site for biopsy. EMG typically reveals increased insertional activity and fibrillation potentials with myopathic (low-amplitude, short-duration, polyphasic) motor unit potentials. Ideally, a muscle biopsy should be performed on a superficial muscle with abnormal findings on EMG of the homologous contralateral muscle. Pathologically, the inflammation in PM is perivascular, perimysial, and endomysial. There is no evidence of damage to the capillaries. There is invasion of non-necrotic muscle fibers + ubiquitously expressing major histocompatibility complex (MHC)-1 by cytotoxic CD8 T 228 cells. These findings support the hypothesis that the cytotoxic T cells recognize an antigen bound to major histocompatibility complex-1. The identity and origin of this putative antigen are not known. Major histocompatibility complex-1 is normally not expressed on the surface of muscle fibers. In PM, the inflammation is predominantly in the perivascular or interfascicular space and less + so in the endomysium. The inflammatory infiltrate is primarily composed of B cells and CD4 T cells. Unlike PM, the immune attack appears to be primarily directed against the vascular endothelium. The sequence of events is thought to include antibody deposition on the endothelial cells, followed by complement activation, and, finally, membrane attack complex 229 (MAC)–mediated microvascular injury. Chronic ischemia is thought to produce perifascicular atrophy, a hallmark pathological feature of DM. Corticosteroids are widely recognized as first-line treatment for PM. The typical daily dose is 1
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to 1.5 mg/kg. This dose is continued until strength improves and then a careful, slow taper is started. A number of agents, including azathioprine, methotrexate, or mycophenolate mofetil, may be used concurrently or subsequently for a corticosteroid-sparing effect. In a study comparing the treatment of prednisone to prednisone plus azathioprine, those taking230 both For had a better functional outcome and needed a lower prednisone maintenance dose. 231,232 Plasmapheresis did not refractory cases of DM and PM, IVIg appears to be effective. 233 show a benefit in a double-blind, placebo-controlled trial. Inclusion-Body Myositis IBM is a slowly progressive, debilitating myopathy of unknown cause. It is the most common 234,235 Early involvement of the finger flexors, wrist myopathy in patients older than 50 years. flexors, knee extensors, and ankle dorsiflexors is common. Dysphagia may occur, which may be treated with a cricopharyngeal myotomy. A wide variety of autoimmune diseases have been described in association with IBM. Hyporeflexia is common; some patients have clinical 236 and electrodiagnostic evidence of a peripheral neuropathy. The serum CK level can be normal or up to 10-fold above the upper limit of normal. The EMG findings are similar to those of DM and PM, except that long-duration motor unit potentials are commonly observed and do not exclude the diagnosis of IBM. +
Pathologically, there is endomysial inflammation with a CD8 T-lymphocyte predominance, 237 basophil-rimmed vacuoles with eosinophilic inclusions, and intracellular amyloid deposits detected by fluorescence microscopy of Congo red–stained sections or electron microscopy demonstrating 15- to 18-nm tubulofilaments. The vacuoles contain various products of muscle degradation including myeloid bodies, membrane fragments, and debris. In addition, numerous proteins also expressed in Alzheimer's disease are found in muscle fibers. This has led to the notion that IBM is a degenerative disease associated with aging. It is important to note that vacuolated fibers occur in certain hereditary myopathies and in toxic myopathies caused by colchicine and chloroquine. There is generally no effective immunomodulating treatment, although240individual patients 238,239 mycophenolate mofetil, and high-dose have responded to corticosteroids, IVIg, 241 vitamin C. Sarcoidosis Granulomatous inflammation of muscle is usually associated with sarcoidosis but can244 also be 242,243 inflammatory bowel disease, foreign body reactions, seen in infectious disease, 245 246 thymoma, lymphoma, and myasthenia gravis. It may also occur without any evidence of systemic disease. Asymptomatic involvement of the muscle occurs in 50 to 80 percent of cases of sarcoidosis. Symptomatic involvement occurs in less than 3 percent of cases. Most patients with sarcoid 247 Rarely, patients present myopathy present with slowly progressive, proximal weakness. 248 with acute myositis or a palpable nodular type of myopathy. The response to corticosteroid therapy is unpredictable. Compared with sarcoid myopathy, patients with isolated granulomatous myopathy have milder, predominantly distal weakness, and the response to 249,250 corticosteroids tends to be better. Polymyalgia Rheumatica Polymyalgia rheumatica presents with 251 achiness and morning stiffness in the shoulder and hip girdles in patients older than 50 years. Malaise, fever, and anorexia with weight loss are common. There is an association with temporal arteritis and rheumatoid arthritis. The erythrocyte sedimentation rate is almost always increased. There is no weakness. Although muscle biopsy specimens are generally normal, MRI or ultrasonography of the shoulders 252,253 The symptoms usually respond to low-dose consistently reveals evidence of bursitis. corticosteroids.
Critical Illness Myopathy Patients with critical illness may develop an acute, acquired myopathy associated with 254 exposure to high-dose corticosteroids and neuromuscular blocking agents (Chapter 52). Critical illness myopathy may be suspected first when patients fail to wean from mechanical ventilation. Patients have flaccid, diffuse weakness that affects the limbs, neck flexors, and diaphragm. Tendon reflexes are usually depressed. Approximately one third of ICU patients
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treated for status asthmaticus develop critical illness myopathy. Other risk factors include 256 severe medical illness, renal failure, and hyperglycemia. Patients with critical illness myopathy may also have clinical and electrodiagnostic features of critical illness polyneuropathy. Critical illness myopathy should be distinguished from rhabdomyolysis with myoglobinuria, which can also occur in the ICU setting. Electrodiagnostic testing helps to clarify the diagnosis. Needle EMG reveals fibrillation potentials in limb muscles of some but not all patients. Short, small, poly phasic motor unit potentials are seen. Electrical inexcitability of the muscle to direct needle stimulation occurs in this entity but not in 257 polyneuropathy. Most patients have elevations of serum CK levels, but a normal level does not exclude the diagnosis. Pathologically, there is muscle-fiber atrophy with evidence of a disrupted intramyofibrillar network. Loss of thick filaments (myosin) is a characteristic feature. The pathogenesis is uncertain but may involve glucocorticoid-induced proteolysis of contractile proteins in the setting of muscle-fiber denervation. There is no specific treatment for critical illness myopathy, but corticosteroids and neuromuscular blocking agents should be limited, if possible. Neurological recovery is usually excellent, assuming that the patient 258 recovers from the underlying medical illness.
Metabolic and Toxic Myopathies Alcohol Alcoholics may develop an acute necrotizing or chronic myopathy. The acute form presents as an attack of pain and swelling in a limb, usually the calf or thigh. In severe cases, myoglobinuria occurs. The attack usually occurs in the course of a heavy drinking binge. If probed, patients may recall prior bouts of pain and swelling in the limbs associated with earlier drinking binges. Serum CK levels are often markedly elevated. Recovery usually occurs over 1 to 2 weeks, but patients are prone to have subsequent episodes of acute myopathy if drinking is resumed. The chronic form presents as chronic limb-girdle weakness with preserved reflexes. Serum CK levels are usually normal but may be elevated. Muscle biopsy specimen abnormalities are usually mild and include type II fiber atrophy. Hyperkalemia or Hypokalemia Hyperkalemia causes acute generalized weakness and cardiac arrhythmias. The weakness typically begins in the legs and then generalizes over hours to days. Respiratory failure occurs in about 50 percent of cases. Painful dysesthesias may precede the onset of weakness. Reflexes are usually absent. In most cases, the serum potassium level exceeds 7.5 mEq/L. Paralysis only occurs in patients with some degree of chronic hyperkalemia. Electrodiagnostic testing has shown slowing of259 nerve conduction velocities and low compound muscle action potential amplitudes. The immediate treatment goal is to prevent a cardiac arrhythmia, which can be achieved with an infusion of calcium gluconate. Hypokalemia may be associated with acute paralysis or subacute myopathy. Acute hypokalemic paralysis occurs in patients with chronic potassium depletion. The onset of weakness occurs over hours to days. Once it starts, the weakness tends to accelerate. In mild cases, weakness may be limited to the legs, but in severe cases, tetraplegia with neuromuscular respiratory failure may occur. Extraocular muscles are spared. The potassium level is always below 3.0 mEq/L. The subacute myopathy associated with hypokalemia is characterized by the onset of proximal limb weakness over weeks to months. Serum CK levels are elevated, sometimes markedly. Pathologically, there is muscle-fiber necrosis with multiple vacuoles in some muscle fibers. Occasionally, the course may be more rapid, associated with myalgia, tenderness, and myoglobinuria. Once the hypokalemia is corrected, recovery is rapid and complete. Uremia Uremic myopathy refers to the clinical syndrome characterized by proximal weakness, limited endurance, and rapid fatigability seen in patients with end-stage renal disease. It usually only 260 occurs with glomerular filtration rates below 25 ml/min. It has been estimated that approximately 50 percent of dialysis patients have this condition. Often, the weakness is mild, and EMG and serum CK levels are normal. Pathologically, there is atrophy of type II muscle fibers. A number of metabolic derangements are thought to contribute to this condition, including secondary hyperparathyroidism, impaired vitamin D metabolism, carnitine 261 deficiency, and reduced clearance of toxic “middle molecules.” Insulin resistance,
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alterations of mitochondrial metabolism, and anemia may also have roles in pathogenesis. Although there is currently no specific treatment for uremic myopathy, an emphasis should be placed on preventing secondary hyperparathyroidism and improving the patient's nutritional 262 status. Carnitine supplementation may be considered. Finally, renal transplantation offers the best chance for improvement.
Medication-Induced Myopathy Many different medications cause a myopathy (Chapter 36). Most of these cause a necrotizing myopathy that presents clinically with the acute to subacute onset of generalized weakness. In severe cases, myoglobinuria occurs. Myalgias may occur. Serum CK values are usually elevated. Pathologically, there are necrosis and regeneration of muscle fibers with myophagocytosis. 3-Hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (atorvastatin, simvastatin, and other statins), fibric acid derivatives (clofibrate, gemfibrozil, and others), organophosphates, ε-aminocaproic acid, and hypervitaminosis E are all associated with a necrotizing myopathy. Any medication that lowers potassium levels, including diuretics, licorice, and laxatives, may produce a myopathy. A few medications (e.g., zidovudine) cause a mitochondrial myopathy. Once the offending medication is discontinued, most patients make a rapid and full recovery. RHABDOMYOLYSIS AND MYOGLOBINURIA Myoglobin is an oxygen-carrying protein in the sarcoplasm of muscle cells. Its functions include oxygen storage and “buffering” of oxygen to prevent mitochondrial anoxia. Any cause of muscle injury leads to an increase in serum concentration of myoglobin. If the concentration of myoglobin in the urine surpasses 250 mg/ml (normal is <5 ng/ml), the urine will have a cola-color tinge. This reflects destruction of more than 100 g of muscle. Rhabdomyolysis occurs with direct injury to the sarcolemma or when energy failure occurs. Patients with rhabdomyolysis often complain of myalgia, weakness, and muscle swelling. Recognition of myoglobinuria is important because of the potentially life-threatening complication of acute tubular necrosis. Prevention of acute renal failure includes hydration with alkaline fluids and induced diuresis with hyperosmolar agents such as mannitol. Electrolyte imbalances, such as hyperkalemia or hypocalcemia, may cause cardiac arrhythmias and require prompt reversal. The prognosis for neurological recovery is usually excellent given the tremendous regenerative capacity of skeletal muscle. 263
The many potential causes of myoglobinuria are outlined in Table 60-12. Click here to view this table....
Crush injuries may result in myoglobinuria. There may be direct trauma to muscle. Limb ischemia combined with muscle trauma also leads to swelling of the muscle. In the forearm and lower legs, osteofascial septa limit the degree of expansion of swollen muscles and interstitial tissue pressures rise, leading to further embarrassment of the vascular supply. The resulting compartment syndromes will lead to extensive muscle breakdown if decompressive fasciotomies are not performed. Many different viral and bacterial agents cause myoglobinuria. The mechanisms of myoglobinuria involve either direct infection of muscle, effects of a toxin, or hyperthermia. Various medications may cause myoglobinuria, especially if an underlying genetic susceptibility is also present. Inhaled anesthetics with or without depolarizing muscle relaxants may trigger the malignant hyperthermia syndrome in susceptible individuals. This syndrome is characterized by muscle rigidity, hyperventilation, tachycardia, fever, autonomic instability, cyanosis, and lactic acidosis. Mutations in the sarcoplasmic reticulum ryanodine receptor gene or the dihydropyridine-sensitive, L-type, voltage-dependent calcium channel lead to susceptibility to this condition. In all cases, the myoglobinuria appears to be caused by increased intracellular calcium concentrations. Neuroleptic malignant syndrome causes myoglobinuria through muscle contraction and hyperthermia. It is a complication of neuroleptic medications or sudden withdrawal from antiparkinsonian medications. Antipsychotic medications can also cause myoglobinuria without neuroleptic malignant syndrome. Electrolyte disturbances, including severe hypokalemia, may cause myoglobinuria. Hypocalcemia most likely causes myoglobinuria through trismus and excessive muscle contraction. Metabolic states characterized by hyperthermia or increased muscle metabolism sometimes
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cause myoglobinuria. Such states include pheochromocytoma, thyroid crises, hyperthermia, heat stroke, fever, and sickle cell trait with overexertion. Prolonged hypothermia and near-drowning can cause myoglobinuria through uncertain mechanisms. Overexertion may lead to adenosine triphosphate deficiency with resulting energy failure. A variety of medical conditions, such as delirium tremens, status asthmaticus, and status epilepticus cause involuntary overexertion of muscles and, rarely, myoglobinuria. Recurrent myoglobinuria, regardless of whether it is associated with exercise, should prompt an investigation into a metabolic myopathy. Glycogen storage diseases, fatty acid oxidation disorders, and mitochondrial cytopathies have all been associated with recurrent myoglobinuria. Diagnosis of these disorders usually requires the analysis of specific enzyme activities in muscle biopsies. ACKNOWLEDGMENT This chapter contains contributions by Eric Yuen, MD, who wrote the text that appeared in the previous edition of this book. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 61 Stroke as a Complication of General Medical Disorders PHILIP R. DELIO • GREGORY W. ALBERS •
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HOMOCYSTEINE LIPOPROTEIN (a) PROTEIN C, PROTEIN S, AND ANTITHROMBIN III DEFICIENCY ACTIVATED PROTEIN C RESISTANCE SICKLE CELL ANEMIA SYSTEMIC LUPUS ERYTHEMATOSUS ANTIPHOSPHOLIPID ANTIBODIES, LUPUS ANTICOAGULANT, AND ANTICARDIOLIPIN ANTIBODIES Sneddon's Syndrome CRYOGLOBULINS AND STROKE STROKE AND MALIGNANCY Direct Tumor Effects Coagulopathy Nonbacterial Thrombotic Endocarditis Strokes Related to Cancer Therapy Intracerebral Hemorrhage MEDICATION USE AND THE RISK OF STROKE Oral Contraceptive Use Cocaine Amphetamines Triptans Alcohol
Stroke is currently the third leading cause of death in the United1 States. In 1996, more than 700,000 first or recurrent strokes occurred in the United States. Stroke is increasingly recognized as a sequela of other medical diseases, and a number of medical conditions may predispose individuals to stroke and cerebrovascular disease. In this chapter some newly recognized risk factors are highlighted and the relationship between a number of common medical diseases and the risk of stroke is examined. The effects of hypertension and of diabetes are discussed in Chapters 7 and 21, respectively. HOMOCYSTEINE Homocysteine is an intermediate in the metabolism of the amino acid methionine. An
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elevated level of plasma total homocysteine increases the risk of vascular disease and is an independent risk factor for stroke. The association between serum homocysteine level and 2 stroke does not appear to differ by race. Hyperhomocysteinemia can be caused by an error in metabolism of sulfur-containing amino acids. Other causes of elevated homocysteine levels include nutritional deficiencies of folate or vitamin B12 or B6, or a genetic defect in the methylenetetrahydrofolate reductase (MTHFR) gene. Although an elevated serum homocysteine level is an independent risk factor for 3 cerebrovascular disease, it is unclear whether elevated homocysteine levels have a causative role in the pathogenesis of vascular disease or are merely a secondary effect of some other underlying causal process. Cell culture studies suggest that homocysteine may 4 have prothrombotic effects on endothelium and vascular smooth muscle. Homocystinuria, a rare genetic disorder caused by homozygosity of the defective MTHFR 5 gene, causes premature atherosclerosis as well as strokes in affected individuals. Heterozygosity for the defective gene has been reported in 30 to 41 percent of the general population, although studies suggest that the presence of this mutation is not an independent 6–9 risk factor for cerebrovascular disease. A number of vascular and hematological abnormalities are associated with elevated serum homocysteine levels. Mild hyperhomocysteinemia is an independent risk factor for increased 10 carotid artery wall thickness and plaque formation. Smooth muscle cells cultured in the presence of11homocysteine show significant increases both in cell density and collagen production. Other reported pathophysiological changes include endothelial cell injury, increased platelet aggregation, and abnormalities of the clotting cascade by activation of 5 factors V, X, and XII. One study showed that intimal wall thickness of the carotid artery, as measured by B-mode ultrasonography, was significantly greater in individuals with plasma 12 homocysteine levels higher than 11.5 μmol/L. Several large studies have documented the association between hyperhomocysteinemia and cerebrovascular disease. Yoo and colleagues performed a case-control study of 78 men with cerebral infarction and 140 control subjects and found an odds ratio of 1.7 (adjusted for total cholesterol, hypertension, smoking, age, and diabetes) for stroke in patients with the highest 13 5 percent of homocysteine levels. Furthermore, the plasma homocysteine levels of patients who had two or three stenosed vessels on magnetic resonance angiography was significantly 13 greater than those in patients with only one or no abnormal vessels. In a substudy of the Framingham Study, 1,947 elderly participants were followed 14 prospectively and nonfasting homocysteine levels were measured. After the investigators had adjusted for other risk factors, the relative risk for stroke associated with nonfasting homocysteine levels of 14.24 to 219.84 μmol/L compared with levels of 4.13 to 9.25 μmol/L 14 was 1.82 (95% confidence interval [CI]: 1.04 to 2.16). The Rotterdam Study examined the relationship between elevated homocysteine levels in the elderly and the risk of stroke and myocardial infarction and found a risk increase of 6 to 7 percent for every 1 μmol/L increase 15 in total plasma homocysteine. The association between stroke and elevated homocysteine 16 levels has also been demonstrated in young patients. In a case-control study of 80 patients with stroke between the ages of 18 and 44 years, a 4.8-fold increased risk of ischemic stroke 16 was found in those with postmethionine load elevations in 17–19 plasma homocysteine levels. A number of other studies have also shown this association. Although supplementation with folate, pyridoxine (vitamin B6), or cobalamin (vitamin B12) can reduce homocysteine levels, whether these supplements lower the risk of subsequent vascular events has been the topic of a number of recent studies. The first large, randomized trial (Vitamin Intervention for Stroke Prevention Trial [VISP]) evaluated the effects of high doses of folic acid, vitamin B6, and vitamin B12 in patients with a recent ischemic stroke. No benefit was shown in the prevention of future stroke, myocardial infarction, or death despite a 20 dose-dependent reduction in homocysteine levels. Subsequently, the Norwegian Vitamin 21 (NORVIT) trial enrolled myocardial infarction patients and achieved a higher mean reduction in total homocysteine levels (27%) using folic acid plus vitamin B12, but without an effect on the risk of stroke, myocardial infarction, or vascular death. More concerning were the results in the Norwegian Vitamin subgroup treated with folic acid, vitamin B12, and vitamin B6; these patients had an increased risk of serious vascular events (relative risk, 1.22; 95% CI: 1.00 to 1.50; P = 0.05). Furthermore, another study has suggested a harmful effect from combined vitamin B and folate treatment. Lange and associates treated patients who had undergone successful coronary stenting with 22 folic acid, vitamin B6, and vitamin B12 or a placebo for 6 months. Contrary to expectations, the group receiving folic acid and B vitamins had an increased risk of instent restenosis and
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need for target-vessel revascularization. The most recent prospective placebo-controlled trial of vitamin therapy for patients with 23 increase homocysteine is the Heart Outcomes Prevention Evaluation (HOPE) 2 trial. In this trial, patients with atherosclerotic risk factors and elevated homocysteine levels had no reduction in vascular events or death with folic acid and vitamin B therapy. There was, however, a small reduction in stroke in the vitamin-treated group. In summary, despite clear evidence from case-control trials that elevated homocysteine levels are associated with a higher risk of vascular events, prospective treatment trials provide no evidence that folic acid and vitamin B therapy can reduce the risk of subsequent vascular events in patients with elevated homocysteine levels. Furthermore, the combination of folic acid and vitamin B therapy may actually be harmful in some patient subgroups. More research is required to clarify which patients, if any, should receive treatment for elevated homocysteine levels. Therefore, at present, we do not perform routine screening of homocysteine levels in stroke patients and we do not recommend lowering homocysteine levels with folic acid and B vitamins. LIPOPROTEIN (a) Lipoprotein (a) is a low-density lipoprotein (LDL)–like molecule that has been linked to both 24–28 Levels of this lipoprotein are genetically coronary artery and cerebrovascular disease. determined and do not appear to be correlated with25age, sex, blood pressure, smoking is habits, or levels of total cholesterol or triglycerides. The lipoprotein (a) molecule 29 composed of two components: apolipoprotein B and apolipoprotein A, or apo A. Of note, the apo A portion shares significant structural homology with plasminogen, which releases the 30 enzyme plasmin when activated by tissue plasminogen activator. It has been postulated that because of its structural similarity to plasminogen, lipoprotein (a) may compete for plasminogen-binding sites on fibrin and endothelial cells, thereby inhibiting endogenous 30 fibrinolysis. Furthermore, lipoprotein (a) accumulation has been demonstrated histopathologically in coronary atherosclerotic lesions in humans, and modification of lipoprotein (a) by sulfated polysaccharides has been shown to lead to cholesterol deposition in mouse macrophages, similar to the atherogenic process caused by high levels of LDL 27,31,32 Certain authors have suggested that because of its fibrin-binding activity, cholesterol. lipoprotein (a) may help deliver cholesterol to developing thrombi or areas of endothelial 29,33 Despite these data, it remains unclear whether elevated lipoprotein (a) levels injury. actually contribute to atherosclerotic plaque formation or merely reflect the presence of 34 atherosclerotic disease. Lipoprotein (a) has been associated with carotid artery abnormalities in a number of studies; carotid wall thickening, as detected by B-mode ultrasonography, is associated with elevated serum lipoprotein (a) levels. A graded response has been reported between the degree of 28,29,35,36 carotid atherosclerosis and lipoprotein (a) levels. Numerous studies have linked high serum lipoprotein (a) levels to cerebrovascular disease and stroke. Shintani and co-investigators found that, in addition to low high-density lipoprotein levels and hypertension, high lipoprotein 25 (a) levels are an independent risk factor for ischemic stroke in patients younger than 65 years. This association held true for both the perforating artery subtype of stroke (lacunar infarcts) and for the entire stroke group (when patients with atrial fibrillation were excluded). Similarly, a study of Japanese subjects with symptomatic lacunar strokes or cerebrovascular risk factors showed an association between high 37 lipoprotein (a) levels and both symptomatic and “silent” lacunar strokes. These data differ from findings by others who27,38 did not find an association between small, deep perforating artery strokes and lipoprotein (a). These conflicting results reflect the uncertainty surrounding the pathogenesis of lipoprotein (a)–induced vascular disease because perforating artery lacunar-type infarcts usually are associated with hyalinization of vessels rather than typical atherosclerotic plaque formation. However, the link between lipoprotein (a) and inhibition of the thrombolytic cascade by fibrinogen could account for an increased risk of both large-vessel and small-vessel disease-related stroke. Lipoprotein (a) may have an important relation to the development of premature atherosclerosis24,25 and may explain some of the cryptogenic strokes that occur in relatively In a study of white men younger than 45 years, a lipoprotein (a) level young patients. exceeding 30 mg/dl was associated with a significantly increased risk (odds ratio of 3.9, 95% 24 CI: 1.1 to 13.7) for the development of premature peripheral vascular disease. Similarly, among patients younger than 65 years, the incidence of a lipoprotein (a) level greater than or equal to 42.6 mg/dl was significantly increased in patients with stroke compared with
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matched control subjects. In a study of 101 patients with chronic ischemic stroke, the subgroup of patients younger than 50 years at the time of stroke onset had lipoprotein (a) 31 levels that were significantly higher than in control subjects. Even after one has controlled for other risk factors such as hypertension, diabetes, coronary artery disease, and tobacco use, a lipoprotein (a) level higher than 30 mg/dl is an independent risk factor for ischemic stroke, and this26,39,40 association exists even in More recent studies, such as that normocholesterolemic and normolipidemic patients. of the Cardiovascular Health Study Investigators group, showed that elderly men in the highest quintile of serum lipoprotein (a) measurements had three times the unadjusted risk of stroke and almost three times the risk of death from vascular causes. Interestingly, this association was not seen in the elderly women in the study, suggesting there may41be a gender difference in the stroke risk associated with elevated lipoprotein (a) levels. Although lipoprotein (a) levels are genetically determined, they appear minimally affected by age, sex, nutrition, or environmental factors, although higher baseline levels have sometimes 29–31,33 A number of medical conditions have been been found in African Americans. associated with elevated lipoprotein (a) levels, particularly diabetes with poor glycemic control 29 and renal impairment. Also, lower levels of lipoprotein (a) have been reported in women taking hormone replacement therapy (in conjunction with lowering of LDL29cholesterol), although oral contraceptives seem to have little effect on baseline levels. Despite the positive associations between lipoprotein (a) and cerebrovascular disease, there 34 has been little success in finding medications or dietary regimens that reduce serum levels. 42 Diet modification did not alter lipoprotein (a) levels in one study. Some studies show a reduction in29lipoprotein (a) levels when diets are enriched with palm oil and polyunsaturated Alcohol consumption has also been associated with lower serum lipoprotein (a) fatty acids. 29,43 44 as has the use of low-dose (81 mg) aspirin. The most promising pharmacological levels, agents include nicotinic acid and neomycin,45,46 both of which decrease serum lipoprotein (a) A recent study by Guyton and colleagues levels by up to 50 percent in some studies. showed a 36 percent reduction in elevated lipoprotein (a) levels in individuals taking a mean 47 nightly dose of 2,000 mg extended-release niacin. Despite the similarity of lipoprotein (a) to other cholesterol constituents of the blood, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, bile acid sequestrants, and fibric acid derivatives seem to have 33 little effect on lipoprotein (a) concentrations. The paucity of data regarding effective lipoprotein (a)–lowering therapy, coupled with the current lack of evidence of any clinical benefits from lowering elevated lipoprotein (a) levels, makes it difficult to formulate any treatment recommendations. Other risk factors such as dyslipidemia, diabetes, and obesity seem to be associated with, or even enhance, the atherothrombotic risk attributable to lipoprotein (a). Therefore, treatable risk factors should be tightly controlled in patients with 48–50 It is unknown whether lowering lipoprotein (a) levels with niacin is elevated lipoprotein (a). beneficial for reducing subsequent vascular events. Screening for elevated lipoprotein (a) levels can be considered for patients who experience a stroke at a young age (younger than 55 years), patients with premature cardiovascular disease or a family history of premature disease, and patients with stroke who lack other conventional risk factors for stroke such as hypercholesterolemia, hypertension, and diabetes. PROTEIN C, PROTEIN S, AND ANTITHROMBIN III DEFICIENCY Protein C, protein S, and antithrombin III deficiencies account for 14 to 25 percent of cases of familial thrombotic (peripheral as well as central) disease, although the majority of these 51 cases tend to be venous rather than arterial thrombosis. In a review of some of the larger studies to date, hematological disorders accounted for as many as 8 percent of all ischemic 52 53 strokes. Heterozygosity for protein C deficiency has been estimated at 1 in 500 patients, and protein S deficiency has a prevalence of 1:3,000 to 1:15,000. Antithrombin III deficiency 52 has been estimated at 1 in 600 individuals. But whereas the combined prevalence of these deficiencies is 1 percent or less in the general population,54they may account for up to 20 percent of recurrent or familial venous thromboembolism. Deficiencies occur in either the amount (quantitative deficiency) or the molecular function (qualitative deficiency) of these coagulant proteins. 52
Protein C is a vitamin K–dependent factor converted to an active protease by thrombin. Once in active form, it limits coagulation by 52 proteolysis of clotting factors Va and VIIIa. Protein S acts as a cofactor for activated protein C. Antithrombin III acts as a protease inhibitor of most of the clotting factors in the coagulation cascade, except for factors Va and VIIIa, which 51 are regulated by proteins C and S. Combined, these factors serve to maintain the delicate
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balance between vascular hemostasis and fibrinolysis. The risk of venous thrombosis and thromboembolism in patients with inherited deficiencies of protein C, protein S, and antithrombin III has been recognized extensively in the literature, although there are fewer data on arterial thrombotic events. A study by Allaart and colleagues showed that by the age of 45 years, half of the subjects with heterozygous protein C 55 deficiency had venous thromboemboli, and a study by Pabinger and Schneider showed that 80 to 90 percent of subjects with protein C, protein S, or antithrombin III deficiency had some 56 type of thrombotic event (usually venous) by 50 to 60 years. There are a number of reports of ischemic strokes occurring in the setting of protein C deficiency in the absence of other risk 57–62 A study of ischemic stroke in young patients in the “stroke belt,” a factors for stroke. section of the southeastern United States with higher death rates due to stroke not explained by traditional atherosclerotic risk factors, showed hypercoagulable profiles in almost 24 percent of the patients, with protein C and protein S deficiencies accounting for almost 10 63 percent of cases. In contrast, a case control study of 219 patients (mean age 66 years) with first-ever ischemic stroke showed no significant differences in the prevalence of 64 thrombophilia between cases and control subjects or between subtypes of ischemic stroke. When one reviews the literature, inherited deficiencies seem to figure more prominently in the pathogenesis of stroke in young adults and children than in the elderly, who have other age-associated risk factors. In a study of 120 patients with stroke or transient ischemic attack (TIA) and a mean age of 38 years, protein S, protein C, and antithrombin III deficiencies were 65 detected in 20, 3, and 3 patients, respectively. Furthermore, a confirmed coagulation disorder, although not65associated with stroke type, was more common among patients with large-vessel disease. In a retrospective study of 37 children with cryptogenic ischemic stroke, protein C deficiency or protein S deficiency was the only identified risk factor for 5.4 66 percent and 13.5 percent, respectively, of these patients. In another study of 36 patients younger than 40 years examined at least 3 months after cerebral infarction of undetermined cause, protein S deficiency was found in 5 cases, protein C deficiency in 1, and antithrombin 67 testing for these III deficiency in 1. Based on these findings, the authors recommended 67 inherited deficiencies in every young patient with cryptogenic stroke. Protein S deficiency has also been reported in a number of cases of cerebral venous thrombosis, but the association of protein C68–70 and antithrombin III deficiency with cerebral venous thrombosis is less well established. When testing for these deficiencies, it is important to recognize that activity levels may be influenced by other nongenetic factors. Most hereditary deficiencies are quantitative, although qualitative deficiencies, either primary 66 or secondary, are becoming more widely recognized with both since the advent of qualitative assays. Acute-phase reactants may interfere 65 quantitative levels and qualitative function of these anticoagulant proteins. Because low levels of protein C may occur in the setting of acute stroke,52any studies with abnormal results should be repeated 3 months after the acute stroke period. Protein S levels may be lowered in chronic or acute illness, such as liver disease, nephrotic syndrome, and disseminated 52 intravascular coagulation (DIC), and in the immediate postoperative period. Similarly, low levels of protein C and S have been reported with pregnancy and with the use of oral 52 anticoagulants because of their vitamin K–depleting effect. The most common causes of secondary protein C and S deficiencies are inflammatory illnesses in which the complement 71 system is activated, leading to increased serum binding of these proteins. The interactions between antithrombin III and heparin are important to recognize when testing for antithrombin III deficiency. Heparin increases the activity of antithrombin III by 66 approximately 100-fold. Because the anticoagulant effect of heparin is mediated by antithrombin III activity, heparin resistance is a clue to possible antithrombin III deficiency. Treatment with heparin causes a decline in antithrombin III levels that usually normalizes 66 within 48 to 72 hours after cessation of treatment. Treatment decisions in patients with any of the inherited deficiencies should be made on an individual basis because there are inadequate prospective studies evaluating treatment regimens and duration of therapy. Some authors recommend that any patient with protein C, 54 protein S, or antithrombin III deficiency should be considered for lifelong anticoagulation. Antithrombin III deficiency has the highest risk of recurrence of thrombotic events, and any patient with an inherited deficiency should be advised of the risks of thrombosis with oral 72 contraceptive use, prolonged bed rest, and pregnancy. The optimal duration of treatment with anticoagulants is unclear and some authors recommend treatment only during periods of heightened thrombotic risk (e.g., bed rest, pregnancy, postoperative periods). There have been numerous reports of severe warfarin-induced skin necrosis occurring in individuals with protein C deficiency, and52physicians should be aware of this potentially serious complication of anticoagulant therapy.
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ACTIVATED PROTEIN C RESISTANCE Normal hemostasis involves a complex interaction between procoagulant and anticoagulant components in the blood. These components act, through a complex system of feedback mechanisms, to cause hemostasis at sites of vessel injury while simultaneously ensuring that clots do not form in areas of normal, undamaged endothelium. A number of inherited coagulation disorders predispose individuals to a prothrombotic state and may result in cerebral ischemic events. Protein C, protein S,71and antithrombin III deficiencies are the most common of the inherited prothrombotic states. Dahlback and associates have described 73 activated protein C resistance in a number of patients with venous thromboembolic events. Some authors now recognize activated protein C resistance as the single most common 51,52 cause of hereditary thrombophilias. At a site of blood vessel or endothelial injury, thrombin activates platelets, leading to aggregation. Fibrinogen is converted to fibrin, which binds the aggregated platelets to form a platelet plug. In addition to its procoagulant effects, thrombin plays an anticoagulant role in a feedback mechanism by binding to thrombomodulin. Once bound to thrombomodulin, thrombin loses its procoagulant activity and then activates protein C (activated protein C), which acts with co-factor protein S to inactivate factors Va and VIIIa of the clotting cascade, protein C also inhibits thereby preventing further clotting (Fig. 61-1). In addition, activated 51 tissue plasminogen activator inhibitor to stimulate fibrinolysis.
FIGURE 61-1 The protein C anticoagulant pathway. Thrombin converts factor
VIII and factor V to their activated forms, factor VIIIa and factor Va. A complex of thrombin with the endothelial cell receptor thrombomodulin activates protein C (APC). APC inactivates factor VIIIa and factor Va on the platelet surface, and this reaction is accelerated by APC cofactor and free protein S. (From Bauer KA: Hypercoagulability: a new cofactor in the protein C anticoagulant
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pathway. N Engl J Med 330:567, 1994, with permission. © 1994, Massachusetts Medical Society. All rights reserved.) Although there is probably a host of genetic and environmental factors that contribute to activated protein C resistance, a genetic defect in factor V is the most commonly described causative factor, accounting for 85 to 95 percent of activated protein C resistance in some 51,74 This dysfunctional factor V,74referred to as the factor V Leiden, is caused by a series. G-to-A mutation on the factor V gene. This amino acid substitution renders factor V resistant to protein C–induced enzymatic cleavage, thereby negating the anticoagulant 51 V Leiden is inactivated by properties of activated protein C. In vitro studies show that factor 51 activated protein C 10 times more slowly than normal factor V. The prevalence of the factor V Leiden mutation in the general population is not entirely clear. One study found the mutation in 4.4 percent of European subjects, although only 4 percent of 75 men in the Physician's these were homozygous for the mutation. A study of the 15,000 76 Health Study showed a carrier rate of approximately 6 percent. There appears to be an uneven geographical distribution of the factor V Leiden mutation, which occurs more rarely in 51 Japanese, Asian, and Middle Eastern populations than in Europeans. It is estimated that only 6 percent of those with the genetic defect will actually develop venous thrombosis over a 51 30-year period. Most data regarding activated protein C resistance point to this defect as a risk for venous, rather than arterial, thrombotic events, and the association between arterial60,76–78 disease and The activated protein C resistance and the factor V Leiden mutation is not clear presence of the factor V Leiden mutation has79been associated with an almost fivefold increased risk of ischemic stroke in children. However, the mutation was not found to be more prevalent in 468 patients younger than 60 years with acute stroke or TIA compared with healthy controls, although women80who smoked and had the factor V mutation had an almost risk of carotid ninefold increased risk of stroke. In a population-based study of 826 men, the 73 stenosis increased linearly with a decreased response to activated protein C. This association applied to those both with and without the factor V Leiden mutation, suggesting that there are important hormonal and environmental factors that contribute to activated protein C resistance. It is possible that the reported events represented venous rather than arterial infarcts or that venous thromboemboli reached the cerebral vasculature by means of a patent foramen ovale or other cardiac defect. In a study of 34 patients with cryptogenic stroke and patent foramen ovale diagnosed by transesophageal echocardiography, prothrombotic states such as activated protein C resistance, protein C/S deficiencies, and antiphospholipid antibodies were 67 found in 76 percent of patients. Other studies, however, have failed to confirm this association. Studies looking at the role of activated protein C resistance in cerebral venous thrombosis are less numerous. In a study by Deschiens and colleagues of 40 patients with cerebral venous thrombosis, 6 cases (15%) had an underlying thrombophilia of protein C deficiency, 72 protein S deficiency, or activated protein C resistance. Five of six cases were associated with other risk factors, suggesting that the presence of activated protein C resistance or other thrombophilia may predispose individuals or make them more susceptible to thrombogenic environmental or physiological factors. In a study of 12 German patients with cerebral venous thrombosis, 25 percent had the factor V Leiden mutation, compared with only one patient in 81 the control group with the mutation, a difference that was statistically significant. In a case-control study of 19 patients, Zuber and associates found a similar prevalence of the factor V Leiden mutation in 21 percent of patients compared to 2 percent of control 82 subjects. Most of the literature consists of case reports, rather than prospective studies, but the number of these reports points 83–85 to a strong relationship between the factor V Leiden mutation Moreover, the subjects of these case studies often have and cerebral sinus thrombosis. other thrombogenic risks, such as oral contraceptive use, coexisting thrombophilias, trauma, and prolonged immobilization, again speaking to the manner in which the gene mutation may predispose individuals to an exaggerated effect of these other prothrombotic conditions, rather than being the sole causative factor. These contributing risk factors, particularly the concomitant use of oral contraceptives, may pose a greater risk than initially appreciated. A French study of 321 women with the factor V Leiden mutation showed a 50-fold increased risk of venous thrombosis in heterozygotes taking oral contraceptives and a greater than 100-fold increased risk in homozygotes using 86 oral contraceptives. These data prompted some authors to recommend testing for factor V
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Leiden in all women receiving oral contraceptives, although the issue is still unsettled. There is still a limited amount of data on cerebral venous thrombosis and venous infarcts, and the risk of cerebral venous thrombosis cannot confidently be extrapolated from the data on peripheral venous disease. However, it seems unreasonable to assume that the prothrombotic effects of the factor V Leiden mutation are isolated primarily to the peripheral venous system. The decision to test for activated protein C resistance and factor V Leiden mutation should be made on an individual basis. Reasonable guidelines are to test young patients with stroke without other prominent risk factors, those with a family history of thrombotic or venous occlusive disease, patients with cerebral venous infarcts, and those with a history of thrombotic events. In addition, given the data suggesting the increased susceptibility of activated protein C–resistant patients to thrombosis from other genetic or environmental factors, it may be helpful to test for activated protein C resistance in patients in whom stroke occurred during pregnancy or the postpartum period or while oral contraceptives were being taken, or when there is a known inherited thrombophilia such as protein C, protein S, or antithrombin III deficiency. Laboratory testing for activated protein C resistance measures the activated partial thromboplastin time (aPTT) in the presence and absence of activated protein C. It is expressed as a ratio of aPTT with the addition of activated protein C to aPTT in the absence of activated protein C. Because anticoagulants may increase the aPTT, tests should be 51 with a ratio performed only after the cessation of heparin and oral anticoagulants. Persons 54 of less than 2.0 are considered to have resistance to activated protein C. If activated protein C resistance is discovered, it is appropriate to test for the factor V Leiden mutation. Some authors recommend screening for the mutation in any patient with stroke younger than 55 years when other definable risk factors are absent, with the understanding that results should be interpreted judiciously because as many as 52 5 percent of the general population may be heterozygous for the factor V Leiden mutation. Testing for factor V Leiden is preferable in some instances because the results are not affected by anticoagulant 54 use or treatment. Family members should also be considered for testing if a genetic defect is established in the patient. No definitive recommendations can be made regarding treatment of activated protein C resistance or any of the aforementioned hereditary thrombophilias. The decision to treat with oral anticoagulation, rather than antiplatelet therapy, can be based on a number of factors, including age of the patient, family history of thrombophilias or thrombotic disease, the occurrence of prior thrombotic events, and the presence of concomitant genetic or environmental risk factors for venous occlusive disease. Particular attention should be paid to those with cerebral venous infarcts, women who are pregnant or taking oral contraceptives, and patients with a patent foramen ovale, which may act as a passageway for venous thromboemboli to reach the arterial system. No studies have established an adequate 56 treatment regimen and optimal length of therapy with anticoagulants. SICKLE CELL ANEMIA Hematological disorders are estimated to be the causative factor for up to 8 percent of all56,66 ischemic strokes and are particularly important in the etiology of stroke in young patients. Sickle cell anemia, in addition to causing a host of peripheral complications, such as sickle cell crises, has been linked to cerebrovascular events. Strokes occur in 8 to 17 percent of patients with sickle cell anemia, although cerebral ischemic events usually do not occur in the 65 context of a sickle cell crisis. Homozygotes (designated HbSS) for the disease represent 0.03 to 0.16 percent 87 of the population, and heterozygotes with sickle cell trait (HbSA) represent 8.5 percent. Sickle C disease88(HbSC) has a prevalence of 0.02 to 0.21 percent among blacks in the United 88 States. Approximately 15 percent of homozygotes experience a cerebral ischemic event. There are conflicting data as to whether individuals with sickle cell trait and sickle C disease are at increased risk of stroke. The estimated prevalence of stroke is 1.5 to 2.0 percent in blacks with88HbSA, which is essentially the same as the incidence in the overall black population. However, the risk of stroke in those with HbSC has87been reported as 2 to 5 percent, which suggests a higher risk of stroke in these patients. The prevalence of stroke by age 20 may be as high as 11 percent, although many of these may be clinically asymptomatic and detected only by magnetic resonance imaging (MRI) of the brain. The average age of87,88 stroke onset is relatively young, with a reported mean age of 7 to 9 years in Some studies report that approximately 8 percent of 66 all children with HbSS patients. sickle cell anemia experience a cerebrovascular event by the age of 15. The actual risk of
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stroke may be significantly higher, however, because up to 24 percent of patients with 89 HbSS have silent infarcts, present on neuroimaging, with no apparent clinical manifestations. Most strokes in patients with sickle cell disease are ischemic, although a number of studies 66,87 suggest that older individuals are also at increased risk of hemorrhagic cerebral events. With regard to clinical presentation, hemiparesis is the most common feature, although strokes may occasionally be heralded by signs or symptoms of sickle cell crisis such as 87,90 Thrombosis of large vessels, including carotid and 87 fevers or abdominal or bone pain. vertebral arteries, is common, although venous sinus thrombosis has also been reported. Some evidence exists that individuals with particularly severe sickle cell disease, manifested by a high number of crises and complications, are more prone to cerebrovascular events, possibly because of higher blood viscosity and greater endothelial damage. The pathophysiological process of stroke in patients with sickle cell anemia (discussed in Chapter 13) is still under investigation. It was initially believed that the lowered solubility of deoxygenated hemoglobin S resulted in aggregation and sickling in small vessels, but increasing evidence suggests large-vessel stenosis as the primary etiology of cerebrovascular events. In one study, cerebral angiograms performed in seven patients with sickle cell anemia and stroke revealed partial or complete occlusion of the internal carotid artery in six, with concurrent vertebral and large intracranial artery stenosis in a number of 91 arterial disease was found in 10 of others. Similarly, angiographic evidence of large-vessel 92,93 12 patients and 23 of 30 patients in two other studies. The vascular damage, when examined histologically, consists of segmental thickening due to 90,94 Once these vascular changes intimal proliferation of fibroblasts and smooth muscle cells. 90 occur, vessel occlusion likely results from in situ thrombus formation or embolization. Some authors also suggest that obstructed flow in the vasa vasorum, due to erythrocyte sickling, leads to ischemia and subsequent necrosis 87 of the vessel wall, which further promotes intimal thickening and subsequent vessel stenosis. Given that HbSS erythrocytes are abnormally adherent to the vascular endothelium, this cascade of events could lead to vessel 95 thrombosis, occlusion, and subsequent stroke. Arterial narrowing and occlusion may lead to a pattern like that of moyamoya on conventional 66,87 Radiographic dyes used during angiography may enhance intravascular angiography. 66 Arteriography is considered safe sickling, so angiography should be performed with caution. 88 if the hemoglobin S level is less than 20 percent. Conventional imaging studies such as computed tomography (CT) and MRI typically show infarcts in a watershed or border zone distribution, consistent with the large-vessel 65,95,96 Some authors have shown transcranial Doppler involvement of the disease. ultrasonography to be a useful diagnostic imaging tool because increased middle cerebral artery flow velocities may indicate the presence of underlying arteriopathy and increased 90,97 The risk of stroke during childhood in those stroke risk in patients with sickle cell disease. with sickle cell disease is 1 percent per year, but patients with transcranial Doppler ultrasonographic evidence of high cerebral blood-flow velocities (>200 cm per second) have a 98 stroke rate in excess of 10 percent per year. A study using transcranial Doppler imaging in 190 children with sickle cell disease showed that in those with Doppler imaging evidence of vessel stenosis, 26 percent went on to sustain cerebrovascular events, compared with 0.6 99 percent of patients without evidence of stenosis. Once a diagnosis of stroke has been made, immediate therapy to prevent further episodes of brain ischemia should be instituted because the recurrence rate may be as high as 67 66 100 percent, usually within the first 12 to 24 months after the initial event. Some studies have 100 shown that 80 percent of recurrent events occur within the first 3 years of the initial event. The mainstay of preventive therapy is lowering of the percentage of hemoglobin S in the blood. This is most effectively carried out by transfusion therapy, which effectively lowers the percentage of red blood cells that can sickle and was found in the early 1980s to lower 94 hemoglobin S level at less recurrent stroke risk. Most authors recommend maintaining the 90 than 30 percent by performing exchanges every 3 to 4 weeks. In 1995, the National Heart, Lung, and Blood Institute conducted a multicenter, randomized, controlled study in which half of the patients were treated in this manner, with monthly transfusions to keep hemoglobin S levels less than 30 percent. The study was stopped prematurely when a 90 percent stroke 99 reduction was noted in treated patients. Similarly, the Stroke Prevention in Sickle Cell Anemia (STOP) study showed that the risk of stroke could be reduced from 10 percent per 101 year to less than 1 percent per year with routine transfusion therapy. The optimal duration of therapy is unclear. A study by Wilimas and co-workers showed that 7 of 10 patients who had their transfusions stopped after 1 to 2 years went on to have subsequent strokes within 1 92 year. Similarly, Wang and associates reported that 5 of 10 patients had recurrent strokes
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within 1 year of cessation of transfusion therapy. Based on these data, it appears that transfusions may be required indefinitely, although such an extensive treatment regimen should be weighed against the transfusion risks of iron overload, transfusion reaction, and donor-borne transmission of infectious diseases. In addition to transfusion therapy, other 87 methods to lower blood viscosity such as vigorous hydration are also appropriate. There are no convincing data to support the use of antiplatelet agents or anticoagulants for preventive therapy. However, recently published guidelines on primary prevention of ischemic stroke from the American Heart Association American Stroke Association recommend that children 103 with sickle cell disease be screened with transcranial Doppler starting at 2 years of age. Similarly, there is clearly a need for more studies to evaluate the role of other, more novel stroke therapies such as angioplasty or surgical procedures in treating stenotic lesions of large vessels. SYSTEMIC LUPUS ERYTHEMATOSUS Central nervous system (CNS) involvement with systemic lupus erythematosus (SLE) was recognized as early as 1869 by Kaposi, who noted headache, delirium, and coma in a patient 104 with SLE. Years later, in 1903, Osler described episodes of focal cerebral ischemia associated with lupus and postulated that the vasculitic changes seen peripherally in SLE 105 may also cause ischemic symptoms in the CNS. It is now recognized that SLE predisposes affected individuals to a host of neurological disorders, including strokes, seizures, chorea, 106 dementia, psychosis, neuropathy, and myelopathy. In one study, 63 of 91 patients with SLE had central or peripheral neurological dysfunction, with cerebrovascular events being the third 106 most common manifestation, following seizures and delirium. Stroke occurs in 3 to 20 percent of patients with 105 SLE, and hemiparetic or hemiplegic involve episodes have been reported in 4 to 13 percent. These ischemic events typically 105–107 One younger patients with SLE, with a mean age at the time of stroke of 42 years. particular study tracing SLE patients in California hospitals found strokes to be 10 times more 108 frequent in women aged 18 to 44 years than in those of similar age without SLE. In a study of 234107patients with SLE, 5.6 percent had cerebrovascular disease, primarily stroke or after the diagnosis of SLE, TIAs. More than half of the events occurred within 5 years105 are which is in accordance with incidence rates in other studies. At especially high risk 105 elderly patients with SLE, who had stroke rates as high as 57 percent in one study. Besides advanced age, other stroke risk factors such as hypertension, diabetes, and 109 hypercholesterolemia may act synergistically with SLE to increase the stroke risk. Although most infarcts in SLE are ischemic, cerebral hemorrhage has also been reported, 105 usually in the setting of concurrent thrombocytopenia. Subarachnoid hemorrhage in SLE is well documented, although many of the published studies are from Japan where there is an 110 increased risk of hemorrhagic stroke due to ethnic factors. The most frequent etiology for ischemic cerebrovascular events appears 106 to be either cardiogenic embolus or an antibody-mediated hypercoagulable state. In an autopsy study, cardiac valvular disease was discovered in nearly111half of the patients, with Libman–Sacks endocarditis being the most of frequent valvular lesion. Cardiac valvular lesions have been detected in 35 to 59 percent 112 autopsy cases and are often associated with the presence of antiphospholipid antibodies. Based on these findings, echocardiography and laboratory testing for antiphospholipid antibodies are crucial components of the evaluation of any patient with SLE who has an unexplained stroke or TIA. In the autopsy study mentioned earlier, no cases of intracranial vasculitis occurred, and the incidence of cerebral vasculitis has been extremely low or nonexistent in other autopsy studies, thereby disproving Osler's original hypothesis that SLE-induced vasculitic change 107,113 Fibrin-platelet occlusion of intracranial was a frequent cause111 of stroke in lupus. arterioles may occur, and a noninflammatory vasculopathy secondary to vessel wall hyalinization and endothelial proliferation has been the most common cerebrovascular 112 abnormality in other autopsy studies. These lesions appear to correlate with the scattered punctate periventricular and white matter hyperintensities seen on MRI in patients with 112 SLE. The cause of the vasculopathy in SLE is unclear, although postulated mechanisms 112 include endothelial damage by antineuronal antibodies or immune complex deposition. Other pathological findings include isolated large-vessel stenosis, arterial dissection, and 114 fibromuscular dysplasia. Although prospective studies of stroke treatment or prevention strategies in SLE are lacking, the occurrence of multiple infarcts in some patients (up to 64% of patients with SLE and 106 stroke in one study ), as well as a recurrence rate that may be as high as 50 percent, underscores the need for thorough evaluation and identification of modifiable risk factors. In one study, patients with SLE and stroke were retrospectively and prospectively compared
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with patients with SLE without cerebrovascular events. Concurrent cardiac valvular disease, coagulopathy, previous TIA or stroke, and age older than 60 years were all more common in the group with stroke. The use of anticoagulants may reduce the risk of stroke recurrence in patients with 105,115,116 In one nonrandomized study, anticoagulation appeared to reduce the risk of SLE. recurrent focal105 cerebral ischemic events and was associated with very few significant complications. Oral anticoagulation may be warranted in patients with SLE who have concurrent risk factors of cardiac valvular lesions or a history of TIA or stroke. Aspirin appears to be less effective in reducing the risk of recurrence in retrospective studies, 105 particularly in individuals with the lupus anticoagulant. Given the absence of inflammatory vascular lesions in patients with SLE 105,106,112 who have strokes, steroids probably have no role in the although most authors recommend their use in treatment of cerebrovascular events, 114 the setting of systemic vasculitis and high anticardiolipin antibody titers. ANTIPHOSPHOLIPID ANTIBODIES, LUPUS ANTICOAGULANT, AND ANTICARDIOLIPIN ANTIBODIES With the advent of new serological and immunological testing methods, a great deal of confusion has been generated regarding antiphospholipid antibodies and their role in the pathogenesis of stroke and peripheral thrombotic disease. Both the lupus anticoagulant and anticardiolipin antibodies fall under the category of antiphospholipid antibodies, and the two 117 have almost identical antigenic specificities. Both the lupus anticoagulant and anticardiolipin antibodies are recognized as markers for117 increased risk of thrombosis, abortion, cerebral ischemia, and multi-infarct dementia. The prevalence of lupus anticoagulant or anticardiolipin antibodies is estimated at 10 to 50 percent of patients with SLE. The presence of anticardiolipin antibodies in association with thrombotic events has been increasingly recognized in patients without evidence of117connective tissue disease and referred to as primary antiphospholipid antibody syndrome. Thrombotic episodes affecting virtually every organ in the body have been reported in persons with antiphospholipid antibodies, and this association has been particularly well 118 demonstrated for stroke and TIAs (Fig. 61-2). In a study of 80 patients with antiphospholipid antibodies, 31 percent had neurological manifestations consistent with 119 that antiphospholipid antibodies were present in 46 cerebral ischemia. Another study found 120 percent of young patients with stroke, and a review of the literature suggests that antiphospholipid antibodies may be a contributing factor in approximately 10 percent of all 118 cerebrovascular events. Furthermore, the presence of either the lupus anticoagulant or anticardiolipin antibodies in patients with SLE imparts a twofold greater risk of thrombotic 121 events. Studies also show an increased stroke risk with high anticardiolipin 109,122 The immunoglobulin G (IgG) titers, whereas IgM titers appear to be less predictive. association between antiphospholipid antibody levels and stroke is strengthened by evidence that patients with119 higher levels are more likely to have multiple cerebral infarcts than those with lower levels.
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FIGURE 61-2 Angiography showing a middle cerebral artery stem occlusion
(arrow) in a young woman with anticardiolipin antibodies, lupus anticoagulant, and myxomatous mitral valve thickening. (From Coull BM, Levine SR, Brey RL: The role of antiphospholipid antibodies in stroke. Neurol Clin 10:130, 1992, with permission.) Some recent studies have failed to show a clear association between antiphospholipid antibodies and ischemic stroke. Thus, in one study (the APASS study) of all individuals with stroke regardless of age or sex, an increased risk of subsequent vascular occlusive events was not found in patients with rather than without antiphospholipid antibodies, although the 123 follow-up period was relatively short (2 years). Nevertheless, several studies have shown an association between stroke and antiphospholipid antibodies in young women, suggesting 109,124 that these individuals may be at increased risk. The pathophysiological process of antiphospholipid antibody-associated thrombosis remains to speculative (Fig. 61-3). The lupus anticoagulant has been shown in a number of studies 107,117 inhibit prostacyclin, which acts as a vasodilator and inhibitor of platelet aggregation. Other possibilities include117,118 an interference with the activation of protein C, which is needed to Because platelet membranes as well as endothelial cells are regulate thrombogenesis. rich in phospholipids, antiphospholipid 118 antibodies may bind to or damage these membranes, increasing the risk of thrombogenesis. Antiphospholipid antibodies have been associated with an increased incidence of Libman–Sacks endocarditis and left-sided cardiac valvular 125 These cardiac abnormalities are associated with an increased stroke abnormalities. 107,111,112 risk.
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FIGURE 61-3 Proposed mechanism of antiphospholipid antibody-induced
thrombosis. Antiphospholipid antibodies in a complex with β2-glycoprotein-1 bind to platelet or endothelial membrane phospholipids, thereby causing platelet activation and endothelial damage. The ensuing platelet adhesion, aggregation, and impairment of endothelial anticoagulant function promote coagulation activation, vasospasm, and thrombosis. EDRF, endothelium-derived relaxing factor; PGI2, prostacylin. (From Coull BM, Clark WM: Abnormalities of hemostasis in ischemic stroke. Med Clin North Am 77:86, 1993; modified from Eisenberg GM: Antiphospholipid syndrome: the reality and implications. Hosp Pract 27:121, 1992, with permission.) The presence of antiphospholipid antibodies has been frequently noted in patients with SLE; 121 these antibodies may be present in up to 58 percent of such patients. Antiphospholipid antibodies have also been noted in patients with a host of other connective tissue diseases, including Sjögren's syndrome, Behçet's syndrome, mixed connective tissue disease, 118 rheumatoid arthritis, and autoimmune thrombocytopenic purpura. Systemic infections, especially syphilis, Lyme disease, and viral infections, can cause an elevation of antiphospholipid antibodies, but their presence in these conditions usually has little or no 118 may be association with thrombotic events. Furthermore, antiphospholipid antibodies118 present in normal individuals, with a 2 to 5 percent prevalence in some studies. These antibodies are found with increasing frequency in elderly individuals, with a 12 percent 126 prevalence in individuals averaging 70 years of age. The diagnosis of an antiphospholipid antibody syndrome involves both clinical and laboratory criteria. Any individual younger than 55 years with one or more thrombotic events without 127 known vascular risk factors should be screened for the presence of these antibodies. Associated clinical signs include the presence of left-sided cardiac valve lesions, spontaneous abortions, livedo reticularis, migraine headaches, and 127 a prolonged aPTT or a positive Venereal Disease Research Laboratory (VDRL) test result. Because lupus anticoagulant and anticardiolipin antibodies are probably different immunoglobulins, patients should be tested for both; they may occur independently, and it is unclear which antibody is more predictive of thrombosis. In patients with lupus anticoagulant, the aPTT is prolonged in 80 percent of cases, but mixing studies are required to prove that this prolongation is not
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correctable by the addition of normal sera. In the platelet inhibition test, the presence of lupus anticoagulant is confirmed when the inhibitor's activity is neutralized by adding phospholipid, 118 which binds and inactivates the lupus anticoagulant. Enzyme-linked immunosorbent assays are also available for antiphospholipid antibody testing. The exact mechanisms involved in antiphospholipid antibody–associated cerebrovascular disease are unclear, as is the natural history of individuals with incidentally discovered antiphospholipid antibodies. But with estimates of annual stroke rates as high as 6.75 percent 120,122 it is important to clarify the benefit of and annual recurrence rates of 14 percent, preventive therapies. The aforementioned APASS study failed to find any difference in response to aspirin or warfarin treatment in patients with ischemic stroke and 123 antiphospholipid antibodies. Therefore, at present, antiplatelet agents are generally recommended for initial therapy,128 and efforts should be made to identify and treat other conventional stroke risk factors. If patients have recurrent strokes, especially in association with high anticardiolipin levels (particularly IgG), or both the lupus anticoagulant and117,118 anticardiolipin antibodies, some experts recommend the use of oral anticoagulants. Anticoagulants are also often recommended for patients with the primary antiphospholipid antibody syndrome. For patients treated with warfarin, higher international normalized ratio (INR) levels may be more beneficial in patients with antiphospholipid antibodies. In a small study of patients with antiphospholipid antibodies and cerebrovascular events, warfarin prevented or reduced the frequency of cerebral ischemic 117 events in five of eight patients, whereas aspirin did not prevent recurrent events in three. Steroids are probably of no benefit because the mechanism of stroke seems not to involve an inflammatory or vasculitic component.
Sneddon's Syndrome This clinical entity deserves special recognition because it involves ischemic strokes and antiphospholipid antibodies. Sneddon's syndrome is a vascular dementia 118 characterized by multiple strokes and livedo reticularis in the absence of systemic disease. Affected patients may have Raynaud's phenomenon or acrocyanosis of the digits, placing this disorder on a 118 continuum with other rheumatological diseases. Antiphospholipid antibodies are usually prominent, and progressive cognitive deterioration may occur even in the absence of 118 stroke-like episodes. In a study of patients with vascular dementia, patients with positive antiphospholipid antibodies were found to have the onset of dementia almost a decade 119 earlier (average age, 52 years) than patients who tested negative for the antibodies. In his initial description of the clinical syndrome, Sneddon noted that the strokes typically caused minimal129 focal motor or sensory deficits, and dementia was the prominent neurological feature. Accordingly, any young patient presenting with progressive multi-infarct dementia and livedo reticularis should be evaluated for the presence of antiphospholipid antibodies. CRYOGLOBULINS AND STROKE Cryoglobulins are serum proteins with temperature-dependent insolubility, precipitating below 130 37°C. The presence of these proteins may occur idiopathically or in association with a number of autoimmune disorders, including SLE. Among connective tissue disorders, SLE, rheumatoid arthritis, and Sjögren's syndrome are the diseases most frequently associated 131,132 Most of the clinical manifestations of with the presence of cryoglobulins (8% to 48%). cryoglobulinemia are attributed133to the precipitation of cryoglobulins in small vessels and to (most commonly neuropathy) and CNS arterial and venous occlusion. Both peripheral 134,135 Imaging studies of the brain in select patients involvement occur in cryoglobulinemia. with cryoglobulinemia show multiple small hyperintensities compatible with ischemic 136 cold lesions. The association of stroke with cryoglobulinemia may relate to hyperviscosity, 133 agglutinization of erythrocytes, and defective clotting and platelet functions. Stroke may result when blood vessels in the nervous system are injured by mixed cryoglobulin deposition 133 that causes an immune complex–mediated vasculitis. In support of this possibility, Serena and co-workers found evidence of vasculitis in the vasa nervorum in the small vessels of the 134 brain in a patient with multi-infarct dementia secondary to cryoglobulinemia. Plasmapheresis has been effective in some patients with neurological complications of cryoglobulinemia, presumably because of lowering of the cryoglobulinemia and improvement 137 Beneficial results may be obtained in some cases by minimizing of the microcirculation. 135 cold exposure. Immunosuppressive agents have met with limited success, as have cytotoxic agents, and controlled clinical trials are needed before any definitive treatment 135 recommendations can be made. STROKE AND MALIGNANCY
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CNS lesions 138 are present in approximately 30 percent of patients with cancer on postmortem examination. Although the most common manifestation is metastatic disease to the brain, hemorrhagic and ischemic infarcts make up a significant percentage of these lesions. The largest autopsy study, performed at the Memorial Sloan-Kettering Cancer Center on 4,326 patients with cancer, showed a 14.6 percent incidence of cerebrovascular disease on 138 pathological examination. Approximately 50 percent of those with evidence of cerebrovascular disease were symptomatic, although a diffuse encephalopathy, rather than 138,139 focal neurological deficits, was the presenting symptom. The results of one study suggest that, at least in elderly patients with cancer, conventional 140 stroke risk factors account for most ischemic events. Other studies, however, clearly implicate malignancy-specific causes of stroke, and patients with cancer who have cerebrovascular events should be evaluated with these etiologies in mind. There does seem to be a higher incidence of embolic strokes in cancer patients, either due to 141 malignancy-related hypercoagulable states or to cardioembolism. The Sloan-Kettering study described four etiological categories of cerebrovascular events in patients with cancer: direct tumor effects, coagulation disorders, infections, and complications of therapeutic or 138 diagnostic procedures. The cause of cerebrovascular events in patients with cancer often correlates with the type of primary tumor, extent of metastases or disseminated malignancy, and the type of cancer therapy administered. Therefore, an understanding of the 142 malignancy-specific causes of stroke aids in both diagnosis and treatment.
Direct Tumor Effects Direct tumor effects include intratumoral hemorrhage, arterial and venous sinus invasion by tumor mass or leptomeningeal infiltrates, and tumor emboli. Tumor emboli occur rarely and exclusively in patients with solid tumors and are138,142 virtually impossible to distinguish from (Fig. 61-4). Metastatic emboli typically thrombogenic emboli on clinical grounds alone 138 result from heart or lung tumors. Specifically, atrial myxomas may shower tumor fragments into the cerebral or peripheral vasculature, and lung tumor embolism may occur at the time of 138,143,144 Tumors that demonstrate aggressive intravascular invasion such as thoracotomy. 142 Mucin from tumors, choriocarcinoma may also cause embolic cerebrovascular events. 142 especially carcinomas, may embolize to the brain. Neoplastic aneurysms, with subsequent rupture causing stroke, have been described. Tumor emboli may invade an arterial wall142 after acute occlusion of the vessel, eventually resulting in dilatation and aneurysm formation.
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FIGURE 61-4 Brain pathology in patient with anaplastic esophageal carcinoma
and diffuse encephalopathy. At autopsy, there were multiple microinfarcts due to tumor emboli. Figure shows hemorrhagic microinfarct in the white matter of the cerebral cortex, with blood vessels occluded by malignant cells (hematoxylin and eosin, 400×). (From Graus F, Rogers LR, Posner JB: Cerebrovascular complications in patients with cancer. Medicine [Baltimore] 64:16, 1985, with permission. © 1992, McGraw-Hill Companies Inc.) Cerebral venous thrombosis has also been reported in the setting of malignancy, with neuroblastoma, lung carcinoma, and lymphoma infiltrating vessels to produce stasis and 139 subsequent thrombosis. In the Sloan-Kettering autopsy study, 33 patients had evidence of thrombosis of the superior sagittal sinus, transverse sinus, or deep cortical veins, and 27 of these patients had thrombosis related to direct tumor infiltration or compression of the vessel 138 by metastatic tumor.
Coagulopathy 145
Disorders of coagulation affect up to 15 percent of patients with cancer. A hypercoagulable state associated with malignancy was first described by Armand Trousseau in 1865, who 145,146 reported a case of migratory thrombophlebitis in the setting of gastric carcinoma. Trousseau's syndrome has been linked to a broad spectrum of malignancies but is most commonly described with adenocarcinomas, particularly of the pancreas, lung, colon, and 146,147 147 and with prostate and gastric cancer and leukemia. breast, Although not clearly elucidated, a common pathological mechanism for hypercoagulability in patients with cancer 146,147 may involve exposure of tumor cell tissue factor thromboplastin to the Many investigators believe that this sequence of events results in a systemic circulation. 146,147 A DIC-like clinical chronic low-grade prothrombotic state that clinically resembles DIC. picture has been reported in a number of cases of acute promyelocytic leukemia, presumably from the138release of nuclear or granular fractions of tumor cells that have procoagulant have been identified, with tissue factor activity. Similarly, a number of tumor procoagulants 145 and cancer procoagulant being the best recognized. Tissue factor is believed to activate145 factor X in the extrinsic clotting cascade, thereby leading to a tendency toward thrombosis. Tumor cells can also activate platelets in vivo through adenosine diphosphate–dependent 145 mechanisms. Although abnormalities of blood coagulation are reported in 60 to 92 percent of patients with 138 cancer, these coagulopathies rarely produce clinical symptoms. When present, a coagulation disorder145may manifest itself by either superficial or deep venous thrombosis, or arterial thrombosis. In their large series of patients with cancer, Graus and co-workers noted that intravascular coagulation, as evidenced by small thrombotic cerebral infarcts without an identifiable embolic source, was the second most common cause of symptomatic 138 cerebral infarction. Whether these findings are indicative of a type of low-grade DIC or represent a separate malignancy-related coagulation disorder is unclear. Regardless of the pathophysiology, patients tend to have a poor prognosis. These coagulation abnormalities are usually present in the setting of advanced and disseminated disease, particularly leukemia and breast cancer, and death occurred within 3 weeks in all but one patient in the 138 is usually not helpful because abnormalities of Sloan-Kettering series. Laboratory testing 139 routine coagulation studies are often mild. Laboratory analysis is further confounded by the fact that a host of other malignancy-related conditions, such as concurrent chemotherapy or liver disease, may affect normal clotting activity, and approximately 90 percent of patients with metastatic disease have abnormal coagulation parameters, with thrombocytosis and 138,145 increased fibrinogen levels being the most common.
Nonbacterial Thrombotic Endocarditis A case of “thromboendocarditis” was first described by Ziegler in 148 1888, when fibrin deposits were found at autopsy on cardiac valves in a patient with cancer. Since then, the terms marantic and cachectic endocarditis have been used to describe the same clinical entity. Although nonbacterial thrombotic endocarditis (NBTE) may represent a continuum with intravascular coagulation and malignancy-induced DIC, this clinical entity warrants separate consideration because it plays a prominent role in the pathogenesis of cerebrovascular disease and stroke. Although the prevalence of NBTE is relatively low in patients with cancer 149 (approximately 1%), it is a leading cause of stroke in these patients. In the autopsy series mentioned earlier, 51.3 percent of symptomatic cerebral infarcts were due to either NBTE or 138 intravascular coagulation. In patients with carcinoma, NBTE was the leading cause of
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cerebral infarcts. The prevalence of NBTE may be significantly higher than reported in most autopsy studies, however, because the friable150nature of the vegetations may leave only traces or small remnants on the valves at autopsy. Pathologically, NBTE consists of platelet-fibrin vegetations that develop on the cardiac valves, with the aortic and mitral valves (Fig. 61-5) the most common sites of 139,145,150,151 These friable vegetations frequently embolize, causing infarction in involvement. brain, lung, kidney, and cardiac tissue. Symptoms of brain ischemia may occur concurrently with pulmonary embolism, myocardial infarction, or peripheral emboli, and the presence of these clinical events in multiple locations increases the probability of a cardiac embolic 142 source.
FIGURE 61-5 Examples of different types of lesions in nonbacterial thrombotic
endocarditis (NBTE) involving mitral (A) and aortic (B) valves. (From Lopez JA, Ross RS, Fishbein MC, et al: Nonbacterial thrombotic endocarditis: a review. Am Heart J 113:773, 1987, with permission.) NBTE is most frequently described with lung and gastrointestinal tumors, although it has been reported with a host of neoplastic processes. A review of the literature shows adenocarcinoma, particularly of the lung, pancreas, and stomach, to account for 60 to 80 percent of NBTE cases. In one138,142,151 series, lymphoreticular malignancies were reported in 25 Other, noncancerous conditions such as rheumatic percent of patients withNBTE. heart disease, pregnancy, cirrhosis, SLE, anticardiolipin antibodies, vasculitis, severe burns, 148,149 In many cases, stroke and amitriptyline overdose have all been associated with NBTE. caused by NBTE is the first indication of malignancy. The possibility of an underlying malignancy should be considered in any patient lacking conventional stroke risk factors who presents with evidence of embolic cerebral infarction, if no clear embolic source is recognized.
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The pathogenesis of NBTE may relate to an underlying cardiac valvular abnormality that acts as a predisposing factor for the deposition of platelets and fibrin, which is facilitated by 138,149 Once valvular damage occurs, underlying exposed cancer-related hypercoagulability. 148 collagen may act as a nidus for platelet adhesion and subsequent thrombus formation. Most vegetations are multiverrucous and less than 3 mm, which148 accounts for the relatively low diagnostic yield of conventional M-mode echocardiography. Microscopically, the valvular lesions consist148of agglutinated blood and platelet thrombi in the absence of an inflammatory reaction. Embolic fragments are primarily composed of fibrin. Systemic emboli may be found in 50 percent of patients with NBTE, with cerebral, coronary, and renal 148 involvement being most frequent. Antemortem diagnosis of NBTE is often difficult. As previously mentioned, conventional echocardiography typically does not detect the vegetations, which are usually quite 142,151 152 There is a higher diagnostic yield with transesophageal echocardiography. small. Diffusion-weighted MRI of the brain may also be helpful, as these patients usually have 153 multiple strokes of differing sizes in different vascular territories. Patients with stroke often present with aphasia or focal motor deficits, although resolving neurological symptoms 139 because compatible with TIAs may also occur. A new or changing cardiac murmur is rare; 139,149 of their small size, the valvular vegetations rarely interfere with valvular function. Conventional angiography may be helpful because the presence of multiple embolic occlusions, in the absence of a clear cardiac or vascular abnormality, is suggestive of 142 NBTE. The presence of emboli to the skin, extremities, or other end organs may also provide clues to the diagnosis. Laboratory studies tend to be nonspecific. Patients often have abnormalities consistent with low-grade DIC coagulation (thrombocytopenia or an increase in fibrin split products), which suggests that NBTE may represent a continuum with intravascular 138,148,151 coagulation. Once a diagnosis of NBTE is made, treatment of the primary malignancy should be addressed. If there is no recognized malignancy, a thorough search should be undertaken for occult cancer. In addition, a thorough evaluation for autoimmune and rheumatological disease (particularly the antiphospholipid antibody syndrome) should be performed, as NBTE is often associated with these medical disorders in the absence of an underlying 154 Effective treatment of the tumor may limit the development or progression of malignancy. 139 NBTE. In addition to cancer therapy, attempts to control the pathologically altered 148 coagulation mechanism that results in the valvular vegetations should be considered. A study of rabbit heart valves showed that148 heparin was effective in preventing the deposition of platelets and fibrin on damaged valves. Although there have been no prospective studies, a number of case series report clinical benefits of anticoagulation with intravenous heparin. In one series of 12 patients treated with heparin, 1 patient experienced symptomatic improvement, 3 138 patients clinically worsened, and 4 patients worsened after discontinuation of heparin therapy. In another study, a 94 percent “response rate” was noted with intravenous heparin administration, 147 as characterized by resolution of thrombophlebitis or cessation of arterial embolic events. None of the patients who received heparin experienced either subarachnoid or intracerebral hemorrhage. The utility of warfarin for treatment of NBTE is nevertheless still in question. One report considered a combination of aspirin and warfarin to 147 be ineffective. More prospective trials are necessary before any definitive recommendations can be made regarding optimal antithrombotic therapy.
Strokes Related to Cancer Therapy The chemotherapeutic agent l-asparaginase is most frequently associated with cerebral 155 infarction. In most cases, infarction results from cerebral venous sinus thrombosis; consistent with the course of sinus thrombosis from other causes, most patients make a 138 good clinical recovery. Although the cause for the sinus thrombosis is unclear, some studies have shown that l-asparaginase may cause a decreased partial thromboplastin time (PTT) and increased platelet aggregability, as well as antithrombin III and plasminogen 138 deficiencies. A large retrospective study of almost 11,000 cancer patients treated with chemotherapy showed a relatively low incidence of stroke (0.137%), the majority occurring within 10 days of chemotherapy treatment; treatment with platinum compounds was associated with stroke 156 more frequently than other chemotherapeutic agents. In addition to chemotherapeutic cerebrovascular complications, radiation-induced injury to the cervical and intracranial carotid arteries has been recognized as a potential cause of stroke, 139,157 The interval from radiation presumably by causing accelerated atherosclerosis. treatment to onset of occlusive cerebrovascular disease ranged from 6 months to 138,158 57 years in The one report, although most strokes usually occurred at least 1 year after exposure.
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cumulative radiation dose is usually greater than 50 Gy. Angiography reveals occlusion or extensive stenosis of the arteries in the previously applied radiation field, and carotid artery 139 lesions in patients irradiated for head and neck cancers are the most common. Limited data on treatment options are available, but carotid endarterectomy appears to be effective, 159 although technically more difficult. Cerebral angioplasty is another emerging therapeutic option.
Intracerebral Hemorrhage Intracerebral hemorrhage is most commonly reported with leukemic conditions, specifically 139 acute promyelocytic leukemia. Although the pathogenesis of the hemorrhage has been postulated to involve infiltration and rupture of vessels by leukemic nodules or damage to small vessels by hyperviscosity, most patients with intracranial hemorrhage in one study did not have evidence of leukostasis, leukemic nodules, or perivascular leukemic infiltration on 138,139 Among the patients who did have evidence of leukemic histological examination. 31,38 In a study infiltration, the peripheral white blood cell count was usually above 70,000/mm. by Wald and co-workers, intracranial hemorrhage was the cause of death in 15 percent of 160 patients with hyperleukocytosis and in 37.5 percent of adult patients with leukemia. Many patients with intracerebral hemorrhage have had sepsis, severe neutropenia, or severe thrombocytopenia, which may act as predisposing factors for bleeding. In addition to leukemic conditions, malignant lymphoma and multiple myeloma may cause hemostatic deficiencies that predispose to brain hemorrhage through inhibition of fibrin formation by 145 excess immunoglobulins. MEDICATION USE AND THE RISK OF STROKE
Oral Contraceptive Use The association between oral contraceptive use and stroke was demonstrated as early as 161 1969, with reports of up to a sixfold increase in the risk of stroke. However, these early studies involved oral contraceptives that contained relatively high doses of hormones, as opposed to the low-dose estrogen preparations used currently. The World Health Organization (WHO) has performed the largest case-control study of oral contraceptive use and stroke risk. In 697 women aged 20 to 44 years with ischemic stroke, the adjusted odds ratio for stroke occurrence among women who used oral contraceptives compared with those who had never used them was 3.0 (95% CI: 1.65 to 5.4) in Europeans 162 and 2.9 (95% CI: 2.15 to 4.00) in non-Europeans. A history of hypertension or tobacco use increased the risk in both groups, and the risk was lower if women had had a blood pressure measurement before starting the drug. In European subjects, the odds ratio in women using drug preparations containing less than 50 μg of estrogen was 1.53 (95% CI: 0.71 to 3.31), compared with 5.3 (95% CI: 2.56 to 11.0) in those using higher dose preparations. The conclusions from the study were that the overall incidence of stroke in young women is low, and the attributable risk due to oral contraceptive use is small. Women taking oral contraceptives can probably reduce the risk of stroke by modifying conventional risk factors such as tobacco use and hypertension. Another large population-based, case-control study performed at Northern California 163 Kaiser Permanente Medical Centers observed 408 cases of stroke in over 1 million women. A stroke incidence was calculated of 11.3 per 100,000 women-years with an odds ratio of 1.18 (95% CI: 0.54 to 2.59) for ischemic stroke and 1.14 (95% CI: 0.6 to 2.16) for hemorrhagic stroke in oral contraceptive users, most of whom were using low-dose estrogen formulations. As in the World Health Organization study, a positive interaction was noted between oral contraceptives and smoking, with an increase in the risk of hemorrhagic stroke. Based on the findings in this study, low-dose estrogen oral contraceptives did not appear to increase the risk of stroke. In a pooled analysis of two population-based studies, Schwartz and associates found an adjusted odds ratio for ischemic stroke in current low-dose oral contraceptive users of 0.66 (95% CI: 0.29 to 1.47) compared with women who had never used oral contraceptives, and 164 an odds ratio of 0.95 (95% CI: 0.46 to 1.93) for hemorrhagic stroke. The odds ratios increased to 2.08 and 2.15 for ischemic and hemorrhagic stroke, respectively, in current oral contraceptive users who also had a history of migraine headaches. These results should be interpreted with caution, however, because hemiplegic migraines might be miscategorized as stroke, artificially elevating the calculated stroke risk in these patients. Regardless, the data again suggest that women using low doses of oral contraceptives are 165–169 With an incidence rate of 11 cases per 100,000 not at increased risk of stroke.
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women-years, the authors point out that even with an assumed relative risk of 2, only one additional stroke per 100,000 women-years would occur as a result of oral contraceptive use, and the contraceptive and noncontraceptive benefits of the drug far outweigh the potential risks. Similarly, in one of the most comprehensive reviews of the literature to date, Thorogood estimates that the use of low-dose oral contraceptives increases the risk of stroke by not more than one event per 170 50,000 women-years, which is considerably less than the risk of stroke due to pregnancy. Gillum and colleagues found a slightly higher stroke risk in their meta-analysis of 73 studies of ischemic stroke and oral contraceptive use, finding an additional 4.1171 ischemic strokes per 100,000, with a relative risk of 1.93 for low-estrogen preparations. Therefore, although the data are somewhat conflicting, it appears that even if low-dose oral contraceptives increase the risk of stroke, this increase is so small that it should not alter current prescribing practices. However, given the seemingly additive stroke risk conferred by traditional risk factors in oral contraceptive users (such as hypertension, smoking, and diabetes), more careful consideration is required and oral contraceptive use may even need to be discouraged in these “higher risk” patients. There have been three major clinical trials investigating the relationship between stroke and postmenopausal hormone replacement therapy. Two trials focused172 on secondary prevention, and the Women's the Heart and Estrogen/Progesterone Replacement Study (HERS) 173 whereas the third, the Women's Health Initiative (WHI), Estrogen for Stroke Trial (WEST), 174 examined primary prevention. All indicate that postmenopausal hormone therapy is not effective in reducing the risk of a recurrent stroke or death among women with established 175 vascular disease or for prevention of a first stroke. Notably, the Women's Estrogen for Stroke Trial and the Women's Health Initiative studies showed an increased stroke risk in those individuals on active hormone replacement therapy, with a relative risk of 2.3 during the first 6 months in the Women's Estrogen for Stroke Trial and the Women's Health Initiative trial terminated because of an increase in vascular events that included an absolute increase of 8 strokes per 10,000 person-years. Therefore, in general, long-term postmenopausal hormone replacement therapy should be discouraged in individuals at risk of cerebrovascular events. The pathogenesis of stroke with use of oral contraceptive preparations probably involves a variety of mechanisms. Oral contraceptives may cause a predisposition to176hypercoagulability and are associated with a higher risk of venous thromboembolic disease. Furthermore, women already at risk of vascular disease because of other causes, such as tobacco use, hypertension, factor V Leiden mutation, or inherited coagulopathies, may be at even greater 176 risk of stroke when using oral contraceptives. Although the effects of estrogens on the mechanisms of hemostasis are extensive, platelet function tests have provided contradictory 177,178 Estrogens have been shown to increase serum levels of a number of coagulation data. 177 cascade proteins, including fibrinogen; factors II, VII, IX, X, and XII; and protein C. Although estrogen has the potential to induce a hypercoagulable state, the specific mechanisms involved have yet to be elucidated. It is not yet possible to predict which women are at higher risk of thromboembolism during oral contraceptive use, but it is appropriate to screen for underlying coagulopathies (protein C/S deficiency, antithrombin III deficiency, factor V Leiden mutation) in any woman who has a stroke while taking oral contraceptives, because contraceptive use may unmask previously latent clotting abnormalities.
Cocaine 179
Cocaine is the street drug most commonly associated with stroke. Because cocaine's principal pharmacological effect is the blockade of presynaptic norepinephrine and dopamine reuptake, use of the drug causes a sympathomimetic response. The resultant hypertension, vasoconstriction, tachycardia, and ventricular arrhythmias may all contribute to the pathogenesis of stroke in cocaine users. The literature contains a number of case reports involving stroke in young patients using cocaine, although the data are often confounded by other risk factors present in cocaine users, such as heavy cigarette smoking, alcohol abuse, 179,180 and chronic hypertension. Only a few case-control studies have been performed. Petitti and co-workers in the Kaiser Permanente Health Care System in Northern California studied all cases of stroke in young 181 women aged 15 to 44 years. Among 347 cases of stroke, the adjusted odds ratio for women admitting to the use of cocaine or amphetamines before stroke onset was 7.0 (95% CI: 2.8 to 17.9). A retrospective case-control study by others failed to find a similar 182 association. All methods of cocaine use (inhalation and intranasal, intravenous, and intramuscular 183 administration) can be associated with stroke. Furthermore, most cocaine-induced strokes occur within 1 hour of use, although it is difficult to evaluate the possible long-term risks of
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chronic cocaine use. In a study of MRI ischemic changes in long-term cocaine users, a strong association was noted between patient age and the degree of ischemic lesions in both patients and control subjects, but the equivalent severity of ischemic lesions was seen 20 185 years earlier in the cocaine users. In addition to ischemic stroke, both subarachnoid hemorrhage and intraparenchymal hemorrhage may occur immediately after cocaine use (Fig. 61-6). In a review of 47 cases of stroke linked to cocaine use, Klonoff and colleagues noted subarachnoid or intraparenchymal hemorrhage in 35 cases and 183 found evidence of intracranial aneurysms or arteriovenous malformations in 17 patients. It remains unclear whether cocaine plays a pathogenic role in the development of these vascular malformations or whether the drug's effects simply facilitate bleeding from preexisting vascular abnormalities.
FIGURE 61-6 Intraparenchymal hemorrhage due to aneurysm. A, Computed tomography (CT) scan obtained because of a complaint of headache in a 46-year-old chronic cocaine abuser shows an increased-attenuation lesion in the left frontal lobe. A high-attenuation lesion is probably an unruptured aneurysm. A small hemorrhage around the aneurysm is suggested. B, CT scan obtained 2 days later because of increasing headache and neurological signs shows a large hematoma with intraventricular hemorrhage (arrow). The left lateral ventricle is markedly compressed and the midline is shifted. C, Angiogram shows two aneurysms, a larger one (white arrow) in a branch of the middle cerebral artery and a smaller one (black arrow) with associated vasospasm from a lenticulostriate artery. (From Brown E, Prager J, Lee HY, et al: CNS complications of cocaine abuse: prevalence, pathophysiology, and neuroradiology. AJR Am J Roentgenol 159:142, 1992, with permission.)
Besides its direct effects of blood pressure elevation and vasoconstriction, cocaine may186 predispose users to cardiac arrhythmias and resultant embolic cerebrovascular events. In addition, cocaine use is associated with an increased risk of myocardial infarction and resultant left ventricular akinesis. Therefore, a thorough cardiac evaluation should be performed in all patients with stroke who report cocaine use as a precipitant. Several studies also suggest that cocaine use may impair the normal vascular response to endogenous 187,188 relaxation factors. Because the average age of patients with cocaine-induced stroke is 32 to 34 years in 183,184,189 it seems prudent to perform a toxicology screen in all young published studies, patients with stroke, especially if another etiology is not immediately identified.
Amphetamines Amphetamines have also been causally linked to stroke (Fig. 61-7) in a number of 190–192 Methamphetamine, the most common illicitly used type of amphetamine, can studies. be injected, smoked, or inhaled. Similar to cocaine, the presumed pathophysiological process 193,194 of stroke in users involves elevated blood pressure, vasculitis, or other vascular toxicity. 3,4-Methylenedioxymethamphetamine, more commonly known as “ecstasy,” has also been 195,196 Although both ischemic and implicated as thecause of stroke in isolated case reports. hemorrhagic strokes have been reported in the literature, one small study found a higher incidence of hemorrhagic events, which would be consistent with a presumed hypertensive 191 pathophysiological process. This same study failed to find angiographic evidence of vasculitis or vascular malformations in any of the patients.
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FIGURE 61-7 Magnetic resonance image (MRI) of a 41-year-old woman,
showing a large right parietal infarct that occurred in the setting of acute methamphetamine use. The patient had no other risk factors for stroke. Despite its apparent causative role in some stroke cases, amphetamine derivatives have been shown in a number of studies to increase the rate and extent of motor recovery in patients with stroke undergoing 197,198 physical therapy and may exert a neurofacilitatory role in functional recovery from stroke.
Triptans Stroke may occur in the context of triptan administration for the treatment of migraine. Such triptan agents act as serotonin agonists at the 5-hydroxytryptamine type 1 receptor200 and 199 induce potent vasoconstriction of human intracranial arteries in vitro and in vivo. Sumatriptan induces vasospasm in both nonhuman and human basilar artery preparations, 201 perhaps because contractile serotonin receptors are present in large arterial vessels. Coronary vasospasm and myocardial infarction have occurred acutely after administration of sumatriptan,202–204 and renal infarction has been documented with the use of rizatriptan and zolmitriptan. Cases have been reported of arterial or venous infarction after sumatriptan 199,205,206 sometimes with segmental arterial narrowing in multiple intracerebral administration, drugs have also been associated with cerebral vessels (Fig. 61-8). Other serotonergic 207 vasoconstriction and stroke. However, because of the long-recognized association between complicated migraine headaches and ischemic stroke and because ischemic strokes may occasionally present with headaches as the initial symptom, sumatriptan use cannot be implicated as the sole causative factor and may have been incidental. A retrospective study by Hall and associates of 63,575 migraine patients showed no increased risk of stroke in the 13,664 individuals prescribed triptans. Interestingly, the larger group of migraine patients who were not using triptans did have a higher risk of stroke (hazard ratio, 208 1.51), possibly suggesting that untreated migraines may contribute to stroke risk. Another retrospective study of 140,000 migraineurs failed to show an increased risk of stroke in triptan users, although migraineurs were 67 percent more likely to suffer a stroke than 209 nonmigraineurs.
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FIGURE 61-8 Carotid angiograms in a patient after excessive use of
sumatriptan and Midrin. A, Angiogram showing segmental arterial narrowing (arrows) at the time of stroke. B, Normalized angiogram taken 39 days later. (Modified from Meschia JF, Malkoff MD, Biller J: Reversible segmental cerebral arterial vasospasm and cerebral infarction: possible association with excessive use of sumatriptan and Midrin. Arch Neurol 55:713, 1998, with permission.) The large number of triptan users compared with the limited number of cases of triptan-related stroke in the literature suggests that the risk (if any) of cerebrovascular events with the use of this medicine is extremely small. Nonetheless, we exercise caution in using sumatriptan in patients with a history of stroke and refrain from using it in patients with a history of complicated migraine (migraine with neurological deficits) or of coronary artery disease.
Alcohol The relationship between alcohol intake and the risk of stroke is complex. There is strong evidence that heavy alcohol use and chronic alcoholism increase the risk of stroke, although mild to 210 moderate alcohol consumption has been associated with a decreased risk of stroke. Alcohol has long been recognized for its broad range of effects on the CNS (discussed in Chapter 37) Alcohol use was first mentioned as a possible risk factor for stroke as early as 1725, although it has179been only recently that the role of alcohol in cerebrovascular disease has been underscored. In response to a series of studies from the 1970s and 1980s, the World Health Organization and the Stroke Council elevated alcohol to the status 211 of a “less well-documented” risk factor for stroke in 1989. In an extensive review of the literature up until 1989, Camargo and others described a J-shaped association curve between alcohol use and ischemic stroke risk, with a protective effect in light to moderate drinkers and an elevated risk with heavier alcohol 212–215 This association was found predominantly in white populations. In a consumption. cohort of 15,000 men and women in Sweden, an elevated risk of ischemic stroke was found in men (but not216 women) who were intoxicated or reported episodes of “binge drinking” a few times per year. In a group of middle-aged and elderly patients with stroke in urban medical centers, Gorelick and colleagues found that alcohol ingestion within 24 hours of stroke onset was more common among stroke index cases than control subjects, although this effect of217 alcohol disappeared after adjusting for cigarette smoking and other confounding variables. The association between alcohol and stroke risk appears much stronger for intracerebral and subarachnoid hemorrhage than for ischemic stroke. A study of 8,000 men in the Honolulu Heart Program showed that compared with nondrinkers, the risk of hemorrhagic stroke more 218 than doubled for light drinkers and nearly tripled for those considered to be heavy drinkers. In his review of the epidemiological data, Camargo found a positive linear association between moderate alcohol intake (<60 g of alcohol per day, with one drink containing approximately 12 g of alcohol) and the risk of both intracerebral and subarachnoid 212 hemorrhage in diverse populations. A reduction in alcohol consumption may be accompanied by a reduction in the risk of subsequent hemorrhagic stroke, suggesting a possible causal relationship between alcohol use and intracerebral hemorrhage. More recently, a number of key studies have shown that mild to moderate consumption of 219–221 In a study of a multiethnic population in alcohol may actually reduce the risk of stroke. northern Manhattan, Sacco and colleagues found that moderate consumption of up to two drinks per day was significantly protective for ischemic stroke after adjustment for other 220 concurrent risk factors. This study again provided evidence of a J-shaped curve, with an
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increased risk of ischemic stroke among those consuming seven or more drinks per day (Fig. 61-9). Unlike a number of previous studies, these associations held for both men and women and varying ethnicities, including whites, blacks, and Hispanics. No differential protective effect was found among the types of alcohol consumed. Similarly, a recent meta-analysis of 35 studies investigating the relationship between alcohol use and stroke showed that compared with nondrinkers, those consuming greater than 5 drinks per day had a 69 percent increase in ischemic stroke risk. Consumption of less than one drink per day was associated with a reduced risk (relative risk,2220.80), while consumption of 1 to 2 drinks per day conferred the lowest risk reduction (0.72).
FIGURE 61-9 Relationship between alcohol and the risk of ischemic stroke. OR
denotes odds ratio for ischemic stroke. (From Sacco RL, Elkind M, Boden-Albala B, et al: The protective effect of moderate alcohol consumption on ischemic stroke. JAMA 281:57, 1999, with permission. © 1999, American Medical Association.) The Physicians' Health Study found similar protective effects of modest alcohol 193 consumption. Among 22,000 male physicians followed for more than 10 years, those who drank one or more drinks per day had a reduced risk of stroke, even after controlling for other major risk factors. This beneficial effect was observed in men who had as little as one drink per week. Notably, there was no statistically significant association betweenalcohol consumption and hemorrhagic stroke, although heavy drinking was rare in this population. Several pathophysiological relationships may exist between alcohol and stroke. Alcohol may induce cardiac arrhythmias and cause a cardiomyopathy with global akinesis, thereby predisposing to the formation of cardiac emboli. Alcohol has also been linked to hypertension, 223 increased platelet aggregation, and activity of the clotting cascade. Acute increases in systolic blood pressure and alterations in cerebral arterial tone may serve as mechanisms 224 triggering hemorrhagic strokes. Similarly, a decrease in the production of circulating clotting factors by the liver may result in hemorrhagic events. Taken as a whole, the literature suggests a dual relationship between alcohol use and stroke risk. Consumption of up to two drinks per day seems to confer some risk reduction for stroke compared with nondrinkers. However, higher levels of consumption may predispose to an increased risk of hemorrhagic, and possibly also ischemic, stroke through a variety of pathophysiological mechanisms. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 62 Disorders of Consciousness in Systemic Diseases J. CLAUDE HEMPHILL III •
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CONSCIOUSNESS Historical Perspective Definition of Consciousness Anatomy of Consciousness Implications for Systemic Diseases MECHANISMS OF IMPAIRED CONSCIOUSNESS IN SPECIFIC DISEASES Metabolic Encephalopathies Systemic Disorders With Focal Neurological Manifestations Systemic Diseases Presenting as Primary Neurological Disorders CLINICAL APPROACH TO PATIENTS WITH DISORDERED CONSCIOUSNESS Neurological History and Examination Neuroimaging Electrophysiological Studies Cerebrospinal Fluid and Other Laboratory Studies Diagnosis and Treatment: Coordinated Clinical Approach PROGNOSIS BRAIN DEATH PERSISTENT VEGETATIVE STATE
Consciousness is a complex and elusive concept that has been the subject of exhaustive thought and speculation by philosophers, theologians, and scientists since antiquity. Attempts to define consciousness have often related more to the purpose of the individual making the definition than to the usefulness of the definition in providing a1 construct for an under-standing of the multifaceted aspects of consciousness. The fact that consciousness may mean different things depending on the context (philosophy, religion, science) demonstrates the importance that understanding normal and disordered consciousness holds across a wide variety of fields of study. In medicine, it has long been recognized that disorders of consciousness are pervasive among the effects of systemic diseases on the nervous system. Because alterations in consciousness may have important diagnostic, therapeutic, and prognostic implications, a pragmatic approach using the neurological principle of localization and the medical approach of differential diagnosis is most useful in clinical medical care. The spectrum of consciousness, from wakefulness to coma to brain death, has an anatomical and biological substrate. To physicians, this has not only philosophical but practical implications.
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CONSCIOUSNESS
Historical Perspective Ever since the Greek physician Galen (130 to 200 a.d.) recognized that a wound of the brain could affect the mind, the role of consciousness and thought as a manifestation of brain injury 2 and impairment has held a special role. During the Renaissance, the philosopher Descartes (1596 to 1650) was particularly focused on the “mind–brain problem.” He thought that the pineal gland was the seat of the soul, and this structure therefore played a special role in his concept of3,4consciousness, although contemporaries granted this honor to the corpus callosum. Late nineteenth and early twentieth century efforts such as William James' 5 “stream of consciousness” focused on psychological, not anatomical, mechanisms. Although the effect of systemic diseases on consciousness has been recognized since Hippocrates 6 (fifth century b.c.) described “madness on account of bile,” the ability to ascribe testable anatomical and biological correlates to consciousness in systemic disease is distinctly modern. The two main advances that have allowed this to occur are (1) development of an operational definition of consciousness that has practical applicability and (2) understanding of the anatomical substrate of consciousness (as operationally defined). Modern physicians can do something that Galen could not: they can understand the manner and reason that consciousness is impaired in neurological and systemic diseases.
Definition of Consciousness In medicine, consciousness can be defined as the state of awareness of the self and the 7 environment. Thus, decreased consciousness involves impairment of this state of awareness, with coma being its absence. Consciousness and conscious behavior have two basic components: arousal and content. Arousal is behaviorally related to level of alertness or wakefulness. Content describes the complex range of cognitive functions, which includes clear thought, memory, and language. This is an important distinction because, as described later, in a simplified anatomical model of consciousness, arousal and content have different anatomical localizations. Also, arousal and content may be independent but are frequently interdependent. For content to be present or at least to be clinically assessed, some degree of arousal must be present. Conversely, if decreased arousal (e.g., from sedative drug intoxication) is overcome 7by a noxious stimulus, content may be seen to be largely normal until arousal fades again. A description of the state of consciousness of an individual must take into account both level of arousal and quality of content. This is much more than a pedantic exercise because different diseases and different neuroanatomical sites may be implicated, depending on the specifics of the state of consciousness. Although by this definition, an alteration in cerebral cortical function, such as aphasia, would be deemed an alteration in consciousness, the term level of consciousness usually refers to level of arousal (Table 62-1). The slang term altered mental status is nonspecific and should be avoided. Its lack of precise meaning confounds attempts to compare changes in the same patient over time or in different patients. Click here to view this table....
Anatomy of Consciousness Although somewhat of an oversimplification, the two different components of consciousness are mediated by two different neuroanatomical systems (Fig. 62-1). Arousal is mediated by 8 the ascending reticular activating system (RAS). The RAS is located in the brainstem and is a loosely arranged column of neurons extending from approximately the upper third of the pons to the diencephalic structures of the thalamus and hypothalamus. Projections via subcortical relay nuclei, primarily in the9 thalamus, then integrate RAS-mediated arousal with more diffuse cerebral cortical function. The role of the RAS was extensively elucidated by Moruzzi and Magoun, who demonstrated that stimulation of the RAS in a sleeping animal resulted in immediate behavioral arousal. Conversely, when the brainstem RAS was destroyed, no amount of sensory stimulation could reverse coma, even though subcortical 10,11 and cortical structures remained intact.
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FIGURE 62-1 Neuroanatomy of consciousness. The ascending reticular
activating system (RAS) is a loosely arranged column of neurons located in the brainstem. Arousal is largely mediated by the RAS through projections to the cerebral cortex through the thalamus. The content of consciousness is localized more diffusely throughout the cerebral cortex. (Reprinted by permission of Mayo Foundation for Medical Education and Research. All rights reserved, from Wijdicks EFM: Neurologic Catastrophes in the Emergency Department. p. 4. Butterworth Heinemann, Boston, 2000.) The content of consciousness is localized more diffusely throughout the cerebral cortex. Certain cognitive functions are diffusely localized throughout both cerebral hemispheres, whereas other specific functions may have a narrower anatomical localization. Receptive language and expressive language are principally localized to the superior temporal lobe or 12 posterior frontal lobe, respectively, of the dominant hemisphere, usually the left. Although various aspects of memory may be stored diffusely, the mesial temporal lobes and mamillary 13,14 Conversely, bodies are especially related to storage of new short-term memory. processes such as thought, orientation, attention, and planning are localized diffusely, 15 especially among both frontal lobes. Because a severe impairment of receptive language is likely to alter the state of awareness of self or environment (as far as can be deduced by 16,17 Others external examination), some may consider this an altered state of consciousness. place more emphasis on impairment of bihemispheric dysfunction, evidenced by decreased attention, concentration, and coherent thought, as defining altered content of 15 consciousness. The important lesson is that different aspects of the content of consciousness may have different anatomical substrates and that global impairment of cognitive function implies bilateral cerebral hemispheric dysfunction or disease.
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Implications for Systemic Diseases Coma, or unconsciousness, is a state of unarousable psychological unresponsiveness in which the subject has eyes closed and shows no psychologically understandable response to 7 external stimulus or inner need. For coma to be present, one of two general anatomical conditions must be satisfied. There must be significant impairment of either the RAS or both cerebral hemispheres (Table 62-2). This general rule of anatomical localization is fundamental in determining the etiology of coma in a specific patient. Structural lesions usually cause coma through direct brainstem involvement or brainstem displacement or 7,18 These are often primary neurological compression with subsequent RAS involvement. disorders such as intracerebral hemorrhage, traumatic brain injury, subdural hematoma, 19–24 Transtentorial brain tumors or abscesses, or large cerebral infarctions with mass effect. herniation because of a supratentorial mass, direct brainstem impingement from an infratentorial lesion, or direct parenchymal brainstem involvement from hemorrhagic or 7,25 Less commonly, subfalcine herniation or ischemic stroke are various scenarios. bihemispheric mass lesions may lead to coma with an intact brainstem. Metabolic disturbances, by contrast, usually cause coma from diffuse involvement, which presumably results in disconnection between the RAS and subcortical thalamic relay nuclei with the hemispheres. As discussed later, the neurological examination of the comatose patient is an important key in distinguishing the cause and anatomical basis of coma, specifically with regard to the presence or absence of other brainstem and cranial nerve abnormalities such as pupillary or extraocular movement abnormalities. Similarly, the cause of lesser degrees of impaired consciousness can be assessed by determining whether bihemispheric or brainstem dysfunction is responsible. Click here to view this table.... Sleep should be considered as a separate and distinct entity. Externally, patients in coma initially appear asleep, but sleeping individuals can be roused and then respond to the environment. Normal sleep has several stages that have distinct and different 26,27 as discussed in Chapter 32. The EEG findings electroencephalographic (EEG) patterns, in coma may vary, depending on the cause of coma, but, in general, do not resemble those of 28 sleep. Whereas the purpose and nature of sleep are still points of debate, altered consciousness in systemic disease is a pathological state in contrast to sleep, which is a necessary and normal function. MECHANISMS OF IMPAIRED CONSCIOUSNESS IN SPECIFIC DISEASES It seems that almost every systemic disease may in some manner alter consciousness. Thus, a practical approach to determining the cause and nature of disorders of consciousness in systemic disease requires an appreciation for the overall mechanisms by which primary neurological disorders as well as systemic diseases may affect the central nervous system (CNS). The neuroanatomical localization of various aspects of consciousness implies that both focal and global, or diffuse, processes may alter either the level or content of consciousness. Structural causes of impaired consciousness, especially coma, are intuitively easier to understand than many metabolic or diffuse causes. Compression, distortion, or infarction of the brainstem and RAS are processes for which mechanical interventions, such as neurosurgical evacuation of a mass lesion or thrombolysis 29,30 In contrast, metabolic encephalopathies cause of an occluded artery, may be indicated. impaired consciousness (either content or arousal) by interfering diffusely with the metabolic 7 functions of the brain on a biochemical level, either directly or indirectly. However, some metabolic encephalopathies can be considered “structural” on a microscopic level, when they 31–33 Although the mechanisms by which result in diffuse or multifocal cellular brain injury. systemic diseases cause alteration in consciousness are diverse, they can be divided into three broad categories: metabolic encephalopathies, focal neurological manifestations of systemic disorders, and primary neurological disorders caused by systemic disease.
Metabolic Encephalopathies Metabolic encephalopathy is the most frequent cause of disordered consciousness in systemic diseases. A metabolic encephalopathy can be defined as an alteration in consciousness caused by diffuse or global brain dysfunction from impaired cerebral metabolism. This term has come to include essentially any disorder associated with a nonpsychiatric cause of alteration in consciousness that does not have a macroscopic structural basis. Thus, the list of metabolic encephalopathies is extensive and includes such disparate conditions as hypoxic-ischemic encephalopathy, hepatic encephalopathy, encephalopathy due to sedative drug overdose, encephalopathy in bacterial meningitis, and
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the postictal state. The principal reason for grouping this wide variety of disorders under the same general term is that the neurological examination may appear quite similar regardless of the etiology of the metabolic encephalopathy. Nevertheless, the underlying cause of the metabolic encephalopathy is the fundamental determinant of treatment and prognosis. Thus, considering the biochemistry of metabolic encephalopathies is of prime importance in their differentiation. Two common themes emerge with regard to presumptive etiologies of metabolic encephalopathies in systemic disease: impaired substrate delivery (glucose or oxygen) to the brain or release of a circulating substance by the systemic disease, which crosses the blood–brain barrier (or enters through a broken blood–brain barrier) and causes diffuse hypoxic-ischemic neuronal and cellular dysfunction (Table 62-3). The former, implicated in 34,35 The latter, encephalopathy and hypoglycemia, may result in irreversible brain injury. implicated in most metabolic encephalopathies associated with organ system dysfunction (e.g., hepatic, renal) or with systemic infection, may be largely reversible if the underlying 36,37 Although these delineations do not always hold true, this mechanistic disorder is treated. differentiation can be of great importance in determining treatment and prognosis. Click here to view this table.... When substrate delivery to the brain is globally reduced, encephalopathy and eventually coma may result. Hypoxia, and especially hypoxia-ischemia, may result in permanent cerebral damage diffusely or in selective areas such as the hippocampus, cerebellum, and 38 or decreased cerebral blood-flow determine thalamus. The degree and duration of hypoxia 39 the severity and irreversibility of damage. Hypoxic-ischemic encephalopathy most commonly results from global cerebral ischemia during severe hypotension or cardiac arrest and is mediated by the neuronal ischemic injury cascade that includes release of excitatory 40 amino acids, intracellular calcium influx, lipid peroxidation, and cell breakdown. Two clinical trials have demonstrated a beneficial effect for immediate treatment of comatose survivors of cardiac arrest with mild hypothermia (33°C for 12 to 24 hours after out-of-hospital cardiac arrest from ventricular fibrillation or ventricular tachycardia). This treatment is now recommended41–43 by the American Heart Association as part of the standard resuscitation of Hypoglycemic encephalopathy is potentially reversible, but permanent such patients. 44 damage may occur if it is not treated early. In addition, hypertensive encephalopathy may be due to disordered cerebral autoregulation, elevated cerebral vascular resistance, and 45 subsequent globally decreased cerebral blood-flow. Thus, substrate-delivery encephalopathies have altered cerebral oxygen and glucose delivery as a common pathway, regardless of actual cause, and may result in severe permanent neurological damage if not treated urgently and successfully. In contrast, systemic organ failure is a common cause of metabolic encephalopathy and carries a different cause and prognosis from substrate-delivery encephalopathies. Kidney 46–48 Carbon (uremia) and liver failure are common causes of metabolic encephalopathy. dioxide narcosis 49,50 from pulmonary failure and, rarely, pancreatic failure can also cause The biochemical mechanism of uremic encephalopathy is not precisely encephalopathy. known, but decreased ability to utilize adenosine triphosphate by the uremic brain and51,52 In elevated calcium content in cerebral cortex and hypothalamus have been suggested. hepatic encephalopathy, endogenous benzodiazepine-like substances may play a role, as suggested in animal studies and from experience in humans with improvement after 53,54 Also, in hepatic failure, administration of flumazenil, often with no permanent residua. elevated levels of α-ketoglutaramate in the cerebrospinal fluid (CSF) correlate with systemic 55 elevations in ammonia as well as depth of coma.56 Certainly, patients with fulminant hepatic failure may have severe diffuse cerebral edema, and the acutely increased intracranial pressure also provides a structural basis for the coma. Abnormal function of endocrine 57 organs may cause encephalopathy through primary mechanisms (e.g., myxedema coma, 58 59 thyrotoxicosis, hypocortisolemia ) or through changes in electrolytes or the cerebral 60 acid-base environment (e.g., hypercalcemia in hyperparathyroidism). Encephalopathy frequently accompanies sepsis, especially when associated with multisystem 61 organ failure, as discussed in Chapter 52. Critically ill patients with multisystem organ failure may have multiple reasons for encephalopathy, including primary organ failure, especially of kidneys and liver, electrolyte abnormalities, and concurrent use of sedative agents to facilitate 62 critical care interventions such as mechanical ventilation. However, it is clear that sepsis itself is associated with a metabolic encephalopathy. Although proposed causes of septic encephalopathy range from multiple microabscesses throughout the brain to alterations in cerebral blood-flow mediated by nitric oxide, circulating cytokines released63–65 during sepsis or Whether these the systemic inflammatory response syndrome are likely to be implicated. are also involved in the encephalopathy associated with meningitis and encephalitis or relate
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to direct brain involvement by the infectious agents remains unclarified. Thus, metabolic encephalopathy associated with organ dysfunction and sepsis is thought to be mediated through circulating substances that cross the blood–brain barrier and interfere with cerebral energy metabolism. In contrast to substrate-delivery metabolic encephalopathies, these alterations in consciousness are generally thought to be reversible if the underlying organ pathological process or sepsis is reversed. Electrolyte and acid-base disturbances are a common cause of encephalopathy. Among these, hyponatremia, hypernatremia, and hypercalcemia are most commonly associated with a decreased level of consciousness. Some have suggested that hyponatremia results in 66 ischemic cerebral damage, but this is probably a manifestation in extreme cases of global cerebral edema, elevated intracranial pressure, and decreased cerebral blood-flow. In most circumstances, these encephalopathies are reversible, although rapid correction of hyponatremia67should be avoided to decrease the potential of osmotic (central pontine) myelinolysis. A global decrease in cerebral metabolic rate of oxygen consumption may occur during 68,69 These are reversible if substrate profound hypothermia and after sedative drug overdose. delivery is maintained. Thus, general anesthesia can be viewed as a type of reversible metabolic encephalopathy or coma. Metabolic encephalopathy, often without a markedly decreased level of consciousness, may be caused by numerous prescription medications 70 and may be mistaken for dementia in the elderly. Finally, encephalopathy may be a manifestation of collagen vascular disease, such as systemic lupus erythematosus (SLE), or 71,72 Although the latter may be mediated by electrolyte disturbances in the systemic cancer. setting of the syndrome of inappro-priate secretion of antidiuretic hormone or potentially 73 through paraneoplastic antibodies or circulating cytokines, these disorders may cause alterations in consciousness from focal processes related specifically to the underlying cancer or collagen vascular disease.
Systemic Disorders With Focal Neurological Manifestations A variety of systemic disorders may cause alteration of consciousness through infiltration of the CNS or the presence of single or multiple focal lesions. Occasionally, patients in these circumstances may appear clinically to have a diffuse encephalopathy, but close examination reveals focal neurological signs. In this setting, the distinction between metabolic encephalopathy and diffuse multifocal cerebral disease may be clinically difficult and practically only a matter of semantics. Pathologically, however, the processes are quite different, with the latter representing more than just an alteration in substrate delivery or a global process related to circulating systemic factors. The three categories of systemic disease that are most often manifested in this manner are collagen vascular diseases, systemic malignancies, and diffuse infections. 74
Neuropsychiatric complications are frequent clinical manifestations of SLE. Neuropathological findings in these patients vary from normal to the presence of diffuse microinfarcts. Lupus cerebritis, however, commonly manifests as a focal process with pathological findings of 75 bland, and occasionally necrotizing, vasculopathy with perivascular inflammatory infiltrates. There is debate whether this represents a “true” vasculitis or a more infiltrative process. The particular neurological manifestations depend on the lesion location, but aphasia due to focal lesions in the language regions and abulia due to bifrontal lesions are common. Neurosarcoidosis most often manifests as meningeal inflammation or focal cranial neuropathies but rarely occurs as a cerebral mass lesion that can affect 76 consciousness. Systemic cancer affects consciousness in a variety of ways. Cancer may cause metabolic problems related to electrolyte disturbances and primary organ dysfunction. Focal neurological manifestations in patients with cancer more likely suggest metastatic disease to the CNS. In fact, metastatic brain tumors are much more common than primary brain 77 tumors. Most commonly occurring supratentorially, mass effect from metastases may cause cerebral herniation with brainstem compression or bihemispheric dysfunction. Meningeal carcinomatosis often spares consciousness, except when so extensive that 78 intracranial vessels at the base of the brain are affected, resulting in stroke. Cancer treatments themselves may have effects on consciousness. Metabolic encephalopathy may be caused by certain chemotherapeutic agents, and cranial irradiation may result in focal 79 necrosis that is initially difficult to differentiate from recurrent tumor or stroke. Finally, infection may cause focal neurological disturbances of consciousness. Certainly, brain abscess, meningitis, or encephalitis may occur in otherwise normal individuals or in those with compromised immune systems and systemic disease. Depending on abscess
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location and extent of meningitis and encephalitis, alteration in consciousness, either focal or global, may be prominent. Several systemic infections, however, are particularly implicated with focal processes or infiltration of the nervous system. These include human immunodeficiency virus (HIV) infection, syphilis, and Lyme disease. Direct infection of 80 neurons by HIV may result in HIV encephalopathy. Although described as a diffuse encephalopathy, this is probably a “microscopic structural” process related to global infection and infiltration. Progressive multifocal leukoencephalopathy occurs from infection with the JC papovavirus. It manifests principally as cerebral white matter lesions and may involve altered 81 consciousness. Patients immunocompromised from HIV infection are also at risk of a myriad of CNS problems, including primary CNS lymphoma, toxoplasmosis, and other 82 opportunistic infections. Syphilis of the CNS may have a variety of manifestations. Consciousness may be affected by strokes in meningovascular syphilis; a dementia occurs in tertiary syphilis. Lyme neuroborreliosis may cause generalized confusion that has been mistaken for psychiatric disease; it may also manifest as focal brain disease suggestive of 83 demyelination. Several of these systemic disorders may have the neuroimaging appearance of diffuse cerebral white matter (or demyelinating) lesions, and therefore, in certain circumstances, may mimic multiple sclerosis. These include SLE, sarcoidosis, progressive multifocal leukoencephalopathy, syphilis, and Lyme disease.
Systemic Diseases Presenting as Primary Neurological Disorders Seizures, stroke, and acute mass lesions are primary neurological disorders that may occur secondary to systemic diseases. Generalized seizures, by definition, result in alteration or loss of consciousness. Stroke and acute mass lesions may cause alterations in consciousness depending on their neurological localization. Although systemic diseases or conditions such as hypertension and diabetes are implicated in the genesis of stroke and cancer is implicated in metastatic CNS disease, certain conditions have primary neurological 84,85 as diagnoses as a principal manifestation. Seizures have many systemic causes, discussed in Chapter 58. Large-vessel ischemic strokes may occur from either embolic or thrombotic causes. General medical disorders associated with stroke are discussed in Chapter 61. Infective endocarditis or marantic endocarditis (as in SLE or cancer) may result in embolic infarction that may alter 86,87 Hypercoagulable states may occur consciousness depending on stroke location and size. in SLE or systemic cancer and cause thrombotic large-vessel occlusion of the cerebral circulation. Hypercoagulability may also lead to thrombosis of the cerebral venous sinuses; alterations in factors V and VIII during an ulcerative colitis flare are a potentially 88 underrecognized cause. Leukemia with white blood cell counts in excess of 100,000/μl, polycythemia vera with hematocrit greater than 55 percent, and essential thrombocythemia with a platelet count above 1,000,000/μl may result in thrombotic vessel occlusion or stroke 89 due to increased blood viscosity. Small-vessel or lacunar infarcts rarely result in alterations in consciousness. Cerebral vasculitis, however, is often 90 associated with confusion and alteration in behavior and the content of consciousness. Cerebral vasculitis may result in large-vessel infarcts but more commonly creates widespread mid-size and small-vessel infarction. Although cerebral vasculitis may occur in isolation (e.g., granulomatous angiitis of the nervous system), numerous connective tissue disorders, including SLE, polyarteritis nodosa, Churg–Strauss syndrome, and mixed connective tissue disorder, may be 91 implicated. Cerebral mass lesions that cause a decrease in the level of consciousness usually develop rapidly. Primary and secondary brain tumors may manifest in this way, but acute intracranial hemorrhage is the most common acute mass lesion with altered consciousness. 92 Hypertension is the most common cause of intracerebral hemorrhage. Coagulopathy in the setting of liver failure, disseminated intravascular coagulation, or thrombotic thrombocytopenic purpura may precipitate a spontaneous intracerebral, subdural, or epidural hematoma. Mild head trauma, which would otherwise be well tolerated, may lead to severe intracranial bleeding with massive subdural or intraparenchymal hematoma formation if a coagulopathy is present. CLINICAL APPROACH TO PATIENTS WITH DISORDERED CONSCIOUSNESS The fundamental goal of evaluation in patients with disorders of consciousness is to distinguish processes that cause ongoing brain injury from those that are usually well tolerated if other concurrent systemic diseases are adequately treated. The manifestations of systemic diseases in the CNS are protean. “Benign” and “malignant” causes of altered consciousness may appear clinically similar. Thus, an orderly approach to the evaluation of patients with disordered consciousness is essential for timely and accurate diagnosis, which can direct focused treatment. This approach combines clinical neurological assessment with
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judicious use of other diagnostic studies that may include neuroimaging, electrophysiological evaluation, CSF analysis, and other laboratory tests.
Neurological History and Examination The neurological findings in patients with altered consciousness and the history of how the disorder developed are the principal components of patient assessment. All supporting studies, whether neuroimaging, electrophysiological, or CSF studies, or other tests, must be interpreted within the neurological context. The neuroanatomy of consciousness forms the underpinning for neurological assessment; it is this localization that allows the formation of a differential diagnosis of various primary neurological disorders and systemic diseases that may manifest in this way. The first step is to define the nature of the disturbance of consciousness because differential diagnosis and diagnostic studies vary depending on whether the primary disturbance is of arousal or content. When content of consciousness is impaired in patients who are alert and without marked decrease in the level of consciousness, neurological assessment focuses on higher cortical function. Abnormalities of language, visuospatial orientation, and visual fields suggest a focal cerebral cortical lesion. Disordered attention, concentration, and short-term memory usually suggest a more global process involving both cerebral hemispheres. In the former case, stroke, tumor, a demyelinating process, or focal abscess may be considered and neuroimaging may be diagnostic. In disorders of global cerebral content, a diffuse process is implicated. Depending on the history and associated medical and neurological findings, a primary neurological process such as Alzheimer's disease or a global metabolic encephalopathy from organ dysfunction, medications, or postictal state may be implicated. The more urgent circumstance occurs in the patient with decreased level of consciousness, especially coma. Processes, either structural or metabolic, that develop acutely tend to involve a disproportionately decreased level of consciousness compared with those that 7 develop over much longer periods of time. The initial focus of the neurological examination of the stuporous or comatose patient should be in defining the anatomical localization of the process, that is, in distinguishing between brainstem (RAS) and bihemispheric disease. This is also often the distinction between structural and metabolic causes of coma, although the clinical context and associated conditions must be considered. This localization is usually made based on the presence or absence of other brainstem reflexes and on the motor examination. A notable exception is the locked-in state, in which a lesion, usually a stroke, 7,93 Patients who are “locked in” are not involves the brainstem but spares the RAS. comatose; eye opening and blinking are usually retained, whereas ocular movements and appendicular motor function may be absent. Thus, the first step in clinical evaluation of the apparently comatose patient is to exclude the possibility of the locked-in syndrome, which is suggested by the observation that the eyes open and blink to command. Once coma is established, assessment of brainstem and motor function can proceed. Abnormalities of pupillary function, ocular motility, corneal and gag reflexes, and respiratory function help distinguish an intact from an impaired brainstem. Preserved pupillary7function is a hallmark for distinguishing between metabolic and structural causes for coma. Reflex ocular movements (doll's eyes and cold caloric reflexes) are typically preserved in metabolic coma. Occasionally, however, odd conjugate downgaze, skew deviation, and loss of ocular reflexes are found 94,95 in deep coma caused by metabolic disorder, especially liver failure or sedative drug Unilateral absence of the corneal or gag reflex may suggest structural overdose. brainstem impairment. The findings on motor examinations are also important. Motor function is symmetric in coma of metabolic origin. Depth of coma, regardless of cause, may determine whether purposeful response to pain is present. Gross asymmetry of purposeful or reflex response to pain suggests a structural process. Patients in deep coma of metabolic cause, 96 especially from sedative drug overdose, may exhibit symmetric flexor or extensor posturing, with retained brisk pupillary reflexes and intact brainstem reflexes.
Neuroimaging Findings on clinical examination direct the need for neuroimaging and govern the type of neuroimaging likely to be most useful. Most patients without history of head trauma who are somnolent with a global alteration in cognitive function and intact brainstem reflexes have a metabolic encephalopathy. When a known systemic cause of metabolic encephalopathy, such as uremia, moderate liver failure, or sedative or other drug use, is present, neuroimaging may not be necessary. Conversely, all patients with coma of unknown etiology require urgent head imaging. Computed tomography (CT) is now widely available throughout the United States and is an
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invaluable adjunct to the urgent evaluation of the unconscious patient. The principal value of early CT scanning is to demonstrate structural processes causing the coma. CT is particularly effective at demonstrating acute intracranial hemorrhage, even more so than 97 magnetic resonance imaging (MRI). For this reason and because of its rapidity, CT scanning, usually without contrast, is the best first option for neuroimaging in patients with acute alteration or loss of consciousness. CT in acute stroke (within the first 12 hours) may be normal or show only subtle abnormalities such as loss of gray-white differentiation or mild 98 than 92 percent sensitive for acute subarachnoid hemorrhage after edema. CT is greater 99 aneurysm rupture and almost always shows acute intraparenchymal or extra-axial processes such as hemorrhage and mass lesions that are causing cerebral herniation. By contrast, head CT in metabolic encephalopathy is usually negative or nondiagnostic. Thus, in most circumstances, CT scanning can exclude an acute structural process and help to confirm the accuracy of clinical localization of the cause of coma. MRI is much better than CT at delineating specific anatomical structures, especially in the 100 posterior fossa. It is usually not necessary acutely when CT has been performed. An important exception is when cerebral venous sinus thrombosis is suspected. CT with contrast 101 demonstrates a sign known as the “empty delta” in approximately 35 percent of cases. However, MRI, especially when done with magnetic resonance venography, is highly sensitive and specific for thrombosis of the sagittal sinus or other intracranial venous sinus 102 that might be the cause of coma. For patients in whom altered consciousness or coma is not acute, MRI may be preferable to CT because it is more likely to reveal cerebral metastases, subtle signs of infection or cerebral swelling, or changes that are sometimes seen in certain metabolic conditions, such as basal ganglia abnormalities in liver disease or 103 posterior white matter changes in hypertensive encephalopathy or eclampsia. Newer tools such as magnetic resonance spectroscopy can provide a more direct measure of cerebral 104 metabolism in regions of interest ; the role of magnetic resonance spectroscopy, however, is evolving and remains to be clarified.
Electrophysiological Studies EEG and evoked potentials are the major electro-physiological modalities of diagnostic use in patients with altered consciousness. Three principal uses are (1) to exclude seizures, especially nonconvulsive status epilepticus; (2) to confirm the diagnosis of certain metabolic encephalopathies that may have characteristic EEG patterns; and (3) to provide a guide to prognosis in irreversible cerebral injuries, especially hypoxic-ischemic encephalopathy. EEG is indicated in patients with coma of unknown etiology, especially those who have nondiagnostic head imaging studies. Nonconvulsive status epilepticus is a disorder in which generalized seizures continue without 105 gross motor manifestations of convulsions. This may occur in patients who present with seizures and whose brains continue to seize even after clinical evidence of convulsions cease. It includes patients with frequent complex partial seizures or absence status 106 (spike-wave stupor). The incidence of nonconvulsive status epilepticus varies among series, but Jordan found nonconvulsive seizures in 29 of 107 100 patients who were continuously monitored with EEG in a neurological intensive care unit. This form of status epilepticus as the sole reason for decreased level of consciousness is uncommon, but the diagnosis cannot be made without an EEG. However, subclinical electrographic seizures may be identified in up to 20 percent of patients with significant primary neurological injuries (such as stroke or traumatic108,109 brain injury) who undergo continuous EEG monitoring in the neurological intensive Overt status epilepticus, especially myoclonus or nonconvulsive status, after a care unit. 110,111 hypoxic-ischemic cerebral insult carries a uniformly dismal prognosis. Metabolic encephalopathies have a relatively uniform pattern on EEG, with diffuse bilateral slowing of the background rhythm and increasing amplitude. These findings become more prominent as metabolic coma deepens. Triphasic waves may be found in hepatic encephalopathy but are not diagnostic; they may also be present in other metabolic 112 encephalopathies, including uremic and septic encephalopathies. In patients with hepatic encephalopathy who are receiving flumazenil as a diagnostic or therapeutic maneuver, EEG monitoring has demonstrated return of more normal background rhythms concurrent with 113 improvement in level of consciousness. Evoked potential monitoring for level of consciousness is usually reserved for evaluation of 28 evoked responses are usually preserved in comatose patients. Short-latency sensory 28 reversible metabolic encephalopathies. However, in conditions that cause neuronal death, especially hypoxia-ischemia, they may be abnormal and of prognostic value. In hypoxic-ischemic encephalopathy, bilateral absence of the N20 component of the somatosensory evoked potential (SSEP) to median nerve stimulation has been suggested to
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have a positive predictive value of 100 percent for very poor or no neurological recovery. Recent practice parameters from the American Academy of Neurology for prediction of outcome in comatose survivors of cardiopulmonary resuscitation affirmed the utility of these somatosensory evoked potentials as the most valuable laboratory test for outcome prediction within the first 3 days of hypoxic-ischemic coma. However, timely availability and variable 115 expertise in interpretation remain shortcomings to widespread implementation.
Cerebrospinal Fluid and Other Laboratory Studies 116
Since the introduction of the lumbar puncture by Quincke in 1891, analysis of the CSF has been one of the most commonly performed and extensively studied diagnostic tests for evaluation of the CNS. Before advances in neuroimaging (CT in the 1970s and MRI in the 1980s), lumbar puncture was a standard part of the investigation of patients with alterations in consciousness. Currently, however, the principal utility of CSF analysis in these patients is in excluding a primary neurological process, usually infectious, as a cause of decreased level of consciousness. Lumbar puncture is best performed selectively when meningitis and encephalitis are diagnostic possibilities or when the etiology of coma remains elusive despite clinical evaluation, laboratory testing, and neuroimaging. In comatose patients, neuroimaging should be performed before lumbar puncture because of the potential risk of precipitating 117 transtentorial herniation. Much talked about, but rarely seen, this risk is probably overemphasized but cannot be ignored. Two circumstances in which lumbar puncture may be of particular diagnostic utility in patients with an altered level of consciousness related to systemic diseases are hepatic encephalopathy, in which CSF glutamine concentration may be elevated, and unsuspected cerebral venous sinus thrombosis from a hypercoagulable state, in which an elevated opening pressure may be the first diagnostic clue of increased intracranial pressure due to 118,119 Analysis of the CSF may also be helpful for evaluation for venous outflow obstruction. suspected neurosyphilis, Lyme disease, and neurosarcoidosis. In other conditions such as 120 HIV encephalopathy, CSF cell counts may be mildly and nondiagnostically elevated. A CSF pleocytosis may also be present after seizures, even when no apparent CNS infection is 121 present, but this is uncommon and remains a diagnosis of exclusion. Laboratory testing of electrolytes, renal function, and liver function is a fundamental part of the evaluation of essentially all patients with alterations in consciousness. It is important that metabolic derangements found on laboratory testing match the neuroanatomical localization of the patient's syndrome. Otherwise, further laboratory, neuroimaging, electrophysiological, and CSF testing may be required. For example, a patient with liver failure, unilateral impairment of ocular reflexes, and a hemiparesis requires urgent neuroimaging to rule out an intracranial mass lesion such as an acute hematoma, especially because patients with liver failure often have concurrent coagulopathies. Also, if the degree of electrolyte abnormality does not fit with the depth of alteration in consciousness (e.g., deep coma and a serum sodium concentration of 130 mEq/L), more extensive neurodiagnostic testing should not be deferred.
Diagnosis and Treatment: Coordinated Clinical Approach The major concern in the management of patients with altered consciousness is preservation of existing brain function and prevention of worsening. The resuscitation principles of122 maintaining the airway, breathing, and circulation should always be attended to first. By ensuring oxygenation, ventilation, and adequate brain and tissue perfusion, impaired substrate delivery to the brain may be restored and secondary brain injury limited. Neurological assessment should then proceed. Urgent hematological and biochemical screening tests, including renal and possibly hepatic function studies, should be performed concurrently and neuroimaging, usually with CT, arranged. Based on these results, EEG and lumbar puncture can be considered. If alteration in consciousness is mild or of relatively long-standing, investigation is less urgent but no less important. PROGNOSIS Prognostication involves an estimation of probability in an attempt to determine the patient's outcome and the likelihood of that outcome. Unless the sole outcome measure is mortality, outcome is more a continuum than a dichotomous variable (good or bad). The reason to prognosticate is to give patients and families knowledge of reasonable future expectations and to give physicians, patients, and families information that can aid in decisions to proceed with, or withdraw, medical care. Therefore, it is essential that the prognosticator keep in mind the continuum of prognosis and outcome, recognizing that what would be considered a poor
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prognosis to some may be acceptable to others. Coma is the most compelling condition in which prognostication is often sought. Because comatose patients may appear clinically similar across a wide variety of disorders, it is tempting to prognosticate based on the presence of coma itself. However, the most important overall determinant of prognosis in coma is the cause of the coma. This relates to whether the coma is caused by injury to the brain (e.g., from trauma, hypoxia-ischemia, prolonged hypoglycemia) or is secondary to systemic factors (e.g., sedative drug overdose, liver failure, sepsis). In the latter case, prognosis is linked more to the severity of the underlying disease than to the coma itself, although coma in organ failure or sepsis is usually a marker of grave illness that often carries with it a poor prognosis. There are, however, some general principles to prognostication in coma that may apply across illnesses. There is more information regarding prognosis for hypoxic-ischemic encephalopathy after cardiac arrest than for any other cause of altered consciousness in 36 In general, coma of any duration after cardiac arrest carries a grave systemic diseases. 123,124 Specific aspects of the clinical examination performed at different time points prognosis. after cardiac arrest (and resuscitation) are important predictors of long-term functional outcome, at least in general terms, as discussed in Chapter 9. Levy and associates found that of 52 patients with absent pupillary reflex at initial examination, none demonstrated 123 moderate or good recovery. However, most recommend some interval of observation (at least 1 to 3 days) because patients may have received a variety of medications at the time of resuscitation, influencing the clinical findings. In the same series, of 70 patients who did not have withdrawal or better on motor examination at 3 days, 93 percent had no recovery or developed a persistent vegetative state, and 7 percent showed some recovery but had severe long-term disability at 1 year; no patients showed moderate or good recovery. Conversely, of 26 patients with withdrawal (or better) and orienting spontaneous123 eye movements at 3 days, 77 percent showed moderate to good recovery at 1 year. Oculovestibular (cold caloric) reflexes may be an important determinant of severe brainstem damage. Mueller-Jensen and co-workers found that only 8 percent of patients with coma of diverse 125 causes recovered fully or with minimal disability if oculovestibular reflexes were absent. A recent review of numerous studies of prognostic indicators in posthypoxic-ischemic coma have reaffirmed the general utility of these clinical examination 126 findings. The recent practice parameters from the American Academy of Neurology for prediction of outcome in comatose survivors of cardiopulmonary resuscitation emphasize the most pertinent clinical examination findings suggestive of very poor recovery as (1) absence of all brainstem reflexes at any time, (2) absent pupil or corneal reflexes at 3 days, or (3) 115 motor responses that are absent or no better than extensor at 3 days. As noted previously, electrophysiological studies, specifically somatosensory evoked potentials, may also provide 115 prognostic information. Extensive predictors, either clinical or laboratory, for outcome from other causes of metabolic coma are much less available. In a series in which recovery from various forms of coma was assessed, Levy and associates found that 35 percent of patients with hepatic coma and 34 percent of patients with coma caused by renal failure regained independent function, whereas 127 only 12 percent of patients comatose from hypoxia did so. The mortality rate in patients with coma from septic encephalopathy and multisystem organ failure approaches 40 percent; this is, however, similar to the mortality rate of adult respiratory distress syndrome and multisystem organ failure, suggesting that the 128,129 underlying critical illness, not the presence of Specific clinical and electrophysiological coma, defines prognosis in this circumstance. predictors are not as reliable for coma from metabolic causes other than hypoxia-ischemia, but the presence of intact brainstem reflexes (pupils and ocular movements) suggests a more favorable outcome. Presumably, these metabolic causes of coma do not cause permanent cerebral damage, unlike hypoxia-ischemia or prolonged hypoglycemia. Thus, mortality is not caused by the coma itself but is more associated with the severity of the underlying disease. Most patients who recover from their underlying illness recover completely from coma of metabolic origin. This is, however, not always the case and suggests that some patients with metabolic coma from organ dysfunction, sepsis, or electrolyte disturbances may acquire secondary brain injury from either impaired substrate delivery or mechanisms yet to be elucidated. BRAIN DEATH The diagnosis of brain death has medical, legal, and ethical implications. In the United States and most other countries, brain death is a prerequisite to most organ donation,130 although non–heart-beating organ donors are now being used in certain circumstances. Brain death is equivalent to circulatory death (defined by absence of cardiac and respiratory functions) as a medical and legal definition of death, and the time of determination of brain death is
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considered the time of death. The Uniform Determination of Death Act states that “an individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions or (2) irreversible cessation of all functions of the entire brain, including the brainstem, is dead. A determination of death must be made in accordance with accepted 131 medical standards.” Despite ample medical and legal precedent for the concept and importance of brain death, several surveys have 132–134 indicated lack of knowledge about clinical The Quality Standards Subcommittee definitions and diagnostic criteria for brain death. of the American Academy of Neurology has developed standardized criteria for the 135 determination of brain death in adults. These criteria form a reasonable currently accepted medical standard. The determination of brain death is based primarily on clinical criteria (Table 62-4 and Table 62-5), with use of supporting diagnostic tests when necessary. Several prerequisites must be met. It is essential that there be a diagnosis of a CNS catastrophe that is compatible with brain death. These include neurological disorders (e.g., aneurysmal subarachnoid hemorrhage) and systemic diseases (e.g., hypoxic-ischemic encephalopathy, massive brain edema from fulminant hepatic failure). Complicating conditions that may confound the neurological examination must be excluded. These include hypothermia (<32°C), hypotension (systolic blood pressure <90 mmHg), hypoxia (Pao2 <60 mmHg), drug effects such as from neuromuscular blocking agents or sedatives, and facial or cervical trauma that makes it impossible to perform the neurological examination. The three clinical features of brain death, all of which must be demonstrated, are cerebral unresponsiveness, absence of brainstem reflexes, and apnea. Cerebral unresponsiveness is demonstrated by absence of cerebral motor response to painful stimulus (nail-bed and supraorbital pressure) in all extremities. Brainstem reflexes that must be demonstrated as absent include pupillary light reflex (≥4 mm in size), ocular movement (absent doll's eyes and absent response to cold caloric testing), facial sensation and motor response (absent corneal reflex), and pharyngeal response (absent gag and cough reflexes). Apnea is confirmed when the Paco2 is documented to rise above 60 mmHg without clinical evidence of respiratory effort, indicating absence of function of central respiratory chemoreceptors and neurons located in the medulla. Repeat clinical evaluation in 6 hours is recommended but not mandatory. Independent confirmation by a second physician is required for the clinical diagnosis of brain death. Click here to view this table.... Click here to view this table.... Several confirmatory laboratory tests may be used in the determination of brain death but do not supersede the clinical examination. In patients who have received significant doses of sedative agents (e.g., high-dose barbiturates for treatment of elevated intracranial pressure), clinical examination is unreliable for the diagnosis of brain death. In this circumstance, a cerebral blood-flow study demonstrating absence of blood flow to the brain is sufficient for the diagnosis of brain death. Formerly, conventional angiography was performed, but currently a 136 nuclear medicine technetium-99m brain scan is often used. Transcranial Doppler ultrasonography 137 (TCD) (Fig. 62-2) can also be used provided adequate insonation windows can be obtained. When sedative medications are absent, EEG or somatosensory evoked potentials performed to special specifications can be used if a confirmatory test is 138 necessary. The use of confirmatory tests is usually reserved for patients in whom clinical examination cannot be reliably performed because all conditions that may confound clinical neurological assessment cannot be excluded or for circumstances in which family members seek additional supportive evidence of the diagnosis.
FIGURE 62-2 Diagnosis of brain death by transcranial Doppler ultrasonography
(TCD). A, Normal blood flow velocity and direction in the left middle cerebral artery (LMCA). B, Findings in brain death. Direction of flow is reversed during diastole, indicating cerebral circulatory arrest. For the use of transcranial
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Doppler ultrasonography as a confirmatory test in brain death, these findings must be present in both anterior circulations and in the posterior circulation. Several pitfalls or conundrums exist with regard to brain death. Legally, “irreversible cessation of all functions of the entire brain, including the brainstem,” indicates brain death. It has been 138,139 Nevertheless, when left to the medical community to decide how to demonstrate this. accuracy of the stated clinical criteria has been reviewed, the diagnosis of brain death has 7,131,138 Conversely, some have suggested that prolonged been considered secure. unconsciousness or a persistent vegetative state is equivalent to brain death because 140 purposeful consciousness cannot be regained. Although the latter circumstances have been supported in terms of withdrawal of medical support and care because of medical futility, they do not meet the medical or legal definitions of brain death and should not be considered to do so. Also, some individuals and cultures do not accept the notion of brain death as equivalent to circulatory death. This can present challenges regarding ongoing medical care and the medical-legal interface. Further aspects of end-of-life care are discussed in Chapter 63. PERSISTENT VEGETATIVE STATE Brain death could be considered the ultimate loss of consciousness. The neuroanatomy of brain death requires the loss of function of both cerebral hemispheres and the brainstem RAS, although it may not be possible clinically to determine cortical function when the RAS and entire brainstem have been completely destroyed. There are, however, other circumstances of permanent loss of consciousness short of brain death. It7 is uncommon for a sleep-like coma state (eyes closed) to persist for more than 2 to 4 weeks. After this time, patients with permanently disordered consciousness usually evolve to a chronically unresponsive state with eyes open. When subjects exhibit this eyes-open unconsciousness with no awareness of self or the environment for more than 1 to 3 months, the definition of 141 persistent vegetative state is met. This state may result from a variety of insults, including acute conditions such as traumatic brain injury, hypoxic-ischemic encephalopathy, and encephalitis, as well as being an end142 result of chronic neurodegenerative disorders such as Alzheimer's or Huntington's disease. Clinically, it appears to be a state of intact brainstem and entirely absent cerebral cortical function. Autopsy results have largely confirmed this, showing extensive cortical and hippocampal damage after hypoxic-ischemic encephalopathy and subcortical diffuse axonal injury after trauma. Occasional reports have demonstrated 142 severe brainstem damage, but not in isolation. A review of the autopsy of Karen Ann Quinlan, who was the subject of dramatic moral and legal debates in 1975 over withdrawal of medical support of patients in a persistent vegetative state, suggested another view of the neuroanatomy of the vegetative state. Quinlan sustained severe hypoxic-ischemic encephalopathy after cardiopulmonary arrest and entered a persistent vegetative state after a prolonged coma. Postmortem examination demonstrated severe bilateral damage to the thalamus, out of proportion to any damage found in the cortex 143 or brainstem. This suggests that the thalamus is important for cognition and that severing the connections between the RAS and cerebral cortex may be sufficient to impair consciousness, perhaps permanently. Thus, different neuroanatomical lesions may actually lead to the clinical picture of a persistent vegetative state and perhaps even the clinical diagnosis of brain death. Aspects of the care of patients in a persistent vegetative state are discussed further in Chapter 63. Previous
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Michael J. Aminoff
NEUROLOGY and GENERAL MEDICINE 63 Care at the End of Life MICHAEL J. AMINOFF •
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PHYSICIAN–PATIENT INTERACTIONS PROVISION OF CARE SPECIAL NEUROLOGICAL CIRCUMSTANCES Persistent Vegetative and Minimally Conscious States De-efferented State Advanced Dementia Amyotrophic Lateral Sclerosis CONCLUDING COMMENT
With the advent of increasingly sophisticated technology and more powerful pharmacological agents, it has become possible to prolong the last stages of life in patients with severe and irreversible medical disorders, in whom a long-term favorable outcome cannot be achieved. In some instances, the futile use of sophisticated technology to maintain certain bodily functions in individuals with no prospect of useful recovery has involved major financial outlay, an added burden on patients in advanced stages of incurable disease, and unnecessary and prolonged emotional distress to friends and relatives. Indeed, impersonal advances in modern medicine have led to increasing indignity and fear in many individuals as the end of life draws near. Neurologists are often required to look after patients at the end of life either because a primary neurological disorder reaches a terminal phase or because patients with primary medical disorders develop a catastrophic neurological complication leading to consultation. PHYSICIAN–PATIENT INTERACTIONS It is the responsibility of all physicians to provide adequate care for patients who are dying. The focus of care changes from attempts to reverse or cure an underlying disease to providing compassionate and sensitive care for patients facing imminent death. Such care may be required for no more than a few hours or for as long as several months, depending on the nature of the underlying disorder. Physicians must assume responsibility for helping patients to deal with the bleak uncertainty of the future and to cope with the sense of isolation and dependency that is often experienced with the approach of death. Fears concerning pain or discomfort can often be alleviated by proper explanation, and supportive care by family, friends, and medical attendants may help to diminish otherwise overwhelming feelings of
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isolation and uncertainty. Some physicians still feel a certain guilt or responsibility for the death of patients, and this colors their approach to patients who are dying. Such attitudes will change only with the wider appreciation that death is but a natural milestone. With the increasing emphasis on the scientific aspects of modern medicine, the art of the discipline—its human side—is often overlooked. Physicians must be prepared to spend time with their patients to provide support, education, and adequate symptomatic relief and to work with them and their family to enable them to come to terms with events. Unfortunately, however, such discussion and resultant decision-making substantially in advance of death 1 are uncommon. The demands on physicians by patients may be considerable as death approaches. It is especially important for physicians to understand the needs of patients who are unable or unwilling to communicate them. Patients need to know that they will continue to receive support and care from their physician throughout the process of dying. A cursory glance at patients during the course of a busy ward-round is quite inadequate in this regard. The family, also, may require considerable attention from physicians. This requires a sensitivity to their needs and the ability to communicate fully with them at all times, providing adequate responses to their queries; meeting with them after death has occurred often helps to settle unresolved fears and concerns. The care of terminally ill patients usually requires the cooperation of the entire health care team, including nursing staff, social workers, physical and occupational therapists, dietitians, and psychotherapists, as well as physicians. The spiritual needs of the family must not be overlooked, and the clergy have an important role in this context. In many countries, the general public has expressed increasing dissatisfaction with the care received by people who are dying. Fueled by concerns about the quality of end-of-life care, support has grown for the concept that patients with terminal illnesses should have the right to request assistance in dying. The extent to which physicians can assist in this regard is governed by national statutes, and the extent to which physicians choose to become involved in this context is personal and individual. Regardless, many individual physicians support the 2 numerous legalization of medically assisted suicide and voluntary euthanasia, although 3 professional organizations (including the American Academy of Neurology ) are opposed to such an approach. Medically assisted suicide involves providing the means for a patient intentionally to kill himself or herself, whereas voluntary euthanasia consists of the deliberate killing of a patient at his or her request. The provision of appropriate palliative care for dying patients would make such radical alternatives unnecessary in many instances. Pain relief, for example, must be adequate even if, as an unintended side effect, the medications used to control pain lead to some shortening of life in consequence. Some patients with advanced medical disease may seek a particular therapeutic intervention that seems unjustified to their physician. Clinicians should behave in a manner that does not conflict with their own beliefs; if differences with patients and their families cannot be resolved by discussion and explanation, it is sometimes worthwhile to transfer patients to the care of another physician. Physicians have the responsibility of withholding treatment when the distress or other adverse effects of therapy cannot be justified by unrealistic hopes of curing or arresting the underlying medical disorder and of withdrawing life-prolonging maneuvers when these have become too burdensome for patients. Competent adults have the right to refuse medical treatment or to request its discontinuation. Despite this, many patients dying in hospital continue to receive unwanted interventions such 4 as intensive life support that postpone death. Patients' refusals of supportive measures are not necessarily indicative of a wish to die: rather, they often signify simply a wish to do without 5 the burden of life-sustaining medical treatment. The goals of such treatment must constantly be reappraised by patients, relatives, and medical staff. Even routine procedures such as radiographs, blood tests, and respiratory care may become unwelcome and tiresome interruptions during the last days of life, and the need for them must be re-evaluated as the patient's condition deteriorates. When patients do refuse treatment, however, physicians are responsible for ensuring that this is not an impulsive decision but is based on an understanding of the implications of such a choice. For patients to make informed decisions, it is important that they are properly educated by their physician about their options. They should also be encouraged to use advance directives such as a living will to ensure that their own wishes regarding medical intervention are followed if they later become unable to express their preferences because of physical or mental limitations. A durable power of attorney for health care in the United States gives another person the power to make medical decisions for the patient as necessary. It is important that physicians educate patients about such opportunities and the ability to make advance directives. Clinicians must also properly inform proxy decision-makers about the patient's disorder, therapeutic options, and prognosis. They are generally expected to make
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decisions based on what the patient would have wished, and this assumes some knowledge of the patient's preferences. Without such knowledge, the proxy can only balance the benefits of any treatment or course of action against the possible burdens. When the perceived benefits are greater, consent is provided; if the likely burdens exceed any potential benefit, consent is refused. However, there is a discrepancy between theoretical ethical concepts and clinical reality. A study of dialysis patients revealed that many would allow their designated surrogate to override their advance directives if this was in their interests. Subjects varied greatly in how much leeway they would give surrogates to override their advance directives: “no leeway” was given by 39 percent, “a little leeway” by 19 percent, “a lot of leeway” by 11 percent, and 6 “complete leeway” by 31 percent. Another study found that many elderly or seriously ill hospitalized patients (more than 70%) would not want their stated resuscitation preferences to be followed if they were to lose decision-making capacity but preferred that their family and 7 physician make such decisions for them. It seems that proxy decision-makers have the discretion to assess novel and perhaps unforeseen circumstances, make moral judgments, and sometimes make decisions that differ from the patient's original intent,8for example, because the patient's wishes cannot be applied in certain clinical contexts. With these issues in mind and to better understand the moral obligations of the patient-proxy relationship, Fins and colleagues surveyed 50 patient-proxy pairs and 52 individuals who had 8 been proxies for someone who had died. They used structured vignettes of three separate diseases (one of which was acute stroke), and examined whether respondents believed that proxies should follow explicit instructions and thus act contractually regarding life-sustaining therapy or whether more discretionary (or covenantal) judgments were acceptable. Other variables included the “valence” of initial patient instructions (e.g., “to do nothing” or “to do everything”) and the quality of information available to the proxy. They found that the patient–proxy relationship exists on a contractual to covenantal continuum and that disease course, the clarity of prognosis, instructional valence, and quality of patient instructions led to response differences. The use of interpretative or covenantal judgment was desired by patients and proxies when the prognosis was grim, despite initial instructions to pursue more aggressive care. When hopeful feelings modified initial negative instructions, proxies were more uncertain about the propriety of doing nothing. Nonetheless, patients and proxies intended that negative instructions to be left alone should be heeded. Respondents did not adhere to narrow notions of patient self-determination but made nuanced and contextually informed moral judgments that were not viewed by patients or proxies as violations of the principal's autonomy. Although respondents were better educated than the general public and were restricted to self-identified, English-speaking Americans of European origin (to avoid the possible confounders of race and ethnicity), these data suggest that advance-care planning should consider both the exercise of autonomy and the interpretative function assumed by 8 the proxy. Studies indicate that patients would like to discuss advance directives earlier than their physicians and before they are “extremely ill” (Fig. 63-1). Most believe that such discussion 9 should occur when they are still healthy. Both patients and clinicians believe that it is the physician who should initiate the discussion (Fig. 63-2), but physicians are often reluctant or 9–11 Many patients believe that others (e.g., a spouse or “significant other,” fail to do so. 9 children, or parents) should be brought into the discussion. Most also believe that it should occur before hospitalization and over several visits.
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FIGURE 63-1 Patient and physician opinions regarding when advance
directives should be discussed. (From Johnston SC, Pfeifer MP, McNutt R, for the End of Life Study Group: The discussion about advance directives. Patient and physician opinions regarding when and how it should be conducted. Arch Intern Med 155:1025, 1995, with permission.)
FIGURE 63-2 Patient and physician opinions about who should initiate
discussion about advance directives. (From Johnston SC, Pfeifer MP, McNutt R, for the End of Life Study Group: The discussion about advance directives. Patient and physician opinions regarding when and how it should be conducted. Arch Intern Med 155:1025, 1995, with permission.) For patients nearing the end of life, decisions have to be made about whether cardiopulmonary resuscitation should be attempted, if the need arises. In patients with terminal diseases, such decisions often bear more on the issue of how a patient will die than on whether death will occur, and it is important for patients and family members to understand this distinction. A decision by a patient (or family members) needs to be made in advance, so that individual wishes can be taken into account in the event that resuscitation is required. In many European countries, physicians take an active role in advising patients and family members about the most appropriate course of action to follow, whereas many physicians in the United States believe that this is an individual decision that is best left to the patient. It is this author's view that the physician—as the most informed person in the health care team—should make clear recommendations to the patient and family in this regard, even though the final decision must be made by the patient or a surrogate. It is often helpful to discuss the possibility of organ donation with dying patients when this is a
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significant consideration. This makes it easier for family members who may otherwise have to be approached about the issue shortly after the death of their relative. A variety of ethnic, religious, and cultural factors affect attitudes concerning organ donation, and these must be respected. Physicians must appreciate that patients are not obliged to donate organs and may choose to limit any donation that they make. PROVISION OF CARE With their increasing emphasis on surgery and advanced technology, hospitals no longer are able to provide for the long-term care of patients who are dying. By contrast, the needs of the terminally ill are often met more fully in the environment of a hospice, where a multidisciplinary team can focus on their care and support, or at home, if an adequate family structure and medical/paramedical support are available. Care for patients in a home environment requires careful education of the family, reduction of probable causes of stress (such as violence, agitation, or incontinence), support of caregivers by ensuring assistance 12 from other ancillary health care providers, and provision of periodic respite to the family. The interests of patients nevertheless remain the prime concern. When family members appear preoccupied more with their own welfare than that of a severely demented or dying 12 patient, the possibility of patient abuse may require consideration. Abuse of the weak or elderly is becoming an increasing problem and a matter of grave public health concern. The care of terminally ill patients should be focused on improving the quality of life rather than simply on extending the duration of life. This aspect has in general been neglected until recently and still receives relatively little attention in the clinical literature or medical school curricula. Palliative medicine constitutes a newly emerging medical specialty in which the 13 focus is on the quality of life for patients with advanced and progressive disease. The aim is to ensure that patients are as comfortable as possible, even during the process of dying. Curative treatment is not provided for disorders that do not cause discomfort, even if this leads to some shortening of life. Such an approach, traditionally associated with the care of patients with terminal cancer, is also relevant in the management of patients with a number of neurological and general medical disorders, such as amyotrophic lateral sclerosis, severe cerebrovascular disease, locked-in syndrome, or advanced dementia. The emphasis is on 14 the control of symptoms. Pain is the most common symptom in dying patients. Pain, discomfort, distress, fatigue, dyspnea, anorexia, nausea, vomiting, cognitive disturbances, and affective disorders all require particular care. When the ability of patients to communicate is impaired, it is necessary to infer the presence of distress by such signs as agitation, restlessness, tachypnea, and tachycardia and to initiate treatment accordingly. Many patients fear that any later inability to communicate their distress will lead to unnecessary and increased suffering. The relatives of dying patients frequently complain that signs of distress were ignored in patients unable to communicate their needs verbally. No justification exists for limiting symptomatic measures in such circumstances; overtreatment is preferable to undertreatment. Opioids have an important role in providing pain relief when nonopioid analgesia is inadequate. Morphine is also particularly useful in relieving dyspnea. The optimal dose is that providing adequate relief. When it is introduced, morphine is best started in an immediate-release formulation. A starting dose of 5 to 10 mg every 4 hours is often adequate, but higher doses may be needed if patients have previously received another opioid, such as dihydrocodeine. A double dose at bedtime may also be helpful. Rescue supplements of morphine are necessary for “breakthrough” pain. The total daily dose of 15 morphine should be titrated upward rapidly (e.g., by 30% to 50%) if pain relief is inadequate. Once pain is controlled, a modified-release preparation of morphine can be used. Side effects of morphine, especially nausea and constipation, may require concomitant treatment. Delirium resulting from opioid treatment may respond to substitution with an alternative opioid. It may be necessary to administer opioids by a nonoral route in patients with severe vomiting or dysphagia, those with intestinal obstruction or malabsorption, or those who are 15 unable to comply with an oral regimen. Anxiety, agitation, or delirium may respond to benzodiazepines or neuroleptic agents. In one study of critically ill patients, it was found that large doses of sedatives and analgesics were administered to relieve pain and distress during the withholding or withdrawal of life-supporting measures, but that death was not 16 hastened by such medication. Supportive therapy is important. Attention to the environment may be rewarding. The intensive care unit, with its harsh light, endless noise, monitoring and other equipment, and frequent alarms, is an overwhelming place that provides no respite for dying patients. Withdrawal of ventilator support is often particularly distressing for both relatives and medical 4 staff, even though this is ethically no different from limiting other therapeutic or supportive measures. Ventilator withdrawal may be accomplished by extubation or by “terminal weaning”
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(in which ventilator rate, positive end-expiratory pressure, or tidal volume is gradually reduced with the endotracheal tube in place). Regardless of the method used, patient comfort must be ensured, as must the family's perception in this regard. For conscious patients requesting sedation for ventilator withdrawal, Brody and colleagues recommend 2 to 4 mg of midazolam intravenously before withdrawal, and 5 to 10 mg of morphine by intravenous bolus for distress during weaning, followed by continuous infusion (50% of bolus dose per hour);4 in patients with tolerance to such agents because of prior use, higher doses are needed. Others have used pretreatment with the equivalent of 15 mg per hour of intravenous diazepam or 15 mg per hour of intravenous morphine, increasing the dose as necessary to relieve dyspnea and 17 anxiety, even to the point of unconsciousness if required and requested. Neuromuscular blocking agents should be discontinued before withdrawal of ventilator support, and indeed probably in all dying patients, to allow verbal communication when this is otherwise possible and to permit signs of distress to be manifest so that appropriate 4 treatment can be provided. The masking of such signs by neuromuscular paralysis serves no useful purpose, and the inability to exhibit signs of distress in this context cannot be taken to imply that such distress is absent. Attention must be devoted to nutrition, hydration, care of the skin, and sphincter function. The nutrition and hydration of dying patients require careful consideration. The points to consider include whether such support should be provided at all, the manner in which it is best provided, and patients' tolerance of any resulting discomfort, complications, or side effects. There are benefits of withholding nutrition and hydration to shorten life when other treatment is to be discontinued. The artificial provision of nutrition and hydration is a life-sustaining maneuver that does not differ from other maneuvers that supplement or substitute for normal bodily functions. Withdrawal of artificial nutrition and hydration, however, has particular emotional implications for the general public and many clinicians. Such a course therefore demands particular discussion with patients (when communication is possible) and family members, as well as with other members of the health care team who may be concerned. It 18 is avoided by some clinicians who fear it will add to patients' discomfort. In fact, however, it is unlikely to lead to much additional distress, and by shortening life may actually limit further discomfort. When distress does follow 4withdrawal of nutrition or hydration, additional symptomatic measures are necessary. Dryness of the mouth is often relieved by ice chips, glycerin swabs, or petroleum jelly lip balm; withdrawal of medication that may be exacerbating this symptom should also be considered. Mouthwashes may relieve poor oral hygiene, and antimonilial therapy is indicated for candidiasis, antiemetics for nausea, and 4 opiates or benzodiazepines for restlessness or pain. SPECIAL NEUROLOGICAL CIRCUMSTANCES Certain circumstances that are particularly likely to be encountered by neurologists merit brief additional comment here. Difficulties are particularly likely in circumstances in which diagnosis and prognostication are based on purely descriptive aspects of clinical status rather than more objective quantitative laboratory criteria, such as in the management of patients 19 with disorders of consciousness. This requires physicians to be very specific about their limitations in predicting the outcome of certain neurological catastrophes.
Persistent Vegetative and Minimally Conscious States The persistent vegetative state is characterized by loss of awareness despite the presence of sleep-wake cycles. It occurs in patients with destruction of the cerebral cortex but preservation of brainstem function. Such patients may survive for prolonged periods if provided with nutrition and fluids. There is general agreement that they do not experience pain or suffering, based on the lack of any behavioral indications of distress and the presence of extensive cortical damage that destroys the substrate of consciousness. Life-prolonging medical treatment can be withdrawn from a patient in a persistent vegetative state when it is clear that this accords with the previously expressed wishes of the patient and the family concurs with the withdrawal of such support. In general, the provision of nutrition and hydration is not to be withheld when the patient's prognosis is uncertain; its withdrawal at a 20 later date is, however, appropriate when it is clear that the patient's condition is hopeless. 20 This usually requires the vegetative state to have persisted for at least 1 month. However, recovery from a vegetative state may take longer than this, depending in part on the 19 underlying etiology. Indeed, a vegetative state is generally required to last for more than 3 months after an anoxic injury or 1 year after a traumatic brain injury before it is considered 21 permanent, and even then, a slim chance remains of further recovery with time. Thus, decisions to remove life-supporting measures are commonly made while the likelihood and extent of recovery are uncertain and, consequently, may be influenced by the personal biases of treating medical and nursing staff. It is clearly appropriate in such a context to explain the
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prognostic dilemma to family members so that decisions are truly informed ones.
The so-called minimally conscious state designates a state in which patients exhibit inconsistent but discernible evidence of consciousness. It is thus quite distinct from the vegetative state, but it remains difficult to define. Some degree of functional recovery of 22 behaviors suggesting self- or environmental awareness has occurred. Such behaviors may, for example, include basic verbalization or context-appropriate gestures (regardless of accuracy), appropriate emotional responses (e.g., smiling or crying) to the linguistic or visual content of emotional but not neutral stimuli, or more simple activities such as purposive behaviors in response to environmental stimuli (e.g., a finger movement or eye blink apparently to command) or pursuit eye movement or sustained ocular fixation in response to moving or prominent stimuli. Improvement from this state is demonstrated by the restoration of consistent functional communication with the patient. The minimally conscious state may occur in different neurological contexts in which there has been a loss of cerebral function and may be temporary or permanent. Only limited information is available about the natural history or long-term outlook, and it depends in part on the etiology of the underlying neurological disorder. Thus, the prognosis is better for those 23 in whom traumatic brain injury was responsible than in other instances. The likelihood of useful functional recovery declines with time, and patients remaining in a minimally conscious state for more than 12 months are likely to remain severely disabled and without a reliable means of 22 communication. The clinical examination provides only limited help in defining the prognosis and whether imaging and electrophysiological techniques eventually help in this regard and in decision-making remains to be determined. In the meantime, cultural, religious, and family values will govern the responses of relatives to a patient in a minimally conscious state, and health care providers must respect these responses and the previously expressed wishes of patients. In the context of both the persistent vegetative and minimally conscious states, clinicians must be careful about suggesting at an early stage that no hope exists of useful recovery in order to justify decisions to discontinue life-supporting therapy when the 19 evidence is lacking. Instead, a frank discussion of the limited information available and the generally poor (but uncertain) prognosis may be more ethically appropriate and lead to more informed management decisions. The serial clinical assessment of patients in both the acute and chronic setting will help to detect subtle but important changes that may otherwise pass unnoticed and that may affect management. It will also help to clarify for family members the significance of any changes that they have themselves observed. For example, relatives and friends may assume that eye opening, eye movements, swallowing movements, smiling, and other motor activities represent signs of recovery when they develop in a comatose subject, and it is incumbent on physicians to explain that this is not the case so that realistic expectations can be maintained. Functional imaging may also come to be important in the assessment of these patients. In minimally conscious patients, activation patterns similar to those of healthy subjects have 24 been described and suggest conscious awareness. In patients diagnosed as being in a vegetative state, changes in positron emission tomography or functional magnetic resonance imaging sometimes reveal cortical activation, for example, in response26to face-recognition or 25 instructions to imagine motor activity, or to a familiar voice speech-perception paradigms, 27 saying the patient's name. Such findings suggest awareness similar to that in patients in a minimally conscious state and may help to indicate which patients behaviorally classified as in a vegetative state are in fact in a minimally conscious state or are likely to recover clinical 28 signs of awareness, thereby providing a guide to prognosis. There have been occasional anecdotal cases in the lay media of apparently miraculous recovery from a prolonged vegetative or minimally conscious state. The accuracy of these reports is unclear, as is the extent to which any recovery was clinically meaningful. In some 29 instances, imaging studies have raised the possibility of axonal regrowth, but whether this is responsible for any clinical improvement is uncertain. Anecdotal reports of arousal and temporary improvement after administration of zolpidem to patients in a persistent vegetative 30 state also require confirmation. It is the responsibility of medical and paramedical staff to ensure that such reports are not taken out of context and do not result in unrealistic expectations by family and friends attempting to come to terms with the predicament of a patient in a vegetative or minimally conscious state.
De-efferented State Patients in a “locked-in” or de-efferented state are conscious but quadriplegic and incapable of communication except by eye closure or vertical eye movements. They typically are ventilator dependent. Somewhat surprisingly, in one survey of 44 patients in this state, many
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had some social interactions, almost half had a positive attitude, and only 12.5 percent 31 reported being depressed. Thus, the quality of life may be acceptable to patients despite severe handicap. Nevertheless, some de-efferented patients may decide on withdrawal from further life support, and clinicians are obligated to respect these decisions when they have 32 been competently made. The withdrawal of support must be accompanied by measures to minimize further pain and distress while the patient succumbs.
Advanced Dementia The management of patients with advanced dementia may be especially challenging for neurologists. Cognitive decline and the disintegration of personality do not justify any disregard of and loss of respect for the individual patient. Medical problems require as much attention as in patients who are cognitively intact. This is particularly difficult because demented patients are often unable to cooperate fully, making the recognition and management of such problems more demanding. The care of patients with advanced dementia requires close interaction of clinicians with other family members to improve the quality of life and to find practical solutions for the minor problems that complicate daily life. Depression may enhance an apparent cognitive decline and may even be mistaken for dementia; the possibility of its presence always merits consideration. Patients in the early stages of progressive, dementing disorders should be encouraged to make their preferences known by discussion with family and health care providers and by written advance directives while they are still competent. In the absence of such written directives, it eventually is necessary to identify a proxy decision-maker to act for the patient. Although patients with advanced dementia are not necessarily terminally ill, decisions about life-sustaining treatment for them are usually made by reference to the same ethical and34legal 5,33 although there is no unanimity in this regard. In principles as for patients who are dying, such circumstances, for example, the artificial provision of nutrition and hydration in a demented patient who has lost the ability to eat is best decided5,12 based on the previously Palliative care is the expressed wishes of the patient or the decision of a surrogate. preferred approach and is often satisfactorily provided in a nursing home or hospice 29 environment. Nevertheless, ambiguity about the care of severely demented patients is common. Thus, Wray and co-workers found a major difference between the decision to limit care, which usually involved33the patient's family, and the decision to provide full care, which involved families less often. The physicians involved in these decisions often thought that less intensive care would have been more appropriate, but nevertheless provided full care because the acute condition was potentially reversible (e.g., with antibiotics). Morrison and Siu compared the care received by patients admitted to a New York hospital for hip fracture 35 or pneumonia and who had either advanced dementia or intact cognition. The demented patients received as many burdensome procedures as the nondemented patients. Moreover, in the group with hip fracture, patients with dementia received significantly fewer morphine sulfate equivalents daily for pain relief than patients with preserved cognition, and only 24 percent received a standing order for any analgesics, even though such patients are often unable to communicate the presence of pain. Even fewer of the demented than nondemented patients had advance directives, and no documentation was found of any discussion about goals of care or decisions to withhold life-sustaining therapies in 90 percent of the patients with severe dementia. Clearly, closer consultation with family members and surrogates is necessary to define a rational treatment and management approach, which can then be followed.
Amyotrophic Lateral Sclerosis Ganzini and co-workers measured pain, quality of life, suffering, sense of hopelessness, depression, level of disability, desire for life-sustaining medical treatment, and interest in assisted suicide of patients with amyotrophic lateral sclerosis and also asked their caregivers 36 to rate the patients' quality of life, pain, and suffering. Suffering was graded as 4 or more on a 6-point scale by 20 percent of patients and correlated with increasing pain, hopelessness, and level of disability. No relationship was found, however, between ratings of pain, suffering, and quality of life and interest in life-sustaining treatment or physician-assisted suicide. Pain and depression were often unrecognized or inadequately managed by treating physicians. In patients with amyotrophic lateral sclerosis, ventilatory support should be discussed before the devel opment of respiratory symptoms, and noninvasive ventilation should be considered 17 before tracheostomy. The financial, social, and emotional burden of chronic invasive ventilation must be discussed fully with patients and their families so that informed decisions 11 can be made. Many patients on ventilatory support are able to lead high-quality lives. As the
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disease progresses, the goal of treatment evolves from optimizing and maximizing function to palliative care. Two of the most common distressing symptoms in advanced cases are dyspnea and anxiety. Specific guidelines for treatment of intermittent or constant symptoms 17 of this sort are available. Pain may also occur and, if non-narcotic analgesics, anti-inflammatory drugs, and antispasticity agents are inadequate, may necessitate opioids. The wishes of patients with amyotrophic lateral sclerosis concerning life-sustaining therapy 37 are not stable, and preferences frequently change over a 6-month period. Frequent discussion of options is therefore important, and advance directives for end-of-life care require periodic re-evaluation. Patients and caregivers will not agree on all issues. Their attitudes to treatment options and their perceptions on quality of life have been examined. In one study, no significant difference was found between patients and caregivers on depression and quality-of-life scores, but patients tended to overestimate 38 the quality of life of their caregivers, whereas caregivers underestimated that of patients. Over half of both groups endorsed the future use of noninvasive mechanical ventilation, but more patients (41%) than caregivers (5%) were uncertain; just 3 percent of patients responded negatively compared to 32 percent of 38 caregivers. Both groups were generally disinterested in invasive ventilation. Spirituality or religion influences the readiness to accept percutaneous endoscopic gastrostomy, 39 noninvasive assisted ventilation, or a tracheotomy and attitude toward the process of dying. Thus, psychosocial factors, personality traits, and spiritual factors, in addition to symptoms and disability, require consideration and discussion with patients and families throughout the 40 illness. CONCLUDING COMMENT Physical distress remains common in many patients facing the end of life, but fear of suffering is probably even more common. Greater education of health care providers about palliative medicine and easier access for patients to hospice programs and related resources will help to improve care for those who are dying. The apprehensions of dying patients may also be diminished by the knowledge that caregivers are fully committed to prevent, limit, or treat any discomfort that might arise. It is not possible to guarantee an “easy” death, but a commitment to provide optimal care is certainly realistic and reassuring. Such care must take into account the wishes of patients and their families.
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