Human Hypothalamus: Basic and Clinical Aspects, Part 2: Handbook of Clinical Neurology (Series Editors: Aminoff, Boller and Swaab)

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CHAPTER TITLE

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Acknowledgements

I would like to express my gratitude for the continuous help and critical remarks of all those who made this work possible, especially Peter Bakker Afra van den Berg, Ronald Bleys, George Bruyn, Ruud Buijs, Liesbeth Dubelaar, Frank van Eerdenburg, Tini Eikelboom, Bart Fisser, Eric Fliers, Bas Gabreëls, Tony Goldstone, Louis Gooren, Valeri Goncharuk, Joop van Heerikhuize, Michel Hofman, Witte Hoogendijk, Inge Huitinga, Tatjana Ishunina, Marina Kahlmann, Dries Kalsbeek, Wouter Kamphorst, Michiel Kooreman, Berry Kremer, Frank Kruijver, Jenneke Kruisbrink, Gert Jan Lammers, Fred van Leeuwen, Rong-Yu Liu, Paul Lucassen, Gerben van der Meulen, Gerben Meynen, Jan van de Nes, Elly de Nijs, Willeke van Ockenburg, Sebastiaan Overeem, Maria Panayotacopoulou, Joris van der Post, Chris Pool, Rivka Ravid, Erik Scherder, Eus van Someren, Henk Stoffels, Elly Tjoa, Suzanne Trottier, Unga Unmehopa, Paul van der Valk, Wilma Verweij, Ronald Verwer, José Wouda, Jiang-Ning Zhou, all other participants of the Netherlands Brain Bank team, and all staff members, students, and guest workers of the Netherlands Institute for Brain Research. The persons who kept me from working on this book are too numerous too mention.

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CONTENTS

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List of abbreviations

A AADC AC AD ACTH ADHD AGRP AIDS AIP ALD ALS AM AMPA AMDLX ANP APOE AT ATD AVP BDNF BMI BST BSTdspm/ BNSTdspm BSTc BSTm CAG CAH CART CCK CDC CG ChAT CM CMV CNS CRH CSF CT DII

amygdala aromatic L-amino acid decarboxylase anterior commissure Alzheimer’s disease corticotropin attention deficit hyperactivity disorder agouti-related peptide acquired immune deficiency syndrome acute intermittent porphyria adrenoleukodystrophy amyotrophic lateral sclerosis anteromedial subnucleus of the basal nucleus -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid adhesion molecule-like X atrial natriuretic peptide apolipoprotein E angiotensin 1,4,6-androstratriene-3,17-dione (aromatase inhibitor) arginine vasopressin brain-derived neurotropic factor body mass index bed nucleus of the stria terminalis darkly staining posteromedial component of the bed nucleus of the stria terminalis central nucleus of the bed nucleus of the stria terminalis medial nucleus of the bed nucleus of the stria terminalis DNA sequence that codes for glutamine repeats. An expanded sequence is found in Huntington’s disease congenital adrenal hyperplasia cocaine- and amphetamine-regulated transcript cholecystokinin center for disease control and prevention chiasmal gray choline acetyltransferase corpora mamillaria cytomegalovirus central nervous system corticotropin-releasing hormone cerebrospinal fluid computer tomography deiodinase type II

DAX-1 DA DB/DBB DDAVP DES DHEA DHEAS DM/DMN/ DMH DMI DMV DNA DSM-III R/IV

DYN EAE ECT EEG EM ER-/ ERT FAI FO/Fx FSH GA GABA GAD GAP GFAP GHRH GnRH HCG Hcrt1-2 HD H&E HMPG 5-HIAA HIOMT HITF HIV HLA HNS HPA-axis

dosage-sensitive sex-reversal, adrenal hypoplasia, congenital, X-chromosome-1 dopamine diagonal band of Broca 1-desamine-8-D-arginine vasopressin (= desmopressin) diethylstilbestrol dehydroepiandrosterone dehydroepiandrosterone sulfate dorsomedial nucleus of the hypothalamus desmethylimipramine dorsal motor nucleus of the nervus vagus deoxyribonucleic acid diagnostic and statistical manual mental disorders (American Psychiatric Association), third revised edition/fourth edition dynorphin experimental allergic encephalomyelitis electroconvulsive therapy electroencephalogram electron microscope estrogen receptor-/ estrogen replacement therapy free androgen index fornix follicle-stimulating hormone Golgi apparatus gamma-aminobutyric acid glutamic acid decarboxylase gonadotropin hormone-releasing hormoneassociated peptide glial fibrillary acidic protein growth hormone-releasing hormone gonadotropin-releasing hormone (= LHRH) human chorionic gonadotropin hypocretin (orexin) 1-2 Huntington’s disease hematoxylin–eosin staining 3-methoxy-4-hydroxyphenylglycol 5-hydroxyindoleacetic acid hydroxyindole-O-methyltransferase human intestinal trefoil factor human immunodeficiency virus human leukocyte antigen hypothalamoneurohypophysial system hypothalamopituitary–adrenal axis

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HVA 5-HT I III ICC icv IF IFN IGF IHA IL-1 INAH1-4 INSP4 KALIG-1 LC LCA LH LHA LHRH LPH LV LVP MAO MAP(A/B) MCH MCR1-4 MDMA ME MEN MELAS MHPG MHC MPN MRI MS ()MSH (m)RNA NA NADPH NAPH NAT NBB NBM N-CAM NEI NFT NGF NKB NMDA NOS NP

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LIST OF ABBREVIATIONS

homovanillic acid (= serotonin (5-hydroxytryptamine) infundibulum third ventricle immunocytochemistry intracerebroventricularly infundibular nucleus interferon  insulin-like growth factor intermediate hypothalamic area interleukin-1 interstitial nucleus of the anterior hypothalamus 1-4 inositol-(1,3,4,5)-tetrakisphosphate Kallman’s syndrome interval gene-1 locus ceruleus leukocyte common antigen luteinizing hormone lateral hypothalamic area luteinizing hormone-releasing hormone (= gonadotropin-releasing hormone, GnRH) lipotropic hormone lateral ventricle lysine vasopressin monoamine oxidase microtubule-associated protein (A/B) melanin-concentrating hormone melanocortin1-4 receptor 3,4-methylenedioxymethamphetamine (= ecstasy) median eminence multiple endocrine neoplasia mitochondrial encephalopathy, lactic acidosis and stroke-like episode syndrome 3-methoxy-4-hydroxyphenylglycol major histocompatibility complex medial preoptic nucleus magnetic resonance imaging (fMRI = functional MRI) multiple sclerosis -melanotropin (messenger) ribonucleic acid norepinephrine nicotinamide adenine dinucleotide nicotinamide adenine dinucleotide, reduced form N-acetyl-transferase Netherlands Brain Bank nucleus basalis of Meynert neural cell adhesion molecule neuropeptide glutamic acid isoleucine neurofibrillary tangles nerve growth factor neurokinin B N-methyl-D-aspartate nitric oxide synthase neuritic plaque

NPAF NPY-IR NSM NST/NTS NT NT-3, 4/5 NTI NTL OC ORL1 OT OVLT OXT P p75 PACAP PAP PBN PC PCR PD PDD PDYN PENK PET PHM PNS POAH POMC PSP PVA PVN PWS REM RHT RIA RT-PCR SAD SCN SDN(-POA) SHBG SIADH SIDS SN SNP SNRPN SON SOREMPS SPECT SRY SSRI SWS

neuropeptide AF neuropeptide-Y-like immunoreactivity nucleus septalis medialis nucleus of the solitary tract neurotensin neurotrophin-3, 4/5 nonthyroidal illness lateral tuberal nucleus/nucleus tuberalis lateralis optic chiasm opioid receptor-like receptor optic tract organum vasculosum lamina terminalis oxytocin perikarya low-affinity neurotrophin receptor pituitary adenylcyclase-activating polypeptide peroxidase-anti-peroxidase parabrachial nucleus prohormone convertase polymerase chain reaction Parkinson’s disease pregna-4,20-diene-3,6-dione prodynorphin proenkephalin positron emission tomography peptide methionine amine peripheral nervous system preoptic anterior hypothalamic area pro-opiomelanocortin progressive supranuclear palsy periventricular area paraventricular nucleus Prader–Willi syndrome rapid eye movement retinohypothalamic tract radioimmunoassay real-time polymerase chain reaction seasonal affective disorder suprachiasmatic nucleus sexually dimorphic nucleus (of the preoptic area) = INAH-1 sex hormone-binding globulin syndrome of inappropriate secretion antidiuretic hormone sudden infant death syndrome substantia nigra single nucleotide polymorphism small nuclear riboprotein-associated polypeptide supraoptic nucleus REM sleep onset periods single-photon emission computed tomography sex-determining region Y selective serotonin reuptake inhibitor slow-wave sleep

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T3 T4 TBS TENS TG TH THA TH-IR TMN TR TRH

triiodothyronine thyroxine Tris-buffered saline transcutaneous electrical nerve stimulation tuberal gray tyrosine hydroxylase tetrahydroaminoacrine tyrosine hydroxylase-immunoreactive tuberomamillary nucleus thyroid hormone receptor thyrotropin-releasing hormone

Trk A, B, C TSH VR1,2,3 VEP VIP VLPO VMN/VMH VP

tyrosine kinase neurotrophin receptor A, B or C thyrotropin vasopressin receptor 1, 2 or 3 visual evoked potential vasoactive intestinal polypeptide ventrolateral preoptic region of the hypothalamus ventromedial nucleus vasopressin

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Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2) The Human Hypothalamus: Basic and Clinical Aspects, Part II D.F. Swaab, author © 2004 Elsevier B.V. All rights reserved

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CHAPTER 17

Vascular supply and vascular disorders

. . . the vital spirit in the blood from the heart is changed into animal spirit in the rete mirabile . . . (Anderson and Haymaker, 1974)

from the internal carotid artery, the ‘fetal configuration’. In the majority of cases, the P2 segment obtains its blood primarily from the basilar artery, the ‘adult configuration’. Multiple anomalies are found in 13% of the circles. The incidence of all varieties of anomalous vessels is higher in brains with infarcts than in control cases (Alpers et al., 1959; Riggs and Rupp, 1963; Battacharji et al., 1967), indicating that they are a risk factor for pathological changes. The hypothalamic vessels – the anterior, middle and posterior groups – receive their blood supply both from perforating branches (Figs. 17.1, 17.3, 24.1, 24.2) derived from the circle of Willis and from stems of cerebral arteries (see Chapter 17.1g; Table 17.1). The preoptic and anterior parts of the hypothalamus and the septal area are supplied mainly by the anterior cerebral and anterior communicating artery. The tuberal region and the posterior region extending backward to the rostral part of the mamillary body, together with the thalamus in its lower anterior quarter, are mainly supplied by the posterior communicating artery. The posterior portion of the hypothalamus is supplied with blood by branches arising from the bifurcation of the basilar, posterior, cerebral and neighboring parts of the posterior communicating artery. These vessels reach the hypothalamus mainly by way of the posterior perforated substance and supply mamillary bodies, posterior and lateral hypothalamic nuclei, and the subthalamus (Figs. 17.1, 17.3). Venous drainage of the human hypothalamus takes place via the anterior cerebral vein, the basal vein of Rosenthal (Fig. 17.1) and the internal cerebral vein (Fig. 17.3). These channels lead into the great cerebral vein of Galen (for details, see Haymaker et al., 1969, Chapter 5).

. . . the central nervous system regulates the activity of the adenohypophysis by means of a humoral relay through the hypophysial portal vessels (Green and Harris, 1947)

17.1. Blood supply to the hypothalamus and pituitary Arterial blood supply to the human hypothalamus is derived from terminal branches of the internal carotid and basilar arteries and from the anastomoses between them, which form the arterial circle of Willis or circulus arteriosis ceribri (Fig. 17.1). Willis never claimed to be the first to describe the circle, but he is still honored every year on St. Martin’s day, the day he died in 1675 (Wolpert, 1997). In addition, the anastomotic arterial circuminfundibular plexus and a prechiasmal anastomotic arteriocapillary plexus can be considered as a source of spare blood supply to the hypothalamus, should any of the branches be occluded. There are many variations in the pattern of the circle of Willis (Fig. 17.2). A ‘normal’ configuration of the circle of Willis occurs in less than 50% of subjects. The most frequent anomaly is a filiform caliber of one of the component vessels in 27% of the circles, most frequently localized in the posterior communicating arteries. A duplication of vessels is observed in 19%, the anterior communicating artery being the favorite site for such accessory vessels. In 8% of the circles, a midline, persistent corpus callosum branch is present. In 15% of cases, the supply to the postcommunicating part (P2 segment) of the posterior cerebral artery is mainly 3

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Fig. 17.1. Hypothalamic and related vessels as viewed from the basal aspect of the brain: the circle of Willis. (From Haymaker et al., 1969, Fig. 5.1 with permission.)

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Fig. 17.2. Anatomical variations in the circle of Willis. (From Alpers et al., 1959, Figs. 1–9 with permission.)

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Fig. 17.3. Arteries (red) of the hypothalamus and adjacent structures as viewed medially. Veins (blue) draining the superior and rostral parts of the hypothalamus are illustrated. (From Haymaker et al., 1969, Fig. 5.2 with permission.)

(a) Stalk/median eminence region After describing the origin of the portal vessels in the median eminence in 1933, Popa and Fielding erroneously deduced that blood in the portal vessels flowed upwards, from the pituitary to the hypothalamus. On the basis of

histological observations Wislocki and King, in 1936, proposed that the blood flow in the portal vessels (see Chapter 17.1c) was downwards. In 1947 and 1949, using a combination of india ink perfusion techniques and direct microscopic observations in the living rat, Green and Harris subsequently demonstrated that this was indeed

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TABLE 17.1 Arterial supply of the hypothalamus. Anterior group of arteries (from internal carotid, anterior cerebral and posterior communicating)

Intermediate group of arteries (from posterior communicating

Posterior group of arteries (from posterior communicating, posterior cerebral and basilar)

Periventricular system Suprachiasmatic nucleus Medial preoptic area Anterior area Supraoptic nucleus Paraventricular nucleus – – – – – – – –

Periventricular system Lateral hypothalamic area – – – – Infundibular nucleus Ventromedial nucleus Dorsomedial nucleus Nuclei tuberis laterales Posterior nucleus Lateral mamillary nucleus Medial mamillary nucleus Supramamillary area

Periventricular system Lateral hypothalamic area – – – – – – – – Posterior nucleus Lateral mamillary nucleus Medial mamillary nucleus Supramamillary area

From Haymaker, 1969, table 5–1, with permission.

rodents. One can, however, distinguish an upper infundibular stem, located in the suprasellar region, which contains the portal system, and a lower infundibular stem, which contains the fibers running to the infundibular process or neurohypophysis. The pars tuberalis of the pituitary forms the most rostral boundary of the median eminence (McKinley and Oldfield, 1990). The median eminence gets its blood supply from the superior hypophysial arteries that spring from the internal carotid artery (Fig. 17.6; Daniel and Prichard, 1975). The portal system is described in Chapter 17.1).

the case (for historical references, see Meites, 1992; Raisman, 1997). The median eminence is separated from the neighboring tuber by the sulcus infundibularis (Fig. 17.4) and it is continued by the infundibular stem/stalk toward the neural lobe. Thus the median eminence is made up of the proximal segment of the neurohypophysis, attached to the tuber, and this constitutes the walls of the hypophysial recess (Duvernoy, 1972). The median eminence is the site of neurosecretion of a number of releasing and inhibiting hormones that are synthesized in the hypothalamus and act on the adenohypophysis (see, e.g. Chapter 11 for the infundibular nucleus and Chapter 8.5 for CRH and vasopressin from the paraventricular nucleus). The neuropeptides are transported to the anterior pituitary gland by the portal system. On the other hand, peptides produced by the supraoptic nuclei (SON) and paraventricular nuclei (PVN), such as vasopressin and oxytocin, are for the largest part transported to the most distal part of the neurohypophysis, the infundibular process, which is also known as the pars nervosa or the posterior pituitary. At the outer surface of the human hypothalamus, the median eminence is no longer evident, since it is incorporated into the upper part of the infundibular stem. There is also no strict delineation between an internal and external zone as observed in, e.g.

(b) Pituitary The pituitary derives its blood supply, directly or indirectly, from two main sources, one above and the other below the level of the diaphragm sellae, i.e. the superior and inferior hypophysial arteries, respectively (for review, see Daniel and Prichard, 1975; Figs. 17.5 and 17.6). Radiographic microvascular injections showed that the inferior hypophysial artery is, in most cases, the dominant supply to both the neurohypophysis and the portal system (Gebarski, 1993). The superior and inferior hypophysial arteries are both paired vessels and spring from the internal carotid artery on each side, the inferior artery arising from the cavernous segment of the internal 7

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Fig. 17.4. Floor of the diencephalon in man. 1 = optic chiasm, 2 = posterior side of the median eminence and of the stalk crossed by the portal vessels. The arrows indicate the sulcus infundibularis. 3 = postinfundibular eminence or posterior tuber, 4 = mamillary bodies, 5 = optic tracts. (From Duvernoy, 1972, Fig. 24 with permission.)

carotid, and the superior artery having its origin shortly after the carotid has emerged from the cavernous sinus and passed through the dura mater, the supraclinoid part. Both the superior and inferior hypophysial arteries anastomose with their contralateral counterparts. There is also a substantial anastomotic channel which runs through the pituitary gland and connects a branch of the superior hypophysial artery with a branch of the inferior one, i.e. the artery of the trabecula (Figs. 17.5, 17.6; Daniel and Prichard, 1975). (c) Portal system The primary plexus of the portal system is made up of two vascular systems that are intricately linked: the surface network (the rete mirabile of Galenus) and the deep network. The surface network (or mantel plexus) covers the surface of the median eminence. From this network stem numerous short capillary loops that penetrate into the median eminence, where neurosecretory substances are released into them (Duvernoy, 1972). Cajal has already described hypothalamic nerve fibers that terminate on the capillaries of the median eminence, while

Fig. 17.5. Blood supply of the human pituitary gland and hypothalamus (sagittal sections). The sinusoids of the pars distalis are supplied by two types of portal vessels: (i) long portal vessels (LPV) draining capillary loops (C) in the upper infundibular stem (i.e. neural tissue of the stalk); and (ii) short portal vessels (SPV) draining capillary loops in the lower infundibular stem. Cap, capillary bed; H, hypothalamic neurons; IHA, inferior hypophysia artery; P, primary capillary bed; SHA, superior hypophysial artery. For other details see legend to Fig. 17.6. (From Daniel and Prichard, 1975, Fig. 36 with permission.)

Harris and Campbell (1966) have shown that these capillaries are of the specialized fenestrated type also found in other secretory and absorptive organs. Here, the blood–brain barrier is permeable to larger molecules. The deep network is divided into a long capillary loop and a huge subependymal capillary network connected to the rest of the primary portal plexus (Duvernoy, 1972). The deep network is made up of voluminous twisted capillaries. These capillaries are often situated transversally under the ependyma, which lines the pars caudalis tuberis (Fig. 17.7). Those situated near the posterior insertion of the median eminence are drained exclusively into the portal system. However, most of the posterior capillary formations are drained both toward the portal system and towards the lateral hypothalamic veins (Fig. 17.8). The capillaries near the mamillary bodies have a blood supply and drainage that are exclusively in the direction of the hypothalamus and independent of the portal system (Duvernoy, 1972). The main feature of the deep network is the large number of coiled

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Fig. 17.6a–d. Neoprene latex-injected preparations of the human pituitary gland which show some of the main features of the vascular arrangements. (a) The pituitary gland and neighboring structures are viewed from the front. The superior hypophysial artery (SH) is seen springing from the internal carotid artery (IC) on each side, anastomosing in front of the pituitary stalk (S), and giving off branches to supply a primary capillary bed (not visible here) within the stalk. The long portal vessels which drain this bed and run down the stalk into the pars distalis are better seen in (b). The artery of the trabecula (AT), seen also in (b), although plunging into the pars distalis, does not deliver blood directly to this lobe, which has a purely portal venous blood supply. O, ophthalmic artery; OC, optic chiasma. (b) A similar preparation, partially macerated to show the long portal vessels (LPV) running down the stalk (S) and breaking up into the sinusoids (Si) of the pars distalis. AT, artery of the trabecula. (c) Sagittal section of a stalk (anterior surface on right) in which the blood vessels have been displayed by a red cell staining method (benzidine). Note the convoluted capillary loops (C), which are typical of the primary capillary bed in the stalk, draining into a long portal vessel (LPV). One of these capillary complexes is elongated into a spike (Sp) such as the one seen in (d). (d) Neoprene cast of a long spike of convoluted capillaries (C) taken from an injected stalk (all tissue has been macerated). The afferent artery (A) to this capillary complex, and the long portal vessel (LPV) into which it drains, are both seen. (From Daniel and Prichard, 1975, Fig. 18 with permission.)

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Fig. 17.7. Vascularization of the floor of the diencephalon in human. cho, optic chiasm; bo, optic tracts; pc, section of the mesencephalon; cm, mamillary bodies; t, hypophysial stalk; si, sulcus infundibularis. A dotted line surrounds the place occupied by the postinfundibular eminence (PIE). Only the deep network is shown in this drawing. 1 and 19, arterioles which supply the PIE; 2, deep network exclusively drained by tuberal veins (39); 4 and 49, deep capillary network with mixed drainage via lateral tuberal veins and via long posterior portal vessels (5); 59, branch of a portal vessel draining the surface network; this network is not shown in this drawing; 6, deep network exclusively drained toward the hypophysis by portal vessels (5); 7, branch of the superior hypophysial arteries which bend over and reach the deep network of the median emincence (8); this network is drained by deep portal vessels (9). (From Duvernoy, 1972, Fig. 25 with permission.)

capillary loops of characteristic form and varying degree of complexity which are seen in the neural tissue of the upper infundibular stem (Fig. 17.8). Fed by terminal branches of the superior hypophysial artery, these capillary loops form a 1–2 mm long and 50–100 m wide corkscrew of capillaries, called “gomitoli” by Fumagalli (1942; for reference, see Daniel and Prichard, 1975), and they form part of a first capillary bed in a portal system of circulation. Apart from a few vessels near the junction of the stalk with the hypothalamus, the loops drain through long, straight vessels of the venous type, which run down the

stalk into the anterior pituitary and empty there into a second capillary bed. These straight efferent channels are the long portal vessels of the hypophysial portal system, which provide the pars distalis with by far the greater part of its exclusively portal blood supply, serving its anterior and lateral regions. The majority of the long portal vessels are found on the anterior and lateral aspects of the stalk within the superficial sheath of the pars tuberalis, but some lie at a deeper level and others on the posterior surface of the stalk, even where there are no epithelial cells of the pars tuberalis. At the upper extremity of the stalk, a few of the capillary loops drain upwards into veins in the

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Fig. 17.8a, b. A median sagittal section of the floor of the third ventricle. The following elements are shown (from left to right): OCH, optic chiasm; ME, median eminence; IR, infundibular recess; S, stalk; PIE, postinfundibular eminence (posterior tuber) separated from the median eminence by the sulcus infundibularis (SI); MB, mamillary body; 3eV, third ventricle. Vascular tuberohypophysial connections: (a) Anterolateral connections. 1, capillary tufts which belong to the deep network of the primary plexus and which are supplied by the tuberal arterioles (downward-pointing arrow). These tufts have some veinules which join the tuberal veins (upward-pointing arrow); 2, portal vessels; 3, surface network and its drainage. (b) Posterior connections. 4, superficial network lining the PIE. It continues toward the superficial network of the primary plexus (5); 6, portal vessel; 7, drainage of the surface network by a tuberal vein; 8, deep network which is exclusively drained by tuberal veins (arrows); 9, deep network with a mixed drainage toward the hypophysis (arrow). (From Duvernoy, 1972, Fig. 23 with permission.)

tuber cinereum, but apart from this there is no outflow of blood from the capillary bed of the stalk into the systemic venous circulation (Daniel and Prichard, 1975). In the lower infundibular stem, i.e. where the hypothalamo-neurohypophysial tract runs down the stalk and bends sharply backwards to approach the infundibular process, the vascular pattern is also characteristic (Fig. 17.8). There are many short, parallel vessels running into the tissue from below and in front, and ending in coiled

capillary loops similar to those of the pituitary stalk. These capillary loops can receive their blood supply from either the inferior or the superior hypophysial arteries, as their afferent vessels spring from an artery deep within the gland which is continuous at one end with a branch of the inferior or the superior hypophysial artery and at the other with a branch of the superior hypophysial artery, the artery of the trabecula. The efferent limbs of small groups of these capillary loops join together to form short 11

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portal vessels that open into the sinusoids of the adjacent part of the pars distalis. Apart from their smaller size, these short portal vessels are similar to the long portal vessels. There is no drainage from the lower infundibular stem into systemic veins. There are also connections between the vessels of the portal plexus and those of the posterior tuber (Figs. 17.4–17.8). In the posterior tuber there is a vascular formation whose pattern differs from that of the other hypothalamic vessels. The meshes of the surface network in this area are generally smaller than those of the more rostral mantel plexus. From this network stem numerous short capillary loops that penetrate the hypothalamus near the infundibular nuclei. In this respect the conspicuous neurofibrillary pathology, characterized by terminal-like processes contacting the neurohemal vasculature of the infundibular nucleus, is of interest (Chapter 11g). This neurofibrillary degeneration is largely restricted to males over the age of 60 years and seems to be located in the terminals of neurosecretory neurons, whose chemical nature still has to be established (Schultz et al., 1996, 1997a, b, c; see also Chapters 11 and 28.1). (d) Infundibular process The infundibular process or posterior pituitary has the conventional artery–vein pattern of circulation. Its abundant network of capillaries, which are much smaller in calibre than the sinusoids of the pars distalis, is fed by offshoots from branches of the inferior hypophysial artery which encircle the lobe. The drainage of this capillary bed is through veins which empty into one of the surrounding venous sinuses (Daniel and Prichard, 1975). The neurovascular zone behind the tuber cinereum extends almost to the mamillary bodies and it often contains islands of pars tuberalis glandular cells, but this is by no means a constant finding. The zone mainly consists of blood vessels surrounded by connective tissue sheets in which smooth muscle cells, collagen and reticular fibers may be recognized, and by perivascular plexuses of nerve fibers. The contralateral connections between the tuberal vessels and the primary portal plexus are even more numerous in humans than in other mammals. The descending connections, by far the more numerous, are formed of tuberal arterioles that supply the capillary tufts of the deep network. The very rare small veins that form the ascending connections merge into superficial retrochiasmatic veins (Fig. 17.8) (Duvernoy, 1972).

(e) Artery of the trabecula A macroscopic view of the pituitary gland would suggest that the artery of the trabecula (the ‘loral’ artery), a branch of the superior hypophysial artery that plunges into the pars distalis from above (Fig. 17.6), carries arterial blood to this lobe. However, dissection of injected tissues has shown that the artery of the trabecula does not break up into sinusoids; it merely passes through the pars distalis. In a core of fibrous tissue, the trabecula, on its way to supply capillary loops in the lower infundibular stem, anastomoses with a substantial branch of the inferior hypophysial artery that comes up to join it from below (Fig. 17.6). Usually the artery of the trabecula gives off one branch which runs toward the stalk near the upper surface of the pars distalis to supply some of the capillary loops in the lower part of the stalk. The blood circulating through the sinusoids of the pars distalis thus seems to be solely portal venous blood. However, in some instances a very short arterial twig, either from the artery of the trabecula or from the dura mater surrounding the gland, may penetrate among the immediately adjacent epithelial cells. The blood supplied by these twigs is confined to very small areas and only reaches the sinusoids immediately surrounding them (Daniel and Prichard, 1975). (f) Vascular bed of the pars distalis The vascular bed of the pars distalis consists of a dense network of freely anastomosing vessels, interspersed amongst the parenchymal cells. These sinusoids, which are larger than capillaries, receive no arterial blood, but are fed solely by the long or the short portal vessels which bring to them blood which has already passed through a primary capillary bed in the infundibular stem, where the hypothalamic releasing and inhibiting hormones are transmitted into the blood stream (Daniel and Prichard, 1975). Indeed, magnetic resonance imaging (MRI) studies have shown contrast material flowing from the median eminence to the adenohypophysis in vivo in humans (Gebarski, 1993). In contrast, in vivo collection of blood from the pituitary stalk using transphenoidal microsurgery again suggested the possibility of retrograde blood flow from the pituitary to the hypothalamus. Using microsuction and hormone assays of LH, FSH, prolactin, growth hormone, TSH and ACTH immediately after pituitary tumor removal showed 50–600 times higher levels in pituitary stalk blood than in peripheral blood. Apart from

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retrograde blood flow from the pituitary, the authors think that a hypothalamic secretion of these hormones may cause these high levels. It should be noted, though, that the aspiration technique used in that study might have interfered with the normal direction of the blood flow, and that aspiration took place after tumor resection, which might also have disturbed the normal flow. The studies of Daniel and Prichard (1975) have shown that the two groups of portal vessels, long and short, each have their own territories of distribution in the pars distalis; the long portal vessels supply the bulk of the lobe, the short portal vessels supplying only the region adjacent to the lower infundibular stem and the infundibular process. This observation was originally derived from a study of injected preparations but was subsequently confirmed by the distribution of necrotic and living areas found in patients subjected to pituitary stalk section, an operation in which the long portal vessels are severed, but the short portal vessels, together with their afferent supply, remain intact. Having passed through the sinusoids of the pars distalis, the blood is collected by small venules at the periphery of the lobe and finally empties into one of the venous sinuses that surround the pituitary gland (Daniel and Prichard, 1975).

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1960). The precommunicating part of the anterior cerebral artery supplies the nucleus basalis of Meynert. It was hypothesized that the decrease in perivascular nerve density in this segment in Alzheimer’s disease may be related to the decreased neuronal metabolic activity in this region (Bleys and Cowen, 2001). Isolated hypothalamic infarction is an uncommon event, due to the rich vascular supply of this region. Anteromedial arteries arise from the anterior cerebral artery and supply the anterior hypothalamus. Posteromedial hypothalamic perforating arteries arise from the proximal portion of the posterior cerebral artery at the bifurcation of the basilar artery and supply the posterior hypothalamus. Short hypothalamic arteries branch off from the posterior communicating artery. In the case of fetal configuration of the posterior bifurcation of the posterior communicating artery, which occurs in 15% to 30% of all individuals, the blood supply to the hypothalamus can arise solely from the carotid system and may thus be more liable to embolic infarction (Crompton, 1963; Rudelli and Deck, 1979; Austin and Lessell, 1991). (h) Optic chiasm The arterial supply of the human optic chiasm comes from a superior and inferior group of branches of the circle of Willis. The superior group of vessels is derived from the two anterior cerebral arteries and occasionally from the anterior communicating artery above the optic pathways. The inferior group is derived from the basilar, the posterior communicating, the posterior cerebral and the internal carotid arteries (Figs. 17.1, 17.9). The superior group of arteries supplies all optic nerves and tracts, but only the lateral portions of the optic chiasm. The decussating fibers in the central chiasm receive their arterial supply solely from the inferior group. In addition, the inferior group supplies the optic nerves and tracts. During pituitary tumor surgery, the inferior vessels were often distorted, suggesting that the bitemporal hemianopsia caused by pituitary tumors can be the result of ischemia by vascular compression rather than neural compression (Dawson, 1958).

(g) Hypothalamus The vascular supply of the anterior hypothalamus takes place by means of fine arterial branches that arise from the internal carotid artery, the anterior and posterior communicating arteries, and the proximal portion of the anterior cerebral artery (Table 17.1). One to three perforating arteries arise from the anterior communicating artery and penetrate the floor of the third ventricle through the optic tracts and anterior perforated substance (Figs. 17.1, 17.3; Crompton, 1963; De Divitiis et al., 2002). Injection of the anterior cerebral artery has been performed up to the point of the anterior communicating artery, which includes the recurrent artery of Heubner that arises just proximal to the anterior communicating artery, courses backwards and enters the brain in the region of the anterior perforated area. The anterior hypothalamic nuclei, including the preoptic areas, the paraventricular and supraoptic areas up to the region of the infundibulum, the ventromedial and, to a lesser extent, the dorsomedial areas, were constantly injected. The hypothalamic region thus appeared to be irrigated by a few branches from the artery of Heubner (Ostrowski et al.,

(i) Lamina terminalis The lamina terminalis (see Chapter 30.5b for details on its vascularization), which covers the suprachiasmal extension of the third ventricle, separates the lateral 13

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Fig. 17.9. The visual pathways and their arterial supply. It is apparent that the visual pathways pass through the circle of Willis, and the arterical supply can be divided into a superior and an inferior group. The superior group of vessels is derived from the anterior cerebral arteries (ACA) and spares the central chiasm. The inferior group of vessels is derived from the internal carotid artery (ICA), the posterior cerebral artery (PCA) and the posterior communicating artery. The central chiasm containing the decussating fibers derives an arterial blood supply only from the inferior group of vessels. (Fig. 2 from Bergland and Bronson, 1969 with permission.)

groups of arteries that descend from the anterior cerebral arteries to the lateral portion of the chiasm. Indeed, the lamina terminalis and underlying recess preclude the superior group of vessels from directly contribut-

ing to the arterial supply of the central portion of the chiasm. A surgical approach fenestrating the lamina terminalis can be virtually bloodless (Katayama et al., 1994; Chapter 17.2d) and is frequently

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used for lesions that occur within the anterior third ventricle or invade or compress the walls of the chamber (De Divitiis et al., 2002).

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crucial role in the development of intracranial arterial spasm – that is most marked in the anterior part of the circle of Willis – is supported by a number of observations. If vasospasm develops, such an autonomic effect may occur preferentially after the rupture of aneurysms in locations adjacent to the hypothalamus that involve vessels that supply the hypothalamus. There is also postmortem and postoperative evidence for such a mechanism. The ischemic lesions may be not only ipsilateral to the lesion, but also bilateral. Autonomic dysfunction or a hypothalamic basis are also apparent from ECG changes following the rupture of an aneurysm. Various pathogenetic mechanisms that cause the hypothalamic injury and subsequently intracranial arterial spasm have been proposed (Wilkins, 1975). There is a marked preponderance of microhemorrhages in the SON, and they are also more severe than the microhemorrhages that occur in the PVN. This may be due to the location of the SON – close to the pia. The highly vascularized nature of the SON and PVN seems to make them more prone to microhemorrhages than the other nuclei of the hypothalamus. Hypothalamic lesions generally occur together with lesions in the cortex and basal ganglia (Crompton, 1963; Neil-Dwyer et al., 1994).

17.2. Vascular lesions of the hypothalamus (a) Subarachnoidal aneurysm The hypothalamus is occasionally damaged by ruptured subarachnoidal aneurysms of the circle of Willis (for review, see Crompton, 1963). A number of aneurysms, such as those arising from the bifurcation of the internal carotid artery, may become buried in the anterior hypothalamus. Others, such as those arising from the anterior or posterior communicating artery, may bleed directly on the fine arterial branches that arise from the circle of Willis and in this way supply the hypothalamus. Crompton (1963) has reported on a consecutive series of 106 autopsies on patients dying after the rupture of berry aneurysms, 61% of whom were found to have hypothalamic lesions. He confined his studies mainly to the anterior part of the hypothalamus, where the majority of lesions were found. The highest incidence of hypothalamic lesions was found in the case of aneurysms at the anterior or posterior communicating arteries. Although basilar artery aneurysms characteristically damage the mamillary bodies, they may produce lesions much further toward the front of the hypothalamus. Saccular aneurysms may act like pituitary adenomas and cause irreversible hypopituitarism. Such aneurysms have been described as complications of yttrium-90 implantation for pituitary adenomas (Horvath et al., 1997). The hypothalamic lesions caused by ruptured aneurysms were usually ipsilateral to the ruptured aneurysm, or bilateral, especially with aneurysms situated in the midline. The majority of cases involved ischemic lesions. Microhemorrhages were not as common, and massive hemorrhages involved the hypothalamus in only a small number of instances. Microhemorrhages depend to a large degree on the close proximity of the bleeding aneurysm, whereas ischemic lesions may, in addition, depend on vascular hypotension and arterial vasoconstriction or ‘spasm’, which may occur contralateral to the aneurysm (Crompton, 1963). Acquired ischemic deficits account for about 30% of the early complications of a subarachnoidal hemorrhage (Neil-Dwyer et al., 1994). The hypothesis that hypothalamic injury due to subarachnoidal hemorrhage or craniocerebral trauma plays a

(b) Infarction and hemorrhage The most common lesion in the infundibulum is an infarction, taking the form of small areas of necrosis, usually in the midline of the tuber cinereum or upper infundibular stem. These infarcts are characterized by a pooling of neurosecretory material around their periphery and by the presence of adjacent axonal swellings. Occlusion of the proximal part of the anterior cerebral artery due to occlusive arteriosclerosis may cause emotional changes, including weakness, anxiety and poor cognitive skills and personality disorders (Ostrowski et al., 1960; Webster et al., 1960). Ischemic lesions may be at least part of the basis of the neuronal damage found in the nucleus basalis of Meynert and the reduced choline acetyltransferase activity in the cerebral cortex observed after fatal head injury (Murdoch et al., 2002). Horner’s syndrome has been reported due to an ipsilateral posterior hypothalamic infarction that occurred in the absence of other signs of hypothalamic dysfunction. Symptoms of extension of the infarct into the posterior limb of the internal capsule (i.e. contralateral faciobrachial weakness and dysarthria) were present. Occlusion of a hypothalamic branch of the posterior communicating 15

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artery was the likeliest cause of the infarction. Horner’s syndrome can result from an interruption, at any point, of the sympathetic pathway from the hypothalamus to the orbit. Hypothalamic Horner’s syndromes are most often caused by diencephalic tumors and hemorrhages, and least often by infarction (Austin and Lessell, 1991). In addition, a case of a highly selective anterior hypothalamic infarction has been described as a result of avulsion of part of the optic chiasm, together with the anterior perforating arteries passing through it. Following the assault, symptoms such as altered thermoregulation, alternating diabetes insipidus and inappropriate antidiuretic hormone secretion, altered patterns of sleep and arousal, and changing cardiac arrhythmias were found (Rudelli and Deck, 1979). In a child in which perinatal hypoxia was followed by hypothalamic hemorrhage, West syndrome with gelastic seizures was found (Kito et al., 2001; Chapter 26.2). In the pituitary stalk, linear and petechial hemorrhages or later scarring may be seen. Hemorrhages may also occur in the ventromedial nuclei and corpora mamillaria (Treip, 1970b). Trauma may cause posterior lobe hemorrhage, ischemia in the anterior hypothalamus and destruction or avulsion of the pituitary stalk, followed by hypopituitarism. Posttraumatic diabetes insipidus is generally transient (Horvath et al., 1997). Subcortical infarctions may also impact the blood supply of the hypothalamus and interrupt the function of the suprachiasmatic nucleus, as indicated by the greater daytime sleepiness of these stroke patients (Bliwise et al., 2002). Subependymal hemorrhages around the third ventricle are a common occurrence and may also impinge upon the PVN. In 90% of the cases, subarachnoid hemorrhage is accompanied by ischemic lesions of the hypothalamus: small perivascular hemorrhages and edema of the surrounding tissue were found in the periventricular region, including the PVN and SON. It is hypothesized that prolonged sympathetic activity in these patients would cause vasoconstriction, and thus lesions in the hypothalamus and myocard (Doshi and Neil-Dwyer, 1977). Vasopressin plasma levels have been reported to be increased in patients with subarachnoid hemorrhage (Mather et al., 1981), but these findings were not confirmed by others (Franceschini et al., 2001). For hemorrhages in the neurohypophysis, see Chapter 22.1. Hemorrhagic lesions in the subthalamic nucleus may cause hemiballismus, usually at the contralateral side of the body, characterized by violent, involuntary, wild flinging movements (Parent and Hazrati, 1995).

Multiple endocrine abnormalities have been reported in stroke patients, namely: absence of a sleep-related increase in growth hormone plasma levels, elevated prolactin nocturnal release, and blunted serotonin-mediated prolactin release, low basal thyroid-stimulating hormone levels, impaired thyrotropin-releasing hormonestimulated secretion of thyroid-stimulating hormone, and increase in beta-endorphin cerebrospinal fluid levels. Abnormalities of the pituitary-gonadal axis, in particular high LH serum levels and low serum testosterone levels, have also been reported. Furthermore, disruption of some biological rhythms, namely of beta-endorphin and melatonin, have been described. In the past few years, attention has also been devoted to the clinical significance of these endocrine abnormalities, particularly with regard to the possibility that they may worsen the extension of the ischemic area and outcome of stroke. In unprecedented ischemic cerebral infarction patients, mean 24-hour plasma vasopressin levels were higher than in control subjects, and correlated with the severity score of the neurological deficit and with the mean size of the lesion. The increase occurred independently of osmotic and/or baroreceptorial mechanisms, which are known to be the major stimuli for vasopressin secretion. Various mechanisms may account for increased vasopressin secretion during stroke. The heightened intracranial pressure may contort the pituitary stalk and interfere with the regulation of vasopressin release from the posterior pituitary. Alternatively, a release of neuromodulators from the periinfarct lesion into the third ventricle and affecting the cells within the magnocellular nuclei may be suggested. It may also be so that in the course of cerebral ischemia an increased serotoninergic and/or a decreased dopaminergic tone may induce an enhanced vasopressin release from the hypothalamus (Franceschini et al., 2001). (c) Systemic atherosclerosis Whether or not accompanied by arterial hypertension, systemic atherosclerosis is accompanied by degenerative and chronic ischemic neural alterations, which are most marked in the ventromedial nucleus. Ischemic-atrophic lesions, sometimes with nuclear cytoplasmatic vacuolation, and neuronal hyperchromasia with or without glial satellitosis were observed. The SON and PVN tended to show degeneration as well as an intense accumulation of lipofuscin in the cytoplasm. In addition, hyperplastic astrocytes, denoting glial reaction, were found around

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small vessels, as an expression of chronic tissular anoxia. The reactive protoplasmic astrocytes appeared more in the subependymal paraventricular region. In all cases of atherosclerosis, vascular alterations occurred, i.e. thickening of the intima, and hyalinosis and sclerosis of the small vessels (Kelemen and Becus, 1977). The deep perivascular nerves of the basal arteries of the circle of Willis show changes with aging and Alzheimer’s disease. The precommunicating part of the anterior cerebral artery is involved in the vascular supply of the substantia innominata (Bleys et al., 1996) and suggests a relationship between vascular changes and the decreased neuronal activity in the nucleus basalis of Meynert (Salehi et al., 1994, 1998).

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(e) Radiation therapy Radiation therapy may lead to delayed vascular complications such as obliteratur vasculopathy. Radiationinduced microscopic vascular anomalies or telangiectasia may cause hemorrhages. In addition, intracranial fusiform aneurysms may be formed. In chronic occlusive large vessel disease of arteries of the circle of Willis that occurs as a result of radiation therapy, an abnormal network (moyamoya) may develop at the base of the brain (Sinsawaiwong and Phanthumchinda, 1997). Moyamoya disease may also develop following a basal meningitis (Vörös et al., 1997), but the etiology of this vessel abnormality is unknown in most cases. The peak incidence occurs in the first decade and there is a female predominance. In children, moyamoya disease presents most commonly with transient ischemic attacks, and these children may have seizures. It begins with stenosis of the carotid fork and progresses to complete occlusion of the middle and anterior cerebral arteries with the formation of a vascular network of collaterals. The children may present with decreased growth velocity, growth hormone deficiency and hypothyroidism (Mootha et al., 1999). Moyamoya vessels may also have a prenatally determined origin, and some data point to a genetic basis of moyamoya disease (Vörös et al., 1997). Rupture of the overgrown perforating arteries that function as collaterals may be the main cause of single or repeated cerebral hemorrhage in moyamoya disease. The formation of a collateral network is accompanied by aneurysms, arteriovenous malformations and ectasia or fenestration of the cerebral arteries.

(d) Cavernous malformation Cavernous malformation can occur at any location in the central nervous system, including the pineal, chiasmatic and optic nerve regions. Cavernous malformations involving the third ventricle are rare, but several cases have been reported. The clinical manifestations may be visual field defects, endocrine function deficits and hydrocephalus in those with malformation of the foramen of Monro region, and deficits of short-term memory in those with malformations of the lateral wall or floor of the third ventricle. Malformations of the third ventricle, unlike malformations in other brain regions, frequently show rapid growth and mass effects. Cavernous malformations are known to increase in size during pregnancy and to decrease after delivery. Rapid growth of cavernous malformations is attributable to repeated intralesional hemorrhages, but extra lesional hemorrhages are also not uncommon. The treatment of this particular group of malformations will thus have to consist of a more aggressive approach. The risk of regrowth and extralesional hemorrhage appear to be reduced by complete excision by means of the translamina-terminalis approach for the suprachiasmatic region, the transventricular or transcallosal interfornical approach for the foramen of Monro region and the transvelum interpositum approach for the lateral wall of the third ventricle (Katayama et al., 1994). Later a successful zygomatic approach using a Neuro-navigator® was reported for the treatment of a deep-seated cavernous angioma. (Kurokawa et al., 2001). For a case of cerebrovascular cavernous malformation in the mamillary bodies, see Chapter 16.d.

17.3. Choroid plexus of the third ventricle Choroid plexus tissue is found in the roof of the third ventricle. It is made up of elements from the leptomeninges and the ependyma. Highly vascularized tela choroidea evaginates and acquires an epithelium to form the choroid plexus. The choroid plexus is involved in the production of cerebrospinal fluid (CSF), largely due to the secretion of hypertonic saline, which is then brought to isotonicity by diffusion of water through the ependymal cells. The water channels aquaporin-1 and -4 are expressed in the choroid plexus, where they may play a role in CSF formation (Venero et al., 2001). Moreover, microvilli of the choroid plexus may be involved in readsorption. The choroid plexus is a finely regulated selective interface for the delivery of nutrients, hormones and 17

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trophic factors, as well as for the transduction of peripheral signals, an enzymatic protective barrier, a clearance site for deleterious compounds and catabolites, and an immunologically active interface (for review, see Strazielle et al., 2000). The capillaries of this tissue have larger diameters (10–20 m) than regular capillaries and have been designated ‘sinusoids’. The vascular endothelium is fenestrated (McKinley and Oldfield, 1990). The CSF-generating choroid plexus has many V1 binding sites for vasopressin. Vasopressin decreases the CSF formation rate and elicits structural changes in the rat choroid plexus (Johanson et al., 1999). In the choroid plexus of the lateral ventricle of Alzheimer patients, we found an increase in vasopressin-binding sites (Korting et al., 1996). The functional meaning of this alteration is not clear at present. The choroid plexus of the third ventricle has not yet been studied. (a) Colloid cysts Colloid cysts of the third ventricle (Fig. 17.10) are slowgrowing, benign tumors that typically have an onset between 20 and 55 years of age. The incidence is approximately 1:1000, which makes it the most common tumor of the third ventricle. Occasionally colloid cysts can be identified at autopsy, as was the case with Harvey Cushing himself (Akins et al., 1996). Colloid cysts of the third ventricle are sometimes more conspicuous on CT than on MRI. There is a controversy about the origin of these cysts. It has been suggested to be a remnant of the paraphysis, which is situated at the rostral end of the diencephalic roof and which disappears completely prior to birth. However, this theory was challenged by Ariëns Kappers (1955). In his opinion, paraphyseal cystic tumors developing from the choroidal fold between the foramina of Monro in the third ventricle in the adult human brain are, for the most part, not of paraphyseal origin but arise from detached and degenerated embryonic diencephalic vesicular recesses included in the choroidal fold. An endodermal nature of the cysts has also been proposed. Another possible origin could be from the diencephalic ependymal pouches or choroid plexus. However, immunocytochemical and ultrastructural evidence argues against a simple choroid plexus or ependymal origin (Akins et al., 1996). Colloid cysts usually range from a few millimeters to 9 cm in size. They are composed of fibrous connective tissue wall lined by squamous, columnar epithelial cells enclosing a homogenous gelatinous material of cellular debris and eosinophilic

substance. By a narrow pedicle or broad base, the cysts are attached to the choroid plexus at the superior anterior roof of the third ventricle, immediately posterior to the foramina of Monro (Gökalp et al., 1996; Hwang et al., 1996; Fig. 17.10). The cyst wall may occasionally be calcified (Yüceer et al., 1996). The symptoms are generally attributed to acute hydrocephalus. Head positional changes can usually alleviate the symptoms, but a case has been described of colloid cyst rupture while “disco dancing” (Akins et al., 1996). The classic symptoms consist of intermittent paroxysmal headaches with nausea, papilledema and vomiting. Transient diplopia, blurry vision, dizziness, weakness and paresthesia of the extremities, gait disturbances, fever, drop attacks, loss of consciousness, dementia, cognitive state changes and unexpected sudden death have also been reported. The colloid cyst may apply direct pressure on the autonomic centers of the hypothalamus. In the absence of hydrocephalus, patients with colloid cysts may manifest disturbances of memory, emotion and personality and even psychosis, possibly due to compression of the hypothalamus. Colloid cysts have been approached neurosurgically by different routes. The morbidity and mortality rates, however, are considerable. Ventricular shunting has been proposed, but this does not eliminate the cyst. In addition, CT-guided stereotaxic aspiration has been used successfully in some patients. Recurrent cysts following previous aspiration procedures have been reported (Lobosky et al., 1984; Nitta and Symon, 1985; Mathiesen et al., 1993; 1997; Lewis et al., 1994; Cabbell and Ross, 1996; Filkins et al., 1996; Gökalp et al., 1996; Hwang et al., 1996; Carson et al., 1997; Ferrera et al., 1997; Young and Silberstein, 1997). A few cases of familial colloid cysts of the third ventricle have been described. These rare cases suggest that genetic factors may play a role in the pathogenesis of these cysts. Consistent with the idea that colloid cysts are developmental abnormalities is the fact that they are sometimes associated with a variety of congenital defects (Akins et al., 1996; Vandertop, 1996). (b) Xanthogranuloma Xanthogranuloma of the third ventricle is considered to be a degenerated colloid cyst (for a xanthogranulomatous change of a craniopharyngioma, see Chapter 19.5c). The xanthogranulamatous changes occur following hemorrhage and macrophagic reaction. The wall shows aggregations of pale foaming cells, hemosiderin-laden

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Fig. 17.10. Colloid cyst of the third ventricle. Sagittal T-weighted (TR 500 ms; TE 15 ms, flip angle 90) (a) and coronal T1-weighted (TR 600 ms; TE 15 ms) (b) images show that the lesion is diffusely hyperintense. (From Gökalp et al., 1996, Fig. 1 with permission.)

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macrophages, lymphoplasmatic chronic inflammatory infiltrate, cholesterol clefts and foreign body-type giant cells (Kudesia et al., 1996). A case has been reported of xanthogranuloma with massive hematoma in the third ventricle. The 35-year-old woman had a history of 1 month of progressively deteriorating consciousness. The mass in the third ventricle that produced obstructive hydrocephalus was successfully removed (Tomita et al., 1996). (c) Choroid plexus papilloma Choroid plexus papillomas are more common in children than in adults, and the children usually present with signs and symptoms of increased cranial pressure due to obstructive hydrocephalus. Macrocranium and sunset eyes are found, while vomiting or developmental delay are especially seen in children over 2 years of age. A shunting procedure is frequently required. Choroid plexus papilloma is generally a histologically benign and slowly growing tumor, although rapid growth has been described.

They often extend into the lateral ventricle through the foramen of Monro. In a 2-year-old boy, episodic rightward anterolateral head tilt and large-amplitude positional anteroposterior head-bobbing reminiscent of the “bobblehead doo syndrome” has been described, which was due to a cystic choroid plexus papilloma that had arisen within the left lateral ventricle but slipped into the third ventricle through the foramen of Monro. Other clinical features that have been described with the third ventricle papillomas include autonomic diencephalic seizures of Penfield’s type, endocrine disturbances and menstrual irregularities, obesity, precocious puberty, diabetes insipidus, behavioral problems and psychosis (see Chapter 27.1). In one case the choroid plexus papilloma was not attached to the choroid plexus but to the brain parenchyma at the surface of the posterior commissure (Fortuna et al., 1979; Jooma and Grant, 1983; Schijman et al., 1990; Pollack et al., 1995; Shuto et al., 1995; Carson et al., 1997; Costa et al., 1997a; Nakano et al., 1997). For third ventricle chordoid glioma, see Chapter 19.10.

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CHAPTER 18

Disorders of development and growth

syndrome (Christensen et al., 2000), with amphalocele, diaphragmic hernia and kidney anomalies (Mazzitelli et al., 2002). By means of a model of four separate initiation sites for neural tube fusion, based on observations in the mouse, neural tube defects have been explained by failure of fusion of one of the closures or their contiguous neuropores. According to this model, anencephaly results from failure of closure 2 for meroacranium and closures 2 and 4 for holoacranium. Spina bifida cystica is the result of the failure of the rostral and/or caudal closure 1 fusion. Craniorachischisis results from failure of closures 2, 4 and 1 (Van Allen et al., 1993). Closure 3 nonfusion is rare, presenting as a midfacial cleft extending from the upper lip area (stomodeum) through the face (“facioschisis”) and frontal bones, with resulting anencephaly (“faciocranioschisis”) (Van Allen et al., 1993; Urioste and Rosa, 1998). Frontal and parietal cephaloceles occur at the sites of the junctions of cranial closures 3–2 and 2–4 (the prosencephalic and mesencephalic neuropores). Occipital cephaloceles result from incomplete membrane fusion of closure 4. In humans, the most caudal neural tube was presumed to have a 5th closure site involving L2–S2. Closure below S2 is by secondary neurulation (Van Allen et al., 1993). Closure sites were presumed to be controlled by separate genes expressed during embryogenesis, and variations in rate and location of closures would make embryos more susceptible to environmental and other factors. Genetic variations of neural tube closure sites occur in mice and are also evident in humans (Van Allen et al., 1993; Zlotogora, 1995), e.g. familial neural tube defects with Sikh heritage (proposed deficit closure 4 and rostral 1), Meckel–Gruber syndrome (closure 4) and Walker–Warburg syndrome (2–4 neuropore, closure 4). Environmental and teratogenic exposures frequently

18.1. Anencephaly Optimum non nasci

(a) Failures of fusion and the factors involved Anencephaly (Fig. 18.1) is the most severe form of neural tube defects and is due, according to some authors, to a failure in the closure of the rostral neuropore between 16 and 26 days after conception. Others are of the opinion that this happens a little later, i.e. in the 4th postfertilization week (O’Rahilly and Müller, 1999). The incidence of anencephaly generally ranges from 1–10 per 10,000 births. It is etiologically heterogeneous and has genetic and environmental components such as maternal nutrition and exposure to teratogens. Numerous agents can cause anencephaly in laboratory animals (De Sesso et al., 1999; Mazzitelli et al., 2002). Anencephaly is twice more prevalent in females than in males (Lary and Panlozzi, 2001). When genetically determined, the most obvious form is X-linked. For prenatally detected neural tube defects, the estimated aneuploidy rate is estimated from 2% of the isolated neural tube defects to 24% of the multiple congenital malformation cases (Chen et al., 2001). Genetic defects in the gene for 5,10-methylenentetrahydrofolate reductase are associated with a 3.5–7-fold increased risk for neural tube defects (De Sesso et al., 1999). One anencephalic fetus with a mosaic 45,X/146,X, r(X)(p11.22q12) karyotype (Nowaczyk et al., 1998) and a number of anencephalic fetuses with a ring chromosome 13 or a deletion of chromosome 13 (Chen et al., 2001) have been reported. Anencephaly occurs most frequently as an isolated defect, but it has also been described in association with a partially duplicated head (diprosopus), with the acrocallosal 21

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Fig. 18.1. Anencephaly.

affect specific closure sites, e.g. folate deficiency (closures 2, 4 and caudal 1) and valproic acid (closure 5 and canalization) (Van Allen et al., 1993). Closure 3 was seen following maternal exposure to ergot derivates (Urioste and Rosa, 1998). However, recent careful research by precise graphic reconstructions indicates that the model of multiple sites of fusion of the neural folds may not be valid in humans. In human embryos, two de novo sites of fusion of the neural folds appear in succession:  in the rhombencephalic region and  in the procencephalic region, adjacent to the chiasmatic plate (Fig. 18.2). Fusion from site  proceeds bidirectionally (rostral and caudal), whereas that from  is unidirectional (caudal only). The fusions terminate in neuropores, of which there are 2: one rostral and one caudal. Human neural tube defects can thus be classified on the basis of these 3 sites of fusion and 2 neuropores in the human embryo (O’Rahilly and

Müller, 2002). Anencephaly is proposed to originate as an abnormality of mesenchymal structures, while the brain is secondarily lost to injury in utero because of its exposed position (Kashani et al., 2001). (b) Brain pituitary remnants The anencephalic child usually has no definable brain structures rostral of the brainstem (Nakano, 1973). The neural tissue in the more rostral areas, including the hypothalamus, is an amorphous mass of blood vessels and primitive nerve cells (Fig. 18.3). Anencephalic fetuses thus provide a model for pituitary development in the absence of the hypothalamus and for revealing the possible functions of the fetal hypothalamus in intrauterine development and birth. In anencephalics and

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Fig. 18.2. The neural tube at the middle of stage 12, showing the two regions of fusion of the neural folds. Arrows indicate the direction of fusion, and black dots show the position of the two neuropores. The fusion of the neural folds begins first at site  and then at site . At  it spreads in both directions, ending rostrally as the dorsal lip of the rostral neuropore, which meets the terminal lip from . The first four somites are occipital and are stippled, as is also the mesencephalon. The outlines of somites 10, 15, 20 and 25 are included. (From O’Rahilly and Müller, 2002, Fig. 1 with permission.)

the pituitary in any of the seven anencephalics of 30–48 weeks’ gestation (Visser and Swaab, 1979). Anencephalic children do have a pars distalis of the pituitary (Nakano, 1973). In our group of anencephalics, a neurohypophysis was present only in one case, but it did not contain vasopressin or oxytocin (Visser and Swaab, 1979). The normal, very high, umbilical cord levels of vasopressin as found in controls during spontaneous labor do not occur in anencephalics either (Oosterbaan and Swaab, 1987). However, the levels of oxytocin in amniotic fluid and in the umbilical circulation of anencephalic children

fetuses with holoprosencephaly (cyclopsia and median cleft), adenohypophysial tissue was found not only in the sella turcica, but also in the open craniopharyngeal canal and in the pharyngeal connective tissue at the external side of the cranial base. Hormone production in the pharyngeal pituitary was evident from immunocytochemistry (Kjaer and Fischer-Hansen, 1995; Hori et al., 1999). On morphological grounds the pars intermedia and neurohypophysis were reported to be absent in 75% of the anencephalics. We did not find -melanotropin (MSH) staining as a marker of the intermediate lobe of 23

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are similar in anencephalics without hydramnios and in controls. Oxytocin is therefore probably not derived from hypothalamic neurons but from fetal sources other than the fetal brain (Oosterbaan and Swaab, 1987). Oxytocin mRNA has indeed been found in human amnion, chorion and decidua (Chibbar et al., 1993; Chapter 8e). The adrenotropic deficiency of the pars distalis of the pituitary in anencephalic children is apparent from the fact that the adrenal glands are invariably hypoplastic (Nakano, 1973; Visser and Swaab, 1979; Mazzitelli et al., 2002), while the fetal adrenal of anencephalic children can be stimulated in utero by corticotropin (ACTH) (Honnebier et al., 1974). The low level of corticosteroids in anencephalics also seems to be responsible for the increased size of the thymus (Mazzitelli et al., 2002). Fetal adrenal insufficiency goes together with low estriol excretion by the pregnant mother (Macafee et al., 1973). At 17–18 weeks of gestation, the number and size of ACTH cells in the pituitary of anencephalics is normal, but after 32 weeks their number and size are reduced (Pilavdzic et al., 1997). Bégeot et al. (1978) reported that - and -endorphins and -lipotrophin staining were present in the pituitary of anencephalic children, but that the cells were smaller and less numerous than in normal fetuses. Both growth hormone and prolactin are under hypothalamic control during fetal development. In eight anencephalic fetuses of 19–26 weeks of gestation, blood was sampled by cordocentesis. Both growth-hormone and insulin-like growth factor-1 (IGF-1) levels were lower, and prolactin levels higher, than in matched control fetuses, indicating a disorder of hypothalamic function. The reduction of IGF-1 is probably due to decreased secretion of growth hormone (Arosio et al., 1995). At 32 weeks, gonadotropes are almost entirely absent in the anencephalic pituitary (Pilavdzic et al., 1997). On the other hand, it was found that the absence of the hypothalamus in anencephalics does not compromise the maturation of the pituitary-thyroid function between 17 and 26 weeks of gestation (Beck-Peccoz et al., 1992) and the morphology of lactotropes in the anencephalic pituitary is normal (Pilavdzic et al., 1997). After the age of 40 weeks, the amounts of growth hormone and thyrotropin (TSH) in anencephalics were low, while prolactin amounts were within the normal range (Hayek et al., 1973). When there is no more food for the young in the egg and it has nothing on which to live it makes violent movements, searches for food and breaks the membranes. In just the

same way, when the child has grown big and the mother cannot continue to provide him with enough nourishment, he becomes agitated, breaks through the membranes and incontinently passes out into the external world, free from any bounds (Hippocrates, cited from Kloosterman, 1968).

(c) Intrauterine growth and birth Data on intrauterine growth of anencephalic children suggest that the human fetal brain stimulates the growth of the fetus as well as of the placenta. The intrauterine growth rate of the anencephalic fetus is much lower than that of the controls but shows a steady increase that continues beyond term (Fig. 18.4; Honnebier and Swaab, 1973; Mazzitelli et al., 2002). The lowest body weights are found in the cases of associated anencephaly. It is interesting that, at term, the birthweight of anencephalic boys is some 150 g higher than that of girls (Honnebier and Swaab, 1973), showing that the presence of the fetal hypothalamus is not required for the sex difference in birthweight. The placenta of anencephalics also weighs less, which suggests that the fetal brain may normally stimulate the growth of this organ. Indeed, various pituitary hormones were found to stimulate placental growth in a rat model for anencephaly (Swaab and Honnebier, 1974) and, surprisingly, -MSH was found to stimulate fetal growth in rat (Swaab and Honnebier, 1974). It should be mentioned here that the major -MSH-like substance in the human fetal pituitary might not be -MSH itself, but desacetyl -MSH (Tilders et al., 1981), which is presumed to play a role in fetal development. These findings should be followed up. The concept of the fetal brain playing a crucial role in the start of labor originates from observations in cows and sheep. Gestational length was increased in Guernsey cattle with fetal pituitary aplasia (Kennedy et al., 1957) and in cyclop fetuses, due to the poisonous plant veratrum californicum, which caused pituitary aplasia or pituitary dystopia (Binns et al., 1964). These observations were followed by the classic experiments in sheep in which fetal adrenalectomy, fetal hypophysectomy, infusion of ACTH, and glucocorticoids showed that the fetal hypothalamopituitary adrenal axis starts labor in this species (Liggins et al., 1967; Drost and Holm, 1968; Liggins and Kennedy, 1968; Liggins, 1969; Liggins, 2000). Later, a critical experiment was carried out by McDonald and Nathanielsz (1991). They showed that stereotactic destruction of the fetal paraventricular nucleus in sheep was followed by prolonged pregnancy length.

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Fig. 18.3. The neural tissue left in anencephaly is an amorphous mass of bloodvessels and primitive nerve cells. (From C.U. Ariëns-Kappers collection, Netherlands Institute for Brain Research.)

Observations on human anencephalics suggest that the human fetal brain, too, is important for the timing of the correct, at term, moment of birth. As a group, however, anencephalics have a shorter gestational length, since anencephalics with hydramnios are born prematurely (Fig. 18.5; Swaab et al., 1977). Mean gestation length is normal in spontaneously born anencephalics from pregnancies without hydramnios, in contrast to the sheep model. However, a high percentage of prematurely and postmaturely born anencephalic children is found, indicating that a function of the human fetal brain in the timing of birth (Honnebier and Swaab, 1973; Fig. 18.5). It is presumed that fetal corticotropin-releasing hormone (CRH) from the paraventricular nucleus plays a key role in the timing mechanism for the initiation of human birth (see Chapter 8.5).

In addition, the course of labor is protracted in anencephalic children. In particular the expulsion stage and birth of the placenta take too long. This suggests that the fetal brain releases compounds such as oxytocin that may speed up delivery (Swaab et al., 1977; see Chapter 8.1). The fact that about 50% of the anencephalics die during the course of labor (Honnebier and Swaab, 1973) points to the importance of intact fetal brain systems for dealing with the stress of birth. The extremely strong release of fetal vasopressin that normally occurs in spontaneous labor and that is absent in anencephalics (Oosterbaan and Swaab, 1987) may play a role, since fetal vasopressin is involved in redistribution of the fetal circulation to those organs that are of vital importance (Chapter 8.1).

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Fig. 18.4. Birthweight (grams) by gestation length. The curves are the smoothed centile lines of the control group (Kloosterman, 1970). The dots represent the birth weights of 122 anencephalic fetuses. (From Honnebier and Swaab, 1973, Fig.1 with permission.)

(d) Anencephaly, the diagnosis of death and transplantation An interest has arisen for the organs of anencephalics for transplantation purposes. However, only a minority of anencephalics may serve this purpose. Generally some 60% of the fetuses with anencephaly die before or during birth (Honnebier and Swaab, 1973). Eighty percent of liveborns die within 3 days. When death occurs, the organs are usually so deteriorated that they are no longer suitable for transplantation. However, on the parents’ request, a German anencephalic newborn was reanimated in 1987 immediately after birth and kept warm and fed to maintain organ viability, after which the heart was transplanted into another baby, with excellent results (Abbatista et al., 1997). While the organs of anencephalics can be kept viable by means of improved intensive care techniques, it has become increasingly difficult to determine when death has occurred. The legislations of Western cultures unanimously accept the idea that ‘brain death’ means the irreversible loss of all those functions that identify a person, the functions that give him a personality and

cognitive skills. Cerebral trunk deaths make these functions impossible and is thus equivalent to death. Human life can be defined by the presence of cerebral activity or by potential cerebral activity. In anencephalic children cerebral trunk activity is not finalized and other cerebral structures cannot recover in such children. In fact, brain death occurs in anencephalics without cerebral trunk death (Abbattista et al., 1997). In the Uniform Determination of Death Act of the USA, two criteria for determining death are described: irreversible cessation of circulatory and respiratory function, and irreversible cessation of all functions of the entire brain, including the brainstem. Because anencephalic neonates may maintain both a heartbeat and respiration without medical assistance, their situation does not meet the first criterion. Moreover, they may have an active brainstem, which means the second criterion is not met either. Because of the definition of brain death there is thus no practical possibility of using anencephalic infants as organ donors under the ‘dead donor rule’ (see also Chapter 32.4). One of the possible solutions to this problem is to change the present standard for ‘whole brain death’ to make permanent loss of consciousness the critical brain function that defines life

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Fig. 18.5. Frequency distribution of gestation length: (A) for a control group of 49,996 pregnant women; (B) for mothers of all anencephalic fetuses (n = 147); (C) for mothers of anencephalic fetuses (n = 29) without hydramnios, omitting those who had stillborn fetuses with third-degree maceration, fetuses given intrauterine injections or twins, and those in whom labour was induced. (From Swaab et al., 1977, Fig. 3 with permission.)

or death. These children are considered to have a lack of consciousness from birth and an inability to ever gain consciousness or awareness. The same arguments go for prenatally acquired hydrocephaly. In this condition a developmental or encephaloclastic process, often of

infectious, toxic or genetic origin, affects the major vessels of the anterior circulation, resulting in an extensive reduction in brain matter that is replaced with cerebrospinal fluid (McAbee et al., 2000). However, the possible use of organs of such children raises the specter of a 27

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misdiagnosis, resulting in wrongful death. At present, Germany is the only country where live-born anencephalic infants are considered to be legally dead. Another fear is that aggressive life support for anencephalic infants who will serve only as organ banks will erode public confidence in transplantation (Lafreniere and McGrath, 1998). 18.2. Transsphenoidal encephalocele and empty sella syndrome Transsphenoidal encephaloceles are rare anomalies (Chong and Newton, 1993; Morioka et al., 1995). They are sporadic, with some evidence of autosomal recessive inheritance. They are often associated with other midline anomalies such as agenesis of the corpus callosum, cleft palate, hypertelorism and coloboma, a v- or tongue-shaped retinochoroidal depigmentation (Chong and Newton, 1993; Brodsky et al., 1995). Clinically, transsphenoidal encephalocele children present with craniofacial deformities, cerebrospinal fluid (CSF) rhinorrhea, meningitis and often panhypopituitarism (Chong and Newton, 1993; Brodsky et al., 1995). Progressive hypothalamic-pituitary dysfunction, diabetes insipidus and chiasmatic syndromes result from herniation of the pituitary gland, third ventricle and optic chiasm in a meningeal pouch that protrudes ventrally through a large round defect in the sphenoid bone into the nasopharynx (Chong and Newton, 1993; Brodsky et al., 1995; Morioka et al., 1995; Fig. 18.6). Hyperprolactinemia was found in four patients who were considered to have had hypothalamic dysfunction (Morioka et al., 1995). Cerebrospinal fluid rhinorrhea may be treated surgically (Willner et al., 1994; Clyde et al., 1995). It is presumed that the transsphenoidal encephalocele results from an early teratogenic event, occurring between the 4th and 6th week of gestation (Brodsky et al., 1995). Herniation of the third ventricle/arachnoid into the sellar fossa may be caused by surgery or radiation of pituitary adenoma, pituitary apoplexia, bromocryptine treatment of pituitary adenoma or postpartum pituitary necrosis. Increased CSF pressure is presumed to be responsible for primary empty sella syndrome. Visual impairment is frequently associated with intrasellar herniation (Kobayashi et al., 1996). Primary empty sella syndrome is frequently accompanied by growth hormone deficiency and hypogonadotropic hypogonadism, but only rarely by central hypothyroidism (Cannavo et al., 2002;

Fig. 18.6. Sagittal sections of MR image of a child with encephaloceles. (A) 0.22-T MR image (TR/TE 500/40) at 8 years of age. Sphenoethmoidal (arrow) and transsphenoidal (arrowhead) encephaloceles are seen. A part of the transsphenoidal encephalocele protrudes from the roof of the epipharynx (double arrows). (B) 0.5-T MR image (TR/TE 500/30) at 11 years of age. The appearance of the basal encephaloceles remains unchanged compared with 3 years earlier. The stretched pituitary stalk (white arrow) extends into the encephalocele (egg-shaped cavity with low-intensity image). A thin structure, thought to be the pituitary gland, is seen at the posterior inferior wall of the encephalocele (arrowhead). (C) the structure is slightly enhanced by Gd-DTPA. (From Morioka et al., 1995, Fig. 2.)

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Chapters 18.6b, 24.1a). A combination of empty sella, diabetes insipidus and polydipsia with Asperger’s syndrome has been published (Raja et al., 1998).

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Fisher-Hansen, 1995). Endocrine deficiencies, caused by hypothalamic and/or pituitary dysfunction, can be the only clinical problem in milder forms of holoprosencephaly. Holoprosencephaly has also been found in a Klinefelter fetus (Armbruster-Moraes et al., 1999; Michaud, 2001). Holoprosencephaly arises during the first 4 weeks of embryonic development due to failure of ventral forebrain induction by axial mesendoderm. During the blastogenesis there is failure or incomplete division of the prosencephalon into cerebral hemispheres. The most severe form of prosencephaly, cyclopia, is predicted by the requirement of the axial mesendoderm for eye separation. Because of the importance of midline signaling in hypothalamic development, it is not surprising that the hypothalamus is either missing or lacking in structures in holoprosencephalic brains. Multiple genetic causes have been identified, especially in SHH, SIX3, 2IC2 and TGIF, and chromosomal abnormalities, notably trisomies 13 and 18, have been found (Sarnat and Flores-Sarnat, 2001; Patterson, 2002). Asperger’s syndrome has also proposed to be a mild form of midline defect (Tantam et al., 1990). Primary and secondary dysraphia have been reported in fetuses whose mothers used alcohol during pregnancy (Konovalov et al., 1997).

18.3. Congenital midline defects: optic nerve hypoplasia and septo-optic dysplasia (De Morsier’s syndrome) Congenital midline defects include a wide spectrum of impaired midline clearage defects of the embryonic forebrain, including the various forms and grades of severity of holoprosencephaly, that is seen in 80% of trisomy 13 patients (Battaglia, 2003), schizencephaly (Chapter 18.8), septo-optic dysplasia (Chapter 18.3b) and dystopia of the neurohypophysis (Chapter 18.4). The septum pellucidum is generally absent (Chapter 18.8). Holoprosencephaly is the most common brain malformation in humans, with a prevalence rate of 1 in 250 in early embryogenesis, and 1.26 in 10,000 in a prospective birth cohort study (Patterson, 2002). Alobar, semilobar and lobar forms of holoprosencephaly are the different grades of severity. In alobar holoprosencephaly, the prosencephalon fails to cleave sagittally into cerebral hemispheres, transversely into telencephalon and diencephalon, and horizontally into olfactory tracts and bulbs. Minimal manifestations discussed here include absent olfactory tracts and bulbs (arhinencephaly), agenesis of the corpus callosum and hypopituitarism. Feeding difficulties, neurodevelopmental disability, visual impairment and seizures due to hypoglycemia or hyponatremia are common occurrences in congenital midline defects (Takahashi et al., 2001). There is always some degree of noncleavage of the hypothalamus, and the hypothalamus is one of the most severely affected structures. As many as 67% of children with holoprosencephaly exhibit diabetes insipidus. Other endocrinopathies involving pituitary function are less common (Sarnat and Flores-Sarnat, 2001). Most of the patients have multiple pituitary hormone deficiencies, and the severity of endocrine abnormalities correlates with the degree of hypothalamic nonseparation (Plawner et al., 2002). A few patients with midline defects and persistent hyponatremia due to a ‘reset’ osmostat have been described, including one with a chromosome 13 abnormality. The osmosensitive hypothalamic neurons are presumed to be dysfunctional as a result of the chromosome abnormality and/or the anatomic midline defect (Gupta et al., 2000). An open craniopharyngeal canal with adenohypophysial tissue can be present in holoprosencephaly (Kjaer and

(a) Optic nerve hypoplasia Optic nerve hypoplasia is a congenital abnormality of one or both optic nerves associated with a diminished number of axons. After completion of the optic nerves, insults result in atrophy. The abnormality can be associated with several endocrine and central nervous system disorders. The most common is septo-optic dysplasia (see below). Zeki et al. (1992) found that optic nerve hypoplasia can be associated with partial or complete absence of the septum pellucidum (52%), hydrocephaly (38%), parencephaly (24%), dilatation of the suprasella and chiasmatic cisterns (19%), partial or complete absence of the corpus callosum (14%), or an intracranial cyst. Incomplete forms of septo-optic dysplasia have also been reported by others (Furujo and Ichiba, 1998). Behavioral problems in optic nerve hypoplasia were reported to range from attentiondeficit disorders to autistic, aggressive and violent behavior. In literature, optic nerve atrophy has, moreover, been associated with anencephaly, schizencephaly, cerebral atrophy, cerebral infarcts, encephalocoeles, colpocephaly, and congenital suprasellar tumors (Zeki et al., 1992). 29

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(b) Septo-optic dysplasia Septo-optic dysplasia (De Morsier’s syndrome, MIM 182230) is a developmental anomaly of midline structures characterized by uni- or bilateral hypoplasia of the optic nerves, tracts and chiasm, and by absence of the septum pellucidum, that was first noted by Reeves, in 1941, and first described by De Morsier, in 1956. In 88% of the patients the visual system is bilaterally affected (Fig. 18.7). Children with optic nerve hypoplasia in this syndrome are blind in 20–50% of the cases, or severely visually impaired in another 40%. A specific ocular fundus appearance with marked small optic disc and isolated tortuosity of the retinal veins is present. In addition to optic disc dysplasia, morning glory sign has been found as well (Hellström et al., 2000). De Morsier considered the entity to be a part of median cranioencephalic dysrhaphias, while others thought it to be a mild form of holoprosencephaly (Ellenberger et al., 1970) or part of a spectrum of complex midline cranio-facial malformations overlapping with optic nerve hypoplasia, the syndrome of an absent septum pellucidum (see Chapter 18.7), and procencephaly (Hellström et al., 2000). Septooptic dysplasia has also been described as part of schizencephaly, a structural disorder of cerebral cortical development. In addition, septo-optic dysplasia may be associated with cortical developmental malformations, the “septo-optic dysplasia-plus spectrum” (Miller et al., 2000). The scar-like lesions in the walls of the third ventricle and the fusion of the ventricular walls are consistent with a destructive or disruptive lesion, whose nature, however, is not clear (Roessmann et al., 1987). Viral infections, gestational diabetes, and ingestion of large amounts of quinidine in early pregnancy have all been suggested as etiological factors for the sporadic form (Acers, 1981; Costin and Murphree, 1985). In addition, the possibility of a vascular disruption (Miller et al., 2000), drug toxicity, and an association between fetal alcohol effects and a complex cerebral anomaly with features of septo-optic dysplasia and incomplete holoprosencephaly have been reported (Coulter et al., 1993; Hellström et al., 2000). The insult that causes septo-optic dysplasia occurs presumably before 10 weeks and at about 4–6 weeks of gestation, when the ganglion cells of the retina are developing (Patel et al., 1975; Hellström et al., 2000). The homeobox gene HESX1 is implicated in a familial form of septo-optic dysplasia. HESX1 expression begins in prospective forebrain tissue at the anterior extreme of the rostral neural folds and eventually ends

Fig. 18.7. (a) Sagittal image of septo-optic dysplasia: severe hypoplasia of the pituitary gland, the stalk and the chiasma (arrowhead). Partial ectopy of the cerebellar tonsils in the foramen magnum (arrow). (b) Coronal image of septo-optic dysplasia: absence of the septum pellucidum evidenced by the cross. (c) Sagittal image of posterior pituitary ectopia (arrowhead), hypoplastic anterior pituitary, ectopia of the cerebellar tonsils (arrow) and the arachnoid cyst, posterior to the cerebellar hemispheres (cross). (From Zucchini et al., 1995, Figs. 2–4 with permission.)

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in the ventral diencephalon. However, later in development it becomes restricted to Rathke’s pouch. Two siblings with septo-optic dysplasia were homozygous for a missense mutation within the HESX1 homeobox. In addition, heterozygous mutations in HESX1 have been found that are associated with milder pituitary phenotypes (Dattani et al., 1999; 2000; Dattani and Robinson, 2000; Thomas et al., 2001). A four-generation family with septooptic dysplasia has been reported to be associated with Waardenburg syndrome type 1. In addition, a proband exhibited septo-optic dysplasia; a G to C transversion was identified in PAX3 exon 7 (Carey et al., 1998). One 25year-old patient with septo-optic dysplasia and retinitis pigmentosa had an isolated mitochondrial complex III deficiency and a heteroplastic mutation in the cytochrome b gene (Schuelke et al., 2002). Hypopituitarism is also an important component of this syndrome (Hoyt et al., 1970), and the term “septo-opticpituitary dysplasia” has been in use since this study of Hoyet et al. Hypopituitarism has been considered to be secondary to hypothalamic damage rather than to be due to intrinsic pituitary defects. Indeed, one child responded to the administration of growth hormone-releasing hormone (GHRH) with accelerated growth (Leaf et al., 1989). On the other hand, not only a hypoplastic pituitary, but also an empty sella, with or without an ectopic pituitary, may be found (Willnow et al., 1996). The endocrine deficiencies may vary from isolated growthhormone deficiency to panhypopituitarism (Leaf et al., 1989; Willnow et al., 1996). If the endocrinopathies remain unnoticed, the children might suffer from hypoglycemia, adrenal crisis and sudden death (Hellström et al., 2000). Moreover, sexual precocity, delayed puberty, central hypogonadism, adrenal insufficiency, hypothyroidism and vasopressin-responsive diabetes insipidus have been described (Arslanian et al., 1984; Willnow et al., 1996; Antonini et al., 2002). In a series of 23 patients with optic-nerve hypoplasia, hypopituitarism was found in 15 of these patients. Stimulated prolactin levels were higher than in controls (Costin and Murphree, 1985). Smaller studies also showed growth hormone deficiency, hypothyroidism, elevated prolactin, ACTH deficiency and diabetes insipidus (Izenberg et al., 1984). One patient has been described who grew normally despite growth hormone and IGF-1 deficiency. IGF II or insulin levels could not explain this finding either (Bereket et al., 1998). Interestingly, patients have been described without CRH or thyrotropin-releasing hormone (TRH) secretion but with retained gonadotropin secretion. This may be

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explained by the fact that luteinizing hormone-releasing hormone (LHRH) neurons develop outside the hypothalamus, in the nasal placode, and migrate to the hypothalamus after the development of the midline hypothalamic defect, i.e. after the 5th–8th week of pregnancy (see Chapter 24.2). Moreover, the abnormal hypothalamic anatomy may alter the normal suppression of LHRH neuron function, resulting in precocious puberty (Nanduri and Stanhope, 1999). The syndrome is not rare (Roessmann et al., 1987) and is highly variable (Morishima and Aranoff, 1986). In some series of patients with septo-optic dysplasia, 60–100% of them had clinical optic nerve hypoplasia with varying degrees of nystagmus and visual impairment. Only 50–60% lacked the septum pellucidum (Fig. 18.8; Arslanian et al., 1984; Stanhope et al., 1984). During pregnancy adrenal hypoplasia may result in a subnormal maternal urinary oestriol excretion (Macafee et al., 1973). Neurological abnormalities such as epileptic seizures, cerebral palsy, microcephaly and mental retardation do occur (Acers, 1981; Costin and Murphree, 1985; Antonini et al., 2002). With the advent of brain imaging, a number of additional cerebral hemispheric malformations have been reported (Willnow et al., 1996). Patients with septooptic dysplasia are at risk of unexpected death at all ages, although most deaths occur in very early childhood (Gilbert et al., 2001). Neuropathological study of a limited number of cases revealed that the optic nerves were attenuated and contained only a few myelinated fibers (Roessmann et al., 1987). This agrees with the small optic disc that was seen in all patients (Costin and Murphree, 1985). The optic chiasm is also severely atrophic and the lateral geniculate nuclei are small. In the anterior part of the hypothalamus, the tissue may be distorted. The supraoptic and paraventricular nuclei are sometimes absent, or the cells may be abnormally small or few when they are identified by neurophysin staining (Fig. 18.9; Roessmann et al., 1987). This explains the varying degrees of diabetes insipidus and suggests that the term “hypothalamic” should indeed be added to the designations (‘septo-opticpituitary dysplasia’) mentioned above. The changes in the hypothalamus in fact seem to be the most consistent ones. The olfactory bulbs and tracts may also be absent (Patel et al., 1975; Roessmann et al., 1987). The frequent perinatal problems found in this syndrome (Willnow et al., 1996) may be related to the damaged fetal hypothalamopituitary adrenal system that is involved in the timing mechanism of birth (Chapters 8.5, 18.1) and the fetal 31

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Fig. 18.8. Septo-optic dysplasia (De Morsier syndrome) in a girl of 4 years and 5 months (NHB 96-179). (A) The paraventricular nucleus (PVN) is absent in hematoxylin–eosin staining (* = sulcus hypothalamicus, III = third ventricle). Bar represents 0.5 mm. (B) Only a few small PVN neurons were present that stained for the vasopressin precursor by means of an anti-glycopeptide antibody (Boris Y-2). Bar represents 100 m.

hypothalamoneurohypophysial system that normally stimulates the course of labor and protects the fetus against the stress of labor (Chapter 8.1). There may be a narrowing and a fusion of the third ventricular walls anteriorly, with pronounced subependymal glia proliferation; the ependyma of the third ventricle may be distorted; ependymal scars may be found and leptomeningeal astrocytic heterotopics seen at the base of the brain (Roessmann et al., 1987; Fig. 18.10). Aplasia of the fornix may also be found (Willnow et al., 1996). In two patients a hamartomatous mass was found in the region of the cerebral trigone. The posterior pituitary may

be absent or hypoplastic. Posterior pituitary ectopia and infundibular hypoplasia are seen as variable components of septo-optic dysplasia (Brodsky and Glasier, 1993; see Chapter 18.4). Enlargement of the pituitary stalk has also been demonstrated in patients with septo-optic dysplasia and diabetes insipidus (Zeki et al., 1992). In collaboration with A. Dean (London, UK), we examined a case of septo-optic dysplasia with panhypopituitarism and diabetes insipidus for which the patient had received replacement therapy (NHB 96-179). It concerned a girl of 4 years and 5 months who died of bronchopneumonia. Her brain weight was 773 g, which

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Fig. 18.9. Septo-optic dysplasia (De Morsier syndrome) in a girl of 4 years and 5 months (NHB 96-179). (a) An area of necrosis in the hypothalamus (see asterisks) lateral of the PVN. Bar represents 500 m. (b) Calcifications in the lateral part of the hypothalamus. Bar represents 100 m.

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is below the 1st percentile. Her body weight and height were well below the 3rd centile line for age. Growth retardation was detected from 20 weeks of gestation onwards. Labor was induced at 41 weeks of gestation but was diverted into an emergency Caesarian section due to the occurrence of a maternal grand mal seizure and fetal distress. She was born at 41 weeks with a birthweight of 2820 g. There was no evidence of antiepileptic medication during pregnancy. The girl was found to have visual problems and pale hypoplastic optic discs at the age of 3 months. MRI showed a hypoplastic pituitary gland with absent or very small stalk. Neuropathology showed that the thyroid and adrenal were about half the expected weight and that the adrenal cortex was thin. Leptomeningeal and white-matter heterotopias and posterior fossa crowding were found. Concerning the olfactory pathway, the sulcus lateral to the left gyrus rectus contained a discrete island of glioneuronal tissue that blended with the leptomeninges and possessed a small number of myelinated axons. The equivalent sulcus on the right contained a small myelinated tract. The anterior pituitary gland appeared to be normal for the most part, but the neurohypophysis was relatively thin. The pars intermedia was represented by a conspicuous epitheliumlined cleft. Throughout the hypothalamus there were well-circumscribed fields of astrocytosis, with strong glial fibrillary acidic protein (GFAP) staining. In addition, a very strong band of GFAP positivity was present along the lateral and third ventricle. The optic nerve, chiasm and tracts were thin, gray and degenerated. The degenerated part of the optic nerve contained only remnants of myelin. In the region of the optic nerve, the leptomeninga contained GFAP-positive heterotopias. The wall of the third ventricle was not scarred. A lesion was present in the hypothalamus at the level of the sulcus hypothalamicus, in a position that was lateral to the normal location of the paraventricular nuclei (PVN). The PVN and supraoptic nuclei (SON) were, however, virtually absent in this patient (Figs. 18.8, 18.9), but a few small PVN neurons were stained with anti-glycopeptide along the third ventricle above the level of the sulcus hypothalamicus and some thick-beaded fibers were found close to the foramen of Monro. No staining was found with antiglycopeptide in the suprachiasmatic nucleus. The absence of the SCN was also apparent from the type of arrhythmicity in a child with septo-optic dysplasia, who reacted with normal sleep–wake cyclicity to melatonin administration. In the case we studied, the hypothalamus was strongly distorted and calcifications were present in

various areas (Fig. 18.10). However, a number of structures was distinguished, i.e. island of Calleja, diagonal band of Broca, basal nucleus of Meynert, commissura anterior, fornix, nucleus tuberalis lateralis and corpora mamillaria. The arcuate nucleus could not be identified. Anti-vasopressin (Truus, 29-01-86) or anti-oxytocin (O2-T) did not stain cells in the PVN or SON. No staining was found in the infundibular region with anti-vasopressin, anti-oxytocin or anti-glycopeptide (Boris-Y-2). The stalk could not be identified. A case with both septo-optic dysplasia and Cornelia de Lange syndrome (Chapter 32.2) has been described (Hayashi et al., 1996) and the condition of a 16-year-old boy with hypothalamic endocrine disorders, a hypoplastic pituitary gland, decreased posterior pituitary lobe intensity, absence of the left eye, mental retardation and a hypoplastic left optic nerve was also considered to be within the spectrum of septo-optic dysplasia (Miyako et al., 2002). 18.4. Dystopia of the neurohypophysis (a) True ectopia When it occurs as an isolated defect, ectopia of the neurohypophysis is considered to be due to an abnormality in the descent of the neurohypophysis. This congenital abnormality may be part of midline brain anomalies, including septo-optic dysplasia (Zucchini et al., 1995). Posterior pituitary ectopia and infundibular hypoplasia are in fact considered to be variable components of septooptic dysplasia (Kaufman et al., 1989; Brodsky and Glasier, 1993; see Chapter 18.3b) and may be based on a HESX1 mutation (Mitchell et al., 2002). A developmental theory suggests that genetic, teratologic or traumatic factors interfere with the normal development around 6 weeks of gestation. In cases of dystopia of the neurohypophysis, the pituitary fossa contains only adenohypophysial tissue and no endocrine abnormalities. No instance of isolated diabetes insipidus due to dystopia of the neurohypophysis has been reported. Dystopia of the neurohypophysis has been described as an extremely rare accidental finding at autopsy (Fig. 18.10). It may be discovered by MRI as a round structure with a high-intensity signal on T1-weighted MRI images of the region of the median eminence. In general, true dystopia of the neurohypophysis is not associated with perinatal problems or clinical symptoms (Aydan and Ghatak, 1994).

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Fig. 18.10. (a) Inferior view of brain showing a dystopic neurohypophysis posterior to chiasma and anterior to mamillary bodies. (From Aydin and Ghatak, 1994; Fig. 1 with permission.) (b) Dystopic neurohypophysis surrounded by a meningeal capsule. Arrowheads indicate the rim of adenohypophyseal tissue (H&E, magnification 16). (From Aydin and Ghatak, 1994, Fig. 2 with permission.)

On MRI, dystopia of the neurohypophysis may closely simulate tumors such as granular cell myoblastomas, astrocytomas, neuronal hamartomas or meningiomas in the hypothalamic area. The absence of symptoms related to the adeno- and neurohypophysis argues in favor of true dystopia of the neurohypophysis and the consideration of this condition in the differential diagnosis of hypothalamic lesions may prevent unnecessary biopsies or neurosurgical procedures (Aydan and Ghatak, 1994).

in patients with anterior pituitary abnormalities such as pituitary dwarfism (isolated growth hormone deficiency) or multiple pituitary hormone deficiencies, including central diabetes insipidus, or diabetes mellitus. In addition, periventricular heterotopias may be present (Fujisawa et al., 1987a; Kelly et al., 1988; Maghnie et al., 1991; Appignani et al., 1993; Mészáros et al., 2000; Den Ouden et al., 2002; Mitchell et al., 2002). In such cases the adenohypophysis can be hypoplastic, the infundibulum absent and the posterior lobe ectopic at the bottom of the median eminence (Mészáros et al., 2000). A 43-yearold man with eunuchoid habitus and open epilepsies had an agenesis of the pituitary stalk, a small anterior pituitary remnant and an ectopic neurohypophysis. He

(b) Dystopia with anterior pituitary abnormalities Dystopia of the neurohypophysis in individuals without clinical symptoms has to be distinguished from dystopia 35

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had untreated panhypopituitarism. He had always been short for his age but continued to grow and finally reached a length of 193 cm (Den Ouden et al., 2002). In cases of growth hormone deficiency associated with an ectopic posterior pituitary on MRI after gadolinium injection, patients without a pituitary stalk present a more severe form of the disease, with multiple anterior pituitary hormone deficiencies (Chen et al., 1999b). Twin boys with hypopituitarism, hypoplasia of the anterior pituitary gland, ectopic posterior pituitary tissue and paracentric inversions of the short arm of chromosome 1 have been described. This syndrome is probably due to impaired down migration of the posterior pituitary (Siegel et al., 1995). ‘Acquired’ dystopia of the neurohypophysis has often been considered to be the result of perinatal injury causing stalk transsection and subsequent regeneration of the hypothalamoneurohypophysial tract fibers as a newly formed ectopic posterior lobe at the proximal stump (Fujisawa et al., 1987a). A large majority of the patients with anterior pituitary abnormalities indeed have a history of perinatal problems in the form of difficult presentation and perinatal anoxia. However, since only 50% of the patients with multiple pituitary deficiencies and evident MRI damage of the sellar area have such a positive history for adverse perinatal events (Cacciari et al., 1990), doubts have risen about the direct association between neonatal insult and pituitary damage. An alternative explanation from the “interruption during birth” hypothesis, and a much more likely one, is that an early prenatal congenital disconnection defect occurs that leads to hypothalamopituitary and other brain anomalies. Because of the active role of the fetus in the initiation and course of labor, such congenital defects may contribute first to labor problems and later to, e.g. growth hormone deficiency (Maghnie et al., 1991; Argyropoulou et al., 1992; Triulzi et al., 1994; see Chapter 18.6; for a discussion of the question whether a difficult delivery is cause or effect, see Chapter 8.1). 18.5. The optic chiasm The optic chiasm (4 mm thick, 12 mm wide and 8 mm long) lies about 1 cm above the pituitary fossa). About 53% of the fibers decussate and there are about 2 million axons for each nerve. The most frequent complaints of patients with chiasmal compression (Fig. 19.26) from pituitary tumors are progressive loss of central acuity and dimming of the visual field, especially its temporal portion. Interestingly, it has been hypothesized that that could have been what defeated the Philistine giant Goliath, as

described in the Bible book of Samuel; the fact that he was a slow-moving and ponderous acromegalic giant with a pituitary tumor that caused bitemporal hemianopsia (Berginer, 2000). For field defects in chiasmal lesions, see Anders et al. (1999). Chiasmal compression and hypopituitarism have been found a few times in cases of intrasellar chordomas, tumors derived from notochordal rests (Thodou et al., 2000). Optic atrophy is a late sign of chiasmal compression by a pituitary tumor. T2-weighted reversed MR images depicting the optic pathway are useful in selecting the appropriate surgical approach (Eda et al., 2002). Chiasmal apoplexy or hemorrhage into the optic chiasm is generally caused by intrachiasmal cavernous or arteriovenous vascular malformation, but has also been found due to a pituitary macroadenoma hemorrhaging into the optic chiasm (Pakzaban et al., 2000). (a) Misrouting in albinism Retinofugal axons are misrouted in the optic chiasm so that some of the axons from the temporal retina – those that stay on their own side in normal brains – cross in albinos. The abnormality is present in any animal and human individual that lacks pigment in the retinal pigment epithelium, no matter what genetic mechanisms are responsible for the lack of pigment. Abnormalities in the lateral geniculate nucleus of a human albino have been described (Guillery et al., 1975). The abnormal decussation of temporal retinogeniculostriate projections associated with albinism is reflected in the potential distribution of the visual evoked potentials (VEP). Following monocular stimulation, misrouted optic projections produce VEP asymmetry across the occipital left and right hemispheres in 100% of the albinos and not in normal controls (Apkarian et al., 1983). Several reports have suggested that some patients with Prader–Willi syndrome (see Chapter 23.1) also demonstrate the presence of misrouted optic pathway projections (Creel et al., 1986, 1987). In Prader–Willi syndrome, hypopigmentation of hair, skin and eye have indeed been described and proposed to be of neural crest origin. However, Apkarian et al. (1989) did not find the characteristic contralateral hemispheric asymmetry of VEPs as seen in albinism. On the other hand, their VEP profiles were found to be atypical and difficult to interpret. Moreover, an 8-month-old boy has been described with Angelman’s syndrome, with crossed asymmetry in monocular flash VEP scalp distribution, previously considered to be pathognomonic of albinism. He had skin and hair hypopigmentation, but

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Fig. 18.11. Achiasmatic child (111.12). Coronal axial MRI slices demonstrate an abnormality of the chiasmal region. T1-weighted MRI coronal sections with 4-mm-image slice thickness failed to show a normal chiasmal plate but rather two separate tracts adjoining the inferior region of the third ventricle. Midsagittal sections also failed to identify a chiasmal structure or normal supraoptic recesses. Beginning anteriorly: (A) Coronal T1-weighted section shows normal intracranial optic nerves (arrows) lying beneath the frontal lobes and above the pituitary gland; (B) as the coronal sections advance 4 mm posterior to the preceding section, a downward-bulging third ventricle is visualized along with adjacent optic structures on the left and right. However, no chiasmal structure is imaged. (From Apkarian et al., 1993, Fig. 3 with permission.)

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normal ocular pigment and normal maculae. Cytogenetic studies demonstrated a microdeletion of the maternal chromosome 15q11-13 (Thompson et al., 1999). (b) Non-decussating retinal-fugal fiber syndrome In two unrelated children, a visual pathway malformation was found in which nasal retinal-cortical projections were unable to decussate due to an inborn absence of the optic chiasm (Fig. 18.11). These fibers erroneously route ipsilaterally to visual projection targets. Both children had reduced distance visual acuity for their age, alternating esotropia, torticellis, head tremor and ocular motor instability in the form of early-onset nystagmus. When tested for VEPs, using full field monocular stimulation, instead of showing contralateral asymmetry as found in albinism, the VEP profiles of both children revealed misrouted ipsilateral asymmetry (Apkarian et al., 1994). (c) Other optic chiasm pathology For arterial supply of the optic chiasm, see Chapter 17.1h. A case of avulsion of the optic chiasm is described in Chapter 17.2b. In a case of primary bilateral anophthalmia, the supraoptic nucleus was described as lying flat, parallel to the meningeal surface and in one mass, but otherwise normal (Recordon and Griffiths, 1938). A rare, lethal X-linked syndrome with microcephaly, dysmorphic features and normal eyes is accompanied by bilateral optic pathway aplasia. Necrosis of the optic pathways, hypothalamus and brainstem following irradiation of a pituitary tumor has been described. Gliomas in the optic pathway, which tend to occur in young children, may cause vision loss and optic atrophy. For a chiasmatic glioma, see Fig. 19.10. Optic pathway gliomas may be associated with neurofibromatosis type I as described in Chapter 19.4b. Chiasmatic and chiasmatic/hypothalamic gliomas are different entitities. For the chiasmatic/hypothalamic tumors, there was more morbidity and no prolongation of time to progression when radical resections were compared with more limited resections. A less radical resection and radiotherapy for preventing a subsequent progression is, therefore, recommended (Steinbock et al., 2002). The most common site for optic pathway gliomas with neurofibromatosis is the orbital nerve, followed by the optic chiasm, while the most common localization of involvement for the optic pathway gliomas without neurofibromatosis is the optic chiasm (Kornreich et al., 2001).

Neurofibramatosis type 1 is an autosomal dominant genetic disorder, but about half of the cases are spontaneous mutations. Patients with this disorder run an increased risk of developing both benign and malignant tumors. Gliomas, astrocytomas and ependymomas have frequently been reported. A patient with a neurofibromatosis type 1 had a mass in the hypothalamus and anterior optic pathway that disappeared over a 9-month period, suggesting dysplastic changes rather than a neoplasm (Zuccoli et al., 2000). Gangliomas and ganglioneuromas of the optic chiasm have also been described (Shuangshoti et al., 2000). Neurohypophysial germinomas may not only cause diabetes insipidus and anterior pituitary dysfunction but also compression of the optic chiasm (Saeki et al., 2000; Iwaki, 2001). In septo-optic dysplasia the optic nerves and optic chiasm are affected (see Chapter 18.3). The optic chiasm is often affected in neurosarcoidosis (Westlake et al., 1995; Chapter 21.1; Fig. 21.1), in multiple sclerosis (Chapter 21.2; Fig. 21.5) and Wolfram’s syndrome (Chapter 22.7). In addition, Langerhans’ cell histiocytosis (Chapter 21.3) may affect the optic pathway. The histiocytes are characterized by CD1a- and S-100-positive cells, and ultrastructurally by the presence of membranous cytoplasmic structures of 200–400 nm in width and shaped like tennis rackets, which are known as Birbeck granulas. In Wolfram’s syndrome (Dean et al., unpubl. observations) the optic nerves and optic chiasm are atrophied. Although rare, visual loss may result from primary central nervous system lymphoma in AIDS (Lee et al., 2001b). According to some studies, there is optic nerve degeneration in Alzheimer’s disease (Hinton et al., 1986; Chapter 4.3). Slight demyelization of the optic tracts and chiasm has been reported in Laurence–Moon/Bardet–Biedl syndrome (Chapter 23.3) and in acute intermittent porphyria (Perlroth et al., 1966; Chapter 28.3). 18.6. The growth hormone axis in development and aging Growth hormone synthesis and release are regulated by a number of hypothalamic factors that are delivered to the pituitary gland by the pituitary portal system. GHRH forms out of 40–44 amino acids (Schally et al., 2001) and stimulates growth hormone production, while somatostatin (Chapter 8.7b) inhibits its secretion. The endogenous growth hormone pulses are most likely due to episodic release of GHRH and not influenced by somatostatin

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(Dimaraki et al., 2001). Growth hormone-releasing peptide (GHRP), Ghrelin, is an endogenous ligand for the growth hormone secretagogue receptor (Tolle et al., 2003) and stimulates GHRH release (Wren et al., 2002). This growth-hormone secretagogue of 28 amino acids is also an orexigenic peptide, acting through activation of the neuropeptide-Y (NPY) pathway (Kojima et al., 2001; Chapter 23c) and induces a release of CRH and vasopressin (Wren et al., 2002). Ghrelin secretion is sexually dimorphic with women in the late follicular phase having higher levels than men and is suppressed by somatostatin (Barkan et al., 2003). In addition to the growth hormone-releasing and -inhibiting factors, growth hormone secretion is controlled by autofeedback connections (Farhy et al., 2001). In their turn, GHRH and somatostatin synthesis and release are modulated by NPY, pro-opiomelanocortin, galanin, thyroid hormones, gonadal hormones and adrenal corticosteroids. In addition, growth hormone secretion is regulated by acetylcholine that topically inhibits somatostatin in the hypothalamus. In obesity a chronic state of hypersecretion of somatostatin results in inhibition of growth hormone release. Also the noradrenergic system is involved in growth hormone regulation. GHRH is a member of a gene family that also includes genes for vasoactive intestinal polypeptide (VIP; Chapter 4a), pituitary adenylcyclase-activating polypeptide (PACAP), secretin, gastric inhibitory peptide (GIP) and glucagon. The gene consists of 6 exons. Exon 2-4 encodes a GHRH precursor that is cleaved into GHRH and a carboxy-terminal peptide. GHRH is widely expressed in the nervous system, but the most prominent activity is located in the median eminence and infundibular nucleus. GHRH neurons are activated in this nucleus during prolonged illness (Goldstone et al., 2003). GHRH affects growth hormone production, thus stimulating the proliferation of the pituitary somatotrophs by enhancing growth hormone synthesis at the transcriptional level. Growth hormone secretion is also stimulated. In plasma, GHRH is rapidly inactivated by a dipeptidylaminopeptidase to GHRH3-44 with a half life of approximately 7 min (Cordido et al., 1989; Bluet-Pajot et al., 1995; 1998; Baumann and Maheshwari, 1999; Ghigo et al., 2000; Veldhuis et al., 2001). Immediately postnatally, GHRH causes a growth hormone hyperresponsiveness which in all likelihood is due to a reduced pituitary sensitivity to somatostatin. After a period of stable plasma levels, growth hormone responses to GHRH decline after the third to fourth decade in men and after the menopause in women (Müller et al., 1993).

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Sexual dimorphism is present in the regulatory mechanisms involved in growth hormone and IGF secretion (Jaffe et al., 1998). Newborns secrete high levels of growth hormone, but low levels of IGF-I. Estradiol stimulates the IGF-I production in puberty (Ghigo et al., 2000). The brain is also a target for growth hormone. Growth hormone receptor mRNA is expressed in the human brain and growth hormone participates in laboratory animals in the modulation of feeding behavior, sleep and breathing control, and learning and memory. Growth hormone mRNA has so far not been found in human brain samples (Castro et al., 2000). Eutopic and ectopic GHRH hypersecretion by certain tumors may be associated with pituitary growth hormone cell hyperplasia or adenoma and growth hormone hypersecretion. Hamartomas (Chapter 19.3) or gliomas (Chapter 19.4) may secrete high levels of GHRH. Hypersecretion of GHRH occurs in fewer than 1% of the cases of acromegaly. In the large majority of these cases, patients have carcinoid tumors in the bronchus, gastrointestinal tract or pancreas, which secrete high levels of GHRH (Schally et al., 2001). (a) Noonan syndrome In 1963 Noonan and Ehmke first described several children with a typical facial appearance, i.e. hypertelorism, down-slanting palpebral fistures, ptosis and low-set posteriorly rotated ears. The incidence of Noonan syndrome is suggested to be between 1 in 1000 and 1 in 2000. Apparently, there are familial and sporadic cases of this syndrome (Collins and Turner, 1973). Growth reduction is the same for height and weight, while head circumference has a normal distribution. There are additional characteristic features in Noonan syndrome. Polyhydramnios complicates 33% of the affected pregnancies and there is a high incidence of cardiac anomalies. Major milestone delay is a common feature, puberty is often delayed, and there is hypotonia and hyperextensibility in the younger child. Significant feeding difficulties are present in 76% of the children. However, developmental outcome in the older child does not seem to confirm earlier reports of frequent mental retardation. Speech delay may be related to loss of hearing in Noonan syndrome. In fact, abnormal hearing is present in 40% and abnormal vision in 94% of the children with Noonan syndrome (Sharland et al., 1992). Growth hormone secretion, which has been reported to be characterized in Noonan syndrome by low-amplitude and few spontaneous bursts, is held 39

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responsible for the short stature and low growth velocity. The levels of plasma IGF-I, the main mediator of growth hormone actions, would be low or low normal, but these data are controversial (Spiliotis et al., 1984; Ahmed et al., 1991; Tanaka et al., 1992). The evidence for a defect in the growth hormone/IGF-I axis in Noonan’s syndrome has led to growth hormone therapy (Ahmed et al., 1991; Thomas and Stanhope, 1993). The average age at diagnosis of Noonan syndrome is 9 years (Sharland et al., 1992). The differential diagnosis includes Turner’s syndrome, various other chromosomal abnormalities (see below), teratogens such as alcohol and primidone. We have seen the hypothalamus of a 6-year-old girl with Noonan’s syndrome (A253/94) referred to us by Dr. A. Dean (London, UK). She died following a liver graft given because of a liver failure that was probably due to a reaction to repeated exposure to halothane. The hypothalamus revealed normal microscopic anatomy. Following long-microwave treatment of the sections, GHRH-containing neurons became visible in apparently normal amounts in the arcuate nucleus (Fig. 18.12). Quantification was not performed. (b) Multiple pituitary deficiencies, isolated growth hormone deficiency Patients with multiple pituitary deficiencies, including growth hormone deficiencies, generally have an MRI pathology that indicates suprasellar damage that usually also appears from neuroendocrine tests (Cacciari et al., 1990; Den Ouden et al., 2002). The occurrence of acquired severe growth hormone deficiency is extremely common in adult patients bearing non-functional tumor masses in the hypothalamo-pituitary area and increases following neurosurgery or radiation (Corneli et al., 2003; Chapter 25.3). Also in isolated growth hormone-deficient children, the anterior lobe of the pituitary may be hypoplastic, the infundibulum absent and the posterior pituitary ectopic at the bottom of the median eminence (Mészáros et al., 2000). In addition, pediatric patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes were diagnosed with growth-hormone deficiency, most probably based upon a defect in the GHRH neurons (Matsuzaki et al., 2002). Children with organic causes for growth hormone deficiency, i.e. congenital malformation, tumor, radiation, chemotherapy or infiltrating disorders, have elevated responses of the hypothalamo-pituitary adrenal axis, possibly by disruption of central control pathways (Finkelstein et al., 2001; Chapter 25.3).

Interruption of the pituitary stalk by a perinatal insult and regeneration of the posterior pituitary from the proximal stump have been presumed to be the cause of growth hormone defects in children (see Chapter 18.4; Zucchini et al., 1995; Yoo, 1998). However, the absence of perinatal insults and the presence of other brain anomalies, such as microcephaly, facial or sella abnormalities, ectopic or absent neurohypophysis, periventricular heterotopias, thin or absent pituitary stalk, anterior visual pathway anomalies such as optic nerve hypoplasia, and a HESX1 mutation suggest the presence of a congenital developmental defect in some patients (Maghnie et al., 1991; Argyropoulou et al., 1992; Triulzi et al., 1994; Mészáros et al., 2000; Mitchell et al., 2002). An undescended pituitary stalk would be part of such defects. There are patients in this group whose somatotrophs function but whose hypothalamic GHRH release is impaired. In patients with an invisible or thin pituitary stalk on MRI and prenatal or perinatal onset of hypothalamic pituitarism, growth hormone deficiency and ACTH deficiency gradually develop during the first decades of life (Miyamoto et al., 2001). Growth hormone deficiency is also found in septo-optic dysplasia (Chapter 18.3). Prolonged labor and breech delivery have been documented in only 50–60% of the children with growth hormone deficiencies, and one may question, therefore, the idea that disturbed labor is the cause of growth hormone deficiencies. An alternative explanation for the combination of labor problems and pituitary stalk abnormalities is that early prenatal congenital hypothalamic-pituitary abnormalities could contribute to labor problems because of the participatory role of the fetus in the induction and course of labor. Breech delivery and prolonged labor may thus be part of a complex clinical picture, including congenital brain anomalies (Maghnie et al., 1991; Argyropoulou et al., 1992; Zucchini et al., 1995; Chapter 8.1). Abnormal embryonic development, e.g. due to alcohol abuse during pregnancy, could serve as an explanation. It is presumed that growth hormone is the pituitary hormone most likely to be affected by lesions in the hypothalamic region, since it has only a limited reserve capacity for GHRH (Hellström et al., 1998). It is of interest in this respect that isolated growth hormone deficiency may go together with pituitary stalk interruption and ectopic neurohypophysis (Vanelli et al., 1997). In the case of growth hormone deficiency associated with a posterior pituitary hyperintense MRI signal, patients without a pituitary stalk on MRI after gadolinium injection present a more severe form of the disease in

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Fig. 18.12. The immunoreactivity of growth hormone-releasing hormone with antibody 747 in the arcuate nucleus of Noonan’s syndrome, Wolfram’s syndrome and control cases. (a) A Noonan’s syndrome case stained with antibody 747; no. A253/94. (b) The same case as (a), shown at lower magnification. (c) A 6-year-old control; no. 87-305. (d) The same case as (c), shown at lower magnification. Note that there is no clear difference between the Noonan’s syndrome and control cases. Bar = 50 m. (Preparation by A. Salehi.)

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childhood, when associated with multiple anterior pituitary hormone deficiency (Chen et al., 1999b). The idea that growth hormone deficiency is often a result of hypothalamic rather than pituitary dysfunction is supported by the observation that synthetic GHRH analogues can promote accelerated linear growth in such cases (Thorner et al., 1985; Zucchini et al., 1995). Drastic effects of growth hormone deficiency on intelligence have not been found (Meyer-Bahlburg et al., 1978) and children with growth hormone deficiency referred for growth hormone therapy are generally of normal intelligence. However, they do have more learning problems and are also at risk for behavioral problems. Characteristically such children are shy, withdrawn and socially isolated and have problems with mood and attention. Anxiety, depression, somatic complaints and attention deficits have been identified. The frequency of these symptoms declines over a period of 3 years, beginning shortly after the start of the growth hormone replacement therapy, which suggests that growth hormone therapy might have central effects as well (Stabler et al., 1996; Nyberg, 2000). Growth hormone also acts directly on the brain, since growth hormone receptors are present in the brain (Nyberg, 2000). Indeed, growth hormone therapy early in development leads to a rapid catch-up of cranial growth, whereas in isolated growth hormone deficiency head circumference is reduced (Laron et al., 1979). Moreover, hypopituitary women had significantly lower scores in 4 out of 7 neuropsychological tests, although they had received suitable replacement therapy for TSH and ACTH insufficiency. This group of patients had a higher incidence of mental disorders and increased symptoms of mental distress. Although the cause of impairment was most probably multifactorial, growth hormone deficiency probably contributed to the results (Bülow et al., 2002). It thus seems that the central effects of growth hormone should get more attention in the future. Multiple pituitary deficiencies go together more frequently with empty sella (34%) than isolated growth hormone deficiency (less than 10%), in which few abnormalities of the sellar region are found. Empty sella is generally considered to be of congenital origin, possibly a malformation due to an incomplete or deficient sellar diaphragm (Cacciari et al., 1990, 1994). However, empty sella is commonly seen in patients with benign intracranial hypertension and may also be the sequel to pituitary apoplexy. About 50% of the adult patients with primary empty sella have antipituitary antibodies that indicate previous autoimmune hypophysitis (Anderson

et al., 1999). Primary empty sella syndrome is frequently accompanied by growth hormone deficiency and hypogonadotropic hypogonadism, but not by central hypothyroidism (Cannavo et al., 2002). In addition, empty sella accompanied by growth hormone deficiency is observed in Gitelman’s syndrome (Bettinelli et al., 1999). Growth hormone deficiency in combination with empty sella syndrome has also been described in Bardet–Biedl syndrome (Chapter 23.3). Long-term survivors of childhood malignancies who received cranial and craniospinal radiation may result in decreased final height. Substitution of growth hormone after diagnosis of growth hormone deficiency should be considered for these patients at a young age (Müller et al., 1998a; Chapter 25.3). Partial empty sellar syndrome with an atrophied pituitary gland is seen in primary neuroendocrinopathies and in patients with elevations in intracranial pressure and has once been reported in a top body builder with a long history of exogenous abuse of growth hormone, testosterone and thyroid hormone. Whether this was due to negative hormone feedback or frequent elevation of intracranial pressure by weight lifting is not known (Dickerman and Jaikumar, 2001). Moyamoya disease is a rare vascular disease that results in narrowing of the blood vessels of the circle of Willis and the formation of a network of collateral vessels at the base of the brain for compensatory perfusion (see Chapter 17.2). Moyamoya disease may be accompanied by growth hormone deficiency and hypothyroidism (Mootha et al., 1999). In the acute phase of a severe head injury, an augmented tone of both GHRH and somatostatin may be present. The increased IGF-1 levels suggest that these alterations could be advantageous for rapid recovery (De Marinis et al., 1999). Growth hormone deficiency is also a very frequent occurrence after neurosurgery for hypothalamus-pituitary masses. In narcolepsy patients, 50% of the growth hormone secretion takes place in daytime, whereas controls secrete only 25% during the day. Hypocretin deficiency (Chapter 28.4) is thus accompanied by a disruption of circadian GHRH release (Overeem et al., 2003). (c) Genetic forms of GHRH deficiency An autosomal recessive form of hypothalamic GHRH deficiency has been described. This is a genetically heterogeneous group of disorders that are generally inherited

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as an autosomal recessive trait. Autopsy of a 78-year-old dwarf with this syndrome revealed a normal pituitary and hypothalamus (Rimoin and Schechter, 1973). However, no immunocytochemistry or quantification of hypothalamic nuclei was performed. In addition, two siblings have been described with partial trisomy 1 (q31.1-q32.1) due to a familial insertion. Short stature was found with growth hormone deficiency and an ectopic pituitary growth velocity responded well to treatment with growth hormone. Intelligence was normal (Schorry et al., 1998). Humans with GHRH resistance due to an inactivating mutation in the GHRH-receptor gene have been described that resemble in many aspects the ‘little mouse’ model that has a single base change (A → G) in the gene for the GHRH receptor. The human families became known by the occurrence of a Karachi newspaper article on “The dwarfs of Sindh”. The mode of transmission is autosomalrecessive with a high degree of penetrance. Several families with mutations of the GHRH receptor have now been described. The clinical picture of homozygous individuals with the inactivating GHRH-receptor mutation largely resembles that of severe, isolated growth hormone deficiency. The affected individuals have normal proportions and look like miniature versions of normal people. Although intelligence seems to be normal, the skull is considerably smaller (some 4 SD below the normal mean) than what has been described in classic growth hormone deficiency, where head circumferences are near normal to about 2 SD below normal. This is in agreement with the microcephalus described in the ‘little mouse’. The endocrine profile corresponds to that of isolated growth hormone deficiency (Baumann and Maheshwari, 1999). In hereditary Gitelman disease, growth hormone deficiency is associated with a partial vasopressin deficiency, empty sella and a renal tubular disorder. It is caused by mutations in the gene encoding the thiazidesensitive sodium chloride transporter (TSC; SLC12A3) of the distal convoluted tubes (Bettinelli et al., 1999). In addition, a possible familial syndrome of retinitis pigmentosa, growth hormone deficiency and acromegalic skeletal dysplasia has been described (Hedera and Gorski, 2001). In Down’s syndrome the neuronal control of GHRH secretion is impaired, while the pituitary growth hormone pool is fully preserved. It is thought that the precociously impaired tuberoinfundibular cholinergic pathways may lead to somatostatinergic hyperactivity and low growthhormone responsiveness to GHRH (Beccaria et al., 1998; Chapter 26.5).

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(d) Adult growth hormone deficiency After cessation of longitudinal growth, growth hormone continues to serve an important role in the regulation of body metabolism to optimize body composition and function. In all species examined, peripheral growth hormone levels decline with age (Bartke, 1998), probably reflecting age-related neurotransmitter control leading to GHRH hypoactivity (Ghigo et al., 2000). Adults, especially those with a history of hypothalamic or pituitary disease, or those that underwent growth hormone treatment in childhood, may be deficient for growth hormone, which causes adiposity, reduced lean body mass and reduced physical fitness. Although some patients may be asymptomatic, others have specific complaints of fatigue, low energy levels, and impairment of memory and concentration. Patients with growth hormone deficiency can be diagnosed by a provocative test such as an insulin-tolerance test (Newman and Kleinberg, 1998). It has been suggested that the age-related changes in growth hormone secretion in humans may be due to an increased somatostatin tone. Endocrine studies are, however, also compatible with the view that the GHRH neurons may be involved in declining growth hormone secretion during aging (Russell-Aulet et al., 1999). The contribution of GHRH to the maintenance of growth hormone secretion appears to be sexually dimorphic and more important in men than in women (Orrego et al., 2001). The concept that the somatopause is primarily hypothalamically driven is supported by the observation that long-acting derivatives of the hypothalamic peptide GHRH given subcutaneously to healthy 70-year-old men increase growth hormone and IGF-I levels to those encountered in 35-year-olds (Lamberts et al., 1997b). Changes in GHRH neurons during aging have so far not been studied in the human hypothalamus. In many adults who were growth hormone-deficient as children, a high incidence of social phobia and depression has been found. Growth hormone-deficient adults put on growth hormone therapy report improvements in their psychological well-being and health, mental alertness, motivation and working capacity, indicating the presence of central effects of growth hormone in adulthood. This possibility is reinforced by the observation that adult patients with either multiple pituitary hormone deficiencies or isolated growth hormone deficiencies may show subnormal memory performance that may be reversible with growth hormone treatment. Growth hormone receptors are indeed present in the brain 43

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(Deijen et al., 1996; Nyberg, 2000). Growth hormone may prevent the ‘auto-cannibalistic’ effects of acute diseases on muscle mass. Lamberts et al. (1997) have, moreover, shown that, in a randomized placebo-controlled trial of 6 weeks, growth hormone administration in elderly individuals with an acute hip fracture causes a statistically significant earlier return to independent living after the fracture. Growth hormone replacement in elderly people may also have positive effects on body composition, exercise tolerance and lipids. Multicenter, double-blind placebo-controlled long-term follow-up studies are needed to study the long-term central effects and side-effects of such a therapy (Whitehead et al., 1992; Bartke, 1998; Newman and Kleinberg, 1998; Barkan et al., 2000). Probably only a subgroup of elderly people may benefit from growth hormone substitution (Marcus, 1996). Guidelines for the diagnosis and treatment of adults with growth hormone deficiency have been formulated (Invited report of a workshop, 1998). In a report of the Australian multicenter trial of growth hormone treatment in growth hormone-deficient adults, excessive IGF-1 levels were found, together with modest decreases in total and low-density lipoprotein cholesterol, substantial reductions in fat mass and modest improvements in perceived quality of life (Cuneo et al., 1998). Long-term follow-up studies are needed even more now that overexpression of growth hormone above the physiological range in transgenic mice and in patients with acromegaly is known to be associated with reduced life expectancy. In contrast, Ames dwarf mice with hereditary growth hormone, prolactin and thyrotropin deficiency live much longer than normal animals from the same strain (Bartke, 1998). Acute critical illness or injury initially results in an elevation of circulating levels of growth hormone. The number of growth hormone bursts is increased, and the peak growth hormone levels as well as interpulse concentrations are high (Van den Berghe, 1999). The catabolic state of prolonged critical illness is considered to be a natural defense mechanism in case of serious insults, providing the metabolic substrates and host defense required for survival and for the delay of anabolism. This condition of protein wasting is not prevented or reversed by food. The endocrine response to prolonged illness consists of an inactivation of anabolic pathways, i.e. a decreased activity of the thyrotropic axis as found in nonthyroidal illness (Chapter 8.6c), reduced pulsatile secretion of ACTH, TSH, luteinizing hormone (LH) and prolactin, and a low activity of the somatotropic axis, as indicated by reduced pulsatile growth hormone levels and IGF-1 levels.

The pathogenesis apparently has a hypothalamic component, since both axes are readily activated by coinfusion of TRH and growth hormone secretagogues (Van den Berghe et al., 1998). In fact, infusion of growth hormone secretagogues appears to be a novel endocrine strategy to reverse the catabolic state of critical illness (Van den Berghe et al., 1997a, Van den Berghe, 2000). 18.7. Hydrocephalus (a) Hydrocephalus and the subcommissural organ The subcommissural organ lies below the rostral part of the posterior commissure and develops in the second month of intrauterine life, concurrently with the pineal gland, to reach its maximum development during fetal life. It regresses around the time of puberty. In the adult only isolated relics remain. This organ is highly permeable but does not have fenestrated capillaries. Therefore, it formally fails to qualify as a circumventricular organ. There is some evidence that it may be involved in the hypertension produced by aldosterone acting on the brain. The subcommissural organ also contains an appreciable number of prolactin receptors that may be involved in the regulation of water metabolism. Moreover, the subcommissural organ is a secretory organ and the site of origin of Reissner’s fiber, a mucopolysaccharide strand that passes down the center of the brainstem and spinal cord to the filum terminale (Ganong, 2000). In human fetuses of 180–230 mm crown-to-heel length, a subcommissural organ is found that has glandular properties. The posterior lobe of the pineal organ is built up from this specialized ependyma. A Reissner’s fiber, however, has not been formed at that moment (Olsson, 1961). Two main components of the subcommissural organ are distinguished: the ependymal part, forming the secretory cells, and the hypendema, which consists of glia, vascular and parenchymal-like cells. In experimental animals spontaneously showing hydrocephalus, and in induced postnatal hydrocephalus, complete absence or a progressive reduction of the subcommissural organ has been found. In two hydrocephalic brains from spontaneous abortions of 20 and 21 gestational weeks that showed a significant dilation of the lateral and third ventricles, the subcommissural organ was also severely altered. The rostrocaudal length was only 50% of its normal value, and the global volumes were much smaller. The pseudostratified ependymal cells, normally high, were arranged

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Fig. 18.13. Frontal views of the subcommissural organ (SCO) and subjacent ependyma. A, B: SCO of the normal case 3H. D, E: SCO of the hydrocephalic case 1H. C, F: border between SCO and subjacent ependyma of the fetal brain (C, normal; F, hydrocephalus; PC, posterior commissure). Bars: A, D 60 m; B, C, E, F 35 m. (From Castañeyra-Perdomo et al., 1994; Fig. 2 with permission.)

in a narrow layer (Fig.18.13; Castañeyra-Perdomo et al., 1994). These alterations might be interpreted as a consequence of hydrocephalus (Weller and Schulman, 1972), since atrophy of the ependymal lining as well as of the

paraventricular nuclei has been reported in cases of slightly increased pressure of the cerebrospinal fluid (Bauer, 1959). Castañeyra-Perdomo et al. (1994), on the other hand, interpret the presence of a possibly functional 45

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but considerably reduced subcommissural organ in one of their subjects as a precocious involution of the organ, possibly causing pathological changes in the regulation of fetal cerebrospinal fluid, and ultimately leading to hydrocephalus. At present, cause and effect of the dysplastic subcommissural organ changes in the fetus with hydrocephalus are not clear. (b) Hypothalamic symptoms of hydrocephalus In some 38% of hydrocephaly cases, optic nerve hypoplasia is involved (Zeki et al., 1992; Chapter 18.3). A 4-year-old child with optic chiasm glioma, nonobstructive hydrocephalus, optic nerve hypoplasia and hypernatremia without polyuria or polydipsia, possibly due to hypothalamic osmoreceptor dysfunction, has been described. She had postventriculoperitoneal shunting ascites that improved with chemotherapy. The high protein content was presumed to alter CSF adsorption (Shuper et al., 1997). Permanent visual loss is a well-established major sequela of idiopathic intracranial hypertension. One case has been reported of a woman who had visual loss, an empty sella turcica and polycystic ovary syndrome (Au Eong et al., 1997). Hydrocephaly of the child may go together with low estriol excretion by the pregnant mother (Macafee et al., 1973), illustrating the importance of an intact fetal hypothalamic–pituitary–adrenal axis for the production of this maternal hormone. Increased CSF levels of vasopressin have also been recorded in hydrocephalus (Sörensen et al., 1985; Sörensen, 1986). In children, akinetic mutism has been described as an extremely rare complication of obstructive hydrocephalus, possibly due to damage of the ascending dopaminergic projections that run periventricularly. The gradually increasing size of the third ventricle will probably damage the median forebrain bundles that contain the dopaminergic projections coming from the brainstem (Lin et al., 1997). Indeed, parkinsonism has been found to be associated with akinetic mutism in a case of obstructive hydrocephalus that was treated with a shunt. Other patients with akinetic mutism after surgical removal of a tumor from the anterior hypothalamus, or patients with obstructive hydrocephalus, responded to dopamine receptor agonists, but not to presynaptic dopamine mimetics, supporting the idea that the symptoms were due to a loss of dopaminergic input (Ross and Stewart, 1981; Anderson, 1992). Hydrocephalus may also be accompanied by behavioral disorders: a 9-year-old child has been described with a

psychosis due to a third ventricular choroid plexus papilloma and mild to moderate hydrocephalus (Carson et al., 1997; see Chapter 17.3). High serum levels of growth hormone, IGF-I and diabetes mellitus have been reported in a case of obstructive hydrocephalus caused by a diverticulum of the third ventricle. IGF-I is a mediator of growth hormone. The endocrine abnormalities improved after the placement of a ventriculoperitoneal shunt. The diverticulum of the third ventricle might have compressed the aquaduct through the dorsal and ventral aspects of the mesencephalon. It is not clear whether the increased growth hormone levels were due to hypersecretion of GHRH or hyposecretion of somatostatin from the hypothalamus (Okada et al., 1998). Autonomic dysfunction is often associated with hydrocephalus (Thorley et al., 2001) and the cardiovascular failure that may suddenly lead to unexpected death may be due to pressure on the hypothalamus and other brain structures (Rickert et al., 2001). (c) Causes of hydrocephalus Chronic hydrocephalus in later life may result from aquaduct stenosis. Compression of the surrounding parenchyma may result in dysfunction of the hypothalamopituitary axes, leading to precocious puberty, amenorrhea, hyperinsulinemia, impaired growth hormone responses, abnormalities of temperature control, obesity, diabetes insipidus, abnormalities of autonomic regulation, visual symptoms, and disorders of temperature and other biological rhythms. The hypothalamus may ultimately be transformed into a thin membrane with a loss of nuclear architecture and gliosis (Page et al., 1973; Suzuki et al., 1990; Horvath et al., 1997). A cyst of the septum pellucidum is rarely so large that it leads to hydrocephalus, but a number of such cases have been described (Sarwar, 1989; Silbert et al., 1993; Lancon et al., 1996; Chapter 18.8). However, a colloid cyst of the third ventricle may more frequently cause hydrocephalus (Chapter 17.3a; Hwang et al., 1996). Hydrocephaly, in addition, may be caused by cavernous malformations of the third ventricle when these are situated in the region of the foramen of Monro (Katayama et al., 1994; Chapter 17.2a). Diencephalic syndrome may go together with hydrocephalus (Chapter 19.4) and craniopharyngiomas of early childhood can produce hydrocephalus and symptoms of increased intracranial pressure (Costin, 1979; Chapter 19.5a). Also arachnoid cysts may cause hydrocephalus

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(Todd et al., 2000; Chapter 19.10). In addition, hydrocephaly is a symptom of Biemond syndrome type II and related disorders (Verloes et al., 1998; Chapter 23.3b). Endoscopic third ventriculostomy has become a wellestablished procedure for the treatment of various forms of noncommunicating hydrocephalus. Although it is generally considered to be an easy and safe procedure, a case in which the patient suffered a fatal subarachnoidal hemorrhage has been reported in the literature. In order to avoid vascular injury, perforation of the floor of the third ventricle should be performed in the midline, halfway between the infundibular recess and the mamillary bodies, just behind the dorsum sellae. If it is done this way, diabetes insipidus, oculomotor palsy and vascular injury are claimed to be unlikely to occur (Chapter 17.1i).

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months. Moreover, the cavum septum pellucidum is seen in 12–20% of the adult autopsies but in much lower frequencies in neuroimaging studies (i.e. some 2.2%). This discrepancy is probably due to the CSF that is drained from the ventricles at autopsies and the limited resolution of imaging techniques (Bruyn, 1977; Sarwar, 1989). In addition, the prevalence of the cavum septum pellucidum, determined by patient seclection since Pauling et al. (1998) found that the incidence was 1.1% in healthy children vs. 6.9% as the outcome of a clinical pediatric sample. This possibility is supported by the work of Nopoulos (1990). A cyst of the septum pellucidum is arbitrarily defined as a space with a diameter of more than 10 mm. Symptomatic cysts are rare (Sarwar, 1989), but an expanding cyst of the septum pellucidum may cause obstruction of the interventricular foramina and produce headaches, papilledema, emesis and loss of consciousness. Behavioral, autonomic, sensorimotor, neuro-ophthalmic symptoms and hydrocephalus may occur (Lancon et al., 1996). The cavum Vergae (Verga, 1851) is the posterior extension of the cavum septum pellucidum and develops in the 5th month of pregnancy. It is connected to the cavum septum pellucidum by an aquaduct (Fig. 18.14). Embryologically they are a single cavity. The cavum Vergae does not extend further than the recessus suprapinealis of the third ventricle and according to autopsy studies it is present in 100% of the fetuses but only in 30% of the full-term neonates. Anteriorly its boundaries are the anterior limbs of the fornix, superiorly the boundary is the body of the corpus callosum, posteriorly it is the splenium and inferiorly the psalterium and hippocampal commissure (Bruyn, 1977; Sarwar, 1989). A cavum Vergae alone does not identify individuals at risk for cognitive delays, in contrast to a cavum septum pellucidum that may serve as a significant marker of neurodevelopmental abnormalities (Bodensteiner et al., 1998). A cyst of the cavum Vergae causing definite symptoms is a rare occurrence (Leslie, 1940). Although there is a great deal of controversial literature about this subject it seems that there is no statistically significant relationship between the prevalence of a cavum septum pellucidum and cavum Vergae, either on their own or concurrently, and neurological or psychiatric deficits (Bruyn, 1977; Sarwar, 1989; Schaefer et al., 1994; Kwon et al., 1998). Nevertheless, a wide cavum septum pellucidum in which the leaves of the cavum are separated by more than 1 cm is frequently associated with abnormalities of neurological function. Variations in the

18.8. Septum pellucidum abnormalities The septum pellucidum, called septum telencephali by Stephan and Andy (1962), is a thin translucent plate of two laminae and extends from the anterior part of the corpus callosum to the superior surface of the fornix, and from the organum vasculosum lamina terminalis to the splenium of the corpus callosum. The septum pellucidum is continuous with the septum verum (Chapter 7.3). The septum pellucidum is only present in higher primates. It forms at 6–7 weeks of gestation (Groenveld et al., 1994) and contains glia cells, fibers, some scattered neurons and veins that connect with the choroid plexus. It is lined with ependyma on the ventricular side. The septum pellucidum is an important relay station between the hippocampus and hypothalamus (Bruyn, 1977; Sarwar, 1989), but a functional deficit in their ability to navigate was not found in children without a septum pellucidum (Groenveld et al., 1994). The cavum septum pellucidum, first described by the Leyden professor Francois Dubois de la Boë or Silvius in 1671 (Bruyn, 1977), is a space between the mesial blades of the septum pellucidum (Fig. 18.14). The cavum septum pellucidum is thus not part of the ventricular system and should not be considered as the “fifth ventricle”. The one-cell-thick lining of the cavum is not epidymal. It is bordered superiorly by the corpus callosum and anterior commissure and its floor is formed by the fornix. It is macroscopically present as a 1-mm-wide space in 100% of the fetuses, in 85% of the subjects at 1 month postnatally, 45% at 2 months and 15% at 3–6 47

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Fig. 18.14. a–c. Schematic representation of the cerebral ventricular system. (a) Lateral view; hatched area represents the cavum septi pellucidi (1), the aquaductus septi (2) and the cavum Vergae (3). (b, c) Anteroposterior view, showing cavum septi pellucidi (b) and both cava (c) (dotted areas). (From Bruyn, 1977, Fig. 8, p. 303.)

septum pellucidum might represent anomalous development of midline structures and might therefore be one of the markers associated with clinical abnormalities such as mental retardation (Schaefer et al., 1994). Indeed, a number of cases of neurological and psychiatric disorders have been described that are associated with the presence of a cavum septum pellucidum. An increased prevalence of cavum septum pellucidum may be related to boxing injuries, described as dementia pugilistica or punch-drunk syndrome. A cavum septum pellucidum is present in 18% of boxers and in 5% of the general population. The main width of the cavum is 5.2 mm, compared with only 3% of the control subjects, and it is not uncommon for the fornix to become totally severed (Corsellis et al., 1973; Casson et al., 1984; Silbert et al., 1993). Although there is no question that there is a positive association between professional boxing and the presence of a cavum septum pellucidum, it has been hypothesized that this abnormality may be one of the alterations in the limbic system, resulting in a behavior

that makes pugalism a more attractive career choice in this subgroup of people (Bodensteiner and Schaefer, 1997). This possibility can be studied by prospectively scanning those who want a license to fight professionally. Patients with large cysts of the septum pellucidum and cavum Vergae have been reported who suffered from persistent or intermittent obstructive hydrocephalus, intermittent headache and postural loss of consciousness. The symptoms are directly related to pressure effects from the cavum septum pellucidum, since stereotactic puncture of the cyst or shunting produces a sustained remission from further headaches (Silbert et al., 1993). Cases with akinetic mutism have been reported that are related with pathology in the septal area or hypothalamus. Akinetic mutism resulting from obstructive hydrocephalus, e.g. following shunt failure, is thought to be due to damage to the periventricular area, where ascending dopaminergic projections pass. Two of such cases (9 years and 13 years of age) were reported to have a prominent cavum septum pellucidum (Lin et al., 1997). It is, however, not clear what the exact role is of the observed wide cavum septum pellucidum in the pathogenesis of akinetic mutism in these children. Midline cerebral malformations, e.g. cavum Vergae and cavum septum pellucidum, are also more frequently found in schizophrenia (Scott et al., 1993; Kwon et al., 1998; Nopoulos et al., 1998; Rajarethinam et al., 2001). The enlargement of a cavum septum pellucidum may even be more severe in patients with childhood schizophrenia. Moreover, patients with a complete nonfusion of the septal leaflets were observed in this category, lending further support to the probability of a developmental disorder as arising of this disease (Nopoulos et al., 1998; Chapter 27.1). The presence of a cavum septum pellucidum in schizophrenia may be associated with a poor prognosis (Fukuzako and Kodama, 1998). Cavum septum pellucidum not only has increased prevalence in schizophrenia and neurodevelopmental disorders, but also perhaps in other psychotic disorders (Kirkpatrick et al., 1997; Kwon et al., 1998). Indeed, after a comprehensive review, Bruyn (1977) concluded that one-third to onehalf of the patients with cavum septum pellucidum had seizures and 15% often suffered from psychosis, dementia and/or personality changes. This conclusion has been supported by the study of Kwon et al. (1998), who observed an increased prevalence of cavum septum pellucidum, not only in schizophrenia patients but also in patients with affective disorder or schizotypical personality disorder. The combination of cavum septum pellucidum and schizophrenia has been associated with

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part of a spectrum of complex midline craniofacial malformations. Moreover, a case of septo-optic dysplasia in Cornelia de Lange syndrome has been described (Hayashi et al., 1996; Chapter 32.2). Overlap occurs between septooptic dysplasia, optic nerve hypoplasia and the syndrome of an absent septum pellucidum with proencephaly. The septum pellucidum is also absent in holoprocephaly, in Apert’s syndrome (acrocephalosyndactyly), sometimes following neonatal leptomeningitis, or neonatal brain trauma, and can be present in Chiari type II malformations (Bruyn, 1977; Sarwar, 1989; Groenveld et al., 1994). Tumors that originate from the septum pellucidum are extremely rare, but gliomas, astrocytomas and oligodendrogliomas from the corpus callosum may extend into the septum pellucidum. Midline lipomas, sometimes calcified, are usually developmental malformations of the corpus callosum, but a lipoma confined to the septum pellucidum has been described (Sarwar, 1989). Tumors in the septal region may be associated with aggression (Albert et al., 1993). Slowly growing tumors of the anterior midline structures affecting the septum pellucidum and adjacent structures such as the fornix may in addition cause emotional instability and memory problems, while, in fast-growing tumors, increasing stupor is seen (Zeman and King, 1959).

hemizygous deletion of 22q11 chromosome (Catch 22 syndrome), and to partial trisomy of chromosome 5 (Vataja and Elomaa, 1998). In mental retardation or developmental delay, the frequency of septum pellucidum is increased, but a cavum Vergae has been observed with the same frequency as in normal and retarded populations (Bodensteiner et al., 1998). A rare case of an abscess that formed in the cavum septum pellucidum after the elimination of a bacterial meningitis by antibiotics has been reported. The abscess disappeared during continuation of the antibiotics (Kihara and Miyata, 2002). The absence of the septum pellucidum almost always signifies substantial neurological disease, since it is hardly ever an isolated finding. However, isolated absence of the septum pellucidum does exist (Supprian et al., 1999), and the rare absence of the septum pellucidum alone does not predict significant intellectual, neurological or behavioral dysfunction (Groenveld et al., 1994). A few patients present with schizophrenic psychosis (Supprian et al., 1999). Agenesis of the septum pellucidum can be part of a developmental brain disorder such as schizencephaly (Denis et al., 2000) as part of a continuum of the spectrum of proencephaly or the absence can be acquired in case of a long-standing, substantial hydrocephalus. In the developmental category, septo-optic dysplasia should be mentioned (see Chapter 18.3), which is considered to be

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CHAPTER 19

Tumors

19.1. Symptoms due to hypothalamic tumors

(67%), hypothalamic hamartomas (100%) and subarachnoid cysts or arachnoidocele (100%). With the exception of one patient with pineal germinoma, all lesions were localized in the suprasellar area. The data suggested that in glial cell tumors (Chapter 19.4), hamartomas (Chapter 19.3), gangliogliomas of the tuber (Chapter 19.3c) and subarachnoid cysts an unknown factor, probably secreted by the tumors, accelerates luteinizing hormone-releasing hormone (LHRH) maturation (Rivarola et al., 2001). A cranial MRI is thus indicated for children with central precocious puberty (Ng et al., 2003). Tumors of the tuberal and preoptic region of the hypothalamus are often found in hypogonadism (Bauer, 1954). This is the case, e.g. for craniopharyngioma (Chapter 19.5a), infundibuloma (Chapter 19.4c), pineal region tumors (Chapter 19.7), peritheloid sarcomas and angiomas. Other symptoms of hypothalamic tumors are hyperphagia and obesity (Fig. 19.13), subcutaneous fat depletion (Connors and Sheikholislam, 1977), fits of rage (Albert et al., 1993; Chapter 26.3 for ventromedial hypothalamus syndrome), amnesia, and attacks of laughter or crying (Bauer, 1954; Haugh and Markesbery, 1983; Kahane et al., 1994; Chapters 19.2, 19.3, 19.5). Cachexia (diencephalic syndrome; Chapter 19.4a) and markedly elevated leptin plasma levels, with increasing body mass index (Bmi), are found in patients with hypothalamopituitary damage, which suggests unrestrained leptin secretion. Leptin insensitivity is presumed in these patients (Patel et al., 2002). In a patient with a probable hypothalamic germ cell tumor, hypoadrenalism, hypogonadism, diabetes insipidus and hypercalcenia have been found (Hotta et al., 1998). Cushing described patients with hypothalamic tumors associated with a duodenal ulcer and proposed the existence of a parasympathetic center in the hypothalamus, which would send fiber tracts to the vagal center

Primary tumors and metastasis may be the causes of nonspecific symptoms such as headaches, nausea, vomiting, papilledema or seizures, or of more specific hypothalamic symptoms, depending on the size of the tumor and its location. But also in nonspecific symptoms the hypothalamus may be involved. For instance, plasma and cerebrospinal fluid (CSF) levels of vasopressin are increased in brain tumors with brain edema (Tenedieva et al., 1994), and intracranial tumors may accompany increased levels of CSF vasopressin (Sørensen et al., 1985; Sørensen, 1986; Tenedieva et al., 1994). (a) Endocrine and autonomic disturbances Bauer (1954) reviewed 60 cases with various hypothalamic lesions that were collected from the literature and that consisted largely of different kinds of hypothalamic tumors, which are dealt with in Chapters 19.1–19.9. This group of tumors contained low-grade optic gliomas as found in pediatric patients with neurofibromatosis type I (Robben et al., 1995; Chapter 19.4b), an astrocytic hamartoma (Chapter 19.3a), an infundibuloma (Chapter 19.4c), astrocytoma (Chapter 19.4b), ependymoma or germinoma (see Chapter 19.2). Bauer (1954) listed a number of tumors, such as hamartomas, that affect the posterior region of the hypothalamus, in particular the corpora mamillaria, and that may cause precocious puberty (Chapters 19.3, 24.1). Ganglioglioma were found to produce precocious puberty in babies, three times more often in boys than in girls (Sheehan and Kovacs, 1982; Chapter 19.4c). In a more recent study, precocious puberty was found to be associated with glial cell tumors (19%), germ cell tumors 51

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(Carmel, 1985; Dolenc, 1999; Buijs and Kalsbeek, 2001; Chapter 30). Autonomic seizures, paroxism of hypertension, tachycardia and sweating have been found in the diencephalic syndrome (Chapter 19.4a; Connors and Sheikholislam, 1977). When tumors cause ventricular obstruction with a rise in intracranial pressure and/or hydrocephalus, a loss of circadian temperature fluctuations may be found (Page et al., 1973), due to a disorder of the circadian system (Chapter 4). Other hypothalamic symptoms found in cases with tumors are retarded growth, diabetes insipidus, amenorrhea, panhypopituitarism, dysthermia, bulimia, hydrocephalus (Coffey, 1989; see also Chapters 19.2–19.5, 19.7), prolonged fever and hyponatremia

(Spiegel et al., 2002; Chapters 22.6, 30.2). Tumors in the region of the optic pathway or infundibulum may cause optic atrophy, visual deficits (see Chapters 19.2–19.5) or visual hallucinations (Baruk, 1936; Haugh and Markesbery, 1983). Hypothalamic hamartomas (Chapter 19.3) may cause gelastic seizures, but this may also occur after tumors (Chapter 26.2). Following a hypothalamic glioma, a patient’s sexual orientation changed from heterosexual to pedophile with impotence (Miller et al., 1986; Fig. 19.1; Chapter 24.5e). Hypothalamic lesions due to craniopharyngioma or pilocytic astrocytoma may be accompanied by decreased nocturnal melatonin levels and increased daytime sleepiness (Müller et al., 2002a).

Fig. 19.1. An infiltrating hypothalamic glioma in a patient with a change in sexual orientation from heterosexuality to pedophilia. (From Miller et al., 1986, Fig. 3 with permission.)

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astrocytoma (Sorensen et al., 1995). Akinetic mutism was observed following surgical removal of an epidermoid cyst from the anterior hypothalamus that had probably destroyed the median forebrain bundles that contain the dopaminergic projections (Ross and Stewart, 1981; Chapter 18.8). A similar condition has been described in the literature in a case of chronic encephalitis that led to destruction of the posterior hypothalamic nuclei and the mamillary bodies. On the basis of akinetic mutism due to an epidermoid cyst of the third ventricle (Cairns et al., 1941), it was hypothesized nearly 40 years ago that consciousness depends on the synthesis of impressions from the outside world with those from inside the body, and that hypothalamic–thalamic connections, such as the bundle of Vicq d’Azyr and the connection between the posterior hypothalamic nucleus and the medial nucleus of the thalamus, would play a crucial role in this process. From the data that are available now it seems that lesioning of the dopaminergic projections from the brainstem is responsible for the symptoms of akinetic mutism (Chapter 18.8). Removal of a hypothalamic tumor resulted in an overwhelming urge to sleep during daytime. This was hypothesized to be due to destruction of the suprachiasmatic nucleus (Chapter 4) or to an incomplete lesion of the hypocretin/orexin system (Arii et al., 2001; Chapter 14, 28.4). Tumors, especially of the posterior part of the

(b) Cognitive and behavioral disorders Psychiatric symptoms due to the tumors localized in the hypothalamus included psychiatric disturbances, diagnosed, for example, as schizophrenia, psychoneurosis and manic excitement (Malamud, 1967; Chapter 27.1; Fig. 19.2). Another example is a 9-year-old boy with a choroid plexus papilloma of the third ventricle (Chapter 17.3c) who developed a psychosis (Carson et al., 1997; Chapter 19.5a). A patient with craniopharyngioma (Chapter 19.5) or prolactinoma may present with a significant behavioral disturbance accompanied by deteriorated work performance, intermittent explosive disorder, hypersexual behavior, confusional syndromes and hallucinations (Carroll and Neal, 1997). Patients with tumors of the region of the third ventricle may exhibit the symptoms of Korsakoff’s syndrome: some impoverishment of intellect, changes of personality (usually euphoria or apathy), disorientation, confabulation and memory impairment. The memory defects concern both imprinting and retrieval (Williams and Pennybacker, 1954). Tumors causing bilateral destruction of the fornix may cause memory problems (Chapter 16), but there are exceptions (Woolsey and Nelson, 1975). Periods of transient global amnesia have been reported after spontaneous hemorrhage in a hypothalamic pilocytic

Fig. 19.2. Left, periventricular location of tumor in floor, walls, and roof (including fornix) of third ventricle. Right, Histologic appearance of a glioblastoma multiforme with characteristic pleomorphism, giant cells and focal necrosis (hematoxylin – Van Gieson; slightly reduced from  75). The clinical diagnosis was schizophrenic reaction and epilepsia of unknown origin. (From Malamud, 1967, Fig. 4 with permission.)

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hypothalamus, may cause somnolence or altered levels of consciousness (Davison and Demuth, 1946; Coffey, 1989). Coma with hyperthermia is a prominent symptom after acute injury of the hypothalamus, seen, e.g. after removal of craniopharyngial tumors from the floor of the third ventricle (Cairns, 1952). Near total destruction of the anterior and middle part of the hypothalamus and a partial preservation of the more caudal part following total removal of a craniopharyngioma in a child has been described. The child survived for a period of 6 years. The following symptoms were found: diabetes insipidus due to destruction of the supraoptic and paraventricular nucleus (SON and PVN; see Chapter 22.2), chronic hypernatremia, which persisted in spite of vasopressin substitution, absence of thirst (characteristic of a lesion of the anterior hypothalamus; Chapter 22.2), hyperphagia (based upon lesion of the PVN and ventromedial nucleus (VMN)); (Chapters 23.1, 26.3), hypothyroidism and hypoadrenalism due to a lesion of the PVN; Chapters 8.5, 8.6), impairment of temperature regulation (damage of, e.g. the laterocaudal hypothalamus, preoptic area and PVN; Chapter 30–30.2), abnormality of sleep pattern and reversal of diurnalnocturnal sleep rhythms, probably due to a lesion of the suprachiasmatic nucleus (SCN) and posterior hypothalamus; Chapter 4), episodic savage behavior (lesion of the VMN; Chapter 26.3, 26.9) and diabetes mellitus due to hyperphagia (Killeffer and Stern, 1970; Chapter 26.3). Hypothalamic syndromes may also be caused by a large number of different pathological processes that arise in the pituitary or the parasellar region, e.g. due to pituitary masses that undergo silent infarction, cysts, pituitary adenomas, acute or chronic infection with abscess formation, metastasis or aneurysms (Melmed, 1995). The syndrome of idiopathic hypothalamic dysfunction of childhood may accompany permanently dilated pupils, obesity, central hypoventilation, hypersomnia, hyperphagia, personality changes, abnormal temperature regulation, decreased sensitivity to pain, adipsic hypernatremia, hyperprolactinemia, seizures amd precocious puberty (North et al., 1994; Sirvent et al., 2003; Chapter 32.1). It is thought to be a nonmetastatic paraneoplastic syndrome, secondary to a neuronal crest tumor, e.g. to a ganglioneuroma or ganglioneuroblastoma. There can be extensive lymphocytic/histocytic infiltrates in the hypothalamus and other brain areas, associated with some neuronal loss and reactive gliosis. The neoplasm may produce antineuronal antibodies, such as anti-Hu

(Ouvrier et al., 1995), as has also been observed in limbic encephalitis (Alamowitch et al., 1997; Chapter 32.1). Paraneoplastic encephalitis is characterized by personality changes, irritability, depression, seizures, memory loss and sometimes dementia, due to antineuronal antibodies. Patients with anti-Ta (also called anto-Ma2) antibodies are young men with testicular tumors. They frequently show hypothalamic involvement through symptoms such as diabetes insipidus, loss of libido, hypothyroidism, hypersomnia, hyperthermia and panhypopituitarism, and a poor neurological outcome. Sometimes the outcome is favorably influenced by treatment of the tumor (Gultekin et al., 2000). 19.2. Germinoma and teratoma One-third of all brain tumors in the pineal region (see Chapter 19.7) consist of parenchymal tumors (pineocytomas, pineoblastomas), one-third of glia tumors (astrocytomas, ganglion gliomas) and one-third of germ cell tumors, of which less than one-third are germinomas (Styne, 1993; Fig. 19.19). Germinomas and teratomas are tumors of germ cell origin and make up 0.4–9.4% of all childhood brain tumors. Germinomas are the least differentiated of the germ cell group, whereas teratomas differentiate along all three germ cell layers (Fig. 19.3; Chong and Newton, 1993). Germ cell tumors may contain one cell type (“pure”) or more than one cell type (“mixed”) (Schut et al., 1996). Twenty to thirty-five percent of the germinomas are present in the sellar and suprasellar region.The age of the patients is limited to the first three decades. Germinomas were previously known as pinealomas, ectopic pinealomas, atypical teratomas or dysgerminomas (Coffey, 1989; Fujisawa et al., 1991; Styne, 1993; see Chapter 19.7). They tend to be located in the midline area, such as in the pineal region (Chapter 19.7), and in the suprasellar and third ventricular regions. Germinomas of the hypothalamoneurohypophysial axis seem to originate from the neurohypophysis (Saeki et al., 2000). A 5-year-old girl that presented with diabetes insipidus and a loss of the hyperintense MRI signal of the neurohypophysis was found to have an immature hypothalamic teratoma 7 months later (Lee et al., 1996). A 16-year-old boy had polyuria–polydipsia and diplopia. MRI was suggestive of an optic nerve glioma, but the high human chorionic gonadotropin (HCG) levels led to the right diagnosis, i.e. germinoma (Carella et al., 1999). Neurohypophysial germinomas may cause not only diabetes insipidus and

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Fig. 19.3. Suprasellar teratoma. A. Parasagittal MR scan shows an area of hyperintensity in the interpeduncular cistern, representing the fatty component of the tumor. B. Midsagittal section shows the more solid portion of the tumor with irregular areas of hyperintensity and isointensity. C. Midsagittal postcontrast-enhanced MRI scan shows enhancement of the solid portion of the tumor. (From Chong and Newton, 1993, Fig. 27 with permission.)

et al., 1997). The initial endocrine symptoms are generally diabetes insipidus or pituitary insufficiency, but also hyperprolactinemia, hydrocephalus, visual field defects and optic atrophy (Coffey, 1989; Fujisawa et al., 1991; Rutka et al., 1992; Chong and Newton, 1993; Nishio et al., 1993a; Mootha et al., 1997; Saeki et al., 2000; Iwaki, 2001). In addition, polydipsia and adipsia have been reported (Zazgornik et al., 1974). In a woman with a hypothalamic germinoma, profound anterograde amnesia and hyperphagia were reported (Coffey, 1989). Interestingly, the fine structure of the suprasellar germinoma – which can be revealed by transphenoidal biopsy when the lesion progresses or if tumor markers (see below) are positive (Mootha et al., 1997) – is identical to that of the classic testicular seminoma, consisting of primordial germ cells with large pleomorphic nuclei with prominent “bar-like” nucleoli and vacuolated cytoplasm containing alkaline phosphatase (Schut et al., 1996), infiltrated with lymphocytes. In men, germinomas may cause precocious puberty because they may secrete chorionic gonadotropins (HCG), which stimulate the secretion of testosterone. Some germinomas such as endothelial sinus tumors

multiple anterior pituitary deficiencies, but also compression of the optic chiasm and of the hypothalamus (Saeki et al., 2000). What we know of the pineal germinomas also applies to those of the suprasellar region (Schut et al., 1996); they have even been seen synchronously in a few patients (Ellenbogen and Moores, 1997; Saeki et al., 1999; Fig. 19.4), suggesting a common origin. Germinomas are malignant but also highly radiosensitive, which makes early diagnosis of vital importance (Fujisawa et al., 1991; Mootha et al., 1997; Leger et al., 1999). Endoscopic management of a pineal and suprasellar germinoma has been reported (Ellenbogen and Moores, 1997). A combination of radiotherapy and chemotherapy is advocated in order to improve the outcome. However, pituitary dysfunctions often persist after treatment (Saeki et al., 2000). In contrast to craniopharyngiomas, germinomas tend to be homogeneous and rarely have cystic components. The first abnormal, contrast-enhanced MRI finding is generally isolated pituitary stalk thickening (Mootha et al., 1997; Czernichow et al., 2000). The normally hyperdense MRI signal of the posterior pituitary is often absent (Rutka et al., 1992; Chong and Newton, 1993; Mootha 55

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Fig. 19.4. Pineal and suprasellar germinoma. Precontrast (A) and postcontrast-enhanced (B) midsagittal MR imaging scans. A suprasellar-enhancing mass has caused distortion of the anterior third ventricle. Note also the downward displacement of the supratentorial portion of the aqueduct and the anterior displacement of the posterior third ventricle caused by the pineal-region mass (arrows). (From Chong and Newton, 1993, Fig. 26 with permission.)

secrete -fetoprotein or placental alkaline phosphatase, which may also be used as tumor markers (Styne, 1993; Mootha et al., 1997; Carella et al., 1999; Rivarola et al., 2001; Fig. 19.18). Increased serum levels of lactate-dehydrogenase have been proposed as another marker for a germinoma (Carella et al., 1999). HCG is strongly elevated in chorion carcinomas (Schut et al., 1996). With the exception of the benign teratoma, all intracranial germ cell tumors are malignant, capable of CSF dissemination and of forming systemic metastases. Tumors in the suprasellar region may be metastatic when it concerns germinomas involving the pineal gland. Pineal region germinomas (Fig. 19.4) are more common in males, while there is a distinct predilection for females to harbor these tumors in the suprasellar region. Subependymal spread along the lining of the third ventricle is a common feature (Rutka et al., 1992; Chong and Newton, 1993; Iwaki, 2001). In a 25-year-old man, a neurohypophysial tumor that presented with visual disturbance and hyperprolactinemia appeared to be a rare mixture of a germinoma and prolactinoma (Sugiyama et al., 1999). One case of a suprasellar germinoma in a patient with Cornelia de Lange

syndrome has been reported, suggesting a causal relationship between teratogenesis and oncogenesis (Sugita et al., 1986). Teratomas may be mature (benign) or immature (malignant). Teratomas differentiate along all three germ cell layers. Fat and calcifications are often present in teratomas (Chong and Newton, 1993; Fig. 19.3). In one case of primary bilateral anophthalmia, a teratoma of 5  2 mm size containing cysts, glandular structures, intestinal epithelium, fibrous tissues with nerve cells and fibers and cartilage, was found in the region of the mamillary body (Recordon and Griffiths, 1938). Yolk sac or endodermal sinus tumor, choriocarcinoma and embryonal cell tumor represent the less-common nongerminoma germ cell tumors. The endodermal sinus tumor is also found in the ovaries, testes, cervix and vagina of children. A few of such tumors have been identified in the pineal gland region (Chapter 19.7). The tumor has a typical “honeycomb” pattern and is believed to be derived from antecedents of the yolk sac (“yolk sac carcinoma”). It is a highly vascular tumor capable of producing fetoprotein, while the HCG levels are usually negative.

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the tissue. They do contain neurons – large and small – that are similar to those of the tuber and adjacent structures (Driggs and Spatz, 1939; Clarren et al., 1980; Albright and Lee, 1992; Fig. 19.8). Cystic changes have occasionally been observed in huge hypothalamic hamartomas due to intratumoral hemorrhage and liquefactive necrosis (Prasad et al., 2000). Hamartomas were shown to contain neuron-specific enolase, synaptophysin and neurofilaments, and some of them have corticotropinreleasing hormone (CRH), LHRH, metenkephalin (Valdueza et al., 1994a) or growth hormone-releasing hormone (GHRH) (Scheithauer et al., 1983)-containing neurons. Generally, hamartomas are associated with an MRI that is isointense, relative to gray matter. However, a 1.5-year-old patient with a pedunculated hypothalamic hamartoma was described whose T1-weighted MRI images were hyperintense and thus suggestive of adipose tissue. Microscopically an admixture of neuroectodermal elements, namely glial cells, neurons and nerve bundles, was found, along with mesenchymal elements in the form of fibroadipose tissue (Sharma et al., 1998).

It metastasizes early to various regions of the brain, including the hypothalamus (Yen, 1993; Schut et al., 1996) and it has been proposed that these germ cell tumors are derived from errant germ cells origin-ating in the yolk sac endoderm (Chong and Newton, 1993).

19.3. Hamartoma (a) Hypothalamic hamartoma Hypothalamic neuronal hamartomas are rare malformations that may arise from the mamillary bodies or the tuber cinereum and that occur at the ventral aspect of the posterior hypothalamus (Chong and Newton, 1993; Figs. 19.5, 19.6). In rare cases they may have a prechiasmatic location (Valdueza et al., 1994a). They may be pedunculated or sessile, i.e. with a broad and unconstricted interface with the hypothalamus (Albright and Lee, 1992; Valdueza et al., 1994a; Arita et al., 1999; Fig. 19.7). Arita et al. (1999) distinguished a parahypothalamic (= pedunculated) and an intrahypothalamic (= sessile) type. Hamartomas are made up of mature but disorganized neural tissue that shares similarities with the tissue observed in the normal hypothalamus and are therefore considered to be malformations rather than neoplasms. They usually do not grow and do not invade

Symptoms of hamartomas Gelastic seizures, characterized by attacks of laughter, have been noted in 48% of the hamartomas. In addition, attacks of crying have been described (see Chapter 26.2). The epileptic syndrome is characterized by gelastic

Fig. 19.5. Hamartoma of the tuber cinereum. Midsagittal (A) and coronal (B) T1-weighted MR scans. A pedunculated mass (arrows) is noted in the region of the tuber cinereum. The lesion is isointense to the adjacent brain. (From Chong and Newton, 1993, Fig. 24 with permission.)

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Fig. 19.6. Asymptomatic hypothalamic hamartoma (NHB 84186; 29 years of age) in the median eminence/pituitary stalk region stained for its strong vasopressin innervation. The tumor was less densely innervated by oxytocin fibers and did not stain for luteinizing hormone-releasing hormone. Bar = 1 mm.

seizures beginning in early childhood, often in the neonatal period. One child was diagnosed at 3 months of age with spells characterized by hyperpnea, followed by ‘cooing’ respirations, and giggling and smiling at 15–20 min intervals. Single photon-emission computed tomography (SPECT) demonstrated dramatic ictal uptake in the area of the 2.8-cm-diameter tumor, with normalization during the interictal phase (DiFazio et al., 2000). Usually there is a later development of focal seizures and a pattern of symptomatic generalized epilepsy with tonic, atonic and other seizure types in association with low spikeand-wave discharge and cognitive deterioration (Berkovic et al., 1997). In a patient with refractory localizationrelated epilepsy associated with a hypothalamic hamartoma, it was found that the frontal and temporal cortex contributed to slowing of the heart rate, while the lesion per se in the hypothalamus was not involved in that phenomenon (Kahane et al., 1999). SPECT showed

ictal hyperperfusion in the hamartomas, the hypothalamic regions and thalamus only. Depth electrodes implanted in the hamartoma demonstrated focal seizures and electrical stimulation reproduced the typical gelastic events. Stereotactic radio frequency lesioning of the hamartoma resulted in seizure remission. These observations indicate that the gelastic seizures originate from the hypothalamic hamartoma and adjacent structures (Berkovic et al., 1997; Kuzniecky et al., 1997; Freeman et al., 2003). However, the interictal spike-wave does not arise from the hamartoma itself since it did not disappear following hamartoma resection (Freeman et al., 2003). Tasch et al. (1998) could not find any neuronal damage in the temporal lobes of patients with hypothalamic hamartomas and gelastic epilepsy using proton magnetic resonance spectroscopy imaging, which is further evidence that gelastic seizures do not originate in the temporal lobe but in the hamartomas themselves.

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A study of interictal spike electroencephalographic (EEG) source analysis in hypothalamic hamartoma epilepsy also demonstrated that the source of the spike activity was located in the neighborhood of the hamartoma and not in the cortex (Leal et al., 2002). In addition, visual disturbances, precocious puberty (in 74% or more of the cases; Styne, 1997; Rivarola et al., 2001), acromegaly, diabetes insipidus or other endocrinopathies have been reported. A child has been described with precocious puberty due to a hypothalamic hamartoma on the basis of neurofibromatosis type 1 (Biswas et al., 2000). Children with gelastic seizures and hypothalamic hamartoma display a great number of psychiatric disorders, including oppositional defiant disorders (83%), attentiondeficit-hyperactivity disorder (75%), conduct disorder (33%) speech retardation and learning impairment (33%), and anxiety and mood disorders (17%). In 30–58%, significant rates of aggression were noted (Weissenberger et al., 2001). The behavioral and cognitive defects illustrate the role of the hypothalamus in these processes. Hamartomas may be associated with seizure disorders that become drug-resistant (Munari et al., 1995). Moreover, there may be behavioral disorders; the children are restless, violent, emotionally unstable, antisocial and intellectually impaired. All children with gelastic seizures and hypothalamic hamartoma display cognitive deficits ranging from mild to severe (Frattali et al., 2001). The mental decline is often progressive. The behavioral disorders are probably mediated by disruption of the connections between the mamillary bodies and other brain structures. Hamartomas are clinically evidenced in infants ranging between 1 and 7 years of age and may range from 2 to 30 mm in size. The manifestation in a neonate has also been described (Guibaud et al., 1995). The clinical symptoms of hamartomas depend on their size and local-

ization (Valdueza et al., 1994a; Fig. 19.7 and Table 19.1). Precocious puberty usually occurs in small, autonomous LHRH-producing pedunculated hamartomas (types 1a and 1b, according to Valdueza et al., 1994a, Fig. 19.10; Debeneix et al., 2001; Table 19.I), or the parahypothalamic type, according to Arita et al., 1999; Nishio et al., 2001). Precocious puberty may be accompanied by rapid statural growth, persisted breast swelling and pigmented areolae as a sign of the exposure to high levels of oestrogens (Arisaka et al., 2001). Precocious puberty in a case of hypothalamic hamartoma has also been described in association with agenesis of the corpus callosum (Alikchanov et al., 1998). For a differential diagnosis of sexual precocity, see Albright and Lee (1992) and Chapter 24.1. Gelastic epilepsy and associated seizures are observed only in large, ‘sessile’ type IIa and IIb hamartomas (Fig. 19.7), characterized by a broad attachment to the mamillary bodies (Valdueza et al., 1994a; Debeneix et al., 2001). A displacement of the floor of the third ventricle and/or an intrahypothalamic location (type IIb; Fig. 19.7) may cause behavioral abnormalities (Valdueza et al., 1994a). Hyperphagia, obesity, rage and dementia have been described in a 20-year-old woman who had a hamartoma that destroyed the ventromedial hypothalamus. She experienced hallucinations, had hypofunction of the adrenals, gonads, thyroid, diabetes insipidus and diabetes mellitus, and unexplained fever, probably also due to the fact that autonomic regulatory functions were affected (Reeves and Plum, 1969; see VMN syndrome, Chapter 26.3.). However, hamartomas are not always accompanied by symptoms. The lesion can also be found incidentally on postmortem examination (Mahachoklertwattana et al., 1993; Kahane et al., 1994; Valdueza et al., 1994a; Munari et al., 1995). We observed a strong vasopressin innervation and some oxytocin innervations, but no LHRH or CRH in a hamartoma that was

TABLE 19.1. Classification of hypothalamic hamartoma. Type

1a

1b

11a

11b

Size Attachment Origin Hypothalamic displacement Common features

Small–medium Pedunculated Tub cin No PP (or asymptomatic)

Small–medium Pedunculated Mam bod No PP (or asymptomatic)

Medium–large Sessile Tub cin/mam bod Slight Gel, gen

Medium–large Sessile Tub cin/mam bod Marked Gel, gen, beh

Tub cin, tuber cinereum; Mam bod, mamillary body(ies); Gel, gelastic epilepsy; Gen, generalized and/or other epileptic types; Beh, behavioral disorder; PP, precocious puberty. (From Valdueza et al., 1994a.)

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Fig. 19.7. Schematic drawing of different types of hypothalamic hamartomas on sagittal images. (From Valdueza et al., 1994a, Fig. 8 with permission.)

found by accident at autopsy and that was situated in the stalk/median eminence region (Fig. 19.6). Pathogenesis. There are a number of theories on the pathogenesis of endocrinopathies in relation to hamartomas: ii(i) Neurons within a hamartoma would stimulate hypothalamic neuroendocrine systems by direct connections; i(ii) The tumor might have a mechanical effect on the hypothalamus. As an example, a case has been reported of a 1.9-year-old girl with precocious puberty and gelastic seizures due to a hypothalamic hamartoma that was situated dorsally of the SCN. She had melatonin levels that were low for her chronological age but appropriate for the pubertal status, suggesting a causal relationship between lowered melatonin levels and puberty, due to interruption of the connections between the SCN and the pineal gland (Commentz and Helmke, 1995). However, the alternative, i.e. that decreased

melatonin levels are found following induction of puberty by whatever mechanism and without interruption of the connections between the SCN and pineal, seems at least as probable (Chapter 4.5d). (iii) Neurons of the hamartoma would actively secrete a hormone that activates the pituitary (Wolman and Balmforth, 1963; Scheithauer et al., 1983; Mahachoklertwattana et al., 1993). Judge et al. (1977) demonstrated that a hamartoma in a 19-month-old boy with precocious puberty showed all the characteristics of an independent neuroendocrine unit, supporting the latter of the three hypotheses. It contained neurons that resembled those of the hypothalamus, containing 100 nm of neurosecretory granules and blood vessels, with fenestrated endothelium and double basement membranes, characteristics of vessels of the median eminence that would permit release of neurosecretory products into the blood- stream. Each vessel was almost totally surrounded by axons. In addition, immunocytochemically the neurons appeared to contain LHRH. The negative feedback between gonads and brain was intact but partially resistant to steroid suppression. These observations indicate that the hamartoma may have caused precocious puberty by autonomous production and release of LHRH. Also the demonstration of neurosecretory cells and their fibers that end on the portal vessels in a girl with precocious puberty and a hypothalamic hamartoma (Wolman and Balmforth, 1963) supports this concept. In a review on long-term data concerning 10 children with an LHRH-producing hamartoma and their effective treatment with LHRH agonists (see below), Mahachoklertwattana et al. (1993) conclude also that the congenital malformation functions as an ectopic LHRH pulse generator. Scheithauer et al. (1983) described a patient who had a hypothalamic neuronal hamartoma that had been present for 31 years and was associated with hypopituitarism, a growth-hormone-producing pituitary adenoma and acromegaly. Microscopically the hamartoma was composed of ill-defined aggregates of small and large neurons and neuritic processes. The neurons contained an abundance of 75- to 125-nm electron-lucent granules. GHRH (somatoliberin) was demonstrated in these neurons. The pituitary contained a predominantly growth hormone-containing adenoma that was presumed to be secondary to the neuronal abnormality, and a

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minute nodule of prolactin adenoma. So this case, too, supported the third possible pathogenetic mechanism, i.e. hormone secretion by the neurons in the hamartoma. (iv) Hypothalamic hamartomas may induce precocious puberty by the production of trophic factors that are able to activate the normal LHRH network in the patient’s hypothalamus. One of such factors is transforming growth factor-, which facilitates the gliato-neuron signaling process controlling the onset of female puberty in rodents and nonhuman primates. This factor (and not LHRH) has been found in girls with hamartomas that induced precocious puberty (Jung et al., 1999; Rivarola et al., 2001; Jung and Ojeda, 2002).

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However, some patients did report episodes of emotional lability (Feuillan et al., 2000). A number of papers advise against surgery as the initial management of precocious puberty in case of hypothalamic hamartomas, because of the delicate site where the tumor is located, and advised LHRH agonists (Stewart et al., 1998). Surgical resection may, however, be an alternative treatment to LHRH only in the rare instance of mass enlargement or compression of adjacent tissues that is causing progressive neurological deficits or hydrocephalus (see also Albright and Lee, 1992; Valdueza et al., 1994a), or when the seizures are refractory to antiepileptic medication. Successful, complete or nearly complete resection of hypothalamic hamartomas has been achieved by a subtemporal approach (Nguyen et al., 2003), the transcallosal approach (Rosenfeld et al., 2001; Freeman et al., 2003) and by the lamina terminalis approach (Kramer et al., 2001; Chapter 30.5). Resection of hypothalamic hamartomas can alleviate both the seizures and the behavioral and cognitive abnormalities, but complications are frequent (Palmini et al., 2002). However, examinations of a small series of children with precocious puberty who underwent microsurgical treatment, suggested that this treatment was a good decision (Luo et al., 2002). A case has been presented with gelastic seizures associated with a hypothalamic hamartoma. Partial resection failed to reduce the seizures, but subsequent stereotactic radiofrequency ablation resulted in progressive improvement (Parrent, 1999). The new development of noninvasive focal radiation performed with a gamma knife was successful in a number of patients with intractable epilepsy, abnormal behavior and precocious puberty due to an inaccessible hypothalamic hamartoma. MRI performed 12 months later demonstrated complete disappearance of the lesion (Arita et al., 1998; Regis et al., 2000; Dunayer et al., 2002), but no change in the size of the lesion was observed in other cases (Unger et al., 2000, 2002). Gamma knife surgery may be especially useful for small sessile lesions, failed partial resections and patients not appropriate for open surgery (Nguyen et al., 2003). In patients with refractory epilepsy secondary to hypothalamic hamartomas, seizures were also controlled by intermittent stimulation of the left vagal nerve (Murphy et al., 2000). Related disorders. Hypothalamic hamartomas may also be found as part of the orofacial–digital syndrome (MIM 165590; Fujiwara et al., 1999), which is a heterogeneous syndrome and includes at least 11 types. They include hypothalamic hamartomas, developmental delay, multiple

Therapy. The response to antiepileptic drug therapy has invariably been disappointing (Wakai et al., 2002). It should be noted that hamartomas are developmental abnormalities that may well be found with other widespread abnormalities in the brain, which may provide a structural basis for the poor response of seizures to removal of the hamartomas or the presence of other apparently focal epileptogenic zones (Sisodya et al., 1997). An example is a boy who had gelastic epilepsy, hypothalamic hamartoma, precocious puberty and agenesis of the corpus callosum. The child had a dramatically impaired mental function and a ‘split brain’ pattern of the interictal EEG, indicating a developmental anomaly of the commissural structures of the brain (Alikchanov et al., 1998). Mahachoklertwattana et al. (1993) treated nine patients with an LHRH agonist. The basis of this therapy is that interruption of the obligatory pulsatile release of LHRH downregulates the release of follicle-stimulating hormone (FSH) and LH. The response to this therapy was excellent. Later also young children, for example a 1-year-old girl and an 8-year-old boy with precocious puberty, were successfully treated with a super long-acting LHRH analogues that indeed induced regression of the hypothalamic hamartoma (Nishio et al., 2001). Long-term follow-up studies of children treated with LHRH analogues have started only relatively recently (Feuillan et al., 1999). One year after stopping the LHRH therapy, the LHRH-stimulated LH and FSH and testosterone returned to the normal range. By 4 years after therapy, all patients had pubic hair. The dimensions of the patients’ hamartomas did not change with therapy, and no new neurological symptoms or signs after discontinuation of therapy occurred. 61

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gingival granula, hamartomatous nodules on the tongue, low-set ears, micrognathia and polysyndactyly of the hands and feet. Orofacial–digital syndrome type VI (Váradi syndrome) is an autosomal recessive trait of orofacial anomalies, cerebellar dysgenesis and polysyndactyly. Cerebellar hypoplasia and variants of the Dandy-Walker complex are the most common CNS malformations reported in patients with this syndrome. A boy with Váradi syndrome had hypothalamic hamartoma and precocious puberty (Stephan et al., 1994). In addition, a boy was reported with hypothalamic hamartoma and precocious puberty associated with agenesis of the corpus callosum, Dandy-Walker complex and heterotopic gray matter (Gulati et al., 2002). (b) Hamartomatous nodules In a thorough study of 239 consecutive autopsies, Sherwin et al. (1962) found small hamartomatous nodules of the posterior hypothalamus in 21% of the patients, suggesting that such lesions are far from rare. Endocrinological abnormalities and systematic neoplastic processes were significantly associated with the presence of such malformations. An intimate relationship between the nodules and perforating vessels existed. The nodules were located adjacent to or 1 mm lateral to the mamillary body, and 1 mm rostral to the corresponding cerebral peduncle. In all cases a branch of the posterior communicating artery penetrated the center of the nodule. By carefully following the path of this artery, the nodule was often found surrounding its site of entry into the brain (Fig. 19.8). Microscopically, the nodules were composed of an outer layer of compact glial tissue and a central, loose glial tissue containing nerve cells. These harmatomatous nodules should be distinguished from the true hamartomous nodules that arise almost invariably from the central portion of the tuber cinereum caudal from the pituitary stalk. (c) Intrasellar gangliocytoma A tumor related to a hamartoma is an intrasellar neuronal choristoma or intrasellar gangliocytoma with neurons of hypothalamic type, often within growth hormonecontaining pituitary adenomas resulting generally in acromegaly and sometimes in Cushing’s syndrome, galactorrhea and amenorrhea. Sometimes these are endocrinologically nonfunctioning masses (Scheithauer et al., 1983; Asa et al., 1984; Morikawa et al., 1997; Geddes et al., 2000; Chapter 19.10). In a pituitary corticotroph

adenoma, neurons that stained for corticotropin (ACTH) were described (Vidal et al., 2002). The term ‘choristoma’ is preferable to the term ‘hamartoma’ when abnormal neoplastic cells are displaced from the normal anatomical site (Rhodes et al., 1982). However, the term choristoma is confusing, since it is also used for the unrelated pituicyte-derived granular cells of the neurohypophysis (Chapters 19.4c, 22.1; Figs. 19.14, 21.1). Rhodes et al. (1982) call these pituitary tumors ganglionneuromas. In addition, the terms ‘gangliomas’ and ‘gangliocytoma’ are used for this group of tumors (Morikawa et al., 1997). A case report mentioned the presence of a gangliocytoma masquerading as a prolactinoma with suprasellar and temporal lobe extension. The 36-year-old man presented with bitemporal hemianopsia and a high serum prolactin concentration. Later the tumor appeared to consist of dysplastic neurons that were strongly immunoreactive for the neuronal markers synaptophysin and neurofilament, and for prolactin. This appeared to be a prolactin-secreting gangliocytoma (McCowen et al., 1999). Such tumors in acromegalic patients are closely associated with pituitary adenomas and are often growth hormone and prolactin positive (Geddes et al., 2000). It seems as if ganglion cells have differentiated within the adenoma. For the pathogenesis of this type of tumor, the alternative, i.e. that it is primarily a tumor of neurons producing a GHRH inducing secondary adenomas and acromegaly has also been considered by some authors and discounted by others (Geddes et al., 2000). It has also been suggested that a progenitor cell might give rise to both adenohypophysial cells and neurons producing, e.g. GHRH (Asa et al., 1984). The tumors contain ganglion cells, fascicles of unmyelinated neuronal processes, collagen and some glial cells. If they contain neoplastic astrocytes they are termed gangliogliomas. Rhodes et al. (1982) described a ganglion-neuroma with epithelial cysts, the cells of which resembled ependymal cells of the floor of the third ventricle. Some of these cells were glial fibrillary acidic protein (GFAP)-positive. It is supposed to be a tumor of embryonic rests from the ventral neural ridge, displaced early in development (Asa et al., 1980; Rhodes et al., 1982; Morikawa et al., 1997). A ganglioglioma of the tuber is a congenital tumor that at first glance appears to be microscopically similar to an ordinary glioma, but it produces a specific clinical picture: it is characterized by precocious puberty in babies. In addition to astrocytes, it contains nerve cells, sometimes scattered diffusely and sometimes arranged in groups. It is three times as common

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Fig. 19.8. Hamartomatous nodules. A. In the right posterolateral tuber cinereum a conical nodule is shown (arrow). A small artery, arising from the midpoint of the posterior communicating artery, enters its base. Two veins emerge from the nodule. B–F. Representative serial sections are demonstrated through the same nodule, beginning with the mamillary body level and extending to the extreme lateral tuberal area. In B, the band of tissue between the vessels with a reversed “7” shape is the subpial white matter of the nodule. In C, D, and E the perforating artery appears to have pulled down a wedge of tissue from the hypothalamic floor. In F the protuberant nodule exhibits ganglion cells, nerve fibers, and whorled subpial fibers on the right. (From Sherwin et al., 1962, Fig. 13 with permission.)

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in men as in women. The patients usually die before the age of 8 (Sheehan and Kovacs, 1982). Cases without endocrinopathies may represent incomplete expression of the hypothalamic neuronal choristoma-pituitary adenoma complex (Scheithauser et al., 1983). For gangliocytoma of the neurohypophysis, see Chapter 19.10. (d) Hamartoblastomas (Pallister–Hall syndrome) Pallister–Hall syndrome is a developmental disorder consisting of hypothalamic hamartoma, pituitary dysfunction, polydactyly and visceral malformations. This syndrome was first reported in infants. It consists of hamartoblastomas of the hypothalamus with primitive, undifferentiated neurons. For this reason the term ‘hypothalamic hamartoblastoma’ was assigned initially to these tumors. However, when children with this condition survive, the neurons look more or less mature and are admixed with astrocytes and minimal white matter, and they are now thought to be hamartomas (Sills et al., 1993; Kuo et al., 1999). On MR images the classic hypothalamic hamartoma/hamartomablastoma is noncalcified and nonenhancing, homogeneously isointense to gray matter (Kuo et al., 1999). A multilobulated mass arising from the base of the brain that was shown to be a subhypothalamic heterotopia on the basis of a hamartoblastoma has been described by Splitt et al. (1994). This patient also had short or absent olfactory tracts. The disorder is inherited as an autosomal dominant trait with incomplete penetration, variable expressivity or gonadal or somatic mosaicism (Biesecker et al., 1994; Penman Splitt et al., 1994) and has been mapped to chromosome 7p13, colocalizing the PNS locus and the GL13 gene encoding a zinc finger transcription factor (Kang et al., 1997). An unbalanced chromosomal translocation between 7p and 3q has been reported in one patient (Squires et al., 1995). Most cases are sporadic, but one familial case has been reported (Sills et al., 1993; Kuo et al., 1999). Hamartoblastomas arise probably in the 5th week of pregnancy and seem to be part of a complex pleiotrophic congenital syndrome that includes absence of the pituitary, craniofacial abnormalities, cleft palate, malformations of the epiglottis or larynx, congenital heart defects, hypopituitarism, short-limb dwarfism with postaxial polydactyly, anorectal atresia, renal anomalies and abnormal lung lobulation and hypogenitalism. For syndromes that overlap with Pallister–Hall syndrome, see Sills et al. (1993) and Kuo et al. (1999).

Endocrine evaluation showed hypopituitarism, i.e. low serum cortisol, T4, growth hormone and insulin-like growth factor (IGF-1) (Feuillan et al., 2001). One case was treated with growth hormone until final height was reached (Galasso et al., 2001). It was suggested that hypothalamic deficiency would contribute to hypopituitarism in this syndrome. In addition, short olfactory tracts suggest a relation with the arrhinencephaly defects. The neurohypophysis is sometimes absent. The condition was thought to be fatal in the neonatal period, but has also been described in a patient older than 12 years (Clarren et al., 1980; Chong and Newton, 1993; Sills et al., 1993; Squires et al., 1995). The main cause of death in the first cases to be described was acute adrenal insufficiency associated with panhypopituitarism (Kuo et al., 1999). 19.4. Glioma The majority of the gliomas affecting the hypothalamus are diffusely infiltrative fibrillary or pilocytic (hair cell) astrocytomas. Depending on their location, hypothalamic gliomas may manifest themselves in the form of, e.g. eating disorders, disturbances of temperature regulation, precocious puberty, somnolence, rage, visual impairment or hydrocephalus (Dolenc, 1999; Rivarola et al., 2001). Pilocytic astrocytoma causing hypothalamic lesions may be associated with decreased nocturnal melatonin levels and increased daytime sleepiness (Müller et al., 2002a). A rare case of a hypothalamic low-grade astrocytoma causing gelastic seizures has been reported (Coppola et al., 2002; Chapter 26.2). Most pilocytic astrocytomas arise within the visual system. Optic pathway gliomas tend to occur in young children and comprise 5% of the pediatric intracranial tumors (Janss et al., 1995). They may (1) be confined to the optic nerve and cause opthalmological symptoms, including visual hallucinations (Haugh and Markesbery, 1983) or (2) involve the optic chiasm and hypothalamus and cause neuroendocrine symptoms and symptoms of raised intracranial pressure. Chiasmatic/ hypothalamic tumors and tumors involving the chiasm should only be distinguished because they are different entities with a different prognosis and different treatments (Steinbock et al., 2002). In addition, they may give rise to diencephalic syndrome (Russell’s syndrome), spasmus nutans or moyamoya disease. Very rarely does a hypothalamic glioma bleed within the subarachnoid space, into the cerebrum or into the ventricles (Devi et al., 2001). The diencephalic syndrome is seen in infants with

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children (Kornreich et al., 2001). They may give rise to diencephalic syndrome of emaciation in infancy and childhood, which was originally described by Russell in 1951. It is typified by severe weight loss, despite normal linear growth, optic atrophy and signs of hypothalamic dysfunction. In 90% of cases, it is due to a hypothalamooptic glioma (Pelc, 1972; Figs. 19.9–19.13), such as a fibrillary or pilocytic astrocytoma, craniopharyngioma or germ cell tumor. “Pure” optic gliomas are rare. Of the 32 cases of the diencephalic syndrome in which the cellular type of the tumor was established, 25 had an astrocytoma, 4 a polar spongioblastoma (now called juvenile pilocytic astrocytoma), 1 an oligodendroglioma, 1 an astro-oligodendroglioma and 1 an ependymoma (Pelc, 1972). Burr et al. (1976) found a germinoma in one case. The presence of Rosenthal fibers or intracytoplasmatic masses of electron-dense material is characteristic (Styne, 1993). Possible embryological elements were present in tumors of five other patients. It has become apparent that in some 9% of the cases, nondiencephalic tumors appeared

posterior chiasmatic-hypothalamic tumors and is the only neoplastic disorder of the central nervous system associated with infantile failure to thrive. Spasmus nutans is characterized by head bobbing, head tilt and monocular nystagmus in infants and is caused by gliomas that are confined to the optic nerve. Moyamoya disease is an occlusive disorder of the large cerebral arteries of the circle of Willis, causing an abnormal capillary network of moyamoya vessels to develop at the base of the brain. It may occur as a consequence of irradiation of optic pathway gliomas and may lead to massive cerebral hemorrhage (Chapters 17.2e, 25.3; Oka et al., 1981; Chamberlain, 1995; Sinsawaiwong and Phanthumchinda, 1997). (a) Diencephalic syndrome: hypothalamo-optic glioma/optic pathway glioma This low grade astrocytoma accounts for 5% of all brain tumors and for 10–15% of supratentorial tumors in

Fig. 19.9. A. Diencephalic syndrome. Note the severe emaciation of the whole body and the characteristic ‘pseudohydrocephalic’ appearance. B. MRI of the brain. T1-weighted sagittal images (repetition time/echo time: 570/15) after gadolinium enhancement demonstrate the presence of a large tumor involving the hypothalamic region, distorting the chiasm and brainstem, and extending into the third ventricle. Neuropathologically, the tumor proved to be a hypothalamic astrocytoma with pilomyxoid features. (From Zafeiriou et al., 2001, Figs. A, B, with permission.)

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Fig. 19.10. Chiasmatic glioma. Sagittal (A) and parasagittal and coronal (B) MR scans. The tumor has enlarged the left side of the chiasm and the left optic nerve (arrows). (From Chong and Newton, 1993, Fig. 25 with permission.)

to be present with similar clinical features (Burr et al., 1976). The majority of pilocytic astrocytomas are nonaggressive and have a low proliferation index. However, a subpopulation has a propensity for aggressive behavior. Diffuse astrocytomas show a high proliferation index (Cummings et al., 2000). Although most optic gliomas are histologically low-grade astrocytomas, they tend to infiltrate along the optic pathways. In 70% of cases with hypothalamic glioma, involvement of the optic nerves or the whole optic pathway is also present. Some chiasmatic tumors remain quiescent for several years, others grow slowly (Pelc, 1972; Rutka et al., 1992; Perilongo et al., 1997). However, the whole spectrum from pilocytic (WHO grade I) to glioblastoma (WHO grade IV) may be present (Cummings et al., 2000). Gliomas of the optic nerve include highly infiltrative tumors that behave in a malignant manner (anaplastic astrocytomas, WHO grade III; glioblastomas, WHO grade IV) (Cummings et al., 2000). The age of onset ranges from the newborn period to 4 years, with the peak incidence between 2 and 7 months of age (Pelc, 1972). In 63% of cases, death occurs before the 2nd year (Pelc, 1972).

Although extremely rare, diencephalic syndrome of emaciation can occur in an adult harboring a tumor, e.g. a craniopharyngioma, in the anterior hypothalamus (Miyoshi et al., 2003). The main clinical features of the diencephalic syndrome include a failure to thrive, extreme cachexia with normal height, hyperkinesis, alert appearance, vomiting, surprisingly happy affect or euphoria, pallor without anemia, hypothermia, excessive sweating, nystagmus and decreased visual acuity. Nystagmic eye jerking is found in 70% of the cases (Pelc, 1972). Precocious puberty has also been described (Robben et al., 1995) and is probably related to tumor location (CollettSolberg et al., 1997). In addition, disturbances of temperature regulation or appetite, autonomic seizures, paroxisms of hypertension, tachycardia, diabetes insipidus or a syndrome of inappropriate vasopressin secretion are found (Chong and Newton, 1993; Connors and Sheikholislam, 1977; Chapter 22.6). Despite a normal caloric intake, these children lose weight, according to some authors possibly due to their disproportionately high energy output (Braun et al., 1959; Greenes and Woods, 1996). Other factors in emaciation may be the anterior pituitary defect (Russell,

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Fig. 19.11. Inferior surface of brain. The large multiloculated cystic tumor can be seen anterior to the brain stem in the region of the hypothalamus. (From Braun et al., 1959, Fig. 2 with permission.)

gigantism with growth hormone excess (Manski et al., 1994). A 4-year-old child with optic chiasm glioma had nonobstructive hydrocephalus. He had a ventriculoperitoneal shunt following which marked ascites developed. The ascitic fluid was rich in protein, most probably explaining the hydrocephalus he had previously. The CSF protein level and the amount of ascites fluid were influenced by chemotherapy. Very unusual hypernatremia develops in those cases, presumably by osmoreceptor dysfunction (Shuper et al., 1997). Surgery, chemotherapy and radiation therapy have been advocated as therapies for chiasmatic-hypothalamic gliomas (Nishio et al., 1993b; Konovalov et al., 1994; Valdueza et al., 1994b; Chamberlain, 1995; Janss et al.,

1951), elevated growth hormone levels or other endocrine defects (Greenes and Woods, 1996), or subcutaneous fat depletion due to autonomic alterations (Connors and Sheikholislam, 1977). Hydrocephalus is sometimes also present, as are large hands, feet and genitalia. Tumor cells and/or increased concentration of CSF protein is present in most patients. Dissemination via the CSF has also been reported. There may be an inappropriate, even paradoxical, plasma growth hormone response to hyperglycemia and hypoglycemia, and lack of diurnal variation in plasma cortisol (Burr et al., 1976; Costin, 1979Greenes and Woods, 1996). In a 16-month-old boy, an extensive optic pathway glioma – probably infiltrating into somatostatinergic pathways – was observed, accompanied by 67

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Fig. 19.12. Midsagittal section of brain. The cyst is seen to invaginate the wall of the third ventricle. The cyst is ovoid and contains a gelatinous, slightly granular matter. (From Braun et al., 1959, Fig. 3 with permission.)

1995; Greenes and Woods, 1996Silva et al., 2000; Kageji et al., 2003; Khafaga et al., 2003). Decisions about the institution of chemotherapy depend on many factors, such as the age of the patient, whether the child has a neurofibromatose type of tumor (see below), tumor grade and tumor size, tumor location, and the potential sequelae of radiotherapy and chemotherapy (Packer, 2000). A high response rate to cisplatin/etoposide was found in childhood low-grade glioma (Massimino et al., 2002). According to some authors, postoperative radiation therapy is effective and can prevent loss of vision (Grabenbauer et al., 2000). Others start more conservatively with CSF shunting, treating a rapidly expanding tumor with mass surgery and giving chemotherapy. Only

when chemotherapy is found to be ineffective do they advise radiation therapy (Alshail et al., 1997). Treatment of the diencephalic syndrome with carboplatin and vincristine regimen results in demonstrable weight gain, may cause tissue shrinkage and in some cases significantly delays the need for other therapies. Dolenc (1999) points to the recently radically changed treatment which has made atraumatic microsurgical resection the method of choice for hypothalamic gliomas. Gammaknife radiosurgery is effective in low-grade astrocytomas. Complete cure was observed in some cases (Kida et al., 2000). Spontaneous involutions of pilocytic astrocytoma has been reported in some children (Balkhoyor and Bernstein, 2000). It should be noted

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Fig. 19.13. Magnetic resonance images: (a) Coronal brain section showing the normal human hypothalamus at the level of the optic chiasm; and (b) line drawing of the principal structures. (c) Sagittal section through normal pituitary gland and hypothalamus; and (d) line drawing of the principal structures. (e) Coronal section demonstrating suprasellar mass lesion (glioma) with invasion of the mediobasal hypothalamus and distortion of the third ventricle, leading to obesity, and (f) line drawing of the principal structures. (g) Sagittal image showing upward expansion of glioma into medial hypothalamus; and (h) line drawing of the principal structures. (From Pinkney et al., 2002 Fig. 1 with permission.)

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that major causes of endocrine abnormalities in hypothalamic chiasmatic gliomas were field irradiation and tumor surgery (Collett-Solberg et al., 1997). (b) Gliomas of the optic pathways Associated with neurofibromatosis, gliomas of the optic pathway are considered to be separate entities and account for 10–70% of this group of tumors (Kornreich et al., 2001). The diencephalic syndrome, diffuse EEG changes, delayed development and seizures are also found in patients with neurofibromatosis type I (Venes et al., 1984; Chong and Newton, 1993; Robben et al., 1995; Cummings et al., 2000). This is an autosomal, dominant disorder with a prevalence of 1 in 3000 to 4000 and is caused by a mutant gene on the long arm of chromosome 17 (q11.2) (Styne, 1997). Approximately half of the cases are spontaneous mutations (Zuccoli et al., 2000). The neurofibromatose gene encodes a tumor-suppressor factor which interacts with the ras oncogene p21 (Gottschalk et al., 1999). The data provided on the association between glioma of the optic pathway are variable. Ten to seventy percent of the patients with visual-pathway gliomas have neurofibromatosis and 5–15% of patients with neurofibromatosis have a tumor of the optic pathway (Styne, 1993; Valdueza et al., 1999b; Janss et al., 1995). Optic pathway glioma is the most common brain tumor associated with Von Recklinghausen’s disease. In patients with neurofibromatosis, the most common site of involvement is the orbital nerve; the tumor is smaller, the original shape of the optic pathway is preserved and optic components are uncommon (Kornreich et al., 2001). Neurofibromatous type I patients may follow a more aggressive course of the disease (Valdueza et al., 1994b). One of these cases with emaciation, marked increase in serum growth hormone levels, and anaplastic astrocytoma of the optic chiasma–hypothalamic region has been described in an adult (Tanabe et al., 1994). In a 5-yearold boy with neurofibromatosis type I, a chiasmatic glioma caused a rapid visual acuity loss, which improved significantly after radiation (Adams et al., 1997). However, generally there is only minimal tumor enlargement, while in most cases the optic glioma patients without neurofibromatose show a clear propensity (Kornreich et al., 2002). Hydrocephalus as complication (Gottschalk et al., 1999) is extremely rare in neurofibromatosis cases (Kornreich et al., 2001). Endocrine dysfunction occurs less often in neurofibromatosis patients who are treated conservatively (Collett-Solberg et al., 1997). Differential

diagnosis includes germinoma, craniopharyngioma, meningeoma, lymphoma, histiocytosis and inflammatory conditions. Traditionally the treatment has included radiation, surgical resection and, in some special cases, chemotherapy (Gottschalk et al., 1999). The observation of postoperative regression of a biopsy-proven opticochiasmatic glioma strengthens the argument for conservative therapy in young children with neurofibromatosis (Venes et al., 1984). In some patients, mainly children, with neurofibromatosis I as revealed on serial MRI, spontaneous partial or even total remission of the neoplasm in the hypothalamic region was found, implying also that a cautious approach to therapeutic management should be taken in asymptomatic cases (Gottschalk et al., 1999; Zuccoli et al., 2000). (c) Other gliomas Intrinsic astrocytomas of the posterior pituitary (pituicytomas) or stalk (infundibulomas) are rare (Scothorne, 1955). Infundibuloma (or astrocytoma of the third ventricle or glioma of the tuber) occur mainly in childhood or adolescence and often cause death at that stage, although there are long survivors. Histologically it is a fibrillary astrocytoma. In children the capillaries tend to be arranged in plexuses remarkably reminiscent of the gomitoli in the upper part of the pituitary stalk (Chapter 17.1c), suggesting that the tumor is derived from the neurohypophysial tissue of the infundibulum (Sheehan and Kovacs, 1982). In contrast to the granular cell tumors, the cells contain no pigment (Massie, 1979). Only a few pilocytic pituitary astrocytomas or pituicytomas have been described. MRI shows extension of the tumor into the stalk. There may be panhypopituitarism as an early manifestation, whereas diabetes insipidus may be absent, probably by vasopressin release above the level of the tumor (Nishizawa et al., 1997). The astrocytic nature of such a tumor can be confirmed by the presence of GFAP staining. Such tumors closely resemble pilocytic astrocytomas in other parts of the central nervous system (Schothorne, 1955). A 40-year-old man has been described with such a tumor, visual failure and hyperprolactinemia (Rossi et al., 1987). Another case of a pituicytoma presented in a 26-year-old woman with dizziness and visual obscuration. MRI revealed a pituitary mass with suprasellar extension. Immunocytochemistry was positive for GFAP, S-100 and vimentin. This pituicytoma was not a pilocytic variant (Hurley et al., 1994). One case of a pituicytoma causing hypopituitarism and

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Fig. 19.14. Granular cell tumor. NHB 98-010, female, 75 years of age. Hematoxylin–eosin. Bar = 2 mm.

visual impairments or headache (Jenevein, 1964; Symon et al., 1971; Massie, 1979; Horvath et al., 1997; see also Chapter 22.1). Gliomatosis cerebri is an uncommon tumoral pathology, but its incidence may be grossly underestimated. It is a neuroepithelial neoplasm of unknown origin. Less than 200 cases have been reported in the literature. The tumoral proliferation consists of astrocytes, oligodendrocytes or both, with different degrees of maturation. When infiltrating myelinated tracts, the cells often form parallel rows among nerve fibers. In these cases myelin sheaths may be destroyed, but axons survive. Immunocytochemistry may or may not show GFAP expression. Areas of high mitotic activity and microvascular proliferation may be observed, but there is no necrosis. The hypothalamus may be affected, in some cases resulting in a hypothalamic syndrome. However, the most frequent clinical manifestations are mental deterioration and personality changes. In addition, signs of increased cranial pressure, including empty sella, have been reported (Peretti-Viton et al., 2002).

visual disturbances was not only positive for GFAP, vimentin and epithelial membrane antigen, but had aggregates of intermediate filaments in a concentric pathway (fibrous body) and secretory granules. It might also have arisen from the stromal folliculostellate cells of the adenohypophysis (Cenacchi et al., 2001). A special form of gliomas are the granular cell tumors or choristomas that are composed of large cells with granular, lightly eosinophilic, cytoplasm. They are thought to derive from pituicytes, i.e. modified astrocytes in the neurohypophysis. Occasional tumor cells may contain brown pigment similar to that found in pituicytes. The granules in this pigment stain with Sudan black, characterizing it as a lipopigment. Minute nodules of granular cells are commonly found in the posterior pituitary and stalk. They occur in some 5% of the pituitaries, are called tumorlets, granular cell myoblastoma or choristoma, and are generally asymptomatic (Fig. 19.14, 22.1; Horvath et al., 1997). Symptomatic granular cell tumors are rare and may be associated with diabetes insipidus, 71

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For third ventricle chordoid glioma (Pomper et al., 2001), see Chapter 17.3; and, for septum pellucidum tumors, see Chapter 18.8. The subependymal giant cell astrocytoma in tuberous sclerosis is described in Chapter 19.8. 19.5. Craniopharyngioma, Rathke’s cleft cysts and xanthogranuloma (a) Craniopharyngioma A low-grade developmental neoplasm, craniopharyngioma is thought to be derived from Rathke’s pouch, the pituitary anlage and can arise anywhere along the craniopharyngeal canal. This canal is usually obliterated during the 12th week of gestation. Rathke’s pouch occurs in embryos of 8–12 mm (2nd–6th week) and is obliterated

between 6 and 8 weeks (Rottenberg et al., 1994). Rare cases have indeed been described with a persistent craniopharyngeal canal and an intimate relationship that showed up on MRI between the canal and the infrasellar part of a craniopharyngioma (Chen, 2001), or with a nasopharyngeal extension of a normally functioning pituitary gland extending into the nasopharynx (Ekinci et al., 2002). It is the commonest intracranial tumor of nonglial origin and accounts for 7–13% of all intracranial tumors under 14 years of age. The peak age is at 7 years (Costin, 1979), but there is also a second, smaller peak in the sixth decade (Harwood-Nash, 1994; Miller, 1994). A craniopharyngioma arising de novo in middle age has also been reported (Arginteanu et al., 1997). A subset of craniopharyngiomas consists of monoclonal tumors arising from activation of oncogenes located at specific chromosomal loci.

Fig. 19.15. Craniopharyngioma in infundibulum. An incidental autopsy finding. NHB 96.077, male, 63 years of age. Hemotoxylin–eosin. Bar = 200 m.

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but frequently extends into the third ventricle (Tada et al., 1992) and stretches the optic chiasm (Fig. 19.16). Craniopharyngiomas of the third ventricle occur twice more often in men than in women (Tada et al., 1992). Craniopharyngioma is best visualized by MRI (HarwoodNash, 1994; Hald et al., 1995; Fig. 19.16), while white calcifications are best visualized by computed tomography (CT) (Hald et al., 1995). On T1-weighed MRI images, not only peritumoral edema but also edema spreading along the optic tracts can be observed. Patients with large pituitary adenomas or with tuberculous sellae meningiomas have such edema along the visual pathway. Edema along the optic tract is thus a useful MRI finding with which to distinguish craniopharyngiomas from other common parasellar tumors (Nagahata et al., 1998). Neuroradiologically, a third ventricle craniopharyngioma may mimic a choroid plexus papilloma (Tada et al., 1992). Tumors present in early childhood frequently produce hydrocephalus (Chapter 18.7) and symptoms of intracranial pressure (see Chapter 19.1; headache, vomiting, memory loss, seizures, hemiparesis or abnormal behavior), which may obscure the multiple endocrine abnormalities (for review, see Costin, 1979). Craniopharyngioma are present in two distinctive histological patterns: one resembling tooth-forming tissues, i.e. the adamantinomatous craniopharyngiomas, and the

Craniopharyngiomas grow slowly, are usually well encapsulated, and may be solid and contain calcium or may be cystic (Costin, 1979). Pediatric craniopharyngiomas were found to be cystic in 99% and to contain calcifications in 93% (Zhang et al., 2002). The cysts contain ‘machinery oil fluid’ consisting of cholesterol, keratin, proteinaceous fluid, hemorrhage and necrotic debris (Chong and Newton, 1993). Cystic craniopharyngiomas contain moderate to high immunoreactivity for vascular endothelial growth/permeability factor, in contrast to the more solid form of this tumor (Vaquero et al., 1999). Craniopharyngioma are considered to arise from squamous cell nests, thought to be vestigial remnants of Rathke’s pouch and frequently found in the hypophysial stalk. Both the epithelial portions of craniopharyngiomas and the squamous cell nests in the pars tuberalis of the pituitary stalk express keratin (Asa et al., 1981; Fig. 19.15). Craniopharyngiomas do not express cytokeratins 8 and 20 (Xin et al., 2002). Malignant transformation of craniopharyngioma is rare. It was proposed that leukemia inhibitory factor (LIF), which is expressed in the epithelial cells of adamantinomatous craniopharyngiomas, may play a role in the development and progression of craniopharyngiomas (Tran et al., 1999). In the majority of cases, the craniopharyngioma does not remain confined to the sella, causing hypopituitarism,

Fig. 19.16. Suprasellar craniopharyngioma. Precontrast (A) and postcontrast (B) sagittal T1-weighted images. A heterogeneous mass is noted in the suprasellar region, causing marked distortion of the anterior third ventricle. The anterior portion appears to be cystic, with rim-like enhancement after contrast administration. The posterior portion of the tumor, showing low signal intensity on T1-weighted images and heterogeneous enhancement on the post-contrast-enhanced scans, represents the solid portion of the tumor containing calcifications. A pineal cyst is noted incidentally. (From Chong and Newton, 1993, Fig. 18 with permission.)

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less common squamous papillary craniopharyngiomas. These two types of craniopharyngiomas can be distinguished radiologically. The adamantinomatous type has typically large, nonenhancing hyperintense cysts on T1-weighed images, while the squamous-papillary type appears as a hypointense cyst on noncontrast T1-weighed image. The adamantinomatous type simulates adamantogenic tumors. This type of craniopharyngioma may originate from migrated dental progenitor cells which are presumed to accompany the upward extension of Rathke’s cleft in an early embryonal stage (Oka et al., 1997). A few adamantinomatous craniopharyngeomas were found to contain melanin pigment, which attests to the similarities with odontogenic tumors of the jaw (Harris et al., 1999). Transitional or mixed examples of the two types of craniopharyngioma also occur. Previous suggestions that the squamous papillary type is found only in adults, never calcifies, does not invade the brain and is associated with a better outcome (no recurrences, better clinical status) are only partially correct (Miller, 1994; Crotty et al., 1995). The cases studied by Davies et al. (1997) were evenly divided between the adamantinomatous and the papillary types. Although the benign tumor with an aggressive course is believed to develop from the epithelial cell remnants of the hypophysial-pharyngeal duct or Rathke’s pouch, it is difficult to account for squamous papillary tumors on the basis of this hypothesis, since they do not resemble tumors of the tooth-forming epithelium. Also, Rathke’s pouch remnants do not usually have a stratified epithelium (Miller, 1994). Estrogen and progesterone receptors have been demonstrated in both types of craniopharyngiomas, raising the possibility that these tumors can be influenced by steroids (Thaper et al., 1994). Craniopharyngiomas of the third ventricle may originate in ectopic epithelial nests of the infundibulum (Fig. 19.15), or a more distant site of an epithelial nest in the brain around the third ventricle (Tada et al., 1992). They are wholly within the third ventricle and can be distinguished from suprasellar lesions by the presence of an intact floor of the third ventricle. Headache and visual disturbances are the most common presenting features, while, unlike the suprasellar craniopharyngiomas, endocrine disturbances are not a common finding. Subtotal removal followed by radiotherapy has been proposed as the treatment of choice (Davies et al., 1997), but in children younger than 5 years it may be reasonable to follow subtotal resection and to delay radiation until

recurrence, in order to diminish neurocognitive sequelae (Khataga et al., 1998). The signs and symptoms of a craniopharyngioma are characteristically: headache, nausea and vomiting (BinAbbas et al., 2001; Rutka et al., 1992), growth failure, increased intracranial pressure, and visual loss. However, the clinical features depend on the size of the tumor and its location, as well as the age of the patient (Costin, 1979). Presenting endocrine complaints are infrequent but hypothalamic symptoms may include diabetes insipidus, inappropriate antidiuretic hormone secretion, hyperprolactinemia, deficiencies of LH, FSH, ACTH, TSH, cortisol or panhypopituitarism (Miller, 1994; Sklar, 1994; Paja et al., 1995; Gonzales-Portillo et al., 1998; Bin-Abbas et al., 2001), including hypogonadism (Bauer, 1954). Which of these symptoms are due to hypothalamic lesions, to pressure on the hypothalamic pituitary vessels or on the pituitary itself remains debatable, since many of the lesions extend into the third ventricle (Crotty et al., 1995). Growth hormone deficiency is generally present in children with craniopharyngioma. The growth rate of these children may, however, stay normal, since craniopharyngeomas induce an increase in insulin secretion that keeps IGF-1 normal (Pinto et al., 2000). In addition, patients with a craniopharyngiomas often suffer from severe obesity. Significantly, higher leptin levels were found in patients with a suprasellar craniopharyngioma. It has been suggested that these patients develop obesity because their hypothalamic structures become insensitive to leptin, resulting in a disturbed feedback from the hypothalamus to adipose tissue. Severe hypoglycemia and reduction of insulin requirement have been found in a girl with insulin-dependent diabetes mellitus as a first sign of a craniopharyngioma (Lebl et al., 1999). Increased daytime sleepiness and decreased night-time melatonin levels have been found in craniopharyngiomas, probably due to hypothalamic lesions (Müller et al., 2002a). Craniopharyngiomas may also cause psychiatric symptoms, e.g. hypersexual behavior, confusional syndromes, hallucinations, or marked deterioration in occupational performance (Carroll and Neal, 1997). Two cases of patients have been published who meet the DSM-III-R criteria for intermittent explosive disorder. Episodes of rage develop before and/or after surgery for removal of the craniopharyngioma. MRI revealed hypothalamic–hypophysial involvement. It was suggested that hypothalamic lesions played a major role in the development of aggressive behavior in both cases (Tonkonogy and Geller, 1992). Moreover, Killefer and Stern (1970)

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reported a case in which “episodic savage behavior” and “rage spells” developed several weeks after total removal of a craniopharyngioma. Malamud (1967) presented three cases with craniopharyngiomas, respectively diagnosed as schizophrenia, manic excitement and psychoneurosis. A rare case of an adult with a craniopharyngioma presenting with a diencephalic syndrome of emaciation was reported (Miyoshi et al., 2003). Total surgical tumor removal while avoiding hazardous intraoperative manipulation provides favorable early results and a low risk of recurrence of the craniopharyngioma (Fahlbusch et al., 1999; Duff et al., 2000). The frontobasal interhemispheric approach, even made through a small craniotomy window, is a valid choice for the removal of craniopharyngiomas extending outside the sellar–suprasellar region. Tumors can be removed via this approach with preservation of the pituitary stalk, hypothalamic structures and perforating vessels (Shirane et al., 2002). The trans-lamina terminalis hypothalami approach seems to be a valid choice for the removal of purely intraventricular craniopharyngeomas (Maira et al., 2000). Subtotal resection is associated with increased risk of tumor recurrence and is usually followed by radiotherapy. Long-term disease control is excellent after subtotal resection and postoperative radiotherapy, while a high risk of recurrence is found in the subtotal resection without radiation. In that case, approximately one-third of the patients exhibited morbid obesity (Duff et al., 2000; Eisenstat, 2001). Following radiotherapy the periods of tumor shrinkage are often long (mean 29 months). Temporary enlargement of the solid component usually occurs during radiotherapy and does not represent tumor progression. Sometimes cystic enlargement also occurs comparatively early after radiotherapy, and enlarged cysts often shrink spontaneously. After shrinkage, small solid or cystic nodules enhanced with contrast medium often remain. MRI allows assessment of the extent of hypothalamic damage after surgery for craniopharyngioma and thereby prediction of the patients most at risk for severe postoperative weight gain (De Vile et al., 1996). Multiple pituitary hormonal deficiencies are quite frequent following radical surgery (Bin-Abbas et al., 2001). It is worth preserving the pituitary stalk and gland at surgery because of the definite chance that intact anterior pituitary functions may be maintained. Postoperative diabetes insipidus must be accepted as a common complication of complete removal of a craniopharyngioma (Honegger et al., 1999), but judicious use of desmopressin (DDAVP) and ‘stress’ doses of gluco-

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corticoids are advised to guide the patient through the postoperative period (Eisenstatt, 2001). In addition, gamma-knife radiosurgery, external beam irradiation, fractionated stereotactic radiotherapy and intracavitary irradiation give encouraging results (Eisenstatt, 2001; Isaac et al., 2001; Barajas et al., 2002; Schulz-Ertner et al., 2002; Úlfarsson et al., 2002; Varlotto et al., 2002). A phase II study showed that interferon--2a is active against some childhood craniopharyngiomas and may provide an alternative treatment strategy (Jakacki et al., 2000). A small number of craniopharyngiomas with ciliated epithelia has been described. In these tumors, craniopharyngiomatous tissue and Rathke’s cleft epithelium are intermingled, which seems to imply an intimate relationship between these two lesions (Oka et al., 1997). (b) Rathke’s cleft cysts Cysts known as ‘Rathke’s cleft cycsts’ are relatively common incidental microscopic findings, i.e. in some 12–33% of the normal pituitaries at autopsy (Matsudo et al., 2001), and are found during life, with increasing frequency, by CT or MRI scans (Ward et al., 2001). Occasionally the cysts become larger and symptomatic by compression of surrounding structures, i.e. the hypothalamus, pituitary and visual pathways (Concha et al., 1975; Eisenberg et al., 1976). Most of them occur in the zona intermedia of the pituitary and may derive from remnants of Rathke’s pouch, thus sharing a similar origin with craniopharyngioma (Ward et al., 2001). Concomittant pituitary adenoma and Rathke’s cleft cysts are found. The frequency of the combination is some 4% of the pituitary adenomas and 11% of the Rathke’s cleft cysts (Sumida et al., 2001). Patients may develop symptoms such as headache, hyperprolactinemia, galactorrhea, decreased libido, impotence, visual field deficits, diabetes insipidus, inappropriate secretion of vasopressin, amenorrhea or hypopituitarism such as adrenal insufficiency if the cyst is large enough to push against adjacent structures. Repeated aseptic meningitis and spontaneous resolution of Ratke’s cleft cyst are also noted (Matsuno et al., 2001; Ward et al., 2001). The cyst wall is composed of a single layer of columnar, cuboidal or squamous epithelium, which may be ciliated and contain goblet cells. The cyst may contain mucoid yellow and grumous material, serous or CSF-like contents, or cellular debris (Chong and Newton, 1993; Eguchi et al., 1994; Iwai et al., 75

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2000; Ward et al., 2001). In addition, a case with amyloid deposition (Concha et al., 1975) and one with ossification (Nakasu et al., 1999) has been described. These cysts are usually confined to the sella (in older literature the disorder is termed “intrasellar craniopharyngioma”) and usually do not calcify (Harwood-Nash, 1994). The cysts are seldom located entirely in the suprasellar region, which then often leads to the mistaken diagnosis of a craniopharyngioma (Rottenberg et al., 1994). Histologically one may distinguish Rathke’s cleft cysts from craniopharyngiomas, e.g. in biopsies, by staining for cytokeratins. Rathke’s cleft cysts and pars intermedia of the pituitary express cytokeratins 8 and 20, whereas craniopharyngiomas do not express these cytokeratins (Xin et al., 2002). Moreover, Rathke’s cleft cysts do not grow – they lack calcification and machine oil-like fluid content – which distinguishes them from craniopharyngiomas (Chong and Newton, 1993). The unique MRI finding of Rathke’s cleft cysts – high intensity on T1-weighted images and low signal intensity on T2-weighted images – seems to depend on the protein and not on the cholesterol concentration (Hayashi et al., 1999). Symptoms of Rathke’s cleft cysts may include generalized pituitary hypofunction, hyperprolactinemia, multiple endocrinopathies, headaches and visual disturbances (Rutka et al., 1992; Horvath et al., 1997). A few cases have been described with symptomatic pituitary hemorrhage into a Rathke’s cleft cyst with sudden, severe retro-orbital headache, nausea and visual loss (Nishioka et al., 1999). A case has been described of a Rathke’s cleft cyst, surrounded by areas of noncaseous granulomatous tissue with scattered multinucleated giant cells of foreign body type, similar to a sarcoid lesion. Two years later the patient reported a sudden visual impairment due to sarcoidosis of the optic nerve. Remission of neurological symptoms followed corticosteroid therapy. The diagnosis sarcoidosis was firmly confirmed when the patient underwent surgery for new lesions on the acoustic and facial nerves. The pituitary lesions were probably due to secondary granulomatous infiltration of the pituitary gland, where a small congenital asymptomatic Rathke’s cyst was already present (Cannavò et al., 1997). Rathke’s cleft cyst was also found in a mosaic Klinefelter 46,XY/47,XXY patient with hypothalamic panhypopituitarism, partial diabetes insipidus and other endocrine disorders (Gotoh et al., 2002). Overexpression of LIF in mice that are transgenic for LIF was found to lead to invagination of the anterior wall of Rathke’s pouch and the formation of cysts lined by

LIF-immunoreactive epithelial cells. Strong LIF immunoreactivity was also found in human Rathke’s cleft cysts (Tran et al., 1999), suggesting failed differentiation of Rathke’s epithelium to hormone-secreting cells (Akita et al.,1997). Treatment consists of excision of the lesion, and the transnasal transphenoidal approach has been advocated (Ward et al., 2001). (c) Xanthogranuloma Xanthogranulomas (cholesterol granulomas) are considered to be a xanthogranulomatous change of craniopharyngioma (for a xanthogranulomatous degeneration of a colloid cyst, see Chapter 17.3b). They consist of cholesterol clefts, macrophages, chronic inflammatory infiltrates, necrotic debris and hemosiderin deposits. They lack the additional features of adenomatous craniopharyngiomas and some 35% contain squamous or ciliated cuboidal cells. They preferentially occur in adolescents and young adults (mean age 27 years), have a predominant intrasellar localization, smaller tumor size, more severe endocrinological deficits, longer preoperative history, lower frequency of calcification and visual disturbances, better resectability and a more favorable outcome than craniopharyngiomas. They are therefore proposed to be clinically and pathologically distinct from the classic adenomatous craniopharyngiomas (Paulus et al., 1999). 19.6. Dermoid and epidermoid tumors Dermoid and epidermoid cysts may compress the hypothalamus and pituitary and cause hypopituitarism, diabetes insipidus or cranial nerve deficits. Both of these tumors are benign and slow growing. They tend to wriggle around adjacent neural structures, depending on the spaces they occupy. The cyst walls of these tumors contain stratified squamous epithelium and an outer layer of connective tissue. Dermoid tumors occur in children but also in adults. They are most commonly located in the fourth ventricle or the vermis and are less commonly seen in juxtasellar position. The cyst walls of these tumors contain dermal appendages, hair follicles, sebaceous glands and sweat glands, and stratified squamous epithelium. The yellow contents of the cyst consist of a waxy material containing desquamated keratin products, hair and cholesterol crystals. Epidermoid tumors occur in the fourth to fifth decades of life. They are found in the basal cisterns,

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often in a lateral location, and produce remarkably few pressure effects. The cyst walls of these tumors contain a simple stratified squamous epithelium resting on an acute layer of connective tissue. No skin appendages such as sweat glands or hair follicles are found. The cyst contains a waxy material with desquamated keratin products and cholesterol crystals. The cholesterol in the lumen shines through, giving a silvery appearance, so that they are sometimes called “pearly tumors” (Sheehan and Kovacs, 1982; Chong and Newton, 1993). In the case of an epidermoid (Rathke’s pouch) cyst of the third ventricle, a state of akinetic or trance-like mutism has been described in the older literature. A 14-year-old girl slept more hours than normal, but was easily aroused. Her eyes followed moving objects but there were no other voluntary movements. She was quite mute or answered in whispered monosyllables. She suffered loss of emotional expression and painful stimuli caused reflex withdrawal. Repeated commands were carried out occasionally, albeit feebly, slowly and incompletely. She had to be fed, but swallowed readily. There was total incontinence. This syndrome was treated three times by aspiration of the cyst. Each time there was a rapid, almost immediately disappearance of the symptoms. Ten minutes after the cyst was emptied, the child sat up in bed and said “Where am I?”, as if waking from a sleep. The state of akinetic mutism was not due to a general rise of intracranial pressure. Most functions that were affected are considered to be cortical functions, i.e. voluntary movement, including speech, spontaneous activity of all kinds, emotional expression, perception and memory. The state of akinetic mutism was therefore interpreted as an interruption of pathways between hypothalamus and thalamus alongside the third ventricle by local pressure, leading to an interruption of the hypothalamic input to the cortex. The two connections speculated to be involved are the bundle of Vicq d’Azyr and the connection between the posterior hypothalamic nucleus (Chapter 13.3), which is considered to be a controlling center for the sympathetic system and the medial nucleus of the thalamus. The latter fibers run along the third ventricle (Cairns et al., 1941).

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(pineocytoma and pineoblastoma), (iii) glial neoplasms, and (iv) cysts (Fetell and Stein, 1986; Fig. 19.18; Smirniotopoulos et al., 1992). Most pineal region masses are malignant germ cell tumors that occur in young male patients. The most common one is a germinoma (Fig. 19.17). Malignant, aggressive tumors (germinomas, pinealoblastomas, immature teratoma and lymphoma) invade the pineal parenchyma, generally leading to a complete abolishment of melatonin secretion. On the other hand, less aggressive benign tumors (pineocytomas, pilocytic astrocytomas and meningeoma) generally allow normal secretion and circadian rhythm of melatonin (Grimoldi et al., 1998). A child with a germ cell tumor involving the pineal region markedly suppressing melatonin secretion suffered from severe insomnia. Exogenous melatonin restored sleep continuity, thus providing evidence for the essential role of melatonin in normal sleep (Etzioni et al., 1996; see Chapter 4.5). The differential diagnosis of pineal region masses is extensive and includes tumors, vascular lesions and even a case of histiocytosis (Gizewski and Forsting, 2001). (a) Germ cell tumors Primordial germ cells develop from embryonic cells of the yolk sac wall, near the allantois. Between 5 and 8 weeks of gestation, they move into the genital ridges. Misguided germ cells that move into the hypothalamicpineal region are supposed to give rise to extragonadal germ cell tumors. Germ cell tumors occur primarily in children and young adults in midline structures throughout the body, including the pineal and suprasellar region (Smirniotopoulos et al., 1992; Fig. 19.19). For suprasellar and sellar localization, see Chapter 19.2. Pineal region germ cell tumors occur almost exclusively in male patients, while suprasellar germ cell tumors do not have a sex preference. Germ cell tumors are classified according to Teilum’s scheme (Fig. 19.18; Fetell and Stein, 1986). In Fig. 19.18 the presence of the tumor markers HCG and -fetoprotein are also indicated. Such markers can also be used to monitor therapeutic interventions (Massie et al., 1993; Tarng and Huang, 1995). CSF levels of these markers may be more sensitive and precede elevations in serum. Germinomas are generally negative for -fetoprotein, while HCG is usually absent or only slightly elevated. HCG is markedly elevated and -fetoprotein is usually normal with choriocarcinomas (Schut et al., 1996). Germinomas do not have a pineal origin and thus

19.7. Pineal region tumors According to the pathological classification of Russell and Rubinstein, the following types of tumors have to be distinguished in the pineal region: (i) teratomas (including all germ cell-derived tumors); (ii) pineal cell tumors 77

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Fig. 19.17. Intrachiasmal craniopharyngioma. Sagittal (A) and coronal (B) T1-weighted MR scans. The tumor has a slightly heterogeneous appearance and has caused marked expansion of the chiasm (arrows). (From Chong and Newton, 1993, Fig. 20 with permission.)

Fig. 19.18. Teilum’s proposed scheme of differentiation of germ cell tumors. HCG = human chorionic gonadotropin, AFP = -fetoprotein. (Modified by Fetell and Stein, 1986, Fig. 4.)

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generally do not produce melatonin. Only a few rare cases of germinomas have been described that produce melatonin. The melatonin-synthetizing enzymes N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) were present in this case, while the high blood levels of melatonin became undetectable postoperatively (Grimoldi et al., 1998). A germinoma is the most typical pineal region mass. It was formerly called ‘atypical teratoma’ and is histologically identical to ovarian dysgerminoma and testicular seminoma. Male patients are 2–17 times more affected than female patients. The peak age of presentation is in the second decade. A germinoma is a malignant tumor composed of large, multipotential, primitive germ cells and infiltrating lymphocytes, epithelioid cells (probably derived from macrophages) and macrophages. Often the lymphocytes penetrate deeply into the cytoplasm, even into the nucleus of the tumor cell. The infiltrating cells may be directly cytotoxic to the tumor cells (Wei et al., 1992; Grimoldi et al., 1998). Histologically germinomas of the pineal region are identical to those in the suprasellar region (Chapter 19.2; Schut et al., 1996). A germinoma may invade the adjacent brain structure and also spread through the CSF (Fig. 19.19) in 32–37% of cases (Schut et al., 1996). Pure germinomas are associated with low or undetectable HCG levels in serum and CSF (Sklar, 2002). A primitive germ cell that may lead to a malignancy is called an embryonal carcinoma. It may give rise to a differentiated teratoma that is a benign and slow-growing tumor but may also be locally invasive or metastasize. Teratoma also have a male prevalence of a factor 2.8. Teratoma are neoplasms that recapitulate normal organogenesis, usually producing tissues representing a mixture of two or more of the embryonic layers of ecto-, mesoand endoderm. It might produce tissue that mimics the skin and has to be differentiated from a dermoid cyst (Chapter 19.6) by the presence of components of diverse tissues. They contain lipid areas and may have calcifications (Fig. 19.20). Usually -fetoprotein and HCG are elevated or slightly above normal (Schut et al., 1996). Some embryonal carcinomas contain elements of teratoma and are termed teratocarcinomas. An embryonal carcinoma cell is believed to be a precursor malignancy that can also differentiate into a tumor of extraembryonic tissue. These tumors give both elevated -fetoprotein and HCG levels (Schut et al., 1996). If the resulting tumor contains trophoblastic tissue it is called a choriocarcinoma (which usually produces markedly elevated HCG levels) (Schut et al., 1996), if it contains yolk sac elements

Fig. 19.19. Germinoma with seeding. (a) Sagittal T1-weighted MR image of a 22-year-old man demonstrates two lesions (dots) that are homogeneous and are equal in signal intensity to that of gray matter. There is a dominant mass in the pineal region and a second, smaller mass in the suprasellar cistern. (b) Coronal T1-weighted MR image of the same patient after administration of gadopentetate dimeglumine demonstrates abnormal enhancement of the enlarged pituitary infundibulum, which represents seeding from the pineal germinoma. (c) Sagittal gross specimen obtained at autopsy of a different patient also demonstrates two prominent masses. The original germinoma is the large mass in the pineal region. The second mass, in the suprasellar cistern, represents CSF dissemination. Together, these two masses compress and distort the brain stem. The pineal mass extends well below the tentorium and encroaches on the roof of the fourth ventricle. It also spreads anteriorly, to the foramen of Monro, through the cistern of the velum interpositum (*). (From Smirniotopoulos et al., 1992, Fig. 4 with permission.)

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Fig. 19.20. Teratoma. (a) CT scan of a 4-year-old boy demonstrates a heterogeneous mass in the pineal region extending anteriorly into the cistern of the velum interpositum. The mass contains several large chunks of calcification and a darker, cystic-appearing area (arrowhead). Heterogeneity like this, especially when there is lipid material and calcification, is a hallmark of a mature teratoma. (b) After contrast material is administered, there is relatively homogeneous enhancement of the noncalcified solid portions of the tumor. The cystic region does not appear enhanced. (c) T1weighted MR image of the same patient demonstrates a mildly heterogeneous mass largely isointense relative to gray matter. However, there are focal areas of T1-weighted shortening (arrowhead) from lipid material (e.g. sebaceous). The cystic region (*) has higher signal intensity than that of CSF because of proteinaceous material. (d) Sagittal T1-weighted MR image of an 8-year-old boy demonstrates a grossly heterogeneous mass with large amounts of hyperintense lipid material. It extends anteriorly toward the cistern of the velum interpositum and posterior third ventricle. Note the cystic region (*). The signal intensity void of the internal cerebral veins (arrowhead) is superior to the mass, but, in addition, there is a thin rim of hypointensity encircling the mass, suggesting a tumor capsule. (Courtesy of L. Baker, MD, University of California, San Francisco). (e) Sagittal gross specimen of a mature pineal teratoma from a different patient shows a grossly heterogeneous mass that is well encapsulated (arrowhead). The varied contents of this partially cystic mass include a superior portion with a “cheesy” consistency for sebaceous material. In the sagittal plane, it is clear that much of this mass is below the tentorium. (From the L. Rubinstein collection, AFIP.) (From Smirniotopoulos, 1992, Fig. 5 with permission.)

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Fig. 19.21. Yolk sac tumor in a 9-year-old boy. (a) Axial CT scan obtained without the use of contrast material demonstrates a round, relatively homogeneous, low attenuation mass, engulfing the calcifications within the central pineal gland. Germinomas are usually high-attenuation masses; thus, other diagnoses should be considered. However, the appearance is neither specific for nor suggestive of yolk sac tumor. There is an incidental dural osteoma (arrow). (b) Axial CT scan obtained after contrast material is administered shows homogeneous enhancement, which is also non-specific. (c) Axial T2-weighted MR image demonstrates nonspecific homogeneous hyperintensity (higher than the signal intensity of gray matter) of the mass. (d) Sagittal MR image obtained without the use of contrast material demonstrates minimal heterogeneity in the mass, which is slightly hypointense relative to gray matter. (e) Sagittal MR image obtained after administration of gadopentetate dimeglumine shows prominent but slightly heterogeneous enhancement. (Smirniotopoulos, 1992, Fig. 9 with permission.)

it is called an endodermal sinus tumor or yolk sac tumor (which usually produces high levels of -fetoprotein (Schut et al., 1996) (Fig. 19.21). Both are highly malignant (Fetell and Stein, 1986; Smirniotopoulos et al., 1992).

Adjuvant therapy consisting of preoperative chemotherapy with cisplatin and ectoposide and concomitant radiotherapy, followed by radical surgical removal of the tumor, is proposed as a highly effective treatment of 81

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Fig. 19.22. Pineocytoma. (a) Plain CT scan shows a large and relatively homogeneous mass in the pineal region, with peripheral displacement of pineal calcification (arrows). The mass has extended anteriorly along the velum interpositum. This is the exploded pineal appearance that suggests an intrinsic pineal parenchymal neoplasm. (b) Contrast-enhanced CT scan shows homogeneous enhancement in the mass, which assumes a triangular shape as it conforms to the contours of the pulvinar of the thalami and velum interpositum. (c) Axial proton-density-weighted MR image shows the mass is homogeneously hyperintense; it is diamond shaped because it fills the two opposing triangles of the velum interpositum (anterior) and quadrigeminal plate cistern (posterior). (d) Sagittal T2-weighted image shows the mass is under the internal cerebral veins (arrow) and extends anteriorly along the velum interpositum. The mass also extends interiorly, separating the cerebellum from the brain stem, and encroaches on the superior medullary velum (the roof of the fourth ventricle). (From Smirniotopoulos et al., 1992, Fig. 11.)

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pediatric patients with primary intracranial yolk sac tumor, embryonal carcinoma or mixed germ cell tumors containing yolk sac tumor components (Ushio et al., 1999). (b) Pineal parenchymal tumors A pineocytoma (Fig. 19.22) is composed of cells that resemble mature pineocytes (Coca et al., 1992) and are arranged in a glandular pattern. However, it may behave like pineoblastoma, seeding via the CSF. In contrast, a pineoblastoma is histologically identical to a medulloblastoma. It may invade adjacent brain structures spread by the CSF and is considered a primitive neuroectodermal tumor of the pineal region. These tumors have no sexual predilection. Both tumors are malignant and may contain intrinsic calcifications. In addition, pineal parenchymal tumors might have ganglionic and astrocytic differentiation. Neither melatonin nor HIOMT are considered to be useful markers for parenchymal tumors and also HCG and -fetoprotein are usually negative. Tumoral pineal cells differentiate either toward a neurosensory pathway characterized by the presence of sensory elements (vesicle-crowned rodlets or synaptic ribbons and fibrous

elements), or toward a neuroendocrine pathway with the occurrence of many dense-core vesicles (Fetell and Stein, 1986; Smirniotopoulos et al., 1992; Jouvet et al., 1994; Schut et al., 1996). Pineocytomas and a peneoblastoma showed a decrease in the somatostatin receptor subtype sst 2 and a complete loss of sst 5 expression (Champier et al., 2003). (c) Glial neoplasms Glial neoplasms make up about one-third of the pineal tumors. One-third of these tumors are benign; however, astrocytomas may infiltrate the white matter along long tracts. True glioblastomas rapidly become lethal (Fetell and Stein, 1986; Smirniotopoulos et al., 1992). (d) Cysts, tumors of supporting elements and miscellaneous The epiphysis often contains pineal cysts 1994), most of which are of glial origin. they have an ependymal lining and there cavities from the third ventricle (Duvernoy

(Fain et al., Occasionally are vestigial et al., 2000).

Fig. 19.23. Lipoma. (a) Axial CT scan shows a fatty attenuating mass in the pineal region that does not enhance. With its homogeneity and lack of enhancement, the mass is most likely not a teratoma. It occupies most of the quadrigeminal plate cistern. (b) Sagittal T1-weighted MR image shows a mass in the quadrigeminal plate cistern with homogeneous high signal intensity, similar to the signal intensity from the subcutaneous fat and clival marrow. As with many other pineal region masses, it extends inferiorly (below the tentorium) and pushes the cerebellum away from the brain stem. (From Smirniotopoulos, 1992, Fig. 14 with permission.)

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Moreover, malignant rhabdoid tumor (Muller et al, 1995) and malignant melanoma are found. Melanoblasts are present in most parts of the pia and may give rise to tumors (Rubino et al., 1993). In addition, primary myeloblastoma (Voessing et al., 1992), lipoma (Fig. 19.23), meningeomas, spindle cell carcinomas, choroid plexus papilloma, hemangioblastoma, progonoma (a melanocytic neuroectodermal tumor), chemodectomas that presumably arise from sympathetic fibers that innervate the gland, and metastatic neoplasms should be mentioned (Fetell and Stein, 1986; Smiriniotopoulos et al., 1992). (e) Clinical symptoms of pineal region tumors Most patients with pineal region tumors have nonspecific symptoms of increased intracranial pressure, i.e. headaches, nausea, vomiting, visual abnormalities, papilledema and seizures. In addition, short stature, obstructive hydrocephalus causing hypothalamic compression and anterior pituitary deficiency (growth hormone deficiency, hypothyroidism, low cortisol), diabetes insipidus, hypogonadism, high prolactin, and precocious or delayed puberty are found. Precocious puberty due to pineal tumor may be explained by: (i) destruction of the pineal gland by the tumor, interfering with its normal antigonadotropic effect; (ii) destruction of hypothalamic sexual inhibitory centers; and (iii) ectopic secretion of gonadotropins such as -HCG, which acts like LH (Fetell and Stein, 1986; Rivarola et al., 1992, 2001; Smirniotopoulos et al., 1992). There is indeed quite some evidence that hamartomas have cells with the capacity of LHRH pulse generators (see Chapter 19.3). In some cases either a lack of the maximum night melatonin plasma value or higher-thannormal nocturnal melatonin concentrations could indicate a pineal region tumor (Mandera et al., 1999). A patient with histiocytosis that was present as a mass in the pineal gland presented with incomplete ocular palsy (Gizewski and Forsting, 2001). 19.8. Tuberous sclerosis (Bourneville–Pringle syndrome) and tumors of the hypothalamus Tuberous sclerosis is an autosomal dominant hereditary disease, although most cases probably arise sporadically. Its presentation varies, showing lesions in brain and skin, facial angiofibromas, retinal hamartomas, epileptic seizures, mental retardation, autism and attention-deficit

hyperactivity disorder. Among the various epileptic syndromes, West’s syndrome is the most typical (Crino and Henske, 1999; Mizuguchi and Takashima, 2001; Andres, 2003). Embryologically both the brain and the skin are derived from ectoderm; tuberous sclerosis therefore belongs to the neurocutaneous syndromes (Morse, 1998) or phakomatosis with multisystem involvement (Inoue et al., 1998b). Brain lesions in tuberous sclerosis consist of cortical tubers, white matter abnormalities and subependymal nodules that may also occur in the third ventricular wall and that show calcification with increasing age. The cortical tubers and subcortical heterotopic nodules are static, while the uncontrolled growth of subependymal giant cell astrocytomas may lead to hydrocephalus and death (Crino and Henske, 1999; Mizuguchi and Takashima, 2001). The prevalence of tuberous sclerosis is at least 1 in 10,000 (Inoue et al., 1998b; Crino and Henske, 1999). The tumor-like growth may include cells of more than one type, such as glioblasts and neuroblasts. Tuberous sclerosis is caused by mutations in the tumor-suppressor gene TSC1 on chromosome 9q34 or in TSC2 on 16p13.3 (Inoue et al., 1998b; Mizuguchi and Takashima, 2001). TSC1 and TSC2 genes encode distinct proteins, hamartin and tuberin, respectively. TSC2 mutations are more prevalent in sporadic cases (Crino and Henske, 1999). Benign brain tumors are frequently seen in tuberous sclerosis, which may also affect the hypothalamus. Giant cell astrocytomas occur in about 10% of the children with tuberous sclerosis (Gunatilake and Harendra De Silva, 1995). Subependymal giant cell tumors have the tendency to enlarge and occur in 10–15% of tuberous sclerosis patients. Why such tumors occur only in the area of the foramen of Monro is not clear (Inoue et al., 1998b). A few tuberous sclerosis patients have been described with a giant cell astrocytoma filling the third ventricle (Turgut et al., 1996). In his series of 60 autopsy cases with pathological lesions of the hypothalamus, Bauer (1954) described one patient with tuberous sclerosis whose corpora mamillaria were involved, and in whom precocious puberty, convulsions and disturbed water balance were found. Moreover, tuberous sclerosis of the hypothalamus has caused obesity (Bastrup-Madsen and Greisen, 1963) and has been associated in one case with a cavum septum pellucidum (Bruyn, 1977). More recently, a case report was published on a boy who developed precocious puberty at 13 months and who had a hypothalamic hamartoma and periventricular calcified lesions. The manifestations of precocious puberty were based upon

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tuberous sclerosis and were effectively reduced by LHRH (De Cornulier et al., 1993; cf. Chapter 19.3). In addition, a child has been described who suffered from tuberous sclerosis and laughing seizures due to a neoplasm rising from the floor of the left lateral ventricle and extending downwards into the hypothalamus. Ventricular dilatation was noted on the left side as a result of the tumor causing an obstruction of the foramen of Monro (Gunatilake and Harendra De Silva, 1995). It is not known whether children with tuberous sclerosis so often suffer from sleep disturbances because their hypothalamic systems are affected. However, melatonin improves the total sleep time in these patients (O’Callaghan et al., 1999; Hoban, 2000). Only a few cases have been reported of neuroendocrine disturbances on the basis of tuberous sclerosis. Bloomgarden et al. (1981) described hyperprolactinemia, amenorrhea and galactorrhea in a female patient with tuberous sclerosis. The hyperprolactinaemia was unresponsive to protirelin, chlorpromazine, levedopa, bromocriptine mesylate or estrogen. It is not clear whether the hyperprolactinemia was derived from the pituitary or a hamartoma. Tinguy du Pouet et al. (1985) published a case of tuberous sclerosis with diabetes insipidus, hyperprolactinaemia, growth hormone deficiency and delayed puberty, based upon a hypothalamic periventricular hamartoma. Microscopic examination revealed bizarre giant cell clusters to be the main feature of the tubers. These giant cells have both astrocytic and neuronal features, suggesting that they are the product of a dysgenetic event in early development. In the white matter the giant cells align in rows that appear to follow the path of neuronal migration. Probably those cells that migrate to the cortex form the tubers, and those that show incomplete migration give the white matter lesions. Some may not migrate and produce subependymal nodules (Inoue et al., 1998b).

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frequently involving the pituitary stalk and hypothalamus. These tumors may show rapid growth, differentiating the lesion from a benign pituitary adenoma (Chong and Newton, 1993). Also, brain tumors may give rise to hypothalamic metastases. For instance, Bauer (1954) reported metastases to the third ventricle, infundibulum and corpora mamillaria of a frontal lobe tumor. Metastasis of the hypothalamic-pituitary region may also be an atypical postmortem finding in systemic cancer. In symptomatic cases, diabetes insipidus due to a tumor in the infundibulum or neurohypophysis is the usual clinical manifestation, especially seen in the terminal stages (Kimmel and O’Neill, 1983; Schubiger and Haller, 1992; Ten Bokkel Huinink et al., 2000). Serious loss of neurons and gliosis may occur in the supraoptic and paraventricular nucleus when the stalk and neurohypophysis are destroyed by metastases (Duchen, 1966). In addition, circadian rhythm disturbances have been described in case of localization of a metastasis of an adenocarcinoma of the rectum in the suprachiasmatic region (Fig. 4.2). Diabetes insipidus is a rare complication of acute myeloid leukemia and acute lymphoblastleukemia. In most cases a local leukemic infiltrate was found, most often of the posterior lobe, but also in the hypothalamus (Fig. 19.24). In some patients, however, overt leukemic infiltrates were missing and scant thrombosis of small vessels in the hypothalamus and posterior lobe of the pituitary were seen. Moreover, some patients have been described with diabetes insipidus established in the preleukemic phase of acute myeloid leukemia. In one of the patients, diabetes insipidus was a result of a hypothalamic lesion as judged from endocrine studies (Puolakka et al., 1984). When one considers that the posterior lobe, and not the anterior lobe, of the pituitary is directly supplied by arterial blood from the systemic circulation, the predilection for metastasis in this structure is understandable. The anterior lobe is supplied by the portal system. When this system is obstructed by a tumor, it is almost invariably by direct extension of the tumor from the posterior lobe (Duchen, 1966), and microinfarcts of the pituitary are the result (Kimmel and O’Neill, 1983). Other clinical manifestations of metastases in this region are anterior pituitary failure, and visual disturbances due to chiasmatic and optic nerve involvement (Kimmel and O’Neill, 1983). In fact, patients with tumors who develop diabetes insipidus or hypopituitarism most probably harbor pituitary metastases and not an adenoma (Schubiger and Haller, 1992). Once a case with metastatic

19.9. Metastases Brain metastases are common and often occur in patients whose systemic cancer is quiescent. The most common sources of metastatic tumors in the pituitary-hypothalamic region are carcinomas of the lungs or breasts, and leukemia/lymphoma (Schubiger and Haller, 1992; Chong and Newton, 1993). Metastatic carcinoma originating from the gastrointestinal tract have also been described. In cases of metastases, MR images may show an enhancing lesion in the pituitary gland, 85

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Fig. 19.24. Female, 79 years of age, with chronic myeloide leukemia (NHB 88-093). Leukemic infiltration is present in the hypothalamus, just above the supraoptic nucleus (SON). Bar represents 100 m.

spread of a small oat-cell carcinoma of the lung was reported, involving both the posterior pituitary and the pineal (Suganuma et al., 1994). It was proposed by way of explanation that in both structures the blood–brain barrier is absent. In addition, violent hunger and obesity have been reported as clinical evidence of hypothalamic involvement in children with acute leukemia. Massive diffuse leukemic infiltration was present in such cases at the level of the ventromedial nuclei of the hypothalamus (Heaney et al., 1954; Bastrup-Madsen and Greisen, 1963). 19.10. Other tumors In the chiasmal and sellar region, approximately 10% of the neoplasms are meningiomas. They may originate from the superior leaf of the diaphragma sellae anterior or posterior of the pituitary stalk or from the inferior leaf of the diaphragma sellae (Beems et al., 1999).

Meningiomas of the inferior leaf of the sellar diaphragm may produce primarily bitemporal hemianopsia and hypopituitarism. Sometimes they grow around cranial nerves. Sellar region meningiomas may produce hyperprolactinemia by mechanical effects on the pituitary stalk, and may thus mimic prolactinomas. Meningiomas may also cause diabetes insipidus or hypogonadism (Sheehan and Kovacs, 1982; Horvath et al., 1997). Meningiomas without dural attachment are rare (Beems et al., 1999), but meningioma in contact with the pituitary stalk have been described. As the pituitary stalk has no dura mater, the tumor may have originated from the arachnoid membrane of the pituitary stalk. The histological diagnosis was meningotheliomatous meningioma in one case and meningioma in another (Hayashi et al., 1997). Moreover, cases of meningioma of the third ventricle have been described. Posterior third ventricular meningiomas usually originate from the falx–tentorial junction

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or the connective tissue stroma of the pituitary gland. Meningiomas in the anterior part of the third ventricle usually result from the mesenchymal cell populations belonging to the velum interpositum, the tela choroida and the plexus choroidus. The patients have signs and symptoms of increased intracranial pressures, diabetes insipidus, motor disturbances, cranial nerve dysfunction and, sometimes, short-term memory deficit (Pau et al., 1996). Several data indicate that sex hormones may be involved in the pathogenesis of meningiomas. The majority of these tumors start to grow during the period of maximum gonadal activity. These are the only common intracranial tumors with a significantly higher incidence in women, the female-to-male ratio being 2.5:1. In some cases of meningiomas a relapsing course in relation to pregnancy was found. In most cases these tumors were located near the optic or oculomotor nerves. In addition, there is an association between meningiomas and breast cancer. Moreover, meningiomas have steroid hormonebinding sites for estrogens, progesterone, glucocorticoids, mineralocorticoids and androgens (Poisson, 1984). Juxtasellar or suprasellar subarachnoid cysts or arachnoidocele are benign. The subarachnoid space is formed by an expansion of the intercellular space when the cellular components of the meninx primitiva are removed. The increase in the intercellular and primitive subarachnoid space are first observed at about 14 weeks of gestation. Any abnormal event during this process may result in the formation of an arachnoid cyst (Nishio et al., 2001). The cysts may be asymptomatic and patients may present with headache, optic-nerve compression, disorders of growth, puberty, amenorrhea, obesity, disturbed hypothalamopituitary function or hydrocephalus (Adan et al., 2000; Todd et al., 2000). Rivarola et al. (2001) and Starzyj et al. (2003) reported precocious puberty in four children with a subarachnoid cyst. Arachnoid cysts may also be found in autism (Tantam et al., 1990). Fifteen percent of all arachnoid cysts are parasellarly located. They can be congenital in origin, develop from adhesions in the subarachnoid space or be associated with another abnormality, such as a hamartoma. As they continue to expand slowly, they may push against adjacent brain structures, cause hydrocephalus and even remodel the adjacent skull. The differential diagnosis includes an epidymal cyst, a parasitic cyst or a Rathke’s cleft cyst (Chong and Newton, 1993; Nishio et al., 2001). The minimally invasive treatment using stereotactic intracavitary irradiation of arachnoid cysts using chromic colloidal phosphorus-32 proved to be safe and

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Fig. 19.25. Coronal section of brain at midthalamus level with a chordoid tumor obliterating the cavity of the third ventricle (arrow). Note attachments of the mass to the roof of the ventricle and right thalamus, and its downward extension to involve the hypothalamus. (From Vajtai et al., 1999, Fig. 1 with permission.)

effective (Todd et al., 2000). Others have inserted a cyst–peritoneal shunt (Nishio et al., 2001; Starzyj et al., 2003). Hypothalamic chordoma were reported in a few patients. Chordoma are malignant neoplasms thought to derive from fetal notochordal rests. Chordomas and chondromas are usually situated in the basis sphenoid behind the posterior clinoid plate (Commins et al., 1994). Third ventricle chordoid glioma arise from the hypothalamic (suprasellar) third ventricle region (Fig. 19.25). The histology is reminiscent of chordoma or choroid meningeoma. The tumor is composed of cords and clusters of epithelioid cells in a mucoid matrix and a low-grade infiltrate of mature lymphocytes and plasma cells. Russell bodies are present in the latter. Adjacent brain tissue shows gliosis and numerous Rosenthal fibers. The low-grade tumor arises preferentially in middle-aged women. The symptoms may include forgetfulness, headache, lethargy, homonymous hemianopsia, hypothalamic dysfunction and obstructing hydrocephalus. Immunocytochemically, markers such as GFAP and vimentin indicate that they are glia by nature. In imaging studies, the tumor appears as a large, well-circumscribed third ventricular mass, sometimes with a cystic component. The way the epithelioid cells are arranged in clusters suggests a choroid plexus, or a meningothelial or notochordal derivation, but it may also be derived from the subependymal tissue. The current treatment of choice is 87

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surgical resection (Brat et al., 1998; Vajtai et al., 1999; Pomper et al., 2001; Kurian et al., 2002). Sometimes a chordoma can mimic a pituitary adenoma and cause bitemporal hemianopsia due to chiasmal compression and hypopituitarism (Thodou et al., 2000). Occasionally lipomas of 1–3 cm in diameter are found. They might form a polyp hanging by a pedicle from the undersurface of the tuber into the cisterna, or on the ventral side of the mamillary bodies. Lipoma are usually symptomless, located in the midline and found by accident. Macroscopically a lipoma might resemble a hamartoma. Other lipoma might grow as a large mass into the hypothalamus, replacing the entire tuberal region and mamillary bodies. Histologically it is basically a lipoma, but usually there are a few plaques of bone embedded in the fat. Although the tumors are only reported in adults, they are presumably congenital (Sheehan and Kovacs, 1982; Kurt et al., 2002).

Malignant lymphoma is a condition of middle age and affects both sexes equally. This is a type of tumor that occurs more frequently in other parts of the brain than in the hypothalamus and used to be called reticular cell sarcoma. This tumor forms a pinkish solid mass in the infundibulum and neighboring hypothalamus and sometimes extends down the stalk to replace the posterior pituitary. Histologically it is diffuse and nonfollicular in 60–90% of the patients and consists of round or polygonal cells with lobulated nuclei. In 98% of these tumors the cells are derived from B lymphocytes. Clinically the tumor is usually characterized by diabetes insipidus and hypogonadism, sometimes also by obesity, somnolence or psychiatric symptoms (Sheehan and Kovacs, 1982). A case of primary hypothalamic lymphoma was found to mimic neurosarcoidosis by pleocytosis, increased spinal fluid protein, diabetes insipidus, anterior lobe dysfunction, hepatic granuloma,

Fig. 19.26. A 24-year-old woman with a large adenoma of the pituitary (A) Mid-sagittal section. The optic chiasm (arrow) and anterior commissure (AC) are located on and above the adenoma, respectively. Anterior communicating artery complex (ACAC) is located closely in front of optic chiasm and on the adenoma. (B) Coronal section. Optic chiasm (arrow) is flattened and displaced superiorly. (C) Axial section. Optic nerves (arrows) are visible. (D) Axial section 3.5 mm above C. Optic tracts (arrow) and mamillary bodies (MB) are visible. (From Eda et al., 2002 Fig. 3.)

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to radiation therapy (Hasegawa et al., 1995). An endodermal cyst of the third ventricle has histological similarities to the gastrointestinal epithelium and is considered to be derived from the embryonic endodermal layer, i.e. from the most cranial portion of the primitive intestine (Büttner et al., 1997). A central neurocytoma confined to the third ventricle presented clinically as subarachnoid hemorrhage. It was a well-differentiated neoplasm of neuronal origin, with a cystic component and intratumoral hemorrhage. Synaptophysin, neuronspecific enolase, ultrastructurally identified synapses, neurosecretory granules or neuritic processes demonstrated the neuronal lineage of these tumor cells. Neurocytomas of the lateral ventricle may also spread into the third ventricle. A gangliocytoma of the neurohypophysis is a very rare tumor (Chapters 19.3c, 22.1, 22.6). It may produce vasopressin and lead to inappropriate antidiuretic hormone secretion (Fehn et al., 1998; Chapter 22.6). One patient with Cushing’s syndrome appeared to have a gangliocytoma of the neurohypophysis containing ACTH-producing cells. The neurons themselves did not express ACTH or CRH (Geddes et al., 2000). In addition, ganglioglioma of the optic chiasm were found most frequently as mixed glioneuronal tumors and more commonly in children (Shuangshoti et al., 2000). Gliomatosis cerebri is described in Chapter 19.4c.

hypercalcemia, elevated angiotensin-converting enzyme (a carboxy-peptidase that hydrolyzes angiotensin I to angiotensin II; produced, e.g. by epitheloid cells of the sarcoid granuloma). The lack of response to prednisone was, however, atypical for sarcoidosis, and emergency transplenoidal resection disclosed a large B-cell lymphoma, a disease that is usually also steroid-responsive (Bayrakdar et al., 1997). A Large adenoma of the pituitary may push upwards and produce pressure on the front of the chiasm, or between the optic nerves (Fig. 19.26). The first symptom is usually bitemporal hemianoptia, and there is optic atrophy. Less often the tumor may impinge on the back of the chiasma. Pressure on the hypothalamus may lead to fatigue and sleepiness, excessive eating or anorexia, hypothermia, diabetes insipidus, hydrocephalus and hypopituitarism. The patient may also ‘feel cold’ due to hypothyroidism, perform less well and have headaches (Sheehan and Kovacs, 1982; Harris et al., 2002). Gait disturbances and behavioral changes in a 51-yearold woman appeared to be due to a small, blackberry-like subependymal tumor, i.e. a cavernoma behind the interthalamic adhesion in the third ventricle. A huge, mixed cavernous angioma and astrocytoma in the hypothalamus manifested by headache, visual field defect, gait disturbance and convulsions, responded remarkably well

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CHAPTER 20

Hypothalamic infections

20.1. Inflammatory conditions affecting the hypothalamus

region. The granulomatous lesion was composed of small cavities filled with necrotic material. The abscess cavity was encircled by layers of collagen and florid granulomatous tissue with giant cells (Fig. 20.1). There was no evidence of systemic tuberculosis (Indira et al., 1996). In the case of a hypophysial tuberculoma, a thickened pituitary stalk in contrast MRI scans may be useful for the differentiation from pituitary adenomas (Sinha et al., 2000; Páramo et al., 2002). However, in some developing countries, but also in the USA, patients have been described with a hypothalamic tuberculoma, causing the signs and symptoms of panhypopituitarism (Flannery et al., 1993). Intracranial calcifications develop in approximately one-third of the children who recovered from tuberculous meningitis. The calcified lesions may destroy hypothalamic or pituitary tissue and result, e.g. in somatotropic or gonadotropic deficiencies or diabetes insipidus (Asherson et al., 1965; Haslam et al., 1969). Patients with tubercular meningitis may die suddenly, probably due to hypothalamic apoplexia. Hypothalamic damage secondary to infarction has been reported repeatedly. Other patients may develop panhypopituitarism due to chronic scarring and calcification of the hypothalamus (Indira et al., 1996). In cholera cases, the hypothalamus showed a decrease in Gomori-stained neurosecretory material. The paraventricular nucleus (PVN) was sometimes vacuolated (Choudhury, 1969).

(a) Bacterial infections One hundred years ago, tuberculosis was one of the diagnoses most frequently made in the Western countries. In 1893, Starr reported that 50% of all brain “tumors” were due to tuberculosis, and, in the early years of the last century, Cushing said that about 30% of all space-occupying lesions within the cranium were attributable to tuberculosis (Scully et al., 1983). Tuberculous meningitis may cause, e.g. epilepsy, hemiplegia, paraplegia, optic atrophy and blindness, deafness, mental retardation, hydrocephalus and hypothalamopituitary disorders such as diabetes insipidus, obesity, hypogonadism, and, when the periventricular portion of the hypothalamus is involved, precocious sexual development (Bauer, 1954; Lorber, 1958; Asherson et al., 1965). In areas where tuberculosis is endemic, hypothalamic tuberculoma can still form an important radiologically differential diagnosis to be distinguished, e.g. from astrocytoma, craniopharyngioma, hamartoma and germinoma. A case report on a 10-year-old boy may serve as an example. For 6 months this boy had had hypothalamic symptoms, i.e. progressive loss of vision, headaches and vomiting, and it was noticed that he gained weight and ate and slept excessively for 4 months. There was compression of the third ventricle with hydrocephalus. He underwent placement of a ventriculoperitoneal shunt prior to exploration. A biopsy of the suprasellar mass revealed tuberculoma. Postoperatively the patient developed polyuria and hypothermia. The patient died on the 7th postoperative day. At autopsy the suprasellar mass was found to be occupying the entire hypothalamic

(b) Acute viral meningoencephalitis Hypothalamopituitary symptoms such as hypopituitarism, including hypogonadism, hyperprolactinemia and the syndrome of inappropriate secretion of vasopressin may be caused by acute viral meningoencephalitis (Bauer, 91

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Fig. 20.1. Tuberculosis of the hypothalamus (A). A histological preparation shows an abscess cavity field with caseous material bordered by poorly formed granulomas with giant-cell reaction and fibrosis. (B) Higher magnification of the abscess wall shows epitheloid cells and Langerhans’-type giant cells. (From Indira et al., 1996, Fig. 3 with permission.)

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1954; Kupari et al., 1980; Lichtenstein et al., 1982; Ishikawa et al., 2001b). According to Bauer (1954), the periventricular portion of the hypothalamus can be involved in various types of encephalitis and encephalomeningitis, including tuberculosis, which may result in precocious puberty and diabetes insipidus. Acute virus encephalitis frequently goes together with lesions in the hypothalamus. A 12-year-old girl was diagnosed as having acute disseminated encephalomyelitis. She manifested hypersomnia and intense lesions in the hypothalamus. The low hypocretin levels in the cerebrospinal fluid (CSF) of this patient explained the hypersomnia (Kubota and Kabayashi, 2002; Chapter 28.4). Hypothalamic lesions have been reported, e.g. following varicella-zoster, smallpox, measles, coxsackie virus B, poliovirus and inoculation for rabies in patients who died during the acute stage of encephalitis (Ishikawa et al., 2001b). A recent study using MRI confirmed the presence of hypothalamopituitary abnormalities and dysfunctions in rabies (Ishikawa et al., 2001b). Indeed, rabies is virtually always fatal, once symptoms are evident (Pleasure and Fischbein, 2000). Sexual manifestations of rabies, such as priapism, penile hyperexcitability with erection, ejaculation on the slightest touch of the penis, and excessive libido have been reported (Dutta et al., 1996). It has been proposed that rabies may have played a key role in the belief in vampires in the 18th century. Vampires allegedly were dead people who left their graves and killed people and animals (Gómez-Alonso, 1998). Rabies is a zoonosis transmitted by a bite, scratch or inhalation of the virus. Bat-borne rabies can be spread without traumatic exposure. Once inoculated, the virus spreads centripetally via peripheral axons to the central nervous system (CNS), where it is capable of transsynaptic spread. The intimate relationship between the hypothalamus and the autonomous system (Buijs and Kalsbeek, 2002) may thus be the explanation for the frequent involvement of the hypothalamus. The untreated patient with ‘furious (i.e. encephalitic) rabies’ following dog bite frequently manifests a tendency to wander, to be restless, to show signs of autonomic dysfunction, a hypersensitivity to stimuli, a feeling of terror, persistent insomnia, an increasing agitation, hydrophobia and muscular spasms. Paralytic symptoms (‘dumb’ form) and coma may appear before the patient dies. Rabies shows similarities to vampirism. The muscle spasms may cause hoarse sounds, saliva cannot be swallowed and vomiting of bloody fluid occurs. Bat rabies is reported to give a high incidence of focal

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brainstem signs and myoclonus, sometimes hemiparesis or hemisensory deficits, ataxia, chorea or Horner syndrome. The rabid patient may rush at those who approach him, biting and tearing at them as if he were a wild animal. Hypersexuality and violent rape attempts may be striking manifestations of furious rabies. In some men penile erection can last for several days. The literature reports cases of rabid patients who had intercourse up to 30 times a day (Gómez-Alonso, 1998; Pleasure and Fischbein, 2000). Hypothalamopituitary insufficiency has been observed following influenza A and herpes simplex encephalitis (Kupari et al., 1980; Ishakawa et al., 2001). Following herpes simplex encephalitis, MR images showed involvement of the substantia innominata and of the corpora mamillaria in patients who were left with memory difficulties (Kapur et al., 1994). Hypothalamic encephalitis has also caused a marked sinus bradycardia so severe (with a heart rate of less than 30 beats per minute), that a temporary pacemaker had to be implanted (Ishikawa et al., 2001b). (c) Post- and parainfectious encephalomyelitis Hypothalamic lesions are a much less frequent occurrence in the post- and parainfectious encephalomyelitis than in the acute stages of encephalitis. A combination of hyperthermia, hyperphagia and secondary hypothyroidism has been described in a boy after 1 year of high fever due to a varicella infection. Diurnal fluctuations in temperature and water excretion were abnormal, but diurnal fluctuations in serum corticosteroid levels were present. Temperature regulation did not respond to the ordinary regulatory stimuli. At autopsy, focal areas of gliosis and lymphocytic infiltration were only found in the hypothalamus, particularly in the region of the supraoptic nucleus (SON) and tuber cinereum (Lipsett et al., 1962). A case of hypothalamic encephalitis with influenza A/Netherlands/110/72, which was preceded by infectious mononucleosis, showed a severe chronic inflammatory reaction. There were round-cell accumulations in the perivascular spaces, astroglial proliferation, foci of histiocytes, macrophages and edema; nerve cells were affected (Ongerboer de Visser et al., 1976). In bulbar poliomyelitis, diffuse inflammatory hypothalamic changes have been observed in 85% of the cases. The SON is most severely affected, whereas the tuberal and mamillary nuclei are usually spared (Baker et al., 1952). In cases of bulbar poliomyelitis where a prolonged hyperthermia is manifest, 93

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cell damage is the most severe in the rostral portion of the hypothalamus. Because the PVN involvement alone is reported to be exclusively associated with temperature elevations, the PVN has been proposed to be an essential structure as far as lowering body temperature is concerned. In cases of hypothermia, lateral and medial hypothalamic nuclei are involved (Brown et al., 1953). A 3-year-old boy developed obesity and had a fever for half a year. He died of an allergic reaction to penicillin. Autopsy revealed a severe bilateral drop of neurons in the ventromedial hypothalamic nuclei, with diffuse hyperplasia of astrocytes (Wang and Huang, 1991; for ventromedial hypothalamus syndrome, see Chapter 26.3). (d) Fungal infections Persistent fever of unknown origin may be due to a fungal infection such as Candida albicans, aspergillus or mucor species, or other fungi acting on the hypothalamus (Barwick et al., 1994). Patients immunocompromised by acquired immunodeficiency syndrome (AIDS), by immunosuppressive drugs or treated by prolonged antibiotic therapy for gram-negative organisms are also susceptible to central mycotic abscesses (see Chapter 20.3). Associated infections include, e.g. cryptococcosis. Candida albicans causes meningitis, hydrocephalus, cortical microscopic abscesses, cerebritis, granulomas and vasculitis. (e) Other hypothalamic infections The hypothalamus is rather infrequently involved in bacterial infections such as ß-hemolytic streptococcus, pneumococcus and in the neonate Listeria monocytogenes. Posterior lobe microabscesses are a common preterminal incidental finding at autopsy (Horvath et al., 1997). Hypothalamic pituitary deficiency has been described in a case of Weil’s disease, which is due to leptospirosis. Panhypopituitarism was found, but hypothalamic participation could not be demonstrated (Panidis et al., 1994). Neurocysticercosis is a CNS infection caused by Taenia larvae. In patients with such inflammatory lesions in the anterior hypothalamus, obesity and hyperphagia were observed (Lino et al., 2000). Lyme’s disease is a multisystem disorder caused by infection with the Borrelia burgdorferi spirochete. Neuro-ophthalmic and ocular manifestations of Lyme’s disease, including papilledema,

increased intracranial pressure and optic atrophy, have frequently been reported (Balcer et al., 1997). Post-Lyme syndrome is characterized by severe fatigue, malaise and cognitive complaints. The latter component is more pronounced in Lyme’s disease than in chronic fatigue syndrome (Chapter 26.8a). Whipple’s disease is a rare disease characterized by a widespread, chronic granulomatous infiltration of the gastrointestinal, cardiac, pulmonary and nervous systems. There is a 6:1 male predominance. It is caused by the rod-shaped baccillus Tropheryma whippelii, with a delayed hypersensitivity as the underlying mechanism. CNS involvement occurs in 10–20% of cases. Lesions consist of a gliovascular inflammatory reaction with a predilection for hypothalamus, cingulate gyrus, basal ganglia, insular cortex and cerebellum. Large numbers of swollen, gemistocytic astrocytes and smaller collections of the classic foamy macrophages are found. Perivascular cuffs of mononuclear cells and lymphocytes are frequently encountered also. Stuffed microglia frequently surround nerve cells, a process accompanied by a definite loss of neurons. CNS involvement may remain clinically silent. Hypothalamopituitary involvement may include symptoms of insomnia or hypersomnia, weight gain and polydipsia, in combination with ophthalmoplegia. Transient, almost complete sleep loss caused by cerebral manifestation of this disease has been described. Endocrine tests revealed flattening of circadian rhythmicity of cortisol, TSH, growth hormone and melatonin, indicating that the suprachiasmatic nucleus was affected. Whipple’s disease can be treated with antibiotics that effectively cross the blood–brain barrier, such as penicillin, TMP-SMZ or chloramphenicol (Mendel et al., 1999; Voderholzer et al., 2002). 20.2. Encephalitis lethargica (Von Economo’s encephalitis) Encephalitis lethargica was first described by Constantin von Economo in Vienna in 1917. Among the wounded soldiers of World War I, he noted patients with peculiar symptoms, including a remarkable sleepiness for which the syndrome was named. The cause of the epidemic, which affected 5 million victims, was never determined. The histopathology of the acute cases included inflammated cells, congested blood vessels, hemorrhages, cellular necrosis, chromatolysis, neuronophagia and gliosis. The mesencephalic and basal ganglia were the most

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frequent sites of the lesions, but the hypothalamus, too, appeared to be one of the predilection sites, which might relate to some of the neuropsychiatric symptoms, e.g. sleep and circadian disturbances (see Chapter 4), disturbances of sexual behavior (Chapter 24.5), mood (Chapter 26.4), obsessive and compulsive behavior (Chapter 26.6) and aggression (Chapter 26.9). The ‘lethargy’ resembled abnormally profound sleep. Often the patient could be roused, would answer a question intelligently and then relapse into a stupor. Insomnia and marked disturbances of the diurnal pattern were also reported. Von Economo broadly divided encephalitis lethargica into the ‘somnolence-ophthaloplegia type’ with lesions in the posterior wall of the third ventricle near the oculomotor nucleus and the ‘choreatic-insomniac type’, due to an anterior lesion in the lateral wall of the third ventricle near the corpus striatum. In postencephalitis parkinsonism, oculogyric crises were found. They were linked to obsessive and compulsive behavior. Some patients had compulsive sexual or violent thoughts along with oculogyric deviation. Mood disorders were striking, including recurrent mania, episodic depression and bipolar mood disorders (Cheyette and Cummings, 1995). Among the neurological disorders that developed months to years after the acute infection, a 10% incidence of morbid obesity was found. Whether these patients indeed had lesions in the mediobasal hypothalamus was not established (Nagashima et al., 1992). Children tended to manifest somewhat different symptoms in cases of encephalitis lethargica than adults. They were more likely to display an inversion of the sleep rhythm: they often had insomnia at night and slept during the day. Many children displayed behavioral disturbances, including sexual precocity, exhibitionist tendencies and sexual aggression. Although a number of the behavioral symptoms indicate hypothalamic involvement, no relationship has developed between particular hypothalamic lesions and behavioral disturbances in encephalitis lethargica (Cheyette and Cummings, 1995). More recently two patients were described with acute encephalitis, the features of which – including parkinsonism, fever, lethargy, fluctuations of consciousness, pupillary abnormalities, oculogyric crises, delusions, loss of temperature regulation, profuse sweating, disturbances of the sleep cycle and severe dyskineas – suggested encephalitis lethargica. Both patients responded rapidly and dramatically to intravenous methylprednisolone, although some hypothalamic symptoms remained in one patient. The cause is not known (Blunt et al., 1997).

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20.3. Acquired immunodeficiency syndrome (AIDS) Hypothalamic disturbances, such as endocrine or autonomic dysfunction, hyper- or hypothermia and vegetative symptoms, have frequently been reported in patients with AIDS. These include adrenal insufficiency, hyperprolactinemia, central diabetes insipidus and changes in the hypothalamopituitary gonadal axis (Croxson et al., 1989; Dluhy, 1990; Merenich et al., 1990; Sullivan et al., 1992; Moses et al., 2003) as well as weight loss, fever, and fatigue (Hellerstein et al., 1990). Frank hypopituitarism due to destruction or infiltration of the hypothalamic region is rare in patients with AIDS: only a few cases of hypopituitarism have been described in AIDS patients. More subtle defects, due to the human immunodeficiency virus (HIV), or other HIV-mediated factors of hypothalamopituitary function, occur frequently, although in a routine H&E staining generally no obvious signs of local inflammation are observed in the region of the PVN. In some patients periventricular cuffs are present in the hypothalamus (Fig. 20.2). In addition, no obvious difference was seen for leukocyte-common antigen (LCA) or GFAP staining between hypothalamic sections of groups of controls and AIDS patients (Purba et al., 1993). When AIDS causes endocrine problems, the focus in literature is generally on the endocrine end-organs, i.e. the thyroid, adrenal glands, gonads and kidneys, and not on the possible causes on the level of the pituitary, and certainly not on the level of the hypothalamus (Merenich, 1994). However, cytokines such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor (TNF), which are produced by immune cells, may affect hypothalamic corticotropinreleasing hormone (CRH) neurons (Freda and Bilezikian, 1999). Cytomegalovirus (CMV) involvement has sometimes been found in the adenohypophysis, neurohypophysis and hypothalamus (Sullivan et al., 1992; Purba et al., 1993; Merenich, 1994). In the neurohypophysis, Cryptococcus sp., Aspergillus sp., Toxoplasma sp. and Pneumocystes carinii were observed in AIDS patients (Figs. 20.3). In addition to endocrine and autonomic dysfunctions, also visual loss may occur in AIDS. An AIDS patient has been described with a chiasmatic mass due to a primary central nervous system lymphoma (Lee et al., 2001). Vasopressin Central diabetes insipidus has been found in a patient with AIDS due to cytomegalovirus infection of the 95

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Fig. 20.2. Perivascular cuff in the hypothalamus in a case of AIDS ( 42 years). Bar = 200m.

hypothalamus. The patient did not have polyuria because of the accompanying glucocorticoid deficiency. In addition, low testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were found (Moses et al., 2003). Central diabetes insipidus has also been reported in a few AIDS patients in whom anterior pituitary function was preserved. Desmopressin resulted in complete resolution of this symptom (Merenich, 1994). The number of vasopressin-expressing neurons in the PVN in a group of AIDS patients was, however, not significantly lower than in controls (Purba et al., 1993), indicating that, due to destruction of the SON and PVN, hypothalamic diabetes insipidus must be a rare phenomenon. In addition, several AIDS patients with the syndrome of inappropriate antidiuretic hormone secretion have been reported (Merenich, 1994). Hyponatremia occurs in 30–50% of AIDS patients (Sellmeyer and Grunfeld, 1996).

Oxytocin We observed a 40% drop in the number of oxytocinexpressing neurons in the PVN in AIDS patients (Purba et al., 1994). However, no decrease in oxytocin-messenger RNA (mRNA) of the PVN was measured by quantitative in situ hybridization in AIDS patients (Guldenaar and Swaab, 1995), suggesting differences in oxytocin precursor processing in AIDS. If this is indeed the case, it may be of importance for those autonomic functions that are regulated by oxytocin fibers projecting from the PVN to the brainstem (Chapter 30). Oxytocin receptors are present in AIDS-related Kaposi’s sarcoma, an intensely angioproliferative disease, possibly of vascular origin. Oxytocin treatment of Kaposi cells led to a significant increase in cell proliferation and could therefore be considered a possible relevant growth factor involved in Kaposi’s sarcoma progression (Cassoni et al., 2002).

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Fig. 20.3. Toxoplasmosis infection in the hypothalamus in a case of AIDS. Bar = 200 m.

hyperactivity (see above) to subclinical disturbances to frank adrenal insufficiency (Freda and Bilezikian, 1999). Data concerning ACTH secretion are conflicting, which may at least be partly due to the stage of infection (Lortholary et al., 1996). In a group of HIV-positive homosexual men in relatively good health, no difference in cortisol levels was found (Kertzner et al., 1993). This negative finding was presumed to be due to the relatively early stage of the disease (Rotterdam and Dembitzer, 1993), but an attenuated ACTH and cortisol response to a cold stressor challenge was observed in asymptomatic HIV-1 positive persons (Kumar et al., 2002). The HPA axis can show abnormalities in different directions. On the one hand, the adrenal gland is known to be a common site of opportunistic infections (Rotterdam and Dembitzer, 1993). On the other hand, there are studies that report that cortisol is elevated at all stages of infection and particularly in AIDS patients (Christeff et al., 1997).

Hypothalamopituitary–adrenal (HPA) axis Increased serum cortisol levels are the most common finding as AIDS progresses (Grinspoon et al., 1994; Merenich, 1994; Savastano et al., 1994; Lortholary et al., 1996; Sellmeyer and Grunfeld, 1996, Christeff et al., 1997; Freda and Bilezikian, 1999). There has even been a report of a case of Cushing’s syndrome associated with AIDS (Savastano et al., 1994). It has been proposed that the HIV virus may stimulate CRH or corticotropin (ACTH) either directly or indirectly via stimulation of cytokines. In addition, HIV is a major life stressor. HIV viral load is also immediately high in the hippocampus, which inhibits CRH. Moreover, the POMC promotor is 100% homologous to a region of the HIV-1 genome, and HIV viral protein R can interact with corticosteroid receptors. Which of these putative mechanisms is of clinical importance has to be investigated (Kumar et al., 2002). Abnormalities of the HPA axis in AIDS may range from 97

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Adrenal insufficiency also results in low cortisol levels, and a blunted cortisol response to ACTH stimulation has been observed in AIDS patients, accounting, at least partly, for weight loss, general weakness, anorexia (Savastano et al., 1994), and hypotension or hyponatremia, which are all Addison symptoms, in spite of elevated cortisol levels. In fact, 12% of the AIDS patients are glucocorticoid-resistant (Grinspoon et al., 1994; Merenich, 1994; Norbiato et al., 1997). Although histological modification of the adrenal glands has often been described during the late stages of HIV infection, reports of adrenal insufficiency are rare (Lortholary et al., 1996). Suppressed circadian secretion of ACTH in association with increased basal cortisol levels has also been observed in a small number of patients with AIDS. On the other hand, normal and elevated ACTH and cortisol levels have been found in others with preserved adrenal function. Moreover, the development of cortisol resistance has been presumed (Grinspoon et al., 1994; Merenich, 1994). So far, however, there are no direct observations available on activity changes of the CRH neurons in the PVN of AIDS patients. In contrast to cortisol, the serum dehydroepiandrosterone (DHEA) levels generally decreased in each later stage of HIV infection. The increased cortisol levels and the decreased levels of DHEA, an antiglucocorticoid compound, may, at least partly, provoke a drop in CD4+ cells and a shift from type 1 to type 2 cytokine production (Christeff et al., 1997; Clerici et al., 1997). A fall in DHEA levels predicts progression to AIDS, independent of CD4 cell counts (Sellmeyer and Grunfeld, 1996). Antiglucocorticoid drugs may be helpful in HIV disease, as they antagonize the immunosuppression induced by increased levels of cortisol (Norbiato et al., 1997). Whether DHEA administration may influence the disease process favorably has not been studied. Circulating levels of alpha-melanotropin (MSH are elevated in HIV-infected patients (Catania et al., 2000). Hypothalamopituitary–thyroid axis Thyroid function is normal in most patients with HIV infection (Grinspoon et al., 1994). Opportunistic infections of the thyroid have been found, but most of the patients did not present with thyroid dysfunction (Sellmeyer and Greenfeld, 1996). Hypothyroidism has been seen in AIDS patients but is considered to be due to altered peripheral metabolism of thyroid hormone and not to changes on the level of the pituitary or hypothalamus. In the terminal phases of AIDS, thyroid hormone axis changes are similar to those observed in other serious

conditions, i.e. those of the euthyroid sick syndrome (Merenich et al., 1990; Merenich, 1994; Sellmeyer and Grunfeld, 1996; Fliers et al., 1997; Chapter 8.6). Hypothalamopituitary–gonadal axis In the early stages of AIDS, total and free testosterone are elevated and the LH response to LHRH is exaggerated (Merenich et al., 1990). This may be explained by a direct stimulatory effect of the HIV virus on the pituitary or hypothalamic level. However, as AIDS progresses, one-third of the men develop hypogonadism, with lower testosterone levels and higher LH and FSH levels. These changes may affect cognition, mood, libido and energy levels (Croxson et al., 1989; Ng et al., 1994). Testicular atrophy is a common finding in AIDS (Rogers and Klatt, 1988). Some of the medications used may also affect gonadal function (Sellmeyer and Grunfeld, 1996). Prolactin levels are normal or mildly elevated (Croxson et al., 1989; Merenich et al., 1990). The gonadal axis has not been studied adequately in women with AIDS, but menstrual irregularities, decreased libido and hair loss have been reported (Merenich, 1994). Growth hormone Two cases of growth hormone deficiency in AIDS have been reported that were coupled to sex steroid deficiency. One of the cases was associated with gonadotropic failure. The patients had evidence of dysfunction at the hypothalamic, pituitary and end-organ level (Ng et al., 1994). In HIV-infected men who did not show signs of wasting, normal growth-hormone secretion, insulin-like growth factor-1 (IGF-I) and IGF-binding protein-3 concentrations were found (Heijligenberg et al., 1996). Circadian changes When HIV-infected males are compared with controls, significantly higher levels are found for cortisol, and lower ones for DHEA, DHEA-S and ACTH. Plasma testosterone levels decreased in a later stage of HIV infection (Villette et al., 1990). Analysis of the circadian rhythm of plasma hormone levels clearly indicated an altered adrenal hormonal state in HIV-infected male patients, even during the asymptomatic period of the infection. For instance, plasma cortisol at 04.30 h was more than twice as high in HIV-infected patients than in time-matched controls (Villette et al., 1990). Abnormal ACTH and cortisol circadian rhythms have also been reported in stage IVc AIDS patients (Lortholary et al., 1996). Although such data might point to early changes in the suprachiasmatic

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nucleus, these authors did not take into consideration that comparisons were made between HIV-infected men, some of whom were homosexual, whereas sexual orientation of the controls was not specified (Villette et al., 1990). The difference in the suprachiasmatic nucleus in homosexual men as compared to heterosexual men (Swaab and Hofman, 1990) may thus have biased these observations. Circadian growth hormone secretion in asymptomatic HIV infection and AIDS without wasting is not different from that in healthy subjects.

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The external envelope of the HIV virus contains a glycoprotein (gp 120) that has been shown to be neurotoxic and to cause learning deficits in rats. Vasoactive-intestinal polypeptide (VIP) was found to block the gp 120-induced neurotoxicity in culture, and a VIP receptor antagonist displayed toxic properties to neurons in culture. Possible repercussions of these observations for the VIP cells in the suprachiasmatic nucleus (SCN) (Chapter 4c, d) of the hypothalamus in HIV-infected patients have never been studied.

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CHAPTER 21

Neuroimmunological disorders

21.1. Neurosarcoidosis of the hypothalamus

led to the diagnosis of schizophrenia, schizoaffective disorder and dementia. Also, mental status associated with delirium, euphoria, depression, aggression, apathy and cognitive deficits have been described. If neurosarcoidosis occurs, it has a striking predilection for the hypothalamus and pituitary, i.e. in 10–26% of cases (Robert, 1962; Turkington and Macindoe, 1972; Stern et al., 1985; Vanhoof et al., 1992; Oksanen, 1994; Guoth et al., 1998; Schielke et al., 2001). Central diabetes insipidus occurs in about 25% of patients with neurosarcoidosis (Bullmann et al., 2000) and can be the first manifestation of the disease (Konrad et al., 2000). Hyperprolactinaemia may be present (Molina et al., 2002). Other manifestations of hypopituitarism are hypoglycemia, dwarfism, panhypopituitarism, hypogonadism, obesity, and weight gain or weight loss (Bell, 1991; Murialdo and Tamagno, 2002; Randeva et al., 2002). Symptoms also attributed to hypothalamic involvement in sarcoidosis are somnolence, insomnia, hypothermia, extreme variations in body temperature, intolerance to cold, anorexia, hyperphagia, and progressive obesity and personality changes (Robert, 1962; Branch et al., 1971; Bell, 1991; Sommer et al., 1991; Vanhoof et al., 1992). In addition, a patient with hypothalamic sarcoidosis was described who had polyuria, inappropriate vasopressin (VP) release and excessive thirst. The patients fitted the criteria of Schwartz–Bartter (Chapter 22.6a) and the neurosarcoidosis was confirmed by autopsy (Kirkland et al., 1983). Up to 20% of neurosarcoidosis patients have psychiatric manifestations. These can range from mild apathy to severe mental deterioration (Vanhoof et al., 1992; O’Brien et al., 1994). In addition, memory loss associated with confusion has been described (Sharma, 1997). A 67-year old woman who had neurosarcoidosis, which damaged the anteromedial hypothalamus with an

The etiology of sarcoidosis is unknown. Environmental factors, infectious agents or hereditary factors may be involved. The seasonal clustering reported for various types of sarcoidosis (Wilsher, 1998) suggests that circannual fluctuations in the immune system or in infections may be important. Melatonin may mediate circannual immunological fluctuations (Nelson and Demas, 1997). Since a patient developed neurosarcoidosis 22 years after augmentation mammoplasty through the injection of silicone gel (Yoshida et al., 1996), it has been suggested that immunomodulations by foreign bodies such as silicone may also be a pathogenic risk factor in sarcoidosis. (a) Clinical presentation Neurological involvement is rather rare; it occurs in about 5% of the sarcoidosis patients and leads to death in 12–18% of all cases (Vanhoof et al., 1992; O’Brien et al., 1994; Sharma, 1997). Criteria for the diagnosis of possible, probable and definitive neurosarcoidosis have been proposed (Zajicek et al., 1999). Neurosarcoidosis may be confused clinically with multiple sclerosis, Lyme disease, Bechet’s disease, histiocytosis-X, Wegener’s granulomatosis, Whipple’s disease, lymphomatosis, meningeal carcinomatosis and a variety of infections, including cryptococcal meningitis, tuberculosis, syphilis, toxoplasmosis, and fungal infections. The diagnosis of isolated neurosarcoidosis, can only be established by biopsy (Graham and James, 1988; Sommer et al., 1991; Zajicek et al., 1999; Randeva et al., 2002; Chapters 20.1, 21.3). In addition, neurosarcoidosis has 101

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extension into the mamillary bodies, did not only have hyperphagia and hyperdipsia, but also had severe memory failure, characterized by spontaneous confabulations, disorientation and severely impaired free recall with preserved recognition. The authors argued that damage of the anterior hypothalamus rather than of the mamillary bodies was responsible for the confabulary amnesia (Ptak et al., 2001). The exact role of hypothalamic and other lesions in the psychiatric symptoms (see Chapter 26) has to be better defined. The optic nerve is, after the facial nerve, the second most commonly involved cranial nerve in neurosarcoidosis. MR images may show optic nerve enhancement. The characteristic picture is that of an atypical optic neuritis often subacute in onset, which might recover following steroids or cause permanent visual impairment (Zajicek et al., 1999). The optic nerve is affected in some 5% of the patients with sarcoidosis (Sharma and Anders, 1985; Stern et al., 1985; Graham and James, 1988; Westlake et al., 1995; Fig. 21.1). The optic chiasm is also frequently affected (Walker et al., 1990). Space-occupying sarcoid lesions may lead to papilledema and optic nerve atrophy (Sharma and Anders, 1985; Katz et al., 2003). Most of the cases in which sarcoidosis is manifested as an optic nerve tumor were mistaken for optic nerve meningioma (Macafee et al., 1999). Diplopia has also been reported (Molina et al., 2002). One case has been described that presented in a very unusual manner, with anosmia and visual changes. Noncaseating granulomata were subsequently found in the respiratory epithelium and submucosal (Kieff et al., 1997). Once an association was described between a Rathke’s cleft cyst and sarcoidosis lesions scattered around it, causing an intra- and extracellular mass and hypopituitarism without diabetes insipidus (Cannavò et al., 1997). Sudden death resulting from hypothalamic sarcoidosis has been reported a few times. In one case, autopsy revealed neurosarcoidosis with secondary hydrocephalus. The other case was a 23-year-old woman who had experienced 6 months of amenorrhea and a 50-pound weight gain. She had an extensive infiltration of the hypothalamus, including the pituitary stalk, the median eminence/infundibular nucleus, the right optic nerve, mamillary bodies, the supraoptic nucleus and the walls of the third ventricle, including the paraventricular nucleus (PVN). The PVN showed a marked cell loss. Death was proposed to be due to the loss of PVN neurons that innervate autonomic centers, leading to cardiopulmonary arrest (Gleckman et al., 2002).

(b) Pathology Neurosarcoidosis is due to noncaseating granulomas infiltrating the hypothalamus (Graham and James, 1988; Bell, 1991). The granulomas are initially made up of loosely organized epithelioid cells derived from macrophages that are surrounded by a ring of T-lymphocytes. In older granulomas large numbers of epithelioid and giant cells are surrounded by a small number of lymphocytes (Bell, 1991). Around the granulomas nerve cells may disappear, demyelination and gemistocytic reactive astrocytes are found (Robert, 1962). In addition, space-occupying sarcoid lesions can be found at the base of the brain and in the floor of the third ventricle. They may also manifest themselves as a pituitary pseudotumor (Robert, 1962; Timsit et al., 1993) or, e.g. Rathke’s cleft cyst (Cannavò et al., 1997). Whereas earlier postmortem findings pointed mainly to partial or total destruction of the pituitary by granulomas, later examination of both the pituitary and the hypothalamus showed extensive and preferential infiltration of the hypothalamus by granulomatous inflammation or granulomas, and little, if any, involvement of the pituitary itself (Bell, 1991; Fig. 21.2). Autopsy was only performed on a few patients with neurosarcoidosis and showed granulomata diffusely scattered in the median eminence and bilaterally throughout the hypothalamus (Selenkow et al., 1959; Turkington and MacIndoe, 1972). In addition, late stages of hyalinized granulomata have been reported throughout the hypothalamus. They consisted of multiple discrete, round to oval masses of 100–300 m (Branch et al., 1971). One patient has been reported presenting with diabetes insipidus. He had a posterior pituitary mass but no other abnormalities in the pituitary, infundibulum and hypothalamus. The mass showed complete repression after corticosteroid treatment, but diabetes insipidus persisted (Loh et al., 1997). The most common MRI abnormality in cases of neurosarcoidosis is the presence of multiple white-matter lesions (Zajicek et al., 1999). MRI may demonstrate hypothalamic periventricular and meningeal lesions (Bell, 1991) and thickening of the pituitary stalk that extends toward the optic chiasm (Walker, 1990). Only rarely does neurosarcoidosis present itself as an intracranial mass lesion. An example is the case described by Grand et al. (1996; Fig. 21.3) with a lesion resembling a “bunch of grapes” on MR images, extending from the right frontotemporal area toward the midline, involving the hypothalamus. The arachnoid covering the optic chiasm,

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Fig. 21.1. Sarcoidosis involving the optic nerve and hypothalamus. Top: T1-weighted coronal magnetic resonance imaging scan showing asymmetrical thickening of the chiasm (solid arrow). Center: Following gadolinium enhancement, an increased signal can be seen in the hypothalamus, third ventricle (open arrow) and meninges (solid arrow), due to sarcoidosis. Bottom: Sagittal cut showing enhancement in the hypothalamus and pituitary stalk (open arrow), with enlargement of the pituitary gland (solid arrow). (From Westlake et al., 1995, Fig. 1 with permission.)

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Fig. 21.2. Sarcoidosis nodules scattered through the hypothalamus (H&E). (From Sheehan et al., 1982, Fig. 3.45 with permission.)

pituitary stalk and floor of the third ventricle may be opaque, thickened and sprinkled with many miliary nodules (Robert, 1962; Vanhoof et al., 1992). Periventricular enhancement indicates active inflammation (Bell, 1991) and involvement of the ependymal lining often leads to complete obliteration of the third ventricle and to hydrocephalus (Robert, 1962; Scott, 1993). (c) Endocrine changes The prevalence of neuroendocrine disturbances due to neurosarcoidosis has a peak around 30–39 years of age. Hypogonadotropic hypogonadism, polyuria and polydipsia are the most frequently occurring symptoms in patients with sarcoidosis of the hypothalamus and pitu-

itary (Murialdo and Tamagno, 2002). Whereas the symptoms of diabetes insipidus were initially attributed to diabetes insipidus caused by vasopressin deficiency (Selenkow et al., 1959; Robert, 1962; Branch et al., 1971; Stern et al., 1985), later studies indicated that they more often result from primary polydipsia and possibly from destruction of the osmoreceptors, without vasopressin deficiency (Bell, 1991). The displacement of the pituitary bright spot to the upper infundibulum in neurosarcoidosis (Walker et al., 1996) correlates with the presence of diabetes insipidus. A patient has been described with diabetes insipidus and a large posterior pituitary mass that was most probably due to sarcoidosis. A complete regression of the posterior pituitary mass was found after corticosteroid therapy, but the diabetes

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Fig. 21.3. (a, b) Sagittal and (c) coronal T1 images after i.v. gadolinium: sarcoidosis of the hypothalamus. Multiple nodular enhancement resembling a “bunch of grapes” in the right temporal lobe; extension toward the hypothalamohypophyseal region. (d) Axial T2 image: lesions of the intermediate intensity signal surrounded by extensive edema. (From Grand et al., 1996, Fig. 2 with permission.)

insipidus persisted and the patient continued to need his intranasal vasopressin therapy during the 12-month follow-up (Loh et al., 1997). Inappropriate secretion of vasopressin has also been described in neurosarcoidosis (Stern et al., 1985). Deficiency of anterior pituitary hormones most often occurs on the basis of hypothalamic dysfunction, although the pituitary might sometimes be primarily involved as well (Selenkow et al., 1959; Robert, 1962; Stern et al., 1985; Graham and James, 1988; Bell, 1991). Patients may have hypothyroidism, hypogonadism, changes in pubic hair and body hair, loss of libido, secondary amenorrhea, hypoadrenalism, panhypopituitaris, increased serum prolactin and, less often, galactorrhea (Robert, 1962; Turkington and MacIndoe, 1972; Stern et al., 1985;

Graham and James, 1988; Verhage et al., 1990; Bell, 1991; Lipnick et al., 1993, Westlake et al., 1995; Molina et al., 2002; Murialdo and Tamagno, 2002; Randeva et al., 2002). However, it should be noted that Munt et al. (1975) were unable to confirm by radioimmunoassay the high incidence of hyperprolactinemia in patients with neurosarcoidosis involving the hypothalamus. Normally, hypoglycemia stimulates rapid increase of hormones such as catecholamines, glucagon, cortisol and growth hormone to act in concert to increase plasma glucose concentration. This action is regulated by the ventromedial region of the hypothalamus. A patient has been described who had complete loss of the counterregulatory response to hypoglycaemia due to a hypothalamic sarcoid infiltration (Féry et al., 1999). 105

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(d) Therapy Administration of oral corticosteroids, 40–80 mg/day, is the usual first line of therapy for neurosarcoidosis, and often corticosteroids are given long-term, despite the absence of controlled studies of their efficacy and the high frequency of serious side effects (Murialdo and Tamagno, 2002; Randeva et al., 2002). Methylprednisolone pulse therapy has also been applied (Molina et al., 2002). In general, neurosarcoidosis is more resistant to therapy than the pulmonary variety and longterm, high-dose corticosteroid therapy is generally not very well tolerated and not very effective. Methotrexate, cyclosporine-A and cyclophosphamide seem to be more effective (Murialdo and Tamagno, 2002). Recently, the TNF- antagonist infliximab has been tried with some success in the treatment of systemic sarcoidosis and in optic disc swelling in sarcoidosis (Katz et al., 2003). However, in over half of the neurosarcoidosis patients the disease progresses despite corticosteroid or other immunosuppressive therapies (Zajicek et al., 1999).

21.2. Multiple sclerosis (MS) and the hypothalamus MS is an inflammatory demyelinating disease of the central nervous system. It is generally a disease of young adulthood with a peak age of onset between 25 and 30 years of age. The initial course of MS is often characterized by spontaneous relapses and remissions, but it can also run a primary progressive course. Although the exact etiology of the disorder is unknown, there is clinical and laboratory evidence suggesting that it is a multicausal disease with genetic, autoimmune and environmental components (Duquette and Girard, 1993). The premenstrual period triggers exacerbations. In fact, 45% of all exacerbations seem to start in this period (Zorgdrager and De Keyser, 2002). There is a decreasing North–South gradient in risk and there are race and sex differences in predisposition (Limburg, 1950; Kurtzke et al., 1979; Sadovnik and Ebers, 1993). Seasonal fluctuations in peak exacerbation rate depend on the region. Exacerbations of optic neuritis and MS have the highest frequencies in spring and the lowest in winter. The seasonal fluctuations are presumed to be related to a dysregulation of interferon- and viral infections (Balashov et al., 1998; Jin et al., 2000). In addition, stressful life experiences are considered to be risk factors (Goodin et al., 1999; Martinelli, 2000). However, an Israeli paper shows that,

contrary to expectation, the number of relapses during a war and the following months may even be significantly lower (Nisipeanu and Korczyn, 1993). Several genetic factors seem to be involved in the risk of developing MS and in the course of the disease. HLA-DRB1*1501 alleles and estrogen receptor polymorphisms are of importance in this connection and may also be the basis of the sex differences in the prevalence of MS (Kikuchi et al., 2002). In addition, single-nucleotide polymorphism (SNP) in interleukin-1 (IL-1), - and in the IL-1 receptor antagonist influence long-term prognosis in MS (Mann et al., 2002). Apolipoprotein E (ApoE) is involved in the transport of lipids necessary for membrane repair, and is encoded by a gene on chromosome 19q13. MS patients with an ApoE 3/4 genotype have a more severe disease course, according to some studies (Fazekas et al., 2000, 2001), while later onset of chronic progressive MS was observed in patients carrying the ApoE2 allele (Ballerini et al., 2000). However, other studies did not find an association between ApoE4 and adverse outcome in MS (Masterman et al., 2002). An SNP haplotype near ApoE is associated with MS susceptibility (Schmidt et al., 2002). Several other polymorphisms have also been implicated in the susceptibility and course of MS (Cocco and Marrosu, 2000). (a) Autonomic, behavioral and neuroendocrine symptoms A number of autonomic and neuroendocrine functions that are often found to be disturbed in MS point to hypothalamic involvement in this disease. Such autonomic functions include disturbed functions of the bowel and bladder, and of sexual behavior (Matthews, 1991; Hulter and Lundberg, 1995; Mattson et al., 1995), as well as sweating, and respiratory and cardiovascular regulation (Anema et al., 1991; Fowler et al., 1992; Howard et al., 1992), disturbed temperature regulation (Lammens et al., 1989; Tsui et al., 2002), such as acute and chronic hypothermia (Sullivan et al., 1987, White et al., 1996) and poikilothermy (Kurz et al., 1998) and sleep disturbances (Campbell et al., 1982; Clark et al., 1992; Ferini-Strambi et al., 1994; Tachibana et al., 1994; Tsui et al., 2002). One patient had asymmetric sweating of the right forehead and shoulder, due to MS lesions in the left hypothalamus (Ueno et al., 2000). An MS patient was described with a new plaque in the hypothalamus who developed acute hypersomnia and undetectable CSF hypocretin levels (Iseki et al., 2002). A significant

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reduction in tremor has been reported among MS patients after subthalamic ventral intermediate nucleus brain stimulation (see Chapter 15.1). However, patient satisfaction with this procedure was variable (Berk et al., 2002). Sexual dysfunction in patients with MS is typically characterized by diminished libido, erectile and ejaculating dysfunction in men, and poor lubrication and anorgasmy in women. Hypersexual behavior and paraphilias are distinctly uncommon in this group of patients, but have been described associated with focal brain lesions in the hypothalamic and septal regions (Frohman et al., 2002). Some endocrine disturbances in MS are also related to hypothalamic alterations. They include: abnormal testosterone levels (Grinsted et al., 1989; Markianos and Sfagos, 1989), which may lead to hypothalamic hypogonadism, decreased libido and impotence, and may be treated with testosterone (Bourdette et al., 1988); hyperprolactinemia, in five of nine cases accompanied by hypothalamic lesions (Kira et al., 1991; Tsui et al., 2002); altered growth hormone and TSH levels (Klapps et al., 1992); and inappropriate antidiuretic hormone secretion (Apple et al., 1978; Tsui et al., 2002). Alpha-melanotropin (MSH) levels are increased in patients with a greater inability score (Catania et al., 2000). A failure of suppression of cortisol levels was observed following dexamethasone treatment (Reder et al., 1987; Grasser et al., 1996; Fassbender et al., 1998; Kümpfel et al., 1999; Then Bergh et al., 1999), indicating a hyperactive hypothalamopituitary–adrenal (HPA) axis. Cortisol levels in postmortem CSF of MS patients are elevated by some 80% in comparison with controls, which is another indication of an increased HPA activity (Erkut et al., 2002). A severe impairment of the ACTH and metapirone test was reported by some authors (Brambilla et al., 1974), while others did not find a difference in the plasma cortisol response to corticotropin (ACTH) in MS patients (Wei and Lightman, 1997; Kümpfel et al., 1999). The latter group also reported lower dehydroepiandrosterone sulfate (DHEAS) secretion in MS patients. It should be noted that the pathophysiology of hypercortisolism in MS seems to be different (see below) from that in depression. MS is presumed to be associated with increased prominence of hypothalamic VP secretion (Michelson et al., 1994; Michaelson and Gold, 1998; cf. Chapter 26.4). Indeed, the entire increase in corticotropin-releasing hormone (CRH)-expressing neurons in MS appeared to be due to an increase in those CRH neurons that colocalize VP (Erkut et al., 1995; Fig. 21.4). Not only do the CRH

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neurons play an essential role in cortisol regulation, they also influence mood (Chapters 21.2b, 26.4), and it is therefore of particular interest that treating relapsing-remitting MS patients with a combination of corticosteroids and the antidepressant moclobemide favors normalization of the HPA axis (Then Bergh et al., 2001). It has been proposed that the pineal gland may be implicated in the relapsing-remitting nature of the disease. Melatonin was even claimed to be able to cause acute exacerbation of symptoms. Abnormal plasma melatonin levels were found in half of the MS patients during exacerbations. Most of them had nocturnal levels that were below the daytime values. There was also a significant relation between melatonin levels, age of onset of symptoms and the duration of illness. Pineal calcification was found in nearly all the MS patients. These observations were hypothesized to be related to the occurrence of seasonal variations in MS, the influence of climatic variables, and the low incidence of MS in African and American black populations (Sandyk and Awerbuch, 1992). Exactly how the pineal function is related to the MS disease process should be investigated further. Since fatigue and sleep disturbances are frequent and disabling symptoms inMS, and because of the presumed disturbed pineal function, we investigated whether these symptoms might be due to disrupted circadian sleep/wake regulation. However, no evidence was found for a generalized circadian disturbance in MS patients, which indicates that the suprachiasmatic nucleus will generally not be seriously affected in this disease (Taphoorn et al., 1993). Vasopressin levels in CSF, but not in plasma, were found to be decreased in MS (Olsson et al., 1987). It is not clear what exactly the source of this diminished amount of CSF vasopressin is, since we did not find an indication for an activity change in the vasopressin neurons of the PVN in MS (Purba et al., 1995). In addition, Michelson and Gold (1998) presume that MS is associated with increased hypothalamic vasopressin secretion and Erkut et al. (1995) showed that the entire increase in the number of CRH-expressing neurons in MS was due to those CRH neurons that coexpress vasopressin. Desmopressin (DDAVP, nasal spray) is a vasopressin agonist that is effective both in the treatment of nocturnal enuresis and in the treatment of increased daytime urinary frequency, which often seriously disrupts work and social activities in MS patients. A side effect of this therapy might be the development of hyponatremia. Although the patient should be warned about the symptoms of side effects due to hyponatremia, i.e. malaise, headache and nausea 107

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(Hoverd and Fowler, 1998), long-term use of DDAVP has been shown to be safe and effective by others (Tubridy et al., 1999). Lower levels of CSF somatostatin have been found in MS patients during relapse, and a strong relationship has been found between cognitive decline and decrease in CSF somatostatin levels (Roca et al., 1999). It is not known which brain area is responsible for the changes in somatostatin levels. (b) Mood changes Although euphoria was mentioned as the dominant emotional change in MS in an old paper (Cottrell and Wilson, 1926), a fact that is generally known in clinics, more recent literature has repeatedly shown that depression is the major mood change in these patients (Rao

Fig. 21.4. Increased numbers of corticotropin-releasing hormone (CRH) and vasopressin (VP) in multiple sclerosis (MS). Numbers of CRH neurons that do not localize VP (CRH-only) or that colocalize VP (CRH + VP) in the PVN of 8 MS patients and 8 controls. Tissue was obtained from the Netherlands Brain Bank (Amsterdam, the Netherlands). Clinicopathological data (mean ± SEM), age, 51.0 ± 3.8 years (MS), 52.6 ± 5.0 years (controls); postmortem delay 12.9 ± 5.6 h (MS), 13.9 ± 3.9 h (controls); fixation time 49 ± 14 h (MS), 36.7 ± 4.3 h (controls); duration of MS, 23 years; primary progressive MS 2/8 and secondary progressive MS, 6/8. Neurons are counted in the PVN after immunocytochemical double-staining of VP and CRH as described (Erkut et al., 1995). The difference in numbers of CRH/VP neurons between the MS and the control group is significant (p = 0.046). (Based upon Erkut et al., 1995, Fig. 3). Note that the increase in CRH-expressing neurons in MS is solely due to an increase in CRH cells coexpressing VP.

et al., 1992). MS patients are frequently depressed, irritable and short-tempered (Dalos et al., 1983; Schubert and Foliart, 1993; Fassbender et al., 1998). There is a significant interaction between the level of neurological impairment and depression in patients with MS (Mohr et al., 1997b). However, comparison of MS patients with a group of traumatic paraplegics as disease controls also showed a significantly higher incidence of emotional disturbances in the MS patients, especially during periods of relapse (Dalos et al., 1983), and a boost of depression in MS may even occur shortly before neurological symptoms develop (Whitlock et al., 1980; Joffe et al., 1987; Minden and Schiffer, 1990; Millefiorini et al., 1992). so that the mood changes do not only seem to be due to the presence of a neurological disability alone. In agreement with this idea, Fassbender et al. (1998) found that both affective and neuroendocrine disorders in MS were related to the inflammatory disease and not to disability. A relationship is presumed between the hyperactive HPA axis (see previous section) and depression in MS and, indeed, a combined treatment with corticosteroids and the antidepressant moclobemide normalizes HPA axis function in relapsing-remitting MS patients (Then Bergh et al., 2001). A relationship has also been observed between MS lesions in the left arcuate fasciculus, i.e. in the suprainsular white matter and depression in MS (Pujol et al., 1997), while major depression is known also to result from left cortical lesions. The higher levels of depression in MS are associated with sleep complaints (Campbell et al., 1992). The very high rate of depression among MS patients does not have a genetic basis (Sadovnick et al., 1996). Although interferon--1B reduces the frequency and severity of exacerbations of MS in patients with the relapsing-remitting form, it also causes flu-like symptoms and increases depression within the first 6 months after starting this therapy. Subsequent treatment of depression improves the adherence to interferon therapy (Mohr et al., 1997a; Walther and Hohfeld, 1999). (c) The HPA axis in relation to susceptibility and recovery As shown by animal models, the HPA axis, which is a central system in the regulation of immune responses (Rivest, 2001), may influence susceptibility to and recovery from MS. Studies on experimental allergic encephalomyelitis (EAE), the most extensively studied animal model of MS (Polman et al., 1986; Pender, 1987;

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Sobel et al., 1988; McDonald, 1994; Rodriguez and Scheithover, 1994), have indicated that the activity of the HPA axis may be crucial in these processes. In certain rat strains, such as the Lewis rat, low corticosteroid levels are accompanied by a high susceptibility to EAE, whereas, once the disease has been established, elevation of corticosteroid levels is required for spontaneous recovery (MacPhee et al., 1989; Sternberg et al., 1989; Mason et al., 1990; Villas et al., 1991; Kuroda et al., 1994). In line with these findings, glucocorticoids, CRH and urocortin are capable of suppressing EAE in Lewis rats (Bolton and Flower, 1989; Poliak et al., 1997). In relation to the possibility that low corticosteroid levels may lead to increased susceptibility to MS, it is of interest to note that, from the fourth decade of life onwards, CRH neurons become gradually more activated (Chapter 8.5b; Figs. 8.26, 8.27). This is also the age at which MS prevalence starts to decline in the population. Both markers for activity of these neurons, the total number of paraventricular nucleus cells and the proportion of VP-expressing CRH neurons show an age-dependent increase (Raadsheer et al., 1994a, b). No data are available as yet on age-related changes in CRH mRNA in the human PVN. As animal experiments have shown that an increased HPA axis activity may lead to decreased susceptibility to EAE, the age-related increase in CRH activity suggests that this may be an important factor leading to decreasing prevalence of MS with age. Data on CRH neuron activity before the age that MS prevalence increases are at present not available. It has been observed that from 12 to 20 years of age the saliva cortisol level gradually increases (Walker et al., 2001), but the peak age of onset occurs one decade later. Of course it is not known whether those young subjects who have lower HPA axis activity are indeed at risk to contract MS. However, the observation that in EAE the HPA axis is six-fold increased in activity and in MS only 2.5 times (Wei and Lightman, 1997) was proposed to point to a relative deficiency of the HPA axis in MS patients. It is questionable, though, whether these observations in two different species with a different time course in the disease process can indeed be compared so easily. However, this possibility agrees with the observation that the insulin-induced cortisol increase in MS patients was lower than in healthy controls (Teasdale et al., 1967). CRH neurons are clearly activated in MS patients, as appears from the 2.4-fold increase in the number of neurons expressing CRH (Purba et al., 1995) and

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the 4.5-fold increase in neurons coexpressing CRH and VP (Erkut et al., 1995; Fig. 21.4). In fact, the latter study showed that the entire increase in CRH cell numbers in MS was due to an increase in those CRH neurons that colocalized VP, which is different from the situation in depression (see Chapter 26.4). VP potentiates both the peripheral and central effects of CRH (see Chapter 8.5). Our data agree with the increase in plasma levels of corticosteroids reported in MS (Millac et al., 1969; Reder et al., 1987; Michelson et al., 1994) and the presence of an enlarged adrenal gland in this condition (Reder et al., 1987, 1994). Moreover, postmortem CSF cortisol level in MS is elevated by 80%. Cortisol levels in CSF appeared to reflect postmortem serum cortisol, since these levels were highly correlated (Erkut et al., 2002). The dexamethasone–CRH-suppression tests indicated hyperactivity of the HPA axis only in primary and secondary progressive MS, while relapsing-remitting patients had response patterns similar to controls (Heesen et al., 2002). The increased HPA axis activity may be seen as an effort to suppress the disease process. Indeed, exogenous corticosteroids improve the rate of recovery from acute exacerbations of MS and attacks of monosymptomatic optic neuritis. However, there is at present no convincing evidence that glucocorticoid therapy reduces the frequency of MS exacerbations or delays the progression of neurological disability (Milligan et al., 1987; Miller et al., 1992; Frequin et al., 1994; Wenning et al., 1994; Andersson et al., 1998). The strong increase in CRHneuron activity thus seems compatible with the idea that the brain defends itself against the disease process (MacPhee et al., 1989), although it is not entirely successful in this. Indeed, an endocrine paper concluded that the HPA axis activation in MS is a reaction to the disease process, since it correlates with a marker for the acute phase response, white blood cell counts and with gadolinium enhancement in MRI (Wei and Lightman, 1997; Fassbender et al., 1998). The enhanced response in the dexamethasone-suppression test in MS correlated with disease activity and with the clinical subtype of MS in such a way that increased HPA axis activity relates to an increased disease activity or severity (Wei and Lightman, 1997; Then Bergh et al., 1999). In agreement with this idea, Millac et al. (1969) and Grasser et al. (1996) found increased cortisol levels in MS only during exacerbations and a heterogeneity of the HPA system function, possibly at the corticosteroid receptor level. Although the presence of a partial glucocorticoid receptor 109

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deficiency in some MS patients can, at present, not be excluded as the reason for a different course of HPA axis activation, there does not seem to be any gross disorder of the HPA axis in MS (Millac et al., 1969). In line with this conclusion is the observation that, after cessation of the corticosteroid therapy for relapses, HPA axis function is normal and corticosteroid replacement therapy seems unnecessary (Miró et al., 1990). In addition, it has been observed that cortisol release induced by the dexamethasone–CRH test, is negatively associated with the presence and number of gadoliniumenhancing lesions and positively associated with ventricular size. This suggests a protective effect of the HPA axis drive on acute lesion inflammation in MS. These observations can, however, also be explained in a different way. The observation that prolonged treatment with prednisolone significantly decreases brain volume (Hoogervorst et al., 2002) is another reason to have reservations about long-term corticosteroid therapy in MS. CRH itself may also be directly involved in the defense against the disease process, because it has a neuroprotective effect (Fox et al., 1993) and immunomodulating actions (Webster et al., 1998). Moreover, CRH has analgesic properties (Lariviere and Melzach, 2000). It is remarkable that the condition of most women with MS stabilizes or improves during pregnancy, but after delivery they run an increased risk of suffering a relapse. It is estimated that the risk that the condition takes a turn for the worse is between 20% and 75%. However, it is not clear what factors determine susceptibility changes during pregnancy and postpartum (Birk et al., 1990), although steroid hormones are presumed to be implicated. Hormonal changes preceding the menstruation may worsen symptoms in a subgroup of women with relapsing-remitting MS (Zorgdrager and De Keyser, 1997). (d) Inflammation, demyelination and hypothalamic structures MS is an immune-mediated disease characterized by inflammatory demyelinating perivascular lesions in the white matter, disseminated in time and space (Raine, 1994). In addition, brain weight is decreased (Jelliffe and White, 1935; Erkut et al., 1995). Although ample literature covers the neuropathology of MS, little reference has been made to the hypothalamus. Hypothalamic lesions as

mentioned by Brownell and Hughes (1962) are said to make up only 1% of the total lesions, which does not agree with our observations, which showed a large number of demyelinated plaques to be present in hypothalamic and adjacent structures in a high proportion of MS patients (Huitinga et al., 2001). Moreover, acute unilateral optic neuritis is generally not included in “hypothalamic involvement”, while, within 5 years, in some 30% of patients, it was followed by clinically definite MS. Corticosteroids did not influence this risk, nor the degree of neurological disability in a 5-year follow-up study (Optic Neuritis Study Group, 1997). Unilateral optic neuritis occurs often as an initial manifestation of MS. Acute bilateral optic neuritis is less common. Swelling and demyelinating lesions in myelinated bundles can be shown by MRI, also following gadolinium enhancement (Fig. 21.5), and pathology has confirmed the inflammatory nature and demyelination. The optic radiations are almost always involved (Newman et al., 1991; McDonald and Barnes, 1992). MS lesions are mentioned by Bignani (1961) and Peters-Bonn (1958) to be present not only around the walls of the lateral ventricles, but also around those of the third ventricle. Early periventricular lesions are situated around subependymal veins, causing focal perivenous demyelination. The lesions subsequently coalesce with neighboring lesions (Adams et al., 1987). A limited number of other papers mentions the involvement of the hypothalamus in MS: Zimmerman and Netzky (1950) found that the paraventricular nucleus of the hypothalamus is sometimes involved in MS; Bignani et al. (1961) described fresh plaques throughout the whole hypothalamus in a patient with a depression, profuse sweating and hyperthermia. An MS patient has been described with acute relapses associated with drowsiness and hypothermia. Although MRI, endocrine and autonomic studies failed to localize a lesion in the hypothalamus, subsequent necropsy showed plaques of demyelination throughout the hypothalamus, including the area of the posterior hypothalamic nucleus (White et al., 1996). In addition, a woman with MS who had presented with hypothermia, dysphagia, lethargy, dysrhythmicity and bronchopneumonia, showed a large, mature, gray, translucent gliotic plaque involving the hypothalamus at the postmortem. At the microscopic level, there was evidence of current activity in a proportion of that plaque. In addition to gliosis, lymphocytic cuffing of vessels and occasional macrophages containing lipid debris were seen (Edwards et al., 1996a). Kamalian et al. (1975) reported a malignant case of MS in which the disease began with

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in body temperature, depression and an activated HPA axis (see above) we investigated the possible presence of MS lesions in 16 MS patients using myelin Klüver– hematoxylin staining, CR3/43 (anti-HLA-DR, -DP, -DQ) as a marker for activated microglial cells (Graeber et al., 1994), glial fibrillary acidic protein (GFAP, marker for astrocytes), KP1 (recognizes macrophages and microglial cells) and amyloid precursor protein (APP, detects axonal damage; Ferguson et al., 1997). The myelinated bundles in and around the hypothalamus analyzed were the optic system (optic nerves, optic chiasm and optic tract), the fornix, internal capsule and anterior commissure. We distinguished between active demyelinating lesions containing foamy macrophages and microglial cells and chronic, inactive hypocellular gliotic lesions (De Groot et al., 2001; Huitinga et al., 2001; Figs. 21.6–21.10). The hypothalamus of 16 of 17 MS patients contained demyelinated lesions (Fig. 21.6). The incidence of active lesions was high (60%) and outnumbered chronic inactive gliotic lesions in the internal capsule. In 4 out of 17 MS patients, axonal damage was observed and in 3 of 17 MS patients gray matter lesions were apparent. Duration of MS was inversely related to the active hypothalamic MS lesion score. Since comparison of hypothalamic lesions with MS

rapid weight loss and terminated after 17 months with generalized muscle wasting and cachexia. Demyelinating lesions were found in the lateral hypothalamus and a relationship was proposed between the clinical symptoms and the localization of the lesions, because lesions in the lateral hypothalamus may cause aphagia and anorexia (see Chapter 23). The optic nerves and chiasm were almost completely demyelinated and there was intense reactive astrogliosis. The fornix showed a patchy loss of myelin. A plaque-like sclerotic lesion was located in the left lateral hypothalamus. The plaque showed almost complete loss of myelin, a moderate, diffuse astrogliosis and occasional small lymphocytic infiltrates. The right lateral hypothalamus showed slight myelin loss. The dorsomedial and ventromedial nuclei appeared to be unaltered. An old plaque with its pronounced fibrillary astrogliosis continued into the left mamillary body and fornix, surrounded by more cellularly active lesions. There were also subacute lesions with perivascular infiltrates along the third ventricle. In MS patients with hyperprolactinemia, hypothalamic lesions were present in 5 of 9 patients (Kira et al., 1991; Tsui et al., 2002). Because MS patients show “hypothalamic signs and symptoms” such as fatigue, sleep disturbances, changes

Fig. 21.5. Multiple sclerosis patient with optic chiasmal neuritis. MR. T1-weighted images after gadolinium enhancement. Coronal (A) and axial (B) views demonstrating a thickened optic chiasm with focal enhancement (arrows). (From Newman et al., 1991, Fig. 2 with permission.)

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Fig. 21.6. Multiple sclerosis (MS) lesions in the human hypothalamus. A and B: Kluver staining of the hypothalamus of a control subject (82016, (A) and a MS patient (93-051, (B). Myelin is stained blue. Note that, in the control subject the myelinated bundles (IC: internal capsule, FX: fornix, OS: optic system) can easily be distinguished, whereas, in the MS patient, myelin bundles contain large white spots or are even barely visible (i.e. the OS in MS patient 93-051) because of demyelinating MS lesions (*). In the control subject, the anterior commissure (AC) is not present at this level. The left FX in the MS patient is partly demyelinated. IF: infundibulum, P: PVN. Magnification: 4.5 . C and D: Human leukocyte antigen (HLA-DR, -DP, -DQ) staining of an active MS lesion in the internal capsule in MS patient 95-065 (C) and a (p)reactive lesion also in the internal capsule of MS patient 96-026 (D). Note the foamy character of the HLA-positive macrophages in the active lesion in (C), indicative of myelin phagocytosis, and the ramified character of the HLA-positive macrophages in the (p)reactive lesion in (D), indicative of activated microglial cells. Arrow points at perivascular leukocyte cuffing. Magnification: 400 . bv = blood vessel. Tissue was obtained from the Netherlands Brain Bank. (From preparation by I. Huitinga.)

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disease severity in MS (Schrijver et al., 1999) and because priming with IL-1 suppresses EAE in the Lewis rat (Huitinga et al., 2000b). Since demyelinating lesions in fiber bundles in and adjacent to the hypothalamus (i.e. the fornix, anterior commissure, internal capsule and optic system) may be the basis for autonomic and endocrine alterations in multiple sclerosis (MS) patients, we investigated the relationship between the presence of hypothalamic lesions and the state of activation of CRH neurons in MS patients (n = 15). The state of activation of CRH neurons was determined by quantifying the number of CRH neurons that did or did not contain vasopressin, as well as the amount of CRH mRNA expressed in the paraventricular nucleus. The state of activation of CRH neurons in the MS group was compared with that in controls (n = 14). Hypothalamic MS lesions were determined as described above. As found previously (Erkut et al., 1995; Purba et al., 1995), numbers of CRH neurons that colocalize vasopressin are significantly increased in MS. In line with these findings we also found increased levels of CRH mRNA in MS. Interestingly, there was a strong, significant negative relationship between the numbers of CRH neurons that colocalize vasopressin (the population of CRH neurons that is increased in MS) and active MS lesions in the hypothalamus. There was no relation between CRH single positive neurons and the active lesion score. The effect was thus neuron-specific. The chronic inactive lesion score did not correlate with the numbers of CRH that colocalize VP in MS; the effect thus concerns only the immunologically active lesions. The same negative relationship was seen between the amount of CRH mRNA expression and the active lesion score in MS. This relationship, too, concerned only immunologically active lesions and not the chronic inactive gliotic lesions. Interestingly, controls also showed a negative relationship between HLA score (activated microglial cells) and the amount of CRH mRNA expression, indicating that the relationship between activated microglial cells and the decreased activation of CRH neurons is not MS specific. Thus, whereas as a group MS patients have activated CRH neurons, the presence of active lesions and activated macrophages and microglial cells in or around the hypothalamus of MS patients induces a significant decrease in the activation of CRH neurons. Apparently, MS patients with many active lesions in the hypothalamus have a diminished activity of the HPA system (Huitinga et al., 2002). The clinical consequences of such an impaired activity of the HPA

Fig. 21.7. Active and chronic inactive lesion scores (bars) and the incidence of active and chronic inactive lesions per fiber bundle (numbers on top of the bars) in the hypothalamus of multiple sclerosis patients: the internal capsule (IC), anterior commissure (AC), fornix (FX) and optic system (including optic nerve and optic chiasm, OS). Note that the AC and the FX were not present in the sections studied in all patients. The active lesion score includes (p)reactive and active lesions and the chronic inactive lesion score includes only chronic inactive hypocellular gliotic lesions. Bar represents the mean ± SEM. (From Huitinga et al., 2001, Fig. 2 with permission.)

lesions in other areas of the brain in the same patients (n = 7) showed a great similarity as both stage and appearance were concerned, this negative relation in all likelihood reflects the clinical consequences of high disease activity throughout the whole brain. In controls no demyelinating lesions were seen, but, in 11 control cases, HLA expression was observed that was lower than in MS patients. Thus, systematic pathological investigation of the hypothalamus in MS patients reveals an unexpectedly high incidence of active lesions. Preactive lesions were also found in the neurosecretory supraoptic nucleus (SON) (Fig. 21.11). In the oxytocin neurons of the PVN and accessory nuclei, IL-1 was found (Fig. 21.12). In MS patients fewer neurons in the PVN were found to be positive for this cytokine (Huitinga et al., 2000a; Fig. 21.13). This finding may be of particular interest in relation to MS, since a specific combination of IL-1 and IL-1 receptor antagonist is associated with 113

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Fig. 21.8. Microphotographs of multiple sclerosis (MS) lesions. A: CD68-positive foamy macrophages in an active lesion in the internal capsule (IC) of MS patient 95-065. B: Klüver staining of an active lesion in the OS of MS patient 95-065. Arrows point at two foamy macrophages at the edge of the lesion. Arrowheads point at luxol fast blue-positive particles in the macrophages. C: Gliosis in a chronic active lesion in the IC of patient 95-065. Arrows point at glial fibrillary acidic protein (GFAP)-positive hypertrophic astrocytes. D: human leukocyte antigen (HLA-DR, -DP, -DQ)-positive microglial cells (arrow) and HLA-positive leukocytes (arrowhead) in the Virchow–Robin space around a blood vessel (Bv), indicative of a (p)reactive MS lesion in the IC of MS patient 96-026. E: A chronic inactive lesion in the OS of patient 93-051. Arrows point at HLA-DR, -DP, -DQ-positive microglial-like cells and arrowheads point at isomorphic gliosis and widened extracellular spaces typical for gliotic tissue. F: Perivascular accumulation of CD3-positive T cells near an active lesion in the IC of patient 95-065. Bar = 15 m. (From Huitinga et al., 2001, Fig. 3 with permission.)

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Fig. 21.9. Microphotograph of axonal damage and HLA expression in the supraoptic nucleus (SON) and the median eminence. A: Bodian staining of the optic system (OS) of MS patient 93-051. Note the reduced density of axons as compared to the axonal density in Fig. B. B: Bodian staining of the OS of MS patient 96-026. There is no sign of axonal damage in the OS of this MS patient. C: amyloid precursor protein (APP)-immunoreactive axons in the IC of MS patient 91-070. Note the large-diameter (5–7 m) of the APP-immunoreactive axons. Adjacent to this area is an active MS lesion (not shown). D: HLA-DP, -DQ, -DR-positive microglial cells in the SON of MS patient 96-026. Arrow points at an HLA-positive microglial-like cell that seems to be in close contact with an SON neuron. E: HLA-DR, -DP, -DQ-immunoreactive microglial-like cells in the median eminence of control 93-085. Arrows point at HLA-reactive microglial-like cells in close vicinity of blood vessels (Bv). F: HLA-DR, -DP, -DQ-immunoreactive cells in the median eminence of MS patient 95-095. Arrow points at a small lesion of HLA-positive cells. Bar = 15 m. (From Huitinga et al., 2001, Fig. 4 with permission.)

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Fig. 21.10. The relationships between the duration (in years) of multiple sclerosis (MS) and the active lesion score (left panel, p = 0.001, r = –0.719) and chronic inactive lesion score (right panel, p = 0.102, r = –0.410) in the hypothalamus. Note that there is a significant inverse correlation between the active lesion score and the duration of MS, i.e. leading to death, but not between the chronic inactive lesions score and the duration of MS. (From Huitinga et al., 2001, Fig. 5 with permission.)

system in a subgroup of MS patients should be studied further. (e) Differential diagnosis of optic neuritis Acute optic neuritis in MS should be differentiated from Leber’s hereditary optic neuropathy. In children, optic neuritis is often bilateral. It usually follows infections such as measles, chicken pox and infectious mononucleosis in nearly half of cases, and there is a seasonal fluctuation, with the greatest number presenting in April. While the risk of MS after childhood optic neuritis is low (some 15%), the risk factor for adults is 75% (McDonald and Barnes, 1992). The diagnosis of MS has often been applied to patients with a syndrome that has recently been renamed recurrent optic neuromyelitis with endocrinopathies. It has been described in Antillean women from Martinique and Guadeloupe. Myelopathic symptoms and visual problems recurred. Spinal cord involvement consisted of a band-like sensory loss and MRI shows caviation-like images. The endocrinopathies consisted of amenorrhea, galactorrhea,

diabetes insipidus, hypothyroidism or hyperphagia. In the spinal cord, demyelinizing lesions with diffuse spongiosis are found with thickened blood vessel walls without evidence of inflammation. Autonomic abnormalities are present in half of cases. Demyelination of the optic tracts is observed; the optic neuromyelitis is probably of postinfectious origin. In three cases MRI revealed lesions in the pituitary and inferior hypothalamus (Vernant et al., 1997). 21.3. Langerhans’ cell histiocytosis (Hand–Schüller–Christian disease; histiocytosis-X) Hand–Schüller–Christian disease, with its granuloma that are preferentially located in the hypothalamus and pituitary (Gagel, 1941; Treip, 1992; Fig. 21.14) is also known as Langerhans’ histiocytosis or histiocytosis-X (Kepes and Kepes, 1969; Schneider and Güthert, 1975). The terms Gagel’s granuloma, eosinophilic granuloma, Ayala’s granuloma, Letterer–Siwe disease and hypothalamic granuloma have all been used (Horvath et al., 1997;

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Fig. 21.11. Microphotograph of a (p)reactive lesion in the optic nerve (on) and in the supraoptic nucleus (son) in multiple sclerosis (MS) patient 96-307. A: HLA-DP, -DQ, -DR-positive cells in the ON and SON (arrowheads point at HLA-DP, -DQ, -DR-negative SON neurons) in section 601. B: Interleukin-1(IL-1)-staining of section 599. The same area as in A, containing the son and a rim of the on. Arrowheads point at IL1-negative and the arrow points at an IL-1-positive neuron in son. In the on, arrowheads point at IL--ir glial cells. C: Magnification of HLA-DP, -DQ, -DR-positive cells in the on; D: magnification of interleukin-1 (IL-1)-ir cells in the on. Note: in the gray matter in the son, as well as in white matter in the on, HLA-DP, -DQ, -DR-ir glial cells are present that are indicative of a (p)reactive MS lesion in both areas, whereas IL-1-ir cells are only present in the on and not in the son. Bar: 45 m in A, B; 15 m in C, D. (From Huitinga et al., 2000a, Fig. 4 with permission.)

Rosenzweig et al., 1997). The disease may represent an uncontrolled immunological reaction to an unknown antigen (D’Avella et al., 1997; Schmitz and Favara, 1998). In a very small number of families, recurrence of the disease has been reported (Arico and Egeler, 1998). There is a unifocal benign form of the disease in which the hypothalamus and pituitary are spared. It is characterized by a solitary lytic bone lesion. The multifocal form is more aggressive and, in childhood, presents with the

clinical triad – diabetes insipidus, exophthalmus and lytic bone disease – secondary to granulomas in the hypothalamus and pituitary gland. On MR images the pituitary stalk is thickened symmetrically. However, after a few years there is a complete reversal of the pituitary stalk enlargement in a large percentage of the patients. The normal high MRI signal density in the posterior lobe is frequently absent. Associated involvement of the temporal bone supports the diagnosis (Chong and Newton, 117

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Fig. 21.12. Microphotograph of interleukin-1 (IL-1)-ir neurons in the paraventricular nucleus (PVN) in two control cases and two multiple sclerosis (MS) patients illustrative of IL-1 staining intensity in the control versus the MS group. Per patient the rank number in estimated numbers of IL-1-ir PVN neurons in the group (see Fig. 21.13) are given in parentheses: A: control 96-163 (3rd), B: MS 90-246 (1st), C: control 96-019 (9th), D: MS 96-352 (9th). Arrows point at IL-1-positive neurons containing a nucleolus and arrowheads point at IL-1-negative neurons containing a nucleolus. Bar = 15 m. (From Huitinga et al., 2000a, Fig. 6 with permission.)

1993; Fig. 21.15; Rami et al., 1998; Leger et al., 1999; Czernichow et al., 2000). The classic triad of diabetes insipidus, exophthalamus and lytic bone disease is present in only 25% of the cases. Visual disturbances and endocrine dysfunctions such as delayed or precocious puberty, hypogonadism, growth retardation, growth hormone deficiency in the insulin hypoglycemic tolerance test, hypothyroidism, hypoadrenalism, panhypopituitarism, diabetes insipidus, morbid obesity and modest hyperprolactinemia may also be present (Ober et al., 1989; Chong and Newton, 1993; Lin et

al., 1998; Rami et al., 1998; Modan-Moses, 2001; Beswick et al., 2002; Harris et al., 2002). A few cases with polyneuropathy have been described. One such an atypical case is a patient with Langerhans’ cell histiocytosis and polyneuropathy, diagnosed 12 years after the development of diabetes insipidus following head trauma (Malkoç et al., 2000). A girl with Langerhans cell histiocytosis developed diabetes insipidus and central precocious puberty at 7.5 years of age (Municchi et al., 2002). In a late stage of the disease, vegetative disorders, short-term memory deficits, psychic disturbances, disor-

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since then agreement has been reached about the role of the Langerhans cell, a cell with features similar to the Langerhans’ cell of the epidermis, which is now considered to be the principal proliferating cell in the disease (Ober et al., 1989; Schmitz and Favara, 1998). The normal epidermal Langerhans cell is a dendritic, antigenpresenting cell characterized by the intracytoplasmic, tennis racket-shaped Birbeck granule of 200–400 nm in width and by expression of CD1a and S-100. Tissue damage is caused by excessive production of cytokines and prostaglandins (Rosenzweig et al., 1997). Lymphocytes and plasma cells, eosinophils, giant cells and microglia are also found. In one case – an adult male with Langerhans’ cell histiocytosis – diabetes insipidus occurred 5 years before the skin lesions and the hypothalamic mass became evident (Catalina et al., 1995; Horvath et al., 1997). By using positron-emission tomography (PET), both increased and decreased glucose metabolism was found in cases of Langerhans cell histiocytosis. The increased activity probably represents an active, ongoing disease process, and areas of decreased activity either represent a burnt-out brain lesion caused by the disease or a decreased brain metabolism of other origin (Calming et al., 2002). An unusual case of isolated histiocytosis presented as a solitary mass in the pineal gland with incomplete ocular palsy (Gizewski and Forsting, 2001). Spreading may occur through portal vessels or via the systemic circulation (Wilke, 1956). A primary phase of histiocyte proliferation is followed by brain atrophy or demyelination and gliosis of unknown origin (Barthez et al., 2000). Apart from corticosteroids (Harris et al., 2002), chemotherapy and low-dose radiotherapy have been reported to be successful treatments for Langerhans’ cell histiocytosis masses in the hypothalamus (Catalina et al., 1995). At least in those patients with shortterm polyuria or polydipsia, and with an abnormality in water-deprivation tests, rapid treatment with hypothalamopituitary radiation therapy seems justified. However, there seems to be no rationale for treating patients with full diabetes insipidus, as there is no evidence that patients in later stages of the disease will respond to this therapy (Rosenzweig et al., 1997). Although chemotherapy may cause a regression of the Langerhans’ cell histiocytosislesion, even in some cases with good therapeutic results, hormone deficiencies are usually irreversible (Rami et al., 1998). In the case of a solitary hypothalamic granuloma, where Langerhans’ cell histiocytosis was found with diabetes

Fig. 21.13. Total numbers of interleukin-1-immunoreactive (IL-1-ir) neurons in the paraventricular nucleus (PVN). Bars indicate the median. Triangles indicate individual cell counts. Note the high interindividual variation. The total number of IL-1-ir neurons in the PVN was significantly decreased in the multiple sclerosis (MS) group as compared to the control group (p < 0.05). In addition to the reduction in numbers of IL-1-ir neurons in the PVN, also the IL-1 staining intensity was strongly reduced in most MS patients. (From Huitinga et al., 2000a, Fig. 7 with permission.)

ders of temperature regulation and hypersomnolence have been described (Schneider and Güthert, 1975; Yen, 1993; Kaltsas et al., 2000). The disorder may have a waxing and waning course. About 50% of the patients with hypothalamic diabetes insipidus due to histiocytosis-X had antibodies against VP neurons. In a patient who became pregnant, diabetes insipidus remitted at about the 28th week of gestation and recurred after delivery. Improvement of the disease during pregnancy supports the notion of an autoimmune pathogenesis (Scherbaum, 1992). The disease is neuropathologically characterized by infiltration of the hypothalamus and pituitary, including the pars distalis by lipid-laden histiocytes or foam cells that appear to be involved in the autoimmune process (Scherbaum et al., 1986). Autoimmunity to hypothalamic vasopressin cells may be present in a large percentage of patients with central diabetes insipidus and Langhans’s cell histiocytosis (Pivonello et al., 2003). The ‘X’ in the term histiocytosis-X indicated an “unknown cell”, but 119

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Fig. 21.14. Gagel granuloma (Langerhans’ histiocytosis). Sagittal section of the pituitary gland, showing enlargement of the stalk and posterior lobe (on the right) by granulomatous infiltration. Hematoxylin & eosin.  5.5. (From Treib et al., 1992, Fig. 16.11 with permission.)

insipidus and panhypopituitarism, complete microsurgical excision was performed (D’Avella et al., 1997). Some clinicians advocate the combination of surgical excision with postoperative radiation (Çolak, 1998). However, surgical resection and chemotherapy with prednisolone and vinblastine have also been effective (Lin et al., 1998). Dynamic evaluation of pituitary function was not a useful predictor of late endocrine sequelae, with the possible exception of the progressively decreasing thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) (Lin et al., 1998; Maghnie et al., 1998b). Erdheim–Chester disease, first described in 1930 as lipoid granulomatosis, is a rare condition, predominantly

of middle-aged males. The pathological hallmark of this disease consists of xanthogranulomatous infiltrations of a wide variety of tissues by cells of macrophage or histiocyte lineage. Symmetrical predominantly sclerotic bone lesions sparing the epiphysis and the predominance of lipid-laden histiocytes or foam cells in the patient’s retroperitoneal tissues was considered as a diagnostic of Erdheim–Chester disease. This entity is distinct from histiocytosis-X, but the two diseases may represent a disease spectrum. Patients have been described with multiorgan involvement, thrombocytopenia, central diabetes insipidus, panhypopituitarism, hyperprolactinemia, gonadotropin insufficiency, decreased insulin-like growth factor

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Fig. 21.15. Histiocytosis. Sagittal (A) and coronal (B) precontrast and postcontrast-enhanced MR scans. The pituitary stalk (arrows) is markedly enlarged. Prominent contrast enhancement of the stalk is noted. (From Chong and Newton, 1993, Fig. 23 with permission.)

I levels and bilateral adrenal enlargement, suggesting hypothalamic-pituitary dysfunction. The high-intensity signal of the posterior pituitary on T1-weighted images may be absent on MR images, the pituitary stalk and dura may be thickened and a hypothalamic mass has been described. The diagnosis of the rare cranial localizations is usually made on the basis of a biopsy (Tritos et al., 1998a; Oweity et al., 2002; Perras et al., 2002).

21.4. Other neuroimmunological hypothalamic disorders and lesions The idiopathic hypothalamic dysfunction syndrome of childhood (Chapter 32.1) may be based upon a nonmetastatic paraneoplastic syndrome related to the presence of an occult neural-crest tumor. The tumor probably produces antineuronal antibodies that lead to extensive 121

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Fig. 21.16. Granular ependymitis of the third ventricle in a case of sudden death (NHB 96-077, 68). Bar = 400 m.

lymphocytic/histocytic infiltrates in the hypothalamus and other brain areas. Lymphocytic hypophysitis and autoimmune diabetes insipidus are discussed in Chapter 22.2. Granular ependymitis are periventricular lesions characterized by raised pyramidal granulations with focal gliosis in the subependymal region. The overlying ependyma is trophic, eroded or absent (Fig. 21.16). Some of the cases with ependymitis or subependymal gliosis are active, in the sense that they contain lymphocytic

infiltrates. Granular ependymitis is generally associated with ventricular dilatation or meningitis. Although granular ependymitis is more frequently seen in MS, it is certainly not specific for this disease and also found in, e.g. Parkinson’s disease, vascular disease and senile atrophy. In addition, it is found in, e.g. meningococcal or pneumococcal meningitis. In MS, granular ependymitis may provide a possible route for the exchange of inflammatory agents between the brain and the CSF (Adams et al., 1987).

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infections such as viral encephalitis, i.e. following infections with the Epstein-Barr or the Varizella zoster virus (Merriam 1986; Fenzi et al., 1993; Salter and White, 1993; Müller et al., 1998b). Perivascular inflammatory infiltrates and microglial proliferation of nodular type were observed in the hypothalamus (Fig. 28.1), in particular the floor of the third ventricle and in the periaqueductal gray. In two previous cases, inflammatory changes were present in the hypothalamus and in the temporal lobe or they were confined to the thalamus. Prevalence of T-lymphocytes in the affected area was suggestive of an unknown viral antigen responsible for the immuneresponse and is consistent with the observation that in 35% of the Kleine–Levin cases the onset is preceded by respiratory disease or vaccination (Fenzi et al., 1993). In addition, the increased (HLA)DQB1*0201 allele frequency was significantly increased in Kleine–Levin syndrome. This, together with the young age of onset, the recurrence of symptoms and the frequent infectious precipitating factors suggests an autoimmune etiology for Kleine–Levin syndrome (Dauvilliers et al., 2002).

In Guillain–Barré syndrome, inappropriate vasopressin secretion (Chapter 22.6a) and undetectable CSF levels of hypocretin (Ripley et al., 2001; Kanbayashi et al., 2002; Chapter 28.4) have been described, pointing to hypothalamic involvement. Paraneoplastic encephalitis is characterized by personality changes, irritability, depression, seizures, memory loss and sometimes dementia. It is due to antineuronal antibodies. Patients with anti-Ta (anti-Ma2) antibodies frequently have hypothalamic involvement, as appears, e.g. from diabetes insipidus, loss of libido, hypothyroidism, hypersomnia, hyperthermia and panhypopituitarism. The tumor should be treated (Gultekin et al., 2000; Chapter 19.1b, 32.1). For the possible autoimmune destruction of the orexin/hypocretin system in the lateral hypothalamus in case of narcolepsy, see Chapter 28.4. In anorexia and bulimia nervosa patients, autoantibodies against -MSH, ACTH and luteinizing hormonereleasing hormone (LHRH) have been found (Fetissov et al., 2002; Chapters 22.2b, 23.2), but their function has not yet been elucidated. Kleine–Levin syndrome (periodic somnolence and morbid hunger, see Chapter 28.1) may follow viral

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CHAPTER 22

Drinking disorders

As to the function of the posterior lobe, the experimental evidence is unequivocal. Its removal causes no symptoms. Moreover, its structure is nonglandular. Camus and Roussy were quite justified in speaking of it as an atrophied nervous lobe . . . We have, therefore, no evidence that pituitrin is anything more than a pharmacologically very interesting extract (Bailey and Bremer, 1921; from Anderson and Haymaker, 1974).

stretch receptors, which send inhibitory signals to the hypothalamus via an as yet unidentified neuronal pathway. The osmotic threshold for thirst is similar to that for vasopressin release. That a rapid fall in thirst takes place before any significant change in plasma osmolality occurs can be considered as a defense mechanism which protects against overhydration (McKenna and Thompson, 1998). Histamine, produced in the tuberomamillary nucleus (TMN), elicits drinking, increases the release of vasopressin and decreases urine output via H1 and H2 receptors (Brown et al., 2001). Animal experiments have revealed a number of peptides that regulate drinking behavior, such as angiotensin II (Chapter 30.5) and orexin-A, which is also involved in eating (Chapter 23). The kidney concentrates or dilutes urine under the influence of vasopressin. The segmental permeabilities in the nephron correlate with the expression of different members of the aquaporin family, seven members of which have been identified in the kidney. Vasopressindependent expression of aquaporin-2 is found in the apical membrane of the principal cells of the collecting duct (King and Yasui, 2002).

Osmoregulation and thirst. Plasma osmolality is precisely maintained within a remarkably narrow range of 282–298 mosmol/kg, which is achieved by the close integration of the antidiuretic action of vasopressin and the sensation of thirst. Plasma osmolality is the most important physiological determinant of vasopressin secretion (Robertson, 2001; Chapter 8.e). Changes in osmolality were always thought to be detected in the circumventricular organs that are said to send information to the vasopressinproducing neurons (see Chapter 8), but the identification of water channels, or aquaporins, in the supraoptic and paraventricular nucleui (SON and PVN) has challenged this traditional theory. The presence of messenger RNA (mRNA) for aquaporins in the SON and PVN may indicate that these nuclei have osmoreceptors that are independent of the osmoreceptors in the circumventricular organs, such as the subfornical organ and the organum vasculosum laminae terminalis (see Chapter 30.5). Data from a patient with defective osmoregulation of thirst with preservation of osmoregulation of vasopressin release (Hammond et al., 1986) provides corroborative evidence of separate osmoreceptors of thirst and vasopressin release. The osmotic threshold at which secretion of vasopressin begins is 284.3 mosmol/kg. During drinking there is an almost instantaneous suppression of vasopressin secretion, probably due to the activation of oropharyngeal

22.1. Pathology of the neurohypophysis The neurohypophysis consists of: (1) the pars nervosa (neural or posterior lobe); (2) the infundibular process (pituitary stalk), which contains the nerve tracts from the supraoptic and paraventricular nucleus (SON and PVN), a thin tongue of anterior pituitary tissue (pars tuberalis, containing predominantly gonadotrophs, while somatotropic, mammotropic, corticotropic and thyrotropic cells are rare) (Baker, 1977; Osamura and Watanabe, 1978) and the vessels of the portal system (see Chapter 17.1); 125

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and (3) the pars infundibularis (infundibulum). The neurohypophysis is characterized by its rich vascularity, nerve endings, Herring bodies and pituicytes, which are specialized astrocytes that are, at least in part, glial fibrillary acidic protein (GFAP)-positive (Velasco et al., 1982). The capillaries have fenestrated endothelial cells and extensive perivascular spaces. Clinically, pathology of the neurohypophysis may lead to diabetes insipidus (see Chapter 22.2) or to inappropriate secretion of vasopressin (Schwartz–Bartter syndrome; see Chapter 22.6). Apart from disturbances of water metabolism, abnormalities in the posterior pituitary, particularly space-occupying lesions, may cause symptoms such as headache and visual disturbances. In addition, the intracranial pressure may increase, producing anterior-pituitary compression. Damage to the pituitary stalk may interrupt the portal circulation and lead to infarction of the anterior lobe and thus to endocrine impairments. Congenital malformations in the neurohypophysis have also been described, such as agenesis of the posterior lobe of the pituitary in a fetus in the progeny of a mother who used alcohol during pregnancy (Konovalov et al., 1997), and persistence of the infundibular recess by which the third ventricle is protruding into the neurohypophysis. The infundibular recess in the neurohypophysis normally disappears in human embryos by the 45-mm stage (Cabanes, 1978). Moreover, duplication of the pituitary, of the adenohypophysis as well as the neurohypophysis, have been reported (Hori, 1983). The pituitary stalk is rarely duplicated in holoprosencephaly (Sarnat and Flores-Sarnat, 2001). Loss of the infundibulum or pituitary stalk due to traumatic damage has been reported (Grossman and Sanfield, 1994). Dystopia of the neurohypophysis may either be asymptomatic or accompany anterior pituitary anomalies (Aydan and Ghatak, 1994; Chapters 18.4, 18.6). Twin boys, born at 35 weeks of gestation, with hypopituitarism, hypoplasia of the anterior pituitary gland, an ectopically localized posterior pituitary at the base of the median eminence, had a paracentric inversion of the short arm of chromosome 1. The smooth appearance at the base of the median eminence and the absence of the pituitary stalk in these boys implied a developmental alteration. However, the causal relationship to the chromosome 1 anomaly remains to be determined (Siegel et al., 1995). Dystopia of the neurohypophysis is frequently accompanied by growth hormone and other pituitary deficiencies and is now generally considered to be a developmental disorder or

‘disconnection’ rather than an ‘interruption’ of the stalk due to complications at birth (Mészáros et al., 2000; see also Chapters 18.4, 18.6). In the empty-sella syndrome, the intrasellar CSF does not seem to influence posterior lobe function (Zucchini et al., 1995), while hypogonadotropic hypogonadism and growth hormone deficiency frequently occur (Cannavó et al., 2002). The following histological and histopathological phenomena may be found in the neurohypophysis (for some reviews, see also Kovacs, 1984; Treip, 1992; Horvath et al., 1997, 2000). Basophilic corticotropin (ACTH) and beta-melanotropin (MSH)-containing cell invasion (Osamura and Watanabe, 1978; Horvath et al., 2000) is generally not present before the age of 20 years and does not occur before puberty. This phenomenon is frequently (in 30%) seen in older subjects, especially in aging men. ACTH and -endorphin (or pro-opiomelanocortin) cell hyperplasia occurs in 29% of men and 14% of women. Eighty percent of the male and 77% of the female subjects with this hyperplasia were over 50 years of age (Horvath et al., 1999). These cells are generally not related to any endocrine abnormality (Sheehan and Kovacs, 1982; Sano et al., 1993; Horvath et al., 1999). Although some authors consider these cells to be one of the possible origins of basophil pituitary adenomas, in the literature only two cases of basophil adenomas in the posterior lobe have indeed been recorded (Kuebber et al., 1990). In addition, a gangliocytoma (Chapter 19.3c) containing ACTH-producing cells and inducing Cushing’s syndrome has been found in the neurohypophysis (Geddes et al., 2000). Glandular structures (Rasmussen, 1933), i.e. ectopic salivary gland tissue resembling serous acinar and duct cells (Schochet et al., 1974; Osamura and Watanabe, 1978; Horvath et al., 1997) and lymphocytic foci are common incidental findings in the posterior lobe or stalk without clinical consequences, but they are sometimes found in septicemia. The commonest finding in the infundibular stem and process is acute hemorrhage, often petechial, but sometimes large enough to cause appreciable damage to the infundibular process. Necrosis within the infundibular process itself is very rare. Hemorrhages and necroses may be associated with postpartum necrosis of the anterior pituitary, increased cranial pressure, shock, disseminated intravascular coagulation, septicemia and various hematological disorders. Traumatic brain injuries such as a gunshot wound may damage the pituitary stalk, infundibulum, and/or hypothalamus, and cause diabetes

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insipidus (Alaca et al., 2002). Accumulation of neurosecretory material and retraction bulbs are evidence of ruptured axons. In case of thrombotic thrombocytopenic purpura, vessels in the neural lobe may contain hyaline thrombi. Agonal thrombi may also be seen in the vessels of the infundibular stem. Chronic changes following lesions are atrophy and loss of pituicytes. Hemosiderin deposition may be found in longstanding cases and can appear within 8 days of injury (Chapter 25.4). Chronic inflammation with infiltration of lymphocytes, predominantly of the T-cell and CD4+ type, and plasma cells are found in cases of lymphocytic infundibuloneurohypophysitis and may cause diabetes insipidus. This disorder mainly occurs in women and most often in the later stages of pregnancy. It is characterized by thickening of the pituitary stalk, enlargement of the neurohypophysis, absence of the hyperintense MRI signal of the posterior pituitary, diabetes insipidus, visual disturbances and anterior pituitary deficiencies, while sometimes a large mass may involve the hypothalamus, infundibulum, optic nerves, chiasm and tracts (Kamel et al., 1998; Maghnie et al., 1998b; Tubridy et al., 2001; Ouma and Farrell, 2002; see Chapter 22.2b). An autoimmune-mediated process is presumed and the disorder may respond to corticosteroids (Ouma and Farrell, 2002). Panhypopituitarism and diplopia, secondary to fourth nerve palsy, have been described. Fibrosis following infections may also be found in the neurohypophysis. Cystic changes in the infundibular process have been described, as well as squamous keratin positive cell nests (Asa et al., 1981), which are frequently found in the pituitary stalk. Hypovolemic shock of the mother at the time of delivery may not only cause pituitary necrosis, but also affect the tuber cinereum, pituitary stalk, SON and PVN. Hypopituitarism of pregnancy may be accompanied by diabetes insipidus of sudden onset following severe postpartum hemorrhage. However, true diabetes insipidus is rare in Sheehan’s syndrome, and lesions may be present in the posterior lobe without corresponding clinical symptoms. In fact, 50% of the Sheehan’s syndrome patients did not get diabetes insipidus for more than 30 years after the causative event (Otsuka et al., 1998). Probably the amount of damage to the SON and PVN will determine whether or not diabetes insipidus will occur in Sheehan’syndrome, but other factors are certainly not excluded (Sheehan and Kovacs, 1982). Indeed, in some cases of postpartem hypopituitarism,

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considerable degeneration in the SON and PVN has been reported. The estimated numbers of remaining SON neurons was often only some 20–25%. The accessory SON may also disappear. The PVN is sometimes as strongly affected as the SON, but sometimes retains its normal neuronal values. In addition, nearly all cases had petechial hemorrhages in the hypothalamus, apparently related to the terminal coma (Whitehead, 1963). Granulomas may be present on the basis of tuberculosis (see Chapter 20.1), neurosarcoidosis (Loh et al., 1997; see Chapter 21.1), syphylis, a small-vessel vasculitis such as Wegener’s granulomatosis (Woywodt et al., 2000; Chapter 22.2) or granulomatous hypophysitis, histologically characterized by infiltration of multinucleated giant cells, plasma cells and lymphocytes (Fujiwara et al., 2001). The neurohypophysis is also frequently involved in histiocytosis. Diabetes insipidus may be an early sign of this disease (Catalina et al., 1995). On MR images a thickened stalk may be seen as expression of preclinical histiocytosis (Zucchini et al., 1995; see Chapter 21.3). Numerous eosinophilic leukocytes and lipid-laden foamy macrophages may be present or fibrosis may prevail. Erdheim–Chester disease is probably a distinct form of histiocytosis (Tritos et al., 1998a). Granular cell tumors (termed ‘choristomas’ by Sternberg in 1921, and ‘granular cell myoblastomas’ or tumorettes by Shanklin in 1947) are the most common primary neurohypophysial tumors. The term choristoma is confusing, as it is also used for the unrelated neuronal choristomas or gangliocytomas or ‘ectopic ganglion cells’ (see Chapter 19.3c). They occur in some 5–17% of pituitaries (Sano et al., 1993; Fig. 19.16). Granular cell tumors are a special form of glioma (Chapter 19.4c) that are found after the second decade in some 6% of the pituitary glands (Luse and Kernohan, 1955). They consist of large cells with granular, lightly eosinophylic cytoplasm (Fig. 22.1). They are mostly small, 1–2 mm or even smaller, and are not evident from a glancing inspection. They grow slowly, are histologically benign, well demarcated, but unencapsulated. The majority remain asymptomatic. In those rare cases where granule cell tumors are symptomatic, they may cause diabetes insipidus, hypopituitarism, visual impairment or headache (Symon et al., 1971; Massie, 1979; Barrande et al., 1995; Ji et al., 1995) (see Chapter 19.4c). A case has been described of a granular cell tumor of the neurohypophysis that most probably causes acromegaly. The presumed growth hormone-releasing hormone-like 127

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compound has, however, not been identified in the tumor (Losa et al., 2000). Histologically, granular cell tumors are composed of large, spherical, oval or polygonal cells with eccentrically located nuclei and abundant acidophilic cytoplasm, containing PAS positive neuramic acid and carbohydrate-containing granula that appear to be lysosomes under the electron microscope (EM). The brown cytoplasmatic granules (Fig. 22.1) may be sufficiently numerous to import a brown pigmented appearance to the tumor (Massie, 1979). The cells are presumed to originate from pituicytes (Luse and Kernohan, 1955; Jenevein, 1964; Massie, 1979; Müller et al., 1980; Horvath et al., 1997). Granular cell tumors label with lectin, S-100, and not with neuron-specific enolase, myelin basic protein, vimentin, keratin or desmin, but mostly not with GFAP. Some showed reactivity, however, for -1-antitrypsin, 1-antichymotrypsin and cathepsin B. The latter marker suggests a lysosomal disorder. The fact that GFAP does not usually label the tumors does not support the pituicyte as a progenitor of granular cell tumors, but it does not exclude this possibility either (Nishioka et al., 1991; Losa et al., 2000). Indeed, Barrande et al. (1995) and Lafitte et al. (1994) have both reported a granular cell tumor to be positive for GFAP. Metastatic carcinomas in the posterior pituitary constitute the most important neoplasms. They may be derived from, e.g. carcinomas of the bronchus, breast, colon or prostate, or from malignant melanoma, sarcomas, lymphoma, Hodgkin’s disease or leukemia, and may give rise to diabetes insipidus (Schubiger and Haller, 1992; Ten Bokkel Huinink et al., 2000) (see Chapter 19.9). Only seldom are other neoplasms found in the neurohypophysis, i.e. gliomas, pituitary astrocytomas or pituicytomas, which may be derived from pituicytes. Immunocytochemically they may be positive for GFAP, vementin and epithelial membrane antigen. The presence of intermediate filaments in a concentric way (fibrous body), and secretory granules in one case, suggested the possibility that the tumor might also arise from folliculostellate cells of the adenohypophysis (Cenacchi et al., 2001). MRI scans show extension of the tumor into the pituitary stalk. Panhypopituitarism may be an early manifestation of this tumor, while diabetes insipidus may be absent, suggesting vasopressin release to take place above the level of the tumor (Nishizawa et al., 1997). In addition, gangliogliomas, hamartomas (Chapter 19.3; Fig. 19.9), epidermoids, suprasellar germinomas (Chapter 19.2), craniopharyngiomas (Chapter 19.5) and

lipomas have been reported (Hurley et al., 1994). Gangliocytoma or ‘ectopic ganglion cells’ of the neurohypophysis have been described that produce vasopressin (Fehn et al., 1998; Horvath et al., 2000; Chapter 22.6), ACTH (Geddes et al., 2000) or -endorphin (Horvath et al., 2000). It is not clear whether they should be considered the result of abnormal migration during embryonic life, differentiation/maturation of neuroblasts, or transdifferentiation from proliferating pars intermedia cells (Horvath et al., 2000). Germinomas of the neurohypophysis and median eminence may cause diabetes insipidus, multiple deficiencies of the anterior pituitary compression of the optic chiasm and hypothalamus. This tumor can develop simultaneously with a similar tumor in the pineal region (Saeki et al., 1999). The first abnormal MRI sign in cases of germinoma in children and adolescents is pituitary stalk thickening (Mootha et al., 1997). Two cases of a meningioma of the pituitary stalk has been described that must have originated from the arachnoid membrane, since it had no dura attachment (Hayashi et al., 1997; Beems et al., 1999). Neoplasms of the infundibulum are described under various names, i.e. infundibuloma, hamartoma, glioma or astrocytoma (see Chapter 19.4). Extremely rare is a pituitary adenoma located entirely outside the sella turcica arising from the pars tuberalis, causing visual disturbance (Hamada et al., 1990). An early stage of cytoskeletal alterations as revealed by antibodies against abnormally phosphorylated tau (e.g. AT8, PHF-1 or Alz-50) are found in fibers and Herring body-like swellings in some aged patients, even if the brain is devoid of Alzheimer changes. Such changes are hardly detectable with sensitive silver methods. The relationship of these early Alzheimer changes in the neurohypophysis, and those in the SON, PVN and the rest of the brain, should be further investigated. In addition, the functional implications of these cytoskeletal changes are not yet clear (Schultz et al., 1997). For stalk sectioning lesions, see Chapters 18.4, 18.6 and 25.4. The pituitary stalk may also be absent, because it was never formed in development (e.g. Den Ouden et al., 2002; Chapters 18.4, 18.6). A thin or invisible pituitary stalk on MR images may be found in children with prenatal or perinatal-onset hypothalamic hypopituitarism who gradually develop growth hormone and ACTH deficiency (Miyamoto et al., 2001). A very thin stalk ending in a neurohypophysis without the normal MRI hypertensisity (see below) was found in a child with a persistent large craniopharyngeal canal and an enlarged empty sella

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Fig. 22.1. Cells of a granular cell tumor in the neurohypophysis. Note the brown-pigmented cytoplasmic granules (NHB 92-001). Bar = 100 m.

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turcica filled with CSF (Ekinci et al., 2003). A thickened pituitary stalk on MR images may indicate the presence of Langerhans’ histiocytosis (Czernichow et al., 2000; Chapter 21.3), lymphocytic hypophysitis (Iglesias and Díez, 2000; Chapter 22.2b), lymphocytic infundibuloneurohypophysitis (Takahashi et al., 1999; Chapter 22.2b), a germinoma (Leger et al., 1999; Czernichow et al., 2000; Chapter 19.2) or a hypophyseal tuberculoma (Sinha et al., 2000; Páramo et al., 2002). Pathological states of the neurohypophysis may be reflected in a disappearance of the MRI high-intensity signal of the posterior pituitary that is normally present in 90% of subjects (Brooks et al., 1989; Tien et al., 1991). This MRI signal was first thought to be caused by fat within the sella turcica. The source of the hyperintense MRI signal is now presumed to be the neurosecretory granules containing vasopressin (Fujisawa et al., 1989), but no attention has been paid so far to the contribution of oxytocin-containing granules. It should also be noted that, in the case of persistent elevation of vasopressin plasma levels as found in diabetes mellitus and hemodialysis, the hyperintense MRI signal in the neurohypophysis may be decreased, possibly due to depletion of vasopressin storage. When treating for hyperglycemia, plasma levels of vasopressin promptly decrease and the hyperintense MRI signal reappears within 1–2 months (Sato et al., 1995; Fujisawa et al., 1996; Chapter 22.5; Fig. 22.1). The high intensity MRI signal is frequently absent in case of macroadenoma of the anterior pituitary, craniopharyngioma, traumatic stalk transsection, patients with empty sella syndrome and diabetes insipidus. In both primary central diabetes insipidus (Chapter 22.2a) and secondary diabetes insipidus due to, e.g. germinoma, teratoma (Mootha et al., 1997; Chapter 19.2), Wolfram’s syndrome (see Chapter 22.7) or histiocytosis-x, the normal high-intensity MRI signal was not detected. In some patients with macroadenomas, a small, high signal intensity region was seen above the pituitary gland without any high intensity from within the gland itself (Colombo et al., 1987; Fujisawa et al., 1987b), suggesting the presence of a newly formed “miniature-posterior lobe” above the level of the neurohypophysis. The presence of a high-intensity MRI signal on the pituitary adenoma surface in the case of a supradiaphragmatic extension is supposed to be due to blockage of the hypothalamoneurohypophysial fibers, with an accumulation of neurosecretory granules. It generally predicts functional integrity after removal of the large pituitary adenoma (Salehi et al., 2002).

22.2. Diabetes insipidus The brain secretes thoughts as the kidney secretes urine (Jakob Moleschott,1822–1893)

Diabetes insipidus was distinguished from diabetes mellitus in 1674 by the English physician Thomas Willis (for references see Sawin, 2000). Diabetes insipidus is characterized clinically by polyuria (defined as the passage of amounts of diluted urine in excess of 2 l/m2 per 24 h or approximately 40 ml/kg per 24 h) in older children or adults) and polydipsia, and biochemically by inappropriately diluted urine in the face of rising plasma osmolality. Diabetes insipidus may be due to vasopressin deficiency in familial central diabetes insipidus, to a defect in the mechanism of kidney receptors for vasopressin, or to mutations in the vasopressin-regulated water channel of the renal collecting duct aquaporin-2 (Deen et al., 2000, Chapter in nephrogenic diabetes insipidus; Fig. 1.14) or to primary polydipsia (Chapter 22.3). Approximately 3% of the aquaporin-2 in collecting ducts is excreted into urine, and the urinary excretion of this water channel protein correlates positively with plasma vasopressin levels (Ishikawa, 2000). The simultaneous measurement of plasma vasopressin and plasma osmolality in a dehydration test is the most powerful diagnostic tool in the differential diagnosis of diabetes insipidus and primary polydipsia (Diederich et al., 2001). Thirst is the most prominent symptom of hypothalamic diabetes insipidus and is the necessary stimulus to replace urinary losses. The mechanism of regulation of thirst is normal in the vast majority of patients with central diabetes insipidus. On the other hand, the combination of diabetes insipidus and hypodipsia has also been described in association with surgery to the anterior communicating artery aneurysms, head injury, tumors, sarcoidosis, hydrocephalus and toluene exposure. Since patients with adipsia and vasopressin deficiency in response to osmotic stimuli may have entirely normal vasopressin responses to nonosmotic stimuli, such as hypotension and apomorphine, the site of the lesion in these patients seems to be the osmoreceptor (Bayliss and Cheethan, 1998; McKenna and Thompson, 1998). Central diabetes insipidus with thickened pituitary stalk on MR images may indicate the presence of Langerhans’ histiocytosis (Chapter 21.3) or germinoma (Leger et al., 1999; Chapter 19.2). The old treatment, pitressin in oil, given intramuscularly, was effective for 24 h, but the injection was often painful. Desmopressin (1-desamino-8-arginine vasopressin,

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DDAVP), however, does not have the pressor effect as seen with pitressin and lysine vasopressin (LVP) treatment and is effective when given as a nasal spray twice daily. DDAVP is now also available in tablet form. Patients with central diabetes insipidus have an increased heart rate, left ventricular contractility and impaired diastolic function. These alterations, which can be reversed by DDAVP, are probably due to stimulation of the sympathetic nervous activity induced by hypovolemia. In children with diabetes insipidus, the incidence of complications of DDAVP treatment is high, especially in those that are cortisol-deficient or treated with carbamazepine also. Children may develop water intoxication with seizures, as well as asymptomatic hyponatremia, and may even die (Rizzo et al., 2001). The normal high MRI signal of the posterior lobe is generally not detected in familial diabetes insipidus and secondary diabetes insipidus, e.g. due to germinomas, teratomas, Langerhans’ cell histiocytosis, or Wolfram’s syndrome (Fujisawa et al., 1987b; Tien et al., 1991; Rutishauser et al. 1996; Maghnie et al., 2000; Flück et al., 2001; see Chapter 21.3, 22.1, 22.7), although there seem to be exceptions to this rule (Miyamoto, 1991; Maghnie et al., 1992; Hansen et al., 1997). Increased release due to persistent elevation of plasma vasopressin levels, as found in diabetes mellitus (Chapter 22.5), may also accompany a decreased MRI signal intensity of the neurohypophysis (Fujisawa et al., 1996). The source of the hyperintense MRI signal of the posterior pituitary is most probably the neurosecretory granules that contain vasopressin (Fujisawa et al., 1989), although the contribution of oxytocin and its precursor to the bright spot is not known. The presence of a bright spot in diabetes insipidus seems to depend on the type of mutation, the turnover of neuropeptides in the neurohypophysis and possibly also the amount of oxytocin that is present.

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substitution therapy with exogenous vasopressin or analogues. Urine production may amount to some 20 l/day. The urinary excretion of the renal collecting duct water channel aquaporin-2 in central diabetes insipidus is one-eighth of that of controls (Ishikawa et al., 2000). Most mutations are presumed to impair the folding and intracellular trafficking of the preprohormone for vasopressin. In the long run, the mutant precursor seems to be toxic for the neuroendocrine neurons. As an example of the autosomal dominant form of familial diabetes insipidus, members of a Dutch family may be mentioned, who appeared to have a point mutation in one allele of the affected gene, based upon a G to T transversion at position 17 of the neurophysin encoding exon B on chromosome 20p13 (Bahnsen et al. 1992; Fig. 22.2b). Some 40 different mutations have now been found in kindreds with familial hypothalamic diabetes insipidus (Fig. 22.3), including six mutations in the part that encodes the signal peptide, and the rest, in different loci in the neurophysin II moiety, i.e. in exon 1 or 2, including two in vasopressin itself, five nonsense mutations (premature stopcodons) in exon 2 or 3, and one trinucleotide deletion in exon 2 (Ito et al., 1991; Miller, 1993; Yuasa et al., 1993; Nagasaki et al., 1995; Rittig et al., 1996; 2002; Hansen et al., 1997; Grant et al., 1998; Heppner et al., 1998; Calvo et al., 1999; Rutishauser et al., 1999; Siggaard et al., 1999; Abbes et al., 2000; Fuji et al., 2000; Skordis et al., 2000; Flück et al., 2001; Nijenhuis et al., 2001; Boson et al., 2003). All the dominant mutations contrast with the recessive mutation in vasopressin itself. The mutated form of vasopressin is a weak agonist with approximately 30-fold reduced binding to the vasopressin receptor (V2) (Willants et al., 1999). A familial autosomal dominant form of neurohypophysial diabetes was also described that is based upon a missense mutation encoding the vasopressin moiety, leading to a substitution of histidine for tyrosine at position 2 in vasopressin. The pituitary bright spot on MR images was absent. The polyuria and polydipsia started between the ages of 6 months and 3 years in this family (Rittig et al., 2002). The few available postmortem histological observations in families with hereditary hypothalamic diabetes insipidus point to severe neuronal death in the SON and PVN, associated with a loss of nerve fibers in the posterior pituitary (Hanhart, 1940; Braverman et al. 1965; Green et al., 1967; for the mutation of this kind, see Bergeron et al. 1991; Mahoney et al., 2002; Fig. 22.4), suggesting that the mutated product might be toxic to the

(a) Familial central diabetes insipidus Familial hypothalamic diabetes insipidus is transmitted as an autosomal dominant or X-linked recessive disorder (Fig. 22.2a). The gene responsible for the X-linked form of diabetes insipidus has not yet been cloned (Hansen et al., 1997). Familial central diabetes insipidus is a rare disease that accounts for about 5% of all cases of diabetes insipidus (Bayliss and Cheetham, 1998). Affected individuals have low or undetectable levels of circulating vasopressin and suffer from polydipsia and polyuria, and they respond to 131

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Fig. 22.2. (a) Pedigree of a Dutch family with hereditary hypothalamic diabetes insipidus, comprising five generations. Black symbols denote affected individuals, women are indicated by circles and men by squares. Samples were available from individuals marked by arrows. (From Bahnsen et al., 1992, Fig. 1 with permission.) (b) DNA sequencing gel, demonstrating the difference in exon B between the normal and the mutated vasopressin-neurophysin gene allele of the individual IV-3. The missense mutation G-T is indicated by arrows. Numbering of the deduced amino acid sequence corresponds to human neurophysin. (From Bahnsen et al., 1992, Fig. 2 with permission.)

neurosecretory cell. Slowly acting toxicity would also explain the variable age at onset of the disease (Schmale et al., 1993); we observed that diabetes insipidus may not strike until an individual reaches the age of approximately 8–9 years (Bahnsen et al., 1992). Other observations, too, indicate that vasopressin secretion is normal for the first few years of life, or even up to school age, and that diabetes insipidus then develops rapidly, after which it may continue to aggravate slowly for a decade or more (McLeod et al., 1993; Hansen et al., 1997; Grant et al., 1998; Siggaard et al., 1999; Mahoney et al., 2002). Family members with a mutation in vasopressin replacing Pro7

of mature vasopressin with Leu were asymptomatic for at least the first year of life, although no normal vasopressin was produced. Leu-vasopressin had apparently sufficient in vivo activity to delay the symptoms. As for the claim of Mahoney et al. (2002), that in autosomal dominant central diabetes insipidus the magnocellular vasopressin neurons are lost, but the parvocellular neurons that supply vasopressin and corticotropinreleasing hormone (CRH) to the median eminence are preserved, no direct postmortem evidence is available with double staining. Also, Bergeron et al. (1991) presumes that the smaller vasopressin neurons that are

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Fig. 22.3. Schematic diagram of the coding regions of the arginine vasopressin–neurophysin II (AVP-NPII) gene and the primary structure of the preprohormone, showing the location and type of mutations identified in familial hypothalamic diabetes insipidus. (From Rittig et al., 1996, Fig. 1 with permission.)

neurosecretory cells in the various types of familial diabetes insipidus. When the mutant of the Dutch kindred was stably expressed in a mouse pituitary cell line, the mutant precursor was synthesized, but processing and secretion were dramatically reduced and the protein did not seem to reach the trans-Golgi network (Olias et al., 1996). Studies in which various other human mutant vasopressin precursors were expressed in cell lines also showed an accumulation of the mutated vasopressin precursor in the endoplasmic reticulum, a reduced viability of the cells (Ito et al., 1997; Nijenhuis et al., 2001) and a reduced vasopressin expression (Iwasaki et al., 2000). Mutant vasopressin precursors do not fold correctly and probably cannot be processed and routed normally so that they do not move from the endoplasmic reticulum to the Golgi apparatus and neurosecretory granules. By mis-sorting, the mutations interfere with the expression of the normal allele, explaining the dominant nature of the disease. It has been shown in cell culture that the mutant precursor accumulates in the endoplasmic reticulum. Homo- and

preserved may project to nonpituitary targets. However, these smaller neurons may well be degenerating neurons, and there is no proof that these neurons do or do not project to the neurohypophysis. The onset of the symptoms and the severity of the polyuria vary considerably within the families. One missense mutation in neurophysin (1665T>G) is associated with early-onset diabetes insipidus. One index case developed the symptoms at 1 month of age (DiMeglio et al., 2001). On the other hand, in a postmortem case of a 44-year-old man with hereditary diabetes insipidus, no clear cell death was found in the SON and PVN, but immunocytochemically the neurons hardly stained for vasopressin in the PVN (Nagai et al., 1984), which indicated very late degeneration of the vasopressin neurons. One can perhaps consider this as an early phase of degeneration, although the history and several hormonal functions were atypical in these patients (Hansen et al., 1997). More systematic data from age-related studies and postmortem observations using quantitative methods are needed in order to establish the natural history of the 133

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Fig. 22.4. Supraoptic nucleus (SON), medial portion. Severe loss of vasopressin-expressing (VP) neurons in hereditary diabetes insipidus (b, d) as compared to age-matched control (a, c), with only rare immunoreactive cells (arrows). Slight gliosis and attenuation of the capillary network is also evident (d). VP immunostain; a, b  80, c, d  250. (From Bergeron et al., 1991, Fig. 2 with permission.)

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heterodimer formation between wild-type and mutant precursor formation occurs and impairs intracellular trafficking of wild-type precursor from the endoplasmic reticulum to the Golgi apparatus, and may interfere with the production of other proteins that are essential for survival of the neurons. The mutant proteins accumulate in the endoplasmic reticulum and aggregates will form that also contain the wild-type molecules, resulting in the activation of a general degradation system, autophagy, resulting in vasopressin deficiency (Sinha et al., 2000). The swollen autophagic vesicles contain cathepsin D (a lysosomal protease), endolin (a marker for late endosomes) and lysosomal-associated membrane protein-1, suggesting that they may be degradative autolysosomes, as shown in transgenic rats that express a Japanese mutant vasopressin gene (Davies and Murphy, 2002). The facts that most mutations do not affect the vasopressin moiety itself and the slow development of the “misfolding neurotoxicity” is the mechanism (Eubanks et al., 2001; Nijenhuis et al., 2001) that causes the neurosecretory neurons in hereditary hypothalamic diabetes insipidus to degenerate seem to explain why children do not develop diabetes insipidus until later, and why in adulthood degeneration of vasopressin neurons is found. However, the premature 87STOP mutation may have a different pathogenetic mechanism (Eubanks et al., 2001). Central diabetes insipidus is associated with increased baseline ACTH and cortisol secretion, and increased responsiveness of these two hormones to CRH administration. Replacement with DDAVP completely normalizes the ACTH and cortisol response to CRH, but not the baseline secretion of ACTH and cortisol (Pivonello et al., 2002).

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the vasopressin cell bodies (Scherbaum, 1992), but ultimately their presence seems to go together with partial or complete diabetes insipidus (De Bellis et al., 1994, 2002). A longitudinal study of patients with endocrine autoiommune diseases but without overt diabetes insipidus showed that the clinical phase can be preceded by a long subclinical period characterized by antibodies against vasopressin cells without impairing the posterior lobe function. However, the presence of such antibodies indicates a high risk of developing overt diabetes insipidus. The hyperintense MRI signal of the posterior pituitary can persist even in the early phase of the development of diabetes insipidus and only disappear later. Consequently, this is not a useful tool for the prediction of the progression of autoimmune diabetes insipidus (De Bellis et al., 1999, 2002). The pituitary stalk is often thickened on MR images (Maghnie et al., 2000; De Bellis et al., 2002; Pivonello et al., 2003). Interestingly, DDAVP treatment of patients with partial central diabetes insipidus for 1 year showed recovery of posterior lobe function and disappearance of the antibodies against vasopressin cells. These results are in line with the isohormonal therapy given in preclinical stages in some other endocrine autoimmune diseases (De Bellis et al., 1999). Infundibulohypophysitis usually presents with diabetes insipidus and is often associated with disturbances of vision (Tubridy et al., 2001; Ouma and Farrell, 2002). The infiltrate is predominantly composed of lymphocytes and plasma cells and may involve the hypothalamus, infundibulum, optic nerves, chiasm and tracts. A dramatic improvement may take place following administration of corticosteroids (Ouma and Farrell, 2002). Patients with lymphocytic infundibuloneurohypophysitis presenting as diabetes insipidus may have autoantibodies to vasopressin and on MR images show a normal pituitary with a focal nodular thickening of the infundibulum, stalk thickening, and lack of hyperintense signal of the normal neurohypophysis (De Bellis et al., 2002). In fact, most patients with idiopathic central diabetes insipidus have lymphocytic neurohypophysitis (Pivonello et al., 2003). Apart from diabetes insipidus, loss of hyperintense posterior lobe signal and thickened pituitary stalk, lymphocytic hypophysitis can also manifest itself with anterior pituitary disorders. Some 90% of cases with lymphocytic hypophysitis are female and at least 65% are associated with pregnancy. Sixty percent of cases have symptoms such as headache and visual defect, and 40% have hyperprolactinemia with functional involvement of

(b) Autoimmune diabetes insipidus Idiopathic diabetes insipidus is associated with autoimmunity in one third of the cases. Indeed, autoantibodies against the vasopressin-cell surfaces have been found (Fig. 22.5). Autoimmune central diabetes insipidus is very likely in young patients with a clinical history of autoimmune diseases and radiological evidence of pituitary stalk thickening (Scherbaum, 1992; De Bellis et al., 1999, 2002; Pivonello et al., 2003). Conversely, the low titer autoantibodies in patients with non-idiopathic central diabetes insipidus probably represents an epiphenomenon. Autoantibodies are never found in familial central diabetes insipidus (Pivonello et al., 2003). It has not yet been established whether the autoantibodies observed in diabetes insipidus are indeed cytotoxic and might destroy 135

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Fig. 22.5. (a) Autoantibodies to hypothalamic vasopressin cells. An unfixed 7-m cryostat section of human hypothalamus at the level of the supraoptic nucleus (SON) was incubated with native serum from a patient with idiopathic hypothalamic diabetes insipidus and stained with FITClabeled anti-human IgG. Note that the cytoplasm of large cells is stained. It is shown by the four-layer, double-fluorochrome immunofluorescence test with antivasopressin in the second sandwich that vasopressin cells were stained ( 250). (b) The same area of the SON as in (a) incubated with normal human serum and FITC-labeled polyvalent anti-human immunoglobulin. Note that the background is brighter than the dark neurosecretory cell bodies ( 400). (c) The same area of the SON as in (a) incubated with the serum of a patient with systemic lupus erythematosus containing the rare anti-ribosomal antibodies visualized by FITC-labeled anti-human IgG, which may, in very rare cases disturb the detection of vasopressin-cell antibodies. Note the coarsely granulated cytoplasmic staining of the two large cell bodies ( 400). (d) Cryostat section (7 m) of human hypothalamus at the level of the SON. The specimen was obtained from a donor aged 50 years. The section was incubated with normal human serum and FITC-labeled polyvalent anti-human immunoglobulin. The autofluorescent lipofuscin deposits in the cell bodies of large neurosecretory cells hamper the evaluation of test results ( 250). (From Scherbaum, 1992, Fig. 1 with permission.)

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the anterior pituitary (Iglesias and Díez, 2000; Tubridy et al., 2001). Stereotactic biopsies of the neurohypophysis or pituitary stalk revealed chronic inflammation with infiltration lymphocytes predominantly of the CD4+ subpopulation and plasma cells. The natural course of the lymphocytic infundibuloneurohypophysitis generally seems to be selflimited, but glucocorticoid therapy has been given to reduce intracranial hypertension. This therapy is presumed to contribute to the reduction of the mass, although proof of such an effect is lacking (Imura et al., 1993; Koshiyama et al., 1994; Paja et al., 1994; Chico et al., 1998; Kamel et al., 1998; Maghnie et al., 1998a). Specific subtypes of the major histocompatibility complex (MHC), the human leukocyte antigens (HLA), can be correlated with this disease and other autoimmune endocrine disorders. The differential diagnosis of a thickened pituitary infundibulum includes sarcoidosis, tuberculosis, germinoma, infiltrations from pituitary adenoma, hypothalamic glioma or teratoma, and mass lesions such as craniopharyngioma, Rathke’s pouch cyst, tumor of the pituitary infundibulum, metastases, and Langerhans’ cell histiocytosis (Kamel et al., 1998). In fact, autoimmunity to vasopressin-producing cells may be present in a large percentage of patients with central diabetes insipidus associated with Langerhans cell histiocytosis (Pivonello et al., 2003). An 8-year-old child who presented with acute-onset diabetes insipidus followed by an acquired growth hormone deficiency had an enlarged pituitary stalk and absence of posterior pituitary hyperintensity as shown by MRI. At the age of 15 years, a large hypothalamic mass and panhypopituitarism ere found. The perivascular inflammatory lymphocytic infiltrates suggested the presence of a lymphocytic infundibuloneurohypophysitis that reacted favorably to glucocorticoids (Maghnie et al., 1998a). Transient diabetes insipidus associated with lymphocytic infundibuloneurohypophysitis and a thickened pituitary stalk shown on MR images has also been described in a 77-year-old woman (Takahashi et al., 1999). A case of diabetes insipidus caused by nonspecific chronic inflammation of the hypothalamus was reported that had acute multifocal placoid pigment epitheliopathy with an immunogenic predisposition as well as HLA class I antigen A2 and class II antigen DR4, which might also be a case of autoimmune reaction (Watanabe et al., 1994). Cases with necrotizing infundibulohypophysitis and a combination of diabetes insipidus and hypopituitarism have been described. It is possible that this disorder, as

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described by Ahmed et al. (1993), represents an end stage of lymphocytic infundibulitis, but alternatively it may be a unique syndrome. Wegener’s granulomatosis is a systematic necrotisizing vasculitis with neurological symptoms in some 50% of cases. Antineutrophil cytoplasmic antibodies are present. A few cases have been described in which the disease remained confined to the anterior and posterior pituitary, causing hypopituitarism and diabetes insipidus. The patients did not respond to immunosuppressive therapy with cyclophosphamide, but in some patients corticosteroids gave a clinical remission (Rosete et al., 1991; Roberts et al., 1995; Berthier et al., 2000; Woywodt et al., 2000). Transient diabetes insipidus has also been described in Guillain–Barré syndrome (Pessin, 1972). It should also be mentioned that iatrogenic antibodies may be raised by treatment with vasopressin, making the patients refractory to treatment with vasopressin and causing diabetes insipidus (Bisset et al., 1976). On the basis of the limited literature on autoimmune diabetes insipidus, it seems certainly worthwhile to look for autoimmune processes that may be directed toward other hypothalamic neurons and might be an explanation for hypothalamic symptoms in other neurological, psychiatric or neuroendocrine diseases (see, e.g. idiopathic hypothalamic dysfunction syndrome of childhood (Chapter 19.1; 32.1), adipsia (Chapter 22.3), anorexia and bulimia nervosa (Fetissov et al., 2002; Chapter 23.2), obsessive-compulsive disorder (Chapter 26.6), Kleine–Levin syndrome (Chapter 28.1) and narcolepsy (Chapter 28.4). (c) Pregnancy-induced diabetes insipidus During pregnancy a transient form of diabetes insipidus sometimes occurs. The central form may respond to DDAVP but not to vasopressin, because the vasopressin analogue is much less susceptible to degradation to placental vasopressinase (Hansen et al., 1997). Vasopressinase during pregnancy is the same enzyme as cystine-aminopeptidase or oxytocinase. It may, at least partly, be responsible for the fact that the metabolic clearance of vasopressin during pregnancy increases fourfold. The enzyme decreases to undetectable levels in several days postpartum. Cases have been described with a transient diabetes insipidus during pregnancy due to extraordinarily high plasma vasopressinase activity. However, a more likely cause of polydipsia and polyuria during pregnancy is the unmasking of subclinical forms of either central or nephrogenic diabetes insipidus (see Chapter 22.2e). 137

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Apart from the presence of vasopressinase, a decreased threshold for thirst contributes to the aggravation of diabetes insipidus. When, during pregnancy, thirst increases, more water is consumed and the urine volume becomes unacceptable. The lowering of the thirst threshold is accompanied by a similar lowering of the osmotic threshold for the release of vasopressin. The result is that pregnant women drink more water, which may subsequently be retained. The exact mechanism for the altered osmoregulation in pregnancy is obscure, but the combination of changes in water homeostasis and vasopressin metabolism that occurs in normal pregnancy seems to provide an explanation for the transient expression of diabetes insipidus in pregnant women, especially in the case of latent forms of neurogenic or nephrogenic diabetes insipidus (Durr et al., 1987; Iwasaki et al., 1991; Robinson and Amico, 1991; Treip, 1992; Williams et al., 1993; Van der Post et al., 1994; Lindheimer and Davison, 1995; Naruki et al., 1996). On the other hand, a partial central diabetes insipidus, e.g. due to an asymptomatic craniopharyngioma, should also be considered in cases of pregnancy-induced diabetes insipidus (Fluteau-Nadler et al., 1998). The safety of DDAVP treatment for the child during pregnancy still has to be established (cf. Linder et al., 1986). In case of pregnancy-induced diabetes insipidus, the oxytocin levels may be normal, depending on the exact cause of this disorder (Sende et al, 1976; Shangold et al., 1983). (d) Other causes of central diabetes insipidus Diabetes insipidus has also been observed as part of a midline developmental anomaly, e.g. in septo-optic dysplasia (see Chapter 18.3), holoprosencephalic syndromes in which the development of the SON and PVN is disturbed (Sztriha et al.,1998; Robertson, 2001; Sarnat and Flores-Sarnat, 2001) and in dystopia of the neurohypophysis (Chapter 18.4). Structural lesions of the hypothalamus in children may accompany weight gain, diabetes insipidus, osmoreceptor dysfunction (hypernatremia with absent thirst), pituitary deficiencies and hyperprolactinemia (Cianfarani et al., 1993). Partial central diabetes insipidus with an elevated threshold of thirst and enhanced renal water handling to maintain body water was found in a woman who, as a 4-year-old child, had had meningitis, followed by a ventriculoperitoneal shunt operation because of normal-pressure hydrocephalus (Fukagawa et al., 2001). In addition, diabetes insipidus can be present in hypothalamic Langerhans’ cell histiocytosis (Czernichow et al., 2000; Modan-Moses et al., 2001; Municchi et al., 2002; Chapter 21.3),

Erdheim–Chester disease (a distinct form of histiocytosis) (Tritos et al., 1998a), Wolfram’s syndrome (Chapter 22.7) and in association with Laurence–Moon/Bardet– Beidl syndrome (Chapter 23.3), hypoxic/ischemic brain damage, hemorrhage, infarcts, Sheehan’s syndrome (see Chapter 17.2), inflammation and abscess formation (see Chapter 20) and tumors of the hypothalamus, including metastases (see Chapter 19), or of the pituitary. In cases of pituitary adenomas with supradiaphragmatic extension that lead to permanent diabetes insipidus, no high-intensity MRI signal is observed (Saeki et al., 2002). Following craniotomy for a pituitary tumor, a patient developed central diabetes insipidus, with absence of the posterior pituitary bright spot. She survived the severe hyponatremia, but developed permanent (6 months) disorientation to time and place, even after DDAVP administration (Gomez-Daspet et al., 2002). Diabetes insipidus may also be found following traumatic injuries (Chapter 25.1) or be due to toxins (snake venom, tetrodotoxin; Robertson, 2001) and result from surgical manipulations affecting either the SON and PVN or, more frequently, following sectioning of the hypothalamoneurohypophysial tract (see Chapter 25.4) and in Guillain–Barré syndrome (Treip, 1970b; Pessin, 1972; Rudelli and Deck, 1979; Stern et al., 1985; Fujisawa et al., 1987b; Bell, 1991; Laing et al., 1991; Arisaka et al., 1992; Catalina et al., 1995; Bayliss and Cheetham, 1998). Diabetes insipidus may also occur in neurosarcoidosis (see Chapter 21.1), in idiopathic giant cell granulomatous hypophysitis, which is histologically characterized by infiltration of multinucleated giant cells, plasma cells and lymphocytes (Fujiwara et al., 2001), and in paraneoplastic ‘limbic encephalitis’, due, for instance, to anti-Ta (= anti-Ma2) antibodies (Gultekin et al., 2000). Lesions of the neurohypophysis alone may not result in diabetes insipidus when the neurosecretory nuclei remain intact. A syndrome of partial diabetes insipidus has been reported in anorexia nervosa, where vasopressin seems to be secreted erratically, independent of plasma sodium levels (Gold et al., 1983). Although uncommon, central diabetes insipidus may develop following spinal trauma and/or surgery; it is thought that the sympathetic tone is then disturbed and vascular dilation may cause a drop in blood flow in the neurohypophysis and median eminence (Kuzeyli et al., 2001). (e) Nephrogenic diabetes insipidus Nephrogenic diabetes insipidus can be inherited or acquired. It is characterized by an inability to concentrate

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urine despite normal or elevated plasma vasopressin levels (Barberis et al., 1998). About 90–95% of patients with nephrogenic diabetes insipidus are males with the Xlinked recessive form of the disease (OM1M 304800), who have mutations in the vasopressin receptor-2 gene, located on Xq28 (Van den Ouweland et al., 1992; Birnbaumer, 2000; Morello and Bichet, 2001; Fig. 22.6). Severe disease of this X-linked form is expressed in hemizygous boys, whereas heterozygous girls may have moderate expression to no symptoms at all. Sporadic cases are frequent and they usually represent X-linked recessive nephrogenic diabetes insipidus rather than the autosomal form (Bichet et al., 1988; Holtzman et al., 1993; Ala et al., 1998; Deen and Knoers, 1998; Wildin et al., 1998; Rocha et al., 1999; Wildin and Cogdell, 1999). Over 155 mutations within the vasopressin receptor (V2) gene may cause inherited nephrogenic diabetes insipidus (Morello et al., 2001; Chen et al., 2002). The

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loss-of-function vasopressin receptor mutation R137H, which is associated with familial nephrogenic diabetes insipidus, induces constitutive arrestin-mediated desensitization. The binding of arrestins to phosphorylated receptors mediates the agonist-dependent desensitization and internalization of G-protein-coupled receptors. The affinity of arrestin for the phosphorylated G-proteincoupled receptor regulates the ability of the internalized receptor to be dephosphorylated and recycled back to the plasma membrane. Unregulated desensitization can thus induce nephrogenic diabetes insipidus (Barak et al., 2001). Other vasopressin receptor mutants cause nephrogenic diabetes insipidus by other mechanisms, e.g. by a lack of vasopressin binding or signaling, by retention in the endoplasmic reticulum or by a lack of binding of the mutated receptor with the molecular chaperone calnexin (Morello et al., 2001). A large number of vasopressin V2 receptor mutants have been identified (Arthus et al.,

Fig. 22.6. Schematic representation of the V2 receptor and identification of 155 putative disease-causing AVPR2 mutations. A solid circle indicates the location of (or the closest codon to) a mutation; a number indicates more than one mutation in the same codon. There are 78 missense mutations, 42 frameshift mutations, 6 in-frame deletions or insertions and 3 splice site mutations. Eight large deletions and one complex mutation are not shown. (From Morello and Bichet, 2001, Fig. 7 with permission.)

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2000), causing defects in its intracellular trafficking, its membrane localization, ligand-binding affinity and selectivity (Albertazzi et al., 2000; Pasel et al., 2000; Postina et al., 2000). In less than 10% of families, nephrogenic diabetes insipidus has an autosomal-recessive or autosomal dominant (OM1M 222000 and 125800, respectively) mode of inheritance, caused by mutations on chromosome 12q13 in the gene of the water channel protein aquaporin-2 (Deen and Knoers, 1998; Rocha et al., 1999; Wildin and Cogdell, 1999; Morello and Bichet, 2001; Fig. 22.7). One mutant protein leading to the autosomal dominant form was able to form heterotetramers with the wild-type aquaporin-2, in contrast to the mutants found in the recessive form (Kamsteeg et al., 2000). Normally, after binding of vasopressin to the V2 receptor, the receptor activates the G-protein Gs that stimulate a phosphorylation cascade, which promotes translocation of presynthesized aquaporin-2 water channels, which are then inserted into the apical membrane of the renal collecting duct cells and make them permeable for water. Mutations in the aquaporin-2 water channel makes the collecting

duct impermeable for water, as do mutations in the V2 receptor, resulting in nephrogenic diabetes insipidus (Fig. 8.6; Deen and Knoers, 1998; Birnbaumer, 1999; Deen et al., 2000). With the aquaporin-2 mutants, all cases of nephrogenic diabetes insipidus were identified, a unique feature for a genetic disease (Birnbaumer, 2000; Lin et al., 2002a). One mutant was studied in more detail. The mutant protein was mainly retained in the Golgi apparatus (Kamsteeg et al., 2000). Another mutant in a family with dominant nephrogenic diabetes insipidus revealed a single-nucleotide deletion in one aquaporin-2 allele. The mutated protein appeared to be localized in the basolateral membrane and late endosomes/lysosomes, whereas the wild-type protein was expressed in the apical membrane. Upon coexpression, the wild-type and mutated protein complex mistargeted to late endosomes/ lysosomes, resulting in an absence of the wild-type protein in the apical membrane. Misrouting after heteroligomerization, rather than a lack of function, thus seems to be the cause of nephrogenic diabetes insipidus in this family with a deletion in the aquaporin-2 gene (Marr et al., 2002).

Fig. 22.7. A. Schematic representation of the aquaporin-2 (AQP-2) protein and identification of 26 putative disease-causing AQP2 mutations. A monomer with six transmembrane helices is represented. The location of the protein kinase A phosphorylation site (Pa) is indicated. This site is possibly involved in the arginine vasopressin-induced trafficking of AQP2 from intracellular vesicles to the plasma membrane and in the subsequent stimulation of endocytosis. Solid circles indicate the locations of the mutations. B. Representation of the six-helix barrel of the AQP1 protein viewed parallel to the bilayer. (From Morello and Bichet, 2001.)

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Nephrogenic diabetes insipidus generally manifests a few days after birth. It will usually result in profound polyuria and consequent dehydration, vomiting, constipation, fever, irritability and a failure to thrive in infancy. Episodes of dehydration can cause brain damage, permanent mental retardation and even death. There may be a history of hydramnios (Bayliss and Cheetham, 1998; Jonat et al., 1999; Van Lieburg et al., 1999; Wildin and Cogdell, 1999). Nephrogenic diabetes insipidus is characterized by normal or elevated concentrations of vasopressin and an insensitivity to exogenously administered vasopressin analogues. It may be partially controlled by thiazide diuretics, amiloride or indomethacin (Hansen et al., 1997). Polyuria in nephrogenic diabetes insipidus may be completely concealed by concomittant adrenal failure. Polyuria starts immediately after corticosteroid replacement, probably because of an intrarenal mechanism. Cortisol seems to be required for an optimal excretion of water (Iwasaki et al., 1997; Bayliss and Cheetham, 1998). On the other hand, we observed strongly decreased vasopressin staining in the SON and PVN following corticosteroid treatment (Erkut et al., 1998), indicating a lack of free vasopressin that may also contribute to unmasking nephrogenic diabetes insipidus. Selective nonpeptide V2-renal vasopressin receptor antagonist rescued the function of V2-renal receptor mutants by promoting their proper folding and maturation. Such compounds may thus have potentially therapeutic effects (Paranjape and Thibonnier, 2001). In addition, nephrogenic diabetes insipidus may be based on osmotic diuresis (diabetes mellitus; see Chapter 22.5), hypercalcemia, and hypocalcemia (both of which impair the action of vasopressin on the distal nephron), chronic renal disease, drugs such as lithium and demeclocycline, postobstructive uropathy, solute washout from the renal medulla and primary polydipsia (Bayliss and Cheetham, 1998; Chapter 22.3). In rare cases of Gitelman’s syndrome, growth hormone deficiency or multiple pituitary hormone deficiencies are associated with empty sella and diabetes insipidus. The disease is caused by mutations in the gene encoding TSC (SLC12A3) of the distal convoluted tubule (Bettinelli et al., 1999). Cases of transient vasopressin (DDAVP)-resistant diabetes that developed during gestation have been reported. A pathogenetic factor, such as increased production of prostoglandin E2, may cause resistance to DDAVP. The hyperprostoglandin E-syndrome is a variant of Bartter’s syndrome and may be induced by lithium or

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hydronephrosis (Jin-No et al., 1998). Indomethacin and hydrochlorothiazide normalize prostoglandin E levels and decrease urine volumes. A T1-weighed MR image of the posterior pituitary may reveal decreased intensity due to increased vasopressin release. The syndrome remitted in the puerperium (Barron et al., 1984; Ford and Lumpkin, 1986; Jin-No et al., 1998). These thus appear to be cases of nephrogenic diabetes that were unmasked by pregnancy. Defective urine-concentrating ability due to a complete deficiency of aquaporin-1 was described in a few unrelated subjects. Aquaporin-1 is the archetypal waterchannel protein that is abundantly present in the renal proximal tubular epithelium, the thin descending limb of the loop of Henle and the descending vasa recta of the kidney. The gene for aquaporin-1 is localized on chromosome 7. The two subjects with a complete deficiency of aquaporin-1 did not have polyuria, but both had an impaired ability to concentrate their urine maximally when deprived of water. People with a complete deficiency of aquaporin-1 have thus unidentified mechanisms of fluid readsorption in the proximal tubules that compensate for the deficiency of aquaporin-1 (King et al., 2001). 22.3. Primary polydipsia and adipsia (a) Primary polydipsia Primary polydipsia is characterized by thirst, excessive fluid intake and hypotonic polyuria, despite preservation of the ability to secrete appropriate amounts of vasopressin in response to osmotic stimuli. A physiological inhibition of vasopressin is present due to excessive drinking. This condition was reported for the first time by Nothnagel in 1881. He described a man who was kicked by a horse, causing him to fall backward onto the back of his head. Within half an hour he developed a fierce thirst, drank 3 l of water and beer within half an hour and only then did he start to urinate. The thirst persisted for 4 days (Anderson and Haymaker, 1974). The simultaneous measurement of plasma vasopressin and plasma osmolality in a dehydration test is the best diagnostic tool in the differential diagnosis of primary polydipsia and diabetes insipidus (Diederich et al., 2001). In addition to psychiatric disorders, primary polydipsia may be associated with neurosarcoidosis or with congenital absence of the corpus callosum. In the case of tumors in the pineal or suprasellar region, a transient polydipsia can precede a state of adipsia (Zazgornik et al., 1974). 141

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In a patient who suffered from polydipsia secondary to sarcoidosis, a normal reaction to vasopressin was found. Following treatment with vasopressin, abrupt cessation of thirst occurred when serum osmolality had been lowered to 275 mosmol/kg (normally below 290 mosmol/kg). This patient thus had an abnormal sensation of thirst (Mellinger and Zafar, 1983). Polydipsia, polyuria and an increased thirst sensation can also be present during untreated thyrotoxicosis (Harvey et al., 1991). Primary polydipsia is an isolated clinical abnormality characterized by abnormal thirst. Compulsive waterdrinking is sometimes also called dipsogenic diabetes insipidus. However, the term “dipsogenic polydipsia” is generally used for ‘somatic’ patients. The disorder is known to occur in association with damage to the hypothalamus, such as closed head trauma, neurosarcoidosis, infections, multiple sclerosis or medicines such as lithium, or carbamazepine (Robertson, 2001). The vasopressin levels of compulsive water-drinking psychiatric patients are higher, at any given level of osmolality, but vasopressin secretion can only account for hyponatremia – not for polydipsia, the primary problem. Angiotensin II, a known dipsinogen in animals, has also been proposed as a possible etiological factor. Neuroleptics increase angiotensin II, induce thirst in animals and release vasopressin (Verghese et al., 1993), but there are no reports on changes in this peptide with respect to primary polydipsia in patients. The syndrome is characterized by excessive water drinking, explained by the patient as having severe, persistent and unquenchable thirst, and which leads to the production of hypotonic polyuria. A hyperintense T1-weighted MRI signal is clearly present in the neurohypophysis of patients with this syndrome. Three distinct abnormalities of the control of thirst appreciation have been identified in clinical studies. First, the osmotic threshold for thirst appreciation is lowered to such an extent that patients are thirsty even at plasma osmolalities so low that they are associated with a complete lack of vasopressin secretion. The second abnormality is that patients drink more than healthy controls in response to a given rise in plasma osmolality. Finally, their thirst is not suppressed even while they are drinking; they continue to feel thirsty even when imbibing large quantities of water. It has been suggested that primary polydipsia is caused by abnormal function of the osmoreceptors that govern thirst, but the failure of the action of drinking to suppress thirst indicates that nonosmotic control of thirst is also abnormal. It therefore seems likely that there is a second abnormality in the integration of

osmotic and nonosmotic control of thirst in primary polydipsia (Thompson et al., 1991; McKenna and Thompson, 1998). (b) Psychogenic polydipsia Primary polydipsia may be associated with psychiatric disorders and is then generally termed ‘psychogenic polydipsia’ (Thompson et al., 1991). The criterion used for polydipsia is 2.5 l of urine per day, and a urine specific gravity of less than 1008. In one patient with “psychogenic diabetes insipidus” a normal posterior pituitary MRI bright spot was detected (Chiumello et al., 1989), indicating storage of vasopressin. Aquaporin-2 excretion in the urine is not changed in these conditions (Ishikawa, 2000). Associated disorders such as sporadic convulsive seizures, comatose states, hydronephrosis, enuresis, urinary incontinence, projectile-type vomiting and malnutrition may be present (Blum et al., 1983). Polydipsia and water intoxication cause considerable morbidity and mortality in chronic psychiatric patients. Polydipsia in psychiatric patients has been described prior to the use of neuroleptics. Many names are being used in literature for this disorder, which include psychogenic polydipsia or compulsive water drinking, intermittent hyponatremia, polydipsia syndrome and self-induced water intoxication. Water intoxication occurs in 50% of the polydipsic patients, due to cerebral edema caused by hyponatremia. The symptoms include headache, blurred vision, anorexia, nausea, vomiting and diarrhea, muscle cramps, restlessness, confusion, exacerbation of psychosis, convulsion, coma and death. Polydipsia and water intoxication are strongly associated with chronicity of the illness; 80% of the patients suffer from schizophrenia, others from affective disorders, alcohol abuse, mental retardation, organic brain disorders and personality disorders (Chiumello et al., 1989). For unknown reasons, patients with psychogenic polydipsia and intermittent hyponatremia have larger ventricle to brain ratios. Since this ratio and the lateral ventricle volume decrease during water loading, water loading does not account for the diminished brain volume observed in these patients (Leadbetter et al., 1999). (c) Adipsinogenic disorders Inappropriate lack of thirst, with consequent failure to drink in order to correct hyperosmolality, is characteristic of adipsinogenic disorders (Robertson, 2001). The

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patient denies thirst or does not drink spontaneously. Plasma osmolality and plasma sodium are elevated and blood volume is contracted with a raised blood urea. Poor cerebration and drowsiness are common symptoms and the condition can progress to somnolence, fits, hemiplegia, coma, rhabdomyolysis and acute renal failure. Four main patterns of abnormal osmoregulatory function have been described. Type A is characterized by an upward resetting of the osmotic thresholds for both thirst and vasopressin release. This rare condition is sometimes referred to as essential hypernatremia. Patients will usually respond to advice to drink approximately 2 l of fluid daily. Type B is characterized by subnormal thirst and vasopressin release to osmotic stimuli. They are able to secrete some vasopressin and the disorder may be due to partial destruction of the osmoreceptors. Type B adipsia has been described in association with microcephaly and dysplasia of the corpus callosum, early puberty and aggressive behavior, and increased renal sensitivity to vasopressin. Complete destruction of the osmoreceptor is classified as type C osmoreceptor dysfunction. Surgery for ruptured aneurysms associated with clipping of the anterior communicating artery of the circle of Willis, ablation of tumors, granulomata, toluene exposure and head injury may cause this condition. As these patients secrete normal amounts of vasopressin in response to nonosmotic stimuli, the site of the lesion is the osmoreceptor, rather than the SON or PVN. Because thirst and vasopressin deficiencies are complete, the patients are at great risk of life-threatening hyponatremia. In particular some patients who develop adipsic diabetes insipidus following surgery to aneurysms of the anterior communicating artery show significant defects of cognitive function, including shortterm memory loss. They are also unable to manage their fluid intake without assistance (McKenna and Thompson, 1998; Smith et al., 2002). The adipsogenic disorders are supposed to be based upon an osmoreceptor dysfunction and often associated with a defective osmoregulated vasopressin secretion and diabetes insipidus. Patients are at risk for de- and overhydration (Verdin et al., 1985; Ball et al., 1997). The patients usually have structural hypothalamic abnormalities such as germinoma or other tumors such as gliomas (Zazognik et al., 1974; Hammond et al., 1986). In addition, vascular abnormalities, granulomatous diseases, trauma, hydrocephalus, congenital malformations, histiocytosis, microcephaly and ventricular cysts have been found. Surgery or irradiation may also cause this disorder (Hammond et al., 1986; Ball et al., 1997). In one case a

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pseudotumor cerebri and an empty sella turcica were found. Pseudotumor cerebri was diagnosed on the basis of a high intracranial pressure, normal CSF composition, signs of intracranial hypertension and normal radiographic studies. Deficiency of vasopressin secretion was presumed to result from neurohypophysial suppression (Verdin et al., 1985). A number of children with a number of hypothalamic dysfunctions, including hypodipsia, are described in Chapter 32.1. The case of a 9-year-old boy may serve as a first example. In him, the onset of obesity was accompanied by decreased activity, episodes of lethargy, increased perspiration, mood changes, wide temperature oscillations, hypernatremic crises, high prolactin levels, an inability to excrete a water load and hypothyroidism. A follow-up study after 4 years could not identify any demonstrable hypothalamic structural lesion. The patient had a loss of thirst, there was no diabetes insipidus, and no explanation for the strong hypothalamic abnormalities could be offered (Hayek and Peake, 1982). In one case of a 2-year-old child who lacked thirst perception and suffered from polyphagia, obesity and inadequate temperature regulation, autopsy was performed and revealed inflammation of the hypothalamic nuclei (Travis et al., 1967). The possibility that inflammatory or autoimmune processes in the hypothalamus are the cause of this condition should thus be further investigated. In two unrelated boys of 13 and 18 years of age, a hypothalamic syndrome has been described consisting of early puberty dysfunction associated with aggressive behavior (Dunger et al., 1985). The pathogenetic mechanism of this syndrome has not yet been clarified. An absence of thirst has also been reported in Kallmann syndrome (see Chapter 24.3), together with hypernatremia and an elevated osmotic threshold for vasopressin release. The fact that some patients with Kallmann syndrome have osmoreceptor dysfunction and abnormal thirst regulation indicates that there is more extensive hypothalamic involvement in this disorder than previously appreciated (Hochberg et al., 1982). In various reported cases of hypodipsic hypernatremia, associated defects in antidiuretic function occurred. In several patients a deficiency of vasopressin was demonstrated with osmotic but not with nonosmotic stimuli, indicating that the osmoreceptors for thirst and vasopressin occupy overlapping areas in the anterior hypothalamus (Hammond et al., 1986). In addition, a unique patient has been described who had hypernatremia and hypodipsia without any defect in the osmoregulation of vasopressin secretion. This indicates that the neuronal 143

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pathways that mediate osmoregulation of thirst and vasopressin secretion in humans are so discrete that they can be affected separately. Development was delayed in this child and optic atrophy and intracerebral calcifications were found, as, e.g. in the case of a congenital cytomegalovirus infection (Hammond et al., 1986). In one patient with defective hypothalamic osmoreceptors a normal posterior pituitary bright spot was seen on MR images (Chiumello et al., 1989), which also indicates different locations for the two functions. Treatment consists of attempting to prevent chronic fluid deficit, e.g. by adopting a regime of regular water intake based on changes in body weight (Hammond et al., 1986). The hypertonic saline test with measurements of plasma osmolality and vasopressin is useful for distinguishing partial diabetes insipidus from psychogenic polydipsia and for the diagnosis of complex disorders of osmoreceptor and posterior pituitary function (Mohn et al., 1998). 22.4. Nocturnal diuresis Children with nocturnal enuresis, defined by persistent bed-wetting for at least 3 nights a week after the 5th year of age (Müller et al., 2002b), fail to wake in response to the need to void. Nocturnal diuresis or nightly bed-wetting in children older than 7 years affects about 10%. From this age onward there is a spontaneous cure rate of about 15%/year, which means that few children remain affected after the age of 16 years. The problem may lie in the arousal mechanism and/or in the amount of urine produced at night. Vasopressin is involved in both antidiuresis and arousal. Different subgroups of nocturnal enuresis with probably different etiologies are distinguished (Läckgren et al., 1999). For a long time now, DDAVP has been advertised as a treatment for nocturnal diuresis (Klauber, 1989; Janknegt and Smans, 1990; Nevéus et al., 2002). The vasopressin analogue was claimed to lead to total or almost total dryness in approximately two-thirds of the enuretics (Hunsballe et al., 1998). DDAVP has no major effects on sleep in enuretic children as such, but does delay bladder emptying (Nevéus et al., 2002). The possibility of permanent effects of peptides on brain development (Swaab et al., 1988) has, however, never been considered in these young children, although central effects of this compound are very probable (Müller et al., 2002b). In spite of the fact that DDAVP is generally used, the scientific basis for the use

of DDAVP in children with nocturnal diuresis is considered by some to be rather narrow (De Jong and Van der Heyden, 1991) and, when the recommended dose of DDAVP is exceeded, coupled with high fluid intake, it is even liable to cause hyponatremia and seizures (Davis et al., 1992). Hyponatremia resulting in delirium, seizures and/or coma may occur in children and occasionally in adults who are given DDAVP for nocturnal diuresis (Chan, 1997; Donoghue et al., 1998; Chapter 22.6). In addition to DDAVP, alarms are used and behavioral therapy is given (Läckgren et al., 1999). Interestingly, some cases of primary nocturnal enuresis and nephrogenic diabetes insipidus have been found to be caused by mutations in the aquaporin-2 gene which cause this protein to be inactive. Although one would expect DDAVP to be inactive, treatment with DDAVP resolves primary nocturnal enuresis completely. DDAVP consequently does not act exclusively through alteration of the renal concentrating ability but also seems to act by central targets. There are families with primary nocturnal diuresis that have a disease locus at chromosome 12q13-21 around the aquaporin-2 gene locus (Radetti et al., 2001). However, since no mutation in the aquaporin-2 coding sequence has been found, this gene is excluded as a candidate for autosomal dominant nocturnal enuresis in these families. In a significant proportion of patients with nocturnal enuresis, the normal diurnal rhythm in plasma vasopressin and urine output is reported to be absent (Nørgaard et al., 1985; Rittig et al., 1989). However, a later study has shown that such an abolished circadian rhythm is only present in the subgroup of DDAVP-responding diuretics with considerable polyuria and poorly concentrated urine at night (Hunsballe et al., 1998). There is a subgroup of children who respond to high (but not to normal) doses of DDAVP (Nevéus et al., 1999a). Various relevant differences between DDAVP responders and nonresponders have been reported. Nonresponders have a smaller spontaneous bladder capacity, and responders produce less-concentrated urine (Nevéus et al., 1999a). Enuretic children responding to DDAVP treatment have more rapid eye movement sleep than therapy-resistant children (Nevéus et al., 2002). The favorable response of nonresponders to anticholinergic medication supports the hypothesis that these children had nocturnal bladder instability (Nevéus et al., 1999b). In addition, responders have a lower nocturnal aquaporin-2 excretion than nonresponders, while plasma vasopressin levels and osmolality were similar. DDAVP treatment is proposed to increase

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aquaporin-2 secretion in the responders, thus reducing nocturnal water loss (Radetti et al., 2001). With the lack of normal, diurnal vasopressin rhythms in some cases of nocturnal enuresis and the presence of a normal melatonin rhythm (Kirchlechner et al., 2001), one may wonder whether immaturity of the retinohypothalamic tract innervating the SON, or of the suprachiasmatic nucleus (SCN) efferents close to the SON and possibly innervating its dendrites (Dai et al., 1998a; see Chapter 4), may contribute to a subgroup of patients with this disorder. The other possibility, i.e. that the SCN itself is a relatively late-maturing structure (Swaab et al., 1991, 1994), is less likely, because in children with nocturnal enuresis the melatonin rhythm as measured by 6-hydroxy-melatonin sulfate excretion in the urine is normal (Kirchlechner et al., 2001). Alternatively, Hunsballe et al. (1998) and Jonat et al. (1999) propose that nocturnal pituitary vasopressin failure is not the sole mechanism of nocturnal polyuria in enuretics persisting into adulthood, although they also mention that this group of older enuretics, even in adulthood, fail to establish normal rhythms in urine output. A normal day-to-night variation in urine output may account for the poor efficacy of DDAVP in the nonresponders according to these authors. However, another study has shown that enuretic children needed plasma vasopressin levels that are 2–3 times higher in order to maintain osmolality. These data point to a defect at the level of the vasopressin receptor or at the level of the signal transduction pathway (Eggert et al., 1999). Devitt et al. (1999) have shown that enuretic children that have either very low or very high plasma vasopressin levels are unresponsive to DDAVP. The children with very high plasma vasopressin levels are probably children with a nephrogenic diabetes insipidus based on an aquaporin-2 defect, since there is linkage to chromosome 12q. This diagnosis has been questioned since it was discovered that nocturnal enuresis responds to DDAVP. However, a case report has been published on a boy with a nephrogenic diabetes insipidus based upon a molecular-genetically confirmed mutation of the vasopressin V2 receptor gene on chromosome q28. This boy has nocturnal enuresis and DDAVP does not affect urine osmolality. Although the daily intranasal application of DDAVP does not further reduce urine output, it dramatically decreases the frequency of bed-wetting. It has therefore been hypothesized that the target for this DDAVP effect may be the vasopressin V1b receptor, influencing the central regulation of bladder control.

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In a 67-year-old patient with Shy–Drager syndrome (multisystem atrophy), nocturnal polyuria was observed, associated with an abnormal circadian rhythm of vasopressin. The patients’ plasma vasopressin levels were higher during the day than during the night (Ozawa et al., 1993), indicating that a disorder of the SCN was later indeed confirmed in this disease (Ozawa et al., 1998). In order to determine whether the nocturnal decrease in vasopressin secretion into plasma found in this patient with multisystem atrophy was a usual finding in this disorder, Ozawa et al. (1999) determined plasma vasopressin levels in 13 of such patients. The vasopressin levels showed considerable variations, but were indeed lowest during the night. DDAVP can be effective (Mathias et al., 1986). In patients with other causes of autonomic failure nocturnal polyuria and overnight weight loss may also be found. The possible mechanism for diuresis and natriuresis induced by recumbency is not known, but may include resistance to mineralocorticoids, inappropriate secretion of vasopressin, increased renal perfusion from a rise in blood pressure, and release of atrial natriuretic peptide. DDAVP reduces nocturnal polyuria, diminishes overnight weight loss and raises supine blood pressure (Mathias et al., 1986). In geriatric patients the diurnal rhythm of water excretion disappears or is reversed (Minamisawa, 1980; Chapter 4.3), and nocturia is frequent in the elderly (Kallas et al., 1999). After a complete examination has ruled out the most common organic and behavioral causes of nocturia in the elderly, DDAVP may be given and decrease night-time diuresis. Elderly patients who are treated with DDAVP should be monitored periodically for the development of hyponatremia and fluid overload (Kallas et al., 1999; Weiss and Blaivas, 2000). It should be noted that familial hypothalamic diabetes may be mistaken for enuresis nocturna (Hansen et al., 1997). 22.5. Vasopressin hypersecretion in diabetes mellitus Diabetes mellitus is associated with polyuria and polydipsia. In patients with diabetic ketoacidosis, plasma osmolality and vasopressin levels are increased, circulating volume is decreased and urinary excretion of the aquaporin-2 water channel is increased (Kusaka et al., 2002). Polyuria persists despite markedly elevated levels of vasopressin, due to the osmotic effect of hyperglycemia and altered osmoregulation of vasopressin secretion and thirst. Polyuria is classically said to be due to the osmotic 145

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diuresis caused by glucosuria. However, when hyperglycemia is improved by i.v. infusion of insulin and fluid, plasma vasopressin levels decrease promptly, within 6 h, although plasma osmolality is still high. This indicates that both osmotic and nonosmotic stimuli are involved in the hypersecretion of vasopressin. The nonosmotic control of vasopressin may contribute to circulating homeostasis, protecting against severe blood volume depletion in diabetic patients suffering from hyperglycemia and dehydration, and in patients with diabetic coma (Walsh et al., 1979; Ishikawa et al., 1990; Fujisawa et al., 1996). On the other hand, vasopressin may play a critical role in diabetic hyperfiltration and albuminuria induced by diabetes mellitus. Vasopressin elevation is considered to be an additional risk factor for diabetic nephropathy (Bardoux et al., 1999). Attenuated thirst and drinking response may be important factors in the development of the hypernatremic dehydration, which is characteristic of this condition (McKenna and Thompson, 1998). Subnormal osmoregulated thirst sensation and fluid intake could contribute to the development of hypernatremia characteristic of hyperosmolar coma. These patients respond to water deprivation with exaggerated secretion of vasopressin, blunted thirst sensation and attenuated drinking during rehydration. Reduced thirst and drinking in association with exaggerated vasopressin release has also been reported in aging. Therefore a “premature aging” of the osmoreceptor has been proposed to exist in those subjects who are at risk of hyperosmolar coma (McKenna et al., 1998). The MRI signal intensity of the posterior lobe in patients with uncontrolled non-insulindependent diabetes mellitus is lower than in healthy controls. This is thought to be due to a decreased vasopressin content of the posterior lobe, due to persistent hypersecretion, which accompanies the elevation of plasma vasopressin levels. The normal hyperintense signal reappears after diabetic control within 1–2 months (Fujisawa et al., 1996; Fig. 22.8). Plasma vasopressin and urinary excretion of aquaporin-2 are decreased to normal levels promptly in days (Kusaka et al., 2002). During the acute phase of ketoacidosis, cerebral complications may develop. A lethal outcome has been reported in 60–70% of the cases and 15% survive with severe neurological disorders. Neuroendocrine consequences are rare but have been described. A 5-year-old child survived an intracerebral crisis following ketoacidosis with visual impairment due to a vascular occipital lesion. Two to four months after the initial episode, a hypothalamopituitary disorder developed, consisting of growth hormone,

Fig. 22.8. A. The hyperintense signal in the posterior lobe is absent at the first MRI examination of a patient with uncontrolled diabetes mellitus. The signal-intensity ratio of the posterior lobe to the pons is 1.07. B. The hyperintense signal appears after diabetic control (arrow). The signal intensity ratio of the posterior lobe to the pons is 1.54. (From Fujisawa et al., 1996, Fig. 2 with permission.)

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ACTH, TSH deficiencies and central precocious puberty. MR images showed no visible lesion in the hypothalamopituitary region (Tubiana-Rufi et al., 1992). Both vasopressin and oxytocin are released from the neurohypophysis in hypoglycemia. Serotonergic 5-HT3 receptors at least partly mediate the vasopressin response, but not the oxytocin release to hypoglycemia (Volpi et al., 1998). It has been hypothesized that type 2 diabetes mellitus is due to damage of the ventromedial nucleus or to a defect of insulin or insulin receptors in the brain (Das, 2002), but evidence for this idea is lacking at present.

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and adrenal function are normal. Plasma osmolality is below the osmotic threshold for thirst, and drinking is minimal. In fact, the threshold for thirst seems to be reset to ‘protect’ the lower plasma osmolality. In contrast to the situation in nephrogenic diabetes insipidus (Chapter 22.2) total and apical membrane expression of aquaporin2 is increased (Deen et al., 2000; Ishikawa, 2000) and this water channel is excreted in higher amounts in the urine in cases of inappropriate secretion of vasopressin with hyponatremia, also after acute water load (Saito et al., 1998; 2000a; Deen et al., 2000; Ishikawa, 2000). In this syndrome the hydro-osmotic action of vasopressin is exaggerated more than expected from the plasma vasopressin levels, with nonsuppressible but normal vasopressin levels, in spite of the hypo-osmotic condition (Saito et al., 2001). The syndrome was first described following exogenously administered pitressin (Goldstein et al., 1983; McKenna and Thompson, 1998) and may also be due to excessive vasopressin release from the posterior pituitary, despite hypo-osmolality (Ishikawa et al., 1996). It should be noted here that, in cases of nonosmotic baroreceptormediated stimulation of vasopressin release, as in the case of pulmonary hypertension or liver cirrhosis, there is a decrease in “effective” blood volume or arterial underfilling. Therefore the enhanced vasopressin release (Panayotacopoulou et al., 2002), lower plasma sodium and osmolity, e.g. in congestive heart failure (Szatalowicz et al., 1981; Rondeau et al., 1982), cannot be considered to be ‘inappropriate’ but rather as an appropriate reaction to a hemodynamic stimulus. The same holds true for the increased excretion of aquaporin-2, indicating increased vasopressin release in cardiac failure and liver cirrhosis (Cadnapaphornchai and Schrier, 2000; Schrier et al., 2001). It is thus better to exclude the diagnosis of inappropriate secretion of antidiuretic hormone in these conditions (Kovacs and Robertson, 1992). Also the release of vasopressin in children with severe head injury appeared to be appropriate in response to hypovolemia and/or sodium administration (Simma et al., 2001). The inappropriate vasopressin syndrome may be due to ectopic production of vasopressin by extrahypophysial neoplasms, e.g. by a bronchus carcinoma (Table 22.1). Such paraneoplastic symptoms are found, in particular, in head and neck malignancies. Most tumors of this kind are squamous carcinomas with lower numbers of olfactory neuroblastomas or esthesioneuroblastoma, small cell neuroendocrine carcinomas, adenoid cystic carcinomas and undifferentiated carcinomas (Ferlito et al., 1997;

22.6. Inappropriate secretion of vasopressin (a) Syndrome of inappropriate secretion of antidiuretic hormone (Schwartz–Bartter syndrome) The syndrome of inappropriate secretion of antidiuretic hormone (Schwartz–Bartter syndrome) is characterized by high vasopressin levels that are nonsuppressible by acute water load, renal sodium loss (high urine sodium concentrations of more than 40 mmol/l), hypotonic hyponatremia (serum sodium level less than 134 mmol/l), and by urine that is relatively or absolutely hyperosmolar to serum. The clinical features may include confusion, muscle cramps, seizures, fatigue, loss of appetite, nausea, vomiting, some clouding of consciousness and coma (Kovacs and Robertson, 1992; Saito, 2001; Milionis et al., 2002). Electrophysiological evidence indicates that hypoosmolality promotes epileptiform activity by strengthening both the excitatory synaptic communication in the neocortex and the field effects among the entire cortical population (Andrew, 1991). In 61% of patients with central pontine myelinolysis on which autopsy was performed, hyponatremia was found (Brisman and Chutorian, 1970; Burcar et al., 1977; Apple et al., 1978; Hirshberg and Ben-Yehuda, 1997). Indeed, rapid correction of hyponatremia may lead to central pontine and extrapontine myelinolysis, for which alcoholism and malnutrition are risk factors (Chan, 1997). The pathogenetic mechanism involved in this relation-ship is unknown. When postoperative hyponatremic encephalopathy develops, menstruant women are 25 times more likely to die or have permanent brain damage than men or postmenopausal women (Ayus et al., 1992). In inappropriate vasopressin secretion, urine osmolality is usually greater than 300 mosmol/kg, edema-forming states or volume depletion are absent, while renal function 147

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TABLE 22.1. Etiology of the syndrome of inappropriate secretion of vasopressin. In most patients the defect in urinary dilution is caused by ectopic production, exogenous administration, or osmotically inappropriate neurohypophyseal secretion of vasopressin. Congenital Eutopic Malformations Acquired Ectopic Neoplasm Drugs Eutopic Neoplasm Drugs Head trauma Infections Pulmonary Neurologic Metabolic

Agenesis corpus callosum, cleft lip and palate, other midline effects

Carcinoma of bronchus, duodenum, pancreas, prostate, ovary, bladder; thymoma, mesothelioma, sarcoma Vasopressin, pitressin or DDAVP, oxytocin Carcinoma of bronchus Vincristine, carbamazepine, nicotine, phenothiazine, cyclophosphamide, tricyclic antidepressants, monoamine oxidase inhibitors, serotonin reuptake inhibitors Closed, penetrating Bacterial or viral pneumonia, abscess of lung or brain, tuberculosis of lung or brain, aspergilloma, encephalitis, bacterial or viral meningitis Asthma, pneumothorax, positive-pressure respirator Guillain–Barré, multiple sclerosis, delirium tremens, psychosis, amyotrophic lateral sclerosis, hydrocephalus, cerebrovascular occlusion or hemorrhage, cavernous sinus thrombosis Acute porphyria

From Robertson, 2001, p. 688.

Müller et al., 2000b). Such tumors may also be the reason for the high (8–30%) incidence of this syndrome following neck dissection (Zacay et al., 2002). Other neoplasmas that may produce ectopic vasopressin are, e.g. oat cell or adenocarcinomas of the lung, lymphomas, leukemia, Hodgkin’s disease, mesotheliomas, Ewing sarcomas and esthesioneuroblastomas (Kovacs and Robertson, 1992; Horvath et al., 1997). Moreover, brain tumors, both primary brain tumors and metastases (Kovacs, 1984), including a case of craniopharyngioma, a hypothalamic glioma (Brisman and Chutorian, 1970) and a ganglioma of the neurohypophysis, which produced vasopressin and caused inappropriate vasopressin secretion (Fehn et al., 1998), have been described. A case of Ratke’s cleft cyst was accompanied by this syndrome (Iwai et al., 2000). Other diseases which may be accompanied by increased vasopressin release include head injuries in which IL-6 may be the mediator through which the vasopressin secretion is stimulated (Gionis et al., 2003). The syndrome is also associated with fractures in the frontotemperal region extending to the base of the skull (Twijnstra and Minderhoud, 1980), pneumonia, exacerbations of multiple sclerosis, brain infarction, hematoma, traumata, subarachnoid hemorrhage, subdural hematoma, stroke, polyneuritis, asthma, hepatorenal syndrome (Mather

et al., 1981; Kovacs and Robertson, 1992; Pasqualetti et al., 1998) and a case of Wernicke’s encephalopathy (Haak et al., 1990; Gonzalez-Portillo et al., 1998). In addition, a case of anterior hypothalamic infarction that had alternating inappropriate vasopressin secretion and diabetes insipidus has been described (Rudelli and Deck, 1979). Moreover, inappropriate antidiuretic hormone excretion has been described in a few patients with Whipple’s disease, caused by the gram-positive bacterium Tropheryma whippelii. Evidence of hypothalamic involvement, including contrast enhancement in the mamillary bodies, was found by CT and MRI. The patient experienced changes in sleep pattern, memory loss and other neurological symptoms (Marinella an Chey, 1997). In addition, this syndrome was found to accompany central nervous system infections such as meningitis (tuberculosus, or a fungal infection such as coccidioidomycosis), encephalitis, brain abscess and malaria (Haak et al., 1990; Webb et al., 2002). Since interleukin-6 was found to cause a strong elevation of plasma vasopressin levels (Mastorakos et al., 1994), this cytokine may be one of the mediators causing the syndrome of inappropriate vasopressin secretion during active infections or inflammatory diseases. Hypothyroidism may lead to inappropriate vasopressin secretion according to some authors (Hanna and Scanlon, 1977), but may be due to a direct action of

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thyroid hormones on the kidney (Sahun et al., 2001) and should be excluded from this diagnosis by others. The same goes for renal and adrenal insufficiency (Kovacs and Robertson, 1992). Inappropriate vasopressin secretion has also been described in hydrocephalus, cerebellar and cerebral atrophy, delirium tremens, Guillain–Barré syndrome, myocardial infarction and after medicines, e.g. following administration of vasopressin, or of oxytocin when given in large quantities for the induction or augmentation of labor or following excessive self-administration via a nasal spray by nursing mothers. The syndrome of inappropriate vasopressin secretion has been found in patients using psychotropic drugs (Spigset and Hedenmalm, 1995) such as chlorpropamide, carbamazepine, antipsychotics, antidepressants, nonsteroidal antiinflammatory drugs, acetylcholine esterase inhibitors, vincristine, vinblastine, dopaminergic drugs, chlorothiazide, nicotine, phenothiazides, cyclophosphamide, morphine or barbiturates (Pessin, 1972; Hamilton, 1978; Spigset and Hedenmalm, 1995; Chan, 1997; Horvath et al., 1997; Goldman, 1999), after taking ecstacy (Henry et al., 1998) and in a case of Wernicke’s encephalopathy (Haak et al., 1990). The syndrome is also found in schizophrenic patients (Goldman et al., 1997). In fact, polydypsia would be present in some 20% of the chronic psychiatric inpatients and hyponatremia in more than 10% (DeLeon, 2003). In some of these cases, but certainly not in all, this may be due to antipsychotic drugs (Hirshberg and Ben-Yehuda, 1997; see Chapter 27.1). In one patient with schizophrenia, hyponatremia disappeared after recovery from psychosis by electroconvulsive therapy (Suzuki et al., 1992), indicating that Schwartz–Bartter syndrome may be due to the disease process. The treatment of inappropriate vasopressin secretion consists of fluid restriction, urea, furosemide, or a mineral corticoid (Ishikawa et al., 1996; Decaux, 2001; Wong et al., 2003). In addition, effective treatment has been described with demeclocycline, a nonpeptide V2 vasopressin receptor antagonist or diphenylhydantoin (Kamoi et al., 1999; Decaux, 2001; Paranjape and Thibonnier, 2001). No evidence has been found to support fluidrestriction therapy in patients with the syndrome of inappropriate secretion of vasopressin in meningitis (Møller et al., 2001). A subset of psychiatric patients have a version of altered antidiuretic hormone activity known as ‘reset osmostat’, in which urine osmolality and sodium excretion can be suppressed, and hence appear normal, if

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plasma osmolality is sufficiently diminished. This holds true for enhanced vasopressin action on the kidney by neuroleptics, but to a similar degree also for all schizophrenics or acute psychosis that enhances vasopressin secretion as in a subset of polydipsic schizophrenic patients who become water-intoxicated. To exclude this variant the patient should be given an oral waterload. Although urine osmolality and sodium concentration in these patients are low, it is typical for reset osmostat to be considerably higher than what one would be likely to see with normal antidiuretic function (Goldman, 1999). “Reset” osmostat has also been described in a number of patients with central nervous system midline defects, including one with a chromosome 13 anomaly (Gupta et al., 2000). The inappropriate vasopressin secretion reported in acute intermittent porphyria is thought to be due to damage to the SON and PVN (Chapter 28.3). An unusual case of inappropriate antidiuresis in the absence of excess vasopressin due to a nonfunctional pituitary macroadenoma has been reported (Hung et al., 2000). (b) Cerebral/central salt wasting Inappropriate secretion of vasopressin is differentiated from cerebral/central salt wasting caused by excessive renal sodium loss which leads to a decrease in extracellular fluid volume (Kamoi et al., 1999). Also in this syndrome, vasopressin levels are increased, despite hypoosmolality. It has been proposed that inappropriate natriuresis is caused by natriuretic hormones such as atrial natriuretic peptide (ANP) or by an alteration of the neural input to the kidney (Ishikawa et al., 1996). Since mineralocorticoids might improve hyponatremia dramatically, a disorder of the renin–aldosterone system may be involved. Hyponatremia accompanied by renal sodium loss and volume depletion has been reported in patients with primary cerebral tumors, carcinomatous meningitis, subarachnoidal hemorrhage, head trauma and after intracranial surgery or pituitary surgery. The volume condition, which is different from the inappropriate vasopressin secretion syndrome has to be determined by physical investigation and hematocrit (Ishikawa et al., 1996). The treatment consists of sodium and water replacement and a mineralocorticoid (Ishikawa et al., 1996). It has been proposed that damage to the lamina terminalis (Chapter 30.5) – important for the interaction between osmoreceptors and the SON and PVN – may be the cause of this disorder (Kamoi et al., 1999). 149

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(c) Other causes of hyponatremia There may be various causes of hyponatremia (Robertson, 2001). Idiopathic inappropriate secretion of vasopressin is frequently found among elderly hospitalized patients (Goldstein et al., 1983; Chan, 1997; Miller, 1997). In elderly people with the syndrome of inappropriate antidiuretic hormone secretion, 42% were found to be stuporous and 10% had seizures. Sensory impairment was mainly found in patients with sodium levels below 110 mmol/l The majority, i.e. 60% of cases, was idiopathic, while the main causes identified were pneumonia and medication (Hirshberg and Ben-Yehuda, 1997). It should be mentioned that the reduced renal concentrating ability also contributes to enhanced vasopressin secretion in elderly people (see Chapter 8.3). Severe hyponatremia may also occur in some patients with Addison’s disease or untreated hypopituitarism with hypocortisolism and hypothyroidism. They have inappropriately high vasopressin levels in relation to the low plasma osmolality. In addition, hyponatremia not infrequently occurs in elderly patients with secondary adrenal insufficiency. The hyponatremia in patients with adrenal insufficiency can be cured by corticosteroids or corticosteroids combined with mineralocorticoids. These hormones suppress vasopressin secretion and normalize the elevated aquaporin-2 excretion (Ahmed et al., 1967; Salomez-Granier et al., 1983; Oelkers, 1989; Hanna and Scanlon, 1997; Iwasaki et al., 1997, 2001; Yatagai et al., 2003). The synthesis of vasopressin seems thus under the inhibitory control of adrenal corticosteroids (Ahmed et al., 1967). And indeed, in the hypothalamus of patients who had received corticosteroid treatment we not only found a decreased number of CRH-expressing neurons in the paraventricular nucleus, but also a lower vasopressin staining in the supraoptic and paraventricular nucleus (Erkut et al., 1998). Hyponatremia is well recognized in primary hypothyroidism. Some 75% of the hypothyroid patients have raised plasma vasopressin levels, which do not suppress normally after water ingestion. The high plasma vasopressin levels in hypothyroid patients may be due to a nonosmotic stimulus, presumably hypovolemia, resulting in urine concentration, even when plasma osmolality is high. Thyroid replacement will restore sodium concentrations to normal in most patients. However, in refractory or symptomatic cases, moderate fluid restriction may enhance recovery (Hanna and Scanlon, 1997).

Hyponatremia is also found in gastrointestinal bleeding, leading to hypovolemia with nonosmotic stimulation of vasopressin and renal failure, partly because of the decreased clearance of vasopressin (Cadnapaphornchai and Schrier, 2000). 22.7. Wolfram’s syndrome (a) Clinical symptoms Wolfram’s syndrome (DIDMOAD: Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness; OMIM 222300) was first described by Wolfram and Wagener in 1938, although the association between optic atrophy and diabetes mellitus was already known in 1858 by the work of Albrecht von Graefe, a German ophthalmologist (Khardori et al., 1983). It is a disorder involving the presence of vasopressin-sensitive diabetes insipidus, juvenile-onset, insulin-dependent diabetes mellitus, slowly progressive atrophy of the optic nerve and perceptive hearing loss due to degeneration of the cochlear nuclei (Khardori et al., 1983; Mtanda et al., 1986; Rando et al., 1992); but only in 13% of cases are all four components present (Gunn et al., 1976). Juvenile diabetes mellitus and atrophy of the optic nerves, chiasm and tracts are the symptoms that occur most frequently in Wolfram’s syndrome (Scolding, 1996). Diabetes mellitus manifests at a median age of 6 years, followed by optic atrophy at 11 years. Diabetes insipidus occurs in 73% of cases, but Gunn et al. (1976) gives much lower figures, while nephrogenic diabetes insipidus was excluded, (Thompson et al., 1989); deafness occurs in 62% of cases within the second decade and renal tract abnormalities in 58% of cases within the third decade, followed by neurological complications in 62% of cases in the fourth decade (Barrett et al., 1995; Barrett and Bundey, 1997; Dean et al., 2000; Fuqua, 2000). Apart from these features, the clinical picture is highly variable and may include anosmia, degeneration and gliosis of olfactory bulbs and tracts, ataxia, vertigo, dysarthria, dysphagia, nystagmus, mental retardation, diffuse cortical atrophy, psychiatric disorders and seizures (Marquardt and Loriaux. 1974; Carson et al., 1977; Cremers et al., 1977; Shannon et al., 1999; Dean et al., 2002, unpubl. res.). In addition, a focus of MRI signal change in the right substantia nigra was observed in a 12-year old Wolfram patient (Galluzzi et al., 1999).

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Endocrine abnormalities may include growth retardation, hypothyroidism, hypogonadism, amenorrhea, gynecomastia and testicular atrophy (Marquardt and Loriaux, 1974; Rando et al., 1992; Kinsley et al., 1995; Collier et al., 1996; Barrett and Bundey, 1997). Sexual maturation appears to be delayed in some cases. Frequent mention was made of menstrual disorders, sometimes leading to amenorrhea. Defective fertility may occur in patients of both sexes (Editorial, 1986; Thompson et al., 1989; Barrett et al., 1995; Kinsley et al., 1995). According to Khardori et al. (1983) there would be no adrenal atrophy in Wolfram’s syndrome, but Marquardt and Loriaux (1974) found a blunted cortisol response to pyrogen infusion, although they responded normally to metyrapone and ACTH. The hypothalamopituitary adrenal axis in Wolfram’s syndrome thus needs further investigation. The course and management of the diabetes mellitus is different from that of patients with classic type I diabetes (Kinsley et al., 1995). Optic atrophy is probably not secondary to retinal pathology, but part of a generalized process of neurodegeneration (Mtanda et al., 1986). Dilatation of the efferent urinary tract, i.e. hydronephrosis, hydroureter and atonic bladder, may also be present in Wolfram’s syndrome (Cremers et al., 1977). The urinary tract abnormalities were presumed to be secondary to polyuria (Wit et al., 1986), but degeneration of the nerves innervating the bladder is a more likely explanation (Thompson et al., 1989). Sixty percent of the Wolfram syndrome patients die at age 35 (Kinsley et al., 1995) from neurological disorders and urinary tract infections.

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mutations were found in a cohort of 19 Wolfram patients by Hardy et al. (1999). The patients described by Rötig et al. (1993) had pigmented retinopathy and thus probably Kears–Sayre syndrome (Dean et al., 2002, unpubl. res.). The patient with mitochondrial mutations described by Pilz et al. (1994) probably suffered from Leber’s hereditary optic neuropathy (Dean et al., 2002, unpubl. res.). The later finding that WFS1 protein (see below) is not located on mitochondria also argues against the idea that Wolfram’s syndrome would be a mitochondria-mediated disorder (Takeda et al., 2001). Mitochondrial abnormality may, however, be present in a minority of the Wolfram patients (Barrett et al., 1995; Scolding et al., 1996; Rigoli et al., 1998), be a polymorphism rather than a pathogenic point mutation (Jackson et al., 1994), and thus a risk factor for the disease (Hofmann et al., 1997). Barrientos (1996a, b) suggested an opposite relationship, i.e. that the chromosomal defect on chromosome 4p16.1 might predispose to mitochondrial DNA deletions. This possibility remains an interesting point for future research, the more so since a Wolfram patient has been described with mitochondria that was morphologically abnormal and showed a deficient glutamate metabolism (Bundey et al., 1992). A novel gene (WFS1) encoding a putative transmembrane protein was found on chromosome 4p16.1 (Inoue et al., 1998). In the same year another group found the same gene on chromosome 4p, which they called wolframin. Wolframin codes for an 890-amino acids transmembrane protein and carries various loss-of-function mutations in 90% of Wolfram patients (Strom et al., 1998; Khanim et al., 2001). Mutation screening in Wolfram families showed a series of different mutations including stop, frameshift, deletion, nonsense and missense mutations, multiple polymorphisms and insertion mutations, most of them located in exon 8. At present little is known about the intracellular location of the protein or its physiological functions (Gerbitz, 1999; Khanim et al., 2001; Dean et al., 2002; Domènech et al., 2002). The intracellular localization of the WFS1 protein is primarily in the endoplasmic reticulum, suggesting a role in, e.g. membrane trafficking or protein processing. It was suggested that the WFS1 protein was important for the survival of islet -cells. Indeed, missense mutations have been found in the WFS1 gene in type 1 diabetes, suggesting that this gene may play a role in the development of this type of diabetes (Awata et al., 2000). Noninactivating mutations in WFS1 do not lead

(b) Molecular genetics, differential diagnosis and psychiatric symptoms Wolfram’s syndrome is an autosomal-recessive, neurodegenerative disease, generally located on chromosome 4p16.1 (Cremers et al., 1977; Polymeropoulos et al., 1994; Kinsley et al., 1995; Barrientos et al., 1996a, b; Hofmann et al., 1997). However, some Wolfram patients have linkage to chromosome 4q22-24 (El-Shanti et al., 2000). In addition, mutations and multiple deletions of mitochondrial deoxyribonucleic acid (DNA) have been claimed to be present in Wolfram syndrome patients, leading to a respiratory chain defect (Rötig et al., 1993; Hofmann et al., 1997). However, Seyrantepe et al. (1996) found no deletion in mitochondrial DNA of nine Wolfram patients, and neither did we in our patients (Dean et al., 2002, unpubl. res.). No pathogenetic mitochondrial

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to Wolfram’s syndrome, but to low-frequency, sensorineural hearing impairment (Cryns et al., 2002; Lesperance et al., 2003). A new phenotypic variant has been described with absent diabetes insipidus, presence of peptic ulcer disease and bleeding tendency secondary to a platelet aggregation defect. It also turned out to be a genotypic variant with linkage to a second Wolfram syndrome locus (WFS2) on chromosome 4q22-24 (Ajlouni et al., 2002). The exact prevalence of Wolfram’s syndrome is unknown, but probably between 1 in 100,000 (Rando et al., 1992) and 1 in 770.000 (Barrett et al., 1995). A large proportion of the individuals who are homozygous for the condition suffer severe psychiatric symptoms that lead to suicide attempts or psychiatric hospitalization (Swift et al., 1991; Barrett et al., 1995). Of the homozygous Wolfram syndrome patients, 60% experienced episodes of severe depression, psychosis or organic brain syndrome, as well as impulsive verbal and physical aggression, and 25% had a severe mental illness (Swift et al., 1991). Heterozygous carrier frequency is between 1 in 100 (Polymeropoulos et al., 1994) and 1 in 354

(Barrett et al., 1995). It is therefore of great interest that there is some evidence that the heterozygous carriers of the gene for Wolfram’s syndrome may have a predisposition for significant psychiatric illness that is some 26 times larger than that of noncarriers. Wolfram’s syndrome was claimed to account for about 8% of all psychiatric hospitalizations or suicides in the USA. The most prominent psychiatric manifestations are supposed to be depression, violent or aggressive behavior, and organic brain syndrome (Swift et al., 1990; Owen, 1998; Swift et al., 1998). A subsequent study did not, however, confirm those high frequencies of psychiatric illness in heterozygous carriers (Barrett et al., 1995). A number of linkage studies have provided evidence for the existence of a bipolar susceptibility gene on chromosome 4p16. However, so far no evidence has been found that polymorphisms in the Wolfram gene play an important role in determining the susceptibility to affective illness or schizophrenia (Evans et al., 2000b; Middle et al., 2000; Khanim et al., 2001; Torres et al., 2001). Preliminary evidence suggests a role for the WFS1 gene in the pathophysiology of impulsive suicide (Sequeira et al., 2003).

Fig. 22.9. Paraffin sections through the paraventricular nucleus of a Wolfram’s syndrome patient 94-133. (A) With the antibody III-D-7 that recognizes processed vasopressin, no immunoreactivity is found. (B) No immunoreactivity is present either with the antibody PS41 predominantly recognizing the processed form of neurophysin (NP), but (C) many positive cells are stained with the antibody Boris Y-2, recognizing the glycopeptide part of the VP precursor. These data indicate a processing disorder. Bar: 25 m. (From Gabreëls et al., 1998a, Fig. 1 with permission.)

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not to involve an osmoreceptor defect (Thompson et al., 1989). Older publications reported no abnormalities in the hypothalamus of Wolfram patients (Cremers et al., 1977; Khardori et al., 1983; Mtanda et al., 1986). While Karp et al. (1978) had already pointed to loss of neurons and accumulation of iron and calcium in hypothalamic nuclei, the phenomena were not reported by others. The SON and PVN are affected (see below), there is not only atrophy of the optic nerve, optic chiasm and optic tracts, but also demyelination and degeneration of the brainstem and cerebellum (Carson et al., 1977; Scolding et al., 1996). Degeneration has also been reported of the olfactory bulbs and tracts, as well as loss of neurons in the lateral geniculate nucleus, atrophy of the superior colliculus, pons, medullary reticular activating system, loss of fibers of the cochlear nerve, loss of neurons in the cochlear nuclei and inferior colliculus, substantia nigra, superior and inferior olives and cerebellum. Swollen and dystrophic axons were found in the pons, fornix, hippocampus and the deep cerebral white matter.

The prediction that 25% of all patients hospitalized for depression are Wolfram heterozygotes (Swift and Swift, 2000) can now be tested by mutation screening. (c) The hypothalamoneurohypophysial system The differential diagnosis includes olivopontocerebellar atrophy, multisystem atrophy, congenital rubella syndrome, Leber’s hereditary optic atrophy, Kearns–Sayre syndrome, and thiamine-responsive anemia with diabetes mellitus and deafness. The association of diabetes mellitus with optic atrophy also occurs in Friedreich’s ataxia, Refsum’s disease, Alström’s syndrome and Lawrence– Moon/Bardet–Biedl syndrome (Chapter 23.3; Dean et al., 2002, unpubl. res.). Deafness and diabetes also occur in the “3243” mitochondrial DNA mutation (Barrett and Bundey, 1997). The use of three dynamic stimuli, i.e. an osmotic stimulus, hypoglycemia and a baroregulator stimulus, showed the diabetes insipidus to be of hypothalamic origin and

Fig. 22.10. Quantification of the total number of vasopressinergic neurons as stained by the anti-glycopeptide antibody Boris-Y-2 and compared with antivasopressin of controls as stained by Truus 18-9-85 (see Swaab et al., 1995a) showed a normal total number of vasopressin neurons in the PVN of the Wolfram’s syndrome patient 94-133, and a modest decrease in the number of neurons staining for oxytocin (OXT). (From J.S. Purba and D.F. Swaab, unpubl. observations.)

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Fig. 22.11. (a) A control case, (95-33, with very long postmortem delay of 6 days stained with antibody 748 (anti-growth hormone releasing hormone (GHRH)) in the infundibular nucleus. (b) The same case as (a), shown at lower magnification. (c) A Wolfram case, 94-133, with a postmortem delay of 6 days. (d) The same case as (a), shown at lower magnification. Note the lower number of neurons expressing GHRH in this case of Wolfram’s syndrome. In another case of Wolfram’s syndrome (95-68), no GHRH staining at all was found in the infundibular nucleus. Scale bar = 50 m. (From A. Salehi and D.F. Swaab, unpublished results.)

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The latter changes were sufficient to cause a changed MRI signal intensity on MR images of the area around the ventricles (Shannon et al., 1999). MRI can also show atrophy of the optic nerves, hypothalamus, including the unusually wide third ventricle, brainstem, cerebellum and cerebellar hemispheres (Scolding et al., 1996; Genís et al., 1997; Dean et al., 2003, in prep.). The posterior lobe of the pituitary is largely absent (Carson et al., 1977). The absence of a high-intensity MRI signal in the region of the posterior pituitary that normally gives rise to a ‘posterior lobe bright spot’ is in agreement with the degeneration of the hypothalamoneurohypophysial system, but has also been described with various other causes of hypothalamic diabetes insipidus (Rando et al., 1992; Dean et al., 2002, unpubl. res.; see Chapter 22.2). We performed immunocytochemistry in three cases of Wolfram’s syndrome (Dean et al., unpubl. res.). In the two Wolfram patients with diabetes insipidus (94-133 and 96-46) we found that the SON contained hardly any neurosecretory neurons, using thionine staining, and no neurons that stained processed vasopressin. There was, moreover, a strong gliosis present in the SON as stained by GFAP. The PVN did not contain processed vasopressin or neurophysin-expressing neurons either (Fig. 22.9). However, using a potent antibody against the vasopressin precursor (antiglycopeptide 22-39 Boris Y-2; Friedmann et al., 1994), a normal number of vasopressinergic neurons was present in the PVN (Figs. 22.9, 22.10), although the cells were clearly too small (Fig. 22.9). No vasopressinergic neurons were found in the SON with Boris Y-2. Only a partial loss of oxytocin neurons was found in the PVN. In one Wolfram patient, who had a mild form of diabetes insipidus (95-68), there was only a partial absence of processed vasopressin, while no gliosis was present in the SON of this patient. It seems thus that in these patients with diabetes insipidus, there is no global loss of vasopressin neurons in the PVN as has been presumed

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(Thompson et al., 1989), while neuronal loss seems to take place in the SON. Degeneration was thus more severe in the SON than in the PVN, in contrast with the report by Carson et al. (1977). On the other hand, Shannon et al. (1999) found severe loss of the magnocellular neurons in the SON and PVN and no immunoreactivity for vasopressin in a female Wolfram patient of 38 years of age. The conclusion of our own observations on three cases was that the vasopressin neurons were present in the PVN in these Wolfram’s syndrome cases, but did not produce processed vasopressin, possibly due to a deficiency in processing of the precursor with later superadded neuronal loss. In the two Wolfram patients who did not have vasopressin staining, there was indeed also an absence of protein convertase (PC)-2 and the molecular chaperone 7B2, strongly suggesting the presence of a processing disturbance of the vasopressin precursor (Gabreëls et al., 1998a; Dean et al., unpubl. res.). The anterior commissure showed gliosis, loss of axons and scattered mineral concretions. In addition, in two Wolfram cases (94-133 and 95-68), no or only a few growth-hormone-releasing hormone (GHRH)-expressing neurons were observed in the infundibular nucleus (A. Salehi, unpublished results; Fig. 22.11). Indeed, one case of a Wolfram’s syndrome patient has been described with a disturbance in the growth hormone axis (Hofmann, 1997). Growth hormone responded normally to AVP and insulin but also failed to respond to an infusion of pseudomonas polysaccharide complex (Marquardt and Loriaux, 1974). This neuroendocrine axis should thus be studied further in Wolfram’s syndrome. The determinations of 1-44 GHRH in venous plasma of Wolfram patients as an indicator of hypothalamic GHRH release may be an interesting procedure for estimating the central disturbance of this neuroendocrine axis (Kimber et al., 1997).

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CHAPTER 23

Eating disorders (Fig. 23A)

Oh Lord, make my words sweet and appetizing. Tomorrow I may have to eat them (Prof. Head, 1959, cited by G.W. Bruyn, 1997).

Obesity is one of the most pressing health problems in the Western world. It is, among other things, responsible for 65–75% of essential hypertension, diabetes mellitus and cardiovascular problems (Hall et al., 2001). This epidemic is in need of therapeutics, but only limited progress has been made as far as the pharmacotherapy of this condition is concerned (Van der Ploeg, 2000; Clapham et al., 2001). The etiologies of eating disorders such as anorexia nervosa, bulimia nervosa (Chapter 23.2) and obesity are poorly understood. Inherited vulnerabilities, cultural pressures and adverse individual and family experiences are presumed to have a part in the pathogenetic mechanisms (Walsh and Devlin, 1998; Polivy and Herman, 2002), while biological factors have only recently become the subject of studies (Fig. 23.1). Some clinical observations illustrate the importance of hypothalamic mechanisms for governing satiety and hunger (Lustig et al., 1999). Lesions in the ventromedial hypothalamic area cause increased appetite (Chapter 26.3) and obesity (Fig. 19.13), whereas lesions in the lateral hypothalamic area (LHA) may cause anorexia (Chapter 14). Uncommon, intractable hypothalamic obesity syndrome occurs after cranial insults. It is often coupled with other hypothalamopituitary disturbances that may exacerbate the obesity, such as growth hormone deficiency or hypothyroidism, but the obesity remains after hormone replacement. Neurocystiscerosis in the anterior hypothalamus, an infection caused by the presence of Taenia larvae, was accompanied by obesitas and hyperphagia (Lino et al., 2000). Satiation produces significant decreases in bloodflow in the hypothalamus of obese women (Gautier et al., 2001). Using a new temporal clustering technique for focal MRI (fMRI), Liu et al. (2000) observed two eating-related peaks in neural activity at two different

Fig. 23A. Museo del Prado, Madrid. JuanCarréño de Miranda, Eugenia Martinez Vallejo, La Monstrua Desnuda, 1680 (Catalogue no. 2800) Sanz Vega 3079.

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Fig. 23.1. Central and peripheral pathways involved in the regulation of food intake and energy stores. Leptin is secreted by adipose tissue and circulates to the brain, where it crosses the blood–brain barrier to reach the arcuate nucleus (ARC) within the hypothalamus. Here, a cascade is initiated that ultimately regulates feeding behavior, various endocrine systems and other functions. Leptin directly affects neurons (so-called firstorder neurons), in which either the anorexigenic peptides pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) or the orexigenic peptides neuropeptide-Y (NPY) and agouti-related protein (AGRP) are colocalized. The POMC–CART- and NPY–AGRPcontaining neurons, which are regulated in an opposing manner by leptin, project further to other brain centers. These include the ventro- and dorsomedial hypothalamus (VMH, DMH), which also express NPY, the paraventricular nucleus (PVN) and the lateral hypothalamic area (LHA), which express the neuropeptides orexin (ORX) and melanin-concentrating hormone (MCH). The LHA and other brain areas communicate with the cerebral cortex, where feeding behavior is finally coordinated. During and after a meal, various signals are generated in the periphery, which include taste signals from the oral cavity, gastric distention and humoral signals (e.g. cholecystokinin) from secretory cells of the gastrointestinal tract. These afferent signals are transmitted mainly by the vagus nerve, but also by the sympathetic nervous system to the hindbrain, particularly the nucleus of the solitary tract (NTS). This brain region communicates with higher brain areas such as the hypothalamus and the cerebral cortex. (From Chiesi et al., 2001, Fig. 1 with permission.)

times with distinct localization, i.e. in the ‘upper-anterior’ and ‘medial’ region of the hypothalamus. However, these areas cannot be linked at present to the microscopic or chemical anatomy of the hypothalamus, although there

was a dynamic interaction between these fMRI responses and plasma insulin levels. Eating disorders may accompany many diseases. Progressive wasting is a common occurrence in many

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types of cancer, acquired-immunodeficiency syndrome (AIDS) and other infectious diseases, cardiovascular disease and rheumatoid arthritis. The cachexia-anorexia syndrome is one of the main factors that lead to death and is thought to be due to cytokine stimulation of anorexigenic neuropeptides in the hypothalamus (Inui, 1999; Plata-Salamán, 2000). Some 50% of the patients with hypothalamic amenorrhea (Chapter 24.1a) have an eating disorder (Perkins et al., 2001). Eating disorders, either leading to obesity or to underweight, are associated with a number of genetic and epigenetic factors (Chapter 23d, e) and frequently occur in adults with an intellectual disability (Gravestock, 2000; Chapters 26.5, 23.1, 23.3). In addition, cultural influences are considered by some authors to be of crucial importance, as illustrated by historical and cultural differences (Bemporad, 1997). Although a large number of brain areas other than the hypothalamus form a complex network reacting to hunger and satiety (Del Parigi et al., 2002), these areas will not be systematically dealt with in this monograph. Indeed, hunger in normal volunteers is associated with an increased cerebral blood flow not only in the hypothalamus, but also in the insular cortex, orbitofrontal cortex, cingulate cortex and parahippocampal and hippocampal formation, thalamus, caudate, precuneus, putamen and cerebellum. In addition, satiation was associated with changes in blood flow in the ventromedial prefrontal cortex, dorsolateral prefrontal cortex, thalamus, amygdala, cingulate cortex, insular cortex, parahippocampal gyrus, temporal cortex, cerebellum and inferior parietal lobule (Rolls, 1984; Tataranni et al., 1999; Gautier et al., 2001). The larger number of brain structures involved in eating disorders in adolescence may be associated with an elevated risk of developing a broad range of physical and mental health problems. Adolescents with eating disorders run a substantially elevated risk of anxiety disorders, cardiovascular symptoms, chronic fatigue, chronic pain, depressive disorders, limitations in activities due to poor health, infectious diseases, insomnia, neurological symptoms and suicide attempts (Johnson et al., 2002). An interesting example of a nonhypothalamic eating disorder is the “Gourmand syndrome”, characterized by a preoccupation with food and a preference for fine eating, generally due to lesions involving the right anterior cerebral hemisphere (Regard and Landis, 1997). It should be noted that central neural mechanisms and autonomic system function occur in parallel. Sympathetic nervous system activation has a general inhibitory effect on gastrointestinal function, reducing intestinal motility

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and gastric emptying. It also plays a major role in the control of lipolysis in adipose tissue, both directly and due to effects on pancreatic hormone secretion (Snitker et al., 2000). Animal experiments using immunocytochemistry denervations and retrograde transsynaptic tracers have demonstrated parasympathetic and sympathetic control of, e.g. the pancreas by the paraventricular nucleus (PVN) and other hypothalamic centers involved in the regulation of food intake (Buijs et al., 2001). Diet is a potent regulator of adaptive thermogenesis. Starvation can decrease resting metabolic rate by 40%, while feeding acutely increases metabolic rate. Activation of the satiety systems decrease food intake and increase sympathetic nervous system outflow, leading to catabolic effects, whereas activation of the hunger systems increases food intake and parasympathetic nervous outflow, leading to anabolic effects (Nonogaki, 1999). Depression of the sympathetic and parasympathetic system is associated with increasing percentages of body fat (Peterson et al., 1988). Recent animal experimental work has revealed that the autonomic innervations of fat tissue consist not only of the sympathetic system, known for its catabolic effect, but also of a parasympathetic anabolic input. In addition, the observed somatotopic organization of the subcutaneous versus intraabdominal fat has provided an excellent explanation for the dissociation in distribution of these two fat compartments, e.g. in the metabolic syndrome, in Cushing’s syndrome and in AIDS lipodystrophy (Kreier et al., 2002). An important matter is eating, because it brings together those that are apart. Talmoed Bawli

(a) Hypothalamic nuclei involved Classically, lesions in the ventromedial nucleus (VMN; Chapter 26.3) are thought to cause avaricious appetite (Haugh and Markesbery, 1983), whereas lesions in the LHA (Chapter 14) are thought to cause anorexia (Chapter 14). However, lesions that are precisely restricted to the rat VMN do not cause hypothalamic obesity, and it has been proposed that the observed obesity is largely due to damage of the nearby aminergic medial forebrain bundle, rather than to a particular nucleus such as the VMN itself (Gold 1973; Chapter 9). On the other hand, for the feeding-suppressing action of histamine, the VMN appears to be the most important site of action (Brown et al., 2001). Moreover, the presence of hypocretin (orexin) neurons in the lateral hypothalamus, and in 159

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particular in the perifornical region, has brought this structure back into focus with regard to eating regulation (Sakurai et al., 1998; Chapter 14). Recent neurobiological research has revealed a great number of different hypothalamic neuronal systems, such as neuropeptide-Y (NPY), and fibers innervating the hypothalamus such as the aminergic systems, which are involved in the physiology and pathology of food intake. This points to extensive circuits and networks involved in eating behavior, rather than one particular nucleus, such as the VMN or LHA, as the responsible “center” (Flynn et al., 1988; Kalra et al., 1999; Chapter 26.3; Fig. 23.1). One of the most potent stimulants of food intake, NPY, a 36-amino acid member of the pancreatic polypeptide family, is produced in the infundibular nucleus (= arcuate nucleus in rodents; see Chapter 11). The letter “Y’ refers to two tyrosine residues, which occur at both ends of the molecule (Tomaszuk et al., 1996). In the human hypothalamus, moderate amounts of NPY messenger RNA (mRNA) were found not only in the infundibular nucleus but also in the PVN (Jacques et al., 1996). Injections of NPY directly into the PVN elicit a dose-dependent increase in feeding (Stanley et al., 1984). Animal experimental evidence clearly shows that upregulation of NPY and increased receptor availability underlie hyperphagia (Kalra et al., 1999). It is proposed that there is altered processing of NPY in mice with the recessive anorexia mutation (anx), which causes decreased food intake and starvation, which lead to death at 22 days after birth (Broberger et al., 1997). For other feeding regulating peptides in the infundibular nucleus, see Chapter 23c. The highest concentration of NPY in the human hypothalamus is found in the infundibular nucleus and in the VMN (Corder et al., 1990). NPY specifically enables the ingestion of carbohydrates and would have little or no impact on the consumption of fat or protein (Leibowitz, 1992). NPY neurons project to the rat PVN on galanin neurons (Horvath et al., 1996) and corticotropin-releasing hormone (CRH) neurons (Li et al., 2000), which are both involved in the regulation of ingestive behavior. In addition, NPY fibers innervate thyrotropin-releasing hormone (TRH) neurons (Mihaly et al., 2000). In the monkey PVN, NPY-containing terminals are found on cocaine- and amphetamine-regulated transcript (CART)-producing neurons (see below) (Dall Vechia et al., 2000). The PVN is a major appetite-regulating center in which oxytocin, CRH and galanin neurons, and NPY, noradrenaline, dopamine and serotonin terminals meet. It is,

moreover, presumed that NPY serves as a messenger between the neuronal processes that regulate reproduction and those that maintain energy homeostasis, and may thus be a key molecule in the nutritional infertility seen in anorexia (Kalra and Kalra, 1996; see Chapter 23.2). In addition, NPY is one of the strongest genetic factors identified that affect serum cholesterol levels (Uusitupa et al., 1998). Not only the PVN but also the perifornical area is a major focus of NPY effects on feeding behavior (Stanley et al., 1993). The activity of NPY and its receptors fluctuate over the course of the day (Leibowitz, 1992). It has been hypothesized that a defective inhibition of the NPY neuron that colocalizes agouti-related protein (AGRP) (see below) would result in reduced energy expenditure, disturbances of glucose and lipid metabolism, and obesity (Morton and Schwartz, 2001). Our research showed the opposite. The infundibular NPY content is decreased in Prader–Willi patients and nonsyndromal obesity (Goldstone et al., 2002; Fig. 23.8). Surprisingly, the absence of NPY in mice fails to alter their feeding pattern or body weight. Because a deficiency of even a single component of the pathway that limits food intake (such as leptin or the melanocortin (MC)-4 receptor; see above) can result in obesity, it has been suggested that anorexigenic signals are more redundant than those limiting food intake, and that NPY is not the only factor responsible for normal feeding and leptin response (Woods and Stock, 1996; Shimada et al., 1998; see below). NPY effects are mediated by a family of receptor subtypes – Y1-5 – and there is strong evidence for the occurrence of additional receptor subtypes. Inactivation of the Y2 receptor in mice caused increased body weight, food intake, fat deposition and an attenuated response to leptin (Naveilhan et al., 1999). The Y4 and Y5 receptors have been cloned and expressed. The Y5 receptor has been suggested to be the Y1-like receptor in feeding (Gerald et al., 1996; Balasubramaniam, 1997). However, Y5 receptor knock-out mice developed only mild late-onset obesity, so it does not seem to be the most critical feeding receptor in mice (Marsh et al., 1998). The Y5 receptor has also been designated as Y2b, and the confusion increased with the concurrent publication of a different Y receptor that was also called Y5. Y5 mRNA levels are high in the human hypothalamus, while conventional radio ligand techniques do not detect Y5like binding sites (Statnick et al., 1998). Following the International Union of Pharmacology (IUPHAR) recommendations, the Y receptor that has been referred to as both Y5 and Y2b has been designated Y6. The message

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for Y6 is present in the human brain and absent in rat tissue. However, the human Y6 gene appears to contain a frame-shift mutation followed by a stop codon, truncating the receptor at the sixth transmembrane domain, probably rendering the receptor inactive in all primates tested so far (Burkhoff et al., 1998). Throughout the human hypothalamus, 2–5 times more Y1 binding sites than Y2 binding sites were found. The number of binding sites was moderate to low. This is rather surprising, as the hypothalamus is highly enriched in both NPY cell bodies and fibers. Perhaps other receptor subtypes will ultimately appear to be present in higher amounts (Jacques et al., 1997). Dumont et al. (1998, 2000) found a relative paucity of both Y1 and Y5 receptors in the human brain, except for the dentate gyrus of the hippocampus and the bed nucleus of the stria terminalis, where significant amounts of Y1-like and Y2-like receptors were observed. Moderate levels of Y2/Y5 binding sites were reported in the human PVN and dorsomedial nucleus (Dumont et al., 2000). The NPY-Y5 receptor gene was found to be expressed in the infundibular nucleus, PVN, VMN and posterior hypothalamus (Jacques et al., 1998). The suprachiasmatic nucleus (SCN; see Chapter 4) is responsible for the circadian pattern in feeding behavior (Bernardis and Bellinger, 1996). Animal experiments indicate that the neurons of the SCN are involved in the circadian control of the autonomous nervous system and thus in the circadian regulation of glucose metabolism. The SCN may exert these functions by influencing the function of the PVN and dorsomedial nucleus (DMN; Nagai et al., 1996) and other hypothalamic nuclei that project to the parasympathetic dorsal motor nucleus of the vagus or the sympathetic preganglionic spinal cord neurons that innervate, e.g. the pancreas (Buijs et al., 2001). The nucleus basalis of Meynert (NBM) contains feeding cells, and stimulation of this area can mimic the reward value of food (Rolls, 1984).

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(Satoh et al., 1997), possibly by decreasing the production of NPY in the arcuate nucleus (Stephens et al., 1995), although activation of the alternative pathways should also be considered (Eriksson et al., 1996). Plasma leptin levels are significantly higher in obese subjects and Prader–Willi patients. These elevations are proportional to the increased body-mass index (Carlson et al., 1999), suggesting that some obese humans are resistant to leptin. Either leptin deficiency or leptin resistance can cause severe obesity in mice (Schwartz and Seely, 1997). Leptin crosses the blood–brain barrier by a saturable, receptormediated transport system (Couce et al., 1997). However, it should be noted that the arcuate nucleus is presumed to be situated outside the blood–brain barrier. In the arcuate nucleus of the rat, leptin binding increases twofold after a 2-day fast (Baskin et al., 1999). Cerebrospinal fluid (CSF) leptin concentrations in children reflect plasma leptin concentrations, including the rise in leptin levels during the advent of sexual dimorphism at puberty. Only free leptin is detectable in CSF (Landt et al., 2000). Arcuate nucleus NPY neurons and pro-opiomelanocortin (POMC) neurons are principal sites of leptin-receptor expression. Leptin increases the electrical activity of the anorexic POMC neurons, while melanocortin has an autoinhibitory effect on this circuit (Cowley et al., 2001). In addition, leptin may not only act on the arcuate nucleus. In obese rats the strongest leptin response was found in the PVN (Woods and Stock, 1996). Electrophysiological studies on rat PVN slices suggest that leptin acts as a satiety signal to inhibit feeding as a result of its ability to influence the excitability of PVN neurons (Smith et al., 1998). Leptin activates CART neurons, which mostly also contain POMC. Elmquist et al. (1997) found activation as a result of leptin administration not only in the PVN, but also in the VMN, DMN and ventral premamillary nuclei. Leptin may also act via the tuberomamillary histaminergic neurons on feeding behavior (Yoshimatsu et al., 1999). Experiments in rat indicate that leptin decreases food intake induced by melaninconcentrating hormone (MCH), galanin or NPY (Sahu, 1998), suggesting that modulation of the postsynaptic actions of these peptides is one of the mechanisms of action of leptin. The circadian fluctuations in leptin (Mantzoros, 2000) indicate a role of the suprachiasmatic nucleus. The possibility that leptin is produced not only by fat cells, but also in the brain, should certainly not be excluded (Reichlin, 1999). Leptin concentrations in the internal jugular vein are significantly higher than arterial

(b) Leptin Leptin (from the Greek word leptos = thin), a satiety factor that is produced by fat cells, has a potent influence on central mechanisms of food intake and is an essential chain in circuits that act as an adipostat. Leptin is the product of the LEP gene (Zhang et al., 1994; Halaas et al., 1995; Clapham et al., 2001). It informs the brain about the size of the body fat depots by receptors that are present in the arcuate nucleus. It reduces food intake 161

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levels in lean females and in obese (but not in lean) men (Wiesner et al., 1999). Indeed, leptin mRNA was found to be present in the rat hypothalamus and other brain regions. Since leptin mRNA expression in the brain is suppressed by fasting, a role for brain leptin in the central regulation of appetite is suggested (Morash et al., 1999). The leptin receptor occurs in at least five forms as a result of alternative splicing. It is the long form that is the most important for the regulation of the energy balance (Clapham et al., 2001). In the rat brain the leptin receptor is located in the arcuate nucleus, PVN, VMN and lateral hypothalamic area. In addition, the olfactory bulb, neocortex, cerebellar cortex, dorsal raphe nucleus, inferior olive, nucleus of the solitary tract, and the dorsal motor nucleus of the vagus nerve also show immunoreactivity. Western blotting yields the expected 120-kDa major band (Shioda et al., 1998). An immunocytochemical study of the human hypothalamus has shown leptin-receptor staining in a number of human hypothalamic nuclei, i.e. the arcuate nucleus, SCN, mamillary nucleus, PVN, DMN, supraoptic nucleus (SON), posterior nucleus, and the NBM. Moreover, the leptin-receptor is found in extrahypothalamic sites such as the inferior olivary nucleus and cerebellar Purkinje cells (Couce et al., 1997; Burguera et al., 2000), as well as in the choroid plexus, ependymal lining and small vessels wall. It was hypothesized that leptin may cross the blood–brain barrier in this way (Couce et al., 1997). Indeed, high-affinity transport systems mediating leptin uptake were found in the rat hypothalamus and across the blood–CSF barrier. High-affinity binding of leptin was also detected in the choroid plexus. In contrast, low-affinity carriers for leptin were found at the blood–brain barrier outside the hypothalamus (Zlokovic et al., 2000). The gene for the leptin receptor is mutated in fatty (fa/fa) rats and diabetic (db/db) mice (Clapham et al., 2001). The hormonal message of plasma leptin is transduced by the NPY neurons of the arcuate nucleus, e.g. to CRH, TRH and luteinizing hormone-releasing hormone (LHRH) neurons, as shown in animal experiments. The latter finding is a possible basis for coupling of the energy imbalance with menstrual irregularity and infertility (Costa et al., 1997b; Gehlert and Heiman, 1997; see Chapter 23.2). Indeed, low leptin synthesis appeared to be associated with amenorrhea in underweight females. Apparently a critical leptin level is needed, not only to trigger the menarche (Matkovic et al., 1997), but also to maintain menstruation (Köpp et al., 1997). Moreover, a rise of endogenous circulating leptin concentrations precedes the

onset of puberty in humans (Mantzoros et al., 1997). Information about the energy balance that is fed back to the TRH and CRH neurons of the PVN determines consequent effects in thermogenesis and stress reactions. Very high serum leptin levels beyond the expected levels for body mass index are found in idiopathic intracranial hypertension, a neurological disorder mainly affecting obese females, and after hypothalamic surgery, i.e. after craniopharyngeal removal (Lampl et al., 2002). (c) Neuropeptides and hormones involved The effects of leptin (Chapter 23b) and NPY (see Chapter 23a; Table 23.1) on appetite have been discussed previously. The peptide alpha-melanotropin (-MSH) is a POMC-derived peptide (Fig. 23.2) that is produced in the infundibular nucleus (Mihaly et al., 2000) and inhibits feeding behavior by acting on the MC-4 receptor. Opiates such as dynorphin and endorphin stimulate food intake (Williams et al., 1991; Rohner-Jeanrenaud, 1995; Bernardis and Bellinger, 1996; Tritos et al., 1998b; Lustig et al., 1999; Taylor, 1999; Støving et al., 2002). A mouse knock-out for POMC developed hyperphagia and obesity, defective adrenal development and altered pigmentation (Barsh, 1999; Yaswen et al., 1999). Moreover, MSH/ACTH 4-10, the core sequence of all melanocortins, administrated intranasally to human subjects, reduces body fat, plasma leptin and insulin levels (Fehm et al., 2001). It may be of relevance to weight changes after the age of 50 years that the POMC gene expression is decreased in the infundibular nucleus of postmenopausal women (Abel and Rance, 1999). Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia and hyperglycemia. This syndrome recapitulates several of the characteristic features of the agouti obesity syndrome as discussed below (Huszar et al., 1997). In humans, mutations of the G-protein-coupled MC-4 receptor gene are the cause of obesity in some 5% of the subjects. Mutation carriers have severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinaemia. Homozygotes are more affected than heterozygotes. The major phenotype of MC4R mutations is binge-eating (Vaisse et al., 1998; Yeo et al., 1998; Gu et al., 1999; Hinney et al., 1999; Jacobson et al., 2002; Branson et al., 2003; Farooqi et al., 2003). Multiple molecular mechanisms are involved in the disruption of MC4 receptor

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TABLE 23.1 Food consumption-regulating neuroactive compounds in the hypothalamus. Localization cell bodies

Effect on food consumption

Alpha melanotropin (-MSH) Agouti-related protein (AGRP) Cocaine and amphetamine-regulated transcript (CART) Corticotropin (CRH), Urocortin Dopamine Dynorphin Endorphins Galanin Ghrelin Growth hormone releasing hormone (GHRH) Histamine Hypocretin 1 and 2 (or orexin A and B) Leptin Melanin-concentrating hormone (MCH)

Infundibular nucleus (Fig. 23.2) Infundibular nucleus; coexpression in NPY neurons Infundibular nucleus and many other hypothalamic nuclei Paraventricular nucleus Ventral tegmentum Tuberal and caudal hypothalamus (Fig. 31.2) Infundibular nucleus Many hypothalamic nuclei Arcuate nucleus Infundibular nucleus Tuberomamillary nucleus Lateral hypothalamus and perifornical area Fat tissue Lateral, posterior hypothalamus and a number of other hypothalamic areas Locus coeruleus Infundibular nucleus Paraventricular nucleus Raphe nuclei Periventricular nucleus

➝ ➝➝➝➝➝

➝➝ ➝

➝ ➝

➝ ➝

➝ ➝➝

➝➝

Noradrenaline Neuropeptide-Y (NPY) Oxytocin Serotonin (5-HT) Somatostatin

➝

Active compound

➝

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/

NPY neurons (Mihaly et al., 2000). Fasting increases AGRP mRNA (Hahn et al., 1998a) and overexpression of AGRP leads to obesity (Rossi et al., 1998b). In addition, agouti-related peptides, when administered centrally, induce hyperphagia (Rossi et al., 1998b). In Prader–Willi syndrome (PWS) (Chapter 23.1) and nonsyndromic obese patients, we did not find a significant change in AGRP staining in the infundibular nucleus (Goldstone et al., 2002, see Chapter 23.2; Fig. 23.8). Three single nucleotide polymorphisms (SNPs) have been identified in the coding region of the human AGRP. Two of these SNPs were associated with susceptibility for anorexia nervosa (Vink et al., 2001b). Hypocretins 1 and 2, also known as orexins A and B, a pair of hypothalamic peptides, also act on G-proteincoupled orexin 1 and 2 receptors (Kunii et al., 1999). The peptides were called ‘hypocretins’ because they were produced in the hypothalamus and resembled the secretin neuropeptides that help regulate gut function (Samson and Resch, 2000). The word ‘orexis’ means appetite. Orexin A and B cell bodies are located in and around the lateral and posterior hypothalamus and in the perifornical area (Peyron et al., 2000; Chapter 14). These peptides stimulate food consumption and influence metabolic rate and

function by mutations, such as impaired cell surface expression on reduced binding of the ligand (Yeo et al., 2003). Injection of an MC-4 receptor agonist inhibits and injection of an MC-4 receptor antagonist stimulates feeding when injected directly into the rat PVN, where the expression of this receptor is very high (Giraudo et al., 1998). Observations in rat indicate that the satiety effect of leptin is mediated by stimulation of the hypothalamic POMC system. Agouti regulates hair color and body weight and acts as a high-affinity, natural antagonist of the MC-1, MC-3 and MC-4 receptors (Rossi et al., 1998b). Mutations in the agouti coat color gene cause obesity in mice (Fan et al., 1997; Huszar et al., 1997; Schiöth et al., 1997; Barsh, 1999; Nagle et al., 1999). Mutations within the mahogany locus suppress obesity of the agouti-lethal yellow mutant mouse, but do not suppress the obese phenotype of the MC-4 receptor null allele. The mahogany gene is expressed in the ventromedial nucleus and mahogany can suppress diet-induced obesity. The amino acid sequence of mahogany protein suggests that it is a large, single transmembrane-domain receptor-like molecule with a short cytoplasmatic tail. There is an AGRP that is an endogenous MC receptor antagonist that coexpresses in 163

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Fig. 23.2. The protein sequence of the pro-opiomelanocortin (POMC)-derived peptides is shown to illustrate the composition of the single peptides, their position within the precursor POMC and their endoproteolytic cleavage. The first residues containing the signal peptide were given negative numbers. Residues in dark gray represent the paired basic sites that serve as targets for PC1 and PC2; black arrows indicate preferential cleavage by PC1; white arrows indicate preferential cleavage by PC2. The interaction of each peptide with the two sets of receptors and the functional roles, where known, are shown. Note the exclusive binding of the MC2-R by corticotropin (ACTH) and the restricted affinity of gamma-melanotropin (-MSH) to the MC3-R. Because the physiological role of -MSH is not clear, the affinities to the different MC receptors are not included. Residues in light gray represent the binding cores of each peptide. MCR, melanocortin receptor; PC, prohormone convertase. (From Krude and Grüters, 2000, Fig. 1 with permission.)

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arousal. Prepro-orexin mRNA is upregulated after fasting (Sakurai et al., 1998) and genetic ablation of orexin neurons in mice results in obesity (Hara et al., 2001), orexin may act as MC-4 receptor agonists and may also be involved in autonomic and neuroendocrine regulation (Samson and Resch, 2000). Recently it was found that a mutation in the hypocretin (orexin) receptor 2 gene or a disappearance of the hypocretin system is responsible for narcolepsia (Lin et al., 1999; Peyron et al., 2000; Samson and Resch, 2000; Hara et al., 2001; Chapter 28.4). It is interesting though that narcolepsy patients have serum levels of leptin that are more than 50% reduced, pointing to the presence of an alteration in the regulation of food intake and metabolism in this disorder (Schuld et al., 2000). Yet another factor that influences eating behavior is galanin. It stimulates food consumption, preferentially increasing the ingestion of fat and leaving the uptake of carbohydrate and protein unaffected (Leibowitz, 1992; Akabayashi et al., 1994). Galanin is overexpressed in the PVN and median eminence of the obese Zucker rat (Beck et al., 1993), which has no functional leptin receptor. This peptide is present in the arcuate nucleus, SCN, sexually dimorphic nucleus, PVN and tuberomamillary (TMN) and supramamillary nuclei. In the human SON and SCN, as well as in the PVN, galanin is colocalized with vasopressin, oxytocin or tyrosine hydroxylase (Gai et al., 1990). From experimental studies in rat, it appears that only the anterior parvocellular, galanin-containing PVN neurons are involved in the metabolic and behavioral processes of fat metabolism and ingestion (Wang et al., 1998). In early postnatally overfed rats, excess weight and hyperinsulinemia have been observed, accompanied by an increased number of galanin-positive neurons in the PVN at weaning. The galanin neurons in the PVN may thus be involved where perinatal overfeeding is a risk factor for excess weight and diabetes during life (Plagemann et al., 1999). Oxytocin release accompanies treatments known to inhibit food intake (Verbalis et al., 1995), and oxytocin neurons of the PVN are considered to be satiety cells (see Chapter 23.1), probably acting by their projections to the brainstem nuclei (Buijs et al., 1983). The increased oxytocinergic activity observed during depression might therefore be related to the decreased food uptake in this condition (Purba et al., 1996; Chapter 26.4), and the decreased number of oxytocin neurons in the PVN of Prader–Willi patients may be responsible for their insatiable hunger (Swaab et al., 1995a; Chapter 23.1). On the

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other hand, the satiety effects of oxytocin are not without controversy. One research group has shown that long-term oxytocin subcutaneous treatment may result in increased food intake and weight gain, a mechanism that is suggested to be of possible physiological importance in lactationinduced hyperphagia (Björkstrand and Uvnäs-Moberg, 1996; Uvnäs-Moberg et al., 1998). In fact, oxytocin may either increase or decrease food intake, depending on the rat strain studied (Uvnäs-Moberg et al., 1996). Endogenous corticosteroids play a pivotal role in visceral adipose tissue deposition. Subjects with abdominal obesity are characterized by hyperactivity of the hypothalamopituitary–adrenal (HPA) axis, which leads to functional hypercortisolism (Pasquali and Vicennati, 2000a, b). Glucocorticoids stimulate NPY and inhibit CRH, and this combination promotes food consumption and therefore weight gain, e.g. in Cushing’s syndrome or treatment with corticosteroids (Schwartz and Seely, 1977). However, the reversibility of the HPA axis changes with weight loss, suggesting that these changes are consequences of rather than the cause of an expanding intraabdominal fat deposit (Kopelman, 1999), and autonomic innervation of the adrenal and adipous tissue may play a crucial role (Buijs and Kalsbeek, 2001). CRH and urocortin inhibit food intake and are therefore considered to be responsible for at least some of the changes in eating behavior in stress and depression (Holsboer et al., 1992; Raadsheer et al., 1995; Bradbury et al., 2000; see Chapter 26.4). Judging by the data from transgenic mice, the CRH receptor-1 does not, however, seem to play a critical role in the basal regulation of ingestive behavior (Müller et al., 2000a). The observation that CRH in human CSF diminishes after feeding has been interpreted as not supporting the hypothesis that CRH is a central satiety factor in human (Kasckow et al., 2001a). However, CRH levels in CSF do not seem to reflect hypothalamic CRH production (see Chapter 26.4d), while some studies indicate that plasma and salivary cortisol levels are diminished in severely obese patients (Putignana et al., 2001). Others claim that basal cortisol levels are normal in obese women. However, different HPA-activity changes were observed in obese women in relation to abdominal versus subcutaneous fat distribution. A recently discovered satiety factor is the peptide CART, which is produced in the DMN, SON and PVN, posterior hypothalamus, premamillary nucleus, TMN, infundibular nucleus, LHA, bed nucleus of the stria terminalis, amygdala, thalamus and cortex in the human brain 165

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(Hurd and Fagergren, 2000; Elias et al., 2001). In humans, CART contains 116 amino acid residues. CART mRNA is upregulated by leptin and the expressed CART is a potent anorectic peptide that overrides the feeding response induced by NPY (Thim et al., 1998). The CART/POMC neurons innervate sympathetic preganglionic neurons in the spinal cord that may contribute to the increased thermogenesis and energy expenditure and the increased body weight that are observed after leptin administration (Elias et al., 1998). CART administration intracerebroventricularly (ICV) inhibits food intake, induces the expression of c-Fos in the PVN and causes a transient rise in plasma oxytocin levels in rat (Vrang et al., 2000). This suggests that CART might act through the oxytocinergic system to bring about its inhibitory effects on feeding behavior. Oxytocin cells of the PVN are considered to be satiety neurons (Swaab et al., 1995a). Interestingly, preliminary observations by our group indicate that there is a tendency toward a reduction in CART cell number in the infundibular nucleus in PWS (F. Goezinne et al., unpubl. results). MCH is produced in the LHA, perifornical area, tuberomamillary nucleus, posterior nucleus and zona incerta (Pelletier et al., 1987; Bresson et al., 1989; Mouri et al., 1993; Qu et al., 1996; Saito et al., 2000b; see Chapter 14). MCH is overexpressed in the hypothalamus of obese mice and during fasting. ICV injection of MCH in rat increases food consumption (Qu et al., 1996). Mice deficient for MCH have reduced body weight due to hypophagia and an inappropriately increased metabolic rate, despite the reduced amounts of leptin and POMC mRNA in their arcuate nucleus (Shimada et al., 1998). MCH is the cognate ligand for the orphan G-proteincoupled receptor SCL-1, which is expressed in the rat ventromedial and dorsomedial nuclei (Chambers et al., 1999; Saito et al., 1999). Apart from its role in feeding, the MCH receptor may be involved in the regulation of the HPA axis in stress, olfaction and anxiety (Saito et al., 2000). There are at present two G-protein-coupled receptors known for MCH (Sailer et al., 2001). MCHbinding sites are present in the human hypothalamus and other brain areas (Sone et al., 2000). Neurotensin, bombesin and glucagon-like peptide inhibit food intake, and somatostatin increases feeding, while octreotide, a long-acting somatostatin receptor agonist, promotes weight loss, possibly by suppressing excessive insulin secretion. Growth hormone-releasing hormone (GHRH) stimulates feeding (Leibowitz, 1992). Ghrelin is an endogenous growth hormone-release-stimulating peptide

that is produced in the rat arcuate nucleus. ‘Ghre’ comes from the Indo-European root for the word ‘grow’. It also increases feeding in rats and stimulates NPY and AGRP neurons (Nakazato et al., 2001; Lu et al., 2002). It is a peptide of 28 amino acids, which acts through the endogenous ligand for the growth hormone secretagogue receptor (Lu et al., 2002) and antagonizes leptin action through the activation of the NPY/Y1 receptor pathway (Shintani et al., 2001). Recently a mutation was found in the preproghrelin sequence that corresponds to the last amino acid in the mature ghrelin product in heterozygous obese subjects, showing that the ghrelin gene could play a role in the etiology of obesity (Lustig et al., 1999; Ukkola et al., 2001). PWS patients have markedly elevated plasma ghrelin levels, which may contribute to the severe hyperphagia and obesity associated with this syndrome (Cummings et al., 2002; Chapter 23.1). In addition, increased fasting ghrelin plasma levels are found in patients with bulimia nervosa (Tanaka et al., 2002). Ghrelin causes a hypothalamic release of GHRH, CRH, arginine vasopressin (AVP), and NPY (Wren et al., 2002). Injection of serotonin (5-HT) suppresses carbohydrate intake, with little or no change in protein and fat in freely moving animals (Bernardis and Bellinger, 1996); but, in the rat, serotonergic control of feeding behavior has been designated both as suppressant and stimulant. A serotonergic disorder has been presumed in anorexia and bulimia nervosa (Walsh and Devlin, 1998). Dopamine and noradrenaline inhibit food intake and the ‘VMNlesion syndrome’ may be partly if not completely due to interruption of the aminergic innervation of the hypothalamus (see Chapters 9, 26.3; Bernardis and Bellinger, 1996). In genetically obese mice, there are hypothalamic noradrenergic receptor changes and an increased noradrenergic activity is presumed (Boundy et al., 2000). Histamine, derived from the TMN (Chapter 13), suppresses feeding (Brown et al., 2001). Moreover, a number of substances from the periphery affect the balance of nutrient and energy homeostasis, such as cholecystokinin (CCK) from the gastrointestinal tract (Hopkins and Williams, 1997). Corticosteroids, aldosterone, estrogens and the nutrients glucose, fatty acids and amino acids, also affect the energy homeostasis (Williams et al., 1991; Leibowitz, 1992; for leptin, see Chapter 23b). In addition, sex hormones and sex hormone-binding globulin may play a role in obesity and may explain the increased abdominal obesity in menopause-induced estrogen deficiency (Tchernof and

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Després, 2000). The anorectic action of estrogens in rat is mediated by the central estrogen receptor- (Liang et al., 2002). Insulin receptors are present in the human hypothalamus (Hopkins and Williams, 1997). Mice with neuron-specific disruption of the insulin receptor gene show increased food intake and a diet-sensitive obesity, with increases in body fat and plasma leptin levels (Brüning et al., 2000). In patients with suprasellar lesions, documented pituitary, hypothalamic lesions, and profound obesity, T3 supplementation weight loss was promoted (Fernandez et al., 2002).

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humans than in mice. Treatment of this 9-year-old child with recombinant leptin led to sustained reduction in weight, predominantly as a result of a loss of fat. This therapeutic response confirms the importance of leptin in the regulation of body weight in humans and establishes an important role for this hormone in the regulation of appetite (Farooqi et al., 1999). Polymorphisms in the leptin receptor gene are associated with levels of abdominal fat in postmenopausal overweight women (Wouters et al., 2001). Another genetic defect was found in a woman with extreme childhood obesity, abnormal glucose homeostasis, hypogonadotropic hypogonadism, hypocortisolism and elevated plasma proinsulin and POMC concentrations, but a very low insulin level. This disorder seems to be based upon a mutation in the prohormone processing endopeptidase, prohormone convertase 1 (PC1) (Jackson et al., 1997). Severe early-onset obesity, adrenal insufficiency and red hair pigmentation were found to be caused by POMC mutations (Krude et al., 1998; Krude and Grüters, 2000). The patients had severe early-onset obesity and red hair pigmentation due to mutations truncating the POMC molecule and leading to the complete lack of ACTH and -MSH (Krude and Grüters, 2000; MacNeil et al., 2002). However, a cryptic trinucleotide repeat polymorphism in exon 3 of POMC that was associated with elevated leptin levels, appeared not to be associated with obesity (Rosmond et al., 2002). Mutations in the MC-4 receptor gene (MC4R) seem to be a common cause of monogenic human obesity. Up to 4–6% of severely obese humans have defects of the MC-4 receptor gene. Affected individuals have hyperphagia in childhood, which loses its intensity later in life. These individuals of normal height, present with binge-eating as the major phenotype characteristic. Some patients had cyclothymia or bipolar affective disorder (Cone, 1999; Mergen et al., 2001; Kobayashi et al., 2002; Branson et al., 2003; Farooqi et al., 2003). A patient with both extreme obesity and bulimia nervosa has been described, who has a haploinsufficiency mutation in the MC-4 receptor (Hebebrand et al., 2002). A SNP in the AGRP, a natural MC-4 receptor agonist, is thought to increase the risk of developing anorexia nervosa (Vink et al., 2001b). In one patient with both extreme obesity and bulimia nervosa, a haplo-insufficiency mutation was found in the MC-4 receptor (Hebebrand et al., 2002). A novel MC-3 receptor mutation has been observed in an obese girl and her father (Lee et al., 2002). However, MC-3 receptor variantss are common and generally considered not to explain human morbid obesity (SchalinJäntti et al., 2003). In a number of obese subjects a

(d) Molecular genetic factors involved in obesity Human obesity certainly has an important inherited component. In fact, studies in twins, adoptees and families indicate that 80% of the variance in body-mass index is attributable to genetic factors (Rosenbaum et al., 1997). The “obesity gene map 2000” reports on the presence of 47 human cases of obesity caused by single-gene mutation in six different genes, including SIM1, a critical transcription factor for the formation of the SON and PVN in mice. In addition, 24 Mendelian disorders exhibiting obesity as one of their clinical manifestations have now been mapped (Pérusse et al., 2001), yet the genetic factors responsible for most obesity in the general population have remained elusive so far. As far as the single-gene mutations are concerned, obese subjects with a mutation in the gene that encodes for leptin (Montague et al., 1997; Ströbel et al., 1998) or for the leptin receptor (Clément et al., 1998) have been described. The missense leptin mutation described by Ströbel et al. (1998) is associated not only with morbid obesity but also with hypogonadism and primary amenorrhea. The male patient never enters the stage of puberty. The mutation described by Clément et al. (1998) results in a truncated leptin receptor, lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity and lack of pubertal development, patients who are homozygous for this mutation also have reduced secretion of growth hormone, growth retardation and central hypothyroidism. The observations in subjects with mutations in the leptin receptor and leptin itself suggest that leptin not only controls body mass but is also a necessary signal for the initiation of puberty in humans. However, since in a child with congenital leptin deficiency there was no evidence of substantial impairment in basal or total energy expenditure, and her body temperature was normal, leptin may be less central to the regulation of energy expenditure in 167

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mutation in the preproghrelin gene was found that corresponds to the last amino acid of ghrelin (Ukkola et al., 2001), but so far there is no good evidence that sequence variants in the coding region of the ghrelin gene influence body weight (Hinney et al., 2002). However, growth hormone secretogogues such as ghrelin may be important for feeding. When the expression of the receptor for this compound in the arcuate nucleus was blocked, the rats had lower body weight and less adipose tissue than controls (Shuto et al., 2002). A glucocorticoid receptor polymorphism is associated with obesity and dysregulation of the HPA axis (Rosmond et al., 2000). A patient with a mutation in the transcription factor steroidogenic factor 1 had a complete sex reversal and developed obesity in late adolescence (Ozisik et al., 2002). PWS, which is characterized by obesity, hypotonia, mental retardation and hypogonadism, is discussed in Chapter 23.1. Prader–Willi patients usually have a de novo, paternally derived, deletion of the chromosome region 15q11-13. In contrast, Angelman’s syndrome is generally due to a maternally derived deletion of the chromosome 15q11-13 region. Its clinical features comprise severe mental retardation, postnatal microcephaly, macrostomia and prograthia, absence of speech and a happy disposition. A group of patients has been reported who lack most of these features, but present with obesity, muscular hypotonia and mild retardation, i.e. features that are also seen in PWS. The Angelman patients had an apparently normal chromosome 15 of biparental inheritance but possibly an incomplete imprinting defect or cellular mosaicism. For other eating disorders, such as Bardet–Biedl syndrome, see Chapter 23.3.

and some authors propose that cultural factors are of great importance (Bemporad, 1997). Moreover, morbid obesity has been reported following encephalitis lethargica infection and other viral neurological infections (Nagashima et al., 1992; Chapter 20.2). Animal models with human adenovirus-induced adiposity also suggest the possibility of viral involvement (Dhurandhar et al., 2000). In addition, Langerhans cell histiocytosis (Chapter 21.3) and ventromedial hypothalamic lesions (Chapter 26.3) may be accompanied by adipositas. Autoantibodies against MSH, ACTH, and LHRH have been found in anorexia and bulimia nervosa (Fetissov et al., 2002). Both conventional and newer antipsychotics are associated with weight gain. Among the newer agents, clozapine appears to have the largest potential to induce weight gain, and ziprasidone the smallest (Allison et al., 1999). Progressive wasting as found in cancer is considered to be due to a disruption of the physiological mechanisms controling energy intake. Cancer anorexia is multifactorial and may involve most of the neuronal signaling pathways modulating energy intake. Factors probably involved are cytokines, such as tumor necrosis factor , interleukins-1 and -6, interferon-, leukemia inhibitory factor and ciliary neurotrophic factor. They are proposed to stimulate anorexigenic neuropeptides such as CRH in the hypothalamus, and to inhibit neuropeptides of the orexogenic network such as NPY, galanin and opioids, and hormones such as leptin. In addition, neurotransmitters such as serotonin and dopamine are presumed to be involved (Inui, 1999; Laviano et al., 2002). Animal experiments have shown that cachexia induced by lipopolysaccharide administration and by tumor growth is ameliorated by central MC4-R blockade (Marks et al., 2001).

(e) Epigenetic factors in obesity and anorexia cachexia In addition to the genetic factors, epigenetic factors seem to be involved in obesity as well. People exposed to famine, during the first half of pregnancy, in the Dutch hunger winter of 1944–1945, displayed significantly higher obesity rates. Exposure to famine during the last trimester of pregnancy and the first months of life, however, resulted in significantly lower obesity rates (Ravelli et al., 1976). A syndrome of intractable weight gain may result from hypothalamic damage following radiation for a brain tumor in children (Lustig et al., 2003). A wide range of childhood aversions is associated with elevated risk of developing eating disorders during adolescence or early adulthood (Johnson et al., 2002a, b)

23.1. Prader–Willi syndrome (PWS; MIM no. 176270, Fig. 23A) (a) Symptoms and molecular genetics In 1956, Prader, Labhart and Willi described a syndrome in children characterized by grossly diminished fetal activity and hypotonia in infancy, mental retardation (mean IQ of 65) or learning disability, feeding problems in infancy, and later insatiable hunger and gross obesity (Fig. 23.3), hypogonadism and hypogenitalism. Unilateral or bilateral cryptorchism is found in 80–100% of male Prader–Willi patients. Additional features are a variety of minor malformations, including a small forehead,

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almond-shaped eyes, triangular mouth, small hands and feet, short height, decreased pigmentation of skin and hair, which is probably of neural crest origin, and ophthalmic disorders. PWS is the most frequent form of human syndromal obesity (Apkarian et al., 1989; Smeets et al., 1992; Müller, 1997; Butler et al., 1998; Eiholzer et al., 2000). In the USA, PWS is also known as the H3O syndrome, after the four essential features: hypotonia, hypomentia, hypogonadism and obesity. The glucose tolerance test result is often abnormal (Tolis et al., 1974). Diagnostic criteria for PWS have been developed by consensus and two scoring systems have been provided: one for children aged between 0 and 36 months, and another for children from 3 years onwards, into adulthood (Holm et al., 1993). The majority of PWS cases are sporadic, but familial cases have been reported (McEntagart et al., 2000). In 70% of the patients a de novo deletion of the paternally inherited chromosome 15q11-13 is present. About 28% of PWS cases are due to maternal uniparental disomy, that would result in a slightly milder phenotype with better cognitive functions. Paternal deletion and maternal uniparental disomy are functionally similar as they both result in the absence of a paternal contribution to the genome in the 15q11-13 region. A third, and the most severe, phenotype with a high incidence of congenital heart disease are the patients with maternal uniparental disomy 15 with mosaic trisomy 15 (Olander et al., 2000). A few PWS cases with mosaicism for the deletion have been reported (Golden et al., 1999), but definite evidence has not yet been found (Nicholls, 2000). Less than 2% of the cases have an abnormality in the imprinting process, which causes nonexpression of the paternal genes in the PWS-critical region (ASHG/ACMG Report, 1996; Brøndum-Nielsen, 1997). In a 3-yearold, a cryptic interstitial duplication of the entire Prader–Willi/Angelman critical region was found. It was of maternal origin. The phenotype included developmental mental delay, speech problems and seizures (Thomas et al., 1999). Duplication, triplication and tetrasomy of the 15q11-q13 region has been reported with varying degrees of clinical manifestation (Butler et al., 2002). In a clinically atypical PWS patient, a rare, balanced de novo translocation has been observed (Conroy et al., 1997) and several cases with phenotype overlapping with the PWS phenotype had maternal uniparental disomy 14. Some PWS candidate genes have been identified. The SNRPN (small nucleoriboproteinassociated polypeptide N) gene is probably part of the

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putative imprinting center that regulates the expression of several genes in PWS transcriptional domain (Martin et al., 1998a). An intact genomic region and/or transcription of SNRPN exons 2 and 3 seem to play a pivotal role in the manifestations of the clinical phenotype in PWS (Kuslich et al., 1999). However, other human cases tend to exclude SNRPN as the causative gene for PWS genotype (Conroy et al., 1997). In addition, the human necdin gene, NDN, which is maternally imprinted and located in PWS chromosomal region, was considered to be a candidate gene (Jay et al., 1997). Although at first necdin-deficient mice did not develop the hypogonadism, infertility or obesity characteristics of PWS (Tsai et al., 1999), later on Necdin mouse mutants were developed that showed hypothalamic and behavioral alterations reminiscent of the human PWS, including a reduction of 90% in oxytocin neurons and of 25% in LHRH-producing neurons, increased skin-scraping activity (Muscatelli et al., 2000), and a deficiency of respiratory drive (Ren et al., 2003). Others claim that the imprinted genes ZNF-127 and -127 AS may be associated with some of the PWS features (Jong et al., 1999). In addition, there is a small evolutionarily conserved RNA resembling C/D box, small-nucleolar RNA, which is transcribed from PWCR1, a novel imprinted gene in the PWS deletion region, which is highly expressed in brain (De los Santos et al., 2000). PWS occurs in 1 of every 10,000–25,000 births. Epidemiologic studies have shown an increased incidence of paternal preconceptional employment in hydrocarbonexposed occupations (gasoline/petrol) (Cassidy et al., 1989; Åkefeldt, 1995; Martin et al., 1998a). The exact causes of mental retardation, behavioral problems such as fits of temper, depression and sudden aggression in PWS children are not known, but the major symptoms of this syndrome are seen as the result of hypothalamic disturbances (Swaab, 1997). This fits in with the experimental data of Keverne et al. (1996), who showed that cells that carry only paternal genes accumulate in clusters scattered through the hypothalamus, septum, preoptic area and amygdala, while cells that carry only maternal genes accumulate in the cortex and striatum. Misrouting of retinal ganglion fibers at the optic chiasm – a finding previously only reported in forms of albinism – was claimed to be present in PWS (Creel et al., 1986) but could not be confirmed in a later study (Apkarian et al., 1989). The original observation does not, therefore, appear to give a clue for changes in brain development (see Chapter 18.5). 169

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Fig. 23.3. Characteristic pattern of obesity in a patient with Prader–Willi syndrome. (From Kaplan et al., 1991, Fig. 1 with permission.)

(b) Hypothalamic abnormalities Dysfunction of various hypothalamic systems, neuroendocrine and nonneuroendocrine, may be the basis of a number of symptoms in PWS. Severe fetal hypotonia is often already noticed by the mother during pregnancy;

the baby does not seem to move much. Apart from the baby’s underactivity, its position in the uterus at the onset of labor is often abnormal (either a transverse, face or breech presentation). These abnormal presentations result in a high percentage of assisted deliveries. In addition, the percentage of asphyctic infants is at least 8 times

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higher than in the general population. It has often been presumed that the fetal position is caused by hypotonia, the child being too weak to move itself in the correct position. However, there are other congenital disorders in the hypothalamus and pituitary – in which hypotonia is not reported – which are also accompanied by abnormal presentation of the fetus at birth, such as anencephaly and septo-optic dysplasia (De Morsier syndrome) (see Chapters 8.1, 18.3b). The way the hypothalamus is involved in fetal hypotonia is not known at present. The timing of the moment of birth is often also abnormal; too high a percentage of children with PWS are born either prematurely or too late (Wharton and Bresman, 1989), an abnormality also found in anencephaly (Chapter 18.1). An abnormality of the hypothalamus, which plays a central role in the child’s timing of its own birth, may explain these phenomena (see Chapter 8.1). Abnormal function of nerve cells in the hypothalamus containing LHRH is thought to be responsible for decreased levels of sex hormones, resulting in cryptorchism in boys, hypoplastic external genitalia in children of both sexes and delayed or incomplete pubertal development, as well as decreased sexual behavior and insufficient growth during puberty, resulting in short stature (Hamilton et al., 1972; Wannarachue et al., 1975; Cassidy et al., 1997; Müller, 1997; Burman et al., 2001). It should be noted though that there is a considerable degree of variation in the function of the hypothalamopituitary–gonadal axis in PWS and also hypergonadotropic hypogonadism secondary to cryptorchism has been described (Tolis et al., 1974; Müller, 1997). Serum testosterone levels are uniformly low in male PWS, whereas serum estradiol, LH and follicle-stimulating hormone (FSH) levels in females are usually low, which is consistent with hypogonadotropic hypogonadism. The onset of menstruation is often late in girls, if it occurs at all (Müller, 1997). It is not yet known whether the proposed abnormality in LHRH production is due to absence of the LHRH neurons, or due to an abnormal location, or to a deficiency in LHRH production or perhaps to the production of an abnormal form of the hormone. Gonadal function may also be normal in a small number of patients (Rubin and Cassidy, 1988; Cassidy et al., 1997, Müller, 1997; Martin et al., 1998a). In some rare cases, precocious puberty has been observed, once even in combination with empty sella syndrome. In 5% of cases, empty sella syndrome is accompanied by hyperfunction of the pituitary (Linneman et al., 1999). It is generally assumed that PWS patients are infertile. However, one woman with PWS was reported to

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have given birth to a healthy baby girl, presumably related to the treatment with a serotonin reuptake inhibitor (Åkefeldt et al., 1999). In addition it was reported (Schulze et al., 2001) that a 32-year-old woman with PWS had given birth to a girl with Angelman’s syndrome, due to a maternal deletion on chromosome 15q11-13. Treatment of hypothalamopituitary–gonadal failure in PWS remains a controversial issue. More recently, sex hormone replacement therapy is given. This encourages the development of secondary sexual characteristics and potentially improves bone mineral content and density. Given the reports of pregnancy in a few PWS cases, care-givers should, however, be aware of the possible need for contraceptives. If aggressiveness in male PWS patients during testosterone substitution increases, the substitution should be stopped (Burman et al., 2001). Short stature and delayed skeletal maturation are the most frequent features of PWS, probably partly due to hypogonadism (see above) and partly to a growth hormone (GH) deficiency, and are seen in 90% of the PWS patients (Angulo et al., 1996). Some PWS patients have abnormally low spontaneous nocturnal GH and insulin-like growth factor-I (IGF-1) serum levels and blunted GH responses to pharmacological stimuli and to GHRH, suggesting that hypothalamic dysfunction of this axis may be a factor in the short stature (Costeff et al., 1990; Cappa et al., 1993; 1998; Angulo et al., 1996; Grosso et al., 1998; Eiholzer et al., 2000). In addition, insulin-like growth factor (IGF) binding protein-3 levels are low in PWS as compared to healthy obese children (Eiholzer et al., 1998). GH deficiency is independent of weight status (Thacker et al., 1998). The possibility that short stature is due to a deficit at or above the level of the pituitary is reinforced by the fact that GH treatment stimulates body growth in PWS patients. In addition, weight gain decreased and IGF-I (somatomedin C) and insulin levels increased after GH treatment (Lee et al., 1987; Angulo et al., 1991; Eiholzer et al., 1997; Hauffa, 1997; Lindgren et al., 1997b, 1998, 1999; Lindgren and Ritzén, 1999; Myers et al., 1999; 2000; Lee, 2000). GH therapy during a period of up to 4 years continued to give beneficial effects on body composition and growth velocity. Prior improvements in strength and agility were sustained (Carrel et al., 2002). Interestingly, GH treatment appeared to have psychological and behavioral benefits also. Parents reported that the children were more alert, had a more stable temperament, were more interested in other children and were easier to handle than before treatment (Lindgren et al., 1997b). However, the only 171

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difference in cognition or behavior reported in a recent study was an increase in hyperactivity after growth hormone intervention. In GH-deficient PWS children, the overall mean height SD and weight SD changed from –2.2 to –0.8 and from 3.5 to 2.4, respectively, in a period of 2 years of treatment (Angulo et al., 1996). The determination of GH levels, either spontaneous nocturnal ones or after stimulation tests (Grosso et al., 1998), in venous plasma as an indicator of hypothalamic GHRH release is used (Kimber et al., 1997). GHRH that is produced in the arcuate nucleus (Ciofi et al., 1990; Fig. 23.4) was expected to be affected in PWS. However, observations in postmortem material from our group have shown that the number of GHRH-expressing neurons in this nucleus is not decreased in PWS, and increased to the same degree as it is in controls, due to chronic illness, so there is no evidence that the GH deficiency in PWS results from reduced GHRH cell number (Goldstone et al., 2003). The hypothalamopituitary–adrenal and –thyroid axes remain largely intact in PWS, and prolactin and cortisol levels are generally normal (Tolis et al., 1974; Wannarachue et al., 1975; Müller, 1997; Grosso et al., 1998; l’Allemand et al., 2002). Dehydroepiandtosterone (DHEA), DHEA-S and androstenedione levels are elevated (Burman et al., 2001; l’Allemand et al., 2002). Premature adrenarche, characterized by growth of axillary hair and pubic hair is frequently observed in PWS (Linnemann et al., 1999; Burman et al., 2001). One patient has been reported with the rare combination of PWS and congenital hypothyroidism caused by an ectopic sublingual thyroid gland. Although early initiation of thyroid replacement therapy took place, she continued to suffer from hypotonia and developmental delay, after which PWS was discovered (Sher et al., 2002). The observation of an aberrant control of body temperature in PWS is also interpreted as a hypothalamic disturbance (Vela-Bueno et al., 1984). It should be noted, however, that thermoregulatory disturbances are not specific for this syndrome and may occur in any neurodevelopmentally handicapped person (Williams et al., 1994). The abnormal ventilatory control during wakefulness and sleep in patients with PWS may, apart from being linked to sleep apnea, also be related to a hypothalamic disorder, since this brain area modulates both hypercapnic and hypoxic ventilatory responses (Menendez, 1999). Leptin is a satiety factor that is produced by fat cells and acts on the infundibular nucleus and other hypothal-

amic areas in order to inhibit food intake (see Chapter 23b) and was, therefore, presumed to be involved in obesity in PWS. Plasma leptin levels are increased in PWS, but this was generally in relation to the increased body-mass index (Carlson et al., 1999). It was therefore thought to be improbable that an explanation for the increased food intake and obesity could be presented on the basis of a disturbance in the leptin gene (Wallace et al., 1999). However, subtle differences may be present in leptin. The normal sex difference – females have higher leptin levels than males – is not present in PWS, and it is remarkable that the differences between obese and nonobese PWS subjects are small and insignificant. In fact, plasma leptin levels in nonobese male Prader–Willi subjects were nearly 5 times higher than in nonobese control males (Butler et al., 1998). While a difference in the hypothalamic response to leptin could not be excluded on the basis of the study by Lindgren et al. (1997a), our finding that there is less NPY in the infundibular nucleus in PWS patients (see below) seems to exclude a gross disturbance of the leptin–leptin receptor–NPY interaction (Goldstone et al., 2002). Leptin is presumed to inhibit NPY production in the infundibular nucleus (see Chapter 23b). In order to see whether an increased activity of NPY neurons in the infundibular nucleus might explain the eating disorder in PWS patients, we determined the amount of NPY in the infundibular nucleus immunocytochemically, and NPY mRNA, by means of an image-analysis system, in PWS cases, nonsyndromic obese patients and controls. The infundibular nucleus contains NPY cell bodies and an extremely dense network of NPY fibers that generally do not extend to the most ventral part of the median eminence, which contains the portal capillaries. This indicates that most of the NPY fibers have central projections. NPY immunoreactivity and mRNA are decreased in PWS patients, to the same degree as in the other obese patients (Figs. 23.5, 23.6, 23.8). NPY immunocytochemistry and mRNA increases with longer disease duration (Goldstone et al., 2002; Fig. 23.6). Apparently the insatiable hunger in PWS is not due to increased NPY expression, as these neurons show a normal reaction to the obese state and disease duration of these patients. No increase was found in the AGRP staining or mRNA in the infundibular nucleus of PWS patients either (Fig. 23.7, 23.8). This peptide, too, is upregulated with disease duration (Goldstone et al., 2002; Fig. 23.7). AGRP is another peptide that stimulates feeding and is colocalized with NPY, but not with POMC (Figs. 11.3, 11.4). The

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Fig. 23.4. Growth hormone-releasing hormone (GHRH)-immunoreactive neurons in the infundibular nucleus of 3 controls (left column) and 3 Prader–Willi syndrome (PWS) patients (right column). The top row shows the cases with the highest number of GHRH-immunoreactive neurons, the middle row shows cases with the highest number of GHRH-immunoreactive neurons, the middle row shows cases with a median GHRH neuron number and the last row represents the cases with the lowest GHRH-neuron number: (a) control case 96-030, (b) PWS case 43830, (c) control case 85-124, (d) PWS case 96-000, (e) control case 80-271 and (f) PWS case 97-049. Scale bar 50 m. Note that there is a great variability in number of GHRH neurons, both within the control group and in the PWS patient group. Although the PWS patients generally tended to have fewer GHRH neurons and their staining tended to be less intense, this appeared to be due to differences in disease duration and not to PWS per se. (cf. Goldstone et al., 2003, preparation by U. Unmehopa.)

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Fig. 23.5. Hypothalamic neuropeptide-Y (NPY) in human illness and obesity. NPY immunocytochemistry (ICC) staining in the infundibular nucleus of control, Prader–Willi syndrome (PWS) and non-PWS adults, with sudden death, premorbid illness duration of less than 2 wk and more than 6 wk. Note that NPY ICC staining increases with longer periods of illness, but that each illness duration levels are lower in both PWS and nonPWS obese subjects, compared with controls. Bar 50 m. (From Goldstone et al., 2002, Fig. 4 with permission.)

Fig. 23.6. Hypothalamic neuropeptide-Y (NPY) mRNA in human illness and obesity. Representative autoradiographs of NPY in-situ hybridization in the infundibular nucleus of control, PWS, and non-PWS obese adults, with sudden death, premorbid illness duration of less than 2 wk or more than 5 wk. Note that NPY mRNA expression increases with longer periods of illness, but that at each illness duration levels are lower in PWS or non-PWS obese subjects, compared with controls. 3V, third ventricle. (From Goldstone et al., 2002, Fig. 5 with permission.)

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Fig. 23.7. Hypothalamic agouti-related protein (AGRP) peptide in human illness and obesity. Representative autoradiographs of AGRP ICC staining in the infundibular nucleus of control, PWS, and non-PWS obese adults, with sudden death, premorbid illness duration of less than 2 wk or more than 5 wk. Note that AGRP ICC staining increases with longer periods of illness, and that levels are not increased in PWS or non-PWS obese subjects, compared with controls. Bar 50 m. (From Goldstone et al., 2002, Fig. 6 with permission.)

peptide are increased to a level reported to stimulate appetite and food intake (Cummings et al., 2002; Del Parigi et al., 2002; Haqq et al., 2003). The possibility that this peptide also has a source in the human brain should be investigated. The birth weight of PWS children is often too low, but from age two onwards these children tend to grow fatter than other children. Appetite control is exacerbated when there is more severe mental retardation. The obesity may be caused by an increased drive to eat as well as by an impaired mechanism of satiation. Both functions are controlled by the hypothalamus. Animal experiments have shown that the parvocellular oxytocin neurons of the hypothalamic PVN are crucial for the regulation of food intake. Oxytocin release accompanied various treatments that inhibit food intake (Verbalis et al., 1995). In the rat, the oxytocin neurons of the PVN project to brainstem nuclei, for example the nucleus of the solitary tract and the dorsal motor nucleus of the nervus vagus (Buijs et al., 1983; De Vries and Buijs, 1983; Voorn and Buijs, 1983). These connections are held responsible for the satiety effects of oxytocin (Verbalis et al., 1995). Small

decreased NPY and AGRP content of the hypothalamus indicates that the transport of information between the fat cells and the infundibular nucleus to the PVN by the NPY neurons will be largely intact, including leptin and leptin receptors, and that abnormalities have to be searched for in other peptide systems of the arcuate nucleus or in the area of termination of the NPY fibers, such as the PVN (Goldstone et al., 2002). Seemingly in contrast to our data, Åkefeldt et al. (2001) reported that the NPY content of CSF in Prader–Willi children with a mean age of 8 years was higher. However, in two PWS infants of 6 and 8 months, we did not find the reduction in NPY either (Goldstone et al., 2002). The developmental state may thus be of crucial importance in these hypothalamic peptide changes. Preliminary results from our group indicate that there is a reduction of CART-containing neurons in the infundibular nucleus of PWS patients (F. Goezinne et al., unpubl. observ.). Since CART inhibits feeding, this observation has to be followed up. A new putative factor involved in obesity in PWS is ghrelin. This peptide is an orexigenic circulating hormone implicated in meal-time hunger. The plasma levels of this 175

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Fig. 23.8. Hypothalamic neuropeptide-Y (NPY) is decreased and agoutirelated peptide (AGRP) is not increased in obesity. (A) NPY ICC staining volume, (B) NPY mRNA expression by ISH; and (C) AGRP ICC staining volumes, in the infundibular nucleus/median eminence (INF/ME), in control, Prader–Willi syndrome (PWS) and non-PWS obese subjects. + represents females,  hypogonadal females (postmenopausal or PWS),  intact males,  hypogonadal males (castrated controls or PWS). Dashed line represents median for each group. Note that, in obese subjects (PWS and non-PWS) compared with controls, there is a significant reduction in NPY ICC staining and mRNA, but no difference in AGRP ICC staining, when adjusting for significant covariates. P-values: a Mann-Whitney test; b adjusting for differences in premorbid illness duration by ANCOVA; cadjusting for differences in premorbid illness duration and storage time by ANCOVA. (From Goldstone et al., 2002, Fig. 2 with permission.)

lesions in the rat PVN cause overeating and obesity (Leibowitz et al., 1981), suggesting that the PVN usually has an inhibitory effect on eating and body weight. In addition, stimulation of the medial parvocellular subdivision of the rat PVN elicits significant increases in gastric acid secretion (Rogers and Hermann, 1986). Central administration of oxytocin or oxytocin agonists inhibits food intake and gastric motility in rat, whereas these effects are prevented by an oxytocin receptor antagonist (Rogers and Hermann, 1986; Arletti et al., 1989; Benelli et al., 1991; Olson et al., 1991a, b). In a patient whose PVN was bilaterally destroyed by a hypothalamic astrocytoma, obesity and hyperphagia were indeed reported (Haugh and Markesbery, 1983). It should be noted, however, that in this patient one side of the VMN was also affected. We have investigated whether a disorder of the PVN, or, more particularly, of its putative satiety neurons – the oxytocin neurons – might be the basis of the insatiable hunger and obesity in PWS. Apart from gross obesity, oxytocin neurons are also thought to be crucial for various aspects of sexual behavior, including sexual arousal, orgasm, sexual satiety and other aspects of sociosexual interaction (Hughes et al., 1987; Murphy et al., 1987; Argiolas, 1992; Arletti et al., 1992; Carter, 1992; Chapters 8f, 8g). The thionine-stained volume of the PVN appeared to be 28% smaller in PWS patients and the total cell number of the PVN is 38% lower than in controls (Swaab et al., 1995a). Following immunocytochemistry, the immunoreactivities for oxytocin and vasopressin are decreased in PWS patients (Fig. 23.9), although the variation within the groups is high. A large and highly significant decrease (42%) in the number of oxytocinexpressing neurons was found in all five PWS patients (Fig. 23.10). The volume of the PVN containing the OXTexpressing neurons is 54% lower in PWS. The number of vasopressin-expressing neurons in the PVN did not change significantly (Fig. 23.9). The finding that volume and total cell number and oxytocin cell number was so much lower in PWS patients points to a developmental hypothalamic disorder, and agrees with the hypothesis that oxytocin neurons of the PVN may be good candidates for a physiological role as “satiety neurons” in ingestive behavior, also in the human brain (Swaab et al., 1995a). In addition, it seems worthwhile to investigate whether it is possible to curb children’s appetites by administration of oxytocin. It should be noted, though, that the recent observation that oxytocin levels in CSF of five PWS patients were just significantly elevated

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Fig. 23.9. In thionine-stained sections of the paraventricular nucleus (PVN), no qualitative differences were observed between controls (no. 81255; A) and PWS patients (no. 43830; B). The staining of oxytocin (OXT) (C, D) and vasopressin (AVP) (E, F) was generally lower in PWS patients (no. 43830; D, F) than in controls (no. 81255; C, E). G, H, Two PWS patients (no. 1 and 4) had intense and weak OXT staining (no. 93056; G) and only negligible AVP staining (no. 93056; H) in the PVN. Bar 50 m. (From Swaab et al., 1995a, Fig. 1, with permission.)

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Fig. 23.10. Number of oxytocin-expressing (OXT) (left panel) and vasopressin-expressing (AVP) (right panel) neurons in the PVN of 27 controls and 5 Prader–Willi syndrome (PWS) patients. The values of the PWS patients are delineated by a minimum convex polygon. Note that the oxytocin neuron number of these patients is about half of that of the controls (left panel), which is not the case for vasopressin (right panel). (From Swaab et al., 1995a, Fig. 2 with permission.)

seems to be at odds with our observation in the PVN, although it is of course possible that different subpopulations of oxytocin neurons in the PVN, with different projection sites, react in a different way to the disease process (Martin et al., 1998b). Clearly oxytocin should be studied in more PWS patients, both in postmortem hypothalamic material and in CSF. It should be mentioned that, in two of seven of our PWS patients, vasopressin neurons stained only weakly (Swaab et al., 1995a) or not at all (Gabreëls et al., 1994), depending on the antibody used. In these two PWS patients there was no staining with antibodies against 7B2, a neuroendocrine chaperone preventing premature activation of the enzyme prohormone convertase (PC)2. Since the precursor of vasopressin was present in these two PWS patients (Fig. 23.11) and no PC 2 activity was found in the SON and PVN, a processing enzyme disturbance is presumed that also affects the 7B2 gene from the paternal allele (Gabreëls et al., 1994, 1997). The finding that vasopressin expression is occasionally diminished in PWS patients agrees with the demonstration of Miller et al. (1996) that MRI shows a complete absence of the posterior pituitary bright spot in 20% of these patients,

indicating a disturbed function of the hypothalamohypophysial system as found in patients with hypothalamic diabetes insipidus (see Chapter 22.2). Whether a vasopressin defect is indeed present in those Prader–Willi patients that lack the posterior pituitary bright spot in MRI should be proved by further observations. The extensive calcifications found in the brain and spinal cord of a 16-year-old boy with PWS are most probably an incidental finding not directly related to the syndrome (Reske-Nielsen and Lund, 1992). In conclusion, so far hypothalamic research has revealed an intact NPY/AGRP system in PWS syndrome that is inhibited in a normal way by obesity, but the number of oxytocinexpressing neurons in the PVN is clearly diminished. (c) Behavioral disorders Behavioral problems are a frequent occurrence in PWS (Curfs et al., 1991). Symptoms of mood disorder and anxiety laminate the picture of PWS. They can, at least partly, also be considered to be hypothalamic symptoms (Chapter 26.4). In addition, temper tantrums and compulsive behavior such as skin-picking may be present (Martin

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Fig. 23.11. Paraffin sections of the supraoptic nucleus (SON) from Prader–Willi syndrome patient 93-056 shows no immunoreactivity with antibody III-D-7 recognizing processed vasopressin (A), but very intense immunoreactivity with antibody PS41 recognizing neurophysin predominantly in its processed form (B), and very intense immunoreactivity with antibody Boris Y-2 recognizing the glycopeptide part of the vasopressin precursor (C). These data indicate a processing disorder. Bar 25 m. (From Gabreëls et al., 1998b, Fig. 1 with permission.)

patients show hypersomnolence and little or no sleep apnea, but REM-related oxygen desaturation is quite common. In addition, abnormal REM sleep cycles, sleeponset REM periods and fragmented REM sleep with multiple, brief REM periods are present (Kaplan et al., 1991; Hertz et al., 1993; Clift et al., 1994; Richdale et al., 1999; Manni et al., 2001). It is hypothesized that the abnormal sleep findings in this syndrome are related to a disturbance of the posterior hypothalamus (Hertz et al., 1993; Manni et al., 2001). Clift et al. (1994) presume that sleep apnea is also of some importance. An alternative explanation would be disturbed circadian functioning (Vela-Bueno et al., 1984).

et al., 1998a; Holland et al., 2003). Moreover, psychosis and bipolar illness have been reported in PWS cases, but it is not clear whether they are more prevalent in PWS than in the general population (Clarke, 1993; Clarke et al., 1995; Descheemaeker et al., 2002). It is postulated that in PWS an abnormal pattern in expression of a sexspecific imprinted gene on chromosome 15, such as in maternal uniparental disomy, is associated with psychotic illness in early adult life (Boer et al., 2002). Patients with PWS may be especially vulnerable to the development of cycloid psychosis that reacts favorably to lithium (Verhoeven et al., 1998; Descheemaeker et al., 2002). PWS is, moreover, associated with high rates of ritualistic behaviors, such as the need to ask or tell something, insistence on routines, hoarding and ordering objects and repetitive actions and speech (Clarke et al., 2002). In relation to the behavioral disturbances, the increased concentrations of dopamine, 5-HT and metabolites may be of relevance (Åkefeldt et al., 1998). Another symptom that is present in 90% of the PWS patients and may originate in the hypothalamus is the excessive day-time hypersomnolence, accompanied by snoring and early waking (Richdale et al., 1999). PWS

(d) Comorbidity One case of Kleine–Levin syndrome has been described in a boy with PWS (Gau et al., 1996). Kleine–Levin syndrome is characterized by episodes of hypersomnia and hyperphagia and considered to be a hypothalamic syndrome (see Chapter 28.1). The small hypothalamus observed in this patient with MRI (Gau et al., 1996) supports the idea that this brain area is strongly affected. 179

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A case of multiple endocrine neoplasia (MEN) type 1 was found to be accompanied by PWS. MEN-1 (MIM no. 131100) is a syndrome characterized by hyperplastic or neoplastic disorder of endocrine organs. More than 90% of the affected subjects manifest hyperparathyroidism. Pituitary tumors and pancreatic endocrine tumors are seen in 50% of the patients. Mutations of the MEN1 gene on chromosome 11q13 have been identified in most of the affected subjects (Nakajima et al., 1999). Four patients suffering from both PWS and Klinefelter syndrome (47,XXY; see Chapter 24.4) have been described. In the most recent case both parents contributed to the chromosomal abnormalities, supporting the possibility of a coincidental association (Geffroy et al., 1998). Symptoms characteristic of PWS have also been described in a woman with a duplicated X chromosome, random X-inactivation pattern and negative molecular genetic studies for PWS (Monaghan et al., 1998). There are also other observations indicating that on the proximal long arm of the X-chromosome a gene or genes are located that in case of malfunction result in obesity, mental retardation and small hands and feet (Tümer et al., 1998). In addition, PWS patients with trisomy-X syndrome and with XYY syndrome have been described (Honma et al., 1999; Stalker et al., 2003).

23.2. Anorexia nervosa and bulimia nervosa (Fig. 23B) Anorexia nervosa is among the most disabling and lethal of psychiatric disorders (Walsh and Devlin, 1998).

Anorexia nervosa was first described by Laségue (1873) and Sir William Gull (1873) (for references see Li Parry Jones et al., 1994). The prevalence of eating disorders among young females is about 0.3% for anorexia nervosa and about 1% for bulimia nervosa (Hoek et al., 1995). In fact, 93% of anorexia nervosa cases and 75% of bulimia nervosa cases are found in women, an example of a clear sex difference in psychiatric diseases (Chapter 1, Table 1.1). They are relatively rare disorders, with an incidence rate of 0.8/10,000 for anorexia nervosa and 1.2/10,000 for bulimia nervosa. Comorbid psychiatric conditions such as affective disorders, anxiety disorders, substance abuse and personality disorders are frequently present (Halmi, 2002). Cultural pressures are presumed by some authors to play a role in the prevalence of these disorders, as indicated by cultural and historical differences in prevalence (Bemporad, 1997; Walsh and Devlin, 1998). Obstetric complications are mentioned as risk factors for anorexia nervosa (Verdoux and Sutter, 2002). This concerns in particular very early birth and birth traumas.

Fig. 23B. Alberto Giacometti (1901–1966) Piazza, 1947–1948 (cast 1948–1949). Bronze, 21  62.5  42.8 cm. Peggy Guggenheim Collection, Venice (The Soloman R. Cuggenheim Foundation, New York); photograph by David Heald. Photograph © 2003 The Solomon R. Cuggenheim Foundation, with permission.

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The incidence of bulimia nervosa is lowest in rural areas and highest in large cities (0.7/10,000 and 3.8/10,000 women per year, respectively). However, the epidemiological comparisons between different periods are full of pitfalls (Wakeling, 1996). No rural–urban differences were found for anorexia nervosa (Hoek et al., 1995). There is no indication of a secular increase in the incidence of anorexia nervosa (Fombonne, 1995), but the incidence of bulimia nervosa tends to increase (Hoek et al., 1995). The incidence of mortality among anorexia nervosa patients is generally said to range between 5 and 20%. However, in a long-term survival study in Rochester (New York), anorexia nervosa patients did not differ from controls. So the overall mortality was not increased (Korndörfer et al., 2003). On average, less than one-half of the anorexia patients recover, whereas one-third improved. Twenty percent remain chronically ill (Barry and Klawans, 1976; Ratnasuriya et al., 1991; Licinio et al., 1996; Steinhausen, 2002). Suicide attempts are frequent (27.8% of the women), often serious, and multiple. Women who attempted suicide had higher severity of depressive and general symptoms and more impulse-disordered conducts. Evidence is emerging that both anorexia and bulimia nervosa are familial and that clustering in families may arise partly from genetic transmission of risk (Kaye et al., 1999; Strober et al., 2000; Wade et al., 2000; Brambilla, 2001). Twin studies in bulimia indicate substantial genetic variance (44%) and do not support a strong role for shared environmental effects (Rowe et al., 2002). A single patient with extreme obesity and bulimia nervosa had a haplotype-insufficiency mutation in the MC-4 receptor (Hebebrand et al., 2002) and significant linkage was found on chromosome 10 in families with bulimia nervosa (Bulik et al., 2003). SNPs in the AGRP gene were found to be associated with an increased susceptibility for anorexia nervosa and are presumed to be caused by a defective suppression of the MC-4 receptor, leading to a decreased feeding signal (Vink et al., 2001b). One patient has been described with both bulimia nervosa and extreme obesity, and a haploinsufficiency mutation in the MC-4 receptor (Hebebrand et al., 2002). Allele 13 of the polymorphic microsatellite marker D11S911 is significantly overrepresented in the anorexia nervosa population, and the UCP2/UCP3 genes on chromosome 11q13 are thought to play a role in the control of energy expenditure and thermogenesis (Campbell et al., 1999). Modest evidence for linkage of anorexia nervosa with chromosome 4 and better evidence with

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linkage with chromosome 1p was obtained (Grice et al., 2002). Candidate genes for anorexia nervosa in the 1p33–36 linkage region are the serotonin 1D and delta opioid receptor loci (Bergen et al., 2003). In addition, a 5-HT2A promotor polymorphism has been reported in anorexia nervosa (Sorbi, 1998), but a combined analysis of 316 trios from six European centers did not reveal any evidence for a significant role of the 5-HT2A gene in anorexia nervosa (Gorwood et al., 2002). The frequency with which the H (high) allele of the enzyme catecholO-methyltransferase occurs is significantly higher in anorexia nervosa patients than in those not affected. Individuals that are homozygous for the H allele run a two-fold increased risk of developing anorexia nervosa (Frish et al., 2001). Anorexia nervosa was found to be associated with a polymorphism in the novel norepinephrine transporter gene promotor polymorphic region (Urwin et al., 2002). Also variability in the estrogen receptor- may contribute to the genetic susceptibility to anorexia nervosa. An association was found between the heterozygous genotype of the G1082A polymorphism and anorexia nervosa (Eastwood et al., 2002). Genetic factors also substantially contribute to the comorbidity between anorexia nervosa and major depression (Wade et al., 2000). Patients with congenital adrenal hyperplasia – compound heterozygotes for mutations/deletions of the CYP21A2 gene – may be at risk for anorexia nervosa (Brand et al., 2000). Alterations in transmitters as biological factors involved in the pathogenesis of anorexia and bulimia have been proposed repeatedly. Especially noradrenaline and 5-HT levels are lower in bulimia (Brambilla, 2001). Moreover, 5-HT transporter availability is impaired in the hypothalamus (Tauscher et al., 2001). Concerning the latter, studies show that postsynaptic hypothalamic-pituitary serotonergic pathways are altered in anorexia, and that many differences tend to persist despite a weight increase. After recovery, anorexics still have increased levels of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin. This suggests the existence of brain-related serotonergic activation in the brain (Brewerton and Jimerson, 1996; Kaye et al., 1998). In addition, increased activity of the dopaminergic system in anorexia nervosa has been hypothesized (Barry and Klawans, 1976). Anorexia patients are more likely to be born in March to June; a seasonal effect that may, e.g. be due to viral factors (Waller et al., 2002). In 74% of anorexia and bulimia patients, autoantibodies against -MSH, ACTH and LHRH are found. It is not clear how they are involved 181

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in the pathogenesis of these disorders (Fetissov et al., 2002). Sociocultural factors (e.g. media and peer influences), family factors (e.g. enmeshment and criticism, negative affect, low self-esteem and body dissatisfaction) are often mentioned as causal factors in eating disorders (Polivy and Herman, 2002), although hard evidence for such factors is lacking. In the lay press it is often stated that anorexia nervosa is caused by the visually ideal body image as perceived by girls watching extremely thin fashion models. There has been a recent study on the impact on eating behaviors and attitudes following prolonged introduction of television among media-naive, ethnic adolescent Fijian girls. Key indicators of disordered eating were significantly more prevalent following exposure, and narrative data revealed the subjects’ interest in weight loss as a means of modeling themselves after television characters. This indeed suggests a negative impact of television on disordered eating attitudes and behaviors in a media-naive population (Becker et al., 2002). However, clinical diagnoses were not sought in this study, so that we do not know whether the introduction of television may indeed have induced anorexia or bulimia nervosa in this population. On the other hand, a study of six blind patients has been published: the patients developed anorexia nervosa but had been blind since infancy, which suggests that eating disorders can develop independently of cultural conceptions of feminine appearance (Sharp, 1993). . . . It is not known whether minor cytologic changes occur in any part of the hypothalamus to correspond with these functional disturbances. (Sheehan and Kovacs, 1982) The well-known anorexia nervosa of girls seems to me on careful observation to be a melancholia occurring where sexuality is underdeveloped. (Sigmund Freud in The Origin of Psychoanalyisis: Letters to Wilhelm Fleiss, 1959)

(a) Symptoms Anorexia nervosa is characterized by a series of hypothalamic symptoms (for review see Kaplan and Garfinkel, 1988), of which it is often not yet clear whether they are related and primarily due to a hypothalamic process, or state-related and secondary to the cachectic process (Kaye

et al., 1998; Støving et al., 2001). Depressed affect and disturbance of body image have been reported prior to the onset of anorexia in a 14-year-old girl (Morgan and Lacey, 1996), which argues against the idea that these symptoms are secondary to the cachectic process. The same holds true for amenorrhea (see ii, below). Many of these symptoms also occur in bulimia. In fact, the two disorders are closely related: some 15% of the patients with anorexia nervosa develop bulimia nervosa (Ratnasuriya et al., 1991). The fact that third ventricle enlargement in anorexia nervosa is greater than that of the lateral ventricles supports the idea of hypothalamic involvement (Golden et al., 1996). The putative hypothalamic symptoms include: iiv(i) Eating disturbances and weight loss. Neuroimaging shows morphological and functional alterations that are at least partly reversible after weight gain. The reversible shrinkage of the brain (“pseudoatrophy”) also affects the pituitary gland. PET reveals caudate hyperactivity. It is tempting, but purely speculative, to relate the increased caudate dopamine activity to the well-known increased body activity of these patients (Barry and Klawans, 1976). Several mild, right–left asymmetries have been reported in bulimia nervosa (Herholz, 1996). Body image distortion is a core symptom and often persistent, and it continues to pose a threat of relapse, even after weight recovery. Images of their own body induce an activation of the right amygdala and other components of the ‘fear network’, as shown by fMRI (Seeger et al., 2002). iv(ii) Altered levels of steroid hormones, i.e. reduced plasma concentrations of estradiol are found not only in anorexia but also in bulimia nervosa. In addition, secondary amenorrhea, decrease in libido, and loss of secondary sexual characteristics are observed (Kaplan and Garfinkel, 1988; Raboch and Faltus, 1991; Monteleone et al., 1999; 2001; Cotrufo et al., 2000; Støving et al., 2001). Primary amenorrhea occurs in only 4–11% of cases (White et al., 1993). In about 20% of cases, amenorrhea takes place before a great deal of weight loss occurs. Menstrual irregularities and amenorrhea also occur in a high proportion (more than 30%) in patients with a normal weight bulimia syndrome (Ramacciotti et al., 1997). A strong association has been found between bulimia and polycystic ovary

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syndrome (Chapter 24.1d): ultrasonography indicates that some 75% of patients with bulimia have polycystic ovaries. Changes in bulimic eating may mirror changes in ovarian morphology. The two conditions may be linked by changes in peripheral insulin sensitivity (Morgan et al., 2002). Even in the absence of overt menstrual disturbances, altered LH secretion elicited by LHRH stimulation is found, with a more severe impairment in purging than in nonpurging normal-weight bulimia (Ramacciotti et al., 1998). Thus amenorrhea cannot be adequately explained solely on the basis of weight loss, which seems to be in favor of a primary hypothalamic process. Low levels of gonadotropins are generally reported and are possibly related to the low leptin levels (see point xi, below). Both bulimic and anorexia nervosa patients who are underweight demonstrate an ACTH secretion pattern that resembles that of prepubertal girls. In this light it is interesting that anorexia and cachexia go together with signs of hyperactivity in the subregion of the hypothalamic infundibular nucleus, i.e. the subventricular nucleus, probably due to a lack of inhibitory feedback action of sex hormones on this nucleus (see Chapter 11; Hart, 1971). From a follow-up of anorexia nervosa women, it appeared that they had only one-third of the expected fertility, that the rate of prematurity among their offspring was twice as high, and that perinatal mortality was 6 times higher than expected. So far no explanation has been given for these reproductive disorders (Brinch et al., 1988). There is also a relationship between the phase of the menstrual cycle and bulimia symptoms. The symptoms are exacerbated in both the midlateral and premenstrual phases (Lester et al., 2003) indicating a role for steroid hormones. Testosterone plasma levels are reported to be increased in women with bulimia nervosa in one study, and a positive correlation is found between testosterone plasma levels and aggressiveness in patients but not in controls (Cotrufo et al., 2000). In another study, testosterone levels were decreased in anorexia and unchanged in bulimia. Neuroactive steroids such as 3,5-tetrahydroprogesterone, DHEA and DHEAS exhibited increased plasma levels in that study, both in anorexia and bulimia (Monteleone et al., 2001).

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(iii) The HPA axis is generally found to be hyperactive in anorexia and bulimia (Licinio et al., 1996; Monteleone et al., 1999; Cotrufo et al., 2000; Neudeck et al., 2001). Although cortisol secretion is not found to be markedly higher in anorexia nervosa patients than in matched controls, and no relationship has been found with cognitive functions in a later study (Seed et al., 2002), various other studies, with both plasma and salivary hormone assays, have shown that there is an overdrive of the HPA axis (Putignano et al., 2001). Bingeing and vomiting in bulimic patients was associated with modest increases in cortisol secretion (Weltzin et al., 1991; Galderisi et al., 2003) and increased DHEA(S) levels (Galderisi et al., 2003), while normal-weight bulimic women showed normal circadian ACTH and cortisol variations and levels (Vescovi et al., 1996). A recent study showed that elevated cortisol secretion followed exacerbation of bulimic symptoms (Lester et al., 2003). Anorexia and bulimia nervosa patients often have a marked hypercortisolism but normal plasma ACTH. When CRH was given, hypercortisolism was associated with a marked reduction in plasma ACTH as a response to the elevated levels of cortisol. When these patients were studied shortly after their body weight had been restored, hypercortisolism had disappeared, but the abnormal response to CRH remained unchanged. On the other hand, at least 6 months after the loss of weight had been corrected, their responses returned to normal. These observations suggest that hypercortisolism in anorexia reflects a defect at or above the level of the hypothalamus (Gold et al., 1986). In addition, CSF levels of CRH of anorexia patients are elevated (Hotta et al., 1986; Kaye, 1996), which may also reflect a change in extrahypothalamic rather than in hypothalamic function (see Chapter 26.4). It should be noted that CRH administration to experimental animals may produce many of the symptoms of anorexia nervosa, such as hypothalamic hypogonadism, decreased sexual activity, decreased feeding behavior, hyperactivity and depression (Holsboer et al., 1992; Kaye, 1996; Licinio et al., 1996; see Chapter 26.4). It has been hypothesized that self-starvation through physical activity would activate the HPA axis. Stimulated CRH activity would subsequently

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1 activate the reward system consisting of dopaminer2 gic neurons in the ventral tegmentum, whose 3 terminals are located in the nucleus accumbens. 4 Cortisol would enhance the reward by stimulating the 5 release of dopamine in this nucleus. Self-starvation 6 would thus be rewarding (Bergh and Södersten, 7 1996; Wheatland, 2002). Evidence for such a vicious 8 circle as the pathogenic mechanism of anorexia 9 nervosa, however, has yet to be collected. 101 ii(iv) The hypothalamopituitary–thyroid axis is hypo1 active in anorexic patients (Leslie et al., 1978). 2 The alterations fit into the euthyroid sick syndrome 3 (see Chapter 8.6). Thyroid volume is markedly 4 reduced in anorexia nervosa. Thyroid atrophy could, 5 hypothetically, be involved in a vicious circle main6 taining anorectic or depressive symptomatology 7 (Støving et al., 2001). The TSH response in anorexic 8 patients is often low or delayed. Following weight 9 recovery, TRH responses often continue to be 201 abnormal. The thyrotropin (TSH) response to TRH 1 of bulimic patients is blunted. In normal-weight 2 bulimic patients, T4, T3 and TSH levels are also 3 lower, as is the response to TRH (Kiyohara et al., 4 1988; Schreiber et al., 1991b). These observations 5 contradict the idea that thyroid axis hypoactivity is 6 a result of malnutrition and support the idea of a 7 primary hypothalamic process. 8 iii(v) Basal GH levels are elevated in anorexia and IGF9 I levels are lower, probably due to the state of 301 malnutrition. GH response to GHRH, however, was 1 normal, indicating a disturbance at the hypothalamic 2 level in anorexia and bulimia. A hypothalamic 3 subsensitivity of postsynaptic D-2 receptors and a 4 presynaptic dopamine hypersecretion has been 5 proposed (Casanueva et al., 1987; Brambilla et al., 6 2001; Støving et al., 2001) but not proven. The 7 enhanced growth hormone secretion in anorexic 8 patients is the result of an increased frequency of 9 secretory pulses superimposed on an enhanced tonic 401 secretion. These changes suggest the presence of 1 both an increased number of GHRH discharges and 2 a decreased somatostatin tone (Scacchi et al., 1997; 3 Støving et al., 2001). Indeed, the GHRH secreto4 gogue ghrelin was found to be elevated, both in the 5 anorexia nervosa, binge eating/purging-type and in 6 bulimia nervosa purging-type patients. Vomiting 7 may have a strong effect on this gastric peptide. 8 Since this gastric hormone is also an efficient 911

orexigenic factor, the increase of ghrelin levels could be considered an adaptive mechanism, promoting energy intake and fat stores (Tanaka et al.,2003; Tolle et al., 2003). Bingeing and vomiting in bulimic patients was associated with reduced GH secretion (Weltzin et al., 1991). ii(vi) Bingeing and vomiting in bulimic patients is accompanied by moderate prolactin increases according to some authors (Weltzin et al., 1991), and with reduced plasma prolactin concentrations according to others (Monteleone et al., 1999; Cotrufo et al., 2000). More attention should be paid to their possibly altered circadian rhythms (see ix). i(vii) Neurohypophysial disorders are present in anorexia nervosa. A syndrome of partial diabetes insipidus has been reported and vasopressin seems to be secreted erratically, independent of plasma sodium levels (Gold et al., 1983). The response to hypertonic saline is abnormal. The hyperintense MRI signal in the posterior part of the pituitary was reported not to be abnormal (Herholz, 1996). However, an anorexia patient with high serum vasopressin levels and an absence of the posterior pituitary bright spot on MRI has also been described, indicating increased release of vasopressin (Sato et al., 1993). In addition, anorexic patients are not able to excrete a large volume of water (Russell et al., 1966), indicating hypersecretion of vasopressin. Moreover, hypersecretion of vasopressin and reduction of oxytocin have been reported in CSF of underweight anorexics (Demitrack et al., 1989). The elevation of CSF vasopressin was confirmed in women who had recovered from anorexia nervosa/bulimia nervosa. In patients recovered from bulimia nervosa, elevated CSF vasopressin may be related to having a life-long history of major depression (Frank et al., 2000). There is impairment of the oxytocin response to challenging stimuli, such as oestrogens and insulin in underweight anorectic women. After complete weight recovery, the oxytocin response, too, was regained. This neuroendocrine abnormality thus seems to be associated with starvation and/or weight loss. The reduced CSF levels of oxytocin in anorexics (Demitrack et al., 1989) were not expected, because of the feeding behavior inhibiting effect of this peptide (Swaab et al., 1995a). Although a later study showed increased CSF

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oxytocin levels, they may be related to the use of birth control pills and not to the eating disorder in some bulimia patients (Frank et al., 2000). (viii) The basal temperature is unusually reduced, and the temperature regulation in heat and cold is disturbed. Heat and cold intolerance have, however, also been found due to weight loss (Vela-Bueno et al., 1984); ii(ix) In anorexia, circadian variation of blood pressure is absent. This reverts to normal after refeeding (Awazu et al., 2000). In anorectic patients, not only were leptin levels low; their relative diurnal variation was strikingly reduced in one study (Støving et al., 2001), or qualitatively altered (Herpertz et al., 1998); while, in another study (Herpertz et al., 2000), diurnal secretion patterns were found to be preserved, even in the severe state of emaciation. Also, the levels of plasma cortisol often show a loss of the normal diurnal rhythm (Hotta et al., 1986; Herpertz et al., 1998), pointing to a disorder in the circadian timing system. However, others reported that the circadian variations in cortisol remained the same despite an increase in the mean levels of cortisol (Balligand et al., 1998). Hypercortisolism in underweight anorexics reflects hypersecretion of hypothalamic CRH rather than primary glucocorticoid resistance (Kling et al., 1993). Hypercortisolism is presumed to cause a loss of circadian rhythms (Awazu et al., 2000). Our observation that corticosteroid treatment of patients for different reasons decreases vasopressin mRNA in the SCN (Liu et al., 2003, submitted) agrees with this idea. In a subsample of bulimia patients who experienced “reversed symptoms” such as hypersomnia and hyperphagia when they were depressed, low plasma cortisol levels were observed. These lower levels may, however, have been due to circadian phase alterations (Levitan et al., 1997). Prolactin, ACTH, -endorphin and melatonin circadian rhythms are also disturbed in anorexia and bulimia nervosa according to some studies (Ferrari et al., 1990; Kaye, 1996; Pacchierotti et al., 2001) and the circadian rhythm of leptin is completely abolished (Balligand et al., 1998). Bulimic women have blunted nocturnal prolactin patterns (Weltzin et al., 1991). Other studies report that the circadian rhythm of melatonin was unaltered in bulimia and anorexia (Brown, 1992), and that the nocturnal

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Fig. 23.12. Seasonal variation in binge eating, purging and feeling worst among 31 bulimic and 31 comparison subjects. Binge eating (a), purging (b), and feeling worst (c) were determined according to the modified seasonal pattern assessment questionnaire. Number of dark hours was defined as 24 h minus the average photoperiod for each month. (a) A significant group effect (F = 103.99, df = 1, 60, p < 0.001), month effect (F = 9.91, df = 11, 50, p < 0.001) and group by month interaction (F = 7.06, df = 11, 50, p < 0.001) were found. The correlation between number of dark hours and likelihood of binge eating was significant (r = 0.97, df = 12, p < 0.001). (b) A significant group effect (F = 83.77, df = 1, 60, p < 0.001), month effect (F = 3.99, df = 11, 50, p < 0.001) and group by month interaction (F = 2.76, df = 11, 50, p < 0.007) were found. The correlation between number of dark hours and likelihood of purging was significant (r = 0.94, df = 12, p < 0.001). (c) A significant group effect (F = 6.46, df = 1, 60, p < 0.02) and group by month interaction (F = 2.50, df = 11, 50, p < 0.02) were found. The correlation between number of dark hours and likelihood of feeling worst was significant (r = 0.92, df = 12, p < 0.001). (Blouin et al., 1992, Fig. 1 with permission.)

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1 secretion of melatonin was significantly greater in 2 anorectics (Arendt et al., 1992; Luboshitzky et al., 3 2001), or even that there was an enhanced circa4 dian rhythm of melatonin in anorexia nervosa with 5 higher diurnal and nocturnal plasma melatonin 6 levels (Tortosa et al., 1989). That the night levels 7 of serum melatonin in patients with anorexia are 8 increased was confirmed by Manz et al. (1990). 9 Since, a significant decrease in melatonin secretion 101 has been found, coexisting with depression in 1 patients with eating disorders, which may at least 2 partly explain the variable results in the literature 3 on this topic (Kennedy et al., 1990; Brown, 1992). 4 A clear seasonal pattern has been reported in the 5 signs and symptoms of bulimia nervosa. Bingeing 6 behavior and mood disorders were found to be 7 closely associated with the photoperiod in that the 8 symptoms are the most severe in winter and the 9 least severe in summer (Blouin et al., 1992; Fig. 201 23.12). Such seasonal changes are not present in 1 anorexia nervosa (Lam et al., 1996a). In bulimic 2 patients with worsening of mood and eating symp3 toms in winter, bright white light therapy was effec4 tive for both symptoms (Lam et al., 1994), an 5 important observation that has so far not gained 6 much following. However, it should be noted that 7 Pasternak and Zimmerman (2002) did not find 8 higher rates of bulimia in winter in an outpatient 9 psychiatric practice in the USA. 301 iii(x) Various peptides that are involved in the regulation 1 of food intake (Chapters 11, 23c) show alterations. 2 Reduced CSF -endorphin levels have been found. 3 This peptide stimulates feeding behavior (Kaye, 4 1996). Plasma -endorphin concentrations were sig5 nificantly higher in bulimic than in control subjects 6 at all time points (Vescovi et al., 1996). Since nalox7 one has some effects in the treatment of anorexia 8 (Moore et al., 1981), the opiate system, too, should 9 have research attention. It is not remarkable that ele401 vated CSF levels of NPY have been found in anorec1 tics (Krysiak et al., 1999), since this peptide is 2 upregulated by lower levels of leptin (see Chapter 3 23b) (Kaye, 1996; Krysiak et al., 1999). Galanin is 4 an orexigenic peptide that stimulates appetite and 5 fat consumption. The galanin level in the CSF of 6 recovered anorexia nervosa patients is lower than 7 that of controls, and may thus play a role in food 8 restriction and fat avoidance (Frank et al., 2001). 911 Leptin is a satiety factor that is produced by fat

cells. The protein is encoded by the LEP gene and acts on the arcuate nucleus and other hypothalamic areas to reduce food intake (see Chapter 23b). Both serum and CSF leptin levels are lower in anorexia nervosa patients but appropriate to body-weight decrease. However, altered transport of leptin over the blood–brain barrier is presumed. Weight gain in anorexia patients leads to steep increases in leptin plasma levels. Low leptin levels are also associated with amenorrhea. A critical leptin level seems to be needed to maintain menstruation (Grinspoon et al., 1996; Hebebrand et al., 1997; Köpp et al., 1997; Balligand et al., 1998; Herpertz et al., 1998; Støving et al., 1998; Mantzoros, 2000). Recently, increased fasting plasma levels of ghrelin have been reported in patients with bulimia nervosa; this peptide stimulates eating (Tanaka et al., 2002). ii(xi) Using single photon emission computed tomography (SPECT), a reduced hypothalamic and thalamic 5-HT transporter availability was found in bulimia nervosa. The impaired 5-HT transporter availability was more pronounced with longer duration of the illness (Tauscher et al., 2001). The association with the presence of 5-HT2A promotor polymorphism in anorexia (Sorbi et al., 1998) may be related to such alterations. Because elevated concentrations of 5-HIAA were found in the CSF of anorexia and bulimia nervosa patients after recovery, altered 5-HT metabolism is proposed to be a trade-related characteristic (Kaye et al., 1998) and may be the basis of the therapeutic effects of SSRIs. i(xii) One of the most paradoxical features of anorexia nervosa is that, during periods of extreme caloric restriction and weight loss, the majority of patients display abnormally high levels of physical activity. Interestingly, in many kinds of animals, heightened locomotion is a behavioral marker of sensitivity to stress (Davis et al., 1999b). (xiii) Whether the elevated pain threshold in anorexia nervosa, bulimia nervosa and binge-eating disorder (Raymond et al., 1999; see Chapter 23.3) is based upon a hypothalamic pain mechanism (Chapter 31) remains to be investigated. (b) Hypothalamic tumors mimicking anorexia nervosa The possibility that anorexia and bulimia may primarily be a hypothalamic disease is reinforced by a number of

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case histories of patients who were, after they had been diagnosed to suffer from anorexia and sometimes subjected to psychotherapy, at autopsy, found to have a tumor in the hypothalamus. These cases not only include a number of children that had atypical anorexia, but also adults with a “typical” diagnosis of anorexia nervosa. In cases of anorexia it may be difficult to differentiate between “psychogenic” and “organic” causes. Psychological disturbances without neurological manifestations may be due to occult intracranial tumors masquerading as anorexia nervosa (DeVile et al., 1995). In a neonate, an obstinate anorexia and a subsequent failure to gain weight had been present since birth. At autopsy, at 6 months of age, an astrocytoma, probably originating from the meninges and occupying the third ventricle, was found. The tumor was not sharply demarcated from the hypothalamic regions and was continuous with the meninges (Kagan, 1958). A 10-year-old child with a diagnosis of major depression and atypical anorexia nervosa was found to have a teratoma in the hypothalamic region (Chipkevitch and Fernandes, 1993). DeVile et al. (1995) describes three boys with tumors affecting the hypothalamus and invading the brainstem, causing psychological dysfunction and anorectic symptoms without initial neurological signs. The CT scans of all three patients were normal. The children suffered from, respectively, a craniopharyngioma, a disseminating pineal germinoma, and a low-grade astrocytoma. A 13-year-old girl with anorexia nervosa was found to have an infiltrating tumor in the left hypothalamic area. The symptoms abated after the tumor was irradiated (Weller and Weller, 1982). In various adult patients who had been diagnosed to suffer from anorexia nervosa, it also turned out to be a tumor that appeared to be the cause. A 22-year-old girl with a psychiatrist’s diagnosis of anorexia nervosa suddenly lost consciousness, had an epileptic fit and died in coma. She had been obsessed by her weight. Her condition deteriorated after learning that her father suffered from an inoperable carcinoma. She probably also suffered from diabetes insipidus and had developed pneumonia. In retrospect, she suffered from hypopituitarism. She had a hypothalamic tumor, atypical pinealoma (no tumor cells were found in the pineal gland), seminoma, dysgerminoma or atypical teratoma (Clinicopathological Conference, 1973). Another case was that of a 62-year-old woman who became extremely cachectic and refused to eat. According to a psychiatrist she had anorexia nervosa. At autopsy, her brain revealed a cystic lesion on the wall of the

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third ventricle at the level of the infundibulum, which was bordered medially by normal ependymal and subependymal tissue. The cyst had caused a decrease in hypothalamic substance. The lateral hypothalamic nuclei showed paucity of neurons (White and Hain, 1959). A 22-year-old woman with anorexia nervosa first went through a phase of nonspecific and inconsistent signs and symptoms such as sleep disturbances and increased fluid intake. The psychodynamic features were the most striking, but the characteristics of the ventromedial hypothalamic syndrome complicated the psychiatric picture; she had urges to kill people and induced vomiting whenever she overate. Eventually the intractable headaches and loss of visual fields pointed to a hypothalamic tumor. The craniopharyngioma was removed (Climo, 1982). Yet another case report concerns a 25-year-old woman with a history of secondary amenorrhea and weight loss. Her father had died six months earlier, after which she had begun to lose weight. A diagnosis of anorexia nervosa was made. She suffered from sudden losses of consciousness, with low blood sugar levels and died 2 weeks later from an infection. The hypothalamus contained a small, 0.5-cm-diameter, circumscript astrocytoma immediately posterior to the optic chiasm and to the right of the tuber cinereum (Lewin et al., 1972). Although these case histories show that all the signs and symptoms of anorexia nervosa can be found in patients with a hypothalamic tumor, including the characteristic that the psychodynamic features are the most outstanding, it should be noted that these are rare cases and that the majority of the hypothalamic tumors are not associated with symptoms of anorexia nervosa. (c) Association with other disorders Comorbidity between eating disorders and other psychiatric diseases is common, e.g. with depression, anxiety disorders, oppositional defiant disorder and substance abuse (Rowe et al., 2002). Bulimia has been found to be associated with Parkinson’s disease (Rosenberg et al., 1977). Bulimia disappeared in these Parkinson patients following L-DOPA treatment. This indicates that a disorder of the dopaminergic system might be a basis for the change in appetite in bulimia (Rosenberg et al., 1977), but no direct data on this possibility are available. The presence of bulimia in Parkinson patients may also fit in with the idea that oxytocin neurons of the paraventricular nucleus are satiety cells (Swaab et al., 1995a), because their number decreases in Parkinson’s disease 187

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(Purba et al., 1994). Bulimia may also be present in borderline personality disorder. In addition, a greater lifetime presence of binge eating was found among survivors of the Nazi concentration camps, who survived a period of extreme food deprivation (Favaro et al., 2000). Moreover, a 28-year-old man with anorexia and bulimic eating behavior had a hydrocephalus internus, presumably due to a stenosis of the aquaduct (Pauls et al., 1991). Anorexia nervosa associated with Klinefelter’s syndrome has been described in several cases (El-Badri and Lewis, 1991). Primary amenorrhea occurs in 4–11% of the anorexia cases. In case of primary amenorrhea, Kallmann syndrome, for instance, should be excluded (White et al., 1993). Medicine-induced eating disorders have been reported with fluoxetine, clozapine, apomorphine and amphetamine (Barry and Klawans, 1976; Morgan and Lacey, 1996). For bulimia associated with Kleine–Levin syndrome, see Chapter 27.1. On clinical grounds, it is difficult to distinguish anorexia nervosa from Simmond’s pituitary cachexia (Richardson, 1939). Simmond’s disease was described to arise from adenohypophysial failure, but was later also found to occur in patients with an intact pituitary, but with tumors or inflammatory processes in the region of the third ventricle (Kagan, 1958). Heterozygous carriers for Wolfram’s syndrome (see Chapter 22.6) have also been hospitalized for anorexia (Swift et al., 1991). Moreover, a case with acute pandysautonomia presented with the diagnosis anorexia nervosa (Okada, 1990). Since hypothalamic tumors may fully mimic anorexia nervosa (Chapter 23.2b), one should, in the case of eating disorders, look, in postmortem tissue, for hypothalamic conditions that may be involved in the etiology, such as autoimmune processes. The case of anorexia nervosa of the bulemic subtype in a 14-year-old girl following withdrawal of oral prednisolone used in the treatment of asthma (Morgan and Lacey, 1996) supports the possibility of an autoimmune process underlying this condition (although this possibility is not mentioned as such by the authors). No great changes in peripheral immunocompetence are generally found in anorexia nervosa (Marcos et al., 1997; Staurenghi et al., 1997). However, in one case of anorexia nervosa, vacuolization of the TMN was observed with moderate gliosis and myelinization of the vessels. The vacuolization and gliosis extended to the paraventricular nuclei and the massa intermedia, where a strong microglial reaction was observed (Martin, 1958). This observation points to the possibility of a central

immune process as a basis of anorexia nervosa, a concept that is reinforced by changes in cytokine levels observed in anorexia and bulimia nervosa (Holden and Pakula, 1996). The possibility that anorexia and bulimia nervosa are based upon a hypothalamic autoimmune process is strongly supported by the presence of autoantibodies against hypothalamic neuropeptides (Fetissov et al., 2002), and by the five patients mentioned in the literature who were successfully treated with corticosteroids and ACTH (Wheatland, 2002). (d) Therapy For light therapy in bulimia nervosa, see Chapter 23.2a (ix). Cognitive psychotherapy is the treatment of choice in anorexia nervosa (Halmi, 2002) and is reported to be effective in 60–70% of the individuals with bulimia nervosa, while fluoxetine reduces binge frequency, although the relapse rate is considerable (Walsh and Devlin, 1998). Psychoanalytical and family therapy are said to be of specific value in the outpatient treatment of adult patients with anorexia (Dare et al., 2001). In a randomized controlled trial, 16 patients with anorexia and bulimia were trained to eat and recognize satiety by using computer support. Fourteen patients (75%) of the treatment group went into remission in the mean time of 14.7 months, while only 1 untreated control went into remission. Only 7% of those who were treated with this method to remission relapsed, while 93% remained in remission for 12 months, so this method seems to be effective (Bergh et al., 2002). Selective 5-HT reuptake inhibitors are not very useful when anorexia nervosa patients are malnourished and underweight. When given after weight restoration, these medicines may reduce the extremely high rate of relapse seen in anorexia (Brewerton and Jimerson, 1996; Kaye, 1997; Kaye et al., 1998). In addition, fluoxetine adds a modest beneficial effect to cognitive-behavioral therapy in bulimia nervosa (Stunkard, 1997; Walsh et al., 1997). In bulimia nervosa, cognitive behavioral therapy seems to be superior to imipramine alone. In anorexia nervosa the progress in treatment is modest. Family therapy seems to be more effective than standard, individual supportive therapy. In addition, tricyclic antidepressants are effective (Brambilla, 2001). When patients recover from anorexia nervosa, insulin hypersensitivity remained the insulin response to the meal was blunted and apparently delayed. There may be a persistent alteration in pancreatic

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Fig. 23C. René Magritte, Le Sorcier (autoportrait), 1951. Huile sur toile, 35  46. Galerie Isy Brachot, Bruxelles 1992. By C.H. Adagp et Flammarion 4, Paris 6, 19 rue Visconti. Imprimé en France – XF 1055. (Reproduced with permission © René Magritte Le Sorcier, c/o Stichting Beeldrecht.)

dominates; whereas, in the second syndrome, neurological complications are very unusual (Soliman et al., 1996). Because of the overlapping phenotypes between Bardet– Biedl syndrome and Laurence–Moon syndrome, Beales et al. (1999) proposed the name “polydactyly-obesitykidney-eye syndrome” as a unifying descriptive label. Bardet–Biedl syndrome (BBS MIM no. 209900) is genetically heterogeneous, with six known loci: BBS1 (11q13), which is the most frequent one, accounting for about 50% of the cases, BBS2 (16q21), BBS3 (3p13-p12), BBS4 (15q22.3-q23) and BBS5 (2q31) (Haider et al., 1999; Woods et al., 1999; Young et al., 1999; Mykytyn et al., 2002). In families from New Foundland, mutations in the chaperone-like gene MKKS were found to cause obesity, retinal dystrophy and renal malformations associated with Bardet–Biedl syndrome, while mutations in BBS1 to -5 were excluded (Katsanis et al., 2000). BBS6 is caused by mutations in the gene MKKS (Mykyntyn et al., 2001). Mutations in the MKKS gene also cause McKusick–Kaufman syndrome, which is related to Bardet–Biedl syndrome (Schaap et al., 1998; Mykytyn

function, or alternatively this may be a trait marker for anorexia nervosa (Brown et al., 2003b). 23.3. Other eating disorders (Fig 23C) (a) Laurence–Moon/Bardet–Biedl syndrome Laurence–Moon/Bardet–Biedl syndrome is a rare (1:1,000,000), heterogeneous disorder that includes the following cardinal symptoms: obesity starting at 2–3 years, hypogenitalism, mental retardation (predominantly verbal), retinitis pigmentosa (which becomes apparent around 8 years), short stature, renal abnormalities and polydactyly or syndactyly. The disorder is also associated with diabetes mellitus, hypertension and congenital heart disease (Stoler et al., 1995; Soliman et al., 1996; Beales et al., 1999). The syndrome has an autosomal recessive mode of inheritance (Lerner et al., 1995). It is suggested that this syndrome comprises two disorders: the Laurence– Moon syndrome, and the Bardet–Biedl syndrome. In the first syndrome, polydactyly is rare and spastic paraparesis 189

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et al., 2001, 2002). In spite of the obesity and hypogonadism in Laurence–Moon/Bardet–Biedl syndrome, there is so far only little and inconsistent evidence that lesions of the hypothalamus may account for these conditions. In some older case histories fewer large cells were reported in the tuberal nuclei, fewer cells in the corpora mamillaria, and slight demyelination of the optic tracts and chiasm. Also, moderate paraventricular gliosis has been reported, but other studies mention the hypothalamus to be normal (McLoughlin and Shanklin, 1967). Systematic work with quantitative state-of-the-art techniques is needed to establish whether there is indeed hypothalamic involvement in this disorder. (b) Biemond’s syndrome

absence of mental retardation, and the combined occurrence of nerve deafness, diabetes mellitus and chronic nephropathy. Analysis of the family data is compatible with an autosomal recessive mode of inheritance, and the multiple clinical manifestations are, therefore, explained on the basis of homozygosity for mutant genes at a single autosomal locus (Goldstein and Fialkow, 1973). The gene ALMS1, which contains sequence variations, including four frameshift mutations and two nonsense mutations, segregates with Alström’s syndrome in six unrelated families (Collin et al., 2002). (d) Night eating syndrome

Biemond’s syndrome type 2 is a recessive inherited condition (MIM no. 210350) comprising mental retardation, coloboma, obesity, polydactyly, hypogonadism, hydrocephalus and facial dysostosis. Clinically the disorder is closely related to Bardet–Biedl syndrome. Several related clinical forms are distinguished as new nosological entities (Verloes et al., 1997). Short stature and delayed sexual maturation are features also present in Bardet–Biedl syndrome. The growth disturbance may partly be due to the defective testosterone secretion. The presence of an empty sella has also been described in this syndrome. Hypogonadism can be attributed in this disorder to primary gonadal failure with or without hypothalamicpituitary disfunction. Obesity is the major determining factor of hyperinsulinemia, also in Bardet–Biedl syndrome (Soliman et al., 1996). Molecular studies indicate that the syndrome is genetically heterogeneous with major loci at chromosome 11q, 15q, 16q and a rare locus at 3q. The genes have not yet been cloned (Schaap et al., 1998).

A new, related eating disorder that is different from anorexia nervosa, bulimia nervosa and binge eating, is the night eating syndrome. It is characterized by morning anorexia, evening hyperphagia and insomnia and occurs during periods of stress. Its prevalence has been estimated at 1.5% in the general population and some 27% of severely obese persons. The mood of the night eaters falls during the evening. There are circadian changes, such as an attenuation of the night-time rise in melatonin and leptin and elevated levels of plasma cortisol (Birketvedt et al., 1999). Night-time awakenings are far more common among night eaters than among controls and more than half the number of the awakenings are associated with food intake. The typical neuroendocrine characteristics are an attenuation of nocturnal rises in melatonin and leptin and increased diurnal secretion of cortisol. The CRH-induced ACTH and cortisol response are reduced in night eaters (Birketvedt et al., 2002). Observations that light improves the symptoms of night-time eating syndrome (Friedman et al., 2002) should be further tested in controlled studies.

(c) Alström’s syndrome

(e) Binge eating disorder

Alström’s syndrome is characterized by profound blindness due to retinal degeneration, infantile obesity, deafness, diabetes mellitus due to resistance to the action of insulin, and slowly progressive nephropathy. Males have a unique variety of hypogonadism in which normal secondary sexual characteristics occur despite small testes, low plasma testosterone and elevated gonadotropins. The features that distinguish Alström’s syndrome from the Laurence–Moon/Bardet–Biedl syndrome are the

A new diagnostic concept that has provisional status in DSM-IV is binge eating disorder. Like bulimia nervosa it has binge eating as a central feature, but there is little or no weight-control behavior, such as self-induced vomiting and laxative misuse. Some 40% of the binge eating disorder cohort met criteria for obesity in a 5-year follow-up, and this group of patients is highly prevalent (1–30% among often extremely obese subjects seeking weight-loss treatment) (Dingemans et al., 2002; Hsu

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et al., 2002). The rate of childhood emotional abuse is some 2–3 times more prevalent in this eating disorder than in a normative adult female sample. No other forms of childhood maltreatment, such as physical or sexual abuse, or emotional or physical neglect, were increased in binge eating disorder (Grilo and Masheb, 2002). Bingeeating is a major characteristic of subjects with a mutation in the MC4 receptor (Branson et al., 2003). The treatment of choice is currently cognitive behavioral treatment, but interpersonal psychotherapy, self-help and SSRIs seem effective (Dingemans et al., 2002).

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(f) Miscellaneous Other eating disorders include Frölich’s syndrome and the related ventromedial hypothalamic syndrome (Chapter 26.3), Kleine–Levin syndrome (periodic somnolence and morbid hunger; Chapter 28.1) and Prader–Willi-like syndrome, which have a different genetic background (Chapter 23.1d).

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CHAPTER 24

Reproduction, olfaction and sexual behavior (Figs. 24A, B)

Long before the human species appeared, the pinnacle of evolution was already the brain – as it had been before mammals appeared, before land vertebrates, before vertebrates. From this point of view, everything else in the multicellular animal world was evolved to maintain and reproduce nervous systems – that is, to mediate behavior, to cause animals to do things. Animals with simple and primitive or no nervous system have been champions at surviving, reproducing, and distributing themselves, but they have limited behavioral repertoires. The essence of evolution is the production and replication of diversity – and more than anything else, diversity in behavior. T.H. Bullock (1984)

The central peptide for reproduction, luteinizing hormone-releasing hormone (LHRH), is synthesized as a 92-amino acid precursor that is subsequently cleaved to form the decapeptide LHRH. Pulsatile LHRH acts at the LHRH receptor on gonadotropic-hormone-containing neurons in the pituitary and is required to maintain gonadotropin synthesis and secretion. Acute administration of LHRH induces a marked release of LH and follicle-stimulating hormone (FSH). However, chronic administration of LHRH induces an inhibition of the gonadal axis through the process of downregulation of pituitary receptors for LHRH. This is the basis for application of LHRH in gynecology and oncology, e.g. in treating mamillary, ovarian, endometrial and prostate cancer and hamartomas (Chapter 19.3). The pituitary gonadotropins LH and FSH stimulate steroid production and gametogenesis in males and females. Genetic abnormalities have been identified on all levels of the hypothalamopituitary–gonadal axis (Ackerman et al., 2001). The distribution of the LHRH (= GnRH)-synthesizing neurons and fibers in the hypothalamus and adjacent areas is described in Chapters 11 and 24.2, as well as by Stopa et al. (1991) and Dudás

Fig. 24A. Pregnant woman. Marc Chagall, 1913. Stedelijk Museum, Amsterdam, in bruik-leen van: Instituut Collectie Nederland (with permission.)

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Fig. 24B. Activating effects of sex hormones on the brain. Arend van Dam, with permission.

et al. (2000). LHRH is present in the human brain in three isoforms (Chen et al., 1998; Yahalom et al., 1999). The human hypothalamic LHRH pulse-generating mechanism is located entirely within the mediobasal hypothalamus, as shown by in vitro perfusion techniques (Rasmussen, 1992). The frequency and amplitude of LHRH pulses determine gonadotropin subunit gene expression and secretion of pituitary LH and FSH. During ovulatory cycles, an increase in LHRH frequency (more than 1 pulse per hour) during the follicular phase favors LH synthesis prior to the LH surge, while, after ovulation, luteal steroids slow LHRH pulses to favor FSH synthesis. Thus, a changing frequency of LHRH stimulation is one of the mechanisms involved in differential gonadotropin secretion during ovulatory cycles (Seminara et al., 1998; Marshall et al., 2001). A large number of factors modulate the function of the LHRH neurons, and thus the LH pulsatile secretion. As found in many species, also in young healthy men, light exposure increases LH secretion (Yoon et al., 2003). Genetic abnormalities have been identified on all levels of the hypothalamopituitary–gonadal axis (Ackerman et al., 2001). The sequential acceleration and deceleration of the LHRH pulse generator and subsequent LH pulse frequency during the menstrual cycle are to a certain degree determined by cyclic changes in endogenous opioid peptides such as -endorphin, probably derived from the infundibular nucleus (Ferin et al., 1984; Gindoff

et al., 1987; Kalra et al., 1997; Chapter 31.1). In postmenopausal women this inhibitory opioid tone on LHRH release diminishes, as appears from the decreased proopiomelanocortin mRNA expression in the infundibular nucleus (Abel and Rance, 1999). In addition, estradiol and progesterone act at a hypothalamic site to modulate LHRH signals. Estradiol primarily affects the amplitude, while progesterone decreases the frequency of the LHRH pulse (Ferin et al., 1984). Participation of a number of hypothalamic neurotransmitters/neuromodulators in the release of LHRH is apparent, i.e. neuropeptide-Y (NPY), GABA, galanin, excitatory amino acids, substance-P, and nitric oxide (Kalra et al., 1997; Dudás et al., 2000; Dudás and Merchenthaler, 2002), and catecholamines modulate the LHRH release. Tyrosine hydroxylase containing terminals, possibly coming from the supraoptic (SON), paraventricular (PVN) and periventricular nuclei are found on LHRH neurons (Dudás and Merchenthaler, 2001). Melatonin inhibits the hypothalamopituitary– gonadal axis before the onset of puberty (Lavie and Luboshitzky, 1997; Chapter 4.5d). Moreover, melatonin secretion is increased in patients with LHRH deficiency, irrespective of its etiology (Kadva et al., 1998). Testosterone decreases melatonin secretion to normal levels in these patients (Luboshitzky et al., 1995, 1996, 1997a), indicating that pineal function is altered in relation to the gonadal status. High training activity and dark photoperiod independently suppress ovarian function

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(Ronkainen et al., 1985). The strongly diminished estrogen levels in postmenopausal women induce hyperactivity of LHRH neurons (Wise, 1998; Chapter 11f). In the human male, testosterone exerts both direct and indirect feedback on LH secretion, whereas its effects on FSH appear to be mediated largely by aromatization to estradiol, which is thus the predominant regulator in FSH secretion (Hayes et al., 2001). There is an attenuation of LH and testosterone secretory pulse amplitude, and disruption of their orderly patterns of release in healthy older men (Veldhuis, 2000). Testosterone levels decline with age in men, but not so dramatically, and with great interindividual variability (Sternbach, 1998; Feldman et al., 2002), resulting in a moderate stimulation of LHRH neurons (Chapter 11f). Bioavailable testosterone decreases 0.5–3% per year in men. Dehydroepiandrosterone sulfate (DHEAS) and estrone also decline with age, whereas dihydrotestosterone rises (Feldman et al., 2002). The decline of free testosterone in men already starts when men are in their 30s and 40s. In addition, the circadian rhythm of testosterone flattens out in the elderly (Baulieu, 2002; Chapter 4.3). Functional MRI (fMRI) studies show that sexual arousal in males, but not in females, is accompanied by an activation of the right hypothalamus (Arnow et al., 2002; Karama et al., 2002). This technique does not allow determination of exactly which hypothalamic structures are involved. Interestingly, in patients with psychogenic erectile dysfunction, sublingual administration of apomorphine caused extra activation of the hypothalamus during video sexual stimulation. Apomorphine acts on the oxytocinergic neurons in the paraventricular nucleus, which plays a key role in regulating penile erection (Chapter 8g; Montorsi et al., 2003). There is a strong correlation between testosterone levels and male sexual activity, both in cross-sectional and longitudinal studies. In addition, correcting testosterone deficiency in hypogonadal men improves sexual desire, activity and mood (Anderson et al., 1992a; Wang et al., 2000a; Yates, 2000). Testosterone not only stimulates both male and female sexual behavior, it is also enhanced by sexual behavior. Although the salivary testosterone levels in males are much higher (7.4 ng/dl) than in females (1.4 ng/dl), in both sexes a similar increase in testosterone levels is found across the evening when there is intercourse, and a decrease when there is no intercourse (Dabbs and Mohammed, 1992). This relationship between testosterone and coitus must, however, be regarded as tentative in view of the studies finding no change in testosterone

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levels (Meisel and Sachs, 1994). Interestingly, men with paraphilia have a prompt reduction or total abolition of all paraphilic activities, while being treated with a longacting analogue of LHRH that serves to reduce testosterone levels (Rosler and Witzum, 1998). A curious finding is that expectant fathers have lower testosterone and cortisol levels, more frequently detectable estradiol levels, and elevated prolactin levels. The functional meaning of these changes for fatherhood is not known at present (Berg et al., 2001). The ovaries provide approximately half the circulating testosterone in premenopausal women (Shifren et al., 2000). The disappearance of androgens such as androstenedione, testosterone, DHEA and DHEAS after ovariectomy and adrenalectomy in women is accompanied by a complete loss of libido, whereas substitution of androgens maintains sexual desires and fantasies after surgical menopause. Circulating levels of androgens decline gradually with increasing age and the circadian rhythm of testosterone disappears in older age (Bremner et al., 1983). Prudent administration of testosterone to healthy premenopausal women causes increases in vaginal arousal, genital sensations and lust (Shifren et al., 2000; Tuiten et al., 2000; Davis and Tran, 2001; Schill, 2001). Around the menopause in women there is a continuous rise in serum FSH and LH and a concomittant fall in estradiol and estrone levels (Overlie et al., 1999). Some publications report a decline of androstendione and testosterone 3 years before menopause (Overlie et al., 1999), while others observe a small rise of these two androgens in postmenopausal women (Jiroutek et al., 1998). Sex hormones are thought to play a role in cognition also, although the literature on the possible effects of estrogens in Alzheimer’s disease is certainly still controversial (see Chapter 29.1b). In older men low estrogen and high testosterone levels predict better performance on several tests of cognitive function (Barrett-Connor et al., 1999a). Testosterone has a differential effect on cognitive function, inhibiting spatial abilities while improving verbal fluency in eugonadal men (O’Connor et al., 2001). Apart from regulating sex hormones (see below and Chapter 24.5), neuropeptides play a role in sexual behavior, as has been shown, mainly, but not only in animal experiments. A facilitatory role for sexual behavior is assigned to corticotropin (ACTH), alpha-melanotropin (-MSH) and oxytocin. Oxytocin is acutely released after orgasm in men, while vasopressin plasma levels remain unaltered (Krüger et al., 2003; see Chapter 8g). Erectogenesis occurs via the MC-4 receptor and may involve 195

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oxytocinergic pathways (Martin et al., 2002). In contrast, an inhibitory effect on sexual behavior has been found for opioid peptides, CRH, cholecystokinin and NPY (see also Chapter 24.5b). The results of tests with galanin contrast with those of LHRH (Argiolas, 1999). 24.1. Disorders of gonadotropic hormone regulation A woman who does not have regular menstrual periods will endure great suffering and eventually death if the problem is left untreated. Hippocrates, cited by Warren and Fried, 2001.

(a) Hypogonadotropic hypogonadism Patients with hypogonadotropic hypogonadism manifest irreversible pubertal delay, infertility and low serum levels of FSH and LH. Hypogonadotropic hypogonadism may have a number of different congenital causes, including genetic ones (for reviews see Whitcomb and Crowley, 1993; Yen, 1993; Warren, 1996; Hayes et al., 1998; Seminara et al., 1998). Increased melatonin levels were found in patients with hypogonadotropic hypogonadism (Luboshitzky and Lavie, 1999). In its turn, melatonin suppresses the gonadal axis (Chapter 4.5). Mutations have been identified in 5–10% of the patients with hypogonadotropic-hypogonadism (Layman, 1999a). Although no specific mutations have been found in the LHRH gene so far (Layman, 1999a, b), hypogonadism, involving the LHRH locus (Achermann et al., 2001a, b), has been described in some patients with 8p deletions. A family has been described with hypogonadotropic hypogonadism without anosmia with compound heterozygous mutations of the pituitary LHRH receptor genes. The disorder was transmitted as an autosomal recessive trait. One mutation in the first extracellular loop of the receptor dramatically decreased LHRH binding to its receptor. The other mutation, in the third intracellular loop, did not modify the binding of the hormone but decreased the activation of phospholipase C (De Roux et al., 1997; Layman, 1999a, b). Kallmann’s syndrome, characterized by hypogonadotropic hypogonadism and anosmia and based on, e.g. an X-linked recessive mutation of the KAL gene, is discussed in Chapters 24.2 and 24.3. Moreover, patients have been described with hypogonadotropic hypogonadism, inherited obesity, abnormal glucose homeostasis, hypocortisolism, a very low plasma insulin level and elevated plasma proinsulin and pro-opiomelanocortin due to a mutation of the endopeptidase prohormone

convertase 1 (PCSK1), which prevents the processing of various prohormones (O’Rahilly et al., 1995; Jackson et al., 1997). A few families have been described with autosomal recessive mutations in the leptin gene or the leptin receptor gene (see Chapter 23). In addition to morbid obesity, these patients had hypogonadism and did not progress to puberty, suggesting that leptin not only controls body mass but is also a necessary signal for the initiation of puberty in human (Clement et al., 1998; Ströbel et al., 1998). Prader–Willi syndrome is dealt with in Chapter 23.1 and Klinefelter’s syndrome in Chapter 24.4. The fertile eunuch syndrome represents a partial LHRH deficiency with preservation of spermatogenesis (Hayes et al., 1998; Seminara et al., 1998). Moreover, Laurence–Moon/ Bardet–Biedl, Biemond II and Alström’s syndromes (Chapter 23.3) are characterized by hypogonadotropic hypogonadism, possibly due to an abnormality in LHRH secretion accompanied by mental retardation, obesity, retinitis pigmentosa and often by dysmorphic extremities (Whitcomb and Crowley, 1993; Yen, 1993; Warren, 1996; Young et al., 1999). In addition, hypogonadotropic hypogonadism is frequently associated with X-linked congenital adrenal hypoplasia, an autosomal recessive disease due to mutations of the DAX-1 gene (NROB1). This gene is a member of the nuclear hormone receptor family, located on chromosome Xp21, and is responsible for the normal development of the hypothalamopituitary–gonadal axis. More than 60 different mutations have been described in the DAX gene so far (Layman, 1999a, b; Achermann et al., 2001a, b). DAX-1 is an orphan nuclear receptor that is expressed in the adrenal gland, ventromedial hypothalamus and pituitary gonadotropins. NROB1 mutations abrogate its ability to act as a transcriptional repressor of steroidogenic factor-1, also an orphan nuclear receptor (Achermann et al., 2001a, b). Although it is not clear at present whether the origin of this disorder is pituitary, hypothalamic or both, the successful induction of pubertal gonadotropins and sex steroid concentrations after therapy with pulsatile LHRH in some cases suggests a hypothalamic origin. This was, however, not confirmed by others (Seminara et al., 1999). In affected males an intrinsic defect in the spermatogenesis may be present which is not responsive to gonadotropin therapy (Seminara et al., 1999). It is interesting to note that a patient with this disorder showed the normal neonatal increase in testosterone levels, possibly stimulated by human chorionic gonadotropin (HCG) from the placenta (Takahashi et al., 1997; Bassett et al., 1999; Caron et al., 1999; Wang

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et al., 1999). PROP1 gene mutations lead to combined hypogonadotropic hypogonadism and pituitary deficiency, and HESX1 mutations to septo-optic dysplasia (Chapter 18.3b). Idiopathic hypothalamic syndrome of childhood and hypothalamic atrophy are rare disorders, described in Chapters 32.1 and 32.2, respectively. Salla disease, due to sialic acid storage, may also be accompanied by hypogonadotropic hypogonadism (Grosso et al., 2001). The most common cause of adult onset of hypogonadotropic hypogonadism in males is a tumor of the hypothalamic-pituitary region, such as a pituitary tumor, which often goes together with acquired erectile dysfunction (Citron et al., 1996; Ben-Jonathan and Hnasko, 2001). Prolactinoma cause amenorrhea, infertility, decreased libido and increased anxiety and depression. Adult-onset hypogonadotropic hypogonadism may also be due to craniopharyngioma (Chapter 19.5) or hypothalamic tumors such as germinoma (Chapter 19.2), astrocytoma (Chapter 19.4) or hamartoma (Chapter 19.3). Hypothalamic hypogonadism is found in 32% of adult patients who received radiation therapy for brain tumors outside the hypothalamic-pituitary region (Arlt et al., 1997; Chapter 25.3). Insulin-dependent diabetes has been associated with reproductive impairment in both men and women. The neuroendocrine lesion may be at the level of the hypothalamus (Baccetti et al., 2002). Rather rare diseases in which an infiltrating process is involved in hypogonadotropic hypogonadism include neurosarcoidosis (Murialdo and Tamagno, 2002; Chapter 21.1), histiocytosis-X (also called Langerhans-cell histiocytosis or Hand–Schüller–Christian disease; Chapter 21.3), and lymphocytic hypophysitis, an autoimmune process that may cause amenorrhoea in combination with polyuria (Chapters 22.1, 22.2). Exceedingly common are infectious disorders of a viral or bacterial nature that lead to hypogonadotropic hypogonadism. In addition, alcohol may not only act directly on the testes but also affect the LHRH neurons. Moreover, head injuries, especially those sustained in head-on automobile collisions, can cause hypothalamic damage resulting in hypopituitarism and elevated prolactin levels. While mildly elevated prolactin levels can cause interruptions in LHRH secretion in women, this is unusual in men. Whiplash injury may cause transsection of the pituitary stalk. A few cases with amenorrhea, sexual immaturity and a history of head trauma have been described. In a 17-year old girl, provocative testing of the pituitary revealed intact pituitary function with hypothalamic insufficiency. MRI demonstrated loss of

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the hypothalamic infundibulum. Traumatic damage to the infundibulum or pituitary stalk is supposed to lead to hypothalamic atrophy (Grossman and Sanfield, 1994). A male patient with hypothalamic hypogonadism and growth hormone deficiency associated with pituitary stalk amputation was treated with intermittent administration of LHRH. The treatment initially improved LH, FSH and testosterone secretion. However, within 3 years of the start of the treatment, LHRH failed to be effective any longer (Mori et al., 1998). Features that distinguish the failure of pituitary cells from a lack of hypothalamic releasing hormones are: (i) hyperprolactinemia, (ii) pituitary hormone deficiencies in provocative testing, i.e. when exogenous pulsatile LHRH invokes LH and FSH secretion, (iii) visual impairment, (iv) diabetes insipidus, and (v) behavioral manifestations (Yen, 1993; MacColl et al., 2002). In addition, (vi) pulsatile LHRH administration may be used to assess the functional integrity of pituitary gonadotropin (Begon et al., 1993). For therapeutic considerations of hypothalamic hypogonadism, see Hayes et al. (1998). In hypogonadotropic hypogonadal men, testosterone replacement may improve both sexual function and mood (Wang et al., 2000a). Secondary amenorrhea or hypothalamic amenorrhea is a form of hypogonadotropic hypogonadism that may occur after severe dieting, heavy physical training or intensely emotional events, and places women at a greatly increased risk of stress fractures, osteopenia, osteoporosis and other bone complications (Warren and Fried, 2001). Strenuous physical exercise, particularly in runners, strongly affects the hypothalamopituitary–gonadal axis function in women and only mildly in men. The increased CRH drive in this condition may play a role in the pathogenetic mechanism of this type of amenorrhea, since serum testosterone is also reduced by chronic glucocorticoid therapy. Anabolic steroid use by athletes may also cause a hypogonadal state (MacAdams, 1986). Idiopathic hypothalamic hypogonadism (Büchter et al., 1998) in weight-stable nonathletic women may be due to subclinical eating disorders (Laughlin et al., 1998; Chapter 23.2). The condition may be effectively treated by LHRH (Begon et al., 1993; Schopohl, 1993). The phrase “functional hypothalamic amenorrhea” refers to the presumed “nonorganic nature” and the reversibility of this form of secondary amenorrhea. The presence of identifiable psychogenic factors in some cases and the reversal of the amenorrhea following counseling is mentioned as an argument for a suprahypothalamic site as a primary 197

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cause in psychogenic amenorrhea, but neither the hypothalamus nor the suprahypothalamic structures that would be involved have ever been studied in this disorder. A slow frequency of LH pulses is typical in these patients (Genazzani et al., 2001; Marshall et al., 2001). Multihormonal abberations occur in this syndrome and opiate systems are presumed to be involved, since some patients have shown LH secretion improvements following naloxon or naltrexone (Wildt et al., 1993; Yen, 1993). A multitude of neuroendocrine changes are described in secondary amenorrhea. Patients suffering from this syndrome show an increased activation of the hypothalamopituitary–adrenal (HPA) axis as appears from higher basal hormone levels and from an augmented adrenal hormone response to CRH administration. Changes in the adrenal androgen enzymatic pathway are presumed to be present (Genazzani et al., 2001). The hypersecretion of cortisol due to an increased CRH drive in these patients may be reversed by naloxon. Both the increased CRH drive and the increased nocturnal melatonin levels may contribute to the inhibition of LHRH secretion (Nappi et al., 1993; Yen, 1993; Luboshitzky and Lavie, 1999). Animal experiments have shown that increased CRH may either directly or indirectly inhibit LHRH release. Cortisol secretion is higher in women with functional hypothalamic amenorrhea than in women with other causes of anovulation or in eumenorrheic women. These observations thus underscore the concept that functional hypothalamic amenorrhea develops in response to stressinduced alterations in the hypothalamus (Berga et al., 1997). In addition, increased serum levels of melatonin have been reported (Luboshitzky et al., 2001). Although the 24-h serum prolactin levels in psychogenic amenorrhea are lower, the sleep-associated increments are greater. Growth hormone is preferentially increased during the nocturnal hours (Yen, 1993). A specific correlation exists between body-weight loss and the occurrence of amenorrhea. Functional hypothalamic amenorrhoea may be a consequence of low-calorie intake as observed in anorexia nervosa (see Chapter 23.2) and intensive physical exercise (Couzinet et al., 1999). Leptin levels in women with functional hypothalamic amenorrhea are significantly lower than in controls, even in those who have a normal body weight and body-mass index (Andrico et al., 2002). A critical leptin level, produced by fat cells, is necessary to maintain menstruation, as shown in anorectic patients (Köpp et al., 1997; Chapter 23.2). NPY from the infundibular nucleus is presumed to play a

crucial role in this relationship. This peptide, which stimulates food intake, is inhibited by leptin (Chapter 23). In rhesus monkey the LHRH pulse generator activity is inversely related to the activity of the NPY gene, and central administration of an NPY antagonist to juvenile animals elicits precocious LHRH release. NPY thus seems to restrain the onset of puberty. The gonadotropin deficiency that is due to malnutrition is partial and may be reversible after improvement of nutritional intake and body composition (Couzinet et al., 1999). Patients with weight-loss amenorrhea and no signs of anorexia nervosa have an augmented growth hormonereleasing hormone (GHRH)-induced growth hormone response. Some of them have reduced levels of insulinlike growth factor-I (IGF-I) (Genazzani et al., 1996). Despite normal thyrotropin (TSH) levels, T3 and T4 are significantly reduced (Yen, 1993), which may also contribute to the amenorrhea. In functional hypothalamic amenorrhea, a reduced thyroid-binding, globulin-binding affinity explains the disparity between normal levels of free T3, free T4 and binding proteins in the face of reduced levels of total T3 and T4 (Domininguez et al., 1997). Nocturnal melatonin secretion is three-fold increased (Yen, 1993). Women with functional hypothalamic amenorrhea, in addition, show increased cognitive dysfunction and psychiatric morbidity. They have greater difficulty coping with daily stress and more often have a history of psychiatric disorders. Indeed, 31% meet the criteria for major depression, and 19% for generalized anxiety disorder (Giles and Berga, 1993). In those women who recovered from functional hypothalamic amenorrhea, the body-mass index increased or remained stable, while this index decreased or remained stable in women who did not recover in an 8-year follow-up. The body-mass index plays a fundamental role in the resolution of this disorder (Falsetti et al., 2002). In men, adult-onset idiopathic hypogonadotropic hypogonadism is an extremely rare neuroendocrine disorder. Normal puberty is followed by a postpubertal or adult decrease in libido and fertility, pulsatile LH and low serum testosterone. The function of the pituitary–gonadal axis is restored and the erectile and ejaculatory disorders respond well to exogenous LHRH replacement. A cause for this condition has so far not been found (Seminara et al., 1998; Kobayashi et al., 2002). Amenorrhea in anorexia nervosa and bulimia nervosa is dealt with in Chapter 23.2. The critical blood level of leptin that is necessary to trigger reproductive ability in

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women and to maintain menstruation (Köpp et al., 1997) may not be maintained in these disorders. It is, moreover, interesting from an evolutionary point of view that the desert-dwelling hunter-gatherers of the !Kung San (“Bushman”) population of Botswana in the Kalahari desert, South Africa, have a seasonal suppression of ovulation in relation to the seasonal changes in nutrition, body weight and activity (Yen, 1993). In mitochondrial encephalopathies gonadal dysfunctions are found, i.e. amenorrhea, impotence, and poor development of secondary sexual characteristics. Several hypothalamopituitary dysfunctions are found in these patients (Chen and Huang, 1995). Menstrual disorders are also observed in patients with hereditary glucocorticoid resistance (Lamberts, 2001).

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the rhesus monkey embryonic olfactory placode release LHRH in a pulsatile manner at approximately 50-min intervals. This indicates that the pulse generator for LHRH is present within these neurons (Terasawa et al., 1999). The marked increase in amplitude of LHRH-induced LH pulses at puberty is accompanied by much more modest changes in frequency (Seminara et al., 1998). The response of the free -subunit of LH to LHRH administration distinguishes prepubertal individuals with a ‘functional hypothalamic hypogonadism’ from adult males with a permanent hypogonadotropic hypogonadism (Mainieri et al., 1998). Delayed puberty occurs in 1% of the population and may result from decreased LHRH release or gonadal failure. The most common cause of a permanent absence of pubertal development is Kallmann’s syndrome, which combines failure of LHRH activity and impairment of the sense of smell (Chapters 24.2, 24.3). The cause of Kallmann’s syndrome is proposed to be a lack of production of adhesion molecules coded by the KAL gene (KAL1), located at Xp22.3, which prevent the LHRH neurons from migrating from the nasal placode to the hypothalamus (Styne, 1997). Delayed puberty is also found in Klinefelter’s syndrome (Chapter 24.4), Noonan’s syndrome (Chapter 18.6) and in female carriers of NROB1 mutations (Ackermann et al., 1999; Seminara et al., 1999). Precocious puberty is the appearance of any sign of secondary sexual maturation, such as pubic hair, before the age of 8 years (or menarche before the age of 9 years) in girls and 9 years in boys. The female-to-male ratio is approximately 10:1 (Partsch and Sippell, 2001; Table 24.1). Central precocious puberty is, by definition, physiologically normal but chronologically early, resulting from hypothalamic LHRH secretion. True, LHRH-dependent or central precocious puberty is induced by the activation of the hypothalamic LHRH pulse generator. Most girls (95%) and nearly 50% of boys have “idiopathic” true precocious puberty, for which the therapy of choice is the administration of LHRH agonists that inhibit the pulsative release of gonadotropins (Styne, 1997). Before the advent of LHRH analogues, cyproterone acetate was widely used for the treatment of idiopathic precocious puberty. Although this treatment was usually well tolerated, liver toxicity has been recognized as a complication of long-term use (Garty et al., 1999). Following discontinuation of LHRH therapy in boys with precocious puberty due to hypothalamic hamartomas (see Chapter 19.3 and below), these boys reentered puberty (Feuillan et al., 2000).

(b) Disorders of puberty While the exact mechanism that triggers the onset of augmentation of LHRH is still unclear, potential factors involved include decreased melatonin production (Chapter 4.5d), metabolizing enzymes responsible for LHRH secretion, neurotransmitters such as noradrenaline, NPY, which restrains the onset of puberty, aspartate, GABA, glutamate, glial growth factors such as transforming growth factor-, and metabolic signs such as leptin (Seminara et al., 1998; Ebling and Cronin, 2000). A male patient with prelingual deafness due to a connexin26 gene mutation also had a partial hypogonadotropic hypogonadism. This supports the possible role of connexins, the constitutive proteins of gap junctions, in puberty initiation. Connexins may play a part in the coordination and synchronization of LHRH release (Houang et al., 2002). The onset of puberty is associated with increases in gonadotropin and sex steroid levels. The first sign of puberty is a sleep-entrained activation of the reproductive axis (Hayes et al., 1998). Serum LH and FSH levels increase with developing puberty and show day/night rhythms with pulsatile secretions. Serum testosterone levels in boys increase with developing puberty and show a diurnal rhythm with an augmentation in the early morning. However, there is already some diurnal rhythmicity of LH, FSH and testosterone much earlier on, i.e. from 4 to 5 years of age; although serum LH, FSH and testosterone in pubertal boys are higher than in prepubertal boys, and the preparation for the onset of puberty in boys thus seems to begin at the age of 4–5 years (Mitamura et al., 1999). LHRH neurons cultured from 199

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TABLE 24.1 Etiology of central precocious puberty (gonadotropin-dependent, ‘true’ precocious puberty). Category

Underlying disease

Permanent precocious puberty ‘Idiopathic’ true or central precocious puberty

Sporadic Familial (gain of function mutation of LH receptor)

CNS tumors, abnormalities or lesions

Dysmorphic syndromes Chemical effects CNS maturation with central precocious puberty secondary to prolonged sex steroid exposure Transient precocious puberty

Variants of pubertal development (partial or incomplete precocity)

Hypothalamic hamartoma (Chapter 19.3) Tumors (Chapter 19): astrocytoma, craniopharyngioma, ependymoma, glioma often associated with neurofibromatosis, Langerhans cell histiocytosis, LH-secreting adenoma, pinealoma Congenital malformations: arachnoid cyst, suprasellar cyst, phakomatosis, hydrocephalus (± spina bifida), myelomeningocele, septo-optic dysplasia Acquired disease: inflammatory CNS disease, abscess, radiation, chemotherapy, headtrauma, empty sella, vascular lesion Williams–Beuren syndrome, McCune–Albright syndrome, Klinefelter syndrome (Chapter 24.4) Following diabetic ketoacidosis, hyperglycinemia Congenital adrenal hyperplasia Sex steroid-producing tumors Male-limited precocious puberty (constitutively activated LH receptor) Idiopathic sporadic Arachnoid cyst (Chapter 19.10) Hydrocephalus (Chapter 18.7) Premature thelarche Premature pubarche Premature menarche

Adapted from Partsch and Sippell, 2001 and Grumbach, 2002.

A familial form of precocious puberty limited to males, with gain-of-function mutations of the LH receptor, has been reported (Grosso et al., 2000). A cranial MRI is indicated in central precocious puberty since it may be caused by CNS tumors of the suprasellar and pineal areas (Chapters 17.3, 19.1, 19.4; Ng et al., 2003), possibly by factors secreted by the tumors that advance the tempo of LHRH maturation (Rivarola et al., 2001). Radiation therapy (Chapter 25.3) may also cause true, central precocious puberty. Optic and hypothalamic gliomas, often associated with neurofibromatosis (Chapter 19.4) and a patient with precocious puberty has been described with a neurofibromatosis type 1 in the presence of a hypothalamic hamartoma (Biswas et al., 2000), Langerhans’ cell histiocytosis (Municchi et al., 2002), astrocytomas (Chapter 19.4) and, in rare cases, with craniopharyngiomas (Chapter 19.5) or suprasellar arachnoid cysts (Chapter 19.10), may also be the cause of true precocious puberty. Hamartomas of the tuber cinereum contain LHRH neurosecretory neurons and may be associated with true precocious puberty, often before the age of 3 years (Chapter 19.3). In addition, precocious puberty

may occur secondary to encephalitis, brain abscess, static cerebral encephalopathy, sarcoid granulomas, tuberculous granulomas of the hypothalamus with and without tuberculous meningitis, histiocytosis, head trauma, cerebral atrophy, focal encephalomalacia (Styne et al., 1997; Beswick et al., 2002), or following an acute cerebral complication of diabetic ketoacidosis (TubianoRufi et al., 1992). The association between precocious puberty and partial empty sella is exceptional, which is not surprising, as it combines hypoplasia and hyperfunction of the pituitary (Zucchini et al., 1995). Precocious puberty also occurs 5.5-fold more often than expected in Klinefelter’s syndrome (Bertelloni et al., 1999; Chapter 24.4). Also other chromosomal abnormalities may lead to central precocious puberty such as triple-X syndrome, three copies of the Prader–Willi syndrome region on chromosome 15q-1113, and a duplication of the long arm of chromosome 9 (Grosso et al., 2000). Moreover, children with hydrocephalus or arachnoid cysts may have true precocious puberty (Styne, 1997; Starzyk et al., 2003). Precocious puberty that later failed to progress was reported in

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idiopathic hypothalamic syndrome of childhood (Chapter 32.1). In an 11-month-old girl, precocious puberty was observed together with nonketotic hyperglycinemia, probably due to an effect of glycine on N-methyl-D-aspartate (NMDA) receptors. Repression of pubertal development during anticonvulsant therapy with GABA agonists suggests that the stimulatory effect of glycine can be overcome by GABA receptor-mediated inhibition. This idea has been confirmed in animal experiments (Bourguignon et al., 1997). Precocious puberty has also been described in children raised in an environment with malnutrition who were adopted after the age of 3 years (Styne, 1997). Girls with a premature pubarche have lower birth weight than normal girls. The girls who subsequently develop functional ovarian hyperandrogenism have even lower birth weights. The lowest birth weights are found in girls with premature pubarche who also have pronounced hyperinsulinism. This combination of symptoms thus indicates an increased risk of a polyendocrine-metabolic disorder (Ibáñez et al., 1999). In addition, patients with McCune–Albright syndrome, consisting of polyostotic fibrous dysplasia, café-au-lait pigment, autonomous disorders (see Chapter 30), various forms of endocrine hyperfunctions including a risk for developing acromegaly, may have precocious puberty. In girls there is a 50% probability of peripheral precocious puberty at 4 years of age (De Sanctis et al., 1999) by estrogen hypersecretion (Feuillan et al., 1995; Syed and Chalew, 1999). McCune–Albright syndrome is based upon an activating missense mutation at cordon 201 of the GNAS gene encoding the -subunit of the G protein (GS), which stimulates the adenylcyclase, intracellular cyclic AMP and, subsequently, precocious steroid production and pituitary gigantism. In addition, elevated sex hormones, hyperthyroidism, hyperprolactinemia and hypercortisolism have been described in this disorder (Tinschert et al., 1999). Ketoconazole has been used to block gonadal steroidogenesis (Syed and Chalew, 1999). Decreased melatonin levels were observed in precocious puberty (Luboshitzky and Lavie, 1999), suggesting that this inhibitory factor has stopped to suppress the gonadal axis. Menstrual bleeding during the neonatal period is commonly related to the withdrawal of maternal estrogens and not to precocious puberty. Vaginal bleeding has also been reported in female infants with congenital adrenal hyperplasia due to a treatment-induced activation of the hypothalamic-pituitary–ovarian axis. A decline of adrenal androgens after glucocorticoid treatment results in an

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increase in gonadotropin levels, which then triggers the occurrence of menses (Uli et al., 1997). (c) The hypothalamopituitary gonadal axis in aging and menopause Age at menopause has a strong genetic component that is influenced by estrogen receptor polymorphism (Weel et al., 1999). One theory on the genesis of menopause is that it is due to the ovarian exhaustion of follicles. Others maintain that the hypothalamus is the pacemaker that initiates the cascade of events leading to menopause. Hot flushes already occur in normally cycling women during the fourth decade, when there are still many follicles present in the ovary. In addition, the finding of the change of rhythmicity of many neurotransmitters with age has led to the hypothesis that the deterioration of the biological clock, the suprachiasmatic nucleus (SCN), underlies such desynchronization (Wise et al., 1996). Indeed, we have found a loss of circadian and seasonal changes in the SCN after the age of 50 years (Chapter 4.3a). The first hormonal change that indicates the onset of menopause is a rise in FSH, based upon increased LHRH activity in the hypothalamic infundibular nucleus. The increase in LHRH secretion occurs despite the 30% decrease in LHRH pulse frequency with aging (Hall and Gill, 2001). Typical symptoms of the acute climacteric syndrome are vasomotor phenomena, e.g. hot flushes, night sweats, and psychosomatic symptoms such as poor concentration, memory impairment, loss of confidence and insomnia (see Chapter 11f). In aging men total and free testosterone gradually decline as gonadotropins increase, while there is an attenuation of the LH and testosterone secretory pulse amplitude, and an associated disruption of their orderly patterns of release. Detailed research showed that the LH pulsing mechanism in healthy older men maintains an increased mean frequency and lower amplitude of bursting activity, a reduced uniformity of serial LH pulse-mass values, and an impaired variability among interpulse-interval lengths (Keenan and Veldhuis, 2001). In the elderly, the circadian testosterone rhythm attenuates a pattern that is observed for many circadian rhythms (Chapter 4.3). The decreased testosterone levels roughly parallel the decline in sexual activity, libido and potency. Aging and hormonal changes were more strongly related to sexual activity and nocturnal erections than to libido (enjoyment, drive and thoughts) (Davidson et al., 1983; Veldhuis, 2000; Schill et al., 2001). Using total 201

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testosterone criteria, the incidence of hypogonadal testosterone levels increased to about 20% of men over 60, 30% over 70 and 50% over 80 years of age, and even greater percentages when free testosterone index criteria were employed (Harman et al., 2001). Testosterone administration to elderly men improved spatial cognition (Janowsky et al., 1994). Androgen supplementation for 3 months in older men with partial androgen deficiency, using a transdermal dehydrotestosterone gel, demonstrated the expected androgenic effects but no change in physical or cognitive functioning (Ly et al., 2001). (d) Polycystic ovary syndrome Polycystic ovary syndrome is a common disorder in which multiple ovarian cysts are associated with menstrual disorders, bilaterally enlarged ovaries, subfertility, hyperandrogenism such as hirsutism and acne, and often central obesity and hyperinsulinemia. Gonadotropin concentrations are high, with a high ratio of LH to FSH, excessive ovarian androgen production, chronic anovulation and acyclic estrogen production in the prototype form of the syndrome, the Stein–Leventhal type of polycystic ovary syndrome (Hall et al., 1998). LH pulses have a persistently accelerated frequency and higher amplitude of pulses and favor LH synthesis, hyperandrogenism and impaired follicle maturation (Marshall et al., 2001). Heightened LHRH drive of gonadotropin secretion and a steroid-permissive milieu appear to jointly promote LH secretion. Positive feedback of estrogens is also implied (Barontini et al., 2001). An insensitivity of the hypothalamic LHRH pulse generation to estradiol and progesterone is present in polycystic ovarian syndrome (Hall et al., 1998). Hypotheses explaining the disorder include an abnormality on the level of the hypothalamus, and it has been suggested that it may originate during intrauterine development. Animal experiments have shown that the pattern of gonadotropin release by the hypothalamus is programmed by the concentration of androgens during early development. Female rats exposed to high androgen levels during development have persisting changes in sexual physiology, including an ovulatory sterility and polycystic ovaries (Cresswell et al., 1997). However, observations in androgen-treated, female-to-male transsexuals show that the histology of the ovaries met the criteria for the diagnosis of polycystic ovaries, which shows that elevated levels of androgens in adulthood alone may also induce polycystic changes (Pache et al., 1991). Women with polycystic ovary

syndrome have increased melatonin secretion, which is associated with their increased testosterone levels (Luboshitzky et al., 2001). In addition, multifaceted dysregulation of the HPA axis is present in this syndrome (Invitti et al., 1998). The abnormalities of the HPA axis are presumed to be central in origin and abdominal obesity may play a key role in the hyperactivity of the HPA axis when tested with naloxone. There does not appear to be any altered sensitivity of the HPA axis to opioids (Ciampelli et al., 2000). Alternatively, polycystic ovary syndrome may be primarily an ovarian disorder of androgen secretion (Rosenfield, 1997). Familial clustering of cases suggest that genetic factors are present (Goudas and Dumesic, 1997). There is familial aggregation of hyperandrogenemia, with or without oligomenorrhea in polycystic ovary syndrome kindreds. In affected sisters only half have oligomenorrhea and hyperandrogenemia, characteristic of polycystic ovary syndrome, whereas the other half have hyperandrogenemia per se (Legro et al., 1998). Several genes and pathways have been implicated in this syndrome. Evidence is present for a role for the insulin gene minisatellite, for the genes encoding the insulin receptor substrate protein-2, for an the association with insulin variable number of tandem repeats, and for the gene encoding for P450 cholesterol side-chain cleavage in polycystic ovary syndrome and in the mechanism of excessive androgen secretion in this syndrome (Franks et al., 1997; Xita et al., 2002), and for an interstitial deletion of the long arm of chromosome 11 (Meyer et al., 2000). One study has proposed that there are two common forms of polycystic ovary syndrome that probably have different origins in intrauterine life. First, obese, hirsute women with polycystic ovaries have an ovarian secretion of androgens that is higher than normal. They also have high LH levels and are associated with high birth weight and maternal obesity. Secondly, thin women with polycystic ovaries have altered hypothalamic control of LH release, which is found with prolonged gestation; and they have high LH but normal androgen levels. The hypothesis is that an altered hypothalamic-pituitary ‘setpoint’ for LH release occurred in the second type as a consequence of long gestation and the presence of a placental failure associated with postmaturity leading to an increased exposure of androgens (Cresswell et al., 1997). This hypothesis should be further explored, and the hypothalamic changes caused in development still have to be shown. It has also been proposed that a low

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hypothalamic dopamine tone is involved in the inappropriate LH and prolactin secretion. In addition, changes in prolactin bioactivity may play a role in the development of hyperinsulinemia (Hernández et al., 2000). A case has been described of a woman with idiopathic intracranial hypertension, polycystic ovary syndrome and visual loss (Au Eong et al., 1997). A subset of women with polycystic ovarian syndrome may develop hirsutism and virilization in pregnancy, especially in the context of reproduction techniques such as in vitro fertilization (De Bustros and Hatipoglu, 2001). One of the widely used therapies for polycystic ovary syndrome is an estrogen/progesterone combination. However, also LHRH agonists and antiandrogens are used (Toscano, 1998). Administration of progesterone can slow down LHRH pulse secretion, favor FSH secretion and induce follicular maturation (Marshall et al., 2001). In obese women with polycystic-ovary syndrome D-chiro-inositol, a fungal metabolite, induced ovulation and decreased testosterone levels (Nestler et al., 1999). Both clinical and animal experimental observations indicate that electroacupuncture may be an effective treatment. There is a close association between bulimia nervosa (Chapter 23.2) and polycystic ovary syndrome, in that some 75% of bulimic women seem to have this syndrome. The connection between the two conditions may be explained by altered peripheral sensitivity for insulin (Morgan et al., 2002).

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that human olfactory sensibilities are in decline. Some 70% of human olfactory receptor genes are ‘pseudogenes’ (Keverne, 1999). Axons from the olfactory neurons course through the cribiform plate of the etmoid bone, and synapse in the olfactory bulb. From the olfactory bulb, axons project predominantly to the periform cortex in the medial aspects of the temporal lobes via the lateral olfactory tract (Figs. 24.1, 24.2). These connections with the temporal cortex may be crucial in the development of olfactory deficits in Alzheimer’s disease (see below). There are some very small left–right connections transporting olfactory information in the rostral part of the anterior commissure (Sylvester, 1986). In addition, axons project from the olfactory bulb to structures of the limbic system, including the anterior olfactory nucleus, preperiform cortex, periamygdaloid complex and the olfactory tubercle (Figs. 24.1, 24.2). Widespread connections with many other areas, including the hypothalamus, spring from these brain regions. Electrical responses have been recorded in the medial and lateral hypothalamus in these brain areas after electrical and odorant stimulation of the olfactory bulb (Martzke et al., 1997). The olfactory bulb is innervated cholinergically by the nucleus basalis of Meynert (Price, 1990). In contrast to the main olfactory connections, the vomeronasal organ (see below) projects to the accessory olfactory bulbs, and from there directly to the hypothalamus (Tirindelli et al., 1998). (b) Anosmia

24.2. Olfaction, anosmia, the vomeronasal organ (Jacobson’s organ) and the embryology of LHRH neurons

Anosmia can result from a congenital defect, inflammation, head trauma or neoplasm. Congenital anosmia is defined as a complete inability, present from birth, to smell. It arises secondarily to abnormal embryological development of the olfactory system. The disorders range from holoprosencephaly (Chapter 18.3) via Kallmann’s syndrome (Chapter 24.3), to congenital anosmia, the mildest manifestation of the arhinencephalic spectrum. Aplasia or hypoplasia of the olfactory bulbs is revealed by MRI in the case of isolated congenital anosmia. Outgrowth of the fibers from the neurosensory cells of the olfactory pits is necessary for the later induction of the olfactory bulbs and tracts. In congenital anosmia this outgrowth appears to be arrested prematurely for unknown reasons between 7 and 16.5 weeks of gestation. The migration deficiency may be a subtle abnormality of the nasal placodes that normally allow their invagination and, in case of a disorder, prevent the growth and contact

Give me a man with a good allowance of nose . . . I always choose a man, if suitable otherwise, with a long nose. Napoleon Bonaparte

(a) Olfaction Odor perception is the result of stimulation of bipolar neurons in the olfactory mucosa by volatile chemicals. A family of approximately 1000 genes coding for odorant receptors with seven transmembrane helices was discovered. Individual olfactory neurons express a single receptor that recognizes a limited range of ligands. There is a striking convergence of all the neurons expressing one type of receptor to one or a few glomeruli (Tirindelli et al., 1998). However, molecular genetic studies suggest 203

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Fig. 24.1. Olfactory structures within or in close relation to the anterior perforated space. Whereas the monkey (A) has a clearly identifiable olfactory tubercle (Tu), it is more difficult to identify a tubercle in the human (B, C, D). The region indicated by an asterisk in D is usually referred to as the olfactory trigone. Note the continuation between the olfactory peduncle (o. ped.) and the olfactory tract (olf) in the monkey (A). The olfactory tract continues in a caudolateral direction towards the limen insulae (white arrowhead) where it makes a sharp bend to enter the temporal lobe. The olfactory tract is more difficult to appreciate in the human (D). The large arrow in B points to the anterior choroidal artery and the small arrows to striate arteries. AO, anterior olfactory nucleus; Ant perf., anterior perforated space; db, diagonal band; GR, gyrus rectus; olfs, olfactory sulcus; opt, optic tract; ox, optic chiasm; U, uncus. (From Sakamoto et al., 1999, Fig. 1 with permission.)

of the neurosensory cells with the telencephalon. Without that contact the formation of the the olfactory bulbs and tracts never occurs. Alternatively, a deficiency in the molecules necessary for the growth and contact of the olfactory nerves may be the cause of this disorder, as is

proposed for Kallmann’s syndrome. It should be noted, though, that congenital anosmia is not accompanied by hypogonadism. This means that the LHRH neurons have reached their normal destination; some connection between the olfactory pits and the telencephalon should

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In patients with mild cognitive impairment, olfactory identification deficits, particularly with a lack of awareness of olfactory deficits, may even have clinical utility as an early diagnostic marker for Alzheimer’s disease (Devanand et al., 2000). In this respect it may be mentioned that in cognitive-unimpaired elderly people a substantial number of tangles has been observed in the anterior olfactory nucleus, and that the number of tangles increases markedly in very mildly demented cases (Price, 1990). In mildly affected Alzheimer patients, odor detection limits for pyridine were in the normal range, but recognition of a broad spectrum of odors was disturbed (Koss et al., 1987; Rezek, 1987). More recently, Wang et al. (2002) found not only that a group of mildly cognitively impaired patients showed a worse sense of smell in a cross-cultural smell-identification test, but also that subjects with an apolipoprotein E (ApoE) -4 allele were unable to identify as many odors as the subjects without the -4 allele. In a meta-analysis of olfactory deficits in Alzheimer’s disease and Parkinson’s disease, odor identification, recognition and detection threshold were found to be severely disturbed in a similar way (Mesholam et al., 1998). However, a later study, in which impaired odor in patients was followed by neuropathological investigation, came to a different conclusion about anosmia in Alzheimer’s disease than earlier studies, in which no neuropathological validation took place. Patients with Lewy bodies, either in the brainstem or in the cerebral cortex, were more likely to be anosmic than those with Alzheimer’s disease or controls. Patients with Alzheimer’s disease were not more likely to be anosmic than controls, nor was anosmia associated with the degree of neurofibrillary tangles as assessed by Braak stage. Among patients with Lewy bodies, overall cortical Lewy body scores and Lewy body density in the cingulate were higher in those who were anosmic. Consensus clinical criteria for dementia with Lewy bodies had a sensitivity of 64% and specificity of 89%. In the absence of Alzheimer’s disease, the sensitivity was even 100% (McShane et al., 2001). A substrate is present for anosmia in Parkinson’s disease, since Lewy neurites and Lewy bodies are found in the olfactory system, i.e. in the olfactory bulb, olfactory tract and anterior olfactory nucleus . An esthesioneuroblastoma, or olfactory neuroblastoma, is a rare, malignant neuroectodermal tumor originating from neurosensory receptor cells in the nasal mucosa. A case has been described of inappropriate vasopressin secretion by such a tumor (Müller et al., 2000b).

Fig. 24.2. Higher magnification view of anterior perforated space. Although a vague bulge appears behind the anterior olfactory nucleus (AO), it is highly questionable if this should be considered to be homologous with the olfactory tubercle in macrosmatic mammals (see text). The surface topography only hints at the presence of an olfactory tract (between arrows) and its bend (white arrowhead) at the region of the limen insulae. (From Sakamoto et al., 1999, Fig. 2 with permission.)

thus have been present during early development. Since an increased rate of sporadic Kallmann’s syndrome is found in families with congenital anosmia, variable penetration of the same gene is presumed (Assouline et al., 1998). (c) Neurological and psychiatric diseases Large numbers of neurological and psychiatric diseases have been reported to be accompanied by olfactory dysfunction. Examples are: Alzheimer’s disease, Down’s syndrome, Korsakoff’s syndrome, Huntington’s disease, amyotrophic lateral sclerosis, schizophrenia, obsessivecompulsive disorder, Kallman’s syndrome (Chapter 24.3), epilepsy, AIDS, neurosarcoidosis (Kieff et al., 1997; Chapter 21.2) and closed head injury, which are reported to be accompanied by olfactory dysfunction. Anosmia and olfactory bulb and tract atrophy are also characteristics of Wolfram’s syndrome (Dean et al., unpubl. results; Chapter 22.7). However, little is known about the exact site of the lesions in the different brain diseases in case of anosmia (Martzke et al., 1997). In schizophrenia, olfactory deficits were particularly found in the subgroup with severe polydipsia and hyponatremia (Kopala et al., 1998). 205

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As a periscope from the diencephalon, the vomero-nasal system may monitor exogenous hormones, ‘pheromones’. Wysocki (1979)

(d) Olfaction and sex: the vomeronasal organ and the LHRH neurons of the preoptic area Over 100 years ago, in his text book Psychopathia Sexualis, Von Krafft-Ebing described how olfactory stimuli frequently initiated sexual excitement. Von KrafftEbing suggested a close proximity of the olfactory and sexual centers (Casanova et al., 2002). The vomeronasal organ is sensitive to certain airborne chemical signals defined as pheromones or ‘vomeropherins’. Mammalian pheromones are naturally occurring, species-specific volatile compounds that are secreted into the environment in sweat or urine by one individual of a species. They stimulate the vomeronasal organ and exert a behavioral or physiological response in another individual of the same species (Berliner, 1996). The vomeronasal organ responds to exposure to pheromones from the skin of the opposite sex and produces changes in LH by activation of the accessory olfactory system and the pulsatile release of LHRH neurons in the preoptic hypothalamus (Berliner et al., 1996). In the rat, the vomeronasal organ and the vomeronasal pathway are sexually dimorphic ; sex differences are present in the structures that receive vomeronasal input, e.g. the medial amygdala, the medial preoptic area, the ventromedial hypothalamic nucleus and the ventral region of the premamillary nucleus. In addition, sex differences have been described in the rat accessory olfactory bulb, bed nucleus of the accessory olfactory tract, and bed nucleus of the stria terminalis. The vomeronasal organ thus acts in a sex-specific way as an additional sensory system (sixth sense), using the hypothalamus and adjacent structures as a link. It affects psychophysiological homeostasis, hormonal responses and autonomic reflexes by transmitting neural impulses to the hypothalamus. Vomeropherins induce a reduction of cardiac and respiratory rate, increase the conductance of the skin and increase -rhythm of the EEG. In addition, increases in parasympathetic tone, an amelioration of anxiety, and changes in LH and FSH levels have been observed (Berliner, 1996). Menstrual synchrony is often reported by all-female living groups and by mothers, daughters and sisters who are living together. Pheromones are held responsible for this phenomenon (McClintock, 1971; see below). The

vomeronasal organ is often damaged when plastic surgeons rebuild noses. Functional anatomy and histology. It is still generally claimed that adult humans do not have a vomeronasal organ or an accessory olfactory bulb, but that they would be present in the human fetus, where they disappear before birth (e.g. Price, 1990; Savic et al., 2001). Although this is not correct according to quite a number of publications (see below), recent papers also state that the presence of only very few neurons and the lack of vomeronasal nerve bundles suggest that the vomeronasal epithelium, unlike in other mammals, is not a sensory organ in adult humans and has already regressed in the fetus halfway through gestation (Trotier et al., 2000). However, electrical autonomic and psychological responses constitute evidence for a selective and sensitive response from the adult human vomeronasal organ (Meredith, 2001). The accessory olfactory bulb is absent in adult humans and it is thus uncertain exactly how pheromone signals reach the human brain (Keverne, 1999; Savic et al., 2001). The first description of the vomeronasal organ or Jacobson’s organ, in a wounded soldier, was given in 1703 by the Dutch anatomist F. Ruijsch, while L. Jacobson, after whom the organ was named, published his findings in animals in 1811 (Johnson et al., 1985). The vomeronasal organ is enclosed in a cartilaginous capsule that is separated from the main olfactory epithelium. It consists of a pair of blind tubular diverticula, which are found on the most anterior part at the inferior margin of the nasal septum (Fig. 24.3). The closed tubes, 2–8 mm long, which run in the lamina propria of the septal mucosa, in the anteroposterior direction, are blind posteriorly and usually open anteriorly into the nasal cavity (Fig. 24.4). The vomeronasal pit is usually observed 1 cm dorsal to the columella and 1–2 mm above the floor of the nose (Moran et al., 1991; Keverne, 1999). Using a headlight and Killian’s nasal speculum, the opening of the vomeronasal organ can be macroscopically seen in some 40% of the adults (Moran et al., 1991) and with an endoscope and repeated observations in 73% of the population (Trottier et al., 2000). No trend toward involution with increasing age (Johnson et al., 1985) has been observed. The vomeronasal pit measures up to 2 mm (Johnson et al., 1985). The duct of the vomeronasal organ is filled with fluid. The cavernous tissue of this organ undergoes cyclic swelling and emptying under the influence of the autonomic innervation, nitric oxide and vasoactive intestinal polypeptide nerve fibers. Novel stimuli activate the pump-like action for stimulus access.

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In this way pheromones, dissolved in the fluid, reach the receptor cells (Tirindelli et al., 1998; Keverne, 1999). In most cases the organ has a crescentic lumen on coronal section, with the neuroepithelium on the medial wall, while the remaining epithelium is respiratory in type (Johnson et al., 1985). Within the duct the mucosa is tall, ciliated and pseudostratified and differentiates into receptor cells and basal cells. Goblet cells are sometimes present (Johnson et al., 1985; Keverne, 1999). The chemosensitive bipolar neurons, the primary sense neurons of the vomeronasal system, possess apical microvilli and are located in a neuroepithelium. They send a dendrite to the site of the stimulus and an axon to the brain. Like the olfactory receptor neurons, the vomeronasal receptor neurons turn over during the life of an individual and are replaced by new neurons derived from the basal cells. The posterior end of the vomeronasal organ is lined by an epithelium that contains three distinct cell types: (1) basal cells, (2) dark cells, and (3) light cells, which have a round, euchromatic nucleus with a pronounced nucleolus and a clear cytoplasm with a pronounced Golgi apparatus (Moran et al., 1991; Keverne, 1999; Fig. 24.5). These cells are most probably the neurons that subserve the sensory function. The vomeronasal organ neurons contain neuron-specific enolase and protein gene product 9.5, like the olfactory receptor neurons, but no olfactory marker protein (Takami et al., 1993). The latter observation was confirmed by Trottier et al. (2000). In that study it was found that most cells of the vomeronasal epithelium expressed keratin. No nerve bundles were found with anti-S100, and there was a lack of neurons, raising doubt again about the functional significance of this organ in adults. However, functional studies show fundamental differences between the receptor for odor and pheromones. So far, two families of seven transmembrane vomeronasal organ receptors have been identified that appear to activate inositol 1,4,5-triphosphate, in contrast to cyclic adenosine monophosphate. They consist of some 40 and 100 genes, respectively. Two multigene families of G protein-linked receptors (V1 and V2) are each expressed in a distinct region of the vomeronasal organ. Probably one receptor is expressed in each sensory neuron. One receptor displays some kind of sexual dimorphism (Tirindelli et al., 1998; Keverne, 1999). Embryology. The vomeronasal groove appears in the human embryo at 37 days postovulation. At 41 days the olfactory nerve is organized into two plexuses, one lateral

Fig. 24.3. Localization of the vomeronasal cavities (indicated by arrows) in humans, as they were illustrated in the last centuries. (A) Frederic Ruysch, in 1703, was the first to indicate, with two bristles (*), the existence of these canalibus nasalibus. He wrote, in Latin: On both sides of the anterior and inferior part of the nasal septum appears the opening of a duct. I have not read about the existence and utility of that in authors: I consider it serves for the secretion of mucus’ (translation by courtesy of Annick Le Guerer). (B) Anton Kölliker, in 1877, gave the exact position of these cavities in the nasal septum of adult cadavers. (C) Potiquet, 1891, was the first to study the position and length of these cavities in living adult subjects. He inserted a stylet (*) to estimate the length of the vomeronasal cavity that extended toward the back. (from Trottier et al., 2000, Fig. 1 with permission.)

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Fig. 24.4. Coronal section through an adult human septum. On the left, the closing vomeronasal pit can be seen, and on the right, the duct (H&E  80). (From Johnson et al., 1985, Fig. 6 with permission.)

and one medial, the latter mingled with the terminalvomeronasal complex. The olfactory bulb is visible at 44 days, while by 48 days the distinction between olfactory bulb, and nuclei and terminal and vomeronasal nerves can be observed. At 57 days the olfactory and terminalvomeronasal fibers are easily distinguishable. The terminal ganglion is a sensory ganglion with an autonomic contingent. It is attached to the vomeronasal system (Bossy, 1980; Figs. 24.6, 24.7). In the ganglion terminalis, the LHRH-immunoreactive cells are outnumbered by the other neurons (Schwanzel-Fukuda and Pfaff, 1994). The vomeronasal fibers are gathered into two posterior filaments that arrive at the vomeronasal ganglion, in the dorsomedial part of the olfactory bulb, and end in the medial part of it. Both the somata and the axons of about 70% of all terminal neurons are immunoreactive for LHRH and they appear to provide direct input to LHRH neurons in the basal forebrain, medial preoptic nucleus and other anterior parts of the hypothalamus that regulate neuroendocrine functions (Boehm et al., 1994; MontiBloch et al., 1994). The central processes of the terminal

and vomeronasal fibers enter the brain medial and caudal to the olfactory bulb, and in the supraoptic area, septal nuclei, olfactory lobe and islands of Calleja (Bossy, 1980; Schwanzel-Fukuda and Pfaff, 1994). Neuronal cell adhesion molecule (N-CAM) is expressed in both sets of sensory neurons. These cell adhesion molecules are thought to be involved in stabilization connections (Schwanzel-Fukuda et al., 1996; Keverne, 1999; Figs. 24.8, 24.9, 24.10). However, in the N-CAM knock-out mouse, migration of LHRH neurons was not overly affected (Rugarli, 1999). Like the vomeronasal organ itself, nerve cells of the terminal nerve have their embryological origin in the medial olfactory placode. Neuron-specific enolase and LHRH-immunoreactive cells migrate from the primordial vomeronasal organ into the basal forebrain and preoptic hypothalamus (Boehm et al., 1994; Berliner et al., 1996), following the course of the terminal and vomeronasal nerves (Schwanzel-Fukuda and Pfaff, 1994). A notable exception occurs in individuals with Kallmann’s syndrome, one of its features being a lack of development

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Fig. 24.5. Electronmicrograph of the vomeronasal organ epithelium. The ‘dark’ cells (D) have elliptical, heterochromatic nuclei. The cytoplasm in the apical domain of the cells contains mucigen-like granules (M). The ‘light’ cells have round, euchromatic nuclei (N). Note the membranelimited vesicles (V) with contents of moderate electron density in the supranuclear cytoplasm. Golgi stacks (G) are abundant. Several slender microvilli (arrow) extend from the cell surface into the lumen (LU) of the VNO. Small basal cells (B) sit atop the basement membrane (BM).  2100. (From Moran et al., 1991, Fig. 6 with permission.)

of the vomeronasal organ–nervus terminalis complex (see Chapter 24.3). At 5 weeks after conception, LHRH was found in the human hypothalamus (Aksel and Tyrey, 1977). LHRH-expressing neurons were observed in the vomeronasal organ at 8–12 weeks of gestation. At later stages (18–19 weeks) only few or no (19 weeks) LHRH

cells were found close to the vomeronasal organ, which suggests migration of these cells (Kjaer and Fischer Hansen, 1996). Although it has not been established that all human LHRH neurons originate in the nasal placode, two LHRH neuron populations have been found in the rhesus monkey fetus that are both derived from the 209

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Fig. 24.6. Semischematic representation of the main features related to the stage development. Stages 11–15 and 18: transverse sections; stages 19, 20, 22, and 23: sagittal sections. CB, cellular buds; LD, lens disc; ND, nasal disc; NF, nasal field; ON, olfactory nerve; RN, rostral neuropore; TG, terminal ganglion; TVN, terminal-vomeronasal nerve; VNG, vomeronasal groove; VNO, vomeronasal organ; VX, vessels. (From Bossy, 1980, Fig. 2 with permission.)

olfactory placode. The one that occurs earlier migrates mainly to extrahypothalamic sites, i.e. apart from the septum, preoptic region and stria terminalis, also to the medial amygdala, internal capsule and globus pallidus. In contrast the later-occurring LHRH neurons migrate to the preoptic area and basal hypothalamus and are considered to regulate the pituitary–gonadal axis (Quanbeck et al., 1997). Also in the adult human hypothalamus, an accumulation of LHRH neurons and fibers was observed, not only in the infundibular and preoptic region, but also in additional locations in extrahypothalamic regions (Stopa et al., 1991). LHRH in extrahypothalamic regions may be involved in nonreproductive functions. A subpopulation of the LHRH neurons shows colocalization with galanin (Kalra et al., 1997), and LHRH neurons colocalizing -endorphin have been described in the arcuate nucleus, the lamina terminalis and the septopreoptic area of human fetuses of 17–26 weeks of gestation

(Leonardelli and Tramu, 1979). The LHRH content of the female fetal hypothalamus shows a peak at 22–25 weeks and declines after 26 weeks of gestation. In male fetuses a decline of LHRH content was observed from 14–33 weeks. From 34–38 weeks, LHRH content rose to the highest levels attained during gestation. A sex difference is thus already present in human fetal LHRH development (Siler-Khodr and Khodr, 1978). LHRH neurons, cultured from the embryonic olfactory placode of the rhesus monkey, release LHRH in a pulsatile manner at 50 min intervals, supporting the idea that the LHRH pulse generator is situated within these neurons (Terasawa et al., 1999). For the distribution of LHRH neurons in the preoptic septal region, diagonal band of Broca, lamina terminalis and periventricular and infundibular nuclei of the adult human brain, see Rance et al. (1994) and Dudás et al. (2000).

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Fig. 24.7. Schematic representation of the nervous olfactory structures at the stage 23. AON Anterior olfactory nucleus; EL, ependymal layer; EGL, external granular layer; EML, external molecular layer; IGL, internal granular layer; IML, internal molecular layer; LOF, lateral olfactory fila; MCL, mitral cell layer; ML, marginal layer; MOF, medial olfactory fila; MSN, medial septal nucleus; OV, olfactory ventricle; PL, plexiform layer; TG, terminal ganglion; TN, terminal nerve; VNG, vomeronasal ganglion; VNN, vomeranasal nerve; VNO, vomeronasal organ; I, accessory olfactory formation. According to Humphrey (1940), the external granular layer of this formation is deep and does not mix with the vomeronasal fibers, in contrast to the intermingling of olfactory fibers and external granular layer of the olfactory bulb. (From Bossy, 1980; Fig. 3 with permission.)

rienced as an odor. These signals also have immediate or delayed effects on the neuroendocrine reproductive systems of other humans (Weller, 1998). Although the role of the vomeronasal system in aspects of human mothering has been presumed, only indirect evidence for such a function is available at present. Negative potentials with the characteristics of receptor potentials are recorded from the surface of the vomeronasal organ epithelium, in response to vomeropherins in a sex-dependent way. In contrast, no sexual dimorphism

Effects of vomeropherins. Humans, like other animals, emit odors from many parts of the body, such as the axillary area. Olfactory information seems to be quite specific. A mother can identify the odor of her infant or older child by smelling at a T-shirt worn previously by the child. In turn, infants prefer their own mother’s breasts or axillary pads. Children can discriminate between odors and prefer their mother’s odor and the body odors of other kin. Chemical signals from one human can also be detected by another, without their being consciously expe211

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Fig. 24.8. Microprojection drawings of serial, 8 m sagittal sections through the brain and nasal regions of an approximately 42-day-old human embryo. Every 10th section through the migration route, on one side, was drawn. N-CAM-immunoreactive cells are represented by open circles, and N-CAM-immunoreactive fibers by dashed lines. LHRH-immunoreactive cells are represented by black dots. The olfactory pit (OP) has invaginated to form the beginnings of the nasal cavity. N-CAM-immunoreactive cells and fibers form a distinctive plexus or network across the developing nasal septum, linking the epithelium of the olfactory pit (OP) with the forebrain (F), and forming a ‘scaffold’ along which LHRH cells migrate into the forebrain. The migration route is composed of N-CAM-immunoreactive cell bodies (represented by open circles) or axons (dashed lines) of the olfactory (sections 77 and 87) and vomeronasal and terminal nerves (sections 97, 107, 177), extending from the epithelium of the olfactory pit to the forebrain. At 42 days LHRH-immunoreactive cells are seen primarily in the ganglia of the terminal nerve (NTg), and along the caudal part of the cellular aggregate below the forebrain (sections 97, 107, 117). At this age a few LHRH cells enter the brain with central roots of the terminal nerve and may be seen in the medial basal forebrain. (From Schwanzel-Fukuda et al., 1996, Fig. 5 with permission.)

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Fig. 24.9. (1) A luteinizing hormone-releasing hormone (LHRH)-immunoreactive cell (red-brown) is seen in the epithelium of the medial olfactory pit (MOP). Forty-two-day-old human embryo, 8-m sagittal section. Scale bar 7 m. (2) Low-power photomicrograph showing neural cell adhesion molecule (N-CAM)-immunoreactive cells (blue-gray) in the intermediate and basal layers of the epithelium of the medial part of the olfactory pit (MOP). Both N-CAM (blue-gray) and LHRH-immunoreactive cells (red-brown, arrow) are seen in ganglia of the terminal nerve (nervus terminalis, NTg) in the nasal mesenchyme (NM). Large, round cells characteristic of the medial components of the migration route. Fortytwo-day-old human embryo, 8-m sagittal section. Scale bar 45 m. (3) a. Low-power photomicrograph, shows a few LHRH-immunoreactive cells (arrows) along the broad swath of N-CAM-immunoreactive cell bodies and neurites which extend from the epithelium of the olfactory pit (OP) and form an aggregate in the nasal mesenchyme (NM) below the forebrain and the developing olfactory bulb (OB). In serial sections, the N-CAM-immunoreactive axons of the olfactory nerves, which make up a part of the aggregate, are seen in contact with the developing olfactory bulb. Forty-two-day-old human embryo, 8-m sagittal section. b. Higher magnification of the same section shows some of the LHRH-immunoreactive cells (red-brown) along the caudal part of the migration route. Scale bar 90 m in a, 7 m in b. (From Schwanzel-Fukuda et al., 1996, Fig. 1 with permission.)

was found for olfactory epithelial responses by MontiBloch et al. (1994). The steroidal vomeropherin, pregna4,20-diene 3,6-dione (PDD), delivered as pulses in an airstream, produces dose-dependent changes of the electrovomerogram, but had no such effects on the nasal respiratory or olfactory epithelium. However, a sex

difference was observed in the sensitivity to the odor of androsterone. A smaller number of females than males became insensitive to this compound (Dorries et al., 1989), suggesting the presence of sex differences also in the olfactory epithelium. The vomeropherin PDD decreased LH and FSH pulsatility in males, but not in 213

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Fig. 24.10. (A) In contrast to the fairly extensive distribution of the low sialic acid-containing N-CAM, the polysialated PSA-N-CAM is found in particular parts of the migration route. In this photomicrograph, PSA-N-CAM immunoreactivity is seen in fascicles and clusters just outside the epithelium of the medial olfactory pit, in the nasal mesenchyme. LHRH-immunoreactive neurons (red-brown, arrows), are seen in these clusters and fascicles. Forty-two-day-old human embryo, 8-m sagittal section. Scale bar 25 m. (B) PSA-N-CAM-immunoreactive fibers (light gray, solid arrow) are seen along the caudal part of the cellular aggregate (CA) below the rostral forebrain (F), together with a few LHRH-immunoreactive neurons (red-brown, open arrows). A number of blood vessels (bv) and small, darkly stained red blood cells (rbc) are seen nearby. Compare the distribution of PSA-N-CAM here with that of N-CAM in Fig. 24.9(3). Forty-two-day-old human embryo, 8-m sagittal section. (C) This section, adjacent to that seen in (B), was treated with a neuraminidase before incubation in primary antiserum to PSA-N-CAM (see controls). The absence of PSA-N-CAM reaction product (solid arrow) confirms the specificity of our antibodies. LHRH-immunoreactive neurons (red-brown, open arrows) are seen along the caudal part of the cellular aggregate (CA) and in a cluster on its ventral border. Scale bar 45 m in (B) and (C). (From Schwanzel-Fukuda et al., 1996, Figs. 8 and 9 with permission.)

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females, showing a sex-dependent functional connection between the vomeronasal organ and the hypothalamic LHRH neurons. Prolactin levels were not significantly affected. In addition to the effects on gonadotropin pulsatility, autonomic effects have been found as well after vomeronasal organ stimulation. These include decreased respiratory frequency, increased cardiac frequency and event-related EEG changes. In addition, decreased skin temperature has been found (Monti-Bloch et al., 1994, 1998; Berliner et al., 1996). Research pioneered by McClintock (1971) has shown that the menstrual cycle of women who are roommates or close friends tend to converge with time. Although the vomeronasal organ has been proposed to be the most likely candidate system of communication between the women, this has not been proven until recently; however, vomeropherins seem to be involved. Stern and McClintock (1998) collected body odor on cotton pads from female donors. These pads were wiped under the nose of recipient women, who were asked not to wash their faces for the next 6 h. The timing of the ovulation and menstruation of the recipients did indeed change systematically. Odors taken on the day that the donors ovulated and the two following days delayed ovulation, whereas odors from women in the follicular phase of the ovulatory cycle shortened both the time to ovulation and the length of the menstrual cycle. The interpretation of these data is still under debate (McClintock, 1999; Whitten, 1999). Recent positron-emission tomography (PET) studies have shown that smelling an androgen-like compound activates the hypothalamus of women, with the center of gravity in the preoptic and ventromedial nuclei. Men, in contrast, activate the PVN and dorsomedial nuclei when smelling an estrogen-like substance, showing a substrate for a sexually dimorphic reaction to pheromones (Savic et al., 2001; Fig. 24.11). Fig. 24.11. Smelling of odorous sex hormone-like compounds causes sex-differentiated hypothalamic activations in humans. Activated clusters superimposed on a standard brain. The Sokoloff color scale illustrates z values (0.0–4.5). The clusters were thresholded at 3.1; thus, only regions with z > 3.1 and cluster size > 0.8 cm3 are shown. (A) A derivative of testosterone (AND) versus AIR in females. (B) A derivative of estrogens (EST) versus AIR in females. (C) EST versus AIR in males. Subject’s right side is to the left. The Talairach coordinates are given. The same brain sections are shown for the two contrasts within each sex group to illustrate the lack of hypothalamic activation with AND in males and EST in females. Only the significant clusters (p < 0.05) are shown. The AND versus AIR in males showed no clusters at p < 0.05 and is therefore not illustrated. (From Savic et al., 2001, Fig. 1 with permission.)

24.3. Kallmann’s syndrome Kallmann’s syndrome, first described by Maestro de San Juan in 1856 and subsequently by Kallmann et al. in 1944 (Izumi et al., 1999), is an inherited disorder, defined by the joint occurrence of hypogonadotropic hypogonadism and anosmia. Affected patients may exhibit, e.g. cerebellar ataxia, nerve deafness, retinitis pigmentosa, color blindness, synkinesia, nystagmus, and mental retardation (Hochberg et al., 1982; Rugarli and Ballabio, 1993; Gu et al., 1998), but high IQs have also been reported 215

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(Bobrow et al., 1971). In addition, dysplasia of the hippocampus has been reported in two cases of Kallmann’s syndrome, making it clear that the affected systems are not limited to the hypothalamus. Male Kallmann patients do not show an interest in the opposite sex, do not fall in love and have no libido. An absence of homosexuality has been reported, but the study included only 13 patients (Bobrow et al., 1971; Wakeling, 1972; Parhar et al., 1995). In female patients, the differential diagnosis anorexia nervosa with primary amenorrhea should be considered (White et al., 1993). Although many cases of Kallmann’s syndrome are sporadic, autosomal dominant, autosomal recessive and X-linked recessive inheritance patterns have also been described, which indicates genetic heterogeneity. An autosomal locus for Kallmann’s syndrome has been proposed at chromosome 8p11.2 (Vermeulen et al., 2002). The incidence of Kallmann’s syndrome has been estimated at 1:10,000 males and 1:50,000 females, which was interpreted to indicate that the X-linked form is the most frequent one (Rugarli and Ballabio, 1993; Birnbacher et al., 1994). However, more recent data indicate that the X-linked form of Kallmann’s syndrome, which is due to characterized mutations, is the least common of the three modes of inheritance (Gu et al., 1998; Maya-Nuñez et al., 1998). (a) Molecular genetics and migration Genetic defects have been observed in X-linked Kallmann’s syndrome, in a critical region of about 70 Kb in the Xp22.3 region in less than 50% of the patients. This localization has led to the assignment of the KALX or KAL1 gene to a specific 680 amino acid-secreting part within this region (Legouis et al., 1994; Izumi et al., 1999; Rugarli, 1999). Patients with Kallmann’s syndrome carrying small deletions or single-base mutations within the KAL gene, a translocation or a duplication, have been described (Hardelin et al., 1993; Rugarli and Ballabio, 1993; Izumi et al., 1999, 2001; Rugarli, 1999; Söderlund et al., 2002). Final validation of the KAL gene was established with the discovery of nine unique point mutations in this gene (Seminara et al., 1998; Izumi et al., 2001). In addition, the complementary DNA (cDNA) of the candidate gene KALIG-1 (Kallmann’s syndrome interval gene-1), which has been isolated from the same area, Xp22.3. Two brothers with Kallmann syndrome inherited a 3500-bp deletion from their mother that was entirely confined to the KALIG-1 gene (Bick et al., 1992; Caviness, 1992). The sequence revealed homology with

the N-CAM, indicating that the KALIG-1 gene may encode a new type of neuronal migration factor. The KAL1 gene encodes an extracellular matrix glycoprotein of compound molecular structure called anosmin-1, which belongs to the class of cell adhesion molecules. Anosmin1 is present in various extracellular matrices, such as interstitial matrices and basement membranes. Later in embryonic life, KAL1 expression becomes restricted to definite neuronal populations (Hardelin, 2001). Anosmin1 may not only play a role in migration of olfactory and LHRH neurons and in the differentiation of the olfactori bulb, but also in the development of synkinesia and renal agenesis, which are seen in the X-linked form of Kallmann’s syndrome (Jansen et al., 2000; Massin et al., 2003). A nonsense mutation was found in exon 13 of the KAL gene, encoding the region of the fourth fibronectin type III repeat of anosmin-1, which results in an apparently nonfunctional truncated protein (Jansen et al., 2000). In X-linked Kallmann’s syndrome, gonadotropin apulsity is consistent with complete arrest of LHRH neurons at the nasal-forebrain junction. However, the low levels of LH and FSH that have been reported in cases of autosomal Kallmann’s syndrome suggest that a few LHRH neurons have successfully reached their destination in the hypothalamus (MacColl et al., 2002). In addition to the X-linked form, autosomal dominant and recessive kindreds with Kallmann’s syndrome have been reported. These cases do not have a completely apulsatile LH secretion, like the patients with a KAL mutation, but rather enfeebled, but present, LHRH-induced LH pulses (Oliviera et al., 2001). One siblingship has been described where the brother and sister both had Kallmann’s syndrome (anosmia and deficiency of LHRH), and the woman also had streak ovaries. Linkage analysis showed that a gene other than KAL1 at Xp22.3 was implicated in this mutation (Persson et al., 1999). Moreover, autosomal forms of Kallmann’s syndrome with complex chromosomal translocations have been reported (Kroisel et al., 2000). In fact, both autosomal recessive and autosomal dominant modes of transmission have been described in addition to the X-linked form, and many sporadic cases have been reported (Izumi et al., 1999). Consequently, other genes than the Xp22.3 region should be involved in more than 50% of the cases of Kallmann’s syndrome. The KAL gene is expressed in the olfactory bulb and in various other parts of the brain (Rugarli et al., 1993; Lutz et al., 1994). Upregulation of transcription of the KAL gene was found in chickens at the moment when

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the first synaptic contacts between the olfactory axons and mitral cells were established, which may suggest that the primary defect in Kallmann’s syndrome lies in neuronal interaction and/or synaptogenesis rather than in migration. In addition to functions such as adhesion molecule, chemoattractant, and proinvasive factor, KAL was proposed to function as a target-derived stop signal for olfactory neurons (Rugarli, 1999). The observation in humans that at 45 days of embryogenesis, when the KAL gene is not yet expressed, the olfactory nerves have already begun their migration from the nasal epithelium, suggests that the KAL gene is not necessary for early migration. Rather, a defect in neuronal interaction may take place, i.e. when the LHRH neurons enter the olfactory bulb and/or at the moment when contact is established between the incoming olfactory axons and the central neurons of the bulb (Seminara et al., 1998). The migration defect may consequently be secondary to the lack of contact between the olfactory nerves and the forebrain (Rugarli and Ballabio, 1993; Rugarli et al., 1993), and the retrograde degeneration of the olfactory nerve may thus be the result of this lack of contact (Seminara et al., 1998). It has also been presumed that part of the role of the normal Kallmann gene product may be a suppression of a Y gene product (Parhar et al., 1995). Subsequently a mutation was found in the KAL gene part that encodes for the C-terminal portion of a fibronectin type III gene that may be involved in axonal pathfinding (O’Neill et al., 1998). In addition, the KAL1-encoded protein anosmin-1 was found to be a transient and regionally restricted component of extracellular matrices during organogenesis in humans. Anosmin-1 was detected in many organs, including some forebrain regions. In the olfactory bulb the protein was detected from week 5 onward. The protein was restricted to the olfactory bulbs and the medial walls of the primitive cerebral hemispheres along the rostrocaudal migratory pathway of the LHRH neurons at 6 weeks. The protein seems to act as a local rather than a long-range cue during organogenesis (Hardelin et al., 1999).

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been described (Dissaneevate et al., 1998). Patients with partial LHRH deficiencies and incomplete sexual development have been described in the past as fertile eunuchs (Rugarli and Ballabio, 1993). Although gonadotropin deficiency in Kallmann’s syndrome is generally said to be an isolated endocrine disorder, some patients with this syndrome may have osmoreceptor dysfunction and abnormal thirst regulation, indicating more extensive hypothalamic involvement than previously appreciated (Hochberg et al., 1982). In addition to hypogonadism, patients with Kallmann’s syndrome exhibit either nonselective anosmia or hyposmia, due to aplasia or hypoplasia of the olfactory bulbs and tracts. Neuroimaging by MRI provides accurate in vivo demonstration of arrhinencephalia, i.e. absence of the olfactory bulb, olfactory tracts and olfactory sulcus (Rugarli and Ballabio, 1993; Vogl et al., 1994). The receptor cells of the olfactory mucosa cannot innervate the absent olfactory bulb in Kallmann’s syndrome and this disorder is therefore characterized by axonal degeneration, neuronal immaturity and the formation of intraepithelial neuromas (Schwob et al., 1993). Yet at least some olfactory neurons are functionally mature in the olfactory epithelium of Kallmann patients (Rawson et al., 1995) and normal olfactory bulbs are found in 25% of Kallmann’s syndrome patients (Seminara et al., 1998). Typically, patients with hypogonadotropic hypogonadism and anosmia have been diagnosed with Kallmann’s syndrome and those with normal olfaction have been diagnosed with idiopathic hypogonadotropic hypogonadism. However, both of these presentations (i.e. with and without anosmia) can occur in the same family, thus demonstrating the variability of expression of this trait (Seminara et al., 1998). The pathogenetic basis of the association between hypogonadism and anosmia in Kallmann’s syndrome seems to be a migration defect of LHRH neurons (see above). LHRH neurons and olfactory neurons both originate in the olfactory placode. The olfactory placode forms the olfactory epithelium from which the olfactory neurons project to the mitral cells of the olfactory bulb. During development, LHRH neurons migrate from the medial olfactory pit along the terminal nerves and across the olfactory bulb to the hypothalamus and adjacent areas (Parhar et al., 1995; Schwanzel-Fukuda et al., 1996). The presence of LHRH neurons has been demonstrated in the human fetal hypothalamus, by 5–9 weeks of gestation, although functional connections between these neurons and the portal system are not established until 16 weeks

(b) Functional deficits Gonadotropin deficiency in Kallmann’s syndrome is due to a reduced secretion of LHRH by the hypothalamus. LHRH deficiency may be partial or complete. In the complete form, both FSH and LH levels are low, and there is no evidence of sexual maturation. A few Kallmann patients with a pubertal LHRH response have 217

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(Aksel and Tyrey, 1977; Seminara et al., 1998). Whether these LHRH neurons, that are present during early human embryogenesis, indeed originate from the olfactory pits has not been proven. The hypothesis that one of the guidance molecules of migrating neurons would be deficient in Kallmann’s syndrome was supported by histopathological findings in a 19-week-old human fetus with X-linked Kallmann’s syndrome. The outgrowth of the olfactory axons was prematurely arrested in a tangle of nerve fibers in the fetal meningal, between the cribiform plate and the forebrain. LHRH-containing neurons were found to be ‘dammed up’ at the dorsal surface of the cribiform plate. Migration was arrested at the distal end of the olfactory nerves and the neurons accumulated in the meningeal tissue (Schwanzel-Fukuda et al., 1989, 1992, 1996; Rugarli et al., 1993; Parhar et al., 1995; Fig. 24.6). A possible radiological correlate of arrested neuronal migration in Kallmann’s syndrome has been found as heterotopic tissue in this place (Rugarli and Ballabio, 1993). Based on these findings, it has been proposed that the Kallmann’s syndrome gene would encode a factor involved in the migration and targeting of LHRH and olfactory neurons, respectively. In mice it has subsequently been established that N-CAM marks the migration route for LHRH (Parhar et al., 1995), and the properties of the KAL1 gene (Hardelin, 2001) confirm this concept.

Some patients with Kallmann syndrome may have osmoreceptor dysfunction and abnormal thirst regulation (Hochberg et al., 1982), which may be related to the observation of Itoh et al. (1997) that the SON neurons showed hypertrophy. This activation can at least be partly due to a lack of sex hormones (Ishunina et al., 2000; Chapter 8c). The missing hormones have been substituted by exogenous testosterone or estrogens to induce puberty (Dissaneevate et al., 1998). Kallmann’s syndrome can be effectively treated with pulsatile LHRH. Even in a Kallmann’s syndrome patient as old as 43 years, not only androgenization but also spermatogenesis could be induced. Interestingly, a variant of Kallmann’s syndrome has been reported in which endogenous gonadotropin secretion recovers spontaneously in later life. Spontaneous onset of endogenous gonadotropin secretion, evidenced by progressive normalization of testicular volume, and of serum testosterone concentration, occurred in these men over a period of years. This means that Kallmann patients should be reassessed (off androgen replacement therapy) to identify those who no longer require treatment (Quinton et al., 1999).

(c) Endocrine disorders

In 1942, Klinefelter described a man with gynecomastia and infertility, whose Leydig’s cells nevertheless appeared to be normal. He had a low to normal urine excretion of 17-ketosteroids and an increased urinary excretion of FSH. About half of the Klinefelter patients have decreased testosterone levels, while the other half have normal testosterone values (Yoshida et al., 1997). Lower testosterone values may even be present already at birth (Sørensen et al., 1981; Smyth and Bremner, 1998). Cells of the buccal mucosa of Klinefelter males appeared to contain an extra chromatin mass, later termed sex-chromatin or Barr body, which turned out to be a second X chromosome (47,XXY). Klinefelter’s syndrome is the most common sex chromosome disorder (Smyth and Bremner, 1998). Mosaic and polysomic-X variants of Klinefelter’s syndrome are present in 10–20% of the patients. Patients with the XXYY karyotype constitute about 3% of the chromatin-positive males. The incidence of this variant is estimated to be 1:50.000 male births (Bertelloni et al., 1999; Matsuoka et al., 2002). Although it has been proposed to name the 47,XXY

The pituitary of a Kallmann’s syndrome patient shows scant gonadotrophs only weakly staining for LH and FSH, with fewer and smaller secretory granules. Growth hormone, too, stains less intensely, but the other pituitary hormones seem to be normal (Kovacs and Sheehan, 1982; Itoh et al., 1997). In the hypothalamus the lateral tuberal nuclei are undeveloped (Kovacs and Sheehan, 1982; Itoh et al., 1997). Both studies reported that the nucleus subventricularis, the ventral part of the infundibular nucleus, showed hypertrophy, most probably due to a stimulation of sex hormone receptor-containing neurons, as is also observed in menopause and other conditions that display a lack of sex hormones (see also Chapter 11f). The neurons of the tuberomamillary nucleus were described as unusually numerous according to Kovacs and Sheehan (1982), whereas Itoh et al. (1997) reported the tuberomamillary complex neurons to be unusually few, which makes clear that systematic quantitative studies of the Kallmann hypothalamus are needed.

24.4. Klinefelter’s syndrome or testicular dysgenesis

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karyotype ‘Klinefelter disease’ and to call the other variant genotypes/phenotypes ‘Klinefelter’s syndrome’, the latter term will be used here for all variants. Anenploidy involving the X chromosome results either from nondysjunction during the first or second meiotic divisions, or from mitotic nondysjunction in the developing zygote. In 53% of cases the cause is paternal nondysjunction at the first meiotic division, in 34% it is the first maternal meiotic division; 9% of cases were secondary to abnormalities during the maternal second meiotic division. The frequency of 47,XXY is about 1/500 male conceptions but only 1/1000 male live births (Schwartz and Root, 1991; Smyth and Bremner, 1998). In one Klinefelter fetus, holoprosencephaly (see Chapter 18.3) was found (Armbruster-Moraes et al., 1999), and one 46,XY/47,XXY mosaic Klinefelter patient had a Rathke’s cleft cyst with hypothalamic panhypopituitarism, partial diabetes insipidus and other endocrine disorders (Gotoh et al., 2002).

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(1997) study the mean frequency of intercourse was significantly higher than in the control group, possibly because this was a selection of patients who came with the chief complaint of male infertility. Wakeling (1972) reported evidence of homosexual behavior in 4 of 11 Klinefelter patients, which agrees with the idea that sexual orientation develops as a result of interaction of sex hormones and nerve cells (see Chapter 24.5). This observation seems to contrast, however, with an older report mentioning that only 2 of 30 Klinefelter patients were homosexual (Pasqualini et al., 1957). The small numbers in either study do, however, not allow a final conclusion about this topic. Klinefelter’s syndrome is the most common cause of hypogonadism in males. However, due to causes other than chromosomal abnormalities, often types of hypogonadal patients had a more marked hypogonadism and more severe impairment of secondary sexual development than the Klinefelter patients (Wakeling, 1972). Testosterone levels from umbilical cord blood of infants with an XXY have been found to be lower than those of controls, so that decreased testosterone function may be present already in fetal life. Yet, postnatal pituitary– gonadal function is remarkably normal until the later phases of puberty (Smyth and Bremner, 1998). In the first stages of pubertal development, testosterone levels of Klinefelter patients are still in the normal range. Progressive hyalization and fibrosis of the seminiferous tubules begins before puberty. By ages 12–14, basal LH and FSH levels start to increase, then, from this age onwards, testosterone levels stay below the midnormal adult range (Hsueh et al., 1978; Raboch and Mellan, 1978; Schwartz and Root, 1991; Smyth and Bremner, 1998). The attenuated testosterone feedback in Klinefelter’s syndrome is responsible for the greatly amplified pituitary responsiveness to the trophic action of LHRH and this, in part, may lead to the increased LH and FSH levels (Goh and Lee, 1998). Elevations in sex hormone-binding globulin levels in Klinefelter’s syndrome lead to decreased free testosterone concentrations. Plasma estradiol levels are often elevated (Yoshida et al., 1997) and an increase in the estradiol to testosterone ratio may be responsible for gynecomastia (Schwartz and Root, 1991). Both normal and blunted TSH responses to TRH have been reported in Klinefelter’s syndrome; basal prolactin levels are generally normal (Hsueh et al., 1978; Schwartz and Root, 1991). In Klinefelter’s syndrome significant circannual rhythms are present for testosterone and FSH, but not for LH, prolactin or TSH (Bellastella et al., 1986a, b).

(a) Clinical presentation Males with 47,XXY are found during prenatal genetic testing in neonatal screening programs and during evaluation of hypospadias, microphallus, cryptorchism (Schwartz and Root, 1991) or infertility (azoospermia). Damage to the testicular Leydig’s cells and seminiferous tubules can be seen as early as the 1st year of life (Hsueh et al., 1978). Klinefelter’s syndrome features include a smaller head circumference. At school age Klinefelters may have learning problems and behavioral disorders;. in adolescence they may develop gynecomastia (present in 30–60%), tallness, low weight, small testes, sparse body hair and an eunuchoid habitus. Puberty is often delayed; on the other hand, precocious puberty also occurs in Klinefelter’s syndrome. In fact, the association between Klinefelter and precocious puberty is 5.5fold higher than expected. In some Klinefelter boys, precocious sexual development is due to peripheral endocrine active malignancies; in one boy a hamartoma of the third ventricle was found, and a pineal tumor in another. Central precocious puberty may also occur in the XXXY and XXYY variants (Bertelloni et al., 1999). About 67% of the Klinefelter patients have some type of sexual function disturbance (Schwartz and Root, 1991; Sørensen, 1992; Von Mühlendahl and Heinrich, 1994; Smyth and Bremner, 1998). Klinefelter patients are generally said to have a weak libido, but in Yoshida et al.’s 219

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As in other cases of hypogonadism, increased nocturnal melatonin secretion has been found that can be normalized by testosterone treatment (Luboshitzky et al., 1997; Caglayan et al., 2001). The latter authors showed that the increased melatonin levels are due to a change in melatonin metabolism, rather than to a change in melatonin secretion. Until recently, donated sperm or adoption were the options for infertile parents. However, also successful intracytoplasmic injection of sperm, obtained from testicular biopsy samples from patients with Klinefelter’s syndrome have been published. The finding of some spermatozoa with an extra X chromosome implies that Klinefelter’s syndrome may be transmissible by such techniques and is a point of serious concern (Amory et al., 2000). (b) Psychosocial problems Learning disabilities, a low IQ, averaging 82, behavioral problems, psychological distress and (generally mild) mental deficiency have all been found in Klinefelter’s syndrome, as have neuromaturational lag, reduced language skills and dyslexia. Sexual activity generally begins at the usual age. Behavioral and psychiatric disorders include aggressiveness, alcohol abuse and abuse of other substances, criminal behavior, depression, personality disorders and schizophrenia. Speech and language delays have an impact on development. The verbal and language deficits associated with Klinefelter’s syndrome are found to be associated with a reduction in left temporal lobe gray matter, while a history of testosterone supplementation increases verbal fluency scores and preserves the left temporal lobe volume (Patwardhan et al., 2000). It should be noted, moreover, that it has been stated that the diagnosis of Klinefelter’s syndrome is said not to denote an increased likelihood of criminality, psychopathology or mental retardation. Some 6.3% of Klinefelter patients are diagnosed as having schizophrenia and 5.8% as having psychoses of an uncertain type. Testosterone replacement therapy might have positive effects on mood, sexual behavior, self-esteem and other behavioral problems in some subjects (Pasqualini et al., 1957; Johnson et al., 1970; Wakeling, 1972; Nielsen et al., 1988; Mandoki et al., 1991; Schwartz and Root, 1991; Sørensen, 1992; Smyth and Bremner, 1998). Some cases of anorexia nervosa associated with Klinefelter’s syndrome have been described (El-Badri and Lewis, 1991).

24.5. Sexual differentiation of the brain and sexual behavior We must remember that all our provisional ideas in psychology will one day be explained on the basis of organic substrates. It seems then probable that there are particular chemical substances and processes that produce the effects of sexuality and permit the perpetuation of individual life. (Sigmund Freud, “On Narcissism”)

(a) Mechanism of sexual differentiation of the brain Sexual differentiation of the brain is thought to be ‘imprinted’ or ‘organized’ by hormonal signals from the developing male gonads. On the basis of animal experiments, this process is presumed to be induced by androgens during development, following conversion to estrogens by P-450 aromatase (Fig. 24.12). Aromatase is present throughout the human brain, including the hypothalamus, both in men and women (Sasano et al., 1998). Male sexual differentiation of the human brain is thought to be determined in the two first periods during which sexually dimorphic peaks in gonadal hormone levels are found, viz: (i) during gestation, and (ii) during the perinatal period, while (iii) from puberty onwards, sex hormones alter the function of previously organized neuronal systems (“activating effects”) (for references see Forest, 1989; De Zegher et al., 1992; Swaab et al., 1992a). In late gestation, the male fetus is exposed to both high concentrations of testosterone from the fetal testes and high levels of estrogens from the placenta. After the inhibitory effect of maternal estrogens wanes, postnatally, the infant’s gonadotropins – predominantly LH – increase significantly, a process that starts around 1 week after birth. In response there is a rapid rise in testosterone until some 6 months after birth. The female fetus is also exposed to estrogens from the placenta. In postnatal female infants, the surge of FSH is predominant, giving rise to an increase in estradiol, 2–4 months postnatally. FSH secretion begins to decline by 12 months of age (Quigley et al., 2002). Studies in primates indicate that the period of the neonatal testosterone peak is a critical period in the process of sexual and behavioral development (Mann and Fraser, 1996). Testosterone is formed in the fetal Leydig cells in the testicle from about 8 weeks of gestation on (Hiort, 2000). The possible importance of the male testosterone surge for sexual differentiation of the brain following aromatization to estrogens agrees with the observations that girls whose mothers were exposed to

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Fig. 24.12. Schematic overview of the interconversions and relations between steroids with androgenic and estrogenic properties. DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate. 5-ADIOL, 5-androstene-3,17-diol (DHEA after reduction at the 17 position); 4-ADION, 4-androstene-3,17-dione; TESTO, testosterone; DHT, 5-dihydrotestosterone. The arrows indicate the possible conversions in the human body. (From Thijssen, 2002, Fig. 1 with permission.)

hypothalamus of the child, but by chorionic gonadotropins from the placenta as well, since a normal neonatal increase of testosterone was found in a patient with hypogonadism based upon a DAX-1 gene mutation, which causes hypogonadotropic hypogonadism (Takahashi et al., 1997). Although both sexes are prenatally exposed to high estrogen concentrations, only males are subjected to high levels of androgens (Quigley et al., 2002). In human neonates the testosterone level is 10-fold higher in men than in women at 34–41 weeks of gestation (De Zegher et al., 1992). Although the peak in serum testosterone in boys at 1–3 months postnatally approaches the levels seen in adult men, most testosterone is bound to globulin. Yet the amount of free testosterone in male infants is about one order of magnitude larger than that in female infants at this time (Bolton et al., 1989). During the adrenarche, i.e. from 7 years of age to the onset of puberty, the adrenal starts to produce more androgens, predominantly DHEA and DHEAS. After the age of 8 years, testosterone from the adrenal also starts to rise, while a small but significant testicular production of testosterone is also present in prepubertal boys (Forest, 1989). Although the testosterone peak during puberty (Forest, 1989) is generally thought to be involved in activation rather than

diethylstilbestrol during pregnancy run a higher risk of developing bi- or homosexuality (Ehrhardt et al., 1985; Meyer-Bahlburg et al., 1995), and that girls with congenital adrenal hyperplasia, producing high levels of testosterone, are at risk for homosexuality or gender-identity problems (Money et al., 1984; Dittmann et al., 1992; Meyer-Bahlburg et al., 1996; Zucker et al., 1996; Table 24.2) (see below). An association has been found between an estrogen receptor- gene polymorphism and personality traits such as nonconformity in women (Westberg et al., 2003), pointing to effects of estrogens on brain development. Estrogens, produced locally by aromatase, are thought to participate in numerous biological functions, including sexual differentiation of the brain. Aromatase is found throughout the adult human brain with the highest levels in the pons, thalamus, hypothalamus and hippocampus. The amount of aromatase mRNA is also highest in the hypothalamus, thalamus and amygdala, and alternative splicing is found also. However, no difference in aromatase mRNA was detected between the four men and two women studied (Sasano et al., 1998). Such a study has, however, so far not been performed in larger series or in development. The neonatal peak of testosterone is probably not only induced by the 221

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TABLE 24.2 Factors that influence sexual differentiation of the human brain. Gender identity (transsexualism) – Chromosomal disorders

– – – – –

– Phenobarbital/diphantoin

–

– Hormones

– – – – – – –

– Social factors?

–

Rare: 47XYY (male-to-female), 47XXX (female-to-male). Microdeletion on Y-chromosome in 1 male-to-female transsexual (Hengstschläger et al., 2003). Steroidogenic factor-1 mutations (give sex-reversal, no transsexuality; Achermann et al., 2001a, b; Ozisik et al., 2002). Klinefelter XXY male-to-female (Sadeghi and Fakhrai, 2000). Twin studies (Sadeghi and Fakhrai, 2000; Coolidge et al., 2002). Genomic imprinting (Green and Keverne, 2000). (Dessens et al., 1999) Intersex (Zucker et al., 1987; Reiner, 1996), micropenis (Reiner, 2002) Cloacal exstrophy (Zucker, 2002; Zderic et al., 2002) 5--Reductase deficiency, 17-hydroxy-steroid-dehydrogenase-3 deficiency (Imperato-McGinley et al., 1979, 1991; Wilson, 1999). CAH girls with gender problems (Meyer-Bahlburg et al., 1996; Zucker et al. 1996). More polycystic ovaries, oligomenorrhea and amenorhea are found in transsexuals (Futterweit et al., 1986). Complete androgen-insensitivity syndrome results in XY heterosexual females (Wisniewski et al., 2000). However: in congenital deficiency of estrogens due to aromatase deficiency or estrogen resistance, gender identity is not affected (Smith et al., 1994; Morishima et al., 1995; Carani et al., 1997, 1999; Faustini-Fustini et al., 1999; Rochira et al., 2001). (Bradley et al., 1998) not effective: John/Joan/John case (Diamond and Sigmundson 1997; CohenKettenis and Gooren, 1999)

Sexual orientation (homosexuality, heterosexuality) – Genetic factors – Twin studies (Kallmann, 1952; Bailey and Bell, 1993). – Molecular genetics (Hamer et al., 1993; Hu et al., 1995). However, see Rice et al. (1999). – Hormones – CAH girls (Money et al., 1984; Dittmann et al., 1992; Zucker et al., 1996) – DES (Ehrhardt et al., 1985; Meyer-Bahlburg et al., 1995) – Male-to-female sex reassignment (Bailey et al., 1999) – Chemicals – Nicotine prenatally increases the probability of lesbianism (Ellis and Cole-Harding, 2001). – Immune response?

–

– Social factors?

– –

Golombok et al.,

Homosexual orientation in men is most likely to occur in men with a high number of older brothers and shorter stature (Bogaert, 2003). Stress during pregnancy (Ellis et al., 1988; Bailey et al., 1991; Ellis and Cole-Harding, 2001). Raising by transsexual or homosexual parents does not affect sexual orientation (Green, 1978; 1983).

organization, the neuron number of the female domestic pig hypothalamus – to our surprise – showed a twofold increase in a sexually dimorphic hypothalamic nucleus around puberty (Van Eerdenburg and Swaab, 1991), which means that, although this phenomenon may have been programmed earlier, late organizational effects can at present not be excluded. Few data are available on the exact period in development when the human brain differentiates according to sex. Brain weight is sexually dimorphic from 2 years postnatally onwards, taking differences in body weight between boys and girls into

account (Swaab and Hofman, 1984). Sexual differentiation of the human sexually dimorphic nucleus of the preoptic area (SDN-POA) becomes apparent between 4 years and puberty (Swaab and Hofman, 1988, Chapter 5). A similar late sexual differentiation was found in darkly staining posteromedial components of the bed nucleus of the stria terminalis (Allen et al., 1990; Chapter 7). The sex difference in the size of the central subdivision of the bed nucleus of the stria terminalis (BSTc) (Chapter 7.1) only becomes significant in adulthood (Chung et al., 2002). Concluding one might say that the

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limited evidence that is currently available suggests that sexual differentiation of the human hypothalamus becomes apparent between 2 years of age and adulthood, depending on the area involved. This may, of course, be based upon processes that were programmed much earlier, for instance by a peak in sex hormone levels in mid-pregnancy or during the neonatal period (see above). On the basis of existing prenatal serum samples from their mothers, it appeared that, indeed, higher androgen exposure in the second trimester of fetal life may masculinize a girl’s behavior (Udry et al., 1995). Although estrogens, derived from testosterone by aromatization (Fig. 24.12), are considered to be the major mediator for androgenization of the brain during development in rodents, testosterone itself may be of major importance for sexual differentiation of the human brain. In the first place, both sexes are exposed to high levels of estrogens during fetal life, while it is only the males who are subjected to high androgen levels (Quigley et al., 2000). Moreover, the androgen receptor, located on the X-chromosome at Xq11-12, may be mutated in such a way that the subject has a complete androgeninsensitivity syndrome. The pre- and postnatal hormone testosterone surge normally found in male infants most probably also occurs in these children. Apparently the normal surge requires hypothalamic expression of androgen receptors (Quigley et al., 2002). This is at least clear for the postnatal testosterone surge (Bouvattier et al., 2002). In spite of normal testis differentiation and androgen biosynthesis, the phenotype has a normal female external and behavioral appearance (Batch et al., 1992; Thiele et al., 1999). Phenotypic women with complete androgeninsensitivity syndrome perceive themselves as highly feminine. They do not have gender problems and largely report their sexual attraction, fantasies and experiences as being female and heterosexual (Wilson, 1999; Wisniewski et al., 2000). This means that for the development of human male gender identity and male heterosexuality, direct androgen action on the brain seems to be of crucial importance, and that the aromatization theory may even be of secondary importance for human sexual differentiation of the brain. The observation by Mackle et al. (1993), that DNA sequence variation in the androgen receptor is not a common determinant of sexual orientation at first sight, seems to be at variance with this idea, but it should be noted that the DNA variations in that study did not prevent normal androgenization of the subjects studied, so that there was no loss of function of

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this receptor. The point of view that aromatization may be less important than we thought agrees with the lack of gender problems in a brother and sister with aromatase deficiency due to an inactivating mutation of the P-450 gene and in a 27-year-old man with a mutation of the CYP gene (of which aromatase cytochrome is a product), were accompanied by psychosexual orientation appropriate for their genetic and phenotypic sex (Morishima et al., 1995; Rochira et al., 2001; Carani et al., 1997; 1999; Faustini-Fustini et al., 1999; Hermann et al., 2002). Moreover, a 28-year-old man with estrogen resistance due to a mutation of the estrogen-receptor gene was described as tall, with continued linear growth in adulthood, incomplete epiphysal closure and increased estrogen and gonadotropin levels. A change in a single base pair in the second exon of the estrogen-receptor gene was found. However, the patient reported no history of gender-identity disorder, had strong heterosexual interest and normal male genitalia. The elevated serum estrogen levels are explained by a possible compensatory increase in aromatase activity in response to estrogen resistance (Smith et al., 1994; Rochira et al., 2001). On the one hand, the heterosexual XY females resulting from the complete androgen-insensitivity syndrome (Wisniewsky et al., 2000) and the male gender heterosexual behavior of patients with 5-reductase-2 or 17-hydroxysteroid dehydrogenase-3 deficiency (Imperato-McGinley et al., 1991, 1997; Wilson et al., 1993; Wilson, 1999) indicate that a direct action of testosterone may be more important than that of dihydrotestosterone (DHT) (Fig. 24.12) for male heterosexual psychosexual development. The affected 46,XY individuals have normal to elevated to high plasma testosterone levels with decreased DHT levels. They have ambiguous external genitalia at birth, so that they are often raised as girls. Virilization occurs at puberty, frequently with a gender role change. These subjects demonstrate that exposure of the brain to testosterone during development and at puberty appears to have a greater impact in determining male gender identity than do sex of rearing and sociocultural influences (ImperatoMcGinley and Zhu, 2002). The relative contributions of the different sex hormones and other nonhormonal factors on sexual differentiation of the human brain should clearly be a focus for future research, including a more detailed endocrine and psychosexual investigation of the patients with mutations in aromatase or sex hormone receptors. Not only may sex hormones affect sexual differentiation of the brain; on the basis of animal experiments it is expected that all compounds that influence hormone 223

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or neurotransmitter metabolism in development may also affect sexual differentiation of the brain (Pilgrim and Reisert, 1992; Swaab and Boer, 2001). Indeed, prenatal nicotine exposure was found to increase the probability of lesbianism. Also prenatal stress disrupts the hormonal milieu in which the fetal brain is sexually differentiating and feminizes/demasculinizes the male’s sexual orientation (Ellis and Cole-Harding, 2001). Although young adult male mice that were prenatally exposed to alcohol were found to have a decreased preference for females and an increased preference for males (Watabe and Endo, 1994), little support was found for such an effect of prenatal alcohol exposure on sexual orientation in humans (Ellis and Cole-Harding, 2001). Rats exposed to some drugs (e.g. barbiturates) during development show deviations in testosterone levels, persisting into adulthood (Ward, 1992). This agrees with the finding of Dessens et al. (1999) that children born of mothers who were exposed to anticonvulsants such as phenobarbital and diphantoin have an increased probability of transsexuality (see below). Exposure of rats to drugs such as opiates leads to behavioral changes, despite apparently normal adult gonadal hormone levels (Ward, 1992). Similar observations in human sexual differentiation have not yet been reported. However, a study on gender role behavior in children of 42 months of age showed that maternal stress during pregnancy was accompanied by more masculine behavior not only in girls, but also in both boys and girls, older male or female siblings, parental adherence to traditional sex roles, maternal use of tobacco or alcohol during pregnancy, and maternal education (Hines et al., 2002). What these factors mean for gender and sexual orientation in adulthood remains to be seen. It is of great interest that, in addition, there is recent animal experimental evidence for primary genetic control of sexual differentiation that does not involve sex hormones. Results obtained from cultures of embryonic rat brain indicate that dopaminergic neurons may develop morphological and functional sex differences in the absence of sex steroids (Pilgrim and Reisert, 1992). For such hormone-independent effects, the most likely candidates are those genes located on the nonrecombining part of the Y-chromosome and believed to be involved in primary sex determination of the organism. Two candidate genes are the two testis-determining factors, ZFY and the master switch for differentiation of a testis SRY; they are putative transcription factors. We have shown that SRY and ZFY are transcribed in hypothalamus and frontal and temporal cortex of adult men and not in

women. It may well be possible that they function as sexspecific cell-intrinsic signals that are needed for full differentiation of a male human brain, and that continuous expression throughout life may be required to maintain sex-specific structural or functional properties of differentiated male neurons. Sexual differentiation of the human brain may thus be a multifactorial process, although a role of SRY and ZFY in this process still needs to be proved (Mayer et al., 1998a). An alternative mechanism could be the actions of an imprinted X-linked locus (Skuse, 1999). Recent clinical studies on human subjects with mutations in genes involved in sexual differentiation also point to the possibility that the interaction between estrogens and brain development may not be the only mechanism involved in the development of male gender and sexual orientation. In fact, the data obtained so far indicate that in case of congenital deficiency of estrogens in humans due to aromatase deficiency or estrogen resistance, gender identity and sexual orientation are not affected (Carani et al., 1999; Faustini-Fustini et al., 1999; see above). The relative contributions of the different sex hormones and other nonhormonal factors on sexual differentiation of the human brain should clearly be a focus for future research. (b) Sexual differentiation, the hypothalamus and amygdala My brain? It’s my second favourite organ. Woody Allen

Sex differences in the hypothalamus and other limbic structures are thought to be the basis of sex differences in sexual arousal (Kamara et al., 2002), in reproduction (e.g. copulatory behavior in both sexes, the menstrual cycle in women), gender identity (i.e. the feeling one is either male or female), gender identity disorders (transsexuality) and sexual orientation (homosexuality, heterosexuality, bisexuality) (Gooren et al., 1990; Swaab et al., 1992a; Swaab and Hofman, 1995; Chapters 5, 6, 7). In addition, desinhibited sexual activity and paraphilias have been reported following lesions in the hypothalamus and septum (Miller et al., 1986; Frohman et al., 2002). The PVN in rat, and in particular its oxytocin neurons (see Chapter 8g), is involved in erectile functions in copula. In monkey, too, penile erection is induced by elective stimulation of the PVN (MacLean and Ploog, 1962). Not only oxytocin but also -MSH induces erection in rats after intracerebroventricular injection (Mizusawa et al., 2002). In humans, evidence

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supporting the role of melanocortin receptors in sexual function derives from two double-blind, placebocontrolled phase I clinical trials, with the nonselective melanocortin receptor agonist MTII. Subcutaneous lowdose administration of MTII was proerectile in men, with organic (hypercholesterolemia, obesity, hypertension), and psychogenic (no organic cause identified) erectile dysfunctions. In addition, it was shown that the MC-4 receptor mediates proerectile events in rodents (MacNeil et al., 2002; Van der Ploeg et al., 2002). For penile erections initiated by psychogenic stimuli, the medial amygdala, the PVN, and to a lesser extent the BST are involved, while medial preoptic lesions in the rat have little, if any, effect on this type of erections (Liu et al., 1997b). Sexual arousal and orgasm produce long-lasting alterations in plasma prolactin concentrations, both in men and women (Exton et al., 1999), which might be related to postorgasmic loss of arousability (Bancroft, 1999), indicating a role of the medial-basal hypothalamic dopamine neurons. There is extensive animal experimental literature that shows that the medial preoptic area of the hypothalamus is a key structure for male and female copulatory behavior (Pilgrim et al., 1992; Yahr et al., 1994; McKenna, 1998), and that the hypothalamus is involved in seminal vesicle contractions at coitus (Cross and Glover, 1958). Electrical stimulation of the preoptic area in monkeys induces penile erection (MacLean and Ploog, 1962). Although the exact role of its subarea, the SDN-POA, in these functions is less clear (Chapter 5), Gorski (2003) reported that electrical stimulation of the rat SDN-POA markedly enhanced male sexual behavior. Hypothalamic structures involved in sexual orientation in experimental animals is scarce (Kindon et al., 1996; Paredes et al., 1998). Paredes and Baum (1995) found that lesions of the medial preoptic area/anterior hypothalamus in the male ferret not only affected masculine coital performance, but also heterosexual partner preference. Perkins and colleagues have shown that testosterone, estrone and estradiol plasma concentrations are higher in female-oriented rams than in homosexual rams. In the preoptic area the aromatase activity is higher in the female-oriented than in the maleoriented rams, indicating again the possible importance of the preoptic area in sexual orientation (Resko et al., 1996). Edwards et al. (1996b) have observed a decrease in partner preference in male rats following a lesion of the BST. The number of estrogen receptors in the amygdala is similar in both homosexual rams and ewes but lower than the receptor content in heterosexual rams,

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while the estrogen receptor content of the hypothalamus, anterior pituitary and preoptic area of these two groups does not differ. These data suggest that the amygdala might also play a role in sexual orientation. Indeed, in some Klüver–Bucy syndrome cases due to damage of the temporal lobe, the patients’ behavior is reported to change from heterosexual to homosexual, indicating that the temporal lobe might be of importance for sexual orientation (Terzian and Dalle Ore, 1955; Marlowe et al., 1975; Lilly et al., 1983). Also, there are a few case histories of changing sexual orientation, from heterosexual to pedophilic or homosexual, on the basis of a lesion in the hypothalamus or in the temporal lobe, from which the amygdala has strong connections to the hypothalamus (Miller et al., 1968). There is no information available on the exact nature of the preoptic and amygdala neuronal systems and connections that may be involved in sexual orientation. Data on the hypothalamus in relation to gender identity in animals are, of course, nonexistent (for alterations in the BSTc in male-to-female transsexuals, see Chapter 7). There are a few studies in the medical literature that implicate the hypothalamus and adjoining structures in various aspects of sexual behavior. Direct electrical or chemical stimulation of the septum may induce a sexually motivated state of varying degrees up to penile erection in men and building up to an orgasm in both sexes (Heath, 1964). Markedly increased sexual behavior has been observed following the placement of the tip of a ventriculoperitoneal shunt into the septum in two cases (Gorman and Cummings, 1992). Meyers (1961) has described a loss of potency following lesion in the septofornicohypothalamic region. Electrical stimulation of the mamillary body in monkeys induces penile erection (MacLean and Ploog, 1962; Poeck and Pilleri, 1965). Precocious puberty and hypersexuality have been reported following lesions in the posterior part of the hypothalamus, and hypogonadism is an early sign of pathology in the anterior part of the hypothalamus (Bauer, 1954, 1959; Poeck and Pilleri, 1965; Chapter 19.1). In particular hamartomas that affect the posterior region of the hypothalamus, i.e. those that are pendulated and attached to the region of the corpora mamillaria, may cause precocious puberty (Valdueza et al., 1994a; Chapter 19.3). In addition, precocious puberty is found in cases of pineal region tumors that produce gonadotropins (Chapter 19.7). A German stereotactic psychosurgical study (Müller et al., 1973) reported on 22 male, mainly pedo- or ephebophilic (i.e. preferring pubertal boys) homosexuals 225

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(n = 14), and 6 cases with disturbances of heterosexual behavior (hypersexuality, exhibitionism or pedophilia). In 12 homosexual patients a lesion was made in the right ventromedial nucleus of the hypothalamus. In 8 patients homosexual fantasies and impulses disappeared. According to this paper, in 6 patients a ‘vivid desire for full heterosexual contacts’ occurred after the operation. In one pedophilic patient, bilateral destruction of the ventromedial nucleus was performed and he lost all interest in sexual activity after the operation. The heterosexual patients reported a significant reduction of their sexual drive. Unilateral ventromedial hypothalamotomy in 14 cases treated for aggressive sexual delinquency caused a decrease in sexual drive (Dieckmann et al., 1988; Albert et al., 1993). Although at first sight these studies appear to suggest that the human ventromedial nucleus of the hypothalamus is indeed involved in sexual orientation and sexual drive, they are highly controversial from an ethical point of view, and methodologically deficient (Heimann, 1979; Rieber and Sigusch, 1979; Schorsch und Schmidt, 1979; see also Chapter 9). (c) Transsexuality and other gender identity problems Re: new phalloplasty technique proposal; seeking surgeon. P.S. I am interested in a neophallus uncircumcized in appearance. So I am looking overseas, since a natural uncircumcized penis is more common in Europe than in the U.S. (From a letter of a female-to-male transsexual to D.F.S.)

The first definition of the term transsexualism dates from 1953, coined by Benjamin, who associated biological normality with the conviction of belonging to the opposite sex and sex-reassignment request. In this sense, the transsexual is characterized by an unshakeable conviction of belonging to the opposite sex, presenting a most extreme gender identity disorder. Gender identity (gender identity refers to an identity experience expressed in terms of masculine or feminine ‘belongingness’, independent of the anatomical reality of the sex) is therefore totally in disharmony with corporal reality, forcing the individual to request sex-reassignment surgery. Gender-related traits may also resemble those of the opposite sex in transsexuals (Lippa, 2001). Transsexualism as a particular nosological category (gender dysphoria syndrome) was included in the Diagnostic and Statistical Manual of Mental Disorders – III (DSM-III) in 1980, but was then removed from DSM-IV, where it was assimilated into sexual identity disorders. DSM-IV no longer adopts the view that the difference between transsexuals and other

forms of gender dysphoria is an interesting differential criterion. Therefore, as a consequence, highly heterogeneous cases are regrouped together in DSM-IV (Michel et al., 2001). Transsexuality often becomes overt early in development. Parents of boys with gender identity disorders often report that, from the moment their sons could talk, they insisted on wearing their mothers’ clothes and shoes, were interested exclusively in girls’ toys and played mainly with girls (Cohen-Kettenis and Gooren, 1999). At present between 77% and 80% of the transsexuals in the Netherlands receive surgical and/or hormonal treatment, and less than 0.4% express regrets about their sex reassignment. These are all male-to-female transsexuals (Van Kesteren et al., 1996). The annual incidence of transsexuality in Sweden has been estimated to be 0.17 per 100,000 inhabitants. The prevalence rates vary from 1:10,000 to 1:100,000 for men and 1:30,000 to 1:400,000 for women. The sex ratio (genetic male to female) varies from country to country and with age between 1.4:1 and 3:1 (Landén et al., 1996; Van Kesteren et al., 1996; Cohen-Kettenis and Gooren, 1999; Garrels et al., 2000; Michel et al., 2001). There is little information about the factors that may influence gender and cause gender identity disorders and transsexuality in humans (Cohen-Kettenis and Gooren, 1999; Table 24.5.1). The disparate maternal aunt to uncle ratio in male transsexuals has been hypothesized to be due to genomic imprinting (Green and Keverne, 2000). There are only a few reports that have found chromosomal abnormalities in transsexuals. Six cases of male-to-female transsexuals with 47,XYY chromosome and one female-to-male transsexual with 47,XXX have been reported (Turan et al., 2000). A phenotypically female baby with 46,XY sex-reversal, persisting Müllerian structures, and a primary adrenal failure, was reported to have a mutation of steroidogenic factor-1. Subsequently a heterozygous frameshift mutation has been described with 46,XY sex-reversal and cliteromegaly, but no uterus, raising the possibility that other mutations of this transcription factor might have milder or tissue-specific effects in humans. So far these mutations concern complete sex-reversal and not transsexuality (Achermann et al., 2001a, b). Moreover, transsexualism has been reported in a Kleinfelter (XXY) male (Sadeghi and Fakhrai, 2000). Genetic aberrations are generally indetectable in transsexuals when G-banded karyotypes are analyzed, and evidence has been presented that molecular-cytogenetic alterations affecting the androgen

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receptor gene region or the SRY region do not play a role in transsexualism. One carrier of a microdeletion on a Y-chromosome has been detected out of a series of 30 male-to-female transsexuals (Hengstsläger et al., 2003). In addition, pairs of monozygotic female twins have requested sex reassignment, and twin studies and familial cases of gender identity problems are reported, suggesting a genetic basis for this disorder (Green, 2000; Sadeghi and Fakhrai, 2000; Coolidge et al., 2002). The claim of Dörner et al. (2001), that in transsexuals a partial 21-hydroxylase deficiency may be present, has yet to be confirmed. Although only a minority of the transsexuals has an underlying endocrine abnormality (Meyer et al., 1986), there are some indications of a possible disorder of the hypothalamopituitary–gonadal axis in some transsexuals that may have a basis in development, such as a high frequency of polycystic ovaries, oligomenorrhea and amenorrhea in female-to-male transsexualism (Futterweit et al., 1986; Sadeghi and Fakhrai, 2000). These observations may be explained by a difference in the interactions between hormones and the developing brain. Dessens et al. (1999) have reported that 3 children born of a group of 243 women exposed to the anticonvulsants phenobarbital and diphantoin were found to be transsexuals, while there were a few other subjects with gender dysphoria/ cross-gender behavior. Gender problems thus occur remarkably often, in view of the rarity of this disorder. This exciting observation on the effect of compounds that are known to alter steroid hormone levels in animal experiments has to be examined further. In this respect it is of interest to note that phenobarbital has been widely used as prophylactic treatment in neonatal jaundice and greatly elevates the postnatal rise in testosterone (Forest et al., 1981). There has not, however, been a follow-up on gender identity disorders so far. Also, endocrine disruptors, present in food and water, may be considered with respect to gender-identity problems, such as, e.g. veterinary growth promoters such as resveratrol, a phytoestrogen that is present in grapes and wine and that is an agonist for the estrogen receptor (Gehm et al., 1997; Skakkebaek et al., 2000). Long-term effects of endocrine disruptors on human brain and behavior differentiation have, however, not been studied so far. In 1996, MeyerBahlburg et al. reported a gender change from female to male in four 46,XX individuals with classic congenital adrenal hyperplasia. Congenital adrenal hyperplasia, characterized by high androgen levels during prenatal development in 90% due to a defect in 21-hydroxylase, indeed constitutes a risk factor for the development of

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gender-identity problems (Slijper et al., 1998). However, others found only a small increase in risk of atypical gender identity in girls with cogenetical adrenal hyperplasia (Berenbaum and Bailey, 2003). Although it should thus be emphasized that the majority of women with this disorder may not experience a marked gender-identity conflict, the odds ratio that a genetic female with this disease would live, as an adult, in the male social role, compared with genetic females in the general population, was found to be 608:1 (Zucker et al., 1996). These observations support the view that intrauterine or perinatal exposure to abnormal levels of sex hormones may permanently affect gender identity. The finding that both male and female transsexuals were more often non-right-handed than controls is also consistent with the theory of altered prenatal sex hormone origin for transsexualism (Green and Young, 2001). Aside from the biological factors considered during the pre- and perinatal periods, various psychological and social aspects are presumed to play an important role in the etiology of transsexualism. Psychological theories can be placed in two distinct categories: one envisaging transsexualism as the result of a nonconflictual process where gender identity is precociously fixed, and the other considering transsexualism as a conflictual process where gender identity is not fixed and continues to remain ambiguous throughout development (Michel et al., 2001). These theories still await data supporting them. The concept of sexual neutrality at birth, after which the infants differentiate as masculine or feminine as a result of social experiences, was proposed by Money et al. (1955a, b). Gender inprinting was presumed to start at the age of 1 year and to be already well established by 3–4 years of age (Money and Erhardt, 1972). Observations on children with male pseudohermaphroditism due to 5--reductase-2 deficiency were supposed to support the influence of life experience on psycho-sexual make-up (Al-Attia, 1996). However, the conclusion in the available literature is that there is no solid evidence for parental influences on the etiology of transsexuality (Cohen-Kettenis and Gooren, 1999). A classic report which originally strongly influenced the opinion that the environment plays a crucial role in gender development was that described by Money of a boy whose penis was accidentally ablated at the age of 8 months, during a phemosis repair by cautery, and who was subsequently raised as a female. Orchiectomy followed within a year to facilitate feminization and further surgery to fashion a full vagina was performed later. Initially this individual 227

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was described as developing into a normally functioning female. Later, however, it appeared that the individual had rejected the sex of raising and switched at puberty to living as a male again and requested male hormone shots, a mastectomy and phalloplasty. At the age of 25 he married a woman and adopted her children. This famous John–Joan–John story, although it is just one case, illustrates that there is little, if any, support for the view that individuals are sexually neutral at birth and that normal psychosexual development is dependent on the environment (Diamond and Sigmundson, 1997). In a second case of penile ablation, in which the decision was made to reassign the patient to female and raise the baby as a girl, the remainder of the penis and testes were removed at a slightly earlier stage (7 months). Although her adult sexual orientation was bisexual and even though she was mainly attracted to women, her gender identity was female. The different outcome as compared to the former case is explained by the authors on the basis of the decision to reassign the sex at a younger age (Bradley et al., 1998). Male patients with cloacal extrophy have a herniation of the urinary bladder and hindgut and the anatomy leaves them aphaleic in the majority of the cases. In a group of 8 male patients that were gender reassigned as females in the neonatal period, at least in 3 instances gender identity has been questioned by the patients themselves (Zderic et al., 2002) supporting the early programming of gender identity by biological factors and arguing against a dominating role of the social environment. The observation that in a longitudinal series of 16 hormonally normal 46xy males assigned to female sexof-rearing at birth due to the absence of a penis 8 have spontaneously declared themselves male and 15 fall very close to the male-typical spectrum of gender roles (Reiner, 2002) leads to the same conclusion. Reiner et al. (1996) described a 46,XY child with mixed gonadal dysgenesis, one immature testis, hypoplastic uterus and clitoral hypertrophy, who was raised without stigmatization as a girl, but who declared himself male at the age of 14. Following corrective surgery and testosterone substitution, he lived as a boy despite the social factors that were clearly in favor of maintaining the assigned sex. Apparently the deficient testis has been able to organize the brain during development, even though the hormone levels were prenatally so inadequate that ambiguity of the genitalia was induced. A child with true hermaphroditism and 45X (13%) 47XYY (87%) sex chro-

mosome mosaic pattern in blood, uterus, fallopian tubes, phallus, testicular tissue and epididymis, was assigned the male sex at birth. At 5 weeks the decision was made to reassign him to female. At 9 months an operation was performed to make the genitalia female, at 13 months the testicle was removed and at 5 years another operation was done to make the genitalia female. She was raised as a girl, but had masculine interests and when she was around 8 years of age she declared that ‘God had made a mistake’ and that she ‘should have been a boy’. Apparently the male sex hormones to which she had been exposed in utero had imprinted the male gender, although the authors also presumed postnatal psychosocial factors to have played a role (Zucker et al., 1987). Despite sex assignment, genital organ correction soon after birth, psychological counseling of parents and intensive psychotherapy, 13% of the intersex children in the study of Slijper et al. (1998) developed a gender-identity disorder. Yet only one girl (2%) failed to accept the assigned sex. The Imperato–McGinley syndrome, based upon DHT deficiency due to 5-reductase-2 deficiency, also shows that exposure to testosterone during development has a greater impact on male gender identity than the sex of rearing and sociocultural influences (ImperatoMcGinley and Zhu, 2002). We have found a female-sized central nucleus of the BSTc in male-to-female transsexuals. These data were confirmed by neuronal counts of somatostatin cells, the major neuron population in the BSTc and total cell number in the BSTc. Changes in adult hormone levels could not explain this difference (Zhou et al., 1995c; Kruijver et al., 2000; Chung et al., 2002; see Chapter 7). These observations support the hypothesis that gender identity develops as a result of an interaction between the developing brain and sex hormones. Much to our surprise, however, the sex difference in BSTc volume did not become overt until adulthood (Chung et al., 2002). The explanation for the discrepancy between the late occurrence of a sex difference in the volume of this nucleus and the early occurrence of gender problems in transsexualism necessitates further research. Possibly functional sex differences in the BSTc may precede the structural sex differences in the course of development. In male-to-female transsexuals a redirection of the P300 amplitude in the left frontal and temporal areas was found. In addition, a delay of the P300 latency was observed at the central frontal region (Papageorgiou et al., 2003), pointing to alterations in cortical circuits.

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(d) Homosexuality

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increases the occurrence of bi- or homosexuality in girls whose mothers received DES during pregnancy (Ehrhardt et al., 1985; Meyer-Bahlburg et al., 1995) in order to prevent miscarriage (quod non). DES was given between 1939 and the 1960s to millions of pregnant women (TitusErnstoff et al., 2003). However, these authors could not confirm an increase in the likelihood of homosexual behavior in DES-exposed girls or boys in adulthood. The ratio of the 2nd to 4th finger digits, a measure ascribed to the organizational actions of prenatal androgens, was significantly lower in the homosexual males and females as compared to heterosexuals. This observation suggests that homosexual males and females have been exposed to elevated levels of androgens in utero (Rahman and Wilson, 2003). Whether environmental estrogens from plastics can influence sexual differentiation of the human brain and behavior is, at present, in debate but certainly not established. However, the observation that masculine behavior increases in boys with number of years of maternal sport fish consumption (Sandberg et al., 2003) is consistent with this possibility. In addition, phytoestrogens, such as resveratrol, present in grapes and wine, and an agonist for the estrogen receptor, should be considered in this respect (Gehm et al., 1997). Homosexual orientation is most likely to occur in men with a high number of older brothers and a shorter stature. One biological mechanism that could explain this phenomenon is an immune response in women pregnant with successive male fetuses (Bogaert, 2003). Prenatal nicotine exposure has masculinizing/ defeminizing effects on sexual orientation of female offspring and increases the probability of lesbianism (Ellis and Cole-Harding, 2001). Maternal stress is thought to lead to increased occurrence of homosexuality in boys, particularly when the stress occurs during the first trimester (Ellis et al., 1988; Ellis and Cole-Harding, 2001), and girls (Bailey et al., 1991). As an interesting case history of this prenatal environmental factor, Weyl (1987) has mentioned that Marcel Proust’s mother was subjected to the overwhelming stress of the Paris commune during the 5th month of her pregnancy in 1871, and that Mary, Queen of Scots, the mother of the homosexual king of England, James I, toward the end of the 5th month of pregnancy, had the terrifying experience that her secretary and special friend Riccio was killed. Although postnatal social factors are generally presumed to be involved in the development of sexual orientation (Byne and Pearson, 1993;

Thou shalt not lie with mankind, as with womankind: it is abomination. Leviticus XVIII, 22 If a man has intercourse with a man as with a woman, both commit an abomination, They must be put to death. Leviticus XX,13 Xq28 – Thanks for the genes, mom (seen on T shirts in the USA)

Sexual orientation is influenced by quite a number of genetic as well as nongenetic factors (Table 24.2). Genetic factors appear from studies in families, twins and through molecular genetics (Kallmann, 1952; Bailey and Bell, 1993; Hamer et al., 1993; Hu et al., 1995; Turner, 1995; Pillard and Bailey, 1998; Bailey et al., 1999). Hamer and colleagues found linkage between DNA markers on the X chromosome and male sexual orientation. Genetic linkage between the microsatellite markers on the X chromosome, i.e. Xq28, was detected for the gay male families, but not for the lesbian families (Hamer et al., 1993, Hu et al., 1995). In a follow-up study, Rice et al. (1999) studied the sharing of alleles at position Xq28 in 52 Canadian gay male sibling pairs by four markers. Allele and haplotype sharing for these markers was not increased more than expected, which did not support the presence of an X-linked gene underlying male homosexuality. In a reaction to this paper, Hamer (1999) stated that: (i) the family pedigree data from the Canadian study supported his hypothesis, (ii) that three other available Xq28 DNA studies found linkage also, and (iii) that the heritability of sexual orientation is supported by substantial evidence independent of the X chromosome data. In a meta-analysis of the four available studies, he found a significant linkage. Rice et al. (1999) responded extensively and remained convinced that an X-linked gene could not exist in the population with any sizeable frequency. This controversy will undoubtedly continue for a while longer. The claim of Dörner et al. (2001), that in homosexual men a partial 3-hydroxysteroid dehydrogenase deficiency may be present, has to be confirmed. Sex hormones during development also have an influence on sexual orientation, as appears from the increased proportion of bi- and homosexual girls with congenital adrenal hyperplasia (Money et al., 1984; Dittmann et al., 1992; Meyer-Bahlberg et al., 1996). Then there is diethylstilbestrol (DES), a compound related to estrogens that

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Zucker et al., 1996), solid evidence in support of such an effect has not yet been reported. The observation that children raised by lesbian couples or by transsexuals generally have a heterosexual orientation (Green, 1978; Kirkpatrick et al., 1981; Golombok et al., 1983) does not support the possibility of the social environment in which the child is raised as an important factor for determining sexual orientation, nor is there scientific support for the idea that homosexuality has psychoanalytical or other psychological or social learning explanations, or that it would be a ‘lifestyle choice’ (Ellis, 1996). Various hypothalamic structures are structurally different in relation to sexual orientation, i.e. the SCN, INAH-3 and the commissura anterior (see Chapter 4.4), suggesting that a difference in hypothalamic neuronal networks that occur in development may be the basis of differences in sexual orientation. The human hypothalamus is claimed to produce an endogenous Na+–K+ ATPase inhibitor, digoxin. In homosexual men, a decreased circulating digoxin level has been found (Kurup and Kurup, 2002). It is not clear what the exact relationship is between changes in digoxin levels and alterations in hypothalamic nuclei. (e) Sexual dysfunction in hypothalamopituitary disorders Hypothalamopituitary disorders often interfere with the expression of sexuality. In fact, a decreased sexual desire was significantly present in 70–90% of the adult males with a pituitary tumor. One-third of these patients report decreased sexual desire even as the first symptom of the tumor. Decreased sexual drive is the first symptom in 50% of men with pituitary tumors accompanied by hyperprolactinemia. In addition, sexual desire is absent or decreased in two-thirds of the women with hypothalamopituitary disorders. This problem is recorded for 84% of the women with hyperprolactinemia and for only 33% of those with normal serum prolactin. Almost all these women have amenorrhea (Lundberg and Hulter, 1991; Lundberg and Brattberg, 1992; Ben-Jonathan and Hnasko, 2001; Chapter 24.1). As men age, there is a decrease in total and free testosterone levels and an associated increase in gonadotropin levels, while a decrease in sexual activity is also notable (Davidson et al., 1983). Although the hormonal changes during aging are generally considered to contribute only to a minor degree to the decline in sexual function in men, there are many studies that show the relationship between

testosterone levels and sexual activity. Testosterone increases the incidence of all types of male sexual activity in hypogonadal men, whereas the antiandrogen cyproteron acetate inhibits sexual activity (Davidson et al., 1982; Albert et al., 1993; Yates, 2000; Chapter 2.4). There is also clear evidence that testosterone modulates sexual behavior in women: adrenalectomy decreases sexual activity and testosterone replacement restores it (Albert et al., 1993; Tuiten et al., 2000; Chapter 24). Disturbed sexual behavior has, moreover, been reported in a number of different neurological and psychiatric disorders (Chandler and Brown, 1998), such as rabies (Dutta, 1996; Chapter 20.1), encephalitis lethargica (Chapter 20.2), multiple sclerosis (Chapter 21.2), Wolfram’s syndrome (Chapter 22.7), Prader–Willi syndrome (Chapter 23.1), anorexia nervosa and bulimia nervosa (Chapter 23.2), Kallmann’s syndrome (Chapter 24.3), Klinefelter’s syndrome (Chapter 24.4), depression (Chapter 26.4), Down’s syndrome (Chapter 26.5), Kleine–Levin syndrome (Chapter 28.1) and Parkinson’s disease (Chapter 29.3). Antipsychotic treatment in schizophrenia results in more sexual disturbances in men than in women (Hummer et al., 1999). In multiple sclerosis (Chapter 21.3) sexual dysfunction is typically characterized by diminished libido, erectile and ejaculatory dysfunction in men, and poor lubrication and anorgasmy in women. However, in some cases hypersexual behavior and paraphilias have been associated with lesions in the hypothalamus and septum (Frohman et al., 2002). In depression (Chapter 26.4) sexual activity per se is said not to be reduced during the depressed state. Rather, loss of sexual interest appeared to be related to the cognitive set of depressive symptoms, i.e. loss of sexual satisfaction. Nocturnal penile tumescence alterations may be more trait-like than state-like in depression (Nofzinger et al., 1993). A newly discovered group of neurological and reproductive disturbances is due to mutations in sex hormone receptors or aromatase. A complete androgen-insensitivity syndrome leads to a normal female external and behavioral appearance (see Chapter 24.5a). Some abnormalities of the androgen receptor result in the syndrome of androgen resistance, which goes together with normal male differentiation. More recently, mutations of the androgen receptor have also been described in a form of Kennedy’s disease, a motor neuron disease. In Kennedy’s disease (X-linked bulbospinal muscular atrophy), a trinucleotiderepeat expansion occurs in exon A of the androgen receptor gene (MacLean et al., 1995). Subjects with Kennedy’s

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disease have normal virilization, although progressive gynecomastia, testicular atrophy and infertility may occur (MacLean et al., 1996). In addition, mutations of the estrogen receptor may cause estrogen resistance. Cases of female pseudohermaphroditism, hypergonadotropic hypogonadism and multicystic ovaries have been reported to be associated with missense mutations in the gene encoding aromatase (P450). One 14-year-old girl did not develop breasts, the clitoris was enlarged, and circulating androgens and gonadotropins were high, causing hyperstimulation of the ovaries (Conte et al., 1994). Female pseudohermaphroditism has been found to be caused by placental aromatase deficiency. Maternal serum levels of estrogens were low and those of androgens were high in the third trimester, causing maternal virilization and pseudohermophroditism of the female fetus (Shozu et al., 1991). Another mutation of the human gene encoding for aromatase P450 has been reported in male and female siblings. During both pregnancies the mother exhibited signs of progressive virilization. The girl had nonadrenal female pseudohermaphrodism at birth and developed progressive virilization at the age of puberty, had pubertal failure with no signs of estrogen action, hypergonadotropic hypogonadism and polycystic ovaries. The brother was 204 cm tall. He was sexually mature, had elevated testosterone levels, low estrogen levels and high gonadotropins. Interestingly, the psychosexual orientation of both brother and sister was reported to be appropriate for their phenotypic sex (Morishima et al., 1995). There has also been a publication on two mutations in the CYP19A1 gene that were responsible for aromatase deficiency in an 18-year-old girl with ambiguous genitalia at birth, primary amenorrhea, sexual infantilism and polycystic ovaries (Ito et al., 1993). No information is present on the sexual differentiation of the hypothalamus in such subjects.

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Pedophiles show significantly lower baseline plasma cortisol and prolactin concentrations and a higher body temperature than normal volunteers. The chlorophenylpiperazine (mCPP)-induced cortisol responses are significantly greater in pedophiles than in normal volunteers. In normal volunteers, mCPP induces a hyperthermic response, whereas in pedophiles no such response is observed. mCPP induces different behavioral responses in pedophiles than in normal men. In pedophiles, but not in normal men, mCPP increases the sensations of ‘feeling dizzy’, ‘restless’ and ‘strange’ and decreases the sensation of ‘feeling hungry’. It is hypothesized that the results are compatible with a decreased activity of the serotonergic presynaptic neuron and a 5-HT2 postsynaptic receptor hyperresponsivity (Mozes et al., 2000). The possibility that pedophilia is based on a different interaction between sex hormones and the developing brain has to be investigated. In cases of hypothalamic glioma, a patient’s sexual orientation changes from heterosexual to pedophilia (Miller et al., 1986), indicating that the hypothalamus should be a focus for such research. Stereotactic hypothalamotomy aimed at the ventromedial nucleus has been performed during the detention of violent sexual offenders. Sexual drive is reported to be markedly reduced and no relapses occur. Side effects include strong feelings of hunger and weight gain (Dieckmann and Hassler, 1977). In one patient, agitation followed by unconsciousness and hemiparesis resulted from a hemorrhage into the third ventricle after removal of the electrode after such an operation. Another patient became unconscious but later recovered. Stereotactic hypothalamotomy is not only a risky operation, but also a very controversial one, both from an ethical and from a scientific point of view.

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CHAPTER 25

Hypothalamic lesions following trauma and iatrogenic lesions

25.1. Head/brain injury

be accompanied by central leptin insensitivity (Patel et al., 2002). Trauma may cause posterior lobe hemorrhage, ischemia in the anterior part of the hypothalamus, and destruction or avulsion of the pituitary stalk, followed by hypopituitarism. Post-traumatic diabetes insipidus is generally transient (Horvath et al., 1997) and may be accompanied by hypernatremia (Rehman and Atkin, 1999). However, when the lesion affects the hypothalamus, traumatic brain injury caused by, e.g. a gunshot wound, may be permanent (Alaca et al., 2002). In addition, the syndrome of inappropriate antidiuretic hormone secretion (Schwartz–Bartter syndrome; Chapter 22.6a) has been frequently reported following head injury. Interleukin-6 (IL-6) may be the mediator through which vasopressin neurons are stimulated in this syndrome following head trauma (Gionis et al., 2003). The syndrome of inappropriate vasopressin secretion was found to be related to subdural hematoma, and a marked association has been observed with skull fractures in the frontotemporal region, extending to the base of the skull, which would suggest hypothalamic dysfunction as a cause of the syndrome. The effects of this syndrome may be edema, nausea, vomiting and irritability, confusion, lethargy, coma and the occasional seizure, as well as raised intracranial pressure. The syndrome disappears with fluid restriction and/or administration of hypertonic saline (Twijnstra and Minderhoud, 1980). In some 40% of the closed head injuries, two main types of hypothalamic lesions have been described: microhemorrhages and ischemia lesions. The lesions occur in a somewhat haphazard manner throughout the anterior hypothalamus, but the microhemorrhage tends to be located subependymally in the paraventricular nuclei, in the lateral hypothalamus, amongst the fibers of the median forebrain

Wallace LaBaw was a physician who in 1964 sustained a closed brain injury himself (Kapur, 1997), and who wrote an interesting account of his feelings of intense anger (“sham rage”), temperature dysregulation, and hunger and memory problems. His defecatory urge and sexual drive and ability had gone, and he had emotional problems. Although he assumed, probably correctly, hypothalamic involvement, the location of the lesions was not documented. A number of neuroendocrine changes indicating hypothalamic involvement have, however, been reported following head injury. There appears to be a rapid but variable activation of the hypothalamopituitary–adrenal (HPA) axis after head injury. Some authors report an association between the severity of head injury and the extent of the HPA axis response. Others indicate that there is a relationship between plasma cortisol levels and patient outcome. Experimental data indicate the exclusive presence of a corticotropin-releasing hormone (CRH) response (and thus an absence of vasopressin response) following traumatic brain injury (Grundy et al., 2001). Increased HPA axis activity is a key characteristic in depression (Chapter 26.4a, d). In this connection it may be of great importance that the risk of depression remains elevated for decades following head injury and seems to be the highest in those who suffered severe head injury (Holsinger et al., 2002). In the acute phase of severe head injury, increased growth hormonereleasing hormone (GHRH) and somatostatin release may be present. The resulting increased insulin-like growth factor (IGF-I) levels suggest that these changes may be advantageous for recovery (De Marinis et al., 1999). Traumata of the hypothalamopituitary system may 233

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bundle, in the supraoptic nuclei (SON), and in the region of the median eminence. Pituitary infarcts or hemorrhages are frequently present in these patients, in both the anterior and the posterior lobe (Crompton, 1963; Neil-Dwyer et al., 1994). Following closed head injury, diabetes insipidus, and clinical signs as well as symptoms of hypopituitarism frequently occur. An example is a patient who had hypopituitarism 1 year after a basilar skull fracture due to an automobile accident. Endocrinologically provocative testing indicated that the patient’s hypopituitarism was secondary to hypothalamic insufficiency or interruption of the pituitary portal circulation (Woolf and Schalch, 1973). In addition, autonomic hypothalamic disorders are found post-trauma. Hypothermia due to hypothalamic dysfunction has been described (Ratcliffe et al., 1983). A patient was able to sweat normally, but during cold stress he was unable to maintain core temperature. Four years after the original head injury, a CT scan demonstrated damage in the hypothalamus. As patients with traumatic brain injury go through the stages of recovery, acute hypothalamic instability occurs, usually in the form of autonomic dysfunction syndrome (also known as neurostorming or diencephalic seizures or paroxysmal sympathetic storm; Chapter 30). The usual manifestation are intermittent episodes of diaphoresis, tachycardia and hypertension. The syndrome is managed with short-acting opiates or benzodiazepines and then subsequently with antihypertensives, dantrolene and bromocryptine. Other causes of acute hypothalamic instability are the neuroleptic malignant syndrome (Chapter 25.2), malignant hyperthermia (Chapter 30.2) and lethal catatonia. The patients all present with signs and symptoms of hypothalamic instability (Thorley et al., 2001). After fatal head injury, histological evidence of neuronal damage was found in the nucleus basalis of Meynert (NBM). Reduced levels of choline acetyltransferase were observed in the cortex, indicating a loss of cholinergic innervation. Dysfunctioning of this system is thought to contribute to deficits of memory and cognition after head injury (Murdoch et al., 2002). In a review of case-control studies, Fleminger et al. (2003) confirmed that head injury is a risk factor for Alzheimer’s disease. The NBM damage may well contribute to this association. A case of avulsion of the optic chiasm is described in Chapter 17.2b. Intractable obesity has been reported after radiation therapy for leukemia or brain tumors. These patients with hypothalamic obesity demonstrate excessive

insulin secretion. Octreotide (a long-acting somatostatin receptor agonist) administration promoted weight loss in these patients, possibly through reductions in -cell insulin release. After pituitary/hypothalamic surgery, children are not only at risk of developing hormonal deficiencies and obesity, but also of hypersomnolence. The (often severe) daytime sleepiness is not the result of inappropriate hormone replacement (Snow et al., 2002). In a 15year-old girl, a delayed sleep-phase syndrome developed following traumatic brain injury. The sleep–wake rhythm was delayed by almost half a day and returned to normal following treatment with 5 mg of melatonin (Nagtegaal et al., 1997). One patient experienced a lack of REM sleep during hypothalamic injury following excision of a craniopharyngioma (Rehman and Atkin, 1999). Neurosurgery for hypothalamopituitary masses frequently causes growth hormone deficiency (Corneli et al., 2002). Following hypothalamic injury, psychiatric symptoms are common, including attacks of rage, laughing and crying, excessive sexuality, antisocial behavior, hallucinations, coma or somnolence (with posterior lesions) or pathological wakefulness (with anterior lesions), excessive salivation, and bradycardia (Rehman and Atkin, 1999). Whiplash injury may lead to a syndrome characterized by insomnia, impaired concentration and memory, fatigue, neck pain and headache. The injury may cause transection of the pituitary stalk. Cases with amenorrhea, sexual immaturity and a history of head trauma have been described. In a 17-year-old girl, provocative testing of the pituitary revealed hypothalamic insufficiency and intact pituitary function. MRI demonstrated loss of the hypothalamic infundibulum, which may lead to hypothalamic atrophy (Grossman and Sanfield, 1994). In chronic whiplash syndrome patients with delayed melatonin onset, melatonin administration advances melatonin onset and sleep–wake rhythm. The great variability in outcome that is generally observed after traumatic brain injury is only partly explained by age and estimated damage. Genetic factors, too, determine the outcome; i.e. apolipoprotein E-4 genotype predicts a poor outcome (Friedman et al., 1999). 25.2. Neuroleptic malignant syndrome Neuroleptic malignant syndrome is a rare but severe side effect of neuroleptics (Caroff and Mann, 1993). The

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incidence is estimated to be 0.5–1% of all patients exposed to neuroleptics (Guzé and Baxter, 1985). Neuroleptic malignant syndrome is characterized by extrapyramidal signs and hyperthermia. It was first described and named by Delay and Deniker (1968). Other autonomic manifestations are pallor, diaphoresis, blood pressure instability, tachycardia and tachypnea. It is frequently associated with confusion, agitation and hypertonicity of skeletal muscles (Addonizio et al., 1987; Thorley et al., 2001). The symptoms may culminate in stupor and coma, and death occurs in some 20% of the cases (Hendersen and Wooten, 1981; Jones and Dawson, 1989). This syndrome has often been described in young, acutely psychotic patients and has also been called lethal catatonia or fatal catatonia, acute lifethreatening catatonia or fatal hyperthermia syndrome (Kish et al., 1990). The syndrome may in fact represent an iatrogenic form of fatal catatonia and is an uncommon complication of therapy with dopamine receptor blocking agents such as phenothiazines or other neuroleptics, especially with long-acting (depot) neuroleptic dopamine-depleting drugs. Others consider lethal catatonia to be a precursor of neuroleptic malignant syndrome (Thorley et al., 2001). Neuroleptic malignant syndrome has also been reported following discontinuation of an L-DOPA-carbidopa combination (Horn et al., 1988; Jones and Dawson, 1989; Kish et al., 1999), metoclopramine or lithium (Addonizio et al., 1987; Goekoop and Knoppert-Van der Klein, 1990), following the cessation of dopaminergic drugs in patients with Parkinson’s disease (Jones and Dawson, 1989), and in hypothalamic instability following traumatic brain injury (Thorley et al., 2001). In addition, the syndrome can even develop with continued antiparkinsonian medication. Hot weather, dehydration, the premenstrual period and the use of lithium may be risk factors for the development of this disorder (Jones and Dawson, 1989). The pathogenetic mechanism of the neuroleptic malignant syndrome remains unclear. In one instance this syndrome was attributed to a respiratory infection (Itoh et al., 1995). The syndrome is characterized by increased muscular activity and a hypothesized hypothalamic disturbance that would impair heat dissipation (Morris et al., 1980; Henderson and Wooten, 1981). It has been proposed that neuroleptic malignant syndrome is of central origin, while malignant hyperthermia (Chapter 30.2) is of peripheral origin, i.e. due to prolonged muscle contraction on the basis of a primary deficit in the muscle (Guzé

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and Baxter, 1985; Jones and Dawson, 1989). It has also been suggested that the neuroleptic malignant syndrome would result in a disturbance in the hypothalamic–adrenal axis, which is associated with excessive catecholamine secretion (Feibel and Schiffer, 1981). There is a lack of systematic therapeutic studies, but dopamine agonists were reported to reduce mortality significantly (Caroff and Mann, 1993). In addition, several reports have pointed to the usefulness of electroconvulsive therapy in neuroleptic malignant syndrome. One case has been reported where a dramatic improvement indeed occurred after electroconvulsive therapy. The tremor was alleviated after the first application of electroconvulsive therapy and the neuroleptic malignant syndrome symptoms and psychiatric symptoms disappeared after the fourth application of this therapy. It has been suggested that this therapy is effective because it enhances the turnover rate of dopamine and serotonin (Nisijima et al., 1996), but, of course, many other transmitter systems are affected by this treatment. In four cases, brain autopsy has so far not shown any consistent or specific abnormality (Henderson and Wooten, 1981), while no abnormal histological hypothalamic findings were reported in three other cases (Kish et al., 1990). In two cases that were presumed to have chronic neuroleptic malignant syndrome on clinical grounds (92-003; 94-094), we could not find a hypothalamic lesion either. In one case in the literature, scattered, petechial subarachnoid hemorrhages were reported to occur all over the brain, and similar tiny parenchymal and perivascular hemorrhages were also seen in the hypothalamus. These abnormalities were acute, minimal, nonspecific, possibly agonal and of uncertain significance (Jones and Dawson, 1989). The possible association of neuroleptic malignant syndrome with striatonigral degeneration has been reported in other cases (Gibb, 1988; Hayashi et al., 1993; Itoh et al., 1995). There is one interesting, positive neuropathological report on the possible involvement of the hypothalamus in this syndrome (Horn et al., 1988). Microscopic examination revealed bilateral foci of pycnosis, disintegration of neurons, and sponginess of the neuropil in the hypothalamus. The changes were limited to the lateral hypothalamus and lateral tuberal nuclei (Fig. 25.1), but a few pycnotic nuclei were also seen in the ventromedial hypothalamic nucleus. In addition, widespread small foci of nuclear pycnosis were found in the cerebral cortex that were most probably secondary to the extremely elevated body temperature. Neuroleptic syndrome has also been reported in patients with cell loss 235

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died of malignant neuroleptic syndrome, higher guanosine triphosphate cyclohydrolase activity was found, which suggests a possible involvement of biopterin metabolism in the pathophysiology of this syndrome (Ichinose et al., 2003). More systematic neuropathology of patients with this syndrome will be needed in order to link the symptoms, and in particular heat stroke, to the localization of hypothalamic or other lesions that are involved in the mechanism of heat loss and influenced by dopamine (Caroff and Mann, 1993). 25.3. Hypothalamic injury by radiation Fig. 25.1. Circumscribed foci of an early necrosis in the hypothalamus of a patient who died of neuroleptic malignant syndrome. ON, optic nerve; LHA, lateral hypothalamic area; T, tuberal nuclei (probably nucleus tuberalis lateralis); III, third ventricle; VM, ventromedial nucleus. Hematoxylin and eosin staining; approximately  12. Arrows indicate necrosis. (From Horn et al., 1988, Fig. 1, with permission.)

in the NBM, with lesions in the anterior cingulate gyri and mamillary bodies, or with periventricular nuclei in the hypothalamus or in brainstem areas, perhaps as a result of interruption of dopaminergic tracts passing through these regions (Caroff and Mann, 1993). In one patient, who died after 4.5 months of suffering from neuroleptic malignant syndrome, a complete loss of cerebellar Purkinje cells and a moderate reduction of granular neurons were observed, both of which were considered to be heat-induced central nervous system injuries (Lee et al., 1989). The strong loss of large NBM lesions and the resulting decrease in choline acetyltransferase in the cerebral cortex in patients with malignant neuroleptic syndrome has also been reported in a larger-scale sample of schizophrenic patients. Conceivably, the brain cholinergic abnormality in malignant neuroleptic syndrome might have been due to pre-existing developmental dysfunction and may thus lead to a reduced capacity of the brain to respond adequately to stress and/or neuroleptic-induced receptor blockade (Kish et al., 1990), and temperature changes (see Chapter 2). Moreover, a marked reduction in hypothalamic norepinephrine content was observed in patients with malignant neuroleptic syndrome. Norepinephrine is involved in the regulation of body temperature and the decreased hypothalamic levels are proposed, on the basis of animal experiments, to be secondary to the rise in temperature (Kish et al., 1990). In the hypothalamus of Parkinson patients who

(a) Hypothalamic symptoms following radiation of tumors Following previous external radiation, not only of pituitary tumors (Shalet, 1982), but also of tumors some distance away from the adenohypophysis such as posterior fossa tumors, neuroendocrine disturbances have been found, ranging from isolated growth hormone deficiency to panhypopituitarism. The nature of radiation injury is generally thought to be based upon direct neural injury, vasculitis due to radiation, and multifocal microvascular thrombosis due to chemotherapy and secondary gliosis (Ciesielski et al., 1994; Spoudeas et al., 2003). Progressive neural injury can occur following a latent interval of 6 months to several years after radiation (Perry-Keene et al., 1976; Shalet, 1982). The endocrine complications may occur late (Shalet, 1982; Abayomi et al., 1986). Growth hormone regulation is particularly affected, not only following radiation of the pituitary-hypothalamic region but also after radiation of posterior fossa tumors (Spoudeas et al., 2003). The regulation of growth hormone release is predominantly under the control of GHRH and somatostatin (Shalet et al., 1982; Peacey et al., 1998; Chapter 18.6). Hyperprolactinemia is one of the most common dysfunctions in adult female patients with nasopharyngeal carcinoma treated with radiotherapy. MRI revealed no structural abnormality in the hypothalamopituitary region of these patients (Lau et al., 2001). In children, the prevalence of true precocious puberty is increased after cranial radiation for local tumors or leukemia. Even radiotherapy aimed at the pituitary gland may result in true precocious puberty. Several papers underscore that early puberty occurs in children who were treated with high-dose cranial irradiation. In addition, these children often have

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growth hormone deficiency and impaired linear growth. Moreover, they are at risk for adrenal insufficiency and may develop hypothyroidism. Treatment with growth hormone and an LHRH agonist is often indicated and should be considered at a young age (Styne, 1997; Müller et al., 1998a; Oberfield and Garvin, 2000; Daniel, 2002; Spoudeas et al., 2003). Hypothalamic radiation doses higher than 51 Gy are a risk for the development of obesity in children (Lustig et al., 2003). In a study on 32 patients of between 6 and 65 years old who had received cranial radiotherapy for brain tumors 2–13 years earlier, at doses of 3960–7020 rad (39.6–70.2 Gy), 28% had thyroid deficiency and 62% had low serum total or free thyroxine (T4) or total triiodothyronine (T3) levels. Seventy percent of the adult women had oligomenorrhea and 50% had low estradiol concentrations. Of the adult men 30% had low serum testosterone levels. Mild hyperprolactinemia was present in 50% of the patients. One patient had panhypopituitarism (Constine et al., 1993). Other authors, too, pointed to the high frequency of thyroid disturbances (Pasqualini et al., 1987). It should be added that patients with hypopituitarism are at risk for premature mortality due to cardiovascular disease (Rosén and Bengtsson, 1990; Markussis et al., 1992; Rosén et al., 1993). In addition to endocrine changes, intellectual and cognitive capabilities are affected in these subj-ects (Ciesielski et al., 1994). Concerning the effect of radiation therapy on IQ, the risk of adversely affecting the intellectual status of the survivors is clear when subjects are treated with a greater irradiation volume at a young age, while no influence of the location of the tumor was detected (Mulhern et al., 1992). Growth hormone deficiency may contribute to the cognitive disorder of these patients (Bülow et al., 2002). A controlled, cross-sectional study to assess frequency and clinical impact on endocrine dysfunction has been performed in 32 long-term survivors, aged between 25 and 66 years, of primary brain tumors outside the hypothalamopituitary region, which were studied for 1–11 years after radiotherapy with a mean total dose of 62.3 ± 2.8 Gy (mean local dose pituitary 51.1 ± 12.1 Gy and hypothalamus 57.0 ± 7.8 Gy). Fifty-two percent of the patients reported symptoms suggestive of hypothyroidism and 26% showed evidence of hypothalamic hypothyroidism. These patients had significantly lower serum baseline cortisol levels and dehydroepiandrosterone sulfate (DHEAS) than controls. Forty-seven percent

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of the male patients and only 6% of the controls suffered from erectile dysfunction, 42% of the patients had hypothalamic hypogonadism. Twenty-nine percent of the patients presented with hyperprolactinemia, and 4 women concurrently suffered from oligoamenorrhea. A high frequency of clinical complaints was observed in the survivors, and this had a significant impact on their well-being, such as cognitive impairment and reduced drive (Arlt et al., 1997). Growth hormone deficiency may contribute to mental distress and cognitive dysfunction (Bülow et al., 2002). Cranial irradiation for childhood acute lymphoblastic leukemia results in subtle ovulatory disorder in some patients (Bath et al., 2001). The lesion-producing pituitary deficiency in cranial radiation patients is more likely to be situated in the hypothalamus than in the pituitary. This idea is supported by raised serum prolactin levels (Shalet, 1982; Constine et al., 1993), by the occurrence of true precocious puberty and by some sleep disturbances. Since the hypothalamus has nuclei that develop relatively late, i.e. in the postnatal period, such as the sexually dimorphic nucleus of the preoptic area (SDN-POA) (Chapter 5.2), the suprachiasmatic nucleus (SCN) (Chapter 4.2b), and the bed nucleus of the stria terminalis (BST) (Chapter 7), this structure may thus be very sensitive to radiation. Despite all these arguments, hypothalamic neuropathology following radiation injury has so far not been systematically studied in postmortem tissue, either in children or in adults. Disturbances of the circadian regulation of sleep and wakefulness argue for the idea that damage as a result of craniospinal irradiation administered to cure childhood malignancy does not only occur at the level of the pituitary, but also at that of the hypothalamus. High-dose cranial radiation therapy in childhood is associated with both objective (actigraphy) and subjective (questionnaire) changes in the sleep–wake rhythm in adulthood. Surprisingly, a strongly increased sleep duration and a higher amplitude sleep–wake rhythm with less fragmentation was found in young adults who received cranial radiation during childhood, showing that the function of the SCN was intact. The increase in the duration of sleep may, however, indicate hypothalamic damage. In spite of this apparently good sleep, patients, particularly those with low growth hormone and high prolactin and leptin levels, experienced an increased difficulty in overcoming drowsiness and getting started in the morning. Since young adults with isolated growth hormone deficiency 237

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also showed increased total sleep time, at least part of the sleep disturbances may be due to pituitary damage. (b) Tumors after whose treatment these symptoms were found Following field radiation of hypothalamic/chiasmatic gliomas, growth hormone deficiency, hypogonadotropic hypogonadism, hypoadrenalism and diabetes insipidus have been reported (Collett-Solberg et al., 1997). Long-term follow-up of patients treated for optic pathway tumors with radiotherapy, especially young children and patients with neurofibromatosis-1, showed major sequelae, such as cerebrovascular complications and severe intellectual disabilities. The two most frequent endocrine deficiencies were growth hormone deficiency and precocious puberty (Cappelli et al., 1998). In acromegaly the frequency of growth hormone pulses is increased, and this is interpreted by several authors as evidence that acromegaly is due to a primary hypothalamic abnormality with secondary development of a pituitary neoplasm. There are, however, also arguments in support of the idea that acromegaly is due to a primary pituitary defect. Radiotherapy is excellent at halting tumor growth, but the slow reduction of growth hormone concentration, damage to the normal hypothalamic pituitary axis necessitating life-long replacement hormone therapy and the recent evidence to suggest lack of normalization of IGF-I are obvious disadvantages. Radiotherapy is proposed to lead to a reduction, or even a complete loss of endogenous hypothalamic somatostatin tone (Peacey et al., 1998). Patients with nasopharyngeal carcinoma treated with irradiation more than 5 years before had hypothalamic hypothyroidism with low free T4 and normal thyrotropin (TSH). TSH appeared to have decreased bioactivity, which was restored by prolonged TRH administration. These observations indicate that endogenous TRH deficiency after irradiation of the hypothalamohypophyseal region may not always be a transient phenomena (Lee et al., 1995). In fact, progressive impairment of hypothalamic-pituitary functions occurring after cranial irradiation for nasopharyngeal carcinoma can be demonstrated already 1 year after radiotherapy, using estimated doses of 39.8 Gy to the hypothalamus and 61.7 Gy to the pituitary. One year after radiotherapy, there was a

significant decrease in the integrated growth hormone response to insulin. In male patients basal and simulated follicle-stimulating hormone (FSH) levels increased, and luteinizing hormone (LH) decreased, suggesting a decreased LH-releasing hormone (LHRH) pulse frequency. The peak serum TSH response to TRH became delayed in 28 patients, suggesting a defect in TRH release. After 2 years, the basal T4 and plasma cortisol levels had significantly decreased and further impairment in the secretion of growth hormone, FSH, LH, TSH and corticotropin (ACTH) had occurred (Lam et al., 1987). Hyperprolactinemia associated with oligomenorrhea is found especially in women. Adults who had received cranial irradiation in childhood as part of their treatment for acute lymphoblastic leukemia not only had decreased growth hormone levels but also hyperleptinemia. Leptin levels were significantly higher in the group with the lower growth hormone levels. Whether the hyperleptinemia was due to growth hormone-deficiency or to radiation-induced leptin resistance is not known (Brennan et al., 1999a). Cranial irradiation for childhood acute lymphoblastic leukemia may result in subtle ovulatory disorder (Bath et al., 2001). Long-term neuroendocrine deficiencies following craniospinal irradiation for childhood medulloblastoma preferentially take place in the growth hormone axis (Abayomi and Sadeghi-Nejad, 1986). Eight years after therapy with 35 Gy, some 70% of the adult subjects (median age 25 years) had impaired growth hormone secretion, and 35% had an absolute growth hormone deficiency. Young age at treatment was a determinant of growth hormone deficiency in adulthood. In contrast, only 20% showed impairment of the hypothalamopituitary– thyroid or –gonadal axis. Central adrenal insufficiency was not observed, while basal prolactin levels were normal in all subjects. Whether the localization of the damage of the growth hormone axis is at the hypothalamic or at the pituitary level, or both is still a matter of debate (Heikens et al., 1998). Long-term endocrine surveillance seems to be mandatory following craniospinal irradiation, not only for the growth hormone axis. Although radiationinduced ACTH deficiency is relatively uncommon, it may be life-threatening and should be ruled out (Abayomi and Sadeghi-Nejad, 1986). Children with posterior fossa tumors remained severely growth hormone deficient until some 11 years after cranial irradiation. A few of these children also had partial ACTH insufficiency or hypopituitarism (Spoudeas et al., 2003).

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Fig. 25.2. Effect of hypophysectomy on the supraoptic nucleus (SON). Nissl-stained sections through the SO of a normal subject (a) and of two patients who had been hypophysectomized for 4 months (b) and 8 years (c). Note the great loss of nerve cells in the nucleus after hypophysectomy. Or, optic tract. (From Daniel and Prichard, 1975, Fig. 37, with permission.)

of these astrocytomas are high-grade (Collett-Solberg et al., 1997).

(c) Yttrium (Y)-90 implantation in the pituitary A few decades ago, pituitary ablation by stereotactic transnasal yttrium-90 implantation was carried out in patients with advanced metastatic mammary carcinoma in order to curtail the effect of sex hormones on such tumors. Varying degrees of water intoxication (Chapter 22.6), and ultimately diabetes insipidus (Chapter 22.2), followed this operation. A decrease in the number of neurons in the SON and paraventricular nucleus (PVN) was found in patients who died between 5 and 20 months after the operation. The occurrence of diabetes insipidus was related to neuronal loss in the SON and PVN, and to the decreased volume of the SON and PVN (Habener et al., 1966). Saccular aneurysms causing hypopituitarism have been described as a complication of yttrium-90 implantation for pituitary adenomas.

(e) Vascular complications Radiation can cause delayed (up to 20 years later) vascular complications, such as small-vessel obliterative vasculopathy – an important cause of radiation necrosis. Radiation-induced microscopic vascular anomalies or telangectasia may cause hemorrhages, and large vessel damage may manifest itself as occlusive cerebrovascular disease, or cause intracranial fusiform aneurysms. In chronic occlusive large-vessel disease of arteries of the circle of Willis, abnormal capillary network (moyamoya) vessels may develop at the basis of the brain due to radiation therapy (Sinsawaiwang and Phanthumchinda, 1997). Moyamoya disease may lead to massive cerebral hemorrhage (Oka et al., 1981; see Chapter 19.4).

(d) Postradiation tumors

(f) Other complications

As a consequence of radiotherapy for pituitary adenoma or craniopharyngioma, astrocytomas may arise in the hypothalamic region after some 10 years. The majority

Intrasellar herniation of the third ventricle has been described following radiation of pituitary adenoma (Kobayashi et al., 1996). In addition, radiation necrosis

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Fig. 25.3. Effects of hypophysectomy and of pituitary stalk sectioning on the paraventricular nucleus (PV). Parasagittal Nissl-stained sections through the PV of a normal subject (a), and of a patient who died 8 years after hypophysectomy (b). Note the great loss of PV neurons. AC, anterior commissure; F, anterior column of fornix; IF, interventricular foramen; PV, paraventricular nucleus; SR, supraoptic recess of third ventricle. (From Daniel and Prichard, 1975, Fig. 38, with permission.)

of the optic pathways, hypothalamus and brainstem has been described following irradiation of a pituitary adenoma (Delattre et al., 1986). 25.4. Lesion of the pituitary stalk Following surgical hypophysectomy or pituitary stalk sectioning, the SON and PVN show a marked nerve cell loss that is usually more pronounced in the SON than in the PVN (Daniel and Prichard, 1975; Figs. 25.2 and 25.3). Similar changes are found in the SON and PVN when

the stalk is interrupted by metastases (Duchen, 1966; Chapter 19.9). Pituitary stalk sectioning has been used to inhibit hypothalamic stimulation of the pituitary, e.g. in the treatment of metastatic cancer of the breast or diabetic retinopathy. Many of the SON and PVN neurons disintegrate and die by the end of the 2nd week after the operation, and at 3 weeks a loss of nerve cells is definitely apparent. After 3 months, dying cells are a rarity (Daniel and Prichard, 1972, 1975). Morton (1970) found a cell loss of 25% at 3 weeks after the operation. After 3 months, 50% of the nerve cells had disappeared. In contrast to Daniel and Prichard (1975), Morton (1961, 1970) found

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a continuing cell loss until about a year after the operation, when approximately 20% of the nerve cells remained. Some discrepancies in the literature concerning cell loss may be due to the fact that individual variability in cell number in the SON and PVN is considerable (see Chapter 8). No close relationship has been found between the length of the remaining stalk and the number of residual cells in the SON and PVN. In the SON and PVN of stalk-sectioned patients gliosis has been reported. An accumulation of Gomori-positive neurosecretory material was reported to occur within a week after the operation; this increased staining disappeared after a month (Daniel and Prichard, 1972, 1975). The immediate effect of stalk sectioning is a venous infarction of the neural tissue of the stump, due to thrombosis of the long portal vessels. Because the arterial blood flow is not cut off by the operation, an intense congestion of the blood vessels in the stump occurs, as well as an extravasation of blood. Necrosis of neuronal tissue may involve irregular areas higher up, up to the junction of the stalk and the optic chiasm. Hemorrhages may extend into the hypothalamus, around the infundibular recess (Daniel and Prichard, 1972, 1975). Diabetes insipidus usually starts 1 day after the operation (Seckl et al., 1990). After a month, the stalk has regenerated and is almost normal in appearance. Patchy innervation and hemosideration granules are observed. After a year, the stalk is reinnervated throughout, although less abundantly, and with a finercaliber fiber than can be found in a normal stalk. In some cases where the pituitary stalk has been transected, a newly formed, small ectopic ‘miniature neurohypophysis’ is found at the proximal stump of the transected stalk. The ectopic posterior lobe secretes vasopressin and shows

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a high-intensity signal on T1-weighted MRI images (Daniel and Prichard, 1975; Fujisawa et al., 1987a). In hypothalamic nuclei other than the SON and PVN, no changes have been reported after stalk sectioning, although not only diabetes insipidus but also hypopituitarism was found after this operation. The cells of the pars tuberalis usually survive. Postpartum hypopituitarism may go together with a similar strong loss of SON and PVN neurons as observed following stalk sectioning (Whitehead, 1963; see Chapter 22.1). Following suprasellar removal of the pituitary, first a polyuria occurred, which was probably due to the acute damage of the hypothalamoneurohypophysial system. This phase was followed by a period of normal urine levels that could be explained by the release of preformed vasopressin. The occurrence of permanent polyuria was frequent but unpredictable. From animal experiments it is estimated that if less than 5–15% of the SON cells remained in the SON, polyuria would occur (Lipsett et al., 1956). Metastases are common in the neurohypophysis. They may cause diabetes insipidus (Schubiger and Haller, 1992). Interruption of the stalk and neurohypophysis by such metastases may lead to neuronal loss and gliosis in the SON and PVN (Duchen, 1966; Chapter 19.9). Damage to the pituitary stalk in the fetus was proposed to lead to perinatal abnormalities such as breech presentation, forceps delivery and asphyxia. It also accompanies idiopathic pituitary dwarfism. However, it may well be that pituitary stalk damage in fact occurs much earlier in the fetus, and that such a developmental defect subsequently leads to perinatal problems (see Chapters 18.4 and 18.6).

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CHAPTER 26

Hypothalamic involvement in psychiatric disorders

Geisteskrankheiten sind Gehirnkrankheiten. W. Griesinger, 1861

1997), proving that the tumor had caused the symptoms. Alpers (1937) has described a case of a dermoid cyst in the third ventricle that severely damaged the hypothalamus, causing severe personality changes and mood swings. The changes generally consisted of maniclike reactions such as euphoria, motor restlessness, push of speech and flight of ideas; also, it was quite easy to elicit rage in this subject. In the older literature, this type of reaction was also reported following operations for hypophyseal adenoma. Alpers (1940) has reported emotional negativism in the case of craniopharyngioma of the hypothalamic region, and violent psychomotor agitation (rage) in the case of a glioma. Another case involving an epidermoid cyst extending into the hypothalamus showed mood swings, from euphoria to mild depression, accompanied by bouts of weeping and laughing (for attacks of laughter see Chapter 26.2). Hypothalamic stimulation leads to sympathetic effects and profound anxiety in patients (Alpers, 1940). On the basis of lesions, the posterior hypothalamus is held responsible for changes in personality and mood (Alpers, 1937). The episodic rage (Chapter 26.9) and emotional instability may be attributed to structures in the ventromedial area (Chapter 26.3). Patients with a third ventricular colloid cyst or tumor without hydrocephalus may manifest disturbances of memory (imprinting and retrieval), emotion and personality (euphoria or apathy) that improve once the tumor has been removed. The symptoms may be attributed to compression or to vascular compromise of the diencephalon (Williams and Pennybacker, 1954; Lobosky et al., 1984). Intermittent explosive disorder, hypersexual behavior and hallucinations have been found in cases of deteriorated work performance due to a craniopharyngeoma or prolactinoma (Carrol and Neal, 1997). Hypothalamic tumors causing symptoms of anorexia

Do not consult the gods to discover the directing soul, but consult an anatomist. Galenus, 2nd century Emotion moves us, hence the world itself. Sir Charles Sherington, cited by Gano et al., 1970.

26.1. Psychiatric symptoms due to tumors of the third ventricle Observations that unsuspected tumors of the region of the third ventricle give rise to predominant psychiatric symptoms confirm the view that the hypothalamus plays a significant role in emotional expression. Malamud (1967) has studied a group of seven patients, four of whom had first been diagnosed to be schizophrenic, two suffered from psychoneurosis and one from manic excitement (Table 26.1). Although these conditions were all due to tumors, only the illness in case 13 was initiated by seizures, and only here could some evidence of an organic disturbance be found also. In all but the terminal stages of the remaining cases was the clinical course dominated by the psychiatric disorder. Visual hallucinations have been described in a patient with a hypothalamic astrocytoma that affected the preoptic area bilaterally and the tuberal region of the hypothalamus at one side (Haugh and Markesbery, 1983). One patient with an isolated absence of the septum pellucidum presented with schizophrenic psychosis (Supprian et al., 1999). Another one, a 9-year-old boy, with a history of behavioral problems and worsening psychosis appeared to suffer from a choroid plexus papilloma. When examined 1 year after the operation, it transpired that he had not experienced any hallucinations since the operation and his behavior was within normal limits (Carson et al., 243

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TABLE 26.1 Tumors in the region of the third ventricle. Case no.

Psychiatric diagnosis

Location of tumor

Diagnosis of tumor

12 13 14 15 16 17 18

Schizophrenia Schizophrenia Schizophrenia Psychoneurosis Manic excitement Psychoneurosis Schizophrenia

Intraventricular Periventricular Floor of third ventricle Floor of third ventricle Floor of third ventricle Roof of third ventricle Roof of third ventricle

Subependymoma Glioblastoma multiforme Craniopharyngioma Craniopharyngioma Craniopharyngioma Colloid cyst Colloid cyst

From: Malamud N. (1967) Psychiatric disorder with intracranial tumors of limbic system. Arch Neurol 17:113–123.

nervosa are discussed in Chapter 23.2 and other symptoms of tumors in the regions of the third ventricle such as transient global amnesia (Sorensen, 1995), akinetic mutism (Ross and Stewart, 1981), somnolence, altered levels of consciousness (Davison and Demuth, 1946; Coffey, 1989) and coma (Cairns, 1952) are discussed in Chapter 19.1b). 26.2. Attacks of laughter (gelastic epilepsy) (Fig. 26A) An honoured gentleman brought his wife to this city to get the advice of Messrs. Le Grand, Duret and myself (physicians), to find why she wept and laughed without reason, and no one could cure her. We treated her with many remedies but could accomplish little; finally he took her away in the same state she had come. Ambroise Paré (1510–1590), cited by Altshuler and Wisdom, 1999.

Gelastic epilepsia (gelos = mirth) is defined as laughter that is inappropriate, stereotyped and not precipitated by either a specific humorous or nonspecific stimulus. Convulsive laughter thus lacks an affective component (Money and Hosta, 1967). The laughter attacks may appear on their own or in conjunction with other types of convulsions (Iannetti et al., 1992) and are characterized by a sudden, paroxysmal onset, a self-limiting nature and a correlation with abnormal cortical discharges (Black, 1982). The spells may be accompanied by hypoapnea, repeated ‘cooing’ respirations, giggling and smiling, and occur as frequently as every 15–20 min (DiFazio and Davis, 2000). Some patients have the symptom of a “pressure to laugh” but often without actually laughing. The symptom is regarded as pleasant and sometimes it

is associated with a sense of happiness (Sturm et al., 2000). Gelastic epilepsy is more common in children than in adults (Askenasy, 1987). It may sound like normal laughing, resemble a caricature of laughter (giggle) or be alternated with crying (Black, 1982). The duration of the laughter attacks is usually short, i.e. less than 30 s. Cognitive deterioration and behavioral problems are common (Sturm et al., 2000) in gelastic epilepsy, which is often associated with precocious puberty and mental retardation (Cascino et al., 1993). Main causes of gelastic epilepsy are: hypothalamic hamartomas (Chapter 19.3), pituitary tumors, astrocytomas of the mamillary bodies, dysraphic conditions and neoplasms of the posterior fossa (Iannetti et al., 1992; Arroyo et al., 1993; Al-Herbish et al., 1997; Colover, 2000; Coppola et al., 2002). In addition, the cingulate cortex may be the origin (Munari et al., 1995). Gelastic epilepsy is only observed in relation to the type of hypothalamic hamartomas that are broadly attached to the mamillary bodies, i.e. type IIa and IIb of Valdueza et al., 1994a (see Chapter 19.3; Fig. 19.7). Gelastic seizures have been found in a 2-year-old girl with multiple brain anomalies , including tectal tumor (possibly hamartoma), multiple subependymal nodules and holoprosencephaly (Akman et al., 2002). One boy has been described with gelastic epilepsy, precocious puberty, hypothalamic hamartoma and agenesis of the corpus callosum (Alikchanov et al., 1998). Pathological laughing and crying also occurs in some 10% of multiple sclerosis patients in a chronic-progressive stage (Feinstein et al., 1997). In addition, laughing seizures have been reported in a child with tuberous sclerosis due to a neoplasma arising from the floor of the left lateral ventricle extending downwards into the hypothalamus (Gunatilake and Harendra De Silva,

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Fig. 26A. Mischievous woman (Edma Balázs), Life and Work. Published 1998 by Robert, Susan and John Balázs, © Robert, Susan and John Balázs, ISBN: 0-9532750-1-9. (With permission.)

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1995). In a 4-month-old infant with West’s syndrome, gelastic seizures in clusters have been observed; smile-like episodes developed every few seconds. PET showed hypoperfusion bilaterally in the hypothalamus, and interictal hypsarrhythmia and ictal EEG revealed desynchronization; ACTH was effective. West’s syndrome is characterized by infantile spasms, mental retardation and hypsarrhythmia (chaotic, high-amplitude slow waves, sharp waves and spikes) on EEG. In this case West’s syndrome was due to perinatal hypoxia followed by hypothalamic hemorrhage (Kito et al., 2001). Gelastic seizures have also been associated with third-ventricle papillomas, tumors of the pineal region, traumas, lesions of the ventromedial nucleus area, encephalitis, meningitis, lipid storage disease (Iannetti et al., 1992), pseudobulbar palsy and psychiatric illness (Altshuler and Wisdom, 1999). Gelastic epilepsy is also found to be associated with general temporal lobe epilepsy (Arroyo et al., 1993). Intense sexual feeling (orgasmolepsy) has been reported in some of these cases in association with the laughing fits (Purdon, 1950; Sethi et al., 1976; Holmes et al., 1980; Jacome et al., 1980). It is not clear exactly how the temporal lobe attacks may be related to altered hypothalamic functions. During the laughing attacks there can be a loss of consciousness (Cascino et al., 1993). Although it is clear that hypothalamic hamartomas are associated with gelastic seizures, it was not believed for a long time that the hypothalamus could be the origin of the seizures, since attempts to remove the hypothalamic lesion failed to control the seizures (Pallas et al., 1969; Cascino et al., 1991; Arroyo et al., 1993). However, later it was found that gelastic fits are strictly linked to ictal discharges that start and may remain well localized in the hamartoma, as shown by stereotactically implanted intracerebral multielectrodes (Munari et al., 1995). Moreover, SPECT demonstrates a dramatic ictal uptake in the area of the tumor, with normalization during the postictal phase (DiFazio and Davis, 2000). Since hyperperfusion of the hypothalamopituitary region is observed by SPECT, together with an ictal pulse of gonadotropins, 17-estradiol and growth hormone, this means that at least neighboring areas are also influenced and that these seizures may cause paroxysmal dysfunction of the hypothalamopituitary axis (Arroyo et al., 1997). Gelastic seizures spread from the hypothalamus through hypothalamus–amygdala connections and spread to mesial temporal structures, causing complex partial seizures and a pattern of symptomatic generalized epilepsy with tonic, atonic and other types of seizures in association with slow

spike and wave discharge and cognitive deterioration (Berkovic et al., 1997; Sturm et al., 2000). Gelastic seizures that have their basis in a hypothalamic hamartoma are accompanied by an abrupt rise in blood pressure and respiratory rate, increased levels of growth hormone, norepinephrine and cortisol, without modification of corticotropin (ACTH) or epinephrine, which indicates an abrupt increase in the activity of the sympathetic system (Tinuper et al., 1994). It should be noted here that a normal, mirthful laughter experience reduces serum levels of cortisol, 3, 4-dihydroxyphenyl acetic acid (DOPAC), epinephrine and growth hormone (Berk et al., 1989). The existence of a center for laughter in or near the hypothalamus has been postulated on the basis of the effects of: (i) astrocytomas (Iannetti et al., 1992); (ii) hamartomas involving the floor of the hypothalamus (see Chapter 19.3); (iii) a case of an aneurysm, compressing the corpora mamillaria and elevating the floor of the anterior part of the third ventricle; (iv) a case of a tumor between the posterior wall of the tuber cinereum and the posterior margins of the mamillary bodies, leaving all hypothalamic nuclei intact; and (v) neurosurgical provocations of outbursts of laughter when swabbing blood from the floor of the third ventricle (Purdon, 1950; Duckman and Chao, 1957). Usually the response of gelastic seizures to antiepileptic drugs is poor. One case of tuberous sclerosis with gelastic seizures has been reported that disappeared after treatment with ACTH (Go, 1999). Surgical resection and stereotactic radiofrequency ablation of hamartomas have been performed (see Chapter 19.3). In addition, luetinizing hormone-releasing hormone (LHRH) antagonists, gamma knife radiation and stimulation of the left vagal nerve have been performed (see Chapter 19.3). 26.3. Ventromedial hypothalamus syndrome and the effect of lesions on aggression Following invasion of a tumor into the area of the ventromedial hypothalamic nuclei (VMN), a tetrad of symptoms have been described, i.e. (i) episodic rage, (ii) emotional lability, (iii) hyperphagia with obesity and (iv) intellectual deterioration. Memory loss is the most prominent feature of intellectual decline. Lesion of the descending columns of the fornix and mamillary bodies may be important in this respect, but a primary role for the VMN in memory has also been postulated (Reeves and Plum,

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1969; Climo, 1982; Flynn et al., 1988; Fig. 26.1). A young woman with anorexia nervosa due to a craniopharyngioma reported urges to kill people (Climo, 1982). Indeed, experimental lesions of the VMN area in animals produce rage and excessive eating, and, in a child with massive leukemia infiltration at the level of the VMN of the hypothalamus, violent hunger, and obesity were reported. In addition to tumors, encephalitis, tuberous sclerosis and vascular lesions have been found to cause hypothalamic obesity (Bastrup-Madsen and Greisen, 1963; Coffey, 1989). It should be noted, though, that lesions that are restricted to the VMN do not produce obesity in rats. It is therefore presumed that damage to the nearby noradrenergic bundle or its terminals might be responsible for obesity (Gold, 1973). Moreover, it should be mentioned that, in a patient with hyperphagia and obesity whose VMN was unilaterally lesioned by a hypothalamic astrocytoma, the paraventricular nucleus (PVN) was bilaterally involved (Haugh and Markesbery, 1983), which may also have caused these symptoms (see Chapter 23.1). In addition to rage attacks in patients with VMN area lesions, marked oscillations between inappropriate laughter and crying have been reported (Chapter 26.2). If VMN lesions indeed have such a notable effect on the production of episodic rage, emotional instability, hyperphagia with obesity and memory loss, it is remarkable, to say the least, that none of these signs and symptoms have been mentioned following stereotactic destruction of the VMN in patients with “sexual deviations” or in drug addicts. Even in the patient who underwent bilateral destruction of the VMN, the only effect reported was a loss of all interest in sexual activity. The authors explicitly state that psycho-organic disturbances did not occur in any of the patients, although they do not define the exact nature of the disturbances they looked for (Müller et al., 1973). One may thus indeed wonder whether structures in the vicinity of the VMN instead of the VMN itself may be essential for the development of a ‘ventromedial’ hypothalamus syndrome. This possibility is reinforced by the observation of a post-traumatic patient with a lesion in the dorsomedial hypothalamic nucleus who had hyperphagia (Shinoda et al., 1993). Moreover, in the rat, aggression can come from an area below the fornix, just lateral and frontal to the VMN in the hypothalamus. This area almost completely coincides with the intermediate hypothalamic area (Kruk et al., 1998; Chapter 14c). On the other hand, a 3-year-old boy who developed obesity on the basis of encephalitis had a severe bilateral outfall of the neurons

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Fig. 26.1. In the course of several years, a young woman developed marked obesity and hyperphagia, associated with aggressive behavior. At autopsy, she was found to have a hematoma that destroyed the ventromedial nucleus. Diagrammatic representation of the tumor projected on midsagittal plane. ac, anterior commissure; al, ansa lenticularis; DM, dorsomedial nuclear region; F, fornix; HL, lateral hypothalamus; I, infundibular stalk; ic, internal capsule; mi, massa intermedia; Mm, mamillary body; ME, median eminence; o ch, optic chiasm; ot, optic tract; Pa, paraventricular nucleus; ph, pallidohypothalamic tract; PH, posterior hypothalamus; pi, pineal body; Pr, preoptic region; t, thalamus; VM, ventromedial nuclear region; zi, zona incerta; and III, third ventricle. (From Reeves and Plum, 1969; Fig. 3, with permission.)

of the VMN (Wang and Huang, 1991), which argues for some role of the VMN in eating behavior. In 1901 Frölich described the case of a 12-yearold boy with a pituitary tumor, sexual immaturity, hypogonadism and obesity, probably caused by a craniopharyngioma (Carmel, 1980). Later this condition was called ‘dystrophic adiposo-genitalis syndrome’. The hypogonadism and dwarf growth were probably due to pituitary deficiencies, while the adiposity is presumed to be due to a VMN lesion by the tumor, so that Fröhlich’s syndrome as an entity has become obsolete (Drukker, 1967). The most common cause of the combination of hypogonadism and adiposity is, indeed, a 247

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craniopharyngioma (Sheehan and Kovacs, 1982). It is not clear what the hypothalamic involvement might be in fat boys or girls with small genitals that are often said to have ‘pseudodystrophia adiposogenitalis’ or ‘pseudoFröhlich’s syndrome’ (Drukker, 1967). Later they develop into normal adults. A transitory functional disturbance of the “satiety center”, the gonadotropin center” and temporary, excessive corticotropin-releasing hormone (CRH) production have been presumed (Sheehan and Kovacs, 1982) but have not been established. There is one report on the opposite effect of the symptom, “episodic rage”, which belongs to the VMN tetrad, i.e. a ‘calming’ effect of posterior hypothalamic lesions, but in fact these lesions were situated just behind the VMN level. In 51 patients with violent, aggressive or restless behavior, bilateral lesions were made in an area 1–5 mm lateral from the wall of the third ventricle in the “ergotropic triangle”. The triangle was in lateral view, bordered by the midpoint of the intercommissural line, the rostral end of the aqueduct and the anterior border of the mamillary body (this means that the major part of the lesion was in fact situated just behind the hypothalamus). Electrical stimulation of this area caused a rise in blood pressure, tachycardia and maximum pupillary dilatation. After bilateral electrocauterization of this area, a “marked calming effect” was found in 95% of the cases. There was a tendency to a decrease in sympathicotonia or an increase in parasympathicotonia (Sano et al., 1970). Similar lesions made by Schvarcz et al. (1972) in 11 patients who had suffered episodes of severe hetero- and/or autoaggressiveness with violent, destructive behavior have resulted in marked improvement without aggressive crises or violent behavior, with social readaptation in 7 cases, improvement in 3 cases and no improvement in 1 case. As is often the case in such stereotactic experimental operations, one can doubt the scientific strength of these observations. 26.4. Depression and mania (Fig. 26B) Deep grief is mortal. That is to say deadly. Shakespeare. It should be generally known that the source of our delight, our joy, laughter and entertainment, as well as of our grief, pain, fear and tears, is no other than the brain. This organ in particular allows us to think, to see, to hear, and to distinguish the ugly from the beautiful, evil from good, pleasurable from disagreeable. The brain is also the seat of madness and insanity, and of the fears and terrors that assail us, often at night, but sometimes during the day; the cause of

sleeplessness and somnabulism lies there, of thoughts that fail to emerge, of obligations forgotten and of strange phenomena. After Hippocrates, ca. 460–377 v. Chr. in: Corpus Hippocratium.

Major depressive disorders are considered to have a neurochemical basis in multiple signaling pathways in different brain areas, and various regional selective impairments of structural plasticity have been reported (Manni et al., 2001). At least seven interacting hypothalamic peptidergic systems are currently considered to be involved in symptoms of depression, as well as 3 aminergic transmitter systems that innervate the hypothalamus. (a) Depression and neuropeptides The role of neuropeptides in depression is summarized: (1)

Depressive illness is presumed to result from an interaction between the effects of environmental stress and genetic/developmental predisposition. The hypothalamopituitary–adrenal (HPA) axis, a key system in stress responses, is considered to be the ‘final common pathway’ for a major part of the depressive symptomatology. The set point of the HPA axis activity and other central systems is programmed by genotype but can be changed to another level by developmental influences and early negative life events. Long-lived hyper(re)activity of the CRH neurons resulting in increased stress responsiveness is seen in these individuals (De Kloet et al., 1997; Heim and Nemeroff, 2001). Promising animal experimental models for depression, i.e. maternal deprivation in neonatal rats, are based upon such a mechanism (Pihoker et al., 1993; Fujioka et al., 1999). Prenatal stress in rat may lead to permanently enhanced CRH mRNA expression in the offspring (Fujioka et al., 1999), and prenatal environmental chemical stressors such as smoking by the mother during pregnancy may sensitize a person for depression, especially children who were either light or heavy at birth (Clark et al., 1996, Clark, 1998). Both hyper- and hypocortisolism may arise as a consequence of fetal programming of the HPA axis during intrauterine life (Kajantie et al., 2002). Animal experiments and observations in human indicate that aversive experiences, both in utero

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Fig. 26B.

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Albrecht Dürer, Melencolia I, 1514, Staatliche Museen zu Berlin Preußischer. Kulturbesitz, Kupferstickkabinett, with permission.

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and in the neonatal period, result in sustained HPA axis activation and in sensitization of emotional and HPA axis responses to subsequent stress. Maternal stress beginning at infancy and concurrent stress on preschoolers is accompanied by sensitization of the children’s HPA axis response to subsequent stress exposure (Checkly, 1996; Holsboer and Barden, 1996; Nemeroff, 1996; Carlson and Earls, 1997; Kraemer, 1997; Clark, 1998; Essex et al., 2002). Stressful life events such as bereavement, child abuse and early maternal separation are also risk factors for depression, anxiety disorder, or both. Childhood physical or sexual abuse is an important early stressor that may predispose individuals to adult-onset depression with permanent hyperactivity. Borderline personality disorder often shows depressive symptoms. A substantial number of these patients show recurrent brief depression (De la Fuente et al., 2002) and a high coincidence of childhood abuse. Interestingly, chronically abused borderline patients had a significantly enhanced ACTH and cortisol response to the dexamethasone/CRH challenge test compared with nonabused subjects (De Bellis et al., 1999; Weiss et al., 1999; Goodyer et al., 2000; Heim et al., 2000; Heim and Nemeroff, 2001; Wise et al., 2001; Rinne et al., 2002). In addition, small size at birth leads to an alteration in set point of the HPA axis and an increased cortisol responsiveness and risk of depression in adulthood (Phillips, 2001; Thompson et al., 2001). The risk of depression remains elevated for decades following head injury in adulthood and seems to be the highest in those who have had a severe head injury (Holsinger et al., 2002). Additive effects for the risk to develop depression are personal disappointment, negative life events, bereavement and stress, reflected in high daily levels of cortisol or dehydroepiandrosterone (DHEA) (Goodyer et al., 2000; Harris et al., 2000). However, patients with major depressed disorders and personality disorders such as avoidant, schizoid, self-defeating, passiveaggressive, schizotypical and borderline personalities are found to have a normal suppression of cortisol following dexamethasone administration (Schweitzer et al., 2001). In contrast to the increased cortisol levels in major depression, a mirthful laughter experience reduces serum cortisol (Berk

et al., 1989). Indeed, a good environment is not a luxury, it is a necessity for optimum brain development and the prevention of depression. In addition, there are genetic risk factors involved. Members of families with a high incidence of depression showed a primary functional defect in corticosteroid signal transduction (Holsboer et al., 1995). All the environmental and genetic risk factors for depression ultimately appear to go together with increased HPA axis activity in adulthood. On the other hand, when patients are treated with antidepressants or electroconvulsive therapy, or when they show spontaneous remission, the HPA axis function returns to normal (Nemeroff, 1996). In adulthood, the HPA axis is activated not only by stressful events, but also by proinflammatory cytokines such as interleukin-6 or exogenous interferon- that activates such cytokines (Cassidy and O’Keane, 2000). The CRH neurons of the PVN that regulate the HPA axis are indeed strongly activated in depression (Raadsheer et al., 1994c, 1995; Figs. 26.2, 26.3 and 26.6) and there is dexamethasone resistance in the great majority of depressed patients (Dinan, 1994; Holsboer, 2000). These findings are of particular interest, not only because CRH is the central drive to the stress response, but also because there are similarities between signs and symptoms of major depression and the behavioral effects of centrally administered CRH in laboratory animals and in transgenic mice with CRH overproduction. It is therefore presumed that antidepressants might elevate mood through their long-term inhibitory effect on the HPA axis (Barden et al., 1995; Plotsky et al., 1998; Holsboer, 2000, 2001). In this connection it is also interesting to note that depressed patients with HPA axis hyperactivity are less responsive to psychotherapy (Thase et al., 1996). In relation to the hyperactivity of the CRH neurons and vasopressin and oxytocin neurons in depression (see below), it is of considerable interest that both placebo treatment and the selective serotonin reuptake inhibitor (SSRI) fluoxetine cause a decrease in hypothalamic metabolic rate as measured by PET scanning (Mayberg et al., 2002). (2, 3) The vasopressin and oxytocin neurons in the PVN of patients with major depression or bipolar disorder are activated, and this activation may have

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Fig. 26.3. The total number of CRH-expressing neurons in the PVN of human subjects at different ages. , 10 control subjects; , 6 bipolar or major depressed patients; , 2 ‘non-major depressed’ subjects with either an organic mood syndrome or a depressive episode not otherwise specified. Note the high number of neurons expressing CRH in bipolar and major depressed patients. (From Raadsheer et al., 1994c, Fig. 2, with permission.)

Fig. 26.2. Total hybridization signal for human corticotropin-releasing hormone (CRH)-mRNA (arbitrary units) in the paraventricular nucleus (PVN). Bars indicate median values per patient group. The PVN of the Alzheimer patients (n = 10) contained significantly more (MW; U = 23.0, W = 0.78, Z = – 2.0, p = 0.04) CRH-mRNA than that of comparison subjects (n = 10). The amount of radioactivity in depressed patients (n = 7) was significantly higher than in comparison cases (MW; U = 7.0, W = 91.0, Z = – 2.7, p = 0.006) and Alzheimer’s disease patients (MW; U = 23.0, W = 0.78, Z = – 2.0, p = 0.05). (From Raadsheer et al., 1995, Fig. 2, with permission.)

functional consequences for the activation of the HPA axis. Vasopressin is known to potentiate the effects of CRH. Von Bardeleben and Holsboer (1989) have already postulated that increased release of vasopressin into the portal capillaries in depression enhances the action of CRH at the pituitary level, and cerebrospinal fluid (CSF) CRH and vasopressin levels are associated with a diminished response of the pituitary to CRH (Newport et al., 2003). Moreover, depression is associated with enhanced pituitary vasopressinergic responsivity (Dinan et al., 1999). Because of their central

(4)

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effects, oxytocin neurons have been connected to the eating disorders in depression (Purba et al., 1996). Although the literature has been quite controversial so far, oxytocin seems to have an inhibitory effect on ACTH release in various species, including human (Legros, 2001). The reduced number of nitric oxide synthase-containing neurons in the PVN of depressed patients is supposed to be related to the increased release of CRH, oxytocin and vasopressin from this nucleus (Bernstein et al., 1998). In the supraoptic nucleus (SON), no change is found in depression (Bernstein et al., 2000). The suprachiasmatic nucleus (SCN), the clock of the hypothalamus, normally shows strong circadian and circannual variations in neuronal activity (Hofman and Swaab, 1992b, 1993) which are supposed to be related to circadian and circannual fluctuations in mood and to sleeping disturbances in depression. In addition, biological rhythms are disturbed in depression (Chapter 26f; Van Londen et al., 2001). A disorder of SCN function, as

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(5)

(6)

(7)

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apparent from the decreased amount of vasopressin mRNA in this nucleus, may not only be the basis of the circadian and sleeping disorders in depression, but also contribute to hyperactivity of the CRH neurons (Zhou et al., 2001). It is presumed that the decreased activity of the SCN in depression is due to the increased corticosteroid levels that are known to inhibit SCN function (Liu et al., 2003, submitted; Figs. 26.4, 26.5 and 26.6). Data on changes in melatonin excretion in depression are controversial (Chapter 4.5e; Kripke et al., 2003). Depressed patients have alterations in the hypothalamopituitary–thyroid axis (Musselman and Nemeroff, 1996). Basal thyrotopin (TSH) and thyroxin levels are found to be altered in melancholic and major depressed patients (Maes et al., 1993b). Moreover, thyroid hormones may increase the efficacy of antidepressant drugs (see below). In CSF of depressed patients, somatostatin is decreased in a state-related way, while in suicide attempters somatostatin levels are significantly increased. The source of these peptide changes still ought to be established (Westrin et al., 2001). The number of -endorphin-containing neurons in the infundibular nucleus (Chapter 11) and the number of -endorphin innervated neurons in the PVN are lower in depressed patients (Bernstein et al., 2002b).

Fig. 26.4. Estimated total amount of arginine vasopressin (AVP) mRNA in the suprachiasmatic nucleus (SCN; expressed as masked area of silver grains) of the controls and the corticosteroid-exposed subjects (CST). The bars and error lines represent the mean and standard error of the mean (SEM). (From Liu et al., 2003, submitted.)

1992), but it has yet to be elucidated whether the serotonergic innervation of the hypothalamus is crucial in this respect. Some conditions, such as major depression, violent suicide and SAD are presumed to be related to the rhythmicity of 5-HT function (Cappiello et al., 1996).

(b) Amines in the hypothalamus and depression Patients with depression have alterations in serotonin (5HT), noradrenaline and dopamine production by the brain (Lambert et al., 2000). The hypothalamus is strongly innervated by the noradrenergic, dopaminergic and serotonergic systems, neurotransmitter systems that are considered to play vital roles in the pathogenetics of depression. The slightly lower prolactin plasma levels in patients with seasonal affective disorder (SAD) are consistent with a hypothalamic dopamine disregulation in this disorder (Oren et al., 1996). Indeed, increased dopamine levels were observed in the hypothalamus of suicide victims who died as a result of carbon monoxide poisoning or drug overdose. However, the possibility that these changes are secondary to hypoxia or due to drug effects should be considered (Arranz et al., 1997). Impulsive aggression and suicidal behavior have been related to a decreased serotonergic activity (Coccaro,

Fig. 26.5. Day–night fluctuation in the total amount of AVP mRNA of the SCN in controls and in the glucocorticoid-exposed subjects (CST). Note that at any moment of the day the values for CST are lower than those of controls. (From Liu et al., 2003, submitted.)

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With respect to the seasonal and circadian fluctuations in mood, the circannual and day/night fluctuations in hypothalamic content of 5HT and dopamine (Carlsson et al., 1980a; Chapter 1.3) may be of particular interest. The rhythmic circadian and circannual fluctuations in amines suggest that the hypothalamic SCN may drive the aminergic neurotransmitter system rather than the other way around. Noradrenaline is increased in the hypothalamus of depressive suicides and suicides who were alcoholics (Moses and Robins, 1975). Depression in suicide victims was also found to be related to the presence of supersensitive 2A-adrenoceptors in the hypothalamus and prefrontal cortex (Meana et al., 1992; Oren et al., 1996), although other data indicated a decrease in postsynaptic 2-adrenoreceptor responsive-

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ness in depression (Mokrani et al., 1997). There are many possible interactions between the peptidergic and aminergic networks and endocrine changes in depression. Corticosteroids exert a variety of effects on aminergic neurotransmission (Holsboer and Barden, 1996), probably by the widely distributed corticosteroid receptors (De Kloet et al., 1997). Moreover, CRH neurons innervate dopaminergic neurons (Thind and Goldsmith, 1989), which might be an additional route for HPA axis influence on monoaminergic systems. Light therapy is presumed to act on the SCN but also affects serotonergic and noradrenergic neurotransmissions. The maintenance of light therapy-induced remission from depression in patients with seasonal mood cycles seems to depend on the functional integrity of the brain serotonergic system,

Fig. 26.6. Depression; schematic illustration of an impaired interaction between the decreased activity of vasopressin neurons (AVP) in the suprachiasmatic nucleus (SCN) and the increased activity of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN). The hypothalamopituitary–adrenal (HPA) system is activated in depression and affects mood, via CRH and cortisol. We found a decreased amount of vasopressin (AVP) mRNA of the SCN in depression. The decreased activity of AVP neurons in the SCN of depressed patients is the basis of the impaired circadian regulation of the HPA system in depression. Moreover, animal data have shown that AVP neurons of the SCN exert an inhibitory influence on CRH neurons in the PVN. Increased levels of circulating glucocorticoids decrease AVP mRNA in the SCN, which will result in smaller inhibition of the CRH neurons. In the light of our data we propose the following hypothesis for the pathogenesis of depression. In depressed patients, stress acting on the HPA system results in a disproportionally high activity of the HPA system because of a deficient cortisol feedback effect due to the presence of glucocorticoid resistance. The glucocorticoid resistance may either be caused by a polymorphism of corticosteroid receptor or by a developmental disorder. Also AVP neurons in the SCN react to the increased cortisol levels and subsequently fail to inhibit sufficiently the CRH neurons in the PVN of depressed patients. Such an impaired negative feedback mechanism may lead to a further increase in the activity of the HPA system in depression. Both high CRH and cortisol levels contribute to the symptoms of depression. Light therapy activates the SCN, directly inducing an increased synthesis and release of AVP that will inhibit the CRH neurons. Antidepressant medication generally inhibits the activity of CRH neurons in the PVN. ACTH, corticotropin.

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suggesting that this system may be involved in the mechanisms of the action of light therapy (Neumeister et al., 1997). Whether hypothalamic changes are responsible for the loss of sexual satisfaction in depression and nocturnal penile tumescence abnormalities (Nofzinger et al., 1993) remains to be studied. Some animal experiments suggest that histamine, the product of the tuberomamillary nucleus (Chapter 13), increases anxiety. Winston Churchill described depression as “the black dog” (Nemeroff, 2001).

(c) Other factors and brain structures involved in the pathogenesis of depression Environmental stress and developmental factors, including a genetic basis, are involved in the pathogenesis of depression and cause hyperactivity of the HPA axis (Chapter 26.4a). Those patients who were born in the northern hemisphere in March–May and those born in the southern hemisphere in September–November have the highest prevalence of suicidal and depressive symptoms. Second-trimester prenatal exposure to influenza is given as an example of this seasonal fluctuation (Joiner et al., 2002). Moreover, a clear gender difference is present in depression. The prevalence, incidence and morbidity risk is higher in females than in males (Regier et al., 1988; Table 2.2), suggesting the organizing or activating action of sex hormones. The high proportion of ‘depression-like’ neuroendocrine, polysomnographic or psychometric features are conspicuous findings observed in 32% of the healthy first-degree relatives of patients with an affective disorder hypothesized to be due to a disturbed receptor function and indicate a genetically transmitted risk factor (Holsboer et al., 1995; Holsboer, 2000; Krieg et al., 2001) such as corticosteroid receptor polymorphism, which leads to corticosteroid resistance. Increased levels of cortisol or DHEA, which are risk factors for depression, may thus also be based upon genetic factors (Goodyer et al., 2000). Interestingly, results of an analysis of twin studies suggest a heritability of the cortisol levels of 62% (Bartels et al., 2003). Although mutations, singlenucleotide polymorphisms and glucocorticoid receptor variants have been found, no association with depression or other psychiatric disorders has been reported. However, such an association has in fact hardly been studied so far (DeRijk et al., 2002). Polymorphisms in the 5-HT transporter promotor and in genes encoding for 5-HT receptors

5-HT2A and 5-HT2C and tryptophanhydroxylase do not play a major role in the pathogenesis of SAD according to some studies (Johansson et al., 2001; see below), although according to others this may be a vulnerability factor (Praschak-Rieder et al., 2002). Carriers of the 5-HT2C ser allele were 12 times more likely to have major depression in Alzheimer’s disease (Holmes et al., 2003). The apolipoprotein E (ApoE) 2 allele is significantly less frequently found in depressive illness and is associated with a later mean age at onset. In contrast, subjects with depressive symptomatology in Alzheimer’s had a higher frequency of the ApoE 2 allele (Holmes et al., 1996b). In Alzheimer patients the ApoE 4 allele is associated with depression in women, but not in men (Müller-Thomsen et al., 2002). Evidence of anticipation for bipolar disorder may be explained by the presence of unstable trinucleotide CAG/CTG repeats that expand from one generation to the next (Vincent et al., 1999). Seasonality of the winter type of depression also seems to run in families (Madden et al., 1996). A 5-HT transporter promoter polymorphism (Sher et al., 1999) and -7 nicotine receptor polymorphisms (Stassen et al., 2000) are known to be associated with this type of depression. In addition, it is hypothesized that mutations or allelic variations in clock genes might contribute to the symptoms of depression in SAD and subgroups of major depression (Bunney and Bunney, 2000). Desan et al. (2000) have reported a single-nucleotide polymorphism in the CLOCK gene, in addition to a preference for activity in the evening, but it is not associated with depression. A polymorphism in the clock gene NPAS2 appeared, however, to be associated with SAD (Johansson et al., 2003). An insertion/deletion polymorphism in the angiotensin-1-converting enzyme gene leads to higher HPA axis activity during major depressive periods (Baghai et al., 2002). For the increased risk factor for depression in heterozygous Wolfram patients (Swift et al., 1991; see Chapter 22.7). There is also preliminary evidence for a role of the Wolfram syndrome1 (WFS1) gene in the pathophysiology of impulsive suicide (Sequeira et al., 2003). Patients with cyclothymia or bipolar affective disorder are present in families with morbid obesity due to mutations of the melanocortin 4 receptor (Mergen et al., 2001). Genetic factors also seem to contribute substantially to the comorbidity between major depression and anorexia nervosa (Wade et al., 2000). Prenatal famine in middle or late gestation is a risk factor for major depression, as shown in studies on subjects

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exposed to the Dutch Hunger winter of 1944–1945. The effects were demonstrated for men and women and for unipolar and bipolar affective disorders (Brown et al., 2000). Whether long term dysfunctions of the HPA axis are present in these subjects has yet to be elucidated. Several hormonal factors may also be involved. Prenatal diethylstilbestrol (DES) exposure increases the risk for depression (Meyer-Bahlburg and Ehrhardt, 1987), while in addition growth hormone-deficient children are at risk for depression and react favorably to growth hormone treatment (Stabler et al., 1996; Chapter 18.6). Hypertension is accompanied by high levels of a feeling of hopelessness (Everson et al., 2000), possibly due to the increased activity of the CRH neurons found in this condition (Goncharuk et al., 2002). Depression is common after stroke. The severity of mood disorders in stroke is increased in patients with left prefrontal frontal cortex lesions or with right posteriodorsal lesions (Robinson et al., 1984; Iacoboni et al., 1995). Postmortem studies have provided morphological evidence for the involvement of the prefrontal cortex in depression. Cell loss takes place in the subgenual prefrontal cortex and cell atrophy is found in the dorsolateral and orbitofrontal cortex (Rajkowksa, 2000). Moreover, the number of glial fibrillary acetic protein (GFAP) positive astrocytes is decreased in the dorsolateral prefrontal cortex of young depressed patients and increased in older depressed patients (Miguel-Hidalgo et al., 2000). PET and SPECT studies have shown that bilateral hypometabolism of the orbitalinferior prefrontal lobe occurs in most types of depression, regardless of the origin of the depression (George et al., 1993; Mayberg et al., 2002; Morris et al., 1996a, b; Galynker et al., 1998). It is a matter of debate whether these metabolic changes in the cortex in depressed patients are cause or effect of the disorder, since increased levels of glucocorticoids inhibit prefrontal cortex metabolism (Fulham et al., 1995; Brunetti et al., 1998) and glucocorticoid receptor dysregulation is found in the neocortex and hippocampus of patients with depression (Webster et al., 2002). In the pathogenesis of depression, the interaction between the prefrontal cortex and the HPA axis is crucial. On the one hand, the prefrontal cortex inhibits the HPA axis, as is clear from the lesions, particularly of the left prefrontal cortex, which may go together with symptoms of depression and hypercortisolism. On the other hand, the hypercortisolism that occurs in depression will inhibit prefrontal cortex activity, and these two effects might even reinforce each other (Swaab et al., 2000).

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Major depressive syndrome has a high (45%) prevalence rate in Alzheimer patients, and may thus be among the most common mood disorders of late life (Zubenko et al., 2003). What the increased HPA axis activity that we observed in Alzheimer patients (Raadsheer et al., 1995) may contribute to this syndrome should be investigated. Depression is considered to be a risk factor for the later development of Alzheimer’s disease (Green et al., 2003). Major depression with melancholic features includes sustained anxiety, dread for the future, and hyperarousal, which are proposed to be based not only on hyperactivity of the CRH system, but also on hyperactivity of the locus coeruleus-norepinephrine system (Gold and Chrousos, 2002; Wong et al., 2000). These two systems are also interconnected. Noradrenaline injection into the rat PVN causes an increase in CRH heteronuclear RNA (Itoi et al., 1999). In connection with the strong noradrenergic innervation of the PVN and other hypothalamic structures, it is of great interest that a number of observations suggested the presence of a relationship between the degree of the loss of neurons in the locus coeruleus and the occurrence of depression, in Alzheimer patients. In demented patients with major depression significantly more degenerative neurons in the locus coeruleus are reported than in nondepressed demented patients, although this finding has not been substantiated by morphometry (Zubenko and Moossy, 1988). Patients with Alzheimer’s disease are reported to have fewer neurons at the middle and rostral level of the locus coeruleus than nondepressed Alzheimer patients according to Zweig et al. (1988). Förstl et al. (1992) have also reported lower neuronal counts in the locus coeruleus of depressed Alzheimer patients compared with nondepressed subjects. Zubenko et al. (1990) have subsequently reported a 10- to 20-fold reduction of noradrenaline in the cortex of demented patients with major depression compared with demented patients who were not depressed. However, recent studies by our group in which we placed special emphasis on longitudinal psychiatric evaluation of the symptoms, matching for the clinical symptoms of dementia severity, matching for neurological comorbidity and for the severity of cortical Alzheimer pathology, and using image-analysis assisted morphometry, could not confirm these results. The mean number of neurons in the locus coeruleus was higher in controls than in depressed and nondepressed Alzheimer patients, while between the two latter groups no significant differences were found. Also the noradrenaline levels in the cortex 255

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of depressed dementia patients did not differ from those of nondepressed Alzheimer patients (Hoogendijk et al., 1999a, b). The discrepancy with the previous papers is probably partly based upon the debatable way degeneration was defined: by combining scores and using one-tailed testing (Zubenko and Moossy, 1988), but the major problem seems to be the insufficient matching of the degree of dementia in the other papers (Hoogendijk et al., 1999a, b). In suicide victims 38% fewer pigmented locus coeruleus neurons have been reported. The reduction is localized in the rostral two-thirds of the locus coeruleus. It is, however, not established whether the loss of noradrenergic neurons is indeed associated with an underlying major depression (Arango et al., 1996). Two other studies have examined the number of locus coeruleus neurons in suicide victims. Biegon and Fieldust (1992) have reported reduced intensity of tyrosine hydroxylase immunoreactivity but no difference in the number of immunoreactive cells in suicide victims. Ordway et al. (1994) have found an increase in the concentration of tyrosine hydroxylase and no difference in the number of pigmented neurons. However, the neuron counting was only performed on two or three sections of the locus coeruleus per case, not taking into consideration the rostrocaudal differences in this nucleus. Thus, so far, a consistent change does not seem to be present in the locus coeruleus of depressed patients. Opioid peptides are known to exert an inhibitory influence on the HPA axis in humans. The increased HPA axis activity in depression is associated with a reduced opioid tone as shown from a reduced cortisol and ACTH response to naloxone in depressed patients. A reduced endogenous opioid tone may explain why some depressed patients self-medicate with opiates (Burnett et al., 1999). The opiate systems in the postmortem human brain have, however, not yet been studied in connection with depression. Cannabis can induce mood changes (Tsai et al., 2001). Moreover, leptin levels (see Chapters 11d and 23b) are low in depressed patients, while the body mass index is normal. This alteration may be related to the changes in appetite, food intake and weight, that are frequently observed in depression (Kraus et al., 2001). Interleukin-2 and interferon- therapy in hepatitis C or cancer patients is frequently associated with depressive symptoms (Capuron et al., 2000; Wichers and Maes, 2002). Major depression is accompanied by an acutephase response including increased plasma interleukin-1 levels (Owen et al., 2001). The mechanism whereby inter-

leukin may induce depression remains elusive at present. In addition, alterations in melatonin secretion patterns have been reported in depression (Pacchierotti et al., 2001). Lower nocturnal bilirubin levels were found in patients with winter seasonal depression. Circulating bilirubin is thought to serve as a photoreceptor (Oren et al., 2002a). For the controversial relationship between a reduced hippocampal volume (Bremner et al., 2000) in depressed patients and activation of the HPA axis, see Chapter 8.5b, e. In children with gelastic seizures (Chapter 26.2) and hypothalamic hamartoma (Chapter 19.3) a high proportion of mood disorders are found (Weissenberger et al., 2001). (d) CRH neurons and the symptoms of depression (Fig. 26.6) Both major depressed patients and patients with bipolar depression show a much stronger CRH neuron activation than aged controls or Alzheimer’s disease patients, as shown by the fourfold increase in total number of cells expressing CRH (Fig. 26.3), the increased total number of CRH neurons showing vasopressin colocalization and the increased amount of CRH mRNA in the PVN (Raadsheer et al., 1994c, 1995; Fig. 26.2). The observation that the number of non-vasopressin-coexpressing CRH neurons increases more in major and bipolar depression than the number of vasopressin-coexpressing CRH neurons (Raadsheer et al., 1994c) seems to indicate that different subtypes of CRH neurons are present in humans and that these are activated differentially in depressed patients (Raadsheer et al., 1995). This view is supported by the different alteration found in multiple sclerosis (Chapter 21.2c) and the finding of two subtypes of CRH neurons in the PVN of experimental animals (Whitnall et al., 1993). One type colocalizes vasopressin and projects to the rat median eminence, whereas the other type does not coproduce vasopressin and projects to the brainstem and spinal cord (Sawchenko and Swanson, 1982). Although in the rat the proportion of nonneuroendocrine neurons represent only a minor subpopulation of the CRH neurons in the PVN (Swanson et al., 1983; Mezey et al., 1984), our data indicate that, if the same principle goes for humans, this proportion may be considerably larger in our species. However, this principle still has to be confirmed for the human brain. At present there are various additional arguments for the increased HPA axis activity in depression. Increased

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plasma and salivary cortisol and cortisone levels, increased urinary free cortisol excretion and disturbed dexamethasone suppression, decreased corticosteroid receptor function, enhanced adrenal response to ACTH, blunted pituitary ACTH response to CRH, and adrenal and pituitary enlargement in depression also indicate HPA axis hyperactivity in this disorder (Krishnan et al., 1991a; O’Brien et al., 1996; Rubin et al., 1996; Modell et al., 1997; Maes et al., 1998; Holsboer, 2000; Weber et al., 2000a). The smaller pituitary volumes found in one study in patients with bipolar disorder (Sassi et al., 2001) and the urinary hyposecretion of cortisol in a small group of elderly depressed patients (Oldehinkel et al., 2001) are difficult to explain. The combined dexamethasone/ CRH test does not only identify, with high sensitivity, a dysfunction of the HPA axis in depression, the elevated cortisol response in the test is also correlated with a four- to six-fold higher risk for relapse than in individuals who had a depression but subsequently showed a normal cortisol response (Zobel et al., 2001). It is of particular interest that the adrenal weight increase in suicide victims is accounted for specifically by increases in the weight of the left adrenal gland (Szigethy et al., 1994). The unilateral activation is consistent with the proposed functional importance of adrenal innervation for regulation of the sensitivity for ACTH of these glands in rat (Buijs et al., 1999). It should be noted, though, that there is individual variability in the degree of HPA axis activation (see also Fig. 26.2). The increased basal plasma cortisol levels are present only in some 25% of the subjects with major depression, while 66% show nonsuppression of cortisol to dexamethasone (Young et al., 2001). In a recent study, Brunner et al. (2002) did not find any indication for an activation of the HPA axis in depressed patients, including suicide attempters, on the basis of the dexamethasone/CRH test, or of plasma cortisol levels. Indeed, most patients with major depression are not hypercortisolemic when studied crosssectionally; however, this does not rule out clinically significant periods of excessive exposure to glucocorticoids. Urinary free cortisol excretion may be elevated for 21 days out of a month in depressed patients, compared with 4–5 days per month in control subjects. Moreover, plasma cortisol levels fluctuate strongly over the day and are elevated and normal at different times of the day in depressed patients (Gold et al., 2002). Moreover, the HPA axis is not overtly abnormal in chronic depression, not even when tested with a sensitive dexamethasone/CRH test (Watson et al., 2002). Subjects with psychotic major

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depression have higher cortisol levels throughout the afternoon than subjects with nonpsychotic major depression, which may also contribute to the variability in cortisol level (Belanoff et al., 2001). In younger depressives adrenal steroid abnormalities are also apparent when the developmentally sensitive steroid DHEA that is a precursor for testosterone and estrogens is determined (Goodyer et al., 1996, 1998). Scott et al. (1999a) have found lower dehydroepiandrosterone sulfate (DHEAS) but no DHEA plasma levels in depressive patients. Elevated baseline cortisol levels are related not only to mood disorders, but also to cognitive impairment in depressed patients (Van London et al., 1998a). In some studies CRH levels in CSF are reported to be higher in major depression than in mania, anxiety or controls (Banki et al., 1992; Mitchell et al., 1998; Wong et al., 2000). There is certainly the possibility that the increased CSF CRH levels reported are due to the stress of the anticipation of the lumbar puncture or the puncture itself (Geracioti et al., 1992). When lumbar CSF is continuously sampled, thus avoiding a stress response, CSF CRH levels are found to be strikingly reduced in depressed patients (Geracioti et al., 1992). In postmortem cisternal CSF, elevated CRH levels have been measured in suicide victims that have an underlying depression (Arató et al., 1989). However, Brunner et al. (2002) did not find a difference in lumbar CSF CRH levels in drug-free, depressed suicide attemptees compared with nonattemptees in this study, and could thus not confirm the earlier observation of increased CSF CRH levels in suicide victims by Arató et al. (1989). Although there is a close association between CSF CRH levels and alterations in the HPA axis in depression (Newport et al., 2003), one may wonder what proportion of CSF CRH comes from the PVN. CRH is produced not only in the PVN, but also in extrahypothalamic areas and in the spinal cord. CRH levels in extra-hypothalamic sites may return to near normal during remission (Mitchell, 1998), indicating their role as a state marker. CSF CRH may, at least for the most part, represent fluctuations in extrahypothalamic CRH such as from the neocortex, limbic and brainstem regions rather than in hypothalamic CRH (Gottfries et al., 1995; Mitchell, 1998; Arborelius et al., 1999; Vythilingham et al., 2000; Galard et al., 2002). The locus coeruleus of depressed subjects contains elevated CRH concentrations. This brain area receives CRH input from the central nucleus of the amygdala and from pontine-medullary projections (Bissette et al., 2003). The observation that CSF CRH levels are increased in anxiety 257

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and depression, even though in anxiety there is supersuppression of cortisol following dexamethasone and there is nonsuppression in depression (Boyer, 2000), pleads for the idea that CSF CRH levels do not necessarily reflect HPA axis activity. Another observation supporting the idea that CRH in CSF is derived from other sources than the HPA axis is that, in spite of the fact that in posttraumatic stress disorder the HPA axis is strongly suppressed (Yehuda et al., 1995a, b), CRH levels in CSF are increased (Bremmer et al., 1997; Kasckow et al., 2001b). Finally, although the HPA axis is activated in Alzheimer’s disease (Chapter 8.5b; Fig. 26.2), some authors have reported decreased CRH levels in the CSF (Geracioti et al., 1992; Gottfries et al., 1995), although others did not confirm this (Martignoni et al., 1990; Banki et al., 1992; Nemeroff, 1996; Valenti, 1996). Concluding, alterations in HPA axis activity do not seem to be directly reflected by CSF CRH levels. There is also uncertainty about the source of plasma CRH, which is increased in depression (Catalán et al., 1998). However, the observation that plasma CRH levels increase in depression and decrease following dexamethasone suppression (Galard et al., 2002) make this measurement a promising tool that should be studied further. An important argument for the crucial role of CRH is that symptoms resembling depression, e.g. decreased food intake, decreased sexual activity, disturbed sleep and motor behavior and increased anxiety, can be induced in experimental animals by intracerebroventricular injection of CRH (Holsboer et al., 1992). In addition, antidepressant drugs attenuate the synthesis of CRH, possibly by stimulation of corticosteroid receptor expression (Fischer et al., 1990; Brady et al., 1991, 1992; Delbende et al., 1991; Reul et al., 1993; Nemeroff, 1996; Reus, 1997). Moreover, the CRH concentrations in CSF in healthy volunteers (Veith et al., 1993) and the CRH levels in CSF of depressed patients (De Bellis et al., 1993; Heuser et al., 1998) decrease due to antidepressant drugs; although, as has been argued before, CSF CRH is probably not, or only partly, derived from the hypothalamus but mainly from other sources, such as the cortex (Vythilingam et al., 2000; see also before). Lastly, a transgenic mouse model with an overproduction of CRH appeared to have increased anxiogenic behavior. i.e. symptoms that are usually related to major depression, which could be counteracted by injection of CRH antagonist (Stenzel-Poore et al., 1994). CRH-receptor antagonists are also suggested to be useful for the treat-

ment of melancholic depression (Grammatopoulos and Chrousos, 2002). A mouse with a genetic deletion of the CRH1 receptor has reduced anxiety-like behavior (Contarino et al., 1999). An interesting new compound in depression research is urocortin, a CRH-related peptide (Chapter 8.5) also has anxiogenic-like properties in animal experiments (Behan et al., 1997; Moreau et al., 1997) and the presence of CRH-binding protein in the brain that also binds urocortin (Behan et al., 1997). The sum of the arguments mentioned above leads to the CRH hypothesis of depression (Fig. 26.6), i.e. that the hyperactivity of a subgroup of CRH neurons that does not project to the median eminence but into the brain may be activated in depression and induce the symptoms of this disorder. The recent development of selective, smallmolecule CRH1 receptor antagonists, which block the effects of CRH both in vitro and in vivo, suggest that these compounds may be effective in the treatment of mood and anxiety disorders (O’Brien et al., 2001b). In an open trial, one of these compounds (R121919) led to a 50% reduction in depressive symptoms, comparable with that obtained with a selective 5-HT reuptake inhibitor (Keck and Holsboer, 2001). There are, however, also observations that may call this concept into question and point rather to the importance of glucocorticoids (Fig. 26.6). A few studies have reported that glucocorticoid antagonists may be effective in the treatment of major depression (Murphy, 1997; Wolkowitz et al., 1999). Inhibitors of cortisol production such as metyrapone, aminoglutethamide or ketoconazole, when administered to major depressed patients, may result in clinical success, which was not to be expected if not cortisol but CRH would indeed cause the symptoms (Reus, 1977; Fava, 1994; Murphy, 1997). The antiglucocorticoids DHEA and DHEAS are also studied for their positive antidepressant and cognition-enhancing effects in mood disorders (Reus et al., 1997; Wolkowitz et al., 1997). The antiglucocorticoid mifepristone is effective in treating psychotic depression, producing clinically relevant responses in some patients in a few days (Gold et al., 2002). The effectiveness of these new compounds may depend on the type of depression that is being treated (also see below). In addition, such compounds induce so many unspecific effects, also at the central level, that the interpretation allowed by some of these experiments is limited (Holsboer and Barden, 1996). On the other hand, the observation that a significant improvement in mood is observed in patients with treatment-resistant depression who receive dexamethasone in addition to their antidepressant treatment

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appears to be in favor of hyperactive CRH neurons playing a causal role in the symptomatology of depression (Dinan et al., 1997). The finding that acute hydrocortisone infusion is associated with rapid and robust reduction in depressive symptoms (De Battista et al., 2000) reinforces this conclusion. The increased drive of the HPA axis in depressed patients could be mediated either by CRH, by vasopressin or by both. Indeed, both CRH receptor antagonists and cortisol synthesis inhibitors or corticosteroid receptor antagonists may be effective in depressed patients (Holsboer, 2000; Gold et al., 2002). Whether disinhibition of sexual behavior is a side effect of CRH antagonists in depressed patients as observed in Syrian hamsters following intracerebroventricular administration (Jones et al., 2002) is not yet known. Gold et al. (1995) and Gold and Chrousos (2002) propose that the classic form of major depression, i.e. “melancholic depression”, that goes with decreased food intake, insomnia, lack of affective responses to external events and a general state of pathological hyperarousal, is due to hyperactivity of CRH neurons. Hypercortisolemia is consistently observed in melancholy. The adrenal is hyperresponsive to ACTH and hypertrophic, while the pituitary cells are appropriately responsive to glucocorticoids. In contrast, “atypical depression” – a state of hyperphagia, hypersomnia, enhanced affected responsiveness to external stimuli, lethargy and fatigue would be based upon increased levels of corticosteroids and decreased levels of CRH (Gold et al., 1995). In this context it is of interest that women not only are more at risk than men for major depression (Chapter 1, Table 1), but also have a significantly higher glucocorticoid and mineralocorticoid receptor mRNA expression than men in the temporal lobe and prefrontal cortex (Watzka et al., 2000). In addition, a well-known side effect of glucocorticoids is depression. A third of the patients receiving glucocorticoids experience significant mood disturbances and sleep disruption. Up to 20% report psychiatric disorders, including depression, mania and psychosis (Mitchell and O’Keane, 1998). Moreover, atypical depression is found in a large proportion of patients with Cushing’s disease. Patients with long-term Cushing’s syndrome are especially at risk for such psychopathology (Dorn et al., 1995; Gold et al., 1995). The fact that atypical depression is so often seen in Cushing’s syndrome indicates that in these patients cortisol causes this type of depression rather than ACTH or CRH. This conclusion is supported by a small study that shows that depression can be treated by ketoconazole,

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an antiglucocorticoid (Wolkowitz et al., 1999) and by the observation that metyrapone successfully treats depression in Cushing patients (Checkley, 1996). However, it should be noted that, also after correction of hypercortisolism in Cushing’s syndrome, atypical depression frequently continues to be present. Suicidal ideation and panic may increase (Dorn et al., 1997a). The pituitary shows a profoundly exaggerated plasma ACTH response to CRH in Cushing’s disease, despite pronounced hypercortisolism. This indicates that the pituitary is grossly unresponsive to glucocorticoid negative feedback. A relationship has also been found between hypercortisolism and violent suicidal behavior. Both in patients who have recently attempted suicide and in those with a history of suicidal behavior increased urinary cortisol excretion and a decreased noradrenergic function is observed (Van Heeringen et al., 2000). Also patients with winter depression and chronic fatigue syndrome meet all the criteria for an atypical depression. In these patients hypofunctional CRH neurons are postulated (Joseph-Vanderpool et al., 1991; Gold et al., 1995; Chapter 26.6), but so far the hypothalamus of these patients has not been investigated. In multiple sclerosis (MS), a disease with an increased incidence of depression, the blunted plasma ACTH response to vasopressin reflects a relative shift from CRH to vasopressin modulation of pituitary adrenal function (Gold et al., 1995), which fits in with our finding of increased numbers of neurons colocalizing arginine vasopressin (AVP) and CRH in MS (Erkut et al., 1995; see Chapter 21.2c). The consistent presence of increased HPA axis activity in depression raises the question of the possible pathogenetic mechanisms underlying the activation of this axis. An imbalance in the ratio between mineralocorticoid and glucocorticoid receptors has been shown in depressed patients (Young et al., 2003), but it is not clear whether this is cause or effect. Impaired negative feedback control of the HPA axis and adrenal hypertrophy are frequent signs of a subgroup of depressed patients (Checkley, 1996; Modell et al., 1997). It coincides with episodes of depression and, at least partially, reverses after recovery from psychopathology. Some observations suggest that the impaired negative feedback effect of corticosteroids on the HPA axis in a number of healthy probants at risk for affective disorder is caused by a disturbed corticosteroid receptor function, indicating a genetically transmitted risk factor (Holsboer et al., 1995; Holsboer, 2000). Genetic variations (polymorphisms) of the glucocorticoid receptor are hypothesized to explain 259

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that only some 50% of the depressed patients show hypercortisolemia (Checkley, 1996; Holsboer, 2000). The expected mutations, deletions and other changes in the glucocorticoid receptor gene for the presence of glucocorticoid resistance have, however, not yet been found (Brönnegård et al., 1996; Holsboer, 2000). A developmental effect inducing altered feedback control of the HPA axis persisting in adulthood is an alternative possibility that may lead to acquired glucocorticoid receptor resistance in some areas (Brönnegård et al., 1996; De Kloet et al., 1997; De Bellis et al., 1999) and receptor hypersensitivity in other brain areas (Nemeroff, 1996). Several types of developmental sequela might be considered in this respect. Depression and anxiety have been found to be more frequent in the sons and daughters of women who had been treated with DES during pregnancy (Vessey et al., 1983; Brown et al., 1995b) and in children of mothers who were pregnant during the hunger winter in the Netherlands during the second world war (Susser et al., 1992, 1996). However, so far the HPA axis has not been investigated in these patients. In addition, psychological stress in development may have permanent activating effects on the HPA axis (see Chapter 26.4a). The observation that the adrenal corticosteroid DHEA improves depression ratings as well as memory performance in elderly depressed patients (Wolkowitz et al., 1997) has yet to be confirmed in double-blind trials. These observations seem to be at odds with the increased DHEAS plasma levels observed in depressed patients (Heuser et al., 1998). (e) Oxytocin and vasopressin neurons and the symptoms of depression As discussed previously, CRH and vasopressin are colocalized in an increased number of PVN neurons in depressed patients (Raadsheer et al., 1994c). We found not only an increased number of vasopressin-coexpressing CRH neurons in depression, but also an increase in the total number of vasopressin and oxytocin-expressing neurons in the PVN, of 56% and 23%, respectively, indicating an increased production of these peptides (Purba et al., 1996). In depressed patients the plasma vasopressin and cortisol levels correlate positively (Brunner et al., 2002). These observations thus confirm the postulate of Von Bardeleben and Holsboer (1989) that the action of CRH in depression is enhanced by vasopressin. In addition, depression is associated with an enhanced pituitary vasopressinergic responsivity (Dinan

et al., 1999). During chronic stress the upregulation of vasopressin released into the portal system may be critical for sustaining corticotroph responsiveness in the presence of high circulating glucocorticoid levels. V1b receptor mRNA levels and coupling of the receptor to phospholipase C are stimulated by glucocorticoids (Aguilera and Rabadan-Diehl, 2000). Indeed Van Londen et al. (1997) have reported increased plasma levels of vasopressin in depressed patients. The melancholic patients have higher plasma levels than the nonmelancholic patients. There appears to be a vague relationship between plasma vasopressin levels and psychomotor retardation and a significantly inverse relationship between these levels and neuroticism (Van London et al., 1997, 1998b). Interestingly, in melancholic patients, increased vasopressin levels in plasma correlates with a weak 24-h periodicity of body temperature (Van Londen et al., 2001). The oxytocin plasma levels of depressed patients only show a trend toward higher levels in this study. In another study Van Londen et al. (1998a) report that patients with higher vasopressin plasma levels perform better in a number of memory tests. Inder et al. (1997) have found that increased vasopressin levels are associated with suicide attempts. Adolescents who are at risk of making suicide attempts appear to display significant elevations of cortisol prior to sleep onset, a time when the HPA axis is normally most quiescent (Mathew et al., 2003). Patients displaying clearly increased activity of the HPA axis in midafternoon have elevated vasopressin levels, as do patients who attempt suicide. Since patients who recently attempted suicide also have increased urinary cortisol excretion (Van Heeringen et al., 2000), various data seem to support the possible synergistic effects of vasopressin and CRH, both on the level of the pituitary when released in the portal system and on a behavioral level when released centrally (Inder et al., 1997). Also, De Winter et al. (2003) have found that patients with anxious-retarded depression have a significantly elevated vasopressin level and a high correlation between vasopressin and cortisol levels. On the other hand, a recent study did not confirm the increased plasma levels in depression and suicide attempts (Brunner et al., 2002), making vasopressin levels as a marker for suicide of questionable value at this moment. The possibility that chronically elevated vasopressin levels may be involved in the induction of depressive symptomatology is supported by the case of a 47-year-old man with an esthesioneuroblastoma with paraneoplastic

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secretion of vasopressin that was associated with the onset of a first episode of major depression. The man displayed chronically elevated plasma vasopressin levels due to paraneoplastic vasopressin secretion by the tumor. Depressive symptoms improved markedly after surgical resection of the tumor and subsequent normalization of plasma vasopressin levels. However, surprisingly, the chronically elevated vasopressin levels also led to a marked desensitization of the HPA axis (Müller et al., 2000b). Heuser et al. (1998) have not observed a changed CSF vasopressin level in depressed patients, nor did they see a change in those levels due to antidepressant therapy. It is not clear how the lower CSF vasopressin levels reported earlier in depression (Gjerris et al., 1985) fit into these observations. The idea that activation of both the CRH and vasopressin neurons is related to the symptoms of depression is reinforced by the observation of De Bellis et al. (1993), who found a significant decrease in CSF levels, not only of CRH, but also of vasopressin levels, accompanied by a decrease in the Hamilton Depression Scale ratings following fluoxetine treatment. The therapeutic effects of this selective 5-HT reuptake inhibitor may thus be related to diminution of these two arousal-promoting neuropeptides. Animal experiments have indicated that not only vasopressin, but also oxytocin may potentiate the effects of CRH (Yates and Maran, 1974; Gillies and Lowry, 1979; Carlson et al., 1982; Gillies et al., 1982; Vale et al., 1983a; Muir and Pfister, 1988; Makara, 1992). However, in later experiments an inhibitory effect of oxytocin on ACTH release was established and later confirmed in various species (Legros, 2001). Oxytocin thus seems to act as an antistress hormone in human (Carter, 1998). In the rat, oxytocin neurons that coexpress CRH are present in the PVN (Sawchenko et al., 1984; Pretel and Piekut, 1990), but in the human PVN this coexistence has not been studied. Such a coexistence may be of particular importance, since in the rat stress increases oxytocin release in the hypothalamic PVN (Nishioka et al., 1998), and animal experiments have implicated oxytocin as a possible central mediator of CRH-induced anorexias (Olson et al., 1991a, b). Even though Van Londen et al. (1997) have found only a trend toward higher peripheral plasma levels in these patients, our finding that oxytocin neurons in the PVN of depressed patients seem to be activated may be of relevance for its central effects (Purba et al., 1996), since the oxytocin cells of the PVN are putative satiety neurons of the brain

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(Swaab et al., 1995a; cf. section 8.3), Centrally acting, increased vasopressin and oxytocin cell activity might thus contribute to mood changes, suicide, decreased food intake and cognitive alterations. However, as a possible confounder in the studies on changes in oxytocin in depression, one should keep in mind that selective 5-HT reuptake inhibitors produce increased oxytocin plasma levels (Uvnäs-Moberg et al., 1999). (f) Biological rhythms in mood disorders Rhythm and Blues. Healy, 1987.

The theory that chronobiological mechanisms play a role in the pathogenetic mechanism of depression is based on the classic diurnal variation of depressive state, early morning awakening and seasonal modulation of onset. In addition, this theory is supported by the antidepressant and occasionally mania-inducing effects of manipulations of the sleep–wake cycle and exposure to light. Several other observations point to a relationship between sleep disturbances and depression. Delayed sleep phase syndrome, a disorder that reflects probably an abnormality in the entrainment of the sleep–wake cycle is often associated with major depression (Regestein and Monk, 1995). Some authors therefore even seek the primary cause of depression in an abnormal functioning of the circadian pacemaker (Van den Hoofdakker, 1994). Interestingly, one of the characteristics of jet lag is exhaustion with mild depression, pointing again to a strong link between affecting disorders and circadian rhythms (Katz et al., 2001). The finding that melatonin may improve not only sleep, but also mood (De Vries and Peeters, 1997; JeanLouis et al., 1998; Lewy et al., 1998a; Bellipanni et al., 2001) supports the idea of involvement of the circadian system. In a normal population, strong seasonal effects in mood are observed. Depression scores are highest in winter and lowest in summer. Hostility, anger, irritability and anxiety also show strong seasonal effects. Seasonal fluctuations in depression scores differ for males and females (Harmatz et al., 2000). In Norway, admission for depression has a significant monthly variation, with the highest peak in November for men and in April for women (Morken et al., 2002). The sex differences in such rhythms may be related to the sex differences in sex hormone receptors in the SCN (Fernández-Guasti et al., 2000; Kruijver and Swaab, 2002). However, higher rates of 261

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onset of major depression in spring or fall, higher rates of depressive symptoms or rates of atypical depression, or higher rates of suicidal ideation in spring were not observed in an outpatient psychiatric practice in the USA (Posternak and Zimmerman, 2002). The mixed support for seasonal changes in depression (and also in suicidal symptoms) may be due, at least partly, to the months of birth, as a confounding factor, as shown by a study of participants currently living in Australia, some of whom were born in the northern hemisphere. Those born in September–November in the southern hemisphere showed the highest suicidal and depressive symptoms than those born in the northern hemisphere in March– May. Season of birth may thus be a risk factor for depressive and suicidal symptoms (Joiner et al., 2002). The classic melancholic symptom of diurnal variation of mood is not specific for endogenous depression, but is also found, for example, in reactive depression or SAD. However, the type of diurnal variation (i.e. morning low, evening low, indifferent pattern) can change from day to day in a given patient. Sleep can vary with mood state. Decreased sleep duration predicts that the next morning’s mood will be manic or hypomanic in patients with rapidcycling bipolar disorder (Leibenluft et al., 1996). Diurnal variations are also present in suicide occurrence. Apart from biological factors, sociorelational factors are presumed to contribute to the diurnal suicide risk by age and gender (Preti and Miotto, 2001). A fairly constant finding that demonstrates a disturbance of circadian rhythms in depression is a decrease in circadian amplitude of body temperature, plasma cortisol, plasma corticosterone, noradrenaline, thyrotropin (TSH) and melatonin (Souêtre et al., 1989; Van den Hoofdakker, 1994; Weber et al., 2000a; Pacchierotti et al., 2001; Van Londen et al., 2001). Changes of the circadian timing system are agedependent. Evening cortisol dysregulation has been found more frequently in child and adolescent major depression patients who exhibit suicidal behavior and sleep dysregulation (Pfeffer et al., 1989; Dahl et al., 1991). Increased vasopressin plasma levels in depressed patients are correlated with a weak 24-h periodicity of body temperature (Van Londen et al., 2001). Comparison of multiple circadian rhythms during depression and after recovery have suggested that a blunted amplitude is the main chronobiological abnormality (Wirz-Justice, 1995). This may be due to the increased cortisol levels, which inhibit SCN function (Liu et al., 2003, submitted; Figs. 26.4–26.7). Depressed patients display sleep disturbances (Rieman et al., 1994) and a less rhythmic, more chaotic

pattern of cortisol release (Madjirova et al., 1995; Yehuda et al., 1996). Not only are the ACTH and cortisol levels found to be higher in depressed patients, but also the frequency of pulses of these hormones is higher during the evening. It has been hypothesized that these changes are due to circadian alterations, possibly caused by changes in mineralocorticoid receptor capacity and function (Deuschle et al., 1997a, b). Altered diurnal rhythms in salivary cortisol and DHEA have also been observed in 8- to 16-year olds with major depression (Goodyer et al., 1996). Cortisol secretion patterns were found to be normal in adolescents with major depression, with the exception of elevated cortisol levels around sleep onset (Dahl et al., 1991). Significant seasonal and circadian rhythms have, moreover, been described in the occurrence of (violent) suicide. It is presumed that the yearly rhythms in ambient temperature or light, and the light/dark cycle can serve as Zeitgeber for the endogenous rhythms (Maes et al., 1993a, c; Altamura et al., 1999). Interestingly, subjects that have strong seasonal fluctuations in mood also have stronger weekly mood cycles (Reid et al., 2000), indicating a possible function of the SCN in such rhythms, too. Some forms of affective illness have a pattern of periodic recurrence, linked to, e.g. hormonal cycles, characteristic sleep disturbances or diurnal or circannual mood fluctuations. The prevalence rate for seasonal affective disorder (SAD) is some 10% of the depressed patients, with higher rates for the more northerly countries and lower rates for the southerly ones (Wicki et al., 1992). Two types of seasonal mood changes have been described in temperate zones, i.e. (1) depression regularly occurring in fall and winter, and (2) depressive episodes in the summer (Neumeister et al., 1997). In the tropics a different pattern of seasonal mood changes is observed, with a high prevalence of summer SAD and a low prevalence of winter SAD. Almost half of the tropical population feels ‘worse’ in summer, probably in response to temperature but not duration of daylight (Sriseerapanont and Intraprosert, 1999). On the mainland of China, several variations in mood are common. Also in this country, summer difficulties are more common than winter difficulties, according to a survey of Chinese medical students (Han et al., 2000). In various countries, seasonal fluctuations in suicide rates have been described (Maes et al., 1993a, c; Castrogiovanni et al., 1998; Altamura et al., 1999), but in England and Wales this pattern seems to have diminished or even vanished, presumably because of changes in lifestyle (Yip et al.,

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Fig. 26.7. The number of arginine vasopressin-immunoreactive (AVP-IR) neurons (A) and the mask area of silver grains of the AVP mRNA (B) in the suprachiasmatic nucleus (SCN) in control subjects (n = 11) and depressed subjects (n = 11). The error bars indicate the SD. Note the change in the balance between the presence of more AVP and less AVP mRNA in depression. There is probably a disorder of the transport of AVP that leads to accumulation of the peptide, in spite of the decreased production rate. (From Zhou et al., 2001, Fig. 2, with permission.)

occurred more frequently after eastbound flights (WirzJustice, 1995), also suggests a relationship between circadian phase changes and mood changes. One may presume that a basis for such changes might be found in the effect of corticosteroids on circadian timing (Madjivora et al., 1995). We have indeed observed an inhibitory effect of corticosteroids on vasopressin mRNA in the SCN (Liu et al., 2003, offered; Figs. 26.4–26.6). The sensitivity of the biological clock to the phaseshifting action of light is the same in depressive patients and controls. In contrast to sleep deprivation, moderate shifts of circadian rhythm do not act as mood-changing stimuli. This does not argue for an important role of circadian phase disturbances underlying depressive mood (Gordijn et al., 1998). In addition, in a 120-h forced desynchrony protocol, no significant differences are observed between SAD patients and controls in the period length or in the timing of the endogenous circadian temperature minimum. This study supports neither the proposed disorder of the pacemaker in SAD nor the psychological or physiological variables investigated (Koorengevel et al., 2003). Alternatively it has been proposed that the mood disturbances should be seen as resulting from changes in the phasing of external

2000). An important distinction in this respect is that seasonality is found to be present in violent but not in nonviolent suicides. The violent suicides peak in spring and summer, whereas the lows occur in winter (Maes et al., 1993b). Also, in southeastern Australia, a clear seasonal pattern is found that is positively linked with prevailing levels of sunlight. The incidence of suicide has a zenith in the spring and summer, and a nadir in winter (Lambert et al., 2003). There is also seasonal variation in manic episodes in bipolar disorder. The frequency of such episodes peaks in early spring, with a nadir in late fall. Mixed manic admissions peak in late summer and have a nadir in November (Cassidy and Carroll, 2002). Various mechanisms are proposed to be the basis of SADs. Whether periodically recurring depressions are indeed based upon primary disturbances in the SCN (see Chapter 4) is unresolved (for a review, see Wirz-Justice, 1995). For the pathophysiology of SAD, disturbances in SCN function such as a phase delay, amplitude change and poor entrainment have been suggested (Oren et al., 1996; Teicher et al., 1997). The observation that incidence of hospitalization for depression is higher after westbound flights than after eastbound ones, whereas hypomania 263

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Zeitgebers rather than of an abnormality of the clock itself (Healy and Waterhouse, 1995). Wehr et al. (2001) have reported the presence of a signal of change of season in patients with SAD. In patients with SAD the duration of the nocturnal period of active melatonin secretion is longer in winter than in summer, but in healthy volunteers there is no change. The data shows that patients with SAD generate a biological signal of change of season that is absent in healthy volunteers and that is similar to the signal that mammals use to regulate seasonal changes in their behavior. An interesting observation is that the serotonin metabolites in the jugular vein are lowest in winter, and that the turnover of serotonin in the brain rises with increased luminosity (Lambert et al., 2002), suggesting that the SCN may act via the serotonergic system on seasonal mood changes. The observation, in Japan, that suicide rates are affected by latitude, i.e. that total yearly sunshine is related to suicide rate (Terao et al., 2002), may be based upon a similar mechanism. There are at present 3 lines of research that support the role of genetic factors in the etiology of SAD: (i) familiality: there is a tendency for seasonal changes in mood and behavior to run in families; especially seasonality of the winter type shows such a predisposition (Madden et al., 1996); (ii) heriditability, based upon twin studies that indicate that genetic factors explain about 29% of the variance in seasonality; and (iii) molecular genetics, showing that a 5-HT transporter promoter polymorphism is associated with SAD and with higher levels of seasonality (Sher et al., 1999). Neither the latter nor other 5-HT-related systems appear, however, in a later study to play a major role in the pathogenesis of seasonal affective disorder (Johansson et al., 2001). A recent paper indicates, however, the importance of a polymorphism in the clock gene NPAS2 for the occurrence of SAD (Johansson et al., 2003). Although a major hypothesis is that SAD is triggered by photoperiod variation, recent observations indicate that the influence of latitude on the prevalence of SAD is small, and that other factors such as climate, genetic vulnerability and sociocultural context can be expected to play a more important role (Mersch et al., 1999). There is probably no seasonal variation in the occurrence of bipolar disorder (Partonen and Lönnqvist, 1996). Recent observations from our group suggest that in major depressed patients normal diurnal rhythm in the number of vasopressin neurons in the SCN has disappeared (Fig. 26.8), the number of neurons expressing

vasopressin has increased and the amount of vasopressin mRNA has decreased (Fig. 26.7). This indicates a decreased synthetic and transport activity of the vasopressin neurons of the SCN (Zhou et al., 2001). Since vasopressin neurons from the rat SCN were shown to inhibit CRH neurons in the PVN (Kalsbeek et al., 1992; Gomez et al., 1997), the observed disorder of this class of SCN neurons in depression may contribute to the increased activity of CRH neurons in depression (see above). The number of neurons staining in the SCN for nitric oxide synthesis or neurophysin are also decreased in depressed patients (Bernstein et al., 2002a), indicating impairment of the SCN in this disorder. In addition we observed a decreased nuclear size of vasoactive intestinal polypeptide (VIP) neurons in the SCN of depressed patients, indicating a changed metabolism in the neurons that are primarily involved in entrainment (J.N. Zhou, unpubl. results). The old observations that CSF VIP levels are decreased in depression (Gjerris et al., 1984) fit in with the idea that the SCN is less active in this disorder, although certainly not all VIP in the CSF will come from the SCN. Also pineal gland function is changed in depressed children and adolescents according to some studies, but this point is at present controversial (see Chapter 4.5e). Several studies have shown that evening/nocturnal levels of melatonin are decreased in depression, SAD and unipolar depression (Fountoulakis et al., 2001; Pacchierotti et al., 2001). Abnormalities in melatonin secretion have been found in a subgroup of euthymic bipolar and unipolar patients (Nurnberger et al., 2000), and in postmenopausal women with a family history of depression (Tuunainen et al., 2002). However, some studies show an increase in melatonin levels (Shafii et al., 1996) or excretion (Kripke et al., 2003). After lights-out the melatonin blood levels rise more in depressed patients than in controls. Moreover, the rise was stronger in depressed patients with psychosis (Brown, 1996). In addition, higher melatonin levels have been reported to occur during the manic phase in patients with a bipolar depression (Penev and Zee, 1997). However, the majority of studies show a decrease in nocturnal serum or urine melatonin levels or a phase shift in the melatonin peak in depressed adults (Brown, 1996). This would fit with the observation that CRH increases in at least some depressed patients (see above) and inhibits melatonin levels (Kellner et al., 1997). A few other studies, however, show no difference in melatonin levels and rhythms (Penev and Zee, 1997; Voderholzer et al., 1997). Normal

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(g) Light therapy and the circadian system These studies “provide the best evidence to date that light is an effective antidepressant in SAD”. Dr. Wirtz-Justice said she hopes the studies will help overcome lingering scepticism by those physicians who regard light therapy as “not molecular enough, a bit too Californian-alternative, a bit too media-overexposed, merely a placebo response by mildly neurotic middle-aged women who don’t like nasty drugs.” Light therapy, she notes, is an outpatient treatment, lacks major adverse effects, and is cost-effective. “Whatever its mode of action,” she asserts, “it demands inclusion in the antidepressant armamentarium, now”. Anna Wirtz-Justice. Arch Ge. Psychiatry, October 1998, Commentary

A state-dependent disorder of circadian rhythmicity characterizes acute episodes of major depression, as appears, e.g. from hormone measurements and sleep detection (Linkowski et al., 1987). A strong argument for a close relationship between the pathogenetic mechanism of depression and the circadian timing system is the effectiveness of light therapy in SAD (Wirz-Justice, 1995; Wileman et al., 2001), in pharmacological treatmentresistant, rapid cycling affective disorders (Kusumi et al. 1995) and in patients with nonseasonal affective disorders (Yamada et al., 1995; Prasko et al., 2002). According to some authors, the effect of bright-light therapy on winter depression takes at least 3 weeks before it becomes apparent (Eastman et al., 1998) but would already act after 1 week according to others (Prasko et al., 2002; W.J.G. Hoogendijk, personal communication). After treatment with light, a significantly greater improvement is reported in patients with seasonal depression than in patients with a nonseasonal pattern of depression. However, another study has reported similar effects of light treatment in seasonal and nonseasonal depression and the effects are faster than psychopharmacological treatment (Kripke, 1998). The latter finding has been confirmed by Prasko et al., 2002. Physical exercise is effective in alleviating depressive symptoms, but is much more effective when combined with bright light (Leppämäk et al., 2002). Depressed patients treated with morning bright light do not show significant differences from those treated with evening bright light in one study (Thalén et al., 1997), or between bright white light at 10,000 lx and dim-red light at 500 lx. For both groups of patients, symptoms reduced by more than 40% during the 4 weeks of the trial. In another study in patients with SAD, bright-light exposure immediately on awakening was found to be more effective (Lewy et al., 1998b).

Fig. 26.8. A. Number of vasopressin-immunoreactive (AVP-IR) neurons plotted against clock time at death of each individual (11 depressed subjects, and 11 control subjects). B. Area of masked silver grain plotted against clock time of death of each individual. The difference between depressed and control subjects is present at different points of the day and there is no overlap between the two groups when you take the clock time at death into account (From Zhou et al., 2001, Fig. 3, with permission.).

circadian profiles have been measured for cortisol, TSH and prolactin in patients with SADs (Oren et al., 1996; Lewy et al., 1998b), observations that should be extended in large, well-controlled studies. Administration of melatonin to depressed patients and to perimenopausal and menopausal women has reduced insomnia and improved mood (De Vries and Peeters, 1997; Bellipanni et al., 2001). In normal human controls, hypothalamus day–night fluctuations in 5-HT are present (Carlson et al., 1980a). It has so far not been elucidated whether these circadian changes are altered in depressed patients, and what the relationship to the changes in HPA axis activity may be. 265

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Terman et al. (2001) have found that the antidepressant effect of light therapy is potentiated by early morning administration, best done 8.5 h after melatonin onset or 2.5 h after the sleep midpoint. A positive total sleep deprivation response in major depressed patients can be predictive of beneficial outcome of subsequent light therapy (Fritzsche et al., 2001). An abnormal architecture of non-REM sleep seems to be a state marker of those patients who benefit from bright-light treatment (Palchikov et al., 1997). In addition, the occurrence of at least two consecutive, seasonally recurring major depressive periods has been found to predict improvement with light (Dittmann et al., 1994). A limitation of studies with light is the question of what the right placebo is. Red light, as used in various light-therapy studies (Prasko et al., 2002) might not be an ideal placebo (Wileman et al., 2001). Surprisingly, exposure to infrared light is as effective as exposure to bright white light, which questions the specific role of visible light in the treatment of SAD (Meesters et al., 1999). Dawn simulation with gradually increasing bedside light in the morning has also given promising results. Although the effects on mood are less marked than lightbox treatment, they are equally persistent (Lingjaerde et al., 1998). Another study has even reported that dawn stimulation is associated with greater remission and response rates compared with placebo and compared with bright-light therapy (Avery et al., 2001). All these observations reinforce the theory that chronobiological mechanisms play a role in the pathogenetic mechanism of depression. Moreover, a placebo-controlled study has shown that bright-light treatment decreases depression in institutionalized older people (Sumaya et al., 2001). Another study of healthy office employees during winter has shown that repeated bright-light exposure improves vitality and reduces depressive symptoms. The beneficial effect is observed not only in healthy subjects with season-dependent symptoms, but also in those not experiencing the seasonal variation (Partonen and Lönnqvist, 2000). Bright-light exposure during winter appears thus to be effective also when it comes to improving the health-related quality of life and alleviating distress in healthy subjects (Partonen and Lönnqvist, 2000). Extraocular light therapy in SAD patients does not exceed its placebo effect (Koorengevel et al., 2001). The mechanisms involved in bright-light treatment are still under investigation. Data from our group indicate a decreased synthesis and transport of vasopressin in the SCN of depressed patients (Zhou et al., 2001; Figs. 26.7

and 26.8). Since vasopressin neurons of the SCN inhibit CRH production in the PVN (Kalsbeek et al., 1992; Gomez et al., 1997), this may contribute to the activation of CRH neurons in depression. Light therapy may stimulate the SCN neurons and thus restore the inhibition of the CRH neurons (Fig. 26.6). Measurements of light exposure have shown that complaints of seasonal mood variations are not caused by a differential pattern in brightlight exposure compared with normal exposure. Whether an increased vulnerability of patients with SAD is due to a more fragile affective state or to a lower sensitivity to light remains to be determined (Guillemette et al., 1998). Light visions can effectively be used to prevent the development of SAD. Since rapid tryptophan depletion reverses the antidepressant effect of bright-light therapy in patients with SAD, the therapeutic effects of bright-light might involve a serotonergic mechanism (Lam et al., 1996b; Neumeister et al., 1997). Measurements of 5-HT metabolites in the jugular vein show that this is indeed the case. The production of 5-HT in the brain rises rapidly with increased luminosity (Lambert et al., 2002). Other data indicate that additional effects may also be involved (Fig. 26.6), such as responses of sleep-regulating, circadian, energy-regulating and sympathicoadrenal systems that may be responsible for at least part of the favorable therapeutic response to bright light (Putilov, 1998). Exposure to bright light during the early hours of darkness not only delays the nocturnal melatonin peak, but also decreases cortisol concentrations and changes in growth hormone, prolactin and nocturnal vasopressin secretion (Kostoglou-Athanassiou et al., 1998a). Light therapy also reduces the urinary output of norepinephrine and its metabolites in autumn/winter seasonal depression (Anderson et al., 1992b). Some authors do not consider light to be antidepressant per se, but rather a way to reverse the phase delay that occurs in the winter (Lewy and Sack, 1996). Circulating nocturnal bilirubin levels are lower in patients with winter seasonal depression. Since bilirubin may serve as a photoreceptor, this molecule, too, may be involved in the mechanism of light therapy (Oren et al., 2002a). A specific example of the importance of circannual rhythms in a disease process and the effectiveness of light is present in the symptoms of bulimia nervosa (see also Chapter 23.2; Fig. 23.12). Not only binge and purge behavior vary with the season, but also mood is worse in the winter period (Blouin et al., 1992). Bright-light treatment appears to be effective for both eating behavior and mood in this disorder (Lam et al., 1994). In addition,

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in a case report, bright-light therapy is reported to be comparable with or superior to treatment with previous medications for depression in a patient with schizoaffective disorder with recurring depressive episodes in winter (Oren et al., 2001). As with all effective therapies, light therapy may also have side effects, although these are rare. There may be risks for the eyes when light exposure lasts for an extended period of time (Remé et al., 1996), and mania and suicide have also been described as possible consequences of this therapy (Kripke, 1998; Meesters and Letsch, 1998). Short-term, 10,000-lx light therapy often produces mild side effects such as headaches or vision problems, but they are neither serious nor prolonged and generally do not interfere with the treatment (Kogan et al., 1998). There is increased risk in light damage to the lens and retina if depressed patients are treated with bright light concurrently with treatment with antidepressant or neuroleptic drugs. Certain drugs, such as iprindol and chlorpromazine, which have absorptions longer than 295 nm, can, moreover, act as photosensitizers, resulting in enhanced damage to the eye (Wang et al., 1992).

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people with sleep–wake disturbances (Jean-Louis et al., 1998) and significantly decreases depression ratings in a patient with insomnia (De Vries and Peeters, 1997) and in a small group of patients with winter depression (Lewy et al., 1998a), supporting the presence of a causal link between circadian rhythm and mood disorders. On the other hand, slow-release melatonin improves the sleep quality in major depressive disorder, but has no effect on the rate of improvement in symptoms of depression, although it is effective in improving sleep (Dolberg et al., 1998). Controlled-release melatonin also significantly improves the quality of sleep and vitality in subjects with subsyndromal seasonal affective disorder, but attenuates improvement in subjects with weather-associated changes in mood and behavior (Leppämäki et al., 2003). Although electroconvulsive therapy (ECT) causes a rise in plasma vasopressin, oxytocin, prolactin and neuropeptide FF levels, these surges are not associated with clinical improvements, seizure duration, time to orientation or memory test performance. This does not support the hypothesis that vasopressin or oxytocin surges contribute to the mechanism of action of ECT (Devanand et al., 1998; Sundblom et al., 1999). In fact, on the basis of our finding of increased vasopressin and oxytocin production in depression (Purba et al., 1996), one may even expect the reverse to be the case. A recently reported, effective nonpharmacological antidepressant therapy is high-density negative air ionization. The effective range, optimum dose and mechanism of action remains uncertain as of 2002 (Terman et al., 1998). Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex has also been found to be useful in the treatment of medication resistant depression (George et al., 1996, 2000; McCann et al., 1998; Davidson et al., 1999; Berman et al., 2000; Eschweiler et al., 2000), although some double-blind controlled stimulation studies have not found a difference between real and sham rTMS (Loo et al., 1999). A meta-analysis of controlled studies indicates, however, that the anti-depressant effects of rTMS are fairly robust from a statistical point of view. However, effect sizes are heterogenous and the durability of the effects is largely unknown (Burt et al., 2002). Interestingly, in in vivo experiments in rat, using microdialysis, rTMS of the frontal brain reduces the vasopressin release in the PVN area by up to 50% (Keck et al., 2000). In healthy subjects rTMS leads to a mild decrease in serum cortisol and TSH levels. These changes may explain at least part of the effect of rTMS (Evers et al., 2001). However, a combined dexamethasone–CRH test

For the rest of my life I will reflect on what light is. Albert Einstein, 1917.

(h) Other therapeutic interventions Antidepressant drugs may act on the HPA axis (Fig. 26.6), but they may also involve the circadian timing system. It has been suggested that antidepressant drugs may shift the circadian period, but the evidence is not consistent (Healy and Waterhouse, 1995). In addition, carbachol may mimic the effect of light (Healy and Waterhouse, 1995), and lithium seems to act on the SCN (Mason and Biello, 1992), which supports the possible involvement of this brain structure in depression. It has also been shown that lithium induces subsensitivity to light (Carney et al., 1988), reinforcing the idea that the mechanism of action is via the circadian system. Although it has been suggested that oxytocin release by selective serotonin reuptake inhibitors may be an important contributing factor for the clinical profile of such antidepressants (Uvnäs-Moberg et al., 1999), one might, on the one hand, expect an opposite effect on eating disorders on the basis of our findings of increased oxytocin activity in depression (Purba et al., 1996), but on the other hand, oxytocin indeed seems to act as an antistress hormone (Legros, 2001). Melatonin treatment improves mood in elderly 267

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after rTMS has shown a persistent HPA-system hyperactivity, and thus a high risk of relapse. This argues for immediate maintenance therapy in the patients responding to this treatment (Zwanzger et al., 2003). Following transcutaneous electrical nerve stimulation (TENS), Alzheimer patients and nondemented elderly persons feel less depressed (Scherder et al., 1995a, b, c, 2000). Vagus nerve stimulation has been delivered by the NeuroCybernetic Prothesis system to treatment-resistant depressed patients. The open trial results suggest that this new technique had antidepressant effects in these patients (Rush et al., 2000). Randomized controlled studies are now needed. A recent paper has reported that electrical stimulation of the subthalamic nucleus in Parkinson patients is antidepressive (Schneider et al., 2003). However, several other studies report depression and even suicide as side effects of this type of deep-brain stimulation (Chapter 15.1). Sleep disorders are common in depression. Interestingly, patients with abnormal sleep profiles have significantly poorer clinical outcomes with respect to symptom ratings, attrition rates and remission rates than the patients with normal sleep profiles (Thase et al., 1997). Sleep deprivation in depressed patients improves mood for 1 day, which clearly demonstrates that the interaction between sleep and mood is not an epiphenomenon but that changes in sleep pattern have pathogenic significance (Wirz-Justice, 1995). In addition, a positive total sleep deprivation response in major depressed patients may predict a beneficial outcome of subsequent light therapy (Fritzsche et al., 2001). Sleep deprivation is accompanied by a fall in testosterone levels and an increase in TSH levels. The latter change is significantly correlated to the clinical response (Baumgartner et al., 1990a, b). The curative effect of sleep deprivation is due to changes in the circadian rhythm (Madjirova et al., 1995). Also, in healthy young subjects, subjective mood is influenced by a complex and nonadditive interaction of circadian phase and duration of prior wakefulness. The nature of this interaction is such that moderate changes in the timing of the sleep–wake cycle may have profound effects on subsequent mood (Boivin et al., 1997). A similar relationship appears also from the observation that exogenous shifts in timing of the sleep–wake cycle in healthy subjects may induce dysphoric mood. Placebo effects are extremely important in the treatment of depression. It has been proposed that 50–75% of the efficacy of antidepressant medication represents the placebo effect. Changes in brain function as measured

by PET or quantitative EEG indicate that placebo effects partly overlap with the effects of an antidepressant medicine. For instance, an increased metabolism is observed in both treatments in the prefrontal cortex, and a decreased metabolism in the hypothalamus. However, differences between the reaction of the various brain areas are also observed (Leuchter et al., 2002; Mayberg et al., 2002). (i) The thyroid axis At present there are several lines of evidence that suggest that the hypothalamopituitary–thyroid (HPT) axis may play an important role in depression. First, early investigations have already shown a markedly depressed mood in a majority of patients with primary hypothyroidism and other thyroid diseases (Asher, 1949; Henley and Koehnle, 1997). The diffuse atrophy of the thyroid gland in anorexia nervosa is presumed to be involved in the depressive symptomatology in that disorder (Støving et al., 2001). In addition, in patients with hypothyroidism, partial substitution of triiodothyronine (T3) may improve mood and neuropsychological function (Buneviˇcius et al., 1999). Moreover, subtle changes in the HPT axis have been described in depressed patients. The most consistent observation in depression is a slightly elevated plasma concentration of thyroxine (T4) and decreased plasma TSH, with a blunted response to stimulation with thyrotropin-releasing hormone (TRH). Basal TSH and thyrotoxin levels correlate with the severity of the depression, but the hyperthyroxinemia is at present unexplained (Gold et al., 1981; Holsboer et al., 1986; Styra et al., 1991; Maes et al., 1993b; Jackson, 1998; Kirkegaard and Faber, 1998). However, others have reported that at least the large majority of depressive patients are euthyroid (Lingjaerde et al., 1995), or that there is no association between thyroid dysfunction and depression (Engum et al., 2002). Yet, in postmortem tissue of patients with unipolar major depression, we found a decreased amount of TRH mRNA in the PVN (Alkemade et al., 2003), which may be due to the higher levels of circulating corticosteroids. In addition to elevated CSF levels of TRH (which may reflect extrahypothalamic sources and was not confirmed in a later study; Roy et al., 1994), an abnormally high rate of thyroid peroxidase antibodies, a condition known as symptomless autoimmune thyroiditis, has been observed (Roy et al., 1994; Musselman and Nemeroff, 1996; Pop et al., 1998). A community-based study has

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pointed to thyroid peroxidase antibodies as a determinant of depression rather than biochemical thyroid dysfunction (Pop et al., 1998). Evidence of T-cell dysfunction in SAD patients supports the hypothesis that SAD may involve subtle autoimmune dysregulation (Raitiere, 1992). In pre-pubertal and early pubertal boys with major depression (in contrast to adult depressive patients; see below), lower T4 levels and lower T3 uptake were found (Dorn et al., 1997b). Especially in rapid cycling bipolar disorder, a high proportion of patients with thyroid hypofunction were reported (Cowdry et al., 1983; Bauer et al., 1990). Although other studies could not confirm the commonly cited relationship between subclinical hypothyroidism and rapid cycling bipolar illness (Post et al., 1997; Cole et al., 2002b), they have provided further evidence that patients with bipolar disorder are particularly sensitive to variation in thyroid hormone function within the normal range. Subjects with lower thyroid function have longer times to remission. In a group of patients with major depression or bipolar disorder, peripheral TSH levels are found to be inversely related to global and regional cerebral blood flow and cerebral glucose metabolism (Marangell et al., 1997a). It seems as if only a particular subgroup of depressed patients may have changes in the HPT axis. A low TSH response to TRH in the presence of normal serum thyroid hormone levels is observed in SAD (Coiro et al., 1994). This reflects a defect in the central regulation of the HPT axis that may, in some patients, be a trait marker (Loosen and Prange, 1982). A circannual pattern of both HPT function and mood are observed in antarctic conditions. These observations indicate that in winter depression a state of relative central nervous system hypothyroidism is present (Palinkas et al., 2001). In a recent study of 105 subjects with major depression, the low or blunted TSH response to TRH challenges was present, but it was not an impressive discriminator between depressed and control subjects (Sullivan et al., 1997). Daily fluctuations of T4 are the only variables significantly different between depressed and control subjects, and a significant relationship has been observed between this parameter and treatment outcome (Sullivan et al., 1997). In untreated depression the diurnal variation in serum TSH is attenuated (Kirkegaard and Faber, 1998). These data point again to the SCN as a crucial structure in depression and to a relationship between the SCN and the thyroid axis in the pathogenesis of depression. In connection with the possible involvement of the TRH neurons in depression, it should be noted that TRH

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is not only released into the portal capillaries to regulate the neuroendocrine HPT axis, but also TRH fibers project into the brain and terminate in many hypothalamic and extrahypothalamic areas, where TRH acts as a neurotransmitter or neuromodulator (Fliers et al., 1994; Chapter 8.6). Changes in the function of centrally projecting TRH fibers are not necessarily reflected in changes in the peripheral HPT axis. Intravenous TRH administration has an antidepressive action (for references see Jordan et al., 1992), although most controlled studies do not confirm these findings (Marangell et al., 1997b), which may be due to the short half-life of TRH and the effective blood–brain barrier for the peptide. However, a doubleblind crossover study has revealed rapid and clinically robust improvements in mood and suicidality of intrathecal TRH given to refractory depressed patients (Marangell et al., 1997b), confirming the antidepressant action of TRH, at least in a subgroup of patients. It has also been reported that T3 or T4 augments the efficacy of various antidepressants. T3 increases the rapidity of action of tricyclic antidepressant agents and is as effective as lithium in converting tricyclic nonresponders to responders (Stein and Avni, 1988; Aronson et al., 1996; Musselman and Nemeroff, 1996). Support for the efficacy of adjunctive T3 treatment has been found in a sample of 14 patients suffering from refractory depression (Birkenhäger et al., 1997). Thyroid hormones may potentiate antidepressant therapy in about onequarter to two-thirds of the treatment-resistant depressed patients (Joffe et al., 1995; Henley and Koehnle, 1997; Jackson, 1998). Patients with the lowest pretreatment evening TSH secretion also have the lowest rates of antidepressant response (Duval et al., 1996). How exactly the change in thyroid-axis function may contribute to treatment resistance in some depressed patients, which subgroup of depressed patients may respond to thyroid hormones, and what the mechanism behind the relationship to HPA axis changes is, should be further investigated. There is growing information to explain the HPT axis changes in depression and the possible beneficial effects of T3 medication. The active thyroid hormone in the brain is T3, which is derived locally from T4 due to the deiodination by type II 5deiodinase (DII) (Henley and Koehnle, 1997; Jackson, 1998; Kirkegaard and Faber, 1998). Endocrine observations suggest that CRH and TRH regulation are at least partly under joint control (Holsboer et al., 1986). Glucocorticoid excess suppresses TSH. The demonstration of glucocorticoid receptor expression by 269

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TRH cells in the rat PVN and the presence of a glucocorticoid response element in the TRH gene suggests that the inhibitory effect of glucocorticoids on TSH secretion involves downregulation of TRH cells in the PVN. This possibility is supported by studies in rats after adrenalectomy, showing increased CRH mRNA and TRH mRNA in the PVN. After dexamethasone treatment, both messengers are markedly reduced (see Jackson, 1998). By inference, hypercortisolism in depression may lead to suppression of the central component of the HPT axis, explaining the low plasma concentrations of TSH. An additional effect of hypercortisolism may be decreased activity of DII, leading to decreased bioavailability of T3 in the CNS. This might be the basis for the potential of T3 as effective comedication in nonresponders to antidepressants. In this respect the recent study by (Buneviˇcius et al., 1999) showing beneficial effects of replacement of a fraction of T4 by T3 in the treatment of hypothyroidism on mood and well-being, is of interest. Organ-specific tissue concentration of T4 and T3 cannot be restored by T4 alone after thyroidectomy (EscobarMorreale et al., 1995). A possible alternative explanation is the reduction in transthyretin, a transport protein to T4. This protein, synthesized by the choroid plexus and secreted into the CSF, is reduced in depressed patients (Sullivan et al., 1999). This could also contribute to “brain hypothyroidism” in depression. It is also noteworthy that TRH is under a constant inhibition by 5-HT, while T3 treatment increases the 5-HT levels in the cerebral cortex of the rat. Both effects may play a part in the pathogenesis and alleviation of depression. Several antidepressants, including tricyclic antidepressive drugs and lithium, increase DII activity and in this way may contribute also to the alleviation of depression. Whether the increased HPA axis activity, decreased DII or decreased 5-HT activity are primary in (subgroups of) depressed patients remains to be elucidated (Jackson, 1998; Kirkegaard and Faber, 1998). The consequences of decreased thyroid activity during lithium therapy in major depression (Bschor et al., 2003) need further study. With respect to the changes observed in the thyroid axis in depression it is curious that the TRH lateralization found in the PVN and VMN of the hypothalamus, with higher concentrations of TRH in the left side (BorsonChazot et al., 1986), was not observed in a subsequent study on suicide victims (Jordan et al., 1992). It should be noted, however, that the controls of the latter study were the same historical ones as those used for the paper by Borson-Chazot et al. (1986), so that the original

observation of TRH asymmetry in the PVN of controls still needs to be confirmed. (j) Sex hormones, depression, premenstrual syndrome, antepartum depression and postpartum mood disorder Unipolar depression and dysthymia are twice as common in women as in men (Seeman, 1997; Piccinelli and Wilkinson, 2000), which may point to either an organizing or an activating effect of sex hormones in the pathogenesis of depression. The observation that adults with a history of prenatal exposure to DES have an increased risk for depression argues for an effect of prenatal estrogens in the organization of brain systems that are involved in affective disorders (Meyer-Bahlburg and Erhardt, 1987). Depression is considered to be more common in women, specifically during times of changing sex hormone levels, such as premenstrual, antepartum and postpartum levels, and during transition to the menopause (Young and Korszun, 2002). Interestingly, M. Bleuer suggested, as early as 1919, that hormone treatment could be a potential antidepressant (Holsboer, 2000). In untreated depressed female patients significantly higher plasma concentrations of testosterone, androstenedione and dehydrostestosterone were found. These findings are best explained as a consequence of an overstimulation of the adrenal glands in hypercortisolemic depressed patients. In contrast to women, depressed men seem to show decreased testosterone levels. In males, the activation of the HPA axis in depression may negatively affect gonadal function at every level of regulation (Albert et al., 1993; Baischer et al., 1995; Schweiger et al., 1999; Sternbach, 1998; Weber et al., 2000b). In the infundibular nucleus, juxtapositions of CRH fibers are found, which form multiple contacts with LHRH neurons. This may be a substrate of such effects (Dudás and Merchenthaler, 2002c). In severely depressed patients, testosterone levels are lower (Heuser, 2002) and older men with lower bioavailable testosterone levels are more depressed (Barrett-Connor et al., 1999b). In addition, low testosterone levels are found in men with dysthymic disorder (Seidman et al., 2002). Both testosterone level and androgen receptor polymorphism are related to the risk middle-aged men run of becoming depressed. Men who have low total testosterone levels and a shorter CAG codon repeat length in the androgen receptor have a greater likelihood of becoming depressed (Seidman et al., 2001). In connection with the observed decreased sex hormone levels in depressed men, it is interesting that,

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in body builders who take supraphysiological doses of testosterone, testosterone levels have a strong negative correlation with depression scores (Dickerman and McCobathy, 1997). Studies in anabolic androgenic steroid users show that some of them develop manic or aggressive reactions to these drugs. Supraphysiological doses of testosterone indeed increase ratings of manic symptoms in normal men (Pope et al., 2000). Depression can also be associated with the use of oral contraceptives, pregnancy and menopause (Parry and Newton, 2001). An interaction between sex hormones and the serotonergic system has been proposed (Rubinow et al., 1998), and we recently found a colocalization of estrogen receptor- and CRH in the human PVN (Bao et al., 2003, submitted), but exactly how sex hormones interact with the mechanisms involved in the pathogenesis of depression should be studied in the future. An interesting new development in this respect is that neurosteroid levels in plasma change during depression (Romeo et al., 1998). The sexual function and mood of hypogonadal men that receive testosterone replacement improves (Seidman and Walsh, 1999; Wong et al., 2000). However, there are not enough controlled studies at present that indicate that testosterone administration is effective in mood disorders (Sternbach, 1998). In women with depression, the blood levels of estradiol are significantly lower, which has been hypothesized to be due to the inhibiting effect of the HPA axis on the reproductive axis, in a way resembling that observed in stress and CRH administration (Young et al., 2000). Not only is the estradiol level lower in depressed women, but also the luteinizing hormone (LH) pulsatility frequency is slower and dysrhythmic (Meller et al., 2001). The estrogen decrease in postmenopausal women may be a factor in both the pathogenesis of late-life depression and in response to therapy. Estrogen replacement therapy may make women with Alzheimer’s disease less vulnerable to depression (Carlson et al., 2000) and may augment a fluoxetine response in elderly depressed patients (Schneider et al., 1997). On the other hand, it should be noted that estrogen substitution in postmenopausal women with depressive symptoms is effective in some studies but not in others (Rubinow et al., 1998; Rasgon et al., 2001). The addition of progestins during sequential hormonal replacement therapy causes negative mood and physical symptoms, symptoms that are accentuated by increasing the estrogen dose (Björn et al., 2003). Premenstrual syndrome or premenstrual dysphoric disorder is characterized by depression, anxiety and

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mood swings during the last week of the luteal phase. Correlations have been reported between the premenstrual or menstrual phase and violent crimes, death as a result of accident or suicide, accidents, admission to hospital with psychiatric problems, taking a child to a medical clinic, and loss of control of aircraft and plane crashes in which the women pilots were said to be menstruating at the time of the crash (Parlee, 1973). A polymorphism in the 5-HT transporter promotor gene region may be a vulnerability factor for this disorder (Praschak-Rieder et al., 2002). Premenstrual dysphoric syndrome is characterized by disturbances in the timing and secretion patterns of circadian rhythms and their response to critically timed light administration, and interventions with bright light improve mood in these patients (Parry and Newton, 2001). Although there is at present no conclusive evidence that premenstrual dysphoric disorder is indeed associated with abnormalities in the levels of sex hormones, both suppression of ovarian function by LHRH agonists or surgical oophorectomy are effective treatments for this type of mood disorder (Steiner, 1996; Rubinow et al., 1998). The observation that no differences are present in plasma levels of ACTH, -endorphin, cortisol or free testosterone does not support a primary endocrine abnormality in women with premenstrual syndrome (Bloch et al., 1998). Timing rather than quantitative measures of cortisol secretion are different in premenstrual dysphoric subjects, both during the menstrual cycle and in response to sleep-deprivation interventions (Parry et al., 2000). Moreover, on the basis of animal experiments, neurosteroids have been proposed as potential etiological factors in this syndrome (Britton and Koob, 1998) and such effects would not be reflected in peripheral hormone changes. The fluid retention in the premenstrual syndrome has been proposed to be related to increased vasopressin levels (Reid and Yen, 1981). This peptide indeed shows fluctuation during the menstrual cycle (Chapter 8f), but the relationship between these fluctuations and psychological symptoms of the premenstrual syndrome has not been shown as yet. Sleep deprivation may help to correct underlying circadian rhythm disturbances during sleep in premenstrual dysphoric disorder (Parry et al., 1999). Antepartum depression is found in some 5% of pregnant women. This condition may be a risk factor for development of preeclampsia and is the strongest predictor of postpartum depression. Maternal depressive symptoms during pregnancy may lead to behavioral changes in the child (Oren et al., 2002b). The safety of 271

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pharmacological treatment of depression of pregnant women is controversial because of the possible behavioralteratological effects (Swaab and Boer, 2001). It is therefore of great practical interest that an open trial has shown that morning light therapy may be effective as an antidepressant during pregnancy (Oren et al., 2002b). A randomized controlled trial is needed to confirm these promising data. In the commonly occurring postpartum mood disorders such as postpartum ‘blues’, depression and psychosis, gonadal hormones have often been presumed to be of pathogenetic importance. The postpartum estrogen withdrawal state has often been held responsible for this disorder. However, available studies show a lack of evidence that serum sex hormones account for mood disturbances in these women. Yet, estradiol might be effective in its treatment. The hypothesis that the postpartum drop in melatonin secretion is responsible for this disorder (Sandyk, 1992b) has so far not been supported by clinical evidence. On the other hand, two women, both suffering from a major depressive episode with postpartum onset, were effectively treated with bright light (Corral et al., 2000). Alterations in the HPA axis that can be attributed to childbearing show remarkable similarity to those observed in depressed women. Postpartum women are also at risk for HPT axis dysfunction that may increase the vulnerability for affective disorders (Sichel et al., 1995; Wisner and Stowe, 1997). It has been proposed that placental CRH might play a role in these endocrine alterations. The third trimester of human pregnancy is characterized by a hyperactive HPA axis, possibly driven, at least partly, by progressively increasing circulating levels of CRH-binding protein (see Chapter 8.5a). A suppressed hypothalamic CRH neuron would be present postpartum that gradually returns to normal, while hypertrophic adrenal cortices become progressively down-sized. The central suppression of postpartum hypothalamic CRH secretion is presumed to cause an increased vulnerability to the affective disorders observed during this period. The suppressed ACTH response to ovine CRH may serve as a biochemical marker of the postpartum blues or depression (Magiakou et al., 1996). Depressive symptoms are common during the transition to menopause, and there are suggestive data that estrogen deficiency may increase the susceptibility for depression (Birkhäuser, 2002). Perimenopause may be a period of risk for mood disturbances that generally do not represent major depression. In fact, depressive

disorders do not occur more frequently during perimenopause (Banger, 2002). Estrogen replacement therapy improves mood in perimenopausal women (Soares et al., 2001) and postmenopausal women (Birkhäuser, 2002). In addition, there are some indications that estrogens may improve the effect of SSRIs in postmenopausal women (Birkhäuser, 2002). (k) Mania I am unable to describe exactly what is the matter with me; now and then there are horrible fits of anxiety, apparently without cause, or otherwise a feeling of emptiness and fatigue in the head . . . . and at times I have attacks of melancholy and of atrocious remorse. There are moments when I am twisted by enthusiasm or madness or prophecy, like a Greek oracle on the tripod. And then I have great readiness of speech. Vincent van Gogh (1853–1890), cited by Blumer, 2002.

As in depression, an association has been reported between early traumatic experiences and mania (Levitan et al., 1997). In addition, there are seasonal fluctuations, since admissions for mania peak in the summer, and fewer admissions occur in winter. It has been proposed that increasing exposure to light may play a role in the onset of manic episodes and that the sensitivity of the eye may facilitate this effect. Supersensitivity to light has been proposed as a possible trademark of manic depressive illness. Melatonin levels of manic depressive patients drop to half the levels of normal controls, while lithium induces subsensitivity to light (Carney et al., 1988). Manic reactions to the use of anabolic androgenic steroids have also been reported (Pope et al., 2000). In his review of secondary or “organic” mania, Cummings (1986) suggests that focal lesions and degenerative disorders of deep midline structures such as basal ganglia, thalamus and hypothalamus are associated with manic symptoms. Vincent van Gogh (1853–1890), who is presumed to have suffered from temporal lobe epilepsy, had not only two distinct periods of depression but also clearly bipolar aspects in his history (Blumer, 2002). Abnormalities in the HPA axis and HPT axis are found not only in depression, but also in mania. We have observed the same hypothalamic changes in CRH, vasopressin and oxytocin in three patients with a bipolar disorder as we had seen in major depression (Raadsheer et al., 1994c, 1995; Purba et al., 1996). Patients with mania have elevated CSF levels and urinary excretion of cortisol, similar to depressed patients. Mixed manics, i.e.

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patients that have both manic and depressive symptoms, even have significantly higher morning plasma cortisol levels, postdexamethasone plasma levels and CSF cortisol than pure manics. Afternoon plasma cortisol and CSF cortisol correlates significantly with depressed mood, while urinary free cortisol correlates with anxiety. None of the cortisol measures correlates with mania or agitation scores (Stokes and Spikes, 1991). In addition, patients with first-episode mania demonstrates significantly larger third ventricular volumes (Strakowski et al., 1993), pointing to strong hypothalamic functional or structural changes. Sørensen (1986) has reported increased CSF levels of vasopressin in mania, while others have shown hypersecretion of vasopressin and its neurophysin not only in CSF, but also in plasma in manic patients (Legros and Ansseau, 1992). These observations warrant further study of the hypothalamic nuclei in mania.

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found. Increased cortisol is significantly associated with behavioral problems in boys and girls (Hessl et al., 2002). In addition, increased melatonin levels are found in fragile-X syndrome, during both the night and the day, possibly due to overactivity of the sympathetic nervous system (Gould et al., 2000). Fragile-X syndrome has also been associated with autistic disorder (Andres, 2002), and about 75–80% of the patients with autism are mentally retarded (Van Karnebeek et al., 2002; Chapter 27.2). Hypothalamic involvement is presumed (but not shown) in Laurence–Moon–Biedl–Bardet and Biemond syndrome, comprising mental retardation, coloboma, obesity, polydactyly, hypogonadism, hydrocephalus and facial dysostosis (Chapter 23.3). Obesity, muscular hypotonia and mild mental retardation have been the symptoms by which a number of children presented who were initially suspected of having Prader–Willi syndrome but who were found, by molecular genetic analysis, to suffer from Angelman syndrome (Gillessen-Kaesbach et al., 1999). In fetal Minamata disease, a toxic encephalopathy due to environmental mercury poisoning, slight neuronal regressive changes are observed in the hypothalamus, but no decrease in the number of nerve cells. In addition, perivascular infiltration of lymphocytes has been noted in this region (Matsumoto et al., 1965). Hypothalamic systems involved. The hypothalamus may indeed be frequently affected in mental retardation, since in 77% of the ‘idiopathic’ cases the third ventricle is found to be larger than normal (Prassopoulos et al., 1996).The possible involvement of neuroendocrine factors in mental retardation is also illustrated by the fact that infantile hypothyroidism may lead to this condition (Loosen, 1992). Thermoregulatory defects that may have a hypothalamic origin are also found in various types of neurodevelopmentally handicapped children (Williams et al., 1994), and menopause occurs some 4 years earlier in women with intellectual disability (Seltzer et al., 2001), pointing to the involvement of LHRH. The circadian system is also often affected. In fragile-X syndrome, increased melatonin levels are found (Gould et al., 2000). A 5-year-old boy with an unspecified form of mental retardation had an extremely low secretion of melatonin, but there was a circadian cortisol rhythm. A congenital deficiency of melatonin secretion was presumed and supplemental melatonin therapy proved effective for treating his non-24-h sleep–wake syndrome (Acaboshi et al., 2000). Mentally handicapped children experience frequent sleeping problems (Quine, 1991; Hoban, 2000; Chapter 30.7) that frequently react favorably to melatonin.

26.5. The hypothalamus in mental deficiency Without folly there is no pleasure in life. Erasmus, The Praise of Folly More brain, O Lord, more brain! George Meredith, Modern Love

Brain malformations account for a significant percentage of patients with mental retardation. Reported estimates of brain malformations from postmortem studies range from 34 to 98% (Shaw, 1987; Schaefer et al., 1994). These data, of course, depend on the sensitivity of the techniques used. Hypothalamus-related abnormalities may be present. Persistence of the cavum septum pellucidum is a marker of cerebral dysgenesis. It is found in 15% of adults with mental retardation and in 0–2% of normal subjects. In contrast, a cavum vergae is seen with the same frequency in normal and retarded populations (Bodensteiner et al., 1998; Chapter 18.8). A hypoplastic anterior commissure has been found in a mentally retarded patient (Shaw, 1987). Hypothalamic changes have been described before in various causes of mental retardation such as septo-optic dysplasia (see Chapter 18.3) and related disorders (Miyako et al., 2002), Noonan’s syndrome (Chapter 18.6), hypothalamic hamartomas (Weissenberger et al., 2001; Chapter 19.3), tuberous sclerosis (Chapter 19.8), Prader–Willi syndrome (23.1), Kallmann syndrome (24.2) and Klinefelter’s syndrome (24.3). Subjects with fragile-X syndrome have an abnormal HPA axis function (Wisbeck et al., 2000). Especially in males, higher levels of salivary cortisol were 273

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Institutionalized children can become less irritable, calmer, happier and more content. They may also socialize better and become more attentive with improved cognitive abilities (Gordon, 2000; Hayashi, 2000; Ross et al., 2002). Sleep in mentally retarded people living in a rehabilitation center at a northern latitude, i.e. in Finland, is more fragmented in winter than in summer. Daily artificial light exposure during the dark season is proposed as therapy (Lindblom et al., 2002). Moreover, eating disorders, probably with a hypothalamic origin, leading to either obesity or underweight, are frequently observed in adults with intellectual disabilities (Gravestock, 2000; Chapter 23). Morgan (1939) described the diencephalon of 16 brains of institutionalized cases of mental deficiency. Cell densities were determined in various hypothalamic nuclei. In all but three cases the third ventricle was compressed inwardly and in some cases parts of the walls of the ventricle were fused. There was evidence of chronic leptomeningitis in 6 cases (proliferation of fibroblasts and endothelial cells, presence of macrophages and sometimes of lymphocytes). Subependymal proliferation of glia was present in 11 cases. Only 2 cases showed normal ependyma of the third ventricle and normal meninges at the base of the brain. With one exception, i.e. the nucleus tuberomamillaris, a reduction of cell density was consistently found in all hypothalamic nuclei. Since the cytoarchitecture of the hypothalamic nuclei was normal, cell reduction was presumed to have occurred in development. Cell density in the PVN was reduced by about 40%. In Down’s syndrome patients, the largest cells of the PVN were almost entirely absent. Cell density in the supraoptic nucleus (SON) was reduced by 35%. The nucleus tuberalis lateralis was affected to a larger degree than any other cell group in the hypothalamus; here cell density reduction was 52% (Morgan, 1939). These observations need confirmation using modern techniques. Down’s syndrome. Originally described by Langdon Down in 1866, Down’s syndrome (trisomy-21) is the most commonly viable aneuploidy and one of the most frequently identified causes of mental retardation. There are various hypothalamic disorders in Down’s syndrome. Growth retardation, which is most marked in early childhood and adolescence, is one of the cardinal features of Down’s syndrome (Hestnes et al., 1991). Both the growth hormone system and hypothyroidism may contribute to the growth retardation in Down’s syndrome. Somatic growth retardation is thought to be due to a partial growth hormone deficiency secondary to hypo-

thalamic dysfunction. A precocious impairment of the cholinergic tuberoinfundibular pathways is presumed to lead to somatostatin hyperactivity and to lower growth hormone responsiveness to growth hormone-releasing hormone (GHRH) (Beccaria et al., 1998). Levodopa and clonidine, drugs that stimulate hypothalamic GHRH release, do not sufficiently stimulate growth hormone release in Down’s syndrome patients. Furthermore, a normal growth hormone response was found after GHRH administration to Down’s syndrome patients. These observations indicate a partial hypothalamic dysfunction in Down’s syndrome (Castells et al., 1996). Although growth hormone plasma levels in Down’s syndrome children are normal, insulin-like growth factor (IGF)-I levels do not rise during early childhood and remain low throughout life. Thus patients with Down’s syndrome have a selective IGF-I deficiency similar to that reported in pygmies. This might account for the growth retardation in Down’s syndrome, since growth hormone does not regulate growth direct, but via IGFs. It has been proposed that there is a delay in the development of the IGF system in Down’s syndrome that results in a diminished sensitivity to growth hormone. Treatment of the partial growth hormone deficiency with human growth hormone appears to accelerate growth in children with Down’s syndrome; their IGF-I levels are restored to normal. Down’s syndrome children have microcephaly, associated with retardation of brain growth. Interestingly, IGFs are also considered to be growth factors for the developing brain and maintenance hormones for the mature brain. Increases in head circumference after human growth hormone therapy have indeed been reported in Down’s syndrome. However, whether early growth hormone therapy does indeed have a positive influence on brain growth and function of the brain is unknown at present. It is possible that the blood–brain barrier for growth hormone and IGFs might prevent such effects (Castells et al., 1992). In the hypothalamus of three Down’s syndrome subjects with trisomy-21 (12–29 years of age) Wisniewski and Bobinski (1991) have found gliosis and a very low cell density in the arcuate (= infundibular) nucleus and VMN. The authors relate this defect to the growth hormone deficiency in Down’s syndrome. It seems worthwhile to repeat these observations on larger numbers of Down syndrome patients and to obtain data on the volume of these hypothalamic structures in order to estimate total cell numbers, and to determine the total number of GHRH stained neurons that are located in the arcuate nucleus (see Chapter 11). The sex of the patients should

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be taken as a possible confounding factor in follow-up studies, because of the sex differences in aging and Alzheimer’s pathology present in this area (see Chapter 11, and below). Various studies show that the prevalence of thyroid diseases is increased in Down’s syndrome (Jaruratanasirikul et al., 1998; Karlsson et al., 1998). The variation in prevalence in the literature may be related to the age variation among the subjects studied. Karlsson et al. (1998) have reported that 50% of Down’s syndrome children develop hypothyroidism at a young age, i.e. before the age of 8 years, while thyroid autoimmunity was only found in one case in the group studied. Hypothyroidism might, in addition to IGF-I deficiency, be another reason for growth retardation in Down’s syndrome. A higher average TSH level is found in Down’s syndrome (Hestnes et al., 1991). Most patients who develop hypothyroidism after 8 years of age have thyroid autoantibodies. Hypothyroidism may give symptoms that are difficult to distinguish from the symptoms found in Down’s syndrome. Although a few patients with Down’s syndrome may develop thyrotoxicoses associated with high concentrations of TSH receptor antibodies, thyroxine replacement treatment should in general be encouraged in Down’s syndrome, even in marginal hypothyroidism (Karlsson et al., 1998). In addition, gonadal insufficiency, reduced male fertility, and poor psychosexual differentiation are well-known neuroendocrine characteristics of Down’s syndrome. Small testes and markedly elevated levels of folliclestimulating hormone (FSH) and LH, indicative of some primary gonadal insufficiency in boys, as well as normal testicular size and normal FSH, LH and testosterone levels have been reported. Estradiol is elevated in male patients. Moreover, pubertal development is reported to be delayed in female patients, but others have found a menarcheal age corresponding to that of the mothers (Campbell et al., 1982; Hestnes et al., 1991; Arnell et al., 1996). Menopause occurs 4 years earlier in Down’s syndrome than in the control population. This may be both a reflection of premature or accelerated aging and a risk factor for estrogen-related diseases such as heart disease, depression and dementia (Seltzer et al., 2001). Cortisol levels seem to be normal (Arnell et al., 1996) and prolactin levels are significantly elevated in Down’s syndrome (Hestnes et al., 1991). Vasopressin expression has increased strongly in the temporal lobe of fetal Down’s syndrome brains, at a stage when brain choline acetyltransferase (ChAT) activities still indicate normal cholinergic function (Labudova et al., 1998). The lower

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body temperature in Down’s syndrome and sleep disorders also indicate hypothalamic disturbances (Hoban 2000; Holtzman and Simon, 2000). Alzheimer changes were described for the first time in Down’s syndrome patients in 1929 (Struwe, 1929). Female, middle-aged Down’s syndrome individuals have an earlier onset and a more severe form of Alzheimer’s disease, which correlates with higher neocortical neurofibrillary tangle densities. Senile plaque counts show no significant sex differences in plaque counts (Raghavan et al., 1994). Especially in older Down’s syndrome patients in the hippocampus, a strong reduction is detected in nicotine binding and ChAT activity (Court et al., 2000). The strong Alzheimer changes that occur in the hypothalamus of presenile demented Down’s syndrome patients are described in Chapter 29.1 and the cholinergic deficit in Down’s syndrome patients in Chapter 2.5. A histaminergic deficiency has been found in the prefrontal cortex of both Alzheimer’s and Down’s syndrome patients, indicating that the tuberomamillary nucleus is affected (Schneider et al., 1997). These Alzheimer changes in Down’s syndrome, together with the earlier menopause experienced in this syndrome (Schupf et al., 1997), indicate an accelerated aging in Down’s syndrome. Down’s syndrome subjects have smaller corpora mamillaria (Raz et al., 1995) and a 50% smaller anterior commissure. The latter is considered to be a congenital malformation (Sylvester, 1986); however, both structures may also be smaller because of the degenerative Alzheimer changes in the temporal lobe (cf. Chapters 6.3 and 16C). ‘She was a perfectly normal girl before 12 months. Then she lost all of her abilities, and we never got her back.’ A mother of a child with Rett syndrome. Adv Pediatr 1993; 40: 217–224.

Rett’s syndrome. Rett’s syndrome (1966) is a progressive disorder that affects early brain growth between infancy and the 5th year of life with a prevalence of 1:10,000–1:22,000. The disease affects mainly, if not exclusively, girls. Girls with Rett’s syndrome are generally reported to be normal at birth, but a loss of communication skills develops soon after and abnormal stereotypical movements appear. The survival rate in reduced to 70% by 35 years of age. Deceleration of head growth is noticeable between 2 and 4 months of age. However, head circumference is already smaller at birth, and perinatal abnormalities are reported in 25% of patients (Leonard and Bower, 1998), indicating that these children 275

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are already compromised at birth. The disease is associated with autistic behavior, cortical atrophy, loss of speech, stereotyped hand movements mimicking hand-washing, severe mental deficiency, gait apraxia and cortical and extrapyramidal dysfunction. Seizures, scoliosis and breathing disturbances such as periodic apnea during wakefulness may become evident (Armstrong, 1997; Miyamoto et al., 1999). Sleep disorders are commonly observed and both free-running rhythms and fragmented sleep patterns have been described. These disorders can be treated effectively with melatonin (McArthur and Budden, 1998; Miyamoto et al., 1999; Yamashita et al., 1999; Hoban, 2000). Sleep time and sleep efficiency are improved by melatonin (McArthur and Budden, 1998). Arrested neuronal development, e.g. on the basis of a lack of appropriate trophic factors, is presumed. Neuropathology shows a generalized brain atrophy involving the cerebrum and cerebellum, without evident general cell loss, inflammation, gliosis or migration defects. Neurons are reduced in size, and there is a reduction in number and size of cholinergic neurons in the nucleus basalis of Meynert (NBM) and a reduction in the melanin-containing neurons of the substantia nigra. Biochemical studies have shown a decrease in ChAT and other cholinergic markers in the neocortex, hippocampus, thalamus and basal ganglia. This neurodevelopmental disorder is presumed to have its greatest effect upon the cholinergic system during the first years of postnatal life. In the prefrontal cortex of Rett’s syndrome patients, a reduced quantity of nerve growth factor was observed (Lipani et al., 2000). This observation agrees well with the atrophy in the NBM, as these neurons need nerve growth factor from the cortex for their metabolism (see Chapter 2.5). Although most cases of Rett’s syndrome are sporadic, a few familial cases and a striking concordance in twins point to a genetic component. One study has suggested that the disorder may be located in two loci, one of which is autosomal (possibly chromosome 11) and one on the X-chromosome (Armstrong, 1997; Naidu, 1997; Wenk, 1997a, b). Recently, mutations in the X-linked MECP2 (methyl CpG binding protein 2 (Rett syndrome)) gene were indeed identified in some sporadic Rett’s syndrome patients. Familial cases are an X-linked dominant disorder that maps on Xq28. A candidate gene is the transcription-silencing MECP2. It contains mutations in 77% of Rett’s syndrome patients. The encoded protein is a global transcriptional repressor (Xiang et al., 2000; Dunn and Macleod, 2001; Shastry, 2001). One must, however, recognize that about 99.5% of cases are

sporadic and that MECP2 testing is not positive in all individuals. The proband’s mother is not routinely tested, because about 90% of the sporadic cases have paternally derived MECP2 mutations (Singer and Naidu, 2001). Other syndromes. In Smith–Magenis syndrome, due to a deletion on chromosome 17p11-2, mental retardation, aggression, tantrums and sleep disturbances are found. The melatonin-secretion cycle is completely inverted, starting around 6 a.m. and with a peak around midday. Tantrums occur when melatonin increases, and sleep attacks take place around the melatonin peak (McBride, 1999; De Leersnyder et al., 2001). Multiple neuroendocrine disorders are observed in Salla disease, which is characterized by increased excretion of sialic acid, mutations in the SLC17A5 gene, psychomotor retardation and ataxia, combined growth hormone deficiency and hypogonadotropic hypogonadism (Grosso et al., 2001). 26.6. Obsessive-compulsive disorder Obsessive-compulsive disorder afflicts 2% of the population (Altemus et al., 1992). Patients are plagued by recurrent intrusive thoughts that often involve the fear that some potential danger has been left unchecked or that they are about to perform an act that is harmful to themselves or others. Compulsive, stereotyped repetitive behaviors, such as handwashing, are often conducted to magically forestall the imagined danger and relieve anxiety. The patients’ lives are so persistently focused on obsessive thoughts and compulsive rituals that it impairs their daily functioning (Altemus et al., 1992). Obsessive-compulsive disorder was once considered to be a psychological disorder or neurosis, but is now considered to be a neurobiological disorder with various etiological factors (Swedo et al., 1997). In this condition increased metabolism occurs in the frontal lobes, caudate nucleus and cingulate gyrus (Rapoport, 1988). There are familial and sporadic cases. Among the familial cases, some appear to be related to Tourette’s syndrome (Leckman et al., 1994). Obsessive-compulsive disorder in families with an eating disorder follows a Mendelian dominant model of transmission (Cavallini et al., 2000). Poststreptococcal autoimmunity has been postulated as another etiological factor. Indeed, an association has been found between obsessive-compulsive disorder and a trait marker of rheumatic fever susceptibility (D8/17) (Swedo et al., 1997). Also the observation that treatments such as plasmapheresis, intravenous immunoglobulins and

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immunosuppressive doses of prednisone, lead to immediate, significant improvements (Allen et al., 1995) points to an immunological mechanism. In addition, children with obsessive-compulsive disorder, antistreptococcal antibodies and antineuronal antibodies are effectively treated with penicillin (Swedo et al., 1994). Higher rates of obsessive-compulsive disorder are observed in patients with thyroid diseases (Placidi et al., 1998).

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with clomipramine hydrochloride (Altemus et al., 1994). In a later study, no significant differences were observed between the obsessive-compulsive disorder patients and controls in CSF oxytocin or neuropeptide Y levels (Altemus et al., 1999). In conclusion, clear and consistent differences in CSF vasopressin and oxytocin levels are probably not present in this disorder. In addition, CSF CRH levels are significantly elevated in patients with obsessive-compulsive disorder (Altemus et al., 1992). For men with this disorder, this observation has been confirmed (Fossey et al., 1996). A similar increase is found in anorexia nervosa patients. In this connection it is interesting that many patients with obsessive-compulsive disorder show evidence of concurrent major depression, in which similar CRH elevations in CSF have been reported, although it is questionable whether the source of this CRH is indeed the hypothalamus (see Chapter 26.4). Increased secretion of the stress hormones vasopressin and CRH are presumed to contribute to persistent behavior, a narrow focus of attention and exaggerated grooming behavior (Altemus et al., 1992; McDougle et al., 1999). During treatment of obsessive-compulsive disorder with clomipramine, CSF levels of CRH decreases (Altemus et al., 1994). However, the fact that Swedo et al. (1992) did not find a relationship between CSF CRH levels and obsessive-compulsive disorder symptom severity does not fit into these observations. No clear disturbance of circadian rhythmicity is observed for plasma melatonin, cortisol or temperature in this disorder (Millet et al., 1998); however, somatostatin levels in CSF are increased (McDougle et al., 1999). The hypothalamus of obsessive-compulsive disorder patients has never been studied.

(a) Neuroendocrine changes Several hypothalamic systems have been reported to have changed in this condition, although these alterations are far from settled. The levels of vasopressin in the CSF of patients suffering from obsessive-compulsive disorder have been found to be significantly elevated, as is the secretion of plasma vasopressin in response to hypertonic saline administration. Moreover, most patients show a loss of the normal relationship between vasopressin levels and osmolality. Patients with anorexia nervosa show a qualitatively similar dysregulation. A significant positive correlation has been found between CSF vasopressin levels and the dopamine metabolite HVA in these patients, as in schizophrenia (Altemus et al., 1992). However, Leckman et al. (1994) did not find differences in CSF concentrations of vasopressin in this syndrome. And in contrast with the data mentioned above, Swedo et al. (1992) have reported a negative correlation between vasopressin CSF levels and several ratings of obsessivecompulsive disorder. Increased oxytocin CSF levels were found in a subset of these patients. In this subset the CSF oxytocin levels were correlated with the severity of the obsessive-compulsive disorder. The authors speculate about the possible role of central oxytocin in cognition, grooming, affiliation and sexual behavior and how these behaviors are disrupted in some forms of obsessiveconvulsive disorders (Leckman et al., 1994). Swedo et al. (1992) have found that the oxytocin CSF levels are positively correlated to depressive symptoms in this disorder. On the basis of the observed increased CSF levels of oxytocin in obsessive-compulsive disorder, one may wonder why oxytocin treatment (Altemus et al., 1992) would be a good strategy to ameliorate obsessivecompulsive disorder; but it would, of course, concur with data of Swedo et al. 1992. In addition, it is difficult to reconcile the reported increased CSF levels of oxytocin (Leckman et al., 1994) and vasopressin (Altemus et al., 1992) in obsessive-compulsive disorder with the decrease in the CSF levels in these patients following treatment

(b) Neuroendocrine therapies Ansseau et al. (1987) have reported symptomatic improvement in one patient with obsessive-compulsive disorder following treatment with oxytocin. This improvement was concurrent with the development of severe memory disturbances, supporting the possible amnestic properties of the peptide. However, the patient also developed psychotic symptoms. Since then a number of authors have reported no appreciable effects of oxytocin in obsessive-compulsive disorder (Salzberg and Swedo, 1992; for references see Epperson et al., 1996). One patient felt that oxytocin decreased his compulsions and stated: “I didn’t check or count my steps when I left the bathroom just now – that is the first time in as long as 277

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I can remember” (Salzberg and Swedo, 1992). However, in 1-week- or 6-week-treatment double-blind placebocontrolled studies, no effect of oxytocin on obsessivecompulsive disorder symptoms has been observed (Den Boer et al., 1992; Epperson et al., 1996). The overall results of the oxytocin therapy thus do not appear to be convincing at present. Naloxone, an opioid receptor antagonist, does not alter symptom severity. However, serotonin reuptake inhibitors seem to be effective in a large proportion of patients with obsessive-compulsive disorder (McDougle et al., 1999). 26.7. Anxiety disorders (a) Panic disorder In panic disorder, anxiety manifests itself as recurrent, unexpected panic attacks and associated avoidance and worry related to the possible recurrence, consequences or health implications of the attacks. One-third to one-half of patients with panic disorder have agoraphobia. Panic disorder is also often associated with other anxiety disorders such as social and simple phobia. Epidemiological data have shown a lifetime prevalence of panic disorder of 1.6–3%, mean age of onset 20 years and a two-fold higher risk for females. Panic disorder is highly familial and an autosomal dominant pattern of inheritance with incomplete penetrance has been proposed for panic disorder. In addition, an interstitial duplication of chromosome 15q24-26 (named DUP25) was found to be significantly associated with panic, agoraphobia, social phobia and panic disorder in nonfamilial cases. DUP25 is present in 7% of the control subjects and is proposed to be a susceptibility factor for panic disorder. The penetrance for the various phenotypes is between 37% and 63%. Other putative susceptibility genes mentioned are MAOA and CCK (Gratacòs et al., 2001). The MAOA G 941T polymorphism is associated with generalized anxiety disorder but not with panic disorder (Tadic et al., 2003). There is also evidence that experiencing traumatic events during childhood and adulthood is associated with panic disorder (Gorman et al., 2000). Moreover, a pathogenetic role of birth seasonality has been found (Castrogiovanni et al., 1999). Different brain circuits have been hypothesized to be involved in the pathogenesis of panic disorder, including the hypothalamus, which is central in the reaction of the adrenals and autonomic nervous system in this disorder

(for reviews see Coplan and Lydiard, 1998; Gorman et al., 2000). Moreover, higher rates of panic disorder have been found in thyroid-diseased patients (Placidi et al., 1998). Anxiety disorder patients in remission are free of psychopathological problems, but they are at risk for future psychiatric episodes. Various data suggest that panic attacks might be partly attributable to exaggerated physiological responses to environmental stresses. Indeed, during a laboratory stress test, patients have greater increases in plasma cortisol levels than controls (Leyton et al., 1996). Patients with panic disorder are characterized by overnight hypercortisolemia and increased activity in ultradian secretory episodes (Abelson and Curtis, 1996a). Another study has shown increased basal total plasma cortisol, free plasma cortisol and salivary cortisol levels in panic disorder (Wedekind et al., 2000). Various observations, moreover, not only indicate hypercortisolemia in panic disorder, but also a normalization of cortisol levels with symptom remission. The HPA axis is, however, not only a state marker in panic. A pretreatment dexamethasone suppression test as well as shifts in ACTH circadian rhythm and cortisol secretion can predict subsequent relapse with medication discontinuation, the patients’ subjective assessments of their own functioning, and greater social and occupational disability years later. Thus, the HPA axis activity may also mark traits associated with long-term vulnerability and functioning. It should also be mentioned that panic patients have elevated overnight cortisol secretion. The cortisol elevations are more pronounced during the night and also occur mainly in the more severely ill panic patients. Others have found a subtle but significant elevation of saliva cortisol levels during spontaneous panic attacks, however, without a relationship with the severity of the attack or the severity of the illness. In addition, patients with frequent panic attacks have reduced ACTH/cortisol ratios and an altered ACTH circadian cycle, suggesting a more chronic central overdrive of the HPA axis (Abelson and Curtis, 1996b; Bandelow et al., 2000a, b). Moreover, hypercortisolinemia, escape of plasma cortisol from dexamethasone suppression and enlargement of the adrenal cortex indicate a dysregulation of the HPA axis. Untreated, nondepressed panic disorder patients fail to show blunted ACTH or cortisol responses to CRH. In fact, the responses are subtly enhanced in that they are more rapid than those of controls. After 12 weeks of alprazolam treatment, repeated testing found cortisol levels similar to those of controls (Abelson et al., 1996; Curtis et al., 1997). CRH-receptor antagonists have been

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suggested as possible treatment for anxiety disorder (Grammatopoulos and Chrousos, 2002). No changes in CSF CRH levels are observed in panic disorder (Fossey et al., 1996), but one may wonder whether this gives any information on the functional state of hypothalamic CRH neurons, since CRH in CSF may, to a large degree, be derived from extrahypothalamic sources (Chapter 26.4). It is hard to explain why Stones et al. (1999), in contrast to the other observations, have found lower salivary cortisol levels in panic disorder patients and an unresponsiveness to novel situations. It should be noted, though, that in panic induced by CO2 inhalation, plasma cortisol levels do not increase but actually decrease significantly (Sinha et al., 1999). These observations lend support to the idea that the pathophysiological mechanisms underlying CO2-induced panic are different from those underlying general or anticipatory stress. Acid–base disturbances may be relevant in panic disorder (Coplan and Lydiard, 1998). Patients with panic disorder experience panic attacks after intravenous lactate infusions. On the basis of animal experiments, it is presumed that the organum vasculosum lamina terminalis may be the primary site that detects lactate infusions, activating an anxiety response in a compromised dorsomedial nucleus (Shekhar and Keim, 1997). However, the hypothalamus of panic patients has so far never been studied. This brain structure does indeed seem to be of interest, because a patient with a cyst in the third ventricle exhibited anxiety periods (Lobosky et al., 1984). Moreover, blood pressure is elevated in fully remitted panic disorder patients (Leyton et al., 1996) and atrial natriuretic factor is increased in patients with panic disorder. This peptide inhibits the CRH-stimulated release of ACTH in humans (Kellner et al., 1992; Dieterich et al., 1997). Increased nocturnal melatonin has been found in panic disorder patients (Brown, 1996; Pacchierotti et al., 2001). There are also other neuroendocrine disturbances in this disorder. Blunted growth hormone responses to clonidine, yohibine, GHRH, caffeine and glucose challenge have been observed. These data indicate a hyporesponsive hypothalamic growth hormone system in panic disorder (Uhde et al., 1992). Benzodiazepines and, in particular, alprazolam produce substantial improvement in clinical status, accompanied by nearly full reduction of pretreatment hypercortisolemia (Abelson et al., 1996). In addition, more than 3 decades ago Klein observed that imipramine was effective (Coplan and Lydiard, 1998). Effective cognitive behavioral therapies have also been reported (Gorman et al., 2000).

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(b) Social anxiety disorder Social anxiety disorder is conceptualized as a chronic neurodevelopmental illness, with excessive fear and/or avoidance of situations in which an individual feels scrutinized by others and is fearful of a negative evaluation by others. There is a low concordance rate for social anxiety in monozygotic twins, suggesting that genetics may play a limited role in its development. In adulthood no peripheral HPA axis pathological change is evident, in contrast to panic disorder. Psychological stressors such as mental arithmetic and a short-term memory test performed in front of an audience resulted in a significantly higher cortisol response in patients with a generalized social phobia than found in controls (Condren et al., 2002). 26.8. Fatigue syndromes . . . Neurasthenia, indeed, has been the central Africa of medicine – an unexplored territory into which few men enter, and those few have been compelled to bring reports that have been neither credited nor comprehended . . . George Beard, 1880, from Demitrack, 1994.

(a) Chronic fatigue syndrome For research purposes the Center for Disease Control and Prevention (CDC) has proposed a working case definition for chronic fatigue syndrome , neurasthenia or benign myalgic encephalomyelitis. Patients must have persistent or relapsing debilitating fatigue for at least 6 months without any medical diagnosis that would explain the clinical presentation. The fatigue should cause a reduction in activity of at least 50%. Symptom criteria also include an abrupt onset, low-grade fever, arthralgia, myalgia, painful adenopathy, postexercise fatigue, neuropsychological complaints and sleep disturbances (Demitrack, 1994; Krupp and Pollina, 1996). The prevalence is estimated to be 112 patients per 100,000 (Buskila, 2001). The neurotransmitter systems probably involved in the mechanism of central fatigue in chronic disease are noradrenaline, 5-HT and CRH (Swain, 2000). Many symptoms experienced by these patients are similar to those experienced by patients who have received long-term glucocorticoid therapy and are undergoing steroid withdrawal (Adler et al., 1999). Moreover, low blood pressure has frequently been reported (Demitrack, 1997). Subjects with chronic fatigue syndrome have 279

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normal core body temperature, despite frequent selfreports of subnormal body temperature and low-grade fever (Hamilos et al., 1998). In addition, the observed T-cell activation indicates the presence of an immunedysregulation disorder (Bell, 1994). This disorder is accompanied by a relative resistance of the immune system to dexamethasone (Kavelaars et al., 2000) and angiotensin-converting enzyme plasma levels are increased. This enzyme is a marker not only for sarcoidosis (Chapter 21.1), but also for diseases involving blood vessels (Bell, 1994). Moreover, abnormalities in essential fatty acid incorporation into phospholipids have been found (Gray and Martinovic, 1994). Chronic fatigue syndrome often starts following a significant period of stress and is worsened by exercise. Acute infections can evolve into chronic fatigue syndrome, and an influenza-like onset of this syndrome is more common in winter than in other seasons (Natelson, 2001). Antibody titers to a variety of viral agents may be present in CSF, including antibodies to herpes, cytomegalovirus and measles virus. However, no single virus has been identified as the cause of chronic fatigue syndrome (Krupp and Pollina, 1996). No circulating autoimmune antimuscle or anti-CNS antibodies in chronic fatigue syndrome have been found (Plioplys, 1997). In some studies, patients with chronic fatigue syndrome are reported to have significantly more abnormal scan results than head trauma/headache controls. The abnormalities are predominantly either single or multiple small areas of increased T2 signal in white matter or evidence of ventricular or sulcal enlargement (Natelson et al., 1993; Schwartz et al., 1994; Lange et al., 1999). Others have not confirmed these findings (Greco et al., 1997). Patients with chronic fatigue syndrome have, moreover, more defects throughout the cerebral cortex, as revealed by SPECT scans, than normal subjects (Schwartz et al., 1994). In addition, there is a significant reduction of the perfusion to several areas of the cortex (Costa et al., 1992; Ichise et al., 1992), but in particular to the hypothalamus and pons in patients with chronic fatigue syndrome (Costa et al., 1992). In spite of the nearly ubiquitous presence of depression, a functional deficit in the HPA axis is found in chronic fatigue syndrome rather than hyperactivity (Demitrack, 1997; Cleare, 2003). Scott et al. (1999c) have found, by CT scanning, that the adrenals in this disorder are 50% smaller. A reduction in evening basal plasma glucocorticoid levels and urinary free cortisol excretion has

been reported in chronic fatigue patients, while plasma ACTH levels are higher (Poteliakhoff, 1981; Demitrack et al., 1991; Scott et al., 1999a). Furthermore, these patients have an enhanced sensitivity to exogenous ACTH and a blunted response to CRH, which may be compatible with a mild insufficiency of the HPA axis. The observation that DDAVP (desmopressin) augments the CRH-mediated pituitary-adrenal responsivity may relate to increased vasopressin regulation of the HPAaxis in this syndrome (Scott et al., 1999b; Cleare et al., 2001). Although glucocorticoid deficiency is generally considered to be central in the symptomatology of this syndrome (Poteliakhoff, 1981; Demitrack, 1994; Adler et al., 1999; Cleare, 2003), some relatively recent studies could not replicate the reduced HPA-axis activity in this syndrome by measurement of daily salivary cortisol secretion (Young et al., 1998) and plasma cortisol levels were not found to be different from control levels either (Scott et al., 1999a). Furthermore, in contrast to previous studies, adrenal sensitivity to infused ACTH was found to be normal (Adler et al., 1999) and the decreased 24-h urinary cortisol excretion of patients with fibromyalgia could not be replicated either (Maes et al., 1998). Reviewing the literature, Parker et al. (2001) statesd that one-third of the studies report baseline cortisol values to be significantly low, usually in one-third of patients. One may presume that more differences might appear if provocation tests of the HPA axis had been used, since reduced HPA function in such tests is more consistent (Parker et al., 2001). Also, differences in dietary sodium or environmental stresses may have played a role in the discrepancies (Adler et al., 1999). This possibility is supported by the observation that vasopressin infusion in chronic fatigue patients produces a reduced ACTH response, which is explained by reduced hypothalamic CRH secretion that acts synergistically with vasopressin on the pituitary level (Altemus et al., 2001). Comparing different types of stress, it is concluded that chronic fatigue patients are capable of mounting a sufficient cortisol response, but that there is a subtle dysregulation of the HPA axis at the central level that becomes overt as a result of or through a lower ACTH response. In all tests these patients had significantly reduced baseline ACTH levels (Gaab et al., 2002). Subtle changes in the HPA axis are also indicated by the observation that the majority of chronic fatigue syndrome patients have a serum DHEA-S deficiency,

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while cortisol and DHEA levels were found to be either normal (Kuratsune et al., 1998; De Becker et al., 1999) or lower (Scott et al., 1999a; Cleare, 2003). A blunted serum DHEA response to intravenous ACTH has been observed (De Becker et al., 1999). DHEA-S is one of the most abundantly produced hormones. It is secreted by the adrenal and is a precursor of sex steroids. These data agree with the opinion of Cleare et al. (2001) that hypocortisolism in chronic fatigue syndrome is secondary to reduced adrenal gland output. Since DHEAS has, in addition, central effects (cf. Scott et al., 1999a; Cleare, 2003), its deficiency may be related to the core symptoms of chronic fatigue syndrome. In addition, basal plasma levels of 3-methoxy4-hydroxyphenylglycol (MHPG), a norepinephrine metabolite, are lower and basal plasma levels of 5hydroxyindoleacetic acid (5-HIAA), a 5-HT metabolite, are significantly higher in patients with chronic fatigue syndrome than in controls (Bell, 1994). Enhanced serotonergic activity is a consistent finding (Parker et al., 2001). The decreased MHPG levels reflect an increase in sympathetic activity which could explain at least part of the fatigue of the syndrome (Bell, 1994). On the basis of a study on cardiovascular control in chronic fatigue syndrome, an autonomic imbalance with sympathetic predominance has been hypothesized (Pagani and Lucini, 1999). On the other hand, Adler et al. (1999) have found an impairment of the sympathoadrenal response to hypoglycemia. A hypofunction of the sympathetic nervous system has been described by several authors and could contribute to adrenal insufficiency (Neeck and Crofford, 2000). Moreover, a significant reduction in the prolactin response to hypoglycemia has been noted (Demitrack, 1997), indicating dopamine involvement. Some 20% of patients with chronic fatigue syndrome describe excessive thirst as a minor symptom. Vasopressin secretion is erratic in patients with postviral fatigue syndrome. Moreover, the baseline vasopressin plasma level in these patients is lower than in controls (Bell, 1994). The diurnal change in cortisol levels is less pronounced in chronic fatigue syndrome than in controls. Morning cortisol levels are lower and evening levels higher (MacHale et al., 1998), indicating a deficient SCN– paraventricular nucleus interaction. Moreover, exhaustive exercise interferes with normal entrainment to 24-h Zeitgebers in chronic fatigue syndrome patients, but not in controls. The patients have a lengthening of the mean circadian period, while the period remains unchanged in

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controls (Ohashi et al., 2002). However, Adler et al. (1999) have found a normal diurnal rhythm of the HPA axis under basal conditions in these patients. In addition, continuous recordings of core body temperature using an ingestible radio-frequency transmitter pill did not reveal any clear differences from controls (Hamilos et al., 2001). It has been suggested that the sleep disorders in chronic fatigue syndrome may result from melatonin deficiency. However, in contrast to this assumption, higher nocturnal melatonin levels were found in these patients (Knook et al., 2000). and melatonin levels were normal in another study (Korszun et al., 1999). The observation that melatonin and bright-light phototherapy are ineffective in chronic fatigue syndrome sufferers (Williams et al., 2002) agrees with the idea that the circadian system is not seriously affected. There is no indication of an abnormal function of the hypothalamopituitary-gonadal axis in chronic fatigue syndrome (Korszun et al., 2000). In approximately one-third of the patients with chronic fatigue syndrome, low dose hydrocortisone reduces fatigue levels in the short term (Cleare et al., 1999; Adler et al., 2002), which seems a rational therapy since the mild hypocortisolism reported in this disorder. In a later study the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone treatment was accompanied by a reversal of the blunted cortisol response to human CRH (Cleare et al., 2001). However, as Scott et al. (1999a) pointed out, the administration of hydrocortisone as a therapeutic measure may further lower the levels of DHEA and DHEAS. The observations of favorable effects of corticosteroids should still be confirmed in controlled longterm followup studies. Although such a treatment was also associated with some improvement in symptoms in another study, the degree of adrenal suppression, the modest benefit, and the overlap of symptoms between chronic fatigue syndrome and glucocorticoid therapy, and the other side effects of glucocorticoids are thought to preclude their practical use for this disorder (McKenzie et al., 1998; Jeffcoate, 1999; Adler et al., 2002). In a pilot experiment it was found that daily administration of DHEA-S induced marked improvements in the daily activities and a reduction of their symptoms (Kuratsune et al., 1998). Although there are thus several reports implicating the hypothalamus in the chronic fatigue syndrome, such as a putative deficiency of the HPA axis (Demitrack et al., 1991; Demitrack, 1997), a reduction of the perfusion of the hypothalamus (Costa et al., 1992), endocrine

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abnormalities of hypothalamic or pituitary function (Bell, 1994), upregulation of 5-HT receptors in the hypothalamus (Bakheit et al., 1992), problems with temperature regulation and disturbed circadian hormone profiles (MacHale et al., 1998), the functional anatomy of the hypothalamus itself has so far not been studied in postmortem material. The debate as to whether chronic fatigue syndrome is “psychiatric” or “organic” no longer appears to be useful. The neuroendocrine alterations found in at least some of these patients strongly argue in favor of the latter possibility. The fact that cognitive behavioral therapy led to improved clinical outcomes in patients with chronic fatigue syndrome, does, of course, not mean that this syndrome is psychological in origin (Natelson, 2001). Patients with chronic fatigue syndrome and post-Lyme syndrome share many features, including symptoms of severe fatigue and cognitive deficits. However, the latter are particularly apparent in patients with post-Lyme syndrome (Gaudino et al., 1997). Symptoms that are comparable with those of chronic fatigue syndrome, and with those of work-related syndromes, are found in burnout patients. They do, however, not have blunted cortisol levels. On the contrary, their morning cortisol levels are elevated. The severity of mental exhaustion is associated with the degree of early morning cortisol level elevation. In addition, higher resting heartrates are observed in burnout patients (De Vente et al., 2003). (b) Fibromyalgic syndrome A rheumatologic syndrome characterized by a widespread musculo-skeletal pain and tenderness, fatigue, neurovegative symptoms and sleep disturbances, fibromyalgic syndrome is related and may even be identical to the chronic fatigue syndrome, although lower numbers of patients showed abnormal suppression to dexamethasone. Furthermore, according to a number of investigations, these patients show reduced diurnal fluctuations of glucocorticoid levels, reduced free cortisol excretion, impaired reactivity of the HPA axis to challenge reduced vasopressin response to water deprivation challenge (Hudson et al., 1984; McCain and Tilbe, 1989; Griep et al., 1993, 1998; Demitrack, 1997; Lentjes et al., 1997; Wikner et al., 1998; Cutolo and Straub, 2000; Buskila, 2001). Moreover, the patients have increased sympathetic and decreased parasympathetic system tones (Buskila, 2001)

and low DHEAS levels were reported (Dessein et al., 2000). Fibromyalgia and irritable bowel syndrome coexist in many patients (Buskila, 2001). Since fibromyalgia patients display a hyperactive ACTH response to CRH and to insulin-induced hyperglycemia, the existence of a deranged negative feedback control of cortisol was proposed. These patients appeared indeed to have an increased cortisol feedback resistance, presumed to be combined with a reduced CRH synthesis or release in the hypothalamus (Lentjes et al., 1997). A later study did not observe a change in the 24-hour urinary excretion of cortisol, however (Maes et al., 1998) and even elevated basal levels of the ACTH and cortisol were found by others (Neeck, 2000). Some other studies claim that fibromyalgia is characterized by hyperactivity of the HPA axis, possibly driven and sustained by stress exerted by chronic pain (Neeck and Crafford, 2000). A defect in the descending spinal cord pathways that modulate pain sensation has been hypothesized, therefore, to be present in fibromyalgia. Reduced nocturnal melatonin levels were reported that were presumed to play a role in the sleep disturbances, in fatigue during the day, and in a changed perception of pain (Wilkner et al., 1998). However, contrary to earlier reports, Korszun et al. (1999) found significantly higher night-time plasma melatonin levels. No abnormalities in the function of the hypothalamopituitary-gonadal axis were found by Korszun et al. (2000), but Neeck (2000) reported increased levels of not only FSH, but also of lowered basal levels of estrogens, androgens, insulin-like growth factor-1, somatomedin C, and free triiodothyronine (T3) (Geenen et al., 2002). The occurrence of daytime somnolence in fibromyalgia patients is one of the most important symptoms. The occurrence is linked to a greater severity of the symptoms of the disease and to more polysomnographic alterations (Sanzi-Puttini et al., 2002). Typical non-REM disturbances are present. Slow-wave sleep abnormalities appear to be more important than REM sleep disturbances. Both the histaminergic tuberomamillary system and the SCN have been hypothesized to participate in these changes (Pillemer et al., 1997; Griep et al., 1998), and a stimulatory serotonergic influence of the serotonergic system on the HPA axis is presumed (Neeck, 2000). However, direct evidence for a disturbance in these systems in fibromyalgia is currently lacking. One third of the patients has an impaired reaction of growth hormone following insulin-induced hypoglycemia and

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arginine stimulation, suggesting an impaired hypothalamic somatotropic reactivity (Dinser et al., 2000). Substance-P, an important nociceptive neurotransmitter, is elevated in the CSF of fibromyalgia patients and not in patients with chronic fatigue syndrome, while metenkephalin levels are low (Pillemer et al., 1997). Beneficial strategies in fibromyalgia include graded aerobic exercise, cognitive behavior, stress reduction therapies, tricyclic antidepressants, growth hormone replacement and DHEAS replacement (Dessein et al., 2000). In a placebocontrolled study of glucocorticoids in fibromyalgia, no favorable effect was found (Adler et al., 2002). In general, little support is obtained from the literature for hormone supplementation therapy in case of fibromyalgia (Geenen et al., 2002).

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26.9. Aggressive behavior “the world was against him” (patient with a medial hypothalamic tumor. Alpers, 1937)

(a) Developmental factors involved in clinical disorders associated with aggression Genetic, developmental and environmental developmental factors play a role in later levels of aggression. That the levels of aggression in adult life may at least to some degree be determined by genetic factors appears from, e.g. the study by Brunner et al. (1993), who described a large Dutch kindred with a form of X-linked mild mental retardation, in which all the affected males showed aggressive and sometimes violent behavior, arson, attempted rape and exhibitionism, which are proposed to be due to changes in the monoamine oxidase type A (MAO-A) locus in Xp11.23-11.14. On the other hand, children with a genotype conferring high levels of MAO-A expression are less likely to develop antisocial behavior when maltreated during childhood (Caspi et al., 2002). Moreover, individual differences in aggressive disposition were shown to be associated with an intronic polymorphism of the tryptophan hydroxylase gene in a nonpatient sample of volunteers. This gene codes for the rate limiting enzyme in 5-HT biosynthesis (Manuck et al., 1999). Large-scale screening studies have refuted the earlier claims that Kleinfelter’s syndrome patients (Chapter 24.4) are prone to criminal behavior (Smyth and Bremner, 1998). Various developmental factors may determine the later degree of aggression. Minor physical abnormalities in newborns that result from some form of genetic transmission or insult during early pregnancy predict short attention span, peer aggression and impulsivity at 3 years of age (Waldrop et al., 1978) and recidivistic violent behavior later (Kandel et al., 1989). In children with gelastic seizures (Chapter 26.2) and hypothalamic hamartomas (Chapter 19.3a), high rates of aggression are found (Weissenberger et al., 2001). A rare syndrome that probably affects the hypothalamus has been described in two unrelated boys who suffered from adipsic hypernatremia, inappropriately low plasma vasopressin levels, possibly due to a selective osmoreceptor dysfunction, hyperprolactinemia and an exaggerated prolactin response to TRH, associated with aggressive behavior. No intracranial lesions were found (Dunger et al., 1985). Moreover,

(c) Postviral fatigue syndrome Another closely related syndrome is postviral fatigue syndrome. It is a chronic disorder with an acute onset and a fluctuating course that occurs either sporadically or in epidemics. The disease follows an acute viral infection and is characterized by overwhelming fatigue. As a rule there is a variable degree of myalgia. Most patients develop, in addition, a number of other symptoms that suggest hypothalamic dysfunction, including changes in body weight and appetite, minor fluctuations in body temperature, excessive sweating, a reversed pattern of sleep, excessive sleep, impaired libido, menstrual irregularities, depression, and sometimes fluid retention. Secretion of vasopressin may be erratic in these patients as appeared from the lack of correlation between serum and urine osmolality and plasma vasopressin levels and the baseline vasopressin levels are low (Bakheit et al., 1993; Bell, 1994). In addition, an increased sensitivity of hypothalamic 5HT receptors was found. The buspirone challenge test to determine the functional activity of hypothalamic 5-HT receptors showed upregulation of these receptors in patients with postviral fatigue syndrome, and not in those with primary depression. An increased prolactin response to this serotonin reuptake inhibitor was found in these patients, most of whom had objective evidence of muscle damage. In contrast, a significantly lower prolactin response to buspirane was found in patients with a primary depression (Bakheit et al., 1992). Patients with primary adrenal failure (Addison’s disease) have increased daytime fatigue, but no more day time sleepiness than normal (Løvås et al., 2003).

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pregnancy or obstetric complications are associated with conduct problems in childhood and with antisocial personality disorder or frank criminality in adulthood. In particular birth complications in combination with early child rejection predisposes to violent crime. The rates of crime are particularly high in a subgroup of subjects with early neuromotor deficits and unstable family environments (Kandel and Mednick, 1991; Raine et al., 1994, 1996). A combination of pregnancy complications and inadequate parenting increases the risk of violent and nonviolent offending only slightly. However, inadequate parenting was experienced by 5 times as many cohort members than was the combination of inadequate parenting and pregnancy complications (Hodgins et al., 2001). In addition, prenatal exposure to wartime famine during the first or second trimester is associated with an increased risk of violent antisocial personality disorder (Neugebauer et al., 1999). A higher potential for physical aggression is found following exposure to androgen-based synthetic progestins during gestation (Reinisch, 1981) and an increased risk factor for conduct disorder, delinquency, and attention-deficit conduct disorder of the offspring is observed following maternal smoking during pregnancy (Rantakallio et al., 1992; Wakschlag et al., 1997; Fergusson et al., 1998; Brennan et al., 1999b; HellströmLindahl and Nordberg, 2002). For women who smoke more than 10 cigarettes per day from the 4th month of pregnancy, it can be predicted almost with certainty that their children will show behavioral problems, including delinquency, 16 years later, according to Bagley (1992). A recent study suggests that the association between maternal smoking during pregnancy and conduct disturbance symptoms in boys may be attributed to the transmission of a latent conduct disorder factor rather than to a direct effect of smoking (Silberg et al., 2003). Low HPA axis activity as is apparent from plasma or salivary cortisol is also a correlate of severe and persistent aggression in children and adolescents as seen in conduct disorder (McBurnett et al., 2000; Pajer et al., 2001). In children with opposite defiant disorder or conduct disorder, the adrenal androgen functioning, as measured by DHEAS levels is elevated. These children are at risk for criminality and antisocial personality disorder in adulthood. It is speculated that the HPA axis is activated due to stress or genetic factors (Van Goozen et al., 2000b). An exciting possibility is that adults with refractory anxiety and/or maladaptive behavior, high DHEAS and low cortisol levels have late-onset congenital adrenal hyperplasia that reacts favorably to treatment of the

endocrine disorder. Ketoconazole normalizes DHEAS and decreases the level of anxiety and aggressive behavior. In victims of intimate-partner physical and sexual violence, the mean cortisol levels are significantly decreased (Seedat et al., 2003). The various data on the possible organizing effects of testosterone on aggressive behavior in humans are not always in agreement (Mazur and Booth, 1998). Although in violent men testosterone levels are not different from those of nonviolent men, the testosterone levels in violent men correlated significantly with hostility. Individuals whose life histories involve numerous antisocial behaviors tend to have higher testosterone levels (Aromäki et al., 1999). In another study personality disorder criminals with multiple offences had high serum testosterone levels (Räsänen et al., 1999). The use of anabolic androgenic steroids may also lead to aggressive reactions (Pope et al., 2000) and accompany antisocial personality traits (Yates, 2000). The aggressiveness in early childhood autism is presumed to be due to excessive brain opioid activity (Leboyer et al., 1992). Aggression, hypersexuality and violent rape attempts have been reported as manifestations of rabies (Gómez-Alonso, 1998). The combination of head injuries, perinatal difficulties, parental psychopathology (e.g. as indicated by the presence of a schizophrenic parent and social deprivation – particularly as manifested by the failure of the physician to diagnose or appropriately treat psychiatric illness or CNS dysfunction, or to failure of society to provide adequate support – is sufficient to create a young offender. This combination of factors occurs frequently (Lewis et al., 1979). Moreover, aggression has been described in attention-deficit hyperactivity disorder (Jensen and Garfinkel, 1988; Siponmaa et al., 2001), pervasive developmental disorder not otherwise specified, Asperger’s syndrome, Tourette’s syndrome (Siponmaa et al., 2001) and neurosarcoidosis (Bona et al., 1998; Chapter 21.1). Aggressive behavior appears as a component of numerous neuropsychiatric diseases including Alzheimer’s disease, affective disorders, schizophrenia, tertiary syphilis, brain tumors, temporal lobe epilepsia, encephalitis, normalpressure hydrocephalus, traumatic brain injury, mental retardation, stroke, infection, developmental disorders, MS, Parkinson’s and Huntington’s disease. Such behavior usually falls into the category of defensive rage and is linked to the limbic hypothalamic-midbrain–periaquaductul gray axis (Ryan, 2000; Gregg and Siegel, 2001), although the structural basis is usually far from proven. Hypothalamic hamartoma (Chapter 19.3) frequently lead

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to oppositional defiant disorders and significant rates of aggression (Weissenberger et al., 2001). A rare cause of aggressive behavior is idiopathic hypothalamic dysfunction, a paraneoplastic syndrome (Chapter 32.1; Ouvrier et al., 1995).

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hypothalamus. One case has been reported of a man with a tumor in the medial hypothalamus who flew into a rage when somebody dared to argue with him. Other cases are known, but the behavioral descriptions are less complete. Some indication that mediohypothalamic lesions may cause aggressive behavior comes from the unilateral hypothalamic lesions in sex offenders some of which would display considerable affective excitability and lack of control and appeared to be less inhibited than before the operation (see Chapter 24.5; Albert et al., 1993). After surgical removal of a craniopharyngioma and damage of the ventral hypothalamus, a 32-year-old man developed a tetrad of neurobehavioral changes, consisting of episodic rage, emotional lability, hyperphagia with obesity and memory impairment with intellectual decline. Not only did he verbally abuse the family, hospital staff and fellow patients, but also impulsively destroyed the contents of a garage, a pool table, patio doors, door bolts, bedroom windows, water fountains, fire extinguishers and numerous pieces of furniture. Caretakers were often injured during attempts to intervene, although the unprovoked violence was rarely directed specifically at individuals (Flynn et al., 1988). A 22-year-old woman with anorexia nervosa due to a craniopharyngioma has reported that she had urges to kill people (Climo, 1982). In the rat, aggression can be induced by a hypothalamic attack area below the fornix, just lateral and frontal of the VMN in the hypothalamus. This area almost completely coincides with the intermediate hypothalamic area and the ventrolateral pole of the hypothalamic VMN (Roeling et al., 1994; Kruk et al., 1998). Neoplastic destruction of the VMN has indeed been associated with unplanned impulsive aggression (Ryan, 2000). The SCN is presumed to be responsible not only for day/night rhythms, but also for circannual rhythms (Chapter 4.3) and may thus be involved in rhythmic occurrence of aggressive behavior. Suicide, which can be considered to be self-directed aggression, occurs more frequently during the day than during the night (Altamura et al., 1999). Aggression toward others is mainly observed in the evening and at night (Laubichler and Ruby, 1986). Profound diurnal activity disturbance with increased diurnal physical activity is found in alcoholic, impulsive, violent offenders with intermittent explosive disorder (Virkkunen et al., 1994). In the United States, an annual rhythm has been found in rapes, assaults and battering of women, with maximum values in summer. In contrast, there is a virtual absence of seasonal changes in numbers of murders. A close relationship has been found between

(b) Hypothalamic structures involved A number of hypothalamic structures and transmitter systems seem to be involved in aggression. Animal experiments have shown that, after cortical ablation, stimulation of the posterior lateral hypothalamus elicits “sham” rage, a combination of hissing, pilo-erection, pupil dilation and extension of the claws. Electrical stimulation of the median preoptic area or the sexually dimorphic nucleus within this area (Chapter 5) in the rat may also elicit or enhance aggression (Merari and Ginton, 1975; Gorski, 2002). Stimulation of the human medioposterior or caudolateral hypothalamus during neurosurgical procedures elicits fear or horror (Carmel, 1980). Tumors in the human septal area are also associated with a heightened defensiveness. Patients have been described with “outbursts of temper and violence” and have become “increasingly irritable, unreasonably angry, abusive verbally and threatened physicians”. “She attacked her husband with a paring knife” (Albert et al., 1993). Some patients have been incarcerated and even died whilst in jail, sentenced because of hypersexuality, fetishism, sexually assaulting a minor and other aberrant sexual behaviors; they were later found to have (by MRI or autopsy) multiple sclerous lesions in the hypothalamus, septum and other brain areas (Frohman et al., 2002). Von Economo (see Chapter 20.2) has suggested that encephalitis lethargica in the anterior part of the hypothalamus is related to aggression. Aggression in humans increases with tumors in the medial hypothalamus. Reeves and Plum (1969) have described a 20-year-old woman with a hamartoma that had destroyed the ventromedial hypothalamus. She developed bulimia, obesity, amenorrhea and diabetes insipidus. In addition she developed outbursts of aggression, hitting, scratching or biting examiners who approached, indicating that the midhypothalamus plays a role in such aggressive behaviors. Another case is that of a 26-year-old woman who showed hyperphagia, obesity and aggressive behavior due to a hypothalamic astrocytoma in the region of the midhypothalamus (Haugh and Markesbery, 1983). A number of other cases have been reported where heightened aggression is associated with a tumor in the medial 285

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assaults, battering and rapes on the one hand and ambient temperature on the other. Human violence seems thus to be influenced by environmental factors such as light and temperature (Michael et al., 1983, 1986). Yearly rhythms in ambient temperature or light/dark cycles can serve as “Zeitgebers” (Altamura et al., 1999). This idea is reinforced by the observation that, under rigorously controlled laboratory conditions and a constant photoperiod, male rhesus monkeys show a clear annual cycle of aggression toward their female partners. Aggression is most severe between August and October, which corresponds with the time when plasma testosterone reaches maximum levels, and with the mating season, when aggression increases normally in the wild (Michael and Zumpe, 1978). Schreiber et al. (1991a) have reported the presence of seasonal rhythms in the opening dates of wars. They base their analysis upon 2,121 acts of hostility. In the Northern hemisphere, the annual opening dates of wars show a peak in August and a nadir in January, while an inverse pattern is seen in the annual rhythms of wars in the Southern hemisphere, with a peak in December–February and a nadir in July. A constant rate of acts of hostility is found throughout the year around the line of the equator. Elongation of the daily photoperiod may thus induce increases in affective aggressiveness. Several studies have reported seasonal variations in suicide with annual and semiannual rhythms. In the Netherlands, train suicides also appeared to be influenced by season (Van Houwelingen and Beersma, 2001). One study has shown seasonality to be present in violent, but not in nonviolent suicide. Peaks are present in March–April and August in younger and elderly persons, respectively, and lows in December–January (Maes et al., 1993a). The latter study could, however, not confirm the seasonality for homicide, as reported by Smolensky et al., 1983. In the study of Morken and Linaker (2000) a seasonal rhythm in violent incidents was found with one peak in May–June and one in October–November. Excessive cholinergic stimulation (perhaps acting on receptors within the hypothalamus) may promote serious aggression in man. In the intact animal, attack behavior can be facilitated by injecting acetylcholine into the hypothalamus, while a cholinergic blocker will eliminate a biting attack, even in naturally aggressive cats or rats (Bear, 1991). One interesting case study comes from a scientist who treated his pets with a tick powder containing a potent cholinesterase inhibitor. His cat initiated predatory stalking and began to kill birds and mice

in large numbers. The scientist developed a concomittant “rage” that led to uncharacteristic violent arguments on many subjects, accompanied by flushing and threats. The aggressiveness led a long-time companion to flee the house. Within a week of terminating the use of the cholinesterase inhibitor, aggression ceased in both cat and man (Bear, 1991). On the other hand, cholinergic deficit in the cortex of Alzheimer patients correlates with aggressive behavior (Minger et al., 2000). Animal experiments and increased vasopressin levels in CSF in humans suggest that central vasopressin plays a facilitary role in aggressive behavior, while 5-HT may play a role in inhibiting aggressive behavior in personality-disordered individuals. The relationship between the CSF vasopressin levels and a life history of aggression is stronger among male than among female subjects. In addition, central catecholaminergic, opiate and ACTH systems are considered to play a role in aggression (Brunner et al., 1993; Coccaro et al., 1998; Manuck et al., 1999; Ryan, 2000). Concerning the latter compounds, it is of interest that, in patients displaying violent suicidal behavior, both in those who have recently attempted suicide and in those with a history of suicidal behavior, increased cortisol excretion and reduced noradrenalin functioning are observed (Van Heeringen et al., 2000). In addition, oppositional deficient disorder, also combined with attention deficit disorders, is accompanied by low cortisol levels in children (McBurnett et al., 2000; Kariyawasam et al., 2002). Perpetrators of domestic violence without alcohol dependence have lower CSF 5-HIAA levels (George, 2001), while the serotonergic system interacts in various ways with hypothalamic and endocrine systems. For instance, alcoholic, impulsive offenders with antisocial personality disorder have low CSF 5-HIAA and ACTH levels (Virkkunen et al., 1994). (c) Sex hormones and aggression Men in society are much more aggressive than women, yet under laboratory conditions similar propensities toward aggression are found. The between-sex differences are about one-third to one-half of the within-sex standard deviation. Although 80% of the homicides in North America are committed by males, this sex difference is not reflected by homicide within marriage. Apparently the situation in which aggression is committed is an important influence on these sex differences (Albert et al., 1993). In addition, in women correlations have been reported between the premenstrual or menstrual

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phase and violent crimes and suicides (Parlee, 1973), indicating a relationship between hormones of the gonadal axes and violence. Women with bulimia nervosa have increased plasma testosterone levels that correlate with aggressiveness in patients but not in controls (Cotrufo et al., 2000). A link between testosterone and aggressive behavior in humans has often been presumed and some studies indeed claim such a relationship (e.g. Dabbs et al., 1987; Ryan, 2000). For instance. in competitive hockey, outbursts of violent behaviors as a response to threat show a positive correlation with serum testosterone levels (Scaramella and Brown, 1978). In addition, it has been found that individuals who have a history of numerous antisocial life histories tend to have higher testosterone levels (Aromäki et al., 1999). Perpetrators of domestic violence with alcohol dependence have higher CSF testosterone levels than such perpetrators without alcohol dependence or healthy controls (George et al., 2001). In addition, higher CSF levels are observed in alcoholic, impulsive offenders with antisocial personality disorder. However, the serum testosterone levels of high- and low-aggression individuals do not differ consistently, aggression does not change at puberty when testosterone levels increase, nor does aggression increase in hypogonadal males when testosterone is substituted. Aggression also does not seem to increase in hirsute females, even though testosterone levels may double, and castration or antiandrogen administration in men is not associated with a consistent decrease in aggression. The antiandrogen cyproterone acetate inhibits sexual activity but not aggression (Albert et al., 1993). A number of studies have indicated that following castration a substantially reduced recidivism rate is found in sexual offenders. In addition, cyproterone acetate may reduce deviant sexual arousal as shown in, e.g. a case study on a sadistic homosexual pedophile of 23 years of age with a serious, chronic organic brain syndrome (Bradford and Pawlak, 1987). Aggression in humans has, according to some authors, a number of features in common with defensive aggression seen in nonprimate mammals, rather than having its biological roots in hormone-dependent aggression based on testosterone (Alpers, 1937; Albert et al., 1993; see also citation at the beginning of Chapter 26.9). Mazur and Booth (1998) share the doubts expressed by Albert et al. (1993) that circulating testosterone directly affects human aggression, i.e. the intentional infliction of physical injury. Instead, they favor the hypothesis that high or rising testosterone encourages dominant behavior

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intended to achieve or maintain high status (implying power, influence and valued prerogatives). Sometimes dominant behavior is aggressive, its apparent intent being to inflict harm to another person, but often dominance is expressed nonaggressively. Sometimes dominant behavior takes the form of antisocial behavior, including rebellion against authority and the breaking of laws. Measurement of testosterone predicts many of these dominant or antisocial behaviors – testosterone levels, aggressiveness and antisocial behavior all peak in the late teens and early twenties, and then slowly decline throughout adult life in men. However, the causal role of testosterone remains an unanswered question. Testosterone not only affects behavior, it also responds to it. Testosterone rises in the face of a challenge. After a competition testosterone rises in winners and declines in losers. In prepubertal boys with a conduct disorder, the adrenal androgen levels of DHEAS and androstenedione were elevated, suggesting that adrenal androgens may play a role in the onset and maintenance of aggression in young boys (Van Goozen et al., 1998b). Aggression in two men with dementia and aggressive physical behavior was recuced after treatment with conjugated estrogen or diethylstilbestrol (Ryan, 2000). (d) Stereotactic hypothalotomy It is alarming to know that hundreds, if not thousands, of patients have undergone primary or secondary stereotactic posteromedian hypothalamotomy for “untreatable aggressiveness”, with claims of high improvement rates. The operation was based upon the animal experimental observation that “sham rage” arose from the hypothalamus (see above). Some surgeons preferred primary unilateral hypothalamotomy (Sano et al., 1970; Schvarcz et al., 1972; Schvarcz, 1977), whereas others performed bilateral amygdalatomy as a first step and proceeded 8–12 weeks later with secondary unilateral hypothalamotomy in those cases where the first operation had not been successful (Ramamurthi, 1988). The patients were reported to become calm, passive, and tractable, and showed decreased spontaneity. Intelligence was not impaired (Sano et al., 1966). However, quantitative data are lacking. Amazingly, many of the patients were children under the age of 15 years, and even as young as 6 or 7 years, who had developed aggressive behavior as a result of some insult of the brain. Although it is not clear, on the basis of scientific evidence, that this region is related to aggressive behavior, the target 287

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area for the stereotactic operations in the posteromedian hypothalamus was identified by autonomous stimulation effects (Chapter 30) such as a rise in blood pressure, pulse rate, apnea and ocular movements. This area was called the “ergotropic triangle”, based upon the subdivision made by Hess. It lies more than 1 mm and less than 5 mm lateral to the lateral wall of the third ventricle, where it occupies a triangle formed by the midpoint of the intercommissural line, the rostral end of the aqueduct and the anterior border of the mamillary body. The larger part of the lesion side thus lies posterior to the hypothalamus, but the area includes at least the posterior part of the posterior hypothalamic nucleus (Sano et al., 1966, 1970; Ramamurthi, 1988; Sano and Mayanagi, 1988; Chapter 13.3). Also children with low IQ and a wild form of aggressiveness (‘oligophrenia erethica’ or ‘agitated idiocy’) have undergone such operations where lesions of less than 6 mm in diameter are made. After the operation all the auto- and heteroaggression disappeared. Agitation also improved enormously, and these children were said to be able to live at home and mix with other children (Arjona, 1974; Rubio et al., 1977;

Laitinen, 1988). The patients became tame and passive and showed decreased spontaneity. The latter two symptoms improved within the 1st month. The patients were not emotionally ‘flat’; but restlessness lessened. In addition, this operation was performed on schizophrenic patients with extremely severe restlessness, agitation and autodestructiveness, with good results, according to Laitinen (1988), who concludes “I feel that posteromedial hypothalamotomy is one of the most rewarding psychosurgical interventions”. At this moment we can ˇ only point to the risks of such operations (Sramka and Nádvorník, 1975; Rubio et al., 1977), to their poor scientific basis and evaluation, to the unacceptable ethical problems involved and to the fact that this procedure has not been confirmed or accepted in the meantime. I am convinced that if we succumb to the temptation to use violence in our struggle for freedom, unborn generations will be the recipients of a long and desolate night of bitterness, and our chief legacy to them will be a neverending reign of chaos. Martin Luther King, from The Words of Martin Luther King, 1958.

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CHAPTER 27

Schizophrenia and autism

I believe that the great diseases of the brain . . . will be shown to be connected with specific chemical changes in neuroplasm . . . It is probable that by the aid of chemistry, many derangements of the brain and mind, which are at present obscure, will become accurately definable and amenable to precise treatment, and what is now an object of anxious empiricism will become one for the proud exercise of exact science. J.L.W. Thudicum. A Treatise on the Chemical Constitution of the Brain – Based throughout upon Original Researches (1884)

and Lawrie, 1995; O’Dwyer, 1997; Rantakallio et al., 1997; Squires, 1997; Van Os and Selten, 1998; Vincent et al., 1999; McNeil et al., 2000; Zornberg et al., 2000; Verdoux and Sutter, 2002). A meta-analysis revealed three groups of obstetric complications to be significantly associated with schizophrenia: (i) complications of pregnancy (bleeding, diabetes, rhesus incompatibility, preeclampsia); (ii) abnormal fetal growth and development (low birth weight, congenital malformations, reduced head circumference); and (iii) complications of delivery (uterine atony, asphyxia, emergency cesarean section). However, pooled estimates of effect sizes were generally less than 2 (Cannon et al., 2002). In addition one may presume that the increased frequency of obstetric complications may be the first sign of a disorder of brain development in schizophrenia, rather than that birth complications have a negative impact on brain development and increase the risk of schizophrenia (see Chapter 8.1). No significant association has been found between prenatal exposure to the maternal stress of the Dutch flood disaster of 1953 and the risk of nonaffective psychosis (Selten et al., 1999a), but the stress of war is a risk factor for schizophrenia (Van Os and Selten, 1998). It has been proposed that jet lag may elicit psychosis and even schizophrenia (Katz et al., 2001). A significant relationship is found between season and schizophrenia incidence, which may be related not only to viral infections, but also to parental procreational habits (Battle et al. 1999; Suvisaari et al., 2001). However, neither influenza nor measles is predictive of schizophrenia prevalence (Battle et al., 1999). In addition, no relationship has been observed between second-trimester exposure to the 1957 influenza

Our hope for the future lies . . . in organic chemistry or in an approach to (psychosis) through endocrinology. Today this future is still far off, but we should study analytically every case of psychosis because the knowledge thus gained will one day direct the chemical therapy. Sigmund Freud in a letter to Marie Bonaparte, 1930 (cited by Nemeroff, 1998).

27.1. Schizophrenia Als ik mijn pillen niet meer neem, word ik meer schizo dan freen. Kees Winkler.1

(a) A developmental disturbance Schizophrenia is considered to be a multifactorial disorder of brain development in which various risk factors may play a role, such as genetic factors (see below), chromosome 22q11 deletion (Chow et al., 2002), advanced paternal age (Malaspina et al., 2002a), viral infections, metabolic factors during pregnancy or early childhood, prenatal exposure to maternal stress or obstetric complications (Susser et al., 1992, 1996; Geddes

1

Without my pills I am more schizo than phrenic.

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Fig. 27A.

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Malle Babbe. Frans Hals (1582/83–1666). Kat. Nr. 801 C, Staatliche Museen, Berlin, Gemäldegalerie. Photograph: Jörg P. Anders, with permission.

pandemic and risk of nonaffective psychosis in the Dutch population (Selten et al., 1999b), which does not support the possible relationship between maternal influenza and schizophrenia reported by others. The first episode of schizophrenic psychosis appears to be spared any seasonal fluctuations (Strous et al., 2001). Exposure to nutritional deficiency, which is a risk factor for schizophrenia, during fetal life in the Dutch hunger winter, is associated with decreased intracranial volume and with an increase in brain abnormalities, predominantly white-matter hyper-

intensities (Hulshoff Pol et al., 2000). Another observation in favor of developmental sequelae in schizophrenia is that the risk of developing not only schizophrenia, but also a schizoid personality is increased following prenatal exposure to famine (Hoek et al., 1998). In addition, breastfeeding postpones the onset of schizophrenia (Amore et al., 2003). Various genetic factors may play a role. 22q11 deletion syndrome is a genetic syndrome associated with an increased risk of developing schizophrenia (Chow et al.,

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2002). Some 6.3% of Klinefelter patients (see Chapter 24.4) are diagnosed as suffering from schizophrenia, and 5.8% of having a psychosis of uncertain type (Wakeling, 1972). A high frequency of 7-nicotine receptor polymorphism has been reported in schizophrenia. It is presumed not only to be involved in the pathogenesis of this disorder, but also to be responsible for the heavy smoking habits of schizophrenics (Stassen et al., 2000). Moreover, catechol-O-methyl transferase gene polymorphism was found to influence the susceptibility to schizophrenia in a Japanese family (Ohmori et al., 1998; Weinbergen et al., 2001), while polymorphism in the tyrosine hydroxylase (TH) gene (Ishiguro et al., 1998) or in the promotor region of the neurotrophin-3 gene (Hattori et al., 2002) was found not to play a major role in the genetic predisposition to schizophrenia by others. It has been proposed that the different risk factors mentioned above may lead to changes in membrane phospholipid metabolism and fatty acid levels, as well as alterations in metabolism in certain brain areas (Horrobin et al., 1991; Pettegrew et al., 1991). Because children of women with schizophrenia are genetically predisposed to schizophrenia, it is of considerable interest that these children are also at risk for adverse pregnancy outcome. Children of women with schizophrenia are generally of lower birth weight, shorter gestational duration and increased risk of prematurity compared with the general population (Bennedsen et al., 1999). A major source of new mutations in humans is the male germ line, with mutation rates monotonically increasing as the father’s age at conception advances, possibly because of accumulating replication errors in spermatogonial cell lines. Paternal age is also a strong and significant predictor of schizophrenia that might thus also be associated with mutations in the paternal germ line. The odds of schizophrenia in offspring of fathers that are 45 years old are 2.8 times as great as in offspring of fathers aged 20–24 years of age (Malaspina et al., 2001, 2002a; Dalman and Allebeck, 2002). The high frequency of structural brain abnormalities reported in schizophrenia agrees with the developmental hypothesis. Enlargement of the ventricles, reduction of brain volume of temporal gyri, of gray matter, hippocampal and of entorhinal cortical volume have been reported. In contrast, the striatum is enlarged. Moreover, according to some studies, the massa intermedia or adhesio interthalamica (Chapter 6.2) is more frequently absent in female schizophrenic patients than in controls (Nopoulos et al., 2001), a difference that is not present in male schizophrenic patients (Meisenzahl et al., 2002).

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In fact, factors that produce normal sexual dimorphisms in the brain may be associated with modulating insults that produce schizophrenia (Goldstein et al., 2002). Cytoarchitectural abnormalities have been observed in the hippocampus and entorhinal cortex; also structures adjacent to the hypothalamus are affected. MRI and CT scans reveal a higher proportion of midline cerebral malformations in schizophrenia, such as cavum vergae and cavum septum pellucidum (Scott et al., 1993; see Chapter 18.8) and isolated absence of the septum pellucidum (Supprian et al., 1999). The prevalence of a cavum septum pellucidum has been found repeatedly to be increased in schizophrenia (Rajarethinan et al., 2001). In an MRI study, the prevalence was 26–30% for schizophrenic patients (Fukuzako and Kodama, 1998; Kwon, 1998) and 19% for schizotypical personality disorder, while in controls the prevalence was 10% (Fukuzako and Kodama, 1998; Kwon et al., 1998). In another MRI study, the frequency of enlarged cavum septum pellucidum was 13% in patients with childhoodonset schizophrenia compared with 1% in healthy volunteers. Two of the three patients with an enlarged cavum septum pellucidum had complete nonfusion of the septal leaflets, underlining the hypothesis that a developmental disorder may lie at the basis of schizophrenia (Nopoulos et al., 1998). Failure of fusion of the cavum septum pellucidum is associated with thought disorder in schizophrenia (Kirkpatrick et al., 1997) and with poor prognosis (Fukuzako and Kodama, 1998). The combination of cavum septum pellucidum and schizophrenia has been linked to hemizygous chromosome 22q11 deletion (Catch 22 syndrome) and to partial trisomy of chromosome 5 (Vataja and Elomaa, 1998). However, there are also studies that do not confirm a higher prevalence of cavum septum pellucidum in schizophrenia (Hagino et al., 2001). In the anterior commissure a reduction in fiber density is found in female but not in male schizophrenia patients (Highley et al., 1999). Olfactory deficits are found in particular in the subgroup of schizophrenic patients with severe polydipsia and hyponatremia (Kopala et al., 1998). In deficit syndrome, i.e. schizophrenic patients with enduring negative symptoms, an olfactory dysfunction was found (Malaspina et al., 2002b). Schizophrenic patients have not only functional olfactory deficits, but also structural ones. The olfactory bulb is 23% smaller than in comparison subjects (Turetsky et al., 2000). Patients without an adhesio interthalamica had significantly higher scores for negative symptoms (Meisenzahl et al., 2002). 291

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Patients with schizophrenia are no more prone to the development of Alzheimer’s disease than the general population (Bozikas et al., 2002). (b) Hypothalamic involvement The intersecting lines above the pituitary fossa were intended by Leonardo da Vinci (1452–1519) to show the senso comune (common sense). This position corresponded approximately to the third ventricle of the brain and, interestingly, was supposedly the locus of the soul in those days (Pevsner, 2002).

The possible involvement of the hypothalamus in the symptomatology of this psychosis is suggested by those cases that were first diagnosed as schizophrenia but appeared to have a tumor of the hypothalamic region (Malamud, 1967; Table 26.1). Psychotic symptoms have also been observed in patients with other hypothalamic disorders. In Prader–Willi syndrome, a hypothalamic syndrome with mental retardation (Chapter 23.1), psychotic episodes have been described, but it is not clear whether they are indeed more prevalent in this syndrome (Clarke, 1993; Clarke et al., 1995). Hallucinations also occur in acute intermittent porphyria (Chapter 28.3), narcolepsy and diencephalic tumors (Carroll and Neal, 1997). An astrocytoma of the visual pathway can lead to visual hallucinations (Haugh and Markesbery, 1983). Moreover, neurosarcoidosis, a disease that preferentially affects the hypothalamus (Chapter 21.1), has been confused with schizophrenia (Bona et al., 1998). Hallucinations were found in one case of Nasu-Hakola syndrome with hypothalamic hemorrhage (Kobayashi et al., 2000). In spite of the fact that hypothalamic processes may lead to schizophrenic symptoms, the neuropathology of the hypothalamus in schizophrenia has received only little attention. Stevens (1982) has reported increased, patchy fibrillary gliosis in the periventricular nuclei of the hypothalamus, bed nucleus of the stria terminalis, septal nuclei, substantia innominata, diagonal band of Broca and preoptic area in schizophrenic patients, suggesting previous or low-grade inflammation, as is found, e.g. secondary to an infectious or immunological disorder. There was no active inflammatory activity in these patients. A morphometric study has shown that the left, but not the right, mamillary body is significantly larger in schizophrenic patients, whereas neuronal numbers are the same on both sides (Briess et al., 1998). Loss of the large, presumably cholinergic neurons of

the nucleus basalis of Meynert has been described (Kish et al., 1990). Several neuroradiological and scanning studies have shown not only enlargement of the lateral ventricles in schizophrenia, but also atrophy of the periventricular gray matter surrounding the third ventricle at the level of the sulcus hypothalamicus (Lesch and Bogerts, 1984). Cullberg and Nybäck (1992) have found that third-ventricle enlargement is significantly associated with the persistence of auditory hallucinations in patients with schizophrenia. In addition, Jones et al. (1994) have shown that there is an association between larger third, but not lateral, ventricular size in affective psychosis. Staal et al. (2000) have found no difference in thirdventricle volume between schizophrenic patients and their healthy siblings. However, both have higher third ventricle volumes than the comparison subjects. From a follow-up study, it was concluded that enlargement of the third ventricle appeared to relate to poor outcome in schizophrenia (Staal et al., 2000). (c) Hypothalamic neurotransmitters, neuromodulators and neurohormones I emerged from irrational thinking ultimately without medicine other than the natural hormonal changes of aging. John Nash, Nobel laureate, who developed schizophrenia at age 32.

The dopamine hypothesis has dominated schizophrenia research for a long time. Increased dopamine activity would lead, in particular, to the positive symptoms of schizophrenia (Tandon, 1999). Dopamine has been called ‘the wind of the psychotic fire’ (Laruelle and AbiDargham, 1999). However, the new atypical antipsychotic drugs improve glutaminergic transmission (Rao and Kölsch, 2003), and it is also becoming clear now that many other neurotransmitter and neuromodulatory systems are affected in different brain areas, including the hypothalamus. Various changes in vasopressin and oxytocin neurons and levels have been reported in schizophrenia. Mai et al. (1993), have observed strongly decreased numbers of neurophysin-containing neurons in the paraventricular nucleus of untreated schizophrenic patients, but not in their supraoptic nucleus (SON). Unfortunately, the staining used by these authors did not distinguish between vasopressin- neurophysin or oxytocin neurophysin. Polydipsia and polyuria are relatively common in drug-free schizophrenic patients. Neuroleptic treatment is associated with a further significant increase in urine volume (Lawson

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et al., 1985). Complex changes in water metabolism with possible involvement of vasopressin have been reported in schizophrenia (Spigset and Hedenmalm, 1995). Compulsive water drinking and polyuria are found in some 20% of chronic schizophrenics (Legros and Ansseau, 1992). Water intoxication is a serious problem in many patients suffering from a chronic psychiatric illness, as are polydipsia and hyponatremia (Goldman et al., 1988; Verghese et al., 1993; McKenna and Thompson, 1998; see Chapter 22.3). So far, these phenomena seem to be due to unexplained defects in urinary dilution, osmoregulation or water intake and in the secretion of vasopressin. A “reset” osmostat and upregulation of vasopressin receptors in the kidney has been presumed (Goldman et al., 1988; Goldman, 1999). For reasons that are not quite clear, 3–5% of chronic schizophrenic patients are hyponatremic, develop the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and experience life-threatening episodes of water intoxication that may lead to seizures, delirium, irreversible neurologic defects, coma and death (Spigset and Hedenmalm, 1995; Goldman et al., 1997). Hyponatremia occurs particularly if patients are treated with drugs that reduce free water clearance, such as carbomazepine and phenothiazines. Acute severe hyponatremia leads to convulsions and coma. Chronic schizophrenic patients with chronic antipsychotic medication develop abnormal vasopressin, aldosterone and atrial natriuretic peptide secretion during anesthesia for abdominal surgery (Kudoh et al., 1998). Exaggerated vasopressin responses to osmotic stimulation have also been reported in comparison with nonpolydipsic schizophrenic patients with normal suppression of vasopressin levels after drinking. The osmotic threshold for thirst falls below that for vasopressin release, so that drinking to suppress plasma osmolality fails to suppress vasopressin release and therefore constant hypotonic diuresis develops (Goldman, 1999). The pathophysiology of abnormal thirst in schizophrenics is unknown, but may be based upon a defect in the central integration of thirst in the higher centers, rather than on a lesion in the osmoreceptors (McKenna and Thompson, 1998). Polydipsia is present in some 20% of chronic psychiatric inpatients and hyponatremia in more than 10% (De Leon, 2003). In the group of polydipsic schizophrenic patients, psychotic exacerbations are associated with chronic hyponatremia and with enhanced plasma levels of vasopressin. The exacerbated psychosis seems to be responsible for the enhanced vasopressin release. However, in a group of closely matched, nor-

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monatremic schizophrenic patients, vasopressin levels rose only a little, if they rose at all (Goldman et al., 1997). Moreover, Frederiksen et al. (1991) have not observed a difference in hypothalamic vasopressin content in schizophrenic patients. There is also no consensus as far as the circulating levels of neurohypophysial hormones in schizophrenic patients are concerned (Legros and Ansseau, 1992). Both the basal levels and the apomorphine challenge test indicated decreased vasopressinergic and increased oxytocinergic functions in one study (Legros et al., 1992). Reduced vasopressin levels and their corresponding neurophysin levels have also been observed in CSF and plasma (Sarai and Matsunaga, 1989); while, in contrast, schizophrenic patients have been reported by others to excrete less water after water loading, which suggests vasopressin hypersecretion (Goldman et al., 1988; Legros and Ansseau, 1992; Spigset and Hedenmalm, 1995; see also Chapter 22.6). Indeed, plasma vasopressin levels are found to be increased in acutely psychotic patients (Raskind et al., 1978). In schizophrenic patients who underwent elective lower abdominal surgery, abnormally high secretion of vasopressin was observed during anesthesia (Kudoh et al., 1998). Although Beckmann et al. (1985) did not find differences in vasopressin levels in the CSF in schizophrenia, the increased oxytocin levels in schizophrenic patients they reported have been confirmed by Legros and Ansseau (1992). CSF oxytocin levels in patients treated with neuroleptics and those from whom neuroleptics were withdrawn were unaltered in another study, suggesting that neither schizophrenia nor neuroleptic medication changed these neuropeptide levels (Glovinsky et al., 1994). Yet it should be noted that various observations indicate antipsychotic medicines might affect the activity of the vasopressinergic system. Psychotropic drugs such as thiothrix, amitriptylene, thioridazine and chlorpromazine might cause inappropriate antidiuretic hormone secretion. Irreversible neurological symptoms and even coma have been reported as a result of such effects (Ajlouni et al., 1974; Tildesley et al., 1983; Ananth and Lin, 1987). Also animal experiments point to a stimulation of SON and paraventricular nuclei (PVN) in rats treated with neuroleptics (Ireland and Connell, 1990). In addition, electroconvulsive therapy (ECT) results in a rise of vasopressin levels both immediately after ECT and 1 week after the last ECT (Narang et al., 1973). However, in one patient with schizophrenia and the syndrome of inappropriate vasopressin secretion, the hyponatremia was found to end after recovery from psychosis by ECT 293

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(Suzuki et al., 1992), suggesting that hyponatremia is related to the disease process. Consequently, a major task is to try to distinguish disease- and treatment-related effects in the reported hypothalamic alterations in schizophrenic patients in future research. Neuroleptics may facilitate vasopressin secretion (Spigset and Hedenmalm, 1995; Chapter 22.6) and dopamine may be a vasopressin-release inhibiting or stimulating factor (Lightman and Forsling, 1980; Chapter 8.2). An interesting question is therefore whether the expression of TH in vasopressin neurons is involved in such effects. In order to investigate which effects schizophrenia and the use of neuroleptics have on the activity of vasopressin neurons in schizophrenic patients we measured TH, mRNA and neurosecretory activity, using the size of the Golgi apparatus in the arginine vasopressin neurons of the dorsolateral SON of drug-treated schizophrenic patients and sex- and age-matched controls (in collaboration with M.T. Panayotacopoulou and Y. Malidelis, University of Athens, Greece). Significant differences were found neither in the amount of general protein synthetic activity of the vasopressin neurons of the SON, nor in the total amount of vasopressin mRNA, nor in the number of TH-immunoreactive neurons of schizophrenic patients as compared to controls. A stimulation of vasopressin production consequently does not seem to be the explanation for the complex changes in water metabolism reported in schizophrenic patients, such as compulsive water drinking, polyuria or symptoms of the syndrome of inappropriate antidiuretic hormone secretion (unpubl. observation). The typical onset of schizophrenia during late adolescence and early adulthood, during which there is a flood of estrogens and testosterone to the brain, and the additional small peak around the age of 45 years, when estrogen levels drop (Riecher-Rössler, 2002), has raised interest in possible hypothalamopituitary–gonadal abnormalities in this disorder. Indeed, menstrual irregularities, a greater variation in cycle length, a later menarche, loss of hair, mid-cycle bleeding and hirsutism have been reported in schizophrenia (Kamstra and Fujii, 2000; Riecher-Rössler, 2002). Estrogens are presumed to constitute a protective factor for schizophrenia that might be at least part of the explanation of the sex differences in this disorder. Moreover, women suffering from schizophrenia have significantly lower estradiol levels and experience the first onset or recurrence of a psychotic episode more often in a

low-estrogen phase of the cycle. However, hypothalamic downregulation of estrogen levels due to the stress of acute hospitalization must be borne in mind as a possible explanation of this phenomenon (Huber et al., 2001). Although administration of transdermal estradiol appears to have a positive impact on psychotic symptoms in women with schizophrenia (Kulkarni et al., 2000), and in postmenopausal schizophrenic women treated with antipsychotic medication (sex hormone replacement therapy may help to reduce negative but not positive symptoms; Lindamer et al., 2001), the presumed protective effect of estrogens does not fit in with the increased incidence of schizophrenia around puberty. Alternatively, androgens may consequently be considered as a risk factor for schizophrenia. A number of other neuroendocrine abnormalities have been reported in schizophrenia, although they may be at least partly influenced by medication. Some, such as an abnormal growth hormone response to thyrotropin (TSH) and luteinizing hormone-releasing hormone (LHRH) in adolescents, but not in adults, may indeed reflect developmental changes. Some patients on longterm neuroleptic therapy show low insulin-like growth factor-I (IGF-I) levels, pointing to a possible interference with the growth hormone axis (Melkersson et al., 1999). There is a high prevalence of thyroid function test abnormalities in chronic schizophrenia that may, at least partly, be due to a central disorder of the hypothalamopituitary–thyroid system (Othman et al., 1994). Some abnormalities seem to be related more directly to the prognosis of the disease process: a rapidly neurolepticresponsive and type of psychotic disorder with a good prognosis appears to be associated with blunted TSH response to thyrotropin-releasing hormone (TRH) and a blunted growth hormone response to apomorphine; a relatively drug-resistant psychotic disorder, whose response requires several weeks of neuroleptic treatment, appears to be associated with an excessive growth hormone response to apomorphine (Garver, 1988). Both basal and stimulated prolactin secretion, which are largely under dopamine control, are said to be normal in schizophrenic patients (Nemeroff, 1991), although in schizophrenic patients on long-term neuroleptic therapy, prolactin levels are elevated in 50% of the women and 10–20% of the men (Melkersson et al., 1999; Kaneda and Fujii, 2000). The normal gradual activation of the hypothalamopituitary–adrenal (HPA) axis between 12 and 20 years may provide an increased risk for schizophrenia in the

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pubescent period (Walker et al., 2001). Stress and the development of a schizophrenic psychosis are inextricably related (Gispen and De Wied, 2000). The sensitivity of the dexamethason/corticotropin-releasing hormone (CRH) test (about 80%) greatly exceeds that of the standard dexamethasone-suppression test (25–44%) (Heuser et al., 1994b). Schizophrenic patients, like other psychiatric patients, are generally reported to release significantly more cortisol and corticotropin (ACTH) after dexamethason and additional CRH administration. Glucocorticoid receptors are decreased in the cortex and hippocampus (Webster et al., 2002). These observations indicate that psychiatric patients are more prone to altered glucocorticoid feedback regulation during the acute illness episode. There is also evidence of a decreased response of the HPA axis in schizophrenic patients to psychological stress or to the stress of lumbar puncture (Jansen et al., 1998; Gispen and De Wied, 2000). Neuroleptics may influence HPA axis function (Kaneda and Ohmori, 2002). In addition, an exaggerated ACTH response to acute metabolic stress exposure is observed in schizophrenic patients who are given 2-deoxyglucose (Elman et al., 1998). A relationship seems to exist between negative symptoms of schizophrenia and nonsuppression in the dexamethasone test (Altamura, 1996). It should be noted that, in spite of the fact that 36% of their schizophrenic patients fulfilled the criteria for major depression, the dexamethasone suppression rates were very low in the study by Ismail et al. (1998), suggesting that depression in schizophrenia may have a different neuroendocrine profile than in major depressive disorder. Patients who are nonsuppressors on the dexamethasone test are more likely to be free of symptoms in a follow-up of up to 1 year. Nonsuppression is thus a prognostically favorable sign (Coryell and Tsuang, 1992). Higher cortisol plasma levels accompany lower metabolic rate in the hypothalamus as measured by PET scanning (Wik, 1996). The reduced number of nitric oxide synthase-containing/ NADP-diaphorase neurons in the PVN of schizophrenic patients is interpreted as being related to an increased release of CRH, vasopressin and oxytocin (Bernstein et al., 1998). Also, Bernstein et al. (2000) have failed to find a change in activity of this enzyme in the SON of schizophrenic patients. The concentration of CSF-CRH is slightly but significantly higher in schizophrenic patients (Banki et al., 1987), but the source of this CRH – i.e. PVN or an extrahypothalamic site such as the cerebral cortex – is not known. Leptin (see Chapters 11d

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and 23b) plasma levels are decreased in schizophrenic patients, while the body mass index remains normal. This may be related to the alterations in food intake, appetite and weight frequently observed in schizophrenia. In chronic schizophrenics, in addition to abnormal dexamethasone suppression, abnormal diurnal variations of cortisol levels are found. Those patients with abnormal diurnal cortisol variations gave higher scores for some negative symptoms (Kaneko et al., 1992). In addition, patients with more disturbed sleep and less robust circadian rhythms perform more poorly on neuropathological tests (Martin et al., 2001). These results show that not only the HPA axis is disturbed in schizophrenia, but possibly also, in a subgroup of patients, the suprachiasmatic nucleus. Indeed, there are several observations showing changes in the circadian rhythm in schizophrenia, suggesting a disturbed functioning of the suprachiasmatic nucleus (SCN) in this condition. The mesor of dopamine is higher in schizophrenic patients than in healthy subjects, while the mesor of prolactin and TSH is lower in drug-free schizophrenic patients than in healthy ones. In addition, a significant phase-advance of serum tryptophan, prolactin and melatonin concentrations was found in schizophrenic women (Rao et al., 1994, 1995). In another study Van Cauter et al. (1991) have concluded, however, that pituitary-adrenal function and circadian timekeeping are normal in schizophrenic men, but that prolactin secretion is hyperresponsive to the physiological stimulus of onset of sleep. In drug-free paranoid schizophrenic patients plasma melatonin circadian rhythm is completely absent, whereas the 24-h profile of plasma cortisol is preserved (Monteleone et al., 1992). On the other hand, on the basis of diurnal rhythms in plasma dehydroepiandosterone (DHEA), a clear distinction can be made between schizophrenic subjects and controls (Erb et al., 1981). The circadian rhythm disturbances in schizophrenic patients are related to levels of illumination, lifestyle factors, behavioral factors, psychiatric symptoms and medication. Although these relations are complex, the strong relationship between sleep and circadian rhythms and functioning (Martin et al., 2001) make biological clock disorders a clinically relevant topic in schizophrenia research. The most consistent sleep disturbance in schizophrenia is an increased sleep latency. Interestingly, the hypocretin levels in the CSF of schizophrenic patients correlate significantly and positively with sleep latency (Nishimo et al., 2002). The neuropeptide hypocretin is produced in

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the perifornical area of the lateral hypothalamus (Chapter 14) and involved in narcolepsy (Chapter 28.4). A hypothalamic system that may be involved in the pathogenesis of schizophrenia is the tuberomamillary nucleus, the source of histamine in the brain, and its sites of termination. Although on the one hand the favorable effect of histamine injections in schizophrenic patients and some quite indirect evidence indicate decreased activity of the histaminergic system (Heleniak and O’Desky, 1999), the elevated levels of histamine metabolites in the CSF of patients with chronic schizophrenia (Prell et al., 1995) suggest, on the other hand, increased activity of the tuberomamillary neurons. Histamine type2 receptor binding is found to be moderately higher in the globus pallidus of schizophrenic patients that are treated with neuroleptics (Martinez-Mir et al., 1993), and a few schizophrenic patients show symptomatic improvements following a histamine type-2 antagonist (Kaminsky et al., 1990; Rosse et al., 1995; Whiteford et al., 1995; Deutsch et al., 1997). Interestingly, recently allelic variation in the histamine H2 receptor gene has been found with an association with schizophrenia (Deutsch et al., 1997). Moreover, downregulation of the histamine H1 receptor has been found in the prefrontal cortex of schizophrenic patients (Nakai et al., 1991). It is of interest that the atypical, antipsychotic drug clozapine has an affinity for histamine too (Stevens, 2002). Postmortem studies on untreated schizophrenic patients and placebo-controlled, double-blind trials are necessary to confirm the possible involvement of the tuberomamillary histaminergic neurons in this disease process. A number of observations indicate that the cholinergic activity may be reduced in schizophrenia. The cholinergic nucleus basalis of Meynert (NBM) shows atrophy, cell loss and other degenerative changes (Von ButtlarBrentano, 1952; Kish et al., 1990; Caroff and Mann, 1993). Some of the earliest pharmacological treatments included cholinergic agents. The cholinergic system exerts a damping effect on the positive symptoms associated with increased dopaminergic activity and an intensification of negative symptoms, and, on the basis of pharmacological studies, an increased cholinergic activity in schizophrenia is presumed (Tandon, 1999). The involvement of the cholinergic system in schizophrenia is thus controversial. An enhanced rate of pineal and habenular calcifications and decreased pineal hydroxyindole-O-methyltransferase (HIOMT) activity is observed in schizophrenic patients. Since these alterations are related to increased third

ventricular width, it has been hypothesized that periventricular damage, in particular to the PVN in schizophrenia, might account for the enhanced calcifications (Sandyk, 1990, 1992a). The increased frequency of pineal calcifications in schizophrenia is also supposed to be related to the diminished nocturnal melatonin secretion that has been reported by various authors in schizophrenic patients (Fanget et al., 1989; Monteleone et al., 1992; Sandyk, 1992a; Brown, 1996; Pacchierotti et al., 2001), but the relationship between pineal calcifications and decreased melatonin production is controversial (Chapter 4.5). Possible medication effects are, however, important, since in the rat haloperidol is found to increase pineal gland melatonin levels (Gaffori et al., 1983). Pineal deficiency in schizophrenia is more evident in chronic disease (Vigano et al., 2001). Therefore, it is of the utmost importance that the observation of decreased nocturnal rise of melatonin in schizophrenia has been confirmed in drug-free patients (Robinson et al., 1991), although in a later study only a phase-advance of melatonin levels was found (Rao et al., 1994), which may contradict the former observations. On the other hand, a smaller pineal gland has been observed in schizophrenia using MRI (Bersani et al., 2002), which is in agreement with the earlierreported, diminished nocturnal melatonin levels. The observation that high-dose melatonin may exacerbate psychosis in schizophrenia (Miles and Philbrick, 1988; Pachierotti et al., 2001) makes the possible relationship between the pineal gland and schizophrenia of even higher interest. No significant differences have been found in the hypothalamic content of neurotensin, somatostatin, galanin, vasopressin, neuropeptide-Y, peptide YY, delta sleepinhibiting peptide or TRH in schizophrenic patients (Frederiksen et al., 1991; Nemeroff, 1991; Breslin et al., 1994). However, aberrant -endorphin metabolism has been found in the hypothalamus of these patients (Wiegant et al., 1992), and the number of -endorphincontaining neurons in the PVN and the innervation of PVN neurons by -endorphin-containing fibers is reduced in schizophrenic patients (Bernstein et al., 2002). A statistically significant but not clinically apparent decrease in schizophrenic symptoms appears after intravenous injection of -endorphin (Berger et al., 1981). The concentrations of - and -endorphins, but not that of -endorphin, were elevated. As the biological activity of -endorphins is disturbed, the antipsychotic effects of -type endorphins in schizophrenic patients is presumed to be based upon a deficiency of this type of endorphin

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in schizophrenia (Wiegant et al., 1992). Winblad et al. (1979) have found reduced concentrations of 5-HT in the hypothalamus of demented schizophrenics which were not believed to be due to the neuroleptic treatment. Increased levels of norepinephrine were found in the bed nucleus of the stria terminalis, ventral septum and mamillary body in postmortem tissue of schizophrenic patients (Farley et al., 1978). One might wonder to what degree the autonomic disturbances reported in schizophrenia (Zahn et al., 1997) may be due to hypothalamic disturbances. From estimation of metabolites in the peripheral blood, upregulation of the hypothalamic digoxin-mediated isoprenoid pathway is proposed in schizophrenia (Kumar and Kurup, 2001b). In conclusion, quite a number of morphological, physiological and endocrine disturbances point to a considerable hypothalamic involvement in schizophrenia. However, neither the enlarged third ventricle size (Chapter 27b) nor the various hypothalamic changes reported in schizophrenia constitute any scientific justification for hypothalamotomy, which has been performed in schizophrenic patients (Balasubramaniam and Kanaka, 1975).

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complications are also mentioned as risk factors (Verdoux and Sutter, 2002). Autism is associated with specific hereditary disorders such as untreated phenylketonuria, fragile-X disorder, chromosome 15q duplications and tuberous sclerosis (Schroer et al., 1998; Insell et al., 1999; Nelson et al., 2001). Increased incidence of thyroid disease of the parents has been proposed as a preconceptional factor for autistic children (Coleman, 1979; Gillberg and Coleman, 1992). On the basis of studies in families and twins, and based on cytogenetics and molecular genetics it is now thought that genetic influences are dominant underlying factors. The relative risk of first relatives is about 100-fold higher than the risk in the normal population and the concordance in monozygotic twin is about 60% (Andres, 2002). Piven (1997) has calculated that the broad heritability is more than 90%. Chromosome anomalies have been reported in autism to involve almost all chromosomes and many types of rearrangements (Van Karnebeek et al., 2002). Numerous candidate genes have been proposed on the basis of their possible functional role in neurotransmission (Korvatska et al., 2002). Abnormalities of chromosome 15q11-13 have emerged as a common cause. This is also the region of the Angelman’s and Prader–Willi syndromes (Andres, 2002). Candidate genes in this region include the three genes for GABAA receptor subunits (Schroer et al., 1998; Wolpert et al., 2000). The regions of chromosome 7q31-35 and 16p13-3 also emerge as significant regions (International Molecular Genetic Study of Autism Consortium 1998; Lauritsen and Ewald, 2001). Another candidate gene is WNT2, which is located on the long arm of chromosome 7 (Wassink et al., 2001). A candidate gene on chromosome 7q is the vasoactive intestinal peptide receptor 2 (Asano et al., 2001). In one case an association of a xeroderma pigmentosa group C-splice mutation on chromosome 3 and autistic behavior has been described (Khan et al., 1998). A strong (65–73%) decrease in the nicotinic acetylcholine receptor has been found in the frontal and parietal cortex and cerebellum in autism. This concerns a selective loss of 4 and 2 immunoreactivity. These data indicate a disorder in the cholinergic basal nuclei (Court et al., 2000; Perry et al., 2001). The cortical muscarinic receptor was only 30% lower. No differences have been found in choline acetyltransferase (ChAT) or acetylcholine esterase activity (Perry et al., 2001). The vertical limb of the diagonal band of Broca shows a decreased cell density and small neurons that are markedly reduced in number (Baumann and Kemper, 1985; Baumann, 1991; Kemper

27.2. Autism Autism is a developmental disorder characterized by stereotypical, repetitive behaviors, disturbed social interactions (‘extreme autistic loneliness’) and difficulties in verbal and nonverbal communications. The incidence of autism is generally reported at less than 0.1%. Affected boys outnumber girls by about 4:1 and the children show a range of cognitive defects. Approximately 75–85% of these children function at a retarded level (Insell et al., 1999; Van Karnebeek et al., 2002). Impairment of reciprocal social interactions, verbal and nonverbal communication, and age-appropriate activities and interests become evident before the age of 3–5 years. The causes of autism are heterogeneous, including a major genetic factor (see below) and environmental insults, infectious causes (e.g. rubella, cytomegalovirus and herpes simplex (Korvatska et al., 2002), teratogenic influences (e.g. phenylketonuria, fetal alcohol syndrome, neonatal jaundice with kernicterus). Perturbations occurring near the time of neural tube closure can lead to autistic manifestations (Van Karnebeek et al., 2002), while arachnoid cysts (Tantam et al., 1990) and obstetric 297

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and Baumann, 1998). The cholinergic system is thus clearly affected in autism. A few observations indicate that the hypothalamus is affected in autism. Case reports have indicated several neuroendocrine disorders in some autistic patients. Gingell et al. (1996) have described a boy with childhood autism as defined by ICD-10. At 18 months of age, he was found to have a deficiency of antidiuretic hormone. He failed to respond to TRH and had a suboptimal growth hormone response. CT scans showed a small pituitary gland with a large CSF space around it. He received thyroxine, hydrocortisone, desmopressin (DDAVP) nasal spray and growth hormone injections. The boy’s history revealed delays in development and continence. His language functioning development and social interaction abilities were impaired, and there was evidence of restricted and repetitive stereotyped patterns of behavior. In addition he showed hyperphagia. The function of the vasopressin receptor 1A polymorphisms observed in autism (Kim et al., 2002) needs further study. Hashimoto et al. (1991) have found that the basal TSH levels and the response of TSH to TRH is lower in autistic patients than in the controls. Mean prolactin levels do not differ. In addition, growth hormone levels are below the normal range and the L-DOPA-stimulated or insulin-stimulated peak of growth hormone is delayed in autistic children. The clonidine-induced growth hormone peak is premature (Realmuto et al., 1990; Ragusa et al., 1993). These findings are interpreted as pointing to abnormalities in both dopaminergic and noradrenergic neurotransmission in autism, but primary hypothalamic defects should not be excluded. In the CSF of children with autism, IGF-I levels are decreased. It is not known whether IGG-I in the CSF is derived from the brain or produced in the periphery (Vanhala et al., 2001). In addition, male autistic children have lower plasma oxytocin levels than controls. Inferences to possible central changes in oxytocin release leading to behavioral disorders in autism have been drawn (Modahl et al., 1998). In addition to decreased plasma oxytocin levels, increased plasma levels of oxytocin at the C-terminal site with 3 amino acids was found. This suggests changes in processing by prohormone convertases (Green et al., 2001). In addition, abnormalities of vasopressin levels have been described (LeBoyer et al., 1992). Since oxytocin and vasopressin are involved in social behaviors (see Chapter 8), Insel et al. (1999) have proposed a connection between changes in these peptides and autism. They also mention an unpublished report indicating that systemic administration of oxytocin to

autistic children would increase social interaction. In a randomized double-blind trial, oxytocin infusion over a period of 4 h significantly reduced repetitive behaviors (Hollander et al., 2003). There are also data that indicate that autism in some children may accompany a dysfunction of the HPA axis. An abnormal diurnal cortisol rhythm or abnormal dexamethasone-suppression test results were found more frequently in poorly developed cases. The authors interpreted these changes in terms of a disorder of the serotonin (5-HT) metabolism (Hoshino et al., 1987), but this is not necessarily the case. The defect may also be primarily situated in the hypothalamic nuclei. On the other hand, serotonin reuptake inhibitors reduce persevering symptoms and aggression and improve language use and general functioning in adult autistics (McBride et al., 1996). Kulman et al. (2000) have reported significantly lower melatonin levels in autistic children and an absence of the nocturnal increase in this hormone. A case study of an autistic child with severe mental retardation has been reported who, when given melatonin at 9 p.m. experienced early morning wakening and fragmented night sleep; while, when melatonin was given at 11 p.m., night sleep was prolonged and sleep–wake rhythm improved (Hayashi, 2000). On the other hand, Chamberlain and Herman (1990) have proposed that a subgroup of autistic individuals have a hypersecretion of pineal melatonin. According to these authors, this could initiate a cascade of events, including hyposecretion of pituitary pro-opiomelanocortin and a hypersecretion of hypothalamic opioid peptides and 5-HT. Hypersecretion of melatonin might also inhibit the release of CRH, which would, in its turn, result in hyposecretion of pituitary ACTH and of -endorphin. Le Boyer et al. (1992) have indeed reported abnormalities in plasma -endorphin levels in autism. Symptoms of early childhood autism may result from excessive brain opioid activity, since the orally effective opioid antagonist naltrexone has yielded some promising therapeutic results (Leboyer et al., 1992). Whether the discrepancy with the data of Chamberlain and Herman (1990) can be explained by the existence of different subgroups of autistic patients or age effects still has to be studied. Neonatal blood concentrations of vasoactive intestinal polypeptide, calcitonin gene-related peptide and the neurotrophin nerve growth factor and neurotrophin 4/5 are increased, but it is not clear from which organ, let alone brain area, these compounds are derived (Nelson et al., 2001).

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Asperger’s syndrome lies within the autistic spectrum and is characterized by greater clumsiness, floppiness of limbs and less-impaired language development. It is associated with intellectuality. There is a male preponderance, and the syndrome has been associated with mental retardation, Tourette’s syndrome, aminoaciduria, Marfan’s syndrome, epilepsy and a colloid cyst of the third ventricle. A developmental defect of midline structures may be the basis of this syndrome (Tantam et al., 1990). A patient with Asperger’s syndrome, central diabetes insipidus, empty sella and primary polydipsia (i.e. compulsive drinking) has been described (Raja et al., 1998). Asperger’s syndrome may also be found in juvenile and young-adult mentally disordered offenders (Siponmaa et al., 2001). In a randomized trial, oxytocin appeared to reduce repetitive behaviors in patients with Asperger’s disorder (Hollander et al., 2003). Sleep disturbances are common in Asperger’s syndrome; in an open trial, melatonin appeared to improve sleep patterns and behavioral measures (Paavonen et al., 2003), but these results need to be confirmed in a controlled study.

Some patients with hypothalamic hamartomas (see Chapter 19.3) have severe autistic behaviors. Interestingly, striking improvements of these behaviors are observed during treatment with intermittent left vagal nerve stimulations (Murphy et al., 2000). Sleep disturbances in autism have been successfully treated with light therapy, chronotherapy (Hoban, 2000) and melatonin (Hayashi, 2000). In spite of the neuroendocrine alterations that have been reported in autism, only a few areas of the hypothalamus have so far been studied. The autistic brains show increased cell-packing density and reduced nerve cell size, e.g. in the mamillary body and the medial septal nucleus (Bauman and Kemper, 1985; Bauman, 1991). These abnormalities noted in brains from autistic patients appear to have been acquired early in development. In addition, numerous swollen axon terminals (spheroids) are located in the cholinergic basal nuclei – the NBM and diagonal band of Broca – in a number of hypothalamic nuclei: infundibular nucleus, mamillary body, PVN, dorsomedial nucleus, ventromedial nucleus, and posterior and lateral hypothalamus in the neocortex, thalamus and brainstem. These abnormalities suggest a defect in axonal transport or synaptic transmissions (Weidenheim et al., 2001).

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CHAPTER 28

Periodic disorders

The symptoms of a variety of disorders whose cause is unknown and that recur regularly are called “periodic diseases”. Depending on the most prominent clinical feature, they are called, e.g. periodic fever or periodic hypothermia, as found, e.g. in Shapiro syndrome (Chapter 28.2), periodic somnolence and morbid hunger, as seen in Kleine–Levin syndrome (Chapter 28.1), periodic neutropenia, cyclic vomiting or periodic apnea during wakefulness as seen in Rett syndrome (Chapter 2.5; Naidu, 1997). Cluster headache has a highly distinctive cyclic recurrence pattern (Chapter 31.3a). Recurrent nocturnal headaches that awaken the patients from sleep at a consistent time have been described as the hypnic headache syndrome (Newman et al., 1990; Chapter 31.3c). Episodes of stupor of unknown origin may also be recurring. During such periods the EEG shows a physiological sleep pattern and the endogenous benzodiazepine receptor ligand endozepine-4 levels may be elevated 40 to 300 times in plasma and CSF (Tinuper et al., 1994). A patient with a circadian pattern of episodes of stupor is described in Chapter 4.6). In addition, cases of menstruation-linked hypersomnia have been described (see below). Circadian and circannual disorders that probably find their origin in the suprachiasmatic nucleus are discussed in Chapter 4. For periodic aspects of depression, see Chapter 26.4f. Although vasomotor disturbances may often be present in headaches, the pathogenetic mechanism and the brain structures involved in other periodic disturbances are unknown (Reimann, 1951). There are, however, also a number of periodic disorders for which there are good indications (narcolepsy is an example of this) that the hypothalamus is involved. They are discussed in this chapter.

28.1. Kleine–Levin syndrome (periodic somnolence and morbid hunger) Attention was first drawn to this disorder by Kleine (1925), who described five patients with periods of excessive sleep, day and night, two of whom also had an excessive appetite, while Levin (1929) confirmed Kleine’s observations and described a young man with attacks of sleepiness and pathological hunger. Critchley (1962) preferred the name ‘periodic hypersomnia and megaphagia’ and described it as “a syndrome composed of recurring episodes of undue sleepiness lasting some days, associated with an inordinate intake of food and often with abnormal behavior”. Adolescent males are affected exclusively or even predominantly, although some girls with similar symptoms have been described (Duffy and Davison, 1968; Gilligan, 1973; Malhotra et al., 1997). In a case of menstruation-linked periodic hypersomnia, an increased turnover of serotonin has been observed (Billiard et al., 1975). The onset is in adolescence and in general the syndrome eventually disappears spontaneously. However, Critchley (1962) has pointed out that a number of female patients did not fulfil the criteria, such as one girl of 7 years who had a ‘pseudotumor’ following a diencephalic disturbance, women with attacks corresponding to the menstrual periods, women with comparable symptoms following encephalitis. Although four female patients with the classic triad, i.e. hypersomnolence, hyperphagia and hypersexuality, have been described (Kesler et al., 2000), it remains questionable whether female patients with somnolence without recurring megaphagia in association with each menstruation should be considered as cases of Kleine–Levin syndrome.

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Gadoth et al. (2001) have found a mean age at onset of 16 years, but records of older patients exist (Badino et al., 1992). The average period between attacks is 6 months, but intervals of 6 years have been described, e.g. in a student aviator (Wygnanski et al., 1996). The mean duration of a single hypersomnolent period is 12 days (Gadoth et al., 2001). During a period of somnolence the patient can always be aroused and wakens spontaneously to empty the bladder. Sleep recordings during a hypersomnolent period show frequent awakenings from sleep stage 2 (Gadoth et al., 2001). Psychiatric manifestations such as sexual disinhibition, confusion, agitation, depersonalization, forgetfulness, disturbed sense of time, vivid imagery and visual and auditory hallucinations are frequent. Waking fantasies of a bizarre and crudely sexuosadistic nature are common (Kahn and Johnson, 1987). The association between sleep disturbance, increased food intake, disordered sexual behavior, a loss of normal diurnal variation of plasma cortisol, abolished corticotropin (ACTH) and cortisol responses to insulin-induced hypoglycemia, high values of thyrotropin (TSH) and prolactin, absent TSH response to thyrotropin-releasing hormone (TRH), luteinizing hormone (LH) abnormalities, and abnormal secretion of growth hormone during the hypersomnia episodes suggests reversible hypothalamic dysfunctions. On the basis of the hormonal changes, a reduced hypothalamic dopaminergic tone is presumed (Duffy and Davison 1968; Gilligan, 1973; Gadoth et al., 1987; Fernandez et al., 1990; Chesson et al., 1991; Fenzi et al., 1993; Malhotra et al., 1997; Müller et al., 1998b). It should be mentioned, however, that other brain areas may also be functionally altered (Landtblom et al., 2002) and that a study of five Kleine–Levin syndrome patients did not reveal any evidence of hypothalamic neuroendocrine or circadian dysfunction. Although these authors found increased melatonin levels in all patients during symptomatic periods (Mayer et al., 1998b), this was not confirmed by Gadoth et al. (2001) in one patient during an attack. In agreement with the clustering of hypothalamic symptoms in a number of studies, perivascular lymphocytic infiltration and microglial proliferation nodules have been found in the hypothalamus, particularly in the floor of the third ventricle, but also in the thalamus, and periaqueductal gray, amygdala and temporal lobe. The infiltrated cells reacted with antibodies against macrophages and T cells (Fig. 28.1; Takrani et al., 1976; Carpenter et al., 1982; Fenzi et al., 1993). It should be noted, though, that there are only a few cases with such

Fig. 28.1. (a) Microglial nodule in the posterior hypothalamic nucleus of a patient with Kleine–Levin syndrome (hematoxylin and eosin,  210). (b) Anti-HAM 56 antibody showing immunoreactivity of microglial cells and their dendritic processes. ABC method. (From Fenzi et al., 1993, Fig. 2, with permission.)

neuropathological changes in the hypothalamus that had unusual clinical features (Katz and Ropper, 2002), including two cases involving girls. The structural lesions in the hypothalamic area reported in some cases of Kleine–Levin syndrome, i.e. hypodense lesions in the suprasellar cistern, suggesting an infundibular lipoma and a large and asymmetrical mamillary body, need to be confirmed in other cases (Landtblom et al., 2002). The relapsing course of the disease, the neuropathological findings, the younger age at onset, and the high allele frequency of HLA-DQB1*0201 suggest an immunemediated process with selective involvement of the

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diencephalon and midbrain structures (Dauvilliers et al., 2002). Prevalence of T lymphocytes points to an unknown viral antigen. In fact, in 35–50% of cases of Kleine–Levin syndrome, the onset is preceded by respiratory tract infection, acute viral encephalitis or vaccination (Merriam, 1986; Fenzi et al., 1993; Salter and White, 1993; Pike and Stores, 1994). Epstein-Barr and varizella-zoster virus have been mentioned in this connection (Müller et al., 1998b). This raises the possibility that a dormant neurotropic virus is activated and causes the attack. In addition, the syndrome has been related to affective disorders on the basis of a positive therapeutic response to lithium (Lemire, 1993; Pike and Stores, 1994). A recent report mentioned, for the first time, two familial cases: a brother and a sister who developed their symptoms in early adolescence, within 5 months of each other, and who shared the HLA-DR2 haplotype, suggesting a potential hereditary cause (Katz and Ropper, 2002). Kleine–Levin syndrome has been associated with various other disorders. Two cases of Kleine–Levin syndrome with Asperger’s syndrome have been described (Berthier et al., 1992). Moreover, the syndrome has been seen in association with head trauma (Visscher et al., 1989), thalamic and multiple cerebral infarctions, and multiple sclerosis (MS). In a 9.5-year-old Prader– Willi patient (Chapter 23.1) in whom the diagnosis was confirmed, showing 15q12 deletion from the paternal chromosome, the clinical features of Kleine– Levin syndrome have also been described, i.e. periodic hypersomnia and hyperphagia. MRI revealed a small hypothalamus (Gau et al., 1996). The relationship between these two syndromes deserves further study. A 54-yearold man has been reported who developed the symptoms of Kleine–Levin syndrome at the age of 50. Four years later Parkinsonian symptoms appeared. The hormonal changes supported the hypothesis that a reduced hypothalamic dopaminergic tone was present in symptomatic periods. The presence of Parkinsonian symptoms suggests a general dopaminergic dysfunction in that patient (Müller et al., 1998b). In addition, a 20-year-old man has been described who presented with episodes of daytime hypersomnia, orthostatic hypotension, psychotic behavior, compulsive masturbation and abnormalities of eating habits. From a clinical point of view, it was suspected that he suffered from Kleine–Levin syndrome. However, eventually it turned out the patient had MS (Testa et al., 1987). One case of Kleine–Levin syndrome induced by triazolam has been described (Menkes, 1992) and one unusual female case of recurrent acromegaly,

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accompanied by Kleine–Levin syndrome, which developed 10 months after single-field radiation therapy, and Munchausen syndrome with self-inflicted anemia (Jungheim et al., 1999). An overlap between Kleine– Levin syndrome and narcolepsy (Chapter 28.5) is present (Gordon, 1992). For a differential diagnosis of Kleine– Levin syndrome, see Khan and Johnson, 1987. Amphetamine (methylfenidate, Ritalin), (Duffy and Davison, 1968; Gilligan, 1973; Visscher et al., 1989) and, for menstruation-linked periodic hypersomnia, estrogens (Billiard et al., 1975) have been proposed as therapy. 28.2. Spontaneous periodic fever, hypothermia, Shapiro syndrome and periodic Cushing’s syndrome Two hypothalamic centers are generally presumed to act reciprocally to maintain body temperature. The anterior, preoptic/septal center controls heat dissipation by stimulating a caudal hypothalamic region which induces vasodilatation and perspiration (see Chapter 30.1). Persistent hypothermia or poikilothermia due to thermoregulatory dysfunction with associated hypothalamic damage are well recognized, and acute brain dysfunction with hypothalamic involvement may cause transient hypothermia (Kloos, 1995; see Chapter 30.2). There are various hereditary periodic fever syndromes, such as: (i) familial Mediterranean fever, which maps to the short arm of chromosome 16. At least 28 mutations in the Mediterranean fever (MEFV) gene have been described. Colchicine prevents febrile attacks in the majority of the patients; (ii) Hyper-IqD-syndrome, which maps to the long arm of chromosome 12; and (iii) tumor necrosis factor (TNF)-receptor associated periodic syndrome or familial Hibernian fever, which maps to the short arm of chromosome 12. Patients with these disorders respond to high doses of oral prednisone (Drenth and Van der Meer, 2001). Chronic recurrent fever of central nervous system (CNS) origin is extremely rare. Recurrent and periodic febrile syndromes have been described under various names, such as Reiman’s syndrome, Welff syndrome, hypothalamic attacks, and autonomic (diencephalic) epilepsy. It has been postulated that in periodic fever the hypothalamic thermostat is reset to a higher level by an as yet unexplained central mechanism. A case has been described where the symptoms began on awakening and followed a 30-day cycle of fever. This disorder may be accompanied by behavioral disturbances (Van Hilten et al., 1997). 303

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In 1929 Penfield reported a patient with a thirdventricle tumor, markedly increased intracranial pressure and a defect of the corpus callosum. He proposed that mechanical irritation would lead to diencephalic autonomic epilepsy; symptoms including flushing, diaphoresis, and a fall in temperature. Abnormal EEG findings and manifest seizures have been reported. On the other hand, the response rate to anticonvulsants is lower than expected for an epileptic phenomenon (Kloos, 1995). Patients with diencephalic epilepsy may have various lesions in the hypothalamus such as angiomas, ischemia, infections, neoplasm, metabolic derangements and trauma (Klein et al., 2001). Periodic hypothermia has been observed in combination with agenesis of the corpus callosum (Shapiro syndrome). This disturbance is considered to be the result of a localized arrest in development of the lamina terminalis (Guihard et al., 1971; Noël et al., 1973). Several authors have reported the association of paroxysmal hypertension with spontaneous periodic hypothermia and Shapiro syndrome (Kloos, 1995). Noël et al. (1973) have described a patient with Shapiro syndrome who had severe neuronal loss and nonspecific fibrillary gliosis in the arcuate nucleus and premamillary region. The testes exhibited a dense interstitial fibrosis. Mitoses in the seminal tubules were rare and no Leydig cells could be observed. These abnormalities may be related to lesions in the infundibular nucleus, since this nucleus produces luteinizing hormone-releasing hormone (LHRH) (see Chapter 11). In a variant of Shapiro’s syndrome, there was a malformation of the corpus callosum, hypoplasia of the anterior commissure and absence of the septum pellucidum and columns of the fornix. The patient had episodic sweating and shivering with reduced temperature (Klein et al., 2001). Spontaneous periodic hypothermia has also been described when hypothalamic abnormalities are present that affect structures related to thermoregulation (Noël et al., 1973) and very rarely without an obvious brain lesion. During episodes varying from hours to weeks, with a periodicity from hours to years (the episodes have been described as periodic, recurrent, intermittent, remittent), these patients have active heat dissipation through vasodilatation and sweating and decreased generation of heat. Generally no abnormalities of thirst or water metabolism are noted during or between the episodes (Kloos, 1995). The pathophysiological mechanism of spontaneous periodic hypothermia remains unknown, but degenerative, irritative, neurochemical or structural abnormalities have been presumed. Engel and Aring (1945) have described

an 18-year-old boy with repeated paroxysms of coldness, shivering, pallor of extremities, fluctuating hypertension, oliguria, tachycardia and spiking temperature followed by abrupt temperature reduction toward normal values accompanied by profuse perspiration and flushing. Also his genitals were underdeveloped. Autopsy revealed cystic degeneration of the dorsomedial nucleus of the thalamus, the internal medullary lamina and the lateral nuclei of the right thalamus, while the hypothalamus itself was intact. The authors proposed that the thalamic lesion would have interrupted corticohypothalamic association fibers. Fox et al. (1970) have described a young man with repeated episodes of hypothermia, who had defects in heat conserving mechanisms of peripheral constriction and shivering. Necropsy revealed fibrillary gliosis in the anterior hypothalamus, i.e. in the preoptic and septal nuclei and in the medial hypothalamic area, the optic chiasm and the optic tracts. The cause of the gliosis was not apparent. There were no vascular, inflammatory or neoplastic lesion in the vicinity. Intermittent neurochemical dysfunctions have also been presumed to be possible causal mechanisms of periodic hypothermia. Catecholamine levels have sometimes been found to be elevated and clonidine might be effective in treating some patients. Dysfunction of vasopressin and endogenous opioids have also been presumed (Kloos, 1995). An inflammatory process, e.g. an autoimmune process, seems unlikely in view of the failure of exogenous steroids to be effective and the absence of histological data supporting such a possibility. An infectious etiology is also unlikely given the prolonged antibiotic trials and the lack of supportive histological data (Kloos, 1995). We have seen one case of spontaneous periodic hypothermia (NHB 94010). She had “hibernation” periods for 30 years, consisting of hypothermia combined with slow, passive behavior, diabetes insipidus, and leuco- and thrombocytopenia. In summer the symptoms abated and the need for vasopressin substitution lessened. She died of respiratory insufficiency, disturbed coagulation and bleeding from a rupture of the pulmonary artery. At autopsy no gross brain abnormalities were found. The neurohypophysis contained some groups of brown pigmented cells that are typical of a granular cell tumor or choristomas. These tumors are, however, generally considered to be asymptomatic (Chapter 22.1). The hypothalamus did not show abnormal microscopic anatomy, so an explanation for this condition was not found. In a 14-year-old boy with a suspected hypothalamic lesion, periodic release of ACTH and adrenal cortico-

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steroids has been reported. He had cyclic manifestations of nausea, vomiting, fever, emotional disturbances and a marked change in weight. Associated findings during the attacks were facial plethora, hypertension, abnormal glucose tolerance, elevated plasma ACTH and adrenal hyperfunction. The patient can thus be considered to have periodic Cushing’s syndrome. The disease process was effectively suppressed by dexamethasone treatment and chlorpromazine. The authors thought it unlikely that dexamethasone had an anti-inflammatory effect on the primary lesion (Wolff et al., 1964).

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exacerbations with discrete hypothalamic changes was reported (Suarez et al., 1997). He expired after being in septic shock. Sections through the hypothalamus revealed a reduction larger than 75% in the number of neurons with reactive astrocytosis in the SON and a reduction larger than 90% in the PVN at the level of the median eminence. In this case, damage to the SON and PVN during AIP exacerbations was also presumed to lead at first to an increase in circulating vasopressin. The cerebral cortex, hippocampus, basal ganglia, thalamus, cerebellum, midbrain, pons and medulla were unremarkable. In the kidney a general autopsy revealed over 75% of sclerotic glomeruli with advanced tubulointerstitial atrophy and interstitial fibrosis characteristics of end-stage renal disease. A 50-year old man had AIP with severe postural hypotension, hallucinations and inappropriate antidiuretic syndrome. A reduction of about two-thirds of the neurons in the SON and PVN occurred, as well as mild astrogliosis and vacuolar changes that did not contain neurosecretory substance in most of the remaining neurosecretory cells (Stein et al., 1972). A 19-year-old pregnant girl with AIP died of pneumonia. She had inappropriate secretion of antidiuretic hormone and neuronal loss in the SON and PVN (Kerr, 1973). Other hypothalamic abnormalities in AIP concern the regulation of growth hormone. Administration of glucose to patients with AIP often produces a paradoxical rise in the level of circulating growth hormone. In other patients the magnitude of the normal decline of growth hormone in response to glucose has been reported to be less. These changes are also probably due to hypothalamic damage (Perlroth et al., 1966).

28.3. Acute intermittent porphyria Acute intermittent porphyria (AIP) is a rare inborn error of metabolism with a prevalence of 1.5–4 per 100,000 and characterized by widespread lesions in the nervous system. The disease is inherited in an autosomaldominant fashion with a women to men ratio of 3 : 2. Biochemically it is characterized by deficiency of the enzyme hydroxymethylbilane synthase (Suarez et al., 1997) and excretion of porphyrin precursors in the urine. Clinically the disease manifests itself in the form of widespread neurological abnormalities with abdominal pain, constipation, nausea, vomiting, tachycardia, hyporeflexia, seizures, cranial nerve involvement, hypertension and fever. Frequently psychiatric manifestations included weakness, delirium, depression and psychosis (Suarez et al., 1997). Since AIP patients with seizures had significantly lower melatonin levels than AIP patients without seizures, melatonin was proposed to have a protective effect on seizures (Bylesjö et al., 2000; see also Chapter 28.5b). This possibility still has to be tested in a systematic way. In an autopsy of a 19-year-old girl with AIP, selective demyelination of the fasciculus gracilis in the cervical segment of the spinal cord, vagus nerve and the rostral optic tracts was found (Perlroth et al., 1966). The latter explains the patient’s blindness. In addition, the syndrome of inappropriate vasopressin secretion was found in this patient. An inflammatory lesion was seen in the median eminence and neurohypophysial stalk. In the supraoptic (SON) and paraventricular nucleus (PVN), respectively, 95% and 65% neuronal loss was found. The inappropriate vasopressin secretion was considered to be due to the fact that vasopressin leaked from the degenerating hypothalamo-neurohypophysial system, while diabetes insipidus was suspected in the terminal stage of this patient. Another case of a 41-year-old patient with multiple episodes of hyponatremia during AIP

28.4. Narcolepsy Sleep, eat and be merry. Orla Smith.

Narcolepsy is a chronic, disabling sleep disorder that affects 1 in 2000 individuals and consists of daytime sleepiness and sleep attacks, generally with a short duration of not more than 10 min or so that occurs several times a day. The patients are easily wakened (by touch or by calling them by name). The attacks are usually coupled with cataplexy (i.e. a sudden diminution of muscle tone, triggered by emotions; Fig. 28.2) and hypnagogic or hypnopompic hallucinations (i.e. hallucinations occurring in the process of falling asleep or while waking up). These hallucinations can be visual or auditory and are usually frightening. In addition, paralysis may occur. 305

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Fig. 28.2. Top: a cataplectic attack in a patient with narcolepsy, here elicited by laughter. Note that the paralysis is not instantly complete; the patient is able to reach out his arms to break the fall. Below: cataplectic attack in a hypocretin-receptor-2 mutated Doberman pinscher. The attack was triggered by the excitement from receiving a piece of palatable food. The attack is partial; the most obvious weakness is in the hindlimbs. (From Overeem et al., 2002, with permission.)

Most cases of narcolepsy start during adolescence and it is human leukocyte antigen (HLA)-associated, i.e. with HLA-DR2/DQB1*0602 and DQA1*0102 (Kadotani et al., 1998; Peyron et al., 2000; Van den Pol, 2000; Lin et al., 2001; Ripley et al., 2001; Thorpy, 2001). The HLA-DQB1*0602 frequency is increased in narcolepsy with typical cataplexy (93% versus 17% in controls), and present in 56% of the narcoleptic patients without cataplexy (Mignot et al., 2002). Because of the tight HLA association, the disorder has been suggested to be autoimmune in nature (Overeem et al., 2001; Thorpy, 2001). Hypocretin neurons are localized in the perifornical region in the human brain (Moore et al., 2001; Fig. 28.3). Their number was estimated to be between 15,000 and 80,000 neurons (Peyron et al., 2000). Recently it has been established by positioning cloning that an autosomal recessive mutation of the hypocretin (orexin) receptor 2 gene (HCRT2) is responsible for the genetic form in a well-established canine model, in Doberman pinschers and Labrador retrievers (Kadotani et al., 1998; Lin et al., 1999). In addition, hypocretin knockout mice exhibit narcolepsy (Chemelli et al., 1999), and modafinil, an antinarcoleptic drug, activates orexincontaining neurons. The hypocretin neurons are known to project to brainstem regions linked to motor inhibition as well as to the locus coeruleus (norepinephrine), raphe nucleus (serotonin), laterodorsal tegmental nuclei (acetylcholine) and ventral tegmentum (dopamine) (Peyron

Fig. 28.3. Section of the hypothalamus of a 58-year-old male control patient (NHB 98-090) stained with rabbit anti-orexin A 1:1250 (Phoenix Pharmaceuticals) according to the ABC method, with DAB-nickel ammonium sulfate as substrate. The fornix is surrounded by immunoreactive orexin neurons and fibers in the lateral hypothalamic perifornical area. Bar 50 m. (Preparation U. Unmehopa and H. den Hartog.)

et al., 2000; Van den Pol, 2000; Moore et al., 2001; Thorpy, 2001). In human narcolepsy the hypocretin neurons have disappeared (Peyron et al., 2000). Hypocretin-1 levels have been reported to be absent or dramatically decreased in the CSF of the majority of patients suffering from narcolepsy (Nishino et al., 2000, 2001; Melberg et al., 2001; Ripley et al., 2001). Hypocretin (CSF) levels below 110 pg/ml are diagnostic for narcolepsy, while values above 200 pg/ml are considered normal. Krahn et al. (2002) found that undetectable hypocretin-1 levels were highly specific for HLA-DQB1*0602 positive narcolepsy patients with cataplexy, whereas Ebrahim et al. (2003) also report deficient hypocretin-1 levels in CSF of patients with monosymptomatic narcolepsy. Hypocretin deficiency was also observed in a case of Niemann-Pick type C with cataplexy (Kanbayashi et al., 2003). Intermediate levels were observed in primary hypersomnia patients and patients with various acute neurological conditions, such as Guillain–Barré syndrome and myxedema coma secondary to Hashimoto thyroiditis (Mignot et al, 2002; Ebrahim et al., 2003). Krahn et al. (2002) have found that undetectable hypocretin-1 levels are highly specific for HLA-DQB1*0602-positive narcolepsy patients with cataplexy, whereas Ebrahim et al. (2003) also report

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deficient hypocretin-1 levels in CSF of patients with monosymptomatic narcolepsy. An MS patient has been reported with a new plaque in the hypothalamus who developed acute hypersomnia accompanied by undetectable hypocretin CSF levels (Iseki et al., 2002). In a case of acute disseminated encephalomyelitis with hypersomnia and hyperintense lesions in the hypothalamus, decreased hypocretin levels were found in the CSF (Kubota and Kanbayashi, 2002). Low hypocretin levels by others have also only been found in a few cases of Guillain–Barré syndrome, and low but detectable levels were found in a subset of patients with acute lymphocytic leukemia, intracranial tumors, craniocerebral trauma and CNS infections (Ripley et al., 2001; Kanbayashi et al., 2002a, b). Plasma hypocretin-1 levels are also supposed to be lower in most (but not all) narcolepsy patients than in age- and gender-matched normal controls (Higuchi et al., 2002). The finding that low plasma levels of orexin-A-like immunoreactivity may be a marker for the reactivity of sleep apnea (Nishijima et al., 2003) needs to be followed-up. Increased hypocretin-1 levels are found in the CSF of patients with restless legs syndrome. The increased CSF levels were most striking in the early-onset form of this sleep disorder (Allen et al., 2002). Immunocytochemical and in situ hybridization data indicate that there is a substantially (85–95%) reduced number of neurons producing hypocretins in narcoleptics (Peyron et al., 2000; Thannickal et al., 2000; Van den Pol, 2000). The detection of increased glial fibrillary acidic protein (GFAP) immunostaining of astrocytes in the perfornical hypocretin area of the brain of narcoleptics (Thannickal et al., 2000; Van de Pol, 2000) argues in favor of some type of neuronal degeneration. However, Peyron et al. (2000) could not confirm the presence of hypothalamic gliosis in narcolepsy. The reason for this discrepancy is not clear at present. Clearly more patients in different phases of the disease should be studied. Some rare polymorphism in the prepro-orexin was claimed to be associated with narcolepsy (Gencik et al., 2001) and a mutated signal sequence of hypocretism in a child with narcolepsy (Peyron, 2000). However, in contrast to animal models, most cases of narcolepsy are not familial (Siegel, 1999). It is thus unlikely that a high proportion of human narcoleptics have a mutation or a polymorphism responsible for narcolepsy, either in the Hcrt gene or in the HCRT-1 or -2 receptors (Ólafsdóttir et al., 2001). Narcoleptic patients were reported to have bilateral decreases in hypothalamic gray matter, using voxel-based morphometry and MRI (Draganski et al., 2002). How this

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finding relates to the observations in the hypocretin system is, at present, not clear. Hypocretins are not only involved in narcolepsy but also in eating behavior and metabolism (see Chapter 23c). The bodymass index is increased in narcolepsy patients, indicating altered energy homeostasis (Schuld et al., 2000; Dahmen et al., 2001). Since leptin levels in serum, are reduced in narcoleptic patients by more than 50% and increased in CSF, narcolepsy seems to be accompanied by complex alterations in the regulation of food intake and metabolism (Schuld et al., 2000; Nishino et al., 2001; Kok et al., 2002). In narcoleptic patients, hypocretin deficiency is accompanied by a disruption of the circadian distribution of growth hormone-releasing hormone release, in such a way that they secrete about 50% of their growth hormone during the day, whereas controls secrete only 25% of their growth hormone during that period (Overeem et al., 2003). This, and these patients’ propensity to fall asleep during the day, supports the notion that the function of the suprachiasmatic nucleus (SCN) is disturbed in this disorder. A large number of brain structures may be functionally or structurally affected in narcolepsy. In canine narcolepsy, neuronal degeneration is found in the amygdala, diagonal band of Broca, substantia innominata, preoptic regions and medial septum (Siegel et al., 1999). In the CSF of narcoleptic patients, substance P and somatostatin, 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmadelic acid (VMA) are decreased, while homovanillic acid (HVA) is increased. These changes seem to be related to the severity of the clinical symptoms of narcolepsy (Strittmatter et al., 1996a). Levels of serotonin and 5-HIAA in the hypothalamus of autopsied narcolepsy patients are significantly increased, whereas their molar ratio does not change (Kish et al., 1992). Symptomatic narcolepsy is not human leucocyte antigen-associated (Aldrich and Naylor, 1989). When CNS disorders and narcolepsy occur together, hypothalamopituitary pathology is the most common association. Association with Kleine–Levin syndrome, MS, diencephalic sarcoidosis, angioma, encephalitis, periventricular ependymal gliosis in the hypothalamus, pituitary adenomas, nonspecific hypothalamic endocrine syndromes and head trauma have been reported (Erlich and Itabashi, 1986; Aldrich and Naylor, 1989; Gordon, 1992; Clavelou et al., 1995; Malik et al., 2001). Narcolepsy has also been described in a 37-year-old man with tissue typing HLA-DR2 and DQ1 and hypothalamic neurosarcoidosis, in particular in the septal region, in the nucleus 307

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basalis of Meynert (NBM) and the rostral part of the amygdala (Servan et al., 1995). In addition, two cases of children with severe narcolepsy secondary to brain tumors have been reported. These children had suprasellar tumors and hypothalamic obesity, so that the hypothalamic hypocretin system may have been affected (Marcus et al., 2002). A young man has been described who developed narcolepsy after a massive hypothalamic stroke. The lesion included much of the region where hypocretin is produced, and his CSF levels of this neuropeptide were low. A loss of the hypocretin system seems, consequently, also to be the cause of secondary narcolepsy (Scammell et al., 2001). A close association has been described between REM sleep behavior disorder and narcolepsy. Sleep motor dyscontrol in narcolepsy may start as a non-REM sleep parasomnia in childhood and then the onset of narcolepsy might represent the turning point for its intrusion into REM sleep (Schenk and Mahowald, 2002). REM sleep disturbances are associated with narcolepsy, and animals studies have shown that the hypothalamus is involved in REM sleep regulation (Aldrich and Naylor, 1989). On the other hand, cortisol and melatonin show normal profiles, suggesting that the function of the circadian timing system is preserved (Van Cauter and Spiegel, 1997), although there is a loss of circadian rhythmicity in leptin levels in narcoleptic patients (Kok et al., 2002). In addition, narcolepsia may be associated with psychosis (Howland, 1997). In schizophrenic patients the CSF hypocretin levels correlate positively and significantly with sleep latency, one of the most constistent sleep abnormalities seen in this disorder (Nishino et al., 2002). 28.5. Epileptic seizures Hypothalamic involvement in epileptic seizures appears from (a) the occurrence of circadian patterns of ictal manifestations (Ellis, 1992) and their relationship to sleep, (b) the release of hypothalamic and pituitary hormones in relation to seizures, (c) epileptic seizures in case of hypothalamic hamartomas (see also Chapter 19.3a and 26.2) and (d) hypothalamic changes in patients with epilepsy, reported in a few autopsy cases. (a) Epilepsy, diurnal rhythms and sleep As early as 1929, Langdon-Down and Brain reported that two-thirds of epileptics manifested a marked difference

Fig. 28.4. Circadian distributions of seizures in a patient with intractable epilepsy who maintained an hour-by-hour seizure diary for over 5 years, denoting occurrence of either episodes of confusion and orofacial automation or episodes of abrupt left hand pain. Location of ictal foci were then documented by intracranial EEG using bilateral hippocampal depth electrodes and bilateral subdural strip electrodes. Whereas right temporal lobe seizures usually occurred diurnally, right parietal lobe seizures occurred nocturnally and out of phase with temporal seizures. Seizures clustered near times of transitions from sleep to wakefulness from either foci. Parietal lobe seizures also clustered at times habitually marked by transitions from wakefulness to sleep. (From Quigg, 2000, Fig. 3, with permission.)

in the diurnal and nocturnal incidence of their convulsions. Sleep may indeed profoundly modify epileptic seizures and interictal epileptic EEG activity. In partial epilepsy, circadian influences are obvious (Autret et al., 1997; Quigg et al., 1999; Fig. 28.4). Janz (1962) has described three types of courses of major seizures governed by the sleep–wake cycle: (1) grand mal attacks predominantly following waking, (2) grand mal epilepsies

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mainly after falling asleep and (3) grand mal epilepsies with irregular dispersed attacks. Frontal brain injuries lead mainly to sleep epilepsy, parietal lesions mainly to irregular epilepsy, while no correlations could be established for awakening epilepsy. On the other hand, there are several reasons to anticipate that the limbic seizures of mesial temporal lobe epilepsy due to hippocampal sclerosis (Chapter 29.7b) will alter circadian rhythms (Quigg et al., 1999).

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(cf. Sperling et al., 1986; Rao et al., 1989), a failure of prolactin to rise consequently does not exclude a diagnosis of complex partial seizures. Thus prolactin measurements do not help to differentiate frontal lobe complex partial seizures from psychogenic attacks of pseudoseizures: a failure to find increased postictal prolactin levels does not exclude the diagnosis of epilepsy (Laxer et al., 1985; Wroe et al., 1989; Meierkord et al., 1992). Norepinephrine, vasopressin and oxytocin, unlike prolactin, remain low during the aura and only rise during the generalized convulsions and motor features. During the state of postictal confusion norepinephrine remained high, but vasopressin and oxytocin decreased (Meierkord et al., 1994). Hyposexuality has been described in association with temporal lobe epilepsy and in patients that underwent temporal lobectomies. Hyposexuality in men may be associated with low levels of LH and elevated prolactin levels. Antiepileptic drugs may add to the hyposexuality, since they enhance testosterone metabolism (Schachter, 1994). Abnormal menstrual function and infertility has been reported in epileptic women. They may have LH, FSH, and testosterone concentrations suggestive of polycystic ovarian syndrome. Melatonin is presumed to have anticonvulsant properties (Bazil et al., 2000; Bylesjö et al., 2000). Saliva melatonin levels are reduced in patients with intractable temporal lobe epilepsy at baseline and increase threefold following seizures (Bazil et al., 2000). In patients with severe intractable seizures, melatonin was confirmed to have antiepileptic properties. This effect is proposed to be based upon its antioxidant activity as a free radical scavenger (Peled et al., 2001), but a more probable explanation is that melatonin is acting through the GABA and benzodiazepine receptor (Rohr and Herold, 2002). A novel class of antiepileptic drugs is also represented by the effects of TRH. TRH treatment has been reported to be efficacious in intractable epilepsies such as infantile spasms, Lennox–Gastaut syndrome, myoclonic seizures and other generalized and refractory partial seizures (Kubek and Garg, 2002). The hypothalamopituitary– adrenal (HPA) axis is also of interest in epilepsy, since corticotropin-releasing hormone (CRH) is a potent proconvulsant, particularly in the immature brain, while ACTH and corticosteroids have been studied mainly as anticonvulsants, useful in the treatment of infantile spasms. Fluctuations in the function of the various components of the HPA axis may thus play a part in the circadian fluctuations in seizures (Quigg, 2000).

(b) Epilepsy and hormone release Postictal elevation of serum prolactin levels has been found following tonic-clonic seizures and in focal epileptic seizures of temporal origin (Meierkord et al., 1992). In addition, following generalized tonic-clonic convulsions, increased plasma levels of ACTH, -endorphin, -lipotropin, LH, follicle-stimulating hormone (FSH; values increased in women only), growth hormone, vasopressin and cortisol were found (Dana-Haeri et al., 1983; Pritchard et al., 1983, Aminoff et al., 1984; Wyllie et al., 1984; Laxer et al., 1985; Wroe et al., 1989; Schachter, 1994). The mechanism underlying the hormonal discharges is presumed to be a spread of ictal discharges to hypothalamic structures that regulate anterior and posterior pituitary functions. Amygdaloid discharges might also be a basis for such hypothalamic alterations in view of the strong hypothalamic projections of this structure (Morales et al., 1995). In unilateral temporal epileptia without secondary generalization, growth hormone and prolactin release were not affected (Matthew and Woods, 1993). In infants, seizures had variable effects on serum prolactin levels. Marked prolactin increases were only noticed with focal tonic seizures and temporal involvement (Morales et al., 1995). In adults, prolactin plasma levels may already rise during the aura of a limbic seizure and may stay high during the phase of onset of generalized convulsions, cessation of motor features and the state of postictal confusion (Meierkord et al., 1994). Meierkord et al. (1992) found that six of the eight complex partial seizures of temporal origin were associated with a marked rise in prolactin plasma levels at 10 min after onset, compared with a rise in only one of eight frontal lobe complex seizures (two of temporal and three of frontal lobe origin) was associated with a marked rise in prolactin levels. Although this difference in prolactin response may help in the clinical differentiation between these seizures 309

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(c) Hypothalamic hamartomas and epilepsy Hypothalamic hamartomas (Chapter 19.3) are malformations containing hypothalamic neurohormones. They may cause gelastic seizures or attacks of laughter (Chapter 26.2). There may be later development of focal seizures, including complex partial seizures and a pattern of symptomatic generalized epilepsy with tonic, atonic and other seizure types in association with slow spike and wave discharge and cognitive deterioration. Since the time of Hughlings, Jackson focal seizures were, however, supposed to be due to discharges in cortical gray matter, and generalized seizures were supposed to arise from a central midline pacemaker. A midline hypothalamic hamartoma causing Lennox both focal and symptomatic generalized patterns of epilepsy thus seemed hard to fit in. However, hypothalamic hamartomas were shown to be intrinsically epileptogenic by direct ictal EEG recordings, increased ictal SPECT hyperperfusion in the hamartoma, hypothalamic region and thalamus only. Electrical stimulation reproduced the gelastic events and stereotactic radiofrequency lesioning of the hamartoma resulted in seizure remission. Laughing seizures thus represent true diencephalic epileptic seizures (Kuzniecky et al., 1997; Delalande et al., 2001; Chapter 19.3), while this is a questionable term for the ‘diencephalic epilepsy’ described by Penfield (1929; see Chapter 28.5a and below). They may even give rise to pseudotemporal lobe seizures, i.e. seizures that begin in the hypothalamic hamartoma and spread by connections to the amygdala and produce focal temporal ictal discharges. Seizures do not, in addition, disappear after temporal resection. There may be absence attacks, tonic, atonic and tonic-clonic seizures with slow spike and wave discharge. These patterns are explained by the connections of the hypothalamus with the thalamus and the cortex (Berkovic et al., 1997; Kuzniecky et al., 1997). The pathogenesis of the epileptic seizures is unknown, but in patients with hypothalamic hamartomas and intractable epilepsy, large, dysplastic ballooned neurons are observed. Dysplastic lesions are considered to be intrinsically epileptogenic. An alternative pathogenetic mechanism may be the production of certain peptides, such as metenkephalin by the hamartoma, or the displacement of adjacent structures. Hypothalamic hamartomas with slow spike and wave discharge might also cause progressive mental decline, possibly through damage to the mamillary bodies or thalamus. Epilepsy may be effectively treated by completely removing the

hamartoma (Berkovic et al., 1997; Kuzniecky et al., 1997). An alternative therapy for medical refractory epilepsy secondary to hypothalamic hamartomas is intermittent stimulation of the left vagal nerve (Murphy et al., 2000). (d) Hypothalamic pathology in epilepsy Mesial temporal sclerosis is the major pathological abnormality in about 60% of patients with intractable temporal lobe epilepsy. A strong concordance between changes in the mamillary bodies, fornix and hippocampus was found in an MRI study, pointing to an important role of these structures in temporal lobe epilepsy (Ng et al., 1997). In autopsy cases of epileptic patients, mamillary body atrophy has been reported, thought to be due to deafferentation of the mamillary bodies in patients with mesial temporal sclerosis (Kim et al., 1995; Mamourian et al., 1995). This relationship is not without controversy, however (see Chapter 17). In an old study (Morgan, 1930), the clearest reduction in cell numbers in epilepsy has been reported to occur in the substantia grisea (periventricular gray), followed by the nucleus tuberalis lateralis. Chromatolysis and gliosis are generally found in these nuclei; and neuronophagia is a common feature. The tuberomamillary nucleus is affected to a lesser extent; the paraventricular nucleus shows a varying amount of chromatolysis. Confirmation of these hypothalamic changes in epileptic patients has not been looked for since 1930. There is evidence that histaminergic neurons (localized in the tuberomamillary nucleus) (see Chapter 13) may control the excitability of neurons and inhibit the generalization of epileptic discharges. In this respect it is interesting that PET studies have revealed abnormal amounts of H1-receptors around the epileptic focus in complex partial seizures. Children are more sensitive than adults to proconvulsive side effects of drugs with H1-receptor antagonistic properties. This agrees with the observation that the CSF concentration of histamine in a group of children with febrile convulsions was lower than in another group of febrile children without convulsions, which suggests a protective effect of histamine against excessive neuronal excitation (Tuomisto et al., 2001). Penfield (1929) first used the term “diencephalic epilepsy” for paroxysmal attacks of autonomic disbalance, e.g. flushing, diaphoresis and temperature drop in a patient with a cholesteatoma compressing the anterior hypothalamus and thalamus, causing intermittent hydrocephalus.

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It is presumed that injuries to the dorsal medial nucleus of the thalamus and its connections are responsible for this disorder (Solomon, 1973). A patient with a hypothalamic astroblastoma with autonomic seizures has also been described in the older literature. The tumor was

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localized between the roots of the fornices and the corpora mamillaria. The tumor did, however, also infiltrate the thalamus so that it is not known whether the hypothalamic structures can be held responsible for “diencephalic epilepsy” (McClean, 1934).

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CHAPTER 29

Neurodegenerative disorders

4 allele and Alzheimer’s disease does not seem to be mediated by vascular factors. The ApoE 4 allele, elevated cholesterol, and high blood pressure seem to be independent risk factors for Alzheimer’s disease (Kivipelto et al., 2002; Lindsay et al., 2002).

Having Alzheimer’s disease means dying twice – first the mind dies, then the body. “. . . is not your father grown incapable / of reasonable affairs? Is he not stupid / with age and alt’ring rheums? Can he speak? Hear? / know man from man? Dispute his own estate? / Lies he not bed-rid? And again does nothing / But what he did being childish?” Shakespeare, A Winter’s Tale, Act IV, scene 4, 390 (Fogan, 1989).

(a) Conventional neuropathology As sisters, we made the hard choice not to have children. Through brain donation, we can help unravel the mysteries of Alzheimer’s disease and give the gift of life in a new way to future generations. (Sister Rita Schwalbe; Snowdon, 2001; Fig. 29B).

29.1. Alzheimer’s disease and the hypothalamus (Fig. 29A) The brain is said to degrade “gracefully”. A computer is brittle. Even a little damage to it, or a small error in its program may cause havoc. A computer degrades “catastrophically” (F. Crick. 1995, p. 178).

The involvement of the hypothalamus in aging and AD is suggested by the increased volume of the third ventricle with age (Murphy et al., 1992b) in spite of the decline of cerebrospinal fluid (CSF) production and turnover rates (Rubenstein, 1998). In AD, the third ventricular volume increases by 74%, as compared to age-matched controls (Tanna et al., 1991). Moreover, it is interesting that the degree of dementia expressed as mini-mental state scores correlates negatively with the volume of the third ventricle (Wahlund et al., 1993). In addition to general brain atrophy (Fig. 29B), MRI has shown atrophy of the hypothalamus, mamillary bodies, fornix, septal area and basal forebrain in AD (Callen et al., 2001). Using conventional stainings on the hypothalamus, the classic Alzheimer changes are only modest. The presence of some silver-stained neurofibrillary tangles (NFTs) (Hirano and Zimmerman, 1962; Ishii, 1966) and a few thioflavin S-positive (Rudelli et al., 1984; Saper and German, 1987) and congophilic neuritic plaques (Simpson, 1988) have been described. Some neuritic plaques containing amyloid may be found in the nucleus basalis of Meynert (NBM), in the diagonal band of Broca

Alzheimer’s disease (AD) is a multifactorial disease that has ‘age’ as the major risk factor. The presence of apolipoprotein E (ApoE) 4 alleles is responsible for some 17% of the cases. Mutations in the amyloid precursor protein presenilin 1 and 2 genes contribute less than 1% to the prevalence of AD. The age at onset of AD is highly hereditary (40–60%), although ApoE has an effect on this parameter (Tol et al., 1999). The ApoE 4 allel is also associated with depression in female Alzheimer patients but not in male patients (Müller-Thomsen et al., 2002). Moreover, linkage is found on chromosome 6 and 10 (Li et al., 2002). Additional possible risk factors are sex, sex hormones, smoking, education, cardiovascular disorders (Chapter 19.1b; De la Torre, 2002; Swaab et al., 2002), brain-derived neurotrophic factor polymorphism (Riemenschneider et al., 2002; Ventriglia et al., 2002), interleukin-1 (IL-1A) polymorphism (Pirskanen et al., 2002), and accumulation of mitochondrial DNA mutations (Li et al., 2002). The association between the ApoE 313

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Fig. 29 A.

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End stage of Alzheimer’s disease. Patient in ‘fetal’ position. (With permission from the relatives of the patient, given to Dr. E.J.A. Scherder.)

(DBB), and in the septal nuclei (Rudelli et al., 1984), albeit not in large quantities (Chapter 2.3; Arnold et al., 1991; Sassin et al., 2000). However, in the NBM and DBB of Alzheimer patients, a considerable number of NFTs may be present (Arnold et al., 1991). In the NBM the first single silver-staining cytoskeletal abnormalities are found very early in the Alzheimer process, i.e. in Braak stages I and II, before any amyloid deposits are found in this particular nucleus. It starts as isolated filaments that aggregate to a spherical NFT. In stages III and IV some ghost tangles are seen (Sassin et al., 2000). Only occasionally are silver-staining NFTs found in the preoptic area and anterior hypothalamus. At the tuberal level, silver-stained tangles are scattered throughout the hypothalamus, but they generally tend to avoid the paraventricular and supraoptic nucleus (PVN, SON) and the nucleus tuberalis lateralis (NTL). Only in a small

percentage of patients are NFTs found in the PVN and SON (Schultzes et al., 1997a). The Alzheimer changes in the infundibular nucleus depend on sex and age. Argyrophylic neurofibrillary pathology was found in the great majority of old men and only in a small percentage of women, independent of the presence of Alzheimer pathology in the neocortex (Schultz et al., 1996, 1997a, b, c, 1999). In Alzheimer patients a few tangles are found in the ventromedial nucleus (VMN). By contrast, large numbers of NFTs are present in the dorsomedial nucleus, in neurons surrounding the medial edge of the fornix and the mamillothalamic tract, and in the large tuberomamillary neurons (Braak et al., 1996, Chapter 13.2). The number of large, histamine-containing neurons of the TMN is reduced in AD (Nakamura et al., 1993), which is in agreement with the histaminergic deficit reported in the cortex of Alzheimer patients. The silver-stained

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Fig. 29 B.

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Brain of Alzheimer patient (top) and control (bottom). Note the atrophy of the Alzheimer brain. (From the Netherlands Brain Bank, photograph G. van der Meulen.

neurofibrillary changes in the TMN (Chapter 13) start at Braak stage IV and quite late in the NTL (Chapter 12), i.e. at Braak stage VI (Braak and Braak, 1991). The medial mamillary nucleus is relatively sparsely involved in Alzheimer changes, but NFTs and neuritic plaques (NPs) are present and the lateral nucleus is usually free of them (Grossi et al., 1989; Braak et al., 1996; see Chapter 16.c). However, the volume of the mamillary body as measured by MRI is clearly diminished in Alzheimer patients (Sheedy et al., 1999). For olfactory deficits in AD, see Chapter 24.2b.

(b) Sex differences and sex hormones According to some studies, the prevalence of AD is higher in women than in men (Bachman et al., 1992; Brayne et al., 1995; Fratiglioni et al., 1997; Launer et al., 1999; Letenneur et al., 2000). In contrast, a study by Hebert et al. (2001) did not reveal a sex-specific risk for AD, but suggested that the excess number of women with this disease was due rather to the longer life expectancy of women. Lindsay et al. (2002) and Gatz et al. (2003) did not find an association of AD with sex either, but a 315

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Dutch study indicated that after the age of 90 years the incidence of AD is higher for women than for men, while the incidence of vascular dementia is higher in men than in women in all age groups (Ruitenberg et al., 2001). Our observation of an increased number of NBM cells containing hyperphosphorylated tau in women, as compared to men (Salehi et al., 2000), and the association found between AD and a locus on the X-chromosome, support the presence of sex differences in AD. In addition, estrogen receptor- (ER) polymorphisms PvuII and XbaI are associated with the risk of developing cognitive impairment (Yaffe et al., 2002); CAG-repeat polymorphism of the androgen receptor is associated with AD in men (Lehmann et al., 2003); the DXS1047 202bp allele on the X-chromosome is twice as common among Alzheimer cases as among controls (Zubenko et al., 1998); and an increased risk by a factor of 7.6 has been observed in homozygous individuals with the PPXX ER genotype (Brandi et al., 1999). Moreover, there is an interaction between estrogen receptor- and - polymorphisms and the risk of developing AD (Lambert et al., 2001). Lower endogenous estradiol levels are correlated with poor cognitive, behavioral and functional status in older but undemented individuals (Farrag et al., 2002; Senanarong et al., 2002; Wolf and Kirschbaum, 2002). In women, higher estradiol levels as well as higher testosterone levels are associated with better verbal memory. Moreover, estradiol is associated with a diminished susceptibility to interference (Wolf and Kirschbaum, 2002). In elderly, nondemented men, higher free testosterone levels are associated with better scores on visual and verbal memory, visuospatial functioning, and visuomotor scanning, and with a reduced rate of longitudinal decline in visual memory (Moffat et al., 2002; Wolf and Kirschbaum, 2002). Several studies have reinforced the idea that the postmenopausal decrease in estrogen levels may be an important factor in triggering the pathogenesis of the disease, since women with high serum concentrations of bioavailable estradiol are less likely to develop cognitive impairment than women with low concentrations (Inestrosa et al., 1998; Manly et al., 2000; Yaffe et al., 2000b). In men, the Rotterdam study has not found a clear association between estradiol levels and risk of dementia, but in women higher levels of estradiol are associated with increased risk of dementia (Geerlings et al., 2003). In AD patients Cunningham et al. (2001) have found higher serum levels of estrone and androstenedione, but not of testosterone or estradiol. The increased

levels of androstenedione in AD have been confirmed, but serum estradiol levels are nonsignificantly increased in women with Alzheimer’s disease in another study (Rasmuson et al., 2002). The negative observations on possible differences in sex hormone levels in AD patients agree with our small pilot study (Table 8.5I and II). Yet an interesting relationship has been observed between CSF levels of estradiol and -amyloid. Estradiol CSF levels are lower in AD patients than in controls, and within the Alzheimer group the estradiol levels are inversely correlated with A-42 concentrations. This observation has been interpreted as corresponding to the beneficial effects of estrogen replacement therapy on AD (Schönknecht et al., 2001). In addition, women with AD who are not taking estrogen replacement therapy are vulnerable to depression (Carlson et al., 2000). Estrogen replacement therapy (ERT) as a preventive measure for AD is becoming increasingly controversial. Epidemiological evidence, randomized controlled trials, and cross-sectional and longitudinal studies have indeed indicated that ERT in postmenopausal women is effective in protecting against a decline in verbal memory in healthy postmenopausal women and in preventing and delaying the onset of AD (Henderson et al., 1996; Stephenson et al., 1996; Tang et al., 1996; Costa et al., 1999; Slooter et al., 1999; Van Duijn, 1999; Sherwin, 2002). In one study, the overall efficacy of hormone replacement therapy was similar for cognition and mood, but larger for activities of daily living (Yoon et al., 2003). No effect on cognition was observed after 4 years of hormone therapy (Grady et al., 2002), and others have reported a small but clinically meaningful cognitive decline following estrogen plus progesterone treatment (Rapp et al., 2003). In contrast, long-term treatment exceeding 10 years of hormone replacement seems to have positive effects (Zandi et al., 2002). ERT is also reported to improve cognitive performance in patients with AD by enhancing the response to the acetylcholinesterase inhibitor tacrine (Schneider et al., 1996), and by influencing the vesicular acetylcholine transporter (Smith et al., 2001). Beneficial effects of ERT on cognition and on noncognitive psychiatric signs have been reported in some studies but not in others, possibly at least partly depending on ApoE genotype (Haskell et al., 1977; Hogervorst et al., 2000; Yaffe et al., 2000a; LeBlanc et al., 2001; O’Connor et al., 2001; Seshadri et al., 2001; Tan and Pu, 2001; Kyomen et al., 2002; Lindsay et al., 2002). Between 2000 and 2003, a number of randomized controlled trials in AD patients did not show meaningful

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effects of estrogens (Henderson et al., 2000; Hogervorst et al., 2000; Mulnard et al., 2000; Wang et al., 2000b). Raloxifene, a selective estrogen-receptor modulator, given for a period of 3 years to postmenopausal women with osteoporosis, did not affect cognitive scores (Yaffe et al., 2001). However, other trials have shown enhanced cognitive functioning, following estrogen treatment, in postmenopausal, nondemented women and women with AD (Asthana et al., 1999; Carlson et al., 2001). In a recent Danish study (Løkkegaard et al., 2002), hormone replacement therapy appeared to postpone age-related decline in cognitive functioning, partly in concentration and partly in visuomotor function. However, women treated with this therapy had better cognitive performance already prior to treatment. On the other hand, women who received estrogen plus progesterone therapy from the age of 65 years and older ran an increased risk of dementia (Shumaker et al., 2003). There is thus a need for long-term, randomized controlled trials with estrogens, starting immediately in the postmenopausal period in mentally unaffected women, in order to get more information on the prevention of AD. At least part of the controversial literature on the possible positive effects of sex hormones in AD may be based upon the different effects that different sex hormones may have on different brain areas, depending on, e.g. age and sex. This is a good a reason for more basic studies on the estrogen and androgen neuronal systems that are involved in memory processes. A clear sex difference in the formation of Alzheimer changes, either stained for hyperphosphorylated tau or by silver, is observed in the hypothalamus. A dense network of large, dystrophic neurites with NFTs interspersed among them was observed in the median eminence (ME) and adjacent infundibular (= arcuate) nucleus (Chapter 11, Fig. 11.3). The terminal-like fibers form a perivascular plexus of bouton-like structures around the vessels of the pituitary portal system. This neurofibrillary pathology reveals a striking sex difference. From 60 years onwards, the frequency of the neurofibrillary lesions in the infundibular nucleus of male subjects rises from 22% to 90%, while such lesions are observed in only 8–10% of the women (Schultz et al., 1997a, b, c, 1999; Fig. 29.1). It is tempting to explain the sex difference in Alzheimer changes in the infundibular nucleus in relation to the strong activation of this structure in postmenopausal women, as is evident from the hypertrophy of the neurons, their increased production of neuropeptides, the increase in nucleolar size, and the presence of multiple nucleoli

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Fig. 29.1. The percentage of men affected by mediobasal hypothalamic (MBH) pathology markedly increases from the age of 60 to 90 years. A marked or severe degree of MBH pathology was identified in 30% of all men at this age (not shown). In contrast, only a small percentage of elderly women are affected. (From Schultz et al., 1997a, Fig. 3a, with permission.)

(see Chapter 11f). In addition, ‘nuclear spheroids’ are found that are cytoplasmic protrusions in the nucleus of the activated infundibular nucleus neurons of postmenopausal women (Hirabayashi et al., 1979). Activation of the infundibular neurons of postmenopausal women seems to protect these women from Alzheimer changes, a phenomenon paraphrased ‘use it or lose it’ (Swaab, 1991). In the NBM of women there are a larger proportion of neurons that contain hyperphosphorylated tau than in the NBM of men (Salehi et al., 1998c). The ApoE 4 allele is associated with shorter survival in men but not in women with AD (Dal Forno et al., 2002). (c) Down’s syndrome Down’s syndrome patients reach their highest mean IQ at the age of 6 months (IQ80). There is a decrease in IQ with age. At the age of 11 years, the IQ has decreased to 40 (Annerén et al., 1990), indicating premature brain aging in Down’s syndrome. This possibility is reinforced by the observation that Down’s syndrome patients experience menopause at an earlier age (Schupf et al., 1997). 317

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The smaller corpora mamillaria (Raz et al., 1995) and anterior commissure (Sylvester, 1986) may be due to degenerative changes in the temporal cortex (see Chapters 6.3 and 16c). Neuroendocrine changes are described in Chapter 26.5. Alzheimer changes are generally present in middleaged Down’s syndrome patients. They were described in Down’s syndrome patients for the first time in 1929 (Struwe, 1929) and have been confirmed many times since then. Female Down’s syndrome patients have an earlier onset and a more severe form of AD, which correlates with higher neocortical neurofibrillary tangle counts rather than with plaque density (Raghavan et al., 1994). In the hypothalamus of middle-aged Down’s syndrome patients, similar but often very pronounced Alzheimer changes are found, accompanied by a cholinergic deficiency in the NBM (see Chapter 2.5). In the NTL of Down’s syndrome patients of between 49 and 59 years old, a variable amount of A has been observed; while Alz-50 stains this nucleus strongly, both for cell bodies and neuropil threads (Van de Nes, 1995; Thesis, Chapter V).

Fig. 29.2. The mean of Alz-50 load (A) and mean percentage of Alz-50 stained neurons (B) in men and women. Note that female subjects showed a significant increase in the mean percentage of Alz-50-stained neurons compared with men. *p = 0.039. (From Salehi et al., 1998c, Fig. 3, with permission.)

(d) Hyperphosphorylated tau and -amyloid Although the occurrence of the classic silver-staining Alzheimer changes in the hypothalamus is modest, antibodies that recognize pretangle cytoskeletal changes in cell bodies, dystrophic neurites, neuropil threads and congo-negative anti--protein/A4 (A)-immunoreactive amorphous senile plaques are present in considerable amounts (Standaert et al., 1991; Swaab et al., 1992b; Van de Nes et al., 1993, 1994, 1998; Salehi et al., 1995b). However, the disposition of A in the diencephalon, including the NBM, does not occur until relatively late, i.e. in the third phase of -amyloidosis (Thal et al., 2002). Several antibodies for cytoskeletal changes in AD reveal, in principle, similar staining patterns in the hypothalamus. This holds true, e.g. for antibodies against paired helical filaments (PHF) e.g. anti-PHF serum 60e and the monoclonal antibody Alz-50, both directed against normal and abnormally phosphorylated tau; the monoclonal antibody tau-1, which recognizes tau, and the monoclonal antibody 3-39, which recognizes ubiquitin (Swaab et al., 1992b). The sensitive antibody AT8, which recognizes hyperphosphorylated tau, was later used in many other studies (e.g. Schultz et al., 1996, 1997a, b). MCI has similar properties (Van Leeuwen et al., 2000). In our studies, staining of the neuropil threads and dystrophic neurites in Alzheimer patients was most

conspicuous following Alz-50 staining (Swaab et al., 1992b). The epitope on tau protein recognized by the monoclonal antibody Alz-50 is discontinuous and requires both an N-terminal segment and the microtubule binding region for efficient binding to this antibody (Carmel et al., 1996). On the other hand, Alz-50 staining of Alzheimer changes should be distinguished from crossreactivity seen with this antibody in some normal neurons and thin beaded neurites, e.g. in the PVN, periventricular and arcuate nucleus and terminals around the portal vessels in the stalk/median eminence region of young, healthy controls (Byne et al., 1991; Swaab et al., 1992; Van de Nes et al., 1994). This control staining is due to cross-reactivity with an unknown compound in somatostatin-containing neurons (Van de Nes et al., 1994). The distribution over the hypothalamus and adjoining areas, such as, e.g. the bed nucleus of the stria terminalis, of both amorphic plaques stained by anti-A and cytoskeletal changes as revealed by Alz-50, is quite characteristic, as shown in Tables 29.1 and 29.2 (Van de Nes et al., 1998). A few AT8-immunoreactive neurons are already present in the NBM at Braak’s stages I and II. The density of such lesions is moderate in stage III and tends to be severe in stage IV (Sassin et al., 2000). In advanced Braak stages, the subthalamic nucleus

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TABLE 29.1 Immunocytochemical staining of amorphous plaques and -amyloid cores in the hypothalamus. Controls 1

Alzheimer’s disease patients 2

3

4

5

6

7

8

9

10

– – – – – – –

– – – – – – –

– ++* + – – – –

– +* – – – – –

– + ± – – – –

– ++ ± – – – –

– ++ ± – – – NA

– ++* ± – – – –

Chiasmatic region of the hypothalamus SON CG SDN SCN PVN PVA ME

– – – – – – –

– – – – – – NA

Tuberal region of the hypothalamus DMN VMN TG TMN NTL NTI

– – – – – –

– – – – – –

– – – – – –

– – – – – –

± + ++ + ± –

± +* +* +++* +++* ±

± ++ +* ++ ++ ±

± ++ +++ + ± –

– + ++ ± ± –

± ++ ++ + ± ±

– – – – – – –

– – – – – – –

– – – – – – –

– – – – – – –

+ + ± ±* ± + +

+ + ++* +++* + +++ ++

+ + ++ +++ + +++ ++

+ ± +* ++ ++ ++* +

– – ± ± – ++ +

± – ± + + ++ +

Adjoining areas NBM DBB BSTc BSTl BSTm ACC CI

NA, not available; –, no or negligible staining; ±, few; +, small amount; ++, considerable amount; +++, large amount. * Congophilic -amyloid cores were present but their amount was too low to score. The antibodies SP28 and 1G102 revealed a similar staining. (Adapted from Van de Nes et al., 1998.)

occur relatively late, i.e. in the third phase of the evolution of -amyloidosis (Thal et al., 2002). A-positive amorphic plaques are found in the following nuclei of Alzheimer patients: the central gray, the sexually dimorphic nucleus of the preoptic area (SDNPOA), the tuberal gray, the dorsomedial hypothalamic nucleus, the VMN, the tuberoinfundibular nucleus, the TMN, and the NTL, as well as in all subnuclei of the bed nucleus of the stria terminalis (BST), the NBM and DBB, nucleus accumbens (ACC), islands of Calleja and in the corpus mamillare. It should be noted, though, that amorphous plaque density in the NBM in AD was found to be in the same range as that of a 90-year-old

(Chapter 15a) shows neurons accumulating hyperphosphorylated tau (Mattila et al., 2002). (e) A immunoreactivity (Table 29.1) The hypothalamus in AD is seeded with amorphic plaques that do not contain epitopes corresponding to other regions of the amyloid  protein precursor (APP) than the A4 region in contrast to the A4-reactive plaques in the cortical areas and hippocampus that are dominated by those that exhibit immunoreactivity for regions of the APPs outside the A4 region (Standaert et al., 1991). However, the A-deposits in the diencephalon and NBM 319

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control (Van de Nes et al., 1998; Thal et al., 2002), emphasizing the absence of a clear border between normal aging and AD. Other regions, such as the SON, suprachiasmatic nucleus (SCN), periventricular area (PVA) and ME, remain devoid of A staining (Van de Nes et al., 1994, 1998; Stopa et al., 1999). While, in the NBM, NFTs are already present in Braak stage I, amyloid deposits are found only in Braak stage II and later stages (Sassin et al., 2000; Thal et al., 2002). In the NTL, considerable amounts of amorphous A deposits were mainly found in young Alzheimer patients of 52 years and younger. In different areas the amorphic plaques have a different morphology (Van de Nes, 1995, Thesis, Chapter V; Van de Nes et al., 1998). Anti-A-reactive blood vessels are only found in some Alzheimer patients in the ACC, the central nucleus of the BST (BSTc) and the TMN. These A deposits are applegreen birefringent with Congo red, and thus represent “congophilic angiopathy”. Congophilic senile plaques are rare in the hypothalamus but are sometimes seen in areas indicated by an asterisk in Table 29.1. Ghost tangles, indicative of cell death, are only rarely seen in AD patients in the chiasmatic gray (CG) and tuberal gray (TG). They stain positive with anti-A, but not with Alz-50. (f) Abnormally phosphorylated tau (Table 29.2) In general, the SON and PVN do not show Alzheimer pathology (Swaab et al., 1992b). Using the antibody AT8 in a small subpopulation of elderly subjects, neurofibrillary pathology has been observed in the PVN (7.5%) and SON (4.5%) (Schultz et al., 1997a). In addition, early cytoskeletal changes, as revealed by antibodies against abnormally phosphorylated tau (i.e. AT8, PHF-1 and Alz-50) are observed in some fibers and Herring bodylike structures in the neurohypophysis of some patients, even if the brain is devoid of Alzheimer changes (Schultz et al., 1997b). Alz-50 immunoreactivity showing cytoskeletal changes in perikarya and dystrophic neurites is present in a number of hypothalamic nuclei of Alzheimer patients and elderly controls. The staining ranges from intense in the NTL to generally none in the SON (Table 29.2; Swaab et al., 1992b; Van de Nes et al., 1993, 1994, 1998). Presenile Alzheimer patients have less Alz-50 staining in the NTL than senile AD patients (Van de Nes, 1995). Accumulation of hyperphosphorylated tau is also found in the subthalamic nucleus (Chapter 15a) in advanced Braak stages (Mattila et al., 2002). It should be noted

that, to the experienced eye, staining of dystrophic neurites with Alz-50 is not superior to that obtained with the Bodian conventional silver-staining method. The sex-specific argyrophilic neurofibrillary changes in the ME and infundibular nucleus as observed by Gallyas silver stainings have been confirmed by antibodies that show the relationship with abnormally phosphorylated tau such as AT8 (Schultz et al., 1996) and Alz-50 (Chapter 11). The presence of Alz-50 and A staining is not necessarily correlated in the various hypothalamic nuclei. For instance, the hypothalamus and BSTc of a young Alzheimer patient (patient 7; Table 29.1) showed relatively intense A staining and little Alz-50 staining (Table 29.2). The SCN in AD remains entirely negative for A, but some staining of neuropil threads is found with Alz-50, while this nucleus shows a clear functional disorder (see Chapter 4.3). Double staining of Alz-50 and A does not show a topical relationship between amorphic plaques and cytoskeletal changes either, so that the pathogenetic mechanism giving rise to these two hallmarks does not seem to be causally related (Van de Nes et al., 1998). In addition, the amount of A staining does not differentiate between controls and Alzheimer patients (Standaert et al., 1991; Van de Nes et al., 1998). In the hypothalamus and adjacent areas, the difference between Alzheimer patients and controls is most obvious in the NBM when this structure is immunocytochemically stained for pretangles or by, e.g. Bodian. The discrepancies between the localization of A accumulation and (pre)tangle formation in the various brain structures is one of the arguments against the amyloid cascade hypothesis as the central mechanism in the pathogenesis of AD (Swaab et al., 1998; Van de Nes et al., 1998; Sassin et al., 2000; Mudher and Lovestone, 2002). (g) Relationship between Alzheimer neuropathology and decreased metabolism In addition to NFTs and plaques, decreased neuronal activity is one of the major characteristics of AD (Swaab et al., 1998). Using the size of the Golgi apparatus (GA) as a histological parameter of chronic metabolic activity changes in neurons, the hypothalamus appears to contain several nuclei that are differentially affected in AD. For instance, the SON is generally not affected by AD changes and even shows hyperactivity during aging, in both controls and AD patients (Swaab et al., 1992b; Lucassen et al., 1994; Chapter 8.3; for a sex difference

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TABLE 29.2 Alz-50 staining for hyperphosphorylated tau of dystrophic neurites (D) and perikarya (P) in the hypothalamus. Controls 1

Alzheimer’s disease patients 2

3

4

5

6

7

8

9

10

– – – – – – –

– – – – – – –

– ± D,P – – – –

– + D,P ±+D,P + P,D – – –

– ± D,P ± D,P ±P – – –

– ±P ± D,P ±P – – –

– ++ D,P ++ D.P + D,P + P,D +P NA

– ± D,P + D,P +P – – –

Chiasmatic region of the hypothalamus SON CG SDN SCN PVN PVA ME

– – – – – – –

– – – – – – NA

Tuberal region of the hypothalamus DMN VMN TG TMN NTL NTI

– – – – – –

– – – – – –

– – – – – –

– – – – – –

± D,P ± D,P ± D,P ± D,P + D,P –

+ D,P + D,P + D,P + D,P + D,P –

± D,P ± D,P ± D,P ± D,P + D,P –

± D,P ++ D,P ±P ++ D,P +++ D,P –

+ D,P + D,P ++ D,P ++ D,P +++ D,P –

+ D,P ± D,P + D,P + D,P ++ D,P –

– – – – – – –

– – – – – – –

– – – – – – –

– – – – – – –

± D,P ± D,P ± D,P ±D ±P ± P,D + P,D

++ D,P ++ D,P + D,P ± D,P + D,P ± P,D ± P,D

++ D,P + D,P ±P – ±P ± P,D ±P

++ D,P + D,P + D,P ± D,P + D,P ± D,P + D,P

++ D,P ++ D,P + D,P ± D,P ± D,P + D,P ±P

++ D,P ++ D,P + D,P D,P +D,P + D,P +D,P

Adjoining areas NBM DBB BSTc BSTl BSTm ACC CI

The order of the letters D or P is related to the relative density of the Alz-50-positive dystrophic neurites of perikarya. The first letter presents the highest relative density. (Adapted from Van de Nes et al., 1998.)

different stages of neurofibrillary degeneration and neuronal activity has been investigated, as well as the question of the possible cause or effect of such a relationship. In order to do so, the relationship between GA size and the different stages of AD changes were assessed for the following characteristics:

see Chapter 8.d). Only in a small part of the population are some cytoskeletal alterations observed in the SON and PVN (Schultz et al., 1997a); this in contrast to the NBM (Chapter 2), which generally shows clear signs of neuronal atrophy (Rinne et al., 1987), cytoskeletal alterations (Swaab et al., 1992b; Van de Nes et al., 1993) and some NP formation (Rudelli et al., 1984). The changes in the NBM are, however, certainly not as outspoken as those in the CA1 area of the hippocampus, a brain region which is clearly affected by cell death (West et al., 1994) and contains an abundance of NFT and a moderate amount of NPs (Mann et al., 1985b). In the hypothalamic and hippocampal tissue from controls and AD patients, the possible presence or absence of a relationship between

Hardly any AD hallmarks The SON of the hypothalamus generally appears to be spared in AD (Chapter 8.3). No classic AD neuropathology is present in the large majority of the patients, and even using antibody Alz-50 as an indicator of early cytoskeletal alterations (Bancher et al., 1989), no staining of SON neurons is generally found (Swaab et al., 1992b; 321

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Fig. 29.3. Supraoptic nucleus of an Alzheimer patient (NHB 96009, male, 86 years of age; Braak stage 3) with a relative, rare involvement of some neurons in the Alzheimer process. Brown staining for hyperphosphorylated tau by AT8 in some cells and dystrophic neurites. (Preparation, T. Ishunina.) Bar 50 m.

Van de Nes et al., 1993). Only in a small number of Alzheimer patients are some cytoskeletal changes present in the SON and PVN (Schultz et al., 1997a; Fig. 29.3). Furthermore, there is no cell loss in the SON, either in aging or AD (Goudsmit et al., 1990; Van der Woude et al., 1995). In the SON signs of hyperactivation with aging were even found (Hoogendijk et al., 1995; Van der Woude et al., 1995). As shown by Lucassen et al. (1994), there is indeed a significant increase in activity, as measured by an increased size of the GA, of vasopressinergic neurons of the SON during aging, both in controls and AD patients, supporting the idea that activation of neurons might protect them against AD changes (Swaab, 1991; Chapter 8.3). Since these studies, we have found that the increased activity of SON

neurons during the course of aging is restricted to women (Ishunina et al., 1999). One may wonder, therefore, whether the cytoskeletal changes observed in the SON of a few individuals (Schultz et al., 1997a) may also be a sexually dimorphic phenomenon. Early cytoskeletal alterations Tau proteins belong to the microtubule-associated proteins. It has been suggested that the occurrence of early cytoskeletal changes due to abnormal phosphorylation of tau as found by a variety of antibodies would precede the appearance of neurofibrillary degeneration as shown by silver staining (Bancher et al., 1989; Braak et al., 1994). Abnormal phosphorylation of tau proteins as found in AD patients may lead to a failure of

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of the GA. Although diminished somatostatin staining may indicate a start of decreased metabolic activity (Van de Nes, 1995, Thesis, Chapter V), pretangle AD changes were not accompanied by reduced metabolic activity as measured by the size of the GA. Late cytoskeletal alterations (NFTs) The appearance of early cytoskeletal alterations is presumed to be followed by the formation of NFTs that are detectable by silver staining (Bancher et al., 1989). The finding (see above) that there is no clear relationship between the appearance of early cytoskeletal alterations and protein synthetic ability as measured by the size of the GA in the NTL raises the question of whether AD changes and decreased metabolism are related in areas with late stages of cytoskeletal alterations, i.e. NFTs and NPs, such as the NBM, TMN and CA1 area of the hippocampus. The NBM is an area of the basal forebrain which is clearly affected in AD (Chapter 2.3). This nucleus shows not only early cytoskeletal alterations, as indicated by Alz-50 staining (Fig. 29.4), but also some silver-staining NFTs and NPs, and some -amyloid accumulation in AD (Rudelli et al., 1984; Swaab et al., 1992b; Van de Nes et al., 1993, 1994; Sassin et al., 2000). Although it was suggested initially that this area shows a dramatic cell death in AD (Whitehouse et al., 1982, 1983b), it turned out that degeneration in the NBM is mainly characterized by cell atrophy rather than by cell death (Pearson et al., 1983; Rinne et al., 1987; Gilmor et al., 1999; Chapter 2.4). A significantly decreased size of the GA is found in NBM neurons in AD, suggesting that protein synthetic activity of NBM neurons is strongly reduced in this brain area (Salehi et al., 1994). The decreased expression of the high-affinity neurotrophin receptors, the trks, in the NBM (Fig. 29.5) in AD may be a crucial phenomenon in the decreased metabolic rate in these neurons. AD patients with one or two ApoE  4 alleles have an extra decrease in metabolic rate, which fully agrees with the more severe cholinergic deficit in the neocortex of these patients and their increased risk to get AD (Salehi et al., 1998a; Fig. 29.5). TMN neurons are clearly affected in AD by NFTs (Nakamura et al., 1993; Chapter 13) in this area of the hypothalamus. As shown by Salehi et al. (1995a), metabolic activity is also significantly reduced in AD. This observation agrees with the decreased hypothalamic, hippocampal and cortical histamine levels found in AD patients (Schneider et al., 1997; Panula et al., 1998), and supports the existence of a relationship

Fig. 29.4. Immunocytochemical staining of Alz-50 in the NBM of an Alzheimer patient with apolipoprotein E 3/4. Note the clear staining of cell bodies, dystrophic neurites and neuropil threads. Scale bar 28 m. (From Salehi et al., 1998c, Fig. 1, with permission.)

tau proteins to bind to microtubules (Lee et al., 1991). This is presumed to result in a failure to maintain axonal transport and neuronal shape. The hypothalamic NTL shows strong cytoskeletal alterations, as appears from the intense staining of NTL neurons by the antibodies Alz-50 and MC1 (both against hyperphosphorylated tau, tau-1 (against tau) and 3-39 (against ubiquitin) (Swaab et al., 1992b; Van de Nes et al., 1993; Chapter 12). Interestingly, silver-stained NFTs and NPs are rare in the NTL of AD brains (cf. Kremer, 1992b). The NTL thus represents a brain area that shows only the early stage of AD changes and does not generally progress towards classic silver staining of neuropathological AD hallmarks (Swaab et al., 1992b; Chapter 12.2b), in spite of the fact that in other regions of the brain of the Alzheimer patient full blown neuropathology is present. This makes the NTL a very suitable structure for a study of the relationship between the presence of pretangles and changes in neuronal activity. In the NTL, decreased staining of somatostatin, its major neuropeptide, often seems to precede the cytoskeletal changes (Van de Nes, 1995). As shown by Salehi et al. (1995b), there is no reduction in neuronal activity in this area in AD. Furthermore, comparison of the intensity of Alz-50 staining with Golgi apparatus size does not show a clear relationship between these two parameters. This indicates that strong cytoskeletal alterations in the NTL are not necessarily accompanied by decreased neuronal activity as measured by the size 323

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Fig. 29.5. The proportion of neurons stained by Trk antibodies in controls and Alzheimer’s disease (AD) patients. Note the strong reduction in the proportion of TrkA-expressing neurons in AD, which is followed by TrkB and TrkC. * p 0.00001; ** p 0.009; *** p 0.004. (From Salehi et al., 1996, with permission.)

between AD pathology and decreased neuronal activity. It has been proposed that the decreased histaminergic activity in AD and Down’s syndrome is due to the decreased levels of histamine-releasing factor that is found in various brain regions (Kim et al., 2001b). The observation of Airaksinen et al. (1991b) that histaminergic neurons in the TMN seldom contain NFTs, may well be explained by the loss of histamine in the affected TMN neurons. The CA1 area of the hippocampus, too, is strongly affected by AD changes (West et al., 1994) and shows strongly decreased neuronal activity in AD patients (Salehi et al., 1995c), but this structure will not be extensively discussed here. The pretangle stage of AD changes is not necessarily related to clear changes in metabolic rate, as indicated by our GA studies in the NTL. However, the clear reduction in GA size in AD affected NBM, TMN and CA1 neurons supports the idea that decreased neuronal activity and the occurrence of the classic AD changes often go together. Of course this does not necessarily mean that these two types of changes are also causally related. On the contrary, observations on the hippocampus reveal that, in principle, these two groups of Alzheimer changes are independent of each other. In CA1 neurons of Alzheimer patients, the neuronal activity is strongly diminished. However, this is independent of the presence or absence of NFTs in the neurons (Salehi et al., 1995c). Moreover, the presence or absence of adjacent plaques in CA1

Fig. 29.6. The size of the mean Golgi apparatus in controls and Alzheimer patients with apolipoprotein E (ApoE) genotype 3/3 compared with Alzheimer patients with ApoE genotype 3/4 and 4/4. Note the clear reduction in the size of Golgi apparatus in Alzheimer patients with one or two ApoE 4 alleles, compared with Alzheimer patients without ApoE 4 alleles. There is no significant difference (P = 0.760) in Golgi apparatus size between Alzheimer patients with one ApoE 4 allele and two 4 alleles. (From Salehi et al., 1998a, Fig.2, with permission.)

does not affect metabolic rate in the neurons of this area either (Salehi et al., 1998b). The classic neuropathological hallmarks (the NFTs and NPs) consequently do not seem to induce decreased metabolic rate. Reactivation of hypothalamic structures in AD In conclusion, it appears that decreased neuronal activity is one of the major hallmarks of AD, accompanying the classic neuropathology. This makes it attractive to study the question whether restimulation of the affected neuronal systems is, in principle, possible in this disorder. The fact that the infundibular nucleus suggests a strong and lasting (up to 100 years of age) neuronal activation in postmenopausal women (Chapter 11f) suggests that activation of neurons in older age can be achieved. The activation of the infundibular nucleus in postmenopausal women is accompanied by protection against Alzheimer changes in this area that are hardly ever seen in older women, whereas such changes are present in up to 90% of the older men (Schultz et al., 1997a, b, c, 1999). The SCN seems an excellent target for clinical reactivation studies, since its main function, i.e. the regulation of circadian rhythmicity, can be monitored. A decreased number of neurons expressing vasopressin (Fig. 29.7),

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Fig. 29.7. In both presenile (n = 7) and senile (n = 8) Alzheimer patients the volume of the vasopressin subnucleus of the suprachiasmatic nucleus (A) and the number of vasopressin-expressing neurons (B) is significantly decreased when compared with young (n = 14) or old (n = 9) agematched controls. In presenile Alzheimer patients only 10% of the number of neurons expressing vasopressin n controls is found. *** p > 0.001, * p > 0.02 (Mann–Whitney U-test). (Unpublished data, D.F. Swaab.)

rhythm of 14 Alzheimer patients indeed showed an improvement in its coupling to Zeitgeber, following TENS treatment (Van Someren et al., 1998; Scherder et al., 1999b). Concluding, both specific stimulation of the SCN by light, and more general peripheral stimulation of the central nervous system by TENS improve circadian rhythms in early and midstage Alzheimer patients, which indicates increased activity of the biological clock. Recent studies indicate that bright-light therapy in demented elderly individuals improves not only circadian rhythmicity but also daytime cognitive performance (Yamadera et al., 2000; Graf et al., 2001).

neurotensin and vasoactive intestinal peptide (VIP) neurons of the SCN in AD (Chapter 4.3; Swaab et al., 1985; Zhou et al., 1995b; Stopa et al., 1999) have been found. In addition, it is clear from the neurofibrillary changes, from the increased number of glial fibrillary acidic protein (GFAP)-positive astrocytes (Swaab et al., 1992b; Van de Nes et al., 1993, 1994, 1998; Stopa et al., 1999) and from the 3 times lower amount of vasopressin mRNA in the SCN of Alzheimer patients (Liu et al., 2000b; Fig. 29.8) that the SCN is affected by AD. The alterations observed in the SCN are accompanied by a disruption of circadian rhythms (see Chapter 4.3), nightly restlessness, and a phase delay in body temperature rhythm (Harper et al., 2001). Indeed, stimulation of the SCN by light improves circadian rhythmicity, decreases behavioral disturbances such as nightly restlessness (Van Someren et al., 1998; Chapter 4.3) and can even improve cognitive performance (Yamadera et al., 2000). In addition, as both direct and indirect spinal projections to the SCN have been described in the rat, we investigated whether transcutaneous electrical nerve stimulation (TENS) could improve circadian rhythm disturbances in AD patients. The actigraphically obtained rest-activity

(h) Hypothalamic changes in neuroactive substances in AD Neuropeptides The changes in the vasopressin and VIP neurons in the SCN in AD patients are described in Chapter 4.3 (see also Figs. 29.7 and 29.8). The vasopressin-producing neurons in the SON and PVN generally remain intact in AD (Van der Woude et al., 1995) and the vasopressinergic neurons even appear to be activated in the course of aging 325

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Fig. 29.8. Day–night fluctuations in vasopressin (AVP) mRNA in the suprachiasmatic nucleus (SCN) expressed as a masked area of silver grains in controls and in Alzheimer patients (AD). Note that at any moment of the day the values for AD patients are lower than those for controls. (From Liu et al., 2000b, Fig. 3, with permission.)

(see Chapters 8d and 8.3). Yet, some studies report changes in circulating vasopressin and oxytocin levels in AD although these data are somewhat equivocal (see Chapter 8.3). The vasopressin CSF levels do not change in dementia according to some authors (Jolkkonen et al., 1989; Gottfries et al. 1995) and are increased (Tsuji et al., 1981) or reduced according to others (Sundquist et al., 1983; Sørensen et al., 1983, 1986; Mazurek et al., 1986; Olsson et al., 1987; Gottfries et al., 1995). The fact that the type of dementia is often not specified may have contributed to these discrepancies. Alterations in osmoreceptor function and vasopressin unresponsiveness to metoclopramide point to alterations in the cholinergic input and/or to changes in the control of processing or release of vasopressin in AD (Norbiato et al., 1988; Lipponi et al., 1990). An impaired vasopressin response to changes in plasma osmolality has been found, but the vasopressin response to hypotension in AD is normal (Norbiato et al., 1988; Chapter 8.3). The changes in vasopressin regulation can, however, probably not simply be primarily attributed to damage of the hypothalamic neurosecretory neurons in AD, as has been proposed in the literature, since their number remains intact in AD (see Chapter 8.3). In agreement with an intact neurose-

cretory vasopressin system is the stable vasopressin innervation that is observed in the locus coeruleus and parabrachial nucleus (Van Zwieten et al., 1994, 1996). Although in an older paper a reduction of vasopressin levels has been found in Brodmann areas 4, 7 and 10 (Fujiyoshi et al., 1987), increased vasopressin levels are measured in the frontal lobe, temporal lobe and occipital lobe of Alzheimer patients (Leake et al., 1991; Labudova et al., 1998). In the choroid plexus we found an increase in vasopressin-binding sites (Korting et al., 1996). A substantial proportion of night-time incontinence in the nursing home residents may be due to changes in circadian regulation (Chapter 4.3b), possibly based on a deficiency in vasopressin production and/or excretion (Ouslander et al., 1998). Clinical trials with vasopressin-like substances in AD were based on the positive action of vasopressin in memory processes, as shown in animal experiments. The effects of vasopressin analogues on memory disorders in AD have largely been negative, although some positive trials have also been reported (Jolles, 1983; Perras, 2003). That a double-blind, placebo controlled multicenter trial with the vasopressin analogue DGAVP (Org 5667) did not show any improvement in clinical rating scales or

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psychometric tests in Alzheimer patients (Wolters et al., 1990) is in agreement with the intactness of the SON and PVN as observed in our studies of these structures (Chapter 8.3). Moreover, we should be aware that the administration of vasopressin analogues is not without danger: paranoid psychosis has been reported as a side effect of desmopressin (DDAVP) in an Alzheimer patient (Collins et al., 1981). The decreased plasma concentrations of estrogenstimulated neurophysin in Alzheimer patients (Christie et al., 1987) do not seem to be due to neuronal degeneration of the oxytocin neurons in the PVN, also because these neurons seem to stay intact (see Chapter 8.3; Wierda et al., 1991). Moreover, oxytocin levels are increased in the hippocampus and temporal cortex and normal in various other brain areas (Mazurek et al., 1987). CSF levels of oxytocin are unchanged according to one study, and decreased according to another (Gottfries et al., 1995; Valenti, 1996). Yet a stable oxytocin innervation, originating in the PVN, and vasopressin innervation of the parabrachial nucleus have been found in AD patients (Van Zwieten et al., 1996), despite the fact that pervasive neuropathological Alzheimer changes are observed in Alzheimer patients in this brain area. These changes are presumed to cause autonomic dysfunction and perhaps even contribute to the mortality in these patients (Parvizi et al., 1998). Various other neuropeptide changes have been reported in the hypothalamus in AD. Galanin and neuropeptide-Y concentrations in the hypothalamus increase in AD (Gottfries et al., 1995). This agrees with the fact that weight loss is common in AD, and is even predictive of mortality (Chapter 23c). Leptin is also decreased in Alzheimer patients, but not inappropriately for the weight loss (Power et al., 2001). CRH neurons in the PVN are moderately activated in AD (Raadsheer et al., 1995, see Chapter 8.5). The decreased CSF levels of CRH that have been reported to occur in AD by some authors (Gottfries et al., 1995; Heilig et al., 1995), but not by others (Martignoni et al., 1990; Banki et al., 1992; Nemeroff, 1996; Valenti, 1996), might thus reflect extrahypothalamic changes rather than PVN changes (Gottfries et al., 1995). Whether the CRH increase in CSF in Alzheimer patients is indeed present only in association with major depression in AD (Valenti, 1996) still has to be confirmed. In the hypothalamus of Alzheimer patients, neurotensin, substance P, and concentrations of -melanotropin (MSH), cholecystokinin (CCK), thyrotropin-releasing hormone (TRH), luteinizing hormone-releasing hormone

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(LHRH) and VIP (but see Chapter 4.4) are unaltered (Ferrier et al., 1983; Arai et al., 1984a, b, 1986; Nemeroff, 1989; Gottfries et al., 1995), although extrahypothalamic -MSH is reduced in Alzheimer patients (Catania et al., 2000). In CSF, VIP levels are reduced in AD (Valenti, 1996). Somatostatin levels in the hypothalamus of Alzheimer patients decrease according to some authors, and increase or stay the same according to others (Nemeroff et al., 1989; Gottfries et al., 1995, Heilig et al., 1995; Valenti, 1996). Muhlbauer et al. (1986) have found an increase in opioid peptide levels in the CSF of AD patients. According to some, the CSF and plasma levels of -endorphin decrease in AD (Kaiya et al., 1983; Heilig et al., 1995), whereas those of ACTH increase. According to others, the levels of -endorphin and -lipoprotein remain the same or increase in this disorder (Franceschi et al., 1988; Nappi et al., 1988). In general, however, the CSF levels of neuropeptides yield only very limited information, probably because of the different brain structures that contribute to these levels and that may show differential changes in AD. Hormones and receptors Also various endocrine alterations indicating hypothalamic changes have been reported in Alzheimer patients. Plasma and salivary cortisol levels are increased in AD and vascular dementia (Davidson et al., 1988; Masugi et al, 1989; Swanwick et al., 1998; Murialdo et al., 2000; Umegaki et al., 2000; De Bruin et al., 2002; Rasmuson et al., 2002; Chapter 8.5b). Although some studies indicate that cortisol levels may even increase in an early stage of AD and may be related to cognitive decline (Umegaki et al., 2000), others have not found increased salivary cortisol levels in mild cognitive impairment, a condition that is considered to be an increased risk for AD (Wolf et al., 2002). The salivary cortisol levels are also correlated with severity of disease, as measured by the mini-mental state examination, and the global deterioration scale (Giubilei et al., 2001). Hypercortisolinemia in AD appears to be related to the clinical progression of the disease but not to aging or length of survival (Weiner et al., 1997). The increased HPA axis activity is presumed to contribute to neurodegenerative changes in aging and AD, a hypothesis we could not confirm (see Chapter 8.5e). There is a linear relationship between plasma and CSF cortisol levels (Fig. 1.14; Erkut et al., 2003, submitted). Indeed, also CSF cortisol levels are increased in AD (Swaab et al., 1994c; Erkut et al., 2003, submitted). While 327

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an increased cortisol in postmortem CSF was only found in presenile AD patients (Swaab et al., 1994c), in lumbar puncture, CSF cortisol levels were found to be elevated in an ApoE-dependent way. The presence of 1 or 2 alleles of 4 was accompanied by higher cortisol CSF levels, in both AD patients and controls (Peskind et al., 2001). In AD, CRH mRNA was found to be increased in the PVN (Raadsheer et al., 1995), causing hyperactivity of the HPA axis (see also Chapter 8.5b, e). How the increased HPA axis activity may contribute to the very high prevalence (45%) of major depression in AD (Zubenko et al., 2003) should be further investigated. Cortisol increase may generate leptin insensitivity (Olsson et al., 1998). A recent study indicates that increased glucocorticoid production is an early feature of AD and may be secondary to enhanced metabolic clearance of cortisol by A-ring reduction (Rasmussen et al., 2001). In demented patients with delirium, HPA axis feedback was found to be disturbed (Robertsson et al., 2001). On the basis of the inflammatory hypothesis of AD, low-dose (10 mg) prednisone was given to Alzheimer patients for 1 year, albeit without any effect on cognitive decline (Aisen, 2000; Aisen et al., 2000). However, after a moderate or high-dose regimen of prednisolone given to nondemented patients, the concentrations of A in CSF decreased, indicating a decreased A production or an increased A degradation in the brain (Tokuda et al., 2002). Plasma growth hormone levels are higher in the morning and plasma TSH concentrations are higher through the day in Alzheimer patients. On the other hand, plasma T3, T4 and rT3 are in the normal range (Christie et al., 1987). A past history of thyroid dysfunction is a risk factor for AD (Smith et al., 2002). Since an epidemiological study suggests that subclinical hyperthyroidism in elderly people increases the risk of dementia and AD (Kalmijn et al., 2000), a detailed study of the hypothalamopituitary–thyroid axis seems to be worthwhile. Melatonin levels in blood, CSF and pineal gland are decreased in AD (Chapter 4.5; Skene et al., 1990; Uchida et al., 1996; Magri et al., 1997; Liu et al., 1999). In particular the nocturnal increase in melatonin secretion is impaired (Ferrari et al., 2000). Moreover, daytime melatonin levels are increased in Alzheimer patients and do not react to bright light (Ohashi et al., 1999). Melatonin levels in postmortem CSF are already decreased in the earliest stages of AD, i.e. between Braak stages 0 and I (Zhou et al., 2003; Fig. 29.9). This observation has yet to be followed up in plasma or saliva. In this connection

Fig. 29.9. Melatonin levels in postmortem cerebrospinal fluid (CSF) in relation to the progression of Alzheimer’s disease as indicated by Braak stages. Note that the decrease in CSF melatonin levels already begins in those aged control subjects that are in the early stages of Alzheimer’s disease (Braak stage I). (From Zhou et al., 2003.)

it is of considerable interest that CSF and plasma levels correlate significantly (Rousseau et al., 1999). It should be noted here that melatonin functions as an antioxidant and neuroprotector (Pappolla et al., 2000; Reiter et al., 2000; Tan et al., 2000) and that it is capable of inhibiting the formation of amyloid fibrils in vitro (Pappolla et al., 1998, 2000). It also prevents the interaction of ApoE 4 and A, and thus the formation of -sheet structures and amyloid fibrils (Poeggeler et al., 2001). The decreased melatonin levels in AD may thus be clinically relevant. In a case report on a monozygotic twin with AD, and in a small retrospective study in Alzheimer patients, melatonin had a beneficial effect on memory function, sleep quality and reduced sundowning (Brusco et al., 1998, 2000). In a double-blind, randomized placebo-controlled trial of 6 mg melatonin in patients with dementia and sleep disturbances for 2 weeks, no evidence was found for improvement of sleep (Serfaty et al., 2002). More long-term, well-controlled studies are needed on the possible effects of melatonin in AD. Circulating DHEAS levels are generally found to be decreased in AD (Ferrari et al., 2000; Hillen et al., 2000; Murialdo et al., 2000; Chapter 8.5c), but unchanged levels have been reported also (De Bruin et al., 2002). Others have even observed increased DHEAS levels in AD patients (Rasmuson et al., 2002). DHEAS is believed to antagonize noxious glucocorticoid effects and to exert neuroprotective activity. In addition, the decreased DHEAS levels correlate to changes in

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hippocampal perfusion in dementia (Murialdo et al., 2000). A variety of steroids can be synthesized in the brain and are known as ‘neurosteroids’. While Brown et al. (2003a) have found increased DHEA and pregnanolone levels in the hypothalamus of AD patients, Weill-Engerer et al. (2002) have found decreased DHEAS and unaltered pregnanolone sulfate levels. Clearly more data is needed that differentiates between the different hypothalamic regions. A small pilot study has not found significant improvement of cognitive performance of DHEA in AD patients (Wolkowitz et al., 2003). Serum concentrations of LH and follicle-stimulating hormone (FSH) are significantly elevated in patients with AD. Testosterone decreases in dementia patients (Bowen et al., 2000; Short et al., 2001). These observations agree with the observations that higher levels of bioavailable estradiol protect against AD (Chapter 29.1b). Elevated gonadotropin levels are especially high in Down’s syndrome patients (Bowen et al., 2000). In the NBM of Alzheimer patients, the proportion of neurons showing nuclear staining for both ER- and ER-, and cytoplasmic staining for ER-, were markedly increased. In AD, the percentage of ER- nuclearpositive neurons increases only in women but not in men (Ishunina and Swaab, 2001; Fig. 29.10). In the vertical limb of the DBB, increased nuclear staining for ER- was also found (Ishunina and Swaab, 2003). Although these observations suggest the presence of a substrate for estrogen replacement therapy acting in interaction with the cholinergic system, there may be serious doubt about the efficacy of estrogen replacement therapy in Alzheimer patients, because each area in the brain seems to react in a different way to the lack of sex hormones and the aging process (see Chapter 29.1b, where also the possible changes in sex hormone levels in AD are discussed).

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choline acetyltransferase activity correlates significantly with the attention/registration scores. Hippocampal choline acetyltransferase activity correlates only with recent memory scores (Pappas et al., 2000). The cholinergic deficit in AD correlates not only with cognitive impairment, but also with behavioral disorders such as hyperactivity and aggression in Alzheimer patients (Minger et al., 2000). The left NBM of one Alzheimer patient was electrically stimulated over a period of 9 months, without any obvious clinical effect. However, glucose metabolism at the ipsilateral, temporal and parietal cortex was preserved in this stimulated patient, while it decreased elsewhere in the cortex (Turnbull et al., 1985), a possible basis for a positive effect that should be extended in well-controlled studies. For cholinergic deficiency in Down’s syndrome patients, see Chapter 2.5. Amines Concerning the amines, reduced concentrations of serotonin, norepinephrine and increased monoamine oxidase (MAO)-B activity have been observed in the hypothalamus (Gottfries et al., 1983); however, this has not been confirmed by Sparks et al. (1991). The hypothalamic decrease in noradrenaline (Arai et al., 1984b) correlates with the severity of dementia and emotional disturbances (Adolfson et al., 1979). The dopamine content of the hypothalamus is unchanged in AD (Adolfsson et al., 1979; Gottfries et al., 1983). However, because of the strong heterogeneity of the hypothalamus, it is difficult to interpret the overall levels of peptides or amines, and immunocytochemical or in situ hybridization studies are needed. Histaminergic deficits have been reported in the cortex and hypothalamus of Alzheimer’s and Down’s syndrome patients. This indicates that the TMN is, indeed, functionally affected in these disorders (MazurkiewiczKwilecki and Wsonwak, 1989; Schneider et al., 1997; Panula et al., 1998; see also Chapter 13). In addition, the in vivo histamine H1-receptor binding as measured by PET is significantly decreased, particularly in the frontal and temporal areas of the AD brain. Moreover, the receptor binding correlates closely to the severity of the disease (Higuchi et al., 2000). Two studies have shown a delay in onset of AD among histamine H2-receptor antagonists (Anthony et al., 2000). Melatonin levels are decreased in AD, which is most probably related to the high percentage of these patients showing “sundowning” agitation. Supplementing melatonin improves sleep and suppresses sundowning (Cardinali et al., 2002; Chapter 4.3, 4.5e).

Acetylcholine In the hypothalamus of demented patients, choline acetyltransferase levels are reduced, as is expected from the observation that the cholinergic neurons of the NBM and DBB are functionally affected by AD (Chapter 2; Carlsson et al., 1980b; Candy et al., 1983; Minger et al., 2000). In the neocortex of patients with AD, there is no apparent reduction of nicotinic acetylcholine receptor subunit mRNA, but there is loss at the protein level, especially of the -4 subunit (Court et al., 2000, 2001). The choline acetyltransferase activity in the medial frontal and inferior parietal cortex significantly correlates with scores on the graphomotor/praxis factor. Medial frontal 329

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Fig. 29.10. Immunocytochemical staining of ER in the NBM of AD patients (A; 91091) and of their matched controls (B; 98081, D; 94074). Note intensive nuclear staining in AD patients as compared to controls. Bar 25 m. (From Ishunina and Swaab, 2001, Fig. 1, with permission.)

Autonomic changes and weight loss Autonomic dysfunction, such as orthostatic hypotension, has been mentioned as a possible complication of AD (Siennicki-Lantz et al., 1999); in addition, weight loss is a common problem. Changes in appetite, food preference and eating habits are frequent occurrences (Ikeda et al., 2002). The risk of weight loss, which is a predictor of mortality among subjects with AD (White, 1998; Power et al., 2001), tends to increase with severity and progression of the disease. Leptin is appropriately decreased in AD (Power et al., 2001). The exact neurobiological basis is not known for either the autonomic dysfunction or the weight loss in AD. 29.2. Dementia with argyrophilic grains Argyrophilic grain disease was first reported as an adult-onset dementia. Recent studies have emphasized

personality change, emotional imbalance and memory problems as clinical features (Togo et al., 2002b). In the brains of individuals with adult-onset dementia, Braak and Braak (1987b, 1989) have found a particular cytoskeletal abnormality, i.e. small, spindle-shaped argyrophilic grains scattered throughout the neuropil. This pathology could, according to Braak and Braak (1987b, 1989), best be recognized in silver impregnations such as the modified Gallyas silver iodide technique (Schultz et al., 1998), but one can visualize them even better with phosphorylation-dependent antibodies such as Alz-50 or AT8, which also label neurons that remain unstained by silver preparations (Fig. 29.11; Schultz et al., 1998). Indeed, the grains contain abnormally phosphorylated tau protein (Ghebremedhin et al., 1998b). Argyrophilic brain disease appears to be characterized by 4 repeats in the microtubule binding domain (Togo et al., 2002a). The argyrophilic grains cannot be recognized in Congo red or

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Fig. 29.11. Nucleus tuberalis lateralis of a patient with dementia with argyrophilic grains. NHB 95034, male, 75 years. Note the Alz-50 staining (hyperphosphorylated tau) of a neuron and grains. Bar 50 m.

phylic grain disease and dementia, personality changes and emotional imbalance may be typical features of this disorder (Togo et al., 2002b). The argyrophylic grains are often accompanied by Alzheimer changes and can therefore best be recognized in or below Braak stage III. The grains are not specific; they can also be found in other neuropathological disorders, including Pick’s disease, Lewy body disease, corticobasal degeneration and progressive supranuclear palsy (Togo et al., 2002a). The argyrophilic grains have been found not only as exclusive pathology, but also in combination with NPs, NFTs and neuropil thread, and together with Parkinsonian pathology (Fig. 29.7) (Braak and Braak, 1987b, 1989). Dementia with argyrophilic grains should be distinguished from atypical forms of progressive supranuclear palsy with 25-nm straight tuberofilamentous structures (Masliah et al., 1991). The

thioflavin S stainings. In addition, mainly within the white matter, close to the cortical gray matter, tau-positive oligodendrocytes (coiled bodies) of silver-stained filaments are observed in this condition. Both argyrophilic grains and coiled bodies contain dense accumulations of straight filaments with a diameter of 9–13 nm in the electron microscope (Braak and Braak, 1987b, 1989; Itagaki et al., 1989; Ghebremedhin et al., 1998). Argyrophilic grain disease is not a rare disorder. In unselected material it is present in a similar frequency to AD; its prevalence increases with age and clinically it may appear as personality changes and/or deterioration of intellectual capabilities (Braak and Braak, 1998b). The frequency of this disorder is estimated on the basis of several other series, present in some 5% of dementia brains, a frequency that is similar to that in nondemented cases. Although there is thus no obligatory relationship between argyro331

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argyrophilic grains show an elongated body with coneshaped poles, occasionally giving off a short, thread-like profile. The argyrophilic grains are found in abundance in CA1 of the hippocampus, in the entorhinal cortex, in the basolateral nuclei of the amygdala and in the hypothalamic lateral tuberal nucleus. The septum and the BST contain modest amounts of grains. Of the hypothalamic nuclei, the NTL (Chapter 12) shows the most severe involvement (Fig. 29.8), whereas the VMN is affected to a moderate degree, and the TMN shows only a few grains (Braak and Braak, 1987b, 1989; Schultz et al., 1998). The subthalamic nucleus (Chapter 15a) shows a clear, hyperphosphorylated tau accumulation in argyrophilic grain disease (Mattila et al., 2002). In addition, conspicuous accumulation of tau-positive oligodendrocytes (coiled bodies) and interfascicular, thread-like fibers are present in the column of the fornix. This pathology is not visible in silver preparations, and absent in AD (Schultz et al., 1998). The slender neuropil threads (dystrophic neurites) can easily be distinguished from the coarse and distended argyrophilic grains. The characteristic argyrophilic grains may go together with the sex-dependent Alzheimer changes in the infundibular nucleus (Chapter 11.g, 29.1) which are also found in male controls and male Alzheimer cases (Schultz et al., 1998). A controversial association has been found between the ApoE 2 allele and argyrophylic grain disease. Individuals affected by this disease revealed a higher frequency of the 2 allele (22%) than controls (2%) (Ghebremedhin et al., 1998b). In contrast, ApoE allele frequencies were found to be similar to those in controls in cases with relatively pure argyrophylic grain disease, while in those with concurrent Alzheimer pathology the allele frequencies were similar to those in AD, i.e. more frequently ApoE4 was found. This supports the notion that argyrophylic grain disease is different from AD (Togo et al., 2002a). 29.3. Parkinson’s disease . . . excessive salivation was to become the greatest tribulation of my life (anonymous, 1952. The account by an anonymous doctor of his Parkinson’s disease).

Various genetic factors play a role in the development of Parkinson’s disease. There are many cases in which an autosomal dominant hereditary factor seems to predispose for Parkinson’s disease. A susceptibility gene has been located on chromosome 4q21-23; another locus for

autosomal dominantly inherited Parkinson’s disease has been localized on chromosome 2p13 (Gasser, 1998). In addition, a gene has been cloned for an autosomal recessive type of familial Parkinsonism that had been mapped on the long arm of chromosome 6 (Mizuno et al., 1998). Missense mutations have been identified in the -synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, and -synuclein (SNCA) is a major component of Lewy bodies (Chase, 1997; Polymeropoulos et al., 1997; Spillantini et al., 1997, 1998c; Lippa et al., 1998). Moreover, some cases are linked to mutations in the parkin (PARK2) and ubiquitin C-terminal hydrolase L1 gene (Solano et al., 2000). In addition to SNCA and PARK 2–8, several other chromosomal regions of interest are present (Foltynie et al., 2002). In elderly people the ApoE 2 allele increases the risk of Parkinson’s disease, in particular with dementia (Harhangi et al., 2000). Age at onset appears to be highly heritable in Parkinson’s disease (40–60%), and linkage is found on chromosome 1p, 6 and 10 (Li et al., 2002). There is a male preponderance in Parkinson’s disease. Men and women acquire the disease at the same mean age, have the same progression and die at the same age, whereas in the general population women have a longer life expectancy than men. It is not known what factor lowers the life expectancy of women to that of men when they get Parkinson’s disease (Diamond et al., 1990). The most obvious feature of Parkinson’s disease is the loss of dopaminergic melanin-laden neurons in the substantia nigra. However, it is not a typical dopaminergic disease, since on the one hand, other dopaminergic systems remain intact (e.g. the tuberoinfundibular neurons in the hypothalamus: see below) while, on the other hand, other transmitter systems and hypothalamic structures, the septum, DBB, NBM and TMN, are affected as well. The predilection sites include the entorhinal region, the CA2 sector of the hippocampal formation, the limbic nuclei of the thalamus, anterior cingulate areas, agranular insular cortex (layer VI) and the amygdala (Braak et al., 1996). Loss of cholinergic innervation may underlie dementia in Parkinson’s disease, and there are a few smaller studies that suggest that treatment with cholinesterase inhibitors may be effective in the treatment of dementia associated with Parkinson’s disease (Emre, 2003). In the Parkinson-dementia complex of Guam, a cholinergic deficit was also observed (Masliah et al., 2001). In the hypothalamus a decrease in the number of

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oxytocin-expressing neurons (Purba et al., 1994), neuronal loss in the SON and an increased somatic, nuclear and nucleolar size of the remaining neurons (Ansorge et al., 1997) have been observed in Parkinson’s disease. The presence of Lewy bodies in hypothalamic nuclei (see below) also indicates that this brain structure is affected. After several years of treatment with levodopa and other drugs, motor fluctuations ranging from bradykinesis to hyperkinesia develop in many patients with Parkinson’s disease. A double-blind study has shown that bilateral implantation of embryonic dopaminergic neurons into the putamen may result in some clinical benefit in young but not in older Parkinson patients (Freed et al., 2001). In other transplantation studies, the degree of improvement may be the same as after a sham operation (De la FuenteFernández et al., 2002). Both electrical stimulation and lesioning of the subthalamic nucleus (Chapter 15) can be effective treatments for Parkinson’s disease. Unilateral and bilateral lesions in the subthalamic nucleus have been performed in small series of Parkinson patients with a good improvement of Parkinsonism. In practice, the current procedure of choice is the chronic electrical stimulation of the subthalamic nucleus. However, this is an expensive treatment, and the effectiveness of electrical stimulation versus lesioning has not been studied in a controlled trial (Kumar et al., 1998; Limousin et al., 1998; Krack et al., 2000; Guridi and Obeso, 2001; Thobois et al., 2002). How deep-brain stimulation of the subthalamic nucleus works is not clear at present. However, PET studies in Parkinsonian patients seem to exclude that this method increases striatal dopamine release (Hilker et al., 2003). Both levodopa (L-DOPA) treatment and stimulation of the subthalamic nucleus may lead to general mood elevation, and even induce euphoria or a psychotic state. In a few patients mirthful laughter has been reported as a side effect (Krack et al., 2001; Thobois et al., 2002). In addition, stimulation of this nucleus causes increased heart rate (Kaufmann et al., 2002). However, the main side effect is the occurrence or worsening of depression (Thobois et al., 2002). Also, suicide attempts should be considered as a side effect of bilateral subthalamic stimulation (Doshi et al., 2002; Fig. 29.12). Hyperactivity of neurons in the subthalamic nucleus has also been postulated to be involved in the pathogenesis of Parkinson’s disease (Rodriguez et al., 1998; Kaufman et al., 2002), but no damage has been found in this brain structure in Parkinsonian patients (Chapter 15).

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Fig. 29.12. Electrode tip (arrow) in the subthalamic nucleus (sth) of a patient (NHB 00-073, female, 59 years of age) who committed suicide. Symptoms of hypokinesia and stiffness had started 9 years earlier. The woman had been depressed for 6 years before death and had attempted suicide 5 years before death. Bilateral implantation of electrodes in the subthalamic nucleus took place 2 years before death. Motor symptoms responded well to stimulation. Neuropathological diagnosis: olivoportocerebellar atrophy with degeneration of the substantia nigra (multisystem atrophy). Cg, cingulate gyrus; cc, corpus callosum; dm, mediodorsal nucleus of the thalamus’ vl, ventrolateral posterior nucleus of the thalamus; ci, capsula interna; cr-c, crus cerebri; ot, optic tract (damaged in this section.)

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(a) Autonomic symptoms Several autonomic and endocrine symptoms in Parkinson’s disease suggest hypothalamic involvement. Examples of autonomic disturbances are dizziness, salivation, seborrhea, excessive sweating, constipation, sphincter disturbances, dysphagia, orthostatic hypotension, blue mottled skin and other vasomotor abnormalities, low resting skin temperatures, heat intolerance, sleep disorders, depression, impotence and disruption of sleep (Appenzeller et al., 1971; Gross et al., 1972; Sandyk, 1989; Takahashi, 1991; Mathias, 2002). Disturbances of autonomic functions are an integral part of the manifestations of Parkinson’s disease and have already been included in the original description of the disease by James Parkinson, although there is controversy about this point (Koike and Takahashi, 1997). Autonomic disorders may, of course, not only develop as a result of hypothalamic pathology, but may also be due to changes in the brain stem or sympathetic ganglia. Measurements of the relationship between blood pressure and pulse rate seem to reflect an imbalance between the sympathetic and parasympathetic nervous system (Murata et al., 1997). According to some authors, cardiovascular reflexes in Parkinson patients are already disturbed in early stages of the disease (stages 1 and 2 on the Hoehn and Yar scale). Some 80% of the patients have abnormalities in heart rate in response to postural change, a function known to be mediated via the parasympathetic innervation of the heart (Awerbuch and Sandyk, 1992). Whether hypothalamic innervation of the vagus–ambiguous complex is indeed involved in these Parkinson symptoms still has to be investigated. Orthostatic hypotension may not only be the result of sympathetic dysfunction, but can also be a side effect of levodopa. Other authors conclude, however, that cardiovascular autonomic dysfunction in Parkinson’s disease is mild, mainly affects blood pressure responses, and occurs only in advanced cases (Van Dijk et al., 1993). Other symptoms of hypothalamic involvement in Parkinson’s disease are weight gain or weight loss. Bulimia has been found in Parkinson’s disease, and the bulimia decreases concomitantly with clinical improvement during levodopa treatment (Gasparinin and Spinnler, 1975; Rosenberg et al., 1977). However, more often weight loss has been observed in Parkinson’s patients not treated with levodopa (Rosenberg et al., 1977; Aimard et al., 1984). A case of a 54-year-old man with Kleine–Levin syndrome who also developed Parkinsonian symptoms has been reported (Müller et al., 1998b;

Chapter 28.1), suggesting a general dopamine deficiency at the basis of the symptoms of this patient. (b) Sleep and circadian rhythms Sleep disturbances in Parkinson patients are much more common than in controls and have been attributed to both the disease and its therapy (Askenasy, 1993; Chaudhuri et al., 2002). Sleep disturbances correlate with increased severity of the disease (Kumar et al., 2002). As Parkinson in his 1817 book phrased it: “The tremulous motion of the limbs occur during sleep and augment until they awaken the patient (Askenasy and Yahr, 1990). A reversal of sleep pattern and a normalization of muscle activity during sleep may occur with dopaminergic treatment (Askenasy and Yahr, 1985). Parkinson patients experience insomnia, parasomnias, such as REM sleep behavior disorders, vivid dreaming, nightmares, psychosis, or excessive daytime somnolence, specifically excessive daytime sleepiness and sleep attacks (Larsen and Tandberg, 2001; Kumar et al., 2002). The study by Van Hilten et al. (1993) has shown that, although the light prevalence of sleep disturbances in patients with Parkinson’s disease may be largely explained by normal aging, the severity of disrupted sleep maintenance is more marked in the patients with Parkinson’s disease than in healthy contemporaries. Nocturia, pain, stiffness, and problems with turning in bed are well recognized causes of disrupted sleep in Parkinson’s disease. Sleep disruption in mildly to moderately affected Parkinson’s patients may also be caused by a dose-dependent effect of levodopa or dopamine agonists on sleep regulation (Van Hilten et al., 1994; Larsen and Tandberg, 2001). However, in more severely affected Parkinson patients, these drugs have a beneficial effect on nocturnal disabilities (e.g. problems with turning over in bed, pain and stiffness) that may cause sleep disruption. As the progression of Parkinson’s disease evolves, the beneficial effect of levodopa or dopamine agonists on nocturnal disabilities predominate over their dose-dependent disrupting effect on sleep regulation. No evidence was found for the association of fatigue with any circadian factor (Van Hilten et al., 1993). Both movements and tremor of Parkinson patients show a very clear circadian pattern, the tremor becoming subclinical during the night. The circadian rhythm of the movements and body core temperature in idiopathic Parkinson patients was normal (Van Someren et al., 1993; Pierangeli et al., 2001), so that the SCN, at least in the studied group of patients subjected to

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stereotactic subthalamic lesions, seems to be largely intact. Indeed, already since the turn of the century, the disappearance of Parkinsonian tremor during the night has been known to be a constant phenomenon. Plasma melatonin in Parkinson patients was also found to be in the normal control range (Critchley et al., 1991). In levodopa-treated Parkinson patients, the circadian plasma level changes in melatonin were very similar to those in age-matched controls, except for a phase advance of the nocturnal melatonin elevation in the Parkinson group (Fertl et al., 1991; Bordet et al., 2003). In one paper, a flattened diurnal cortisol secretory curve has been reported in Parkinson patients, whereas – strangely enough – an intact diurnal profile was found in the same study in Alzheimer patients (Hartmann et al., 1997; compare Chapter 4.3). One Parkinson patient with a 48-h sleep–wake cycle has been described (Mikami et al., 1987). In addition, by way of ‘preliminary results’ it was mentioned that the normal increase in urinary volume occurring during the day was not observed in patients with Parkinson’s disease (Hineo et al., 1992). On the other hand, Parkinson’s disease is associated with a loss of circadian rhythm of blood pressure, increased diurnal blood pressure variability and postprandial hypotension (Bruguerolle and Simon, 2002). The increased occurrence rate of glaucoma in Parkinson’s disease (Bayer et al., 2002a) may result in a diminished input to the SCN and to some alterations in circadian rhythms. However, the body of evidence indicates that circadian rhythms are largely intact in Parkinson patients. Excessive daytime sleepiness, i.e. sudden onset of sleep, is not the result of pharmacotherapy but is related to the pathology of Parkinson’s disease (Arnulf et al., 2002). Rather unexpectedly a significantly higher narcolepsy score was found in Parkinson patients. This was viewed as being due to dopaminergic medication (Happe et al., 2001). It is not known whether the hypocretin neurons in the lateral hypothalamus are affected in this disorder (see Chapter 28.4).

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suggests that the prevalence of moderate or severe major depression is lower than the previously assumed substantial proportion of patients with Parkinson’s disease with less-severe depressive symptoms (Tandberg et al., 1996). Nonsuppression following dexamethasone frequently occurs, which indicates increased activity of the CRH neurons (Kosti´c et al., 1990; Rabey et al., 1990; Meco et al., 1991) and thus hypothalamic involvement (see Chapters 8.5, 26.4). It should be noted, though, that the dexamethasone suppression test in Parkinson patients does not differentiate well between those with depression and those with dementia (Rabey et al., 1990), so that disorders in other brain areas or neurotransmitter systems may affect the dexamethasone suppression test in these patients. In contrast to idiopathic depression (see Chapter 26.4), we did not find an increased number of CRHexpressing neurons in the PVN of Parkinson patients with depression as compared to a nondepressed group of Parkinson patients (Hoogendijk et al., 1998). The most probable explanation is that depression in Parkinson’s disease has a different neurobiological basis from that of idiopathic major depression (see before). The fact, for instance, that the severity of vegetative symptoms increases with advancing Parkinson, but mood and self-reproach do not (Huber et al., 1990), and the fact that the correlation between the severity of motor impairment and depression in Parkinson’s disease is poor (Mayeux et al., 1984), may point toward a psychological, reactive contribution to the etiology of Parkinson’s disease expression. (d) Hormones and neuropeptides in the hypothalamus Endocrine control is also impaired in Parkinson’s disease as indicated by abnormal glucose tolerance and abnormal secretion of prolactin, TSH, growth hormone and increased CSF levels of MSH (Brown et al., 1973; Shuster et al., 1973; Eisler et al., 1981; Cusimano et al., 1991). Idiopathic Parkinson’s disease without autonomic defects can be differentiated from multiple system atrophy by stimulation of growth hormone release by clonidine. Clonidine is a centrally active 2-adrenoceptor agonist that raises growth hormone levels in healthy controls and Parkinson patients, but not in patients with multiple system atrophy. This indicates a specific hypothalamic -adrenoceptor deficit in the latter disorder (Kimber et al., 1997). Alterations in melatonin regulation have also been reported (Catalá et al., 1997). In addition, a diminished number of oxytocin-containing neurons was

(c) Depression Depression symptoms are frequently encountered in Parkinson’s disease (Cummings, 1992; Tandberg, 1997; Happe et al., 2001), but their type and clinical course are different from idiopathic depression (Mayeux et al., 1984). Greater anxiety and less self-punitive ideation (Cummings, 1992) distinguish Parkinson’s depression from other depressive disorders. Recent research also 335

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observed in the PVN (Purba et al., 1994) and vasopressin blood and CSF levels were reported to be decreased in Parkinson’s disease in some studies (Sundquist et al., 1983; Olsson et al., 1987). Indeed, a decreased number of neurons in the SON was found in Parkinson’s disease. These neuroendocrine changes may be related to the disturbed circadian renal fluid handling and blood pressure adaptation of Parkinson patients (Ansorge et al., 1997). With respect to the alterations in antidiuretic hormone levels and the colocalization of vasopressin and tyrosine hydroxylase in the SON and PVN (see Chapter 8) it should also be noted that levodopa has, at least in some Parkinson patients, an effect on renal blood flow, and causes an increased urinary potassium excretion, which causes hypokalemia. The mechanism of these effects is not known (Finlay et al., 1971; Granérus et al., 1977). Pro-opiomelanocortin peptides, CRH and growth hormone-releasing hormone levels remain unaltered in the hypothalamus of Parkinson patients (Conte-Devolx et al., 1985; Pique et al., 1985), but MSH CSF levels increase in Parkinson’s disease (Catania et al., 2000). Slightly higher cortisol levels associated with gait deficit have been reported in Parkinsonism (Charlett et al., 1998). Interestingly, some clinical studies suggest that Parkinson symptoms may be exacerbated after menopause, and transdermal 17-estradiol appeared to have slight antiparkinsonian effects, without consistently altering dyskinesias. Others failed to observe that hormone replacement therapy delayed or alleviated the symptoms (Blanchet et al., 1999; Shulman, 2002). It is presumed that changes in the dopaminergic systems might contribute, at least partly, to the reported endocrine alterations, because dopamine is the major prolactin-inhibiting factor, the secretion of MSH and growth hormone are under dopaminergic control (Brown et al., 1973), and oxytocin release is regulated by dopamine also (Bridges et al., 1976; Clarke et al., 1979; Lightman et al., 1982; Björklund and Lindvall, 1984). In addition, dopamine levels in the hypothalamus decrease by 35–50% in Parkinson’s disease (Conte-Devolx et al., 1985; Pique et al., 1985; Uhl et al., 1985), probably due to nigral degeneration rather than to degeneration of the tuberoinfundibular dopaminergic system of the hypothalamus itself. The number of hypothalamic dopaminergic neuroendocrine neurons, as identified by their melanin content, remains stable in Parkinson’s disease (Matzuk and Saper, 1985), in contrast to those in the substantia nigra. Also, the presence of tyrosine hydroxylase-positive neurons in the hypothalamic PVN

was not affected in Parkinson’s disease (Purba et al., 1994), supporting the notion that dopaminergic neurons in the mesencephalon, but not in the hypothalamus, are affected in Parkinson’s disease. Although the autonomic, sleep, mood and endocrine changes suggest hypothalamic involvement, it must be stated that no firm link between any of these changes in Parkinson’s disease have been related to deficiencies in particular hypothalamic nuclei so far. In addition, hypothalamic compensatory actions to overcome dopamine deficiency may be responsible for symptoms of Parkinson’s disease (Sandyk, 1989). (e) Lewy bodies in the hypothalamus and adjacent areas Lewy bodies are hyalin cytoplasmatic neuronal inclusions that occur in nerve cell somata and processes. Trétiakoff (1919) first described “corps de Lewy” in the substantia nigra (for reference see Gibb, 1986). Lewy bodies are surrounded by a light halo and the core often stains differentially and can be stained by anti-ubiquitin in various brain areas (Kremer and Bots, 1993; Purba et al., 1994). The major components of Lewy bodies are abnormally phosphorylated neurofilaments affecting the cytoskeleton. Additional components include ubiquitin and -synuclein, which normally occurs in the presynaptic membrane (Braak and Braak, 2000). The presence of Lewy bodies is generally considered to be a marker for nerve cell degeneration in Parkinson’s disease (Langston and Forno, 1978). However, Kremer and Bots (1993) have shown that the NTL did contain Lewy bodies but did not show neuronal loss in Parkinson’s disease. Purba et al. (1994) have shown the opposite: an absence of Lewy bodies in the PVN accompanies a decreased number of oxytocinexpressing neurons in this nucleus in Parkinson’s disease. Although these two observations raise doubts about the direct importance of the presence of Lewy bodies for the process of neurodegeneration, it remains, of course, a crucial neuropathological marker for the diagnosis of Parkinson’s disease. On the other hand, Lewy bodies are not specific for this disorder, since they also turn up as incidental findings at autopsy in 7–10% of normal individuals over the age of 60 and in postencephalitic Parkinson’s syndrome. Lewy bodies are also seen in Parkinson-dementia complex, Hallerverder–Spatz syndrome and progressive nuclear palsy (Ohama and Ikuta, 1976). They are rarely found in olivocerebellar atrophy and in Joseph disease (Gibb, 1986). In diffuse Lewy body

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disease, the cortex is also involved, and dementia, paranoid delusions and hallucinations may be present (Gibb, 1986). Although a high frequency of visual hallucinations has been confirmed in Parkinson patients with Lewy bodies in the cortex, a clear relationship between the postmortem neuropathological findings and the clinical presence of psychopathology or dementia has not been observed (De Vos et al., 1995). Lewy bodies are found in different hypothalamic nuclei (Den Hartog Jager and Bethlem, 1960; Langston and Forno, 1978; Gibb, 1986). Lewy himself described, in 1912, serpentine or elongated bodies, not only in the dorsal motor nucleus of the nervus vagus, but also in the NBM, where they are still called Lewy neurites (Chapter 2.6; Braak and Braak, 2000). They occur in Braak stage 3–4 (Braak et al., 2003). Loss of neurons in the NBM was first described by Lewy in 1913, even before cell loss was reported in the substantia nigra (Whitehouse, 1986). Indeed, there is degeneration of the ascending cholinergic pathways in Parkinson’s disease. Deficits in nicotinic receptors have been reported in the caudate nucleus, putamen, neocortex, substantia nigra and ventral tegmental area (Court et al., 2000). In addition, Lewy bodies are present in the periventricular nucleus, dorsomedial nucleus, TMN (which contains the highest concentration of Lewy bodies and Lewy neurites in the hypothalamus) and the BST, while far fewer Lewy bodies are found in the mamillary bodies and NTL (Kremer and Bots, 1993; Braak and Braak, 2000; Braak et al., 2003). In the latter nucleus, Lewy bodies appear to be quite variable: regular, lamellated, distorted or elongated (intraneuritic) forms are seen. Since Lewy bodies vary in size, as Kremer and Bots (1993) have pointed out, the impression that the TMN contains more Lewy bodies than the NTL might, at least partly, be due to the fact that Lewy bodies in the former nucleus are clearly larger, which increases their sampling probability. Unbiased morphometric techniques should therefore be used to obtain a reliable estimation of the different amounts in the different hypothalamic nuclei. On the other hand, the TMN is, without any doubt, severely affected by Lewy bodies in Parkinson’s disease (Braak et al., 2003). Although the term “destruction” has been used in this connection (Braak et al., 1996), it should be noted that this term is only based upon the presence of abundant amounts of Lewy body and Lewy neurites and not on neuronal death. The Lewy bodies would develop in the TMN quite early on in the disease process and are often more pronounced than in the basal forebrain nuclei.

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The histaminergic innervation of the substantia nigra is increased in Parkinson’s disease. Although these nerve fibers are thinner and have enlarged varicosities, these observations agree with a relatively intact TMN in Parkinson’s disease (Anichtchik et al., 2000). Lewy bodies have also been found in the hypothalamic lateral area and posterior nucleus (Ohama and Ikuta, 1976). The mamillary nuclei are virtually spared any Parkinsonspecific changes (Braak et al., 1996). The olfactory bulb, olfactory tract and the cells of the olfactory nucleus are never the sole sites involved in Parkinson-related pathology (i.e. Lewy neurites and Lewy bodies), precluding that the olfactory system would be the site of induction of this disorder (Del Tredici et al., 2002). 29.4. Huntington’s disease Huntington’s disease (HD) is an autosomal, dominantly inherited neurodegenerative disorder, which is characterized by hyperkinetic involuntary movements (chorea), intellectual impairment and selective neuronal loss in the striatum and cerebral cortex (Reddy et al., 1999). The hypothalamic subthalamic nucleus is involved in the production of chorea (Chapter 15a; Weiner, 1997). The molecular basis of HD is an expanded sequence of 36 to 121 CAG repeats, the sequence that codes for glutamine, with the median being 44 in a gene on chromosome 416.3 (Huntington Dis. Coll. Res. Group, 1993; Kremer et al., 1994; Reddy et al., 1999). A significant negative correlation was found between the length of the repeat and the age of onset for the total cohort. In late-onset HD, the median upper allele size for the CAG repeat was 42, with a range of 38–48 repeats. The variation of repeat length accounts only for about 7% of the variation in age of onset for persons over the age of 50 years (Andrew et al., 1993; Kremer et al., 1993a;). For patients who had an age of onset above 60 years, no such significant correlation was found. There is evidence for area specific instability of the CAG-repeat lengths in affected brain regions, such as the basal ganglia and cerebral cortex. The cerebellar cortex displayed the lowest degree of CAG mosaicism (Telenius et al., 1994). The protein encoded for is huntingtin. It is normally located in the cytoplasm, whereas the mutant form is also found in the nucleus (Reddy et al., 1999). Huntingtin is of unknown function, but colocalizes with microtubules, vesicles and synaptic compounds, suggesting a role in cellular transport and neurotransmission (Di Prospero and 337

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Tagle, 2000). An NH2-terminal fragment of the mutated huntingtin has been localized to neuronal intranuclear inclusions and dystrophic neurites in the Huntington cortex and striatum, which are preferentially affected in this disease. Ubiquitin is also found in these neuronal intranuclear inclusions, suggesting that abnormal huntingtin is targeted for proteolysis but is resistant to removal, so that this process is incomplete (DiFiglia et al., 1997). However, the exact mechanism of neurodegeneration in HD is not yet clear (Ross, 1997; Di Prospero and Tagle, 2000). There are endocrine and autonomic abnormalities pointing to hypothalamic involvement in HD. In addition, hypothalamic involvement in HD is presumed on the basis of sleep disturbances and a strong weight loss in conjunction with adequate caloric intake (Kremer, 1992a). Mean basal levels of growth hormone (Durso et al., 1983a, b) and nocturnal growth hormone levels (Murri et al., 1980) are found to be increased. In addition, growth hormone responses to dopamine agonists (Caraceni et al., 1977; Müller et al., 1979; Durso et al., 1983a), glucose (Podolsky and Leopold, 1974), insulin (Keogh et al., 1976; Phillipson and Bird, 1977; Lavin et al., 1981), arginine (Leopold and Podolsky, 1975) and muscimol (Durso et al., 1983a) are exaggerated. Since the paradoxical growth hormone rise after glucose loading only occurs in some HD patients (Diepen, 1962; Podolsky and Leopold, 1975; Kremer et al., 1989), impaired growth hormone regulation seems to be a feature of only some of the HD patients. Plasma cortisol has been reported to be low in some HD patients (Bruyn et al., 1972), whereas the cortisol rise during an insulin tolerance test occurs earlier (Lavin et al., 1981). However, other studies found elevated basal cortisol and ACTH levels in HD patients (Heuser et al., 1991). The CSF levels of -endorphin decrease in HD (Kaiya et al., 1983). Retarded menarche in female HD patients (Oepen et al., 1963) and increased levels of LHRH in the median eminence of female HD patients but not of male HD patients (Bird et al., 1976) have been reported; yet 24-h curves of LH secretion seem to be normal (Durso et al., 1984). Prolactin, FSH, LH, total T4, T3 uptake and TSH are also normal in HD (Kremer, 1992a), as are hormone responses after TRH and LHRH (Lavin et al., 1981). In addition, PD patients who were deprived of water retain their ability to concentrate urine (Lavin et al., 1981), which points to an intact hypothalamoneurohypophysial system. The greater fall in mean blood pressure on tilting in HD patients (Aminoff and Gross, 1974) is suggestive

of sympathetic dysfunction. The same goes for the observation of Den Heijer et al. (1988) of an impaired rise in diastolic blood pressure to sustained hand grip. Parasympathetic dysfunction may be indicated by an increased papillary light reflex latency (Den Heijer et al., 1988). Disturbed sleep patterns with increased sleep latency, reduced sleep efficiency, frequent nocturnal awakenings, more time spent awake, and less slow-wave sleep have also been found in HD patients (Wiegand et al., 1991). So far these changes have not been related to hypothalamic abnormalities. Striking emaciation in HD patients has been shown in clinical follow-ups (Sanberg et al., 1981), anthropometric studies (Farrer and Yu, 1985) with dietary assessment (Morales et al., 1989), as well as in a postmortem study of 217 cases (Oepen, 1963). HD patients lose weight and become cachectic, in conjunction with adequate dietary intake (Sanberg et al., 1981; Morales et al., 1989) or even increased carbohydrate intake (Farrer and Yu, 1985); many patients even have a ravenous appetite (Bruyn, 1968). HD patients are less engaged in strenuous activity than controls (Farrer and Yu, 1985) and tend to lose more weight in their final hypokinetic stages than in their earlier hyperkinetic stages (Sanberg et al., 1981). Also, the curious finding of an inverse relationship between the age of onset of HD and milk consumption in Dutch choreics (Buruma et al., 1987) may reflect the increased caloric intake of these patients. Hypothalamic changes in Huntington’s disease On the basis of a few cases and qualitative observations, changes are presumed in the SON and PVN (Schöpe, 1940; Vogt and Vogt, 1951), and in the VMN (Bruyn, 1973) and TMN (Schöpe, 1940), while quantitatively no significant neuronal loss is found in the NBM (Clark et al., 1983). W. Wahren was the first to report the striking cell loss in the NTL (Wahren, 1952; Wahren 1964). This finding was followed up, in great detail, by Kremer (1992a), who found that the NTL is indeed consistently affected in HD. He found a neuronal loss of up to 90% in the NTL of HD patients. The remaining neurons showed features of degeneration and there was astrocytosis with an unchanged number of astrocytes, whereas the number of oligodendrocytes was reduced by 40%. The large neurons of the TMN are well preserved (Kremer et al., 1990). The log-transformed neuronal counts in the NTL of HD patients correlate closely with age at death (r = 0.66, p < 0.01; Fig. 29.10) and age of onset (r = 0.78, p < 0.001), but not with the duration of the

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disease. Patients who die young or who first display motor disturbances at an early age have a great deal fewer neurons left than patients who die in old age. Neuronal loss in the NTL is not related to striatal changes (Kremer et al., 1991a). It had already been reported by Wahren (1964) that cell death in the NTL of Huntington patients with an early onset (i.e. before the age of 60) is more pronounced. In the neurites and perikarya of the NTL, somatostatin 1-12 immunoreactivity is abundantly present. In Huntington’s disease, somatostatin immunoreactivity is greatly reduced (Fig. 29.11), whereas neostriatal somatostatin neurons escape destruction in this disorder. In general, higher staining intensity is present in Huntington patients who have more NTL neurons left than in those who have fewer NTL neurons left. The data obtained so far suggest that NTL neurons cease to express somatostatin-like peptides quite some time before their actual disappearance (Timmers et al., 1996). In Huntington patients the levels of histamine H2receptor binding sites are found to be markedly decreased in virtually all brain regions investigated, particularly in the putamen and globus pallidus lateralis. The loss of binding sites is related to the grade of the disease (Martinez-Mir et al., 1993). Since the TMN does not show a clear cell loss in this disorder (Kremer et al., 1993), a functional change of the histaminergic system may be expected in Huntington’s disease.

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abnormal gaze and gait (ataxia), and loss of recent memory. With abstinence and high dosage of thiamine, the acute phase of Wernicke’s syndrome clears. However, approximately 25% of the patients develop severe memory disorders: the Korsakoff syndrome or Korsakoff psychosis (Fadda and Rosetti, 1998). Wernicke’s encephalopathy is characterized clinically by the triad of ophthalmoplegia, nystagmus and ataxia, and by a confusional state, while in 82% of cases polyneuropathy is found. Neuropathologically Wernicke’s encephalopathy is characterized by hemorrhagic lesions in the walls of the third and fourth ventricles and Sylvius’ aqueduct and is caused by thiamine deficiency (Spillane and Riddock, 1947; Haak et al., 1990; Blansjaar et al., 1992; Victor, 1994; Ming et al., 1998). In addition, subnormal temperatures that are likely to be due to an involvement of the posterior hypothalamus, including the mamillary bodies, have been reported. The physiological ‘thermostat’ seems to have been reset at a lower level (Koeppen et al., 1969; Haak et al., 1990). Moreover, the direct toxic effect of alcohol on the thyroid gland may be relevant in this respect. This results in a compensatory activation of the hypothalamopituitary axis (HPA axis) with increased thyrotropin (TSH) release and a blunted response to the TRH test, due to a downregulation of pituitary TRH receptors. A reduction in total thyroxine (T4) and total and free triiodothyronine (T3) are, moreover, consistent findings during early abstinence. Also, other hormonal and neurotransmitter disturbances have been described. Acute and chronic alcohol consumption can affect the HPA axis and the hormonal stress response. Plasma cortisol increases have been observed concurrently with alcohol consumption, and also during the alcohol withdrawal period. In abstinent alcoholics, baseline plasma cortisol generally returns to normal values (Umhau et al., 2001; Chapter 8.5d). In male alcoholics sustained increases in serum free and total testosterone levels are found in the presence of inadequately raised LH concentrations. A relative insensitivity toward testosterone might contribute to the high prevalence of sexual dysfunction in this group of patients (Hasselblatt et al., 2003). Poorer cognitive performance in alcoholics is related to more withdrawals and higher cortisol level during a withdrawal. Altered stress regulation of the HPA axis is also related to attenuated stress cortisol responses (Errico et al., 2002). In alcoholism, lower levels of 5-HT and 5-HIAA and MAO-B have been detected in the hypothalamus(Carlsson et al., 1980b). The patient described by Haak et al. (1990) probably had a

29.5. Wernicke’s encephalopathy, Korsakoff’s psychosis and Marchiafava–Bignami disease Alcoholism is a genetically influenced disorder; twin studies have estimated a hereditability of 50–60% for alcoholism. The neuropeptide Y (NPY) is involved in appetite, reward, anxiety and energy balance (Chapter 11.23). The functional Leu7Pro polymorphism in the NPY gene is a risk factor for alcohol dependence (Lappalainen et al., 2002). Chronic alcoholics perform less well in several learning and memory tests. Approximately 10% of chronic alcoholics develop an amnestic disorder – Korsakoff’s syndrome – or alcohol-associated dementia (Fadda and Rossetti, 1998). In 1881 Wernicke described four cases of encephalopathy and ophthalmoplegia in adults with malnutrition who at autopsy were found to have characteristic hemorrhagic lesions (Spillane and Riddock, 1947; Hazell et al., 1998; Figs. 29.12–29.14). Wernicke’s encephalopathy is an neurological crisis characterized by mental confusion, impairment of spatial organization, 339

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Fig. 29.13. Number of remaining nucleus tuberalis lateralis (NTL) neurons (NE) related to age at death in 16 Huntington’s disease (HD) cases (•) and 12 controls (circ). For the controls the mean is indicated (dashed line), as well as the normal range (mean ± 2 SD; shaded area); there was no age-related decline: NE = 61.450 – 31.8  age; n = 12; r = – 0.071; NS. For the HD patients, NE did correlate with age: NE = 6.9 + 0.038  age; n = 16; r = 0.66; p < 0.01. (From Kremer et al., 1991a, Fig.1, with permission.)

temporarily inappropriately high release of vasopressin and a decreased release of prolactin-inhibitory factor, CRH and somatostatin. In Wernicke’s encephalopathy active (acute and subacute) and inactive (chronic) cases are distinguished. The term ‘active’ is used to indicate continuing thiamine deficiency at the time of death (Torvik et al., 1982). Wernicke’s encephalopathy is caused by thiamine (vitamin B1) deficiency and may be due to alcoholism, malnutrition or eating disorders, chemotherapy in cancer patients, or hyperemesis gravidarum or long-term extensive vomiting for other reasons. The patients may respond dramatically to thiamine replacement. Activity of the thiamine-dependent enzyme -ketoglutamate dehydrogenase, a rate-limiting tricarboxylic acid cycle enzyme is significantly reduced in autopsied brain tissue from patients with Wernicke’s encephalopathy. Animal studies suggest that such enzyme deficits result in focal acidosis, cerebral energy impairment, depolarization due to increased glutamate release, and so to excitotoxicity (Hazell et al., 1998). Wernicke’s encephalopathy has also been seen in patients on total

Fig. 29.14. A and B: Comparison of anti somatostatin 1-12 (S320) immunoreactivity in the hypothalamus of a control (control subject 2) (A) to that of a HD patient (no. 10) (B). Note that in the control hypothalamus subdivisions of the NTL are intensively stained by S320, whereas there is no staining at all in the NTL area of the HD patient. Staining intensity of the ventromedial nucleus (vmn) does not differ. HD patient no. 10: S320 immunoreactivity is absent in the NTL (C), whereas in the vmn beaded fibers are still present (D). All sections were pretreated by microwave heating. fx, fornix; ntl, nucleus tuberalis lateralis; ci, internal capsule; to, optic tract; tv, third ventricle. Bars 2.5 mm in A, B; 10 m in C, D. (From Timmers et al., 1996, Fig. 3, with permission.)

parenteral nutrition due to multivitamin shortage. MRI may reveal lesions in the mamillary bodies and other brain structures (Charness and DelaPaz, 1987; Hahn et al., 1998b; Ming et al., 1998). The neuropathological lesions of Wernicke’s encephalopathy are found at autopsy in 0.8–2.8% of the population, and in up to 12.5%

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of the alcoholics, although Wernicke’s encephalopathy is diagnosed in less than 0.04–0.13% of all hospital admissions (Harper et al., 1983; Charness and DelaPaz, 1987). This discrepancy may be caused by the absence of the classical triad-oculomotor dysfunction, ataxia and encephalopathy (Charness and DelaPaz, 1987; Victor, 1994). Despite adequate therapy, many inactive Wernicke’s encephalopathy cases develop Korsakoff’s psychosis, an often irreversible syndrome of selective anterograde and retrograde amnesia, confabulations, and severe learning disabilities. The memory impairment is persistent and irreversible (Kahn and Crosby, 1972; Charness and DeLaPaz, 1987; Blansjaar et al., 1992). However, Korsakoff’s psychosis may also evolve without an antecedent episode of Wernicke’s encephalopathy (Blansjaar et al., 1992; Victor, 1994). Wernicke-Korsakoff syndrome patients of alcoholic etiology with an Apoe-4 genotype are prone to global intellectual deficits (Muramatsu et al., 1997). The distinction between Korsakoff’s psychosis and alcohol dementia may not always be clear (Torvik et al., 1982). Destructive bilateral lesions of the septal areas or in the mamillary bodies interfere with the memory of recent events. Craniopharyngiomas may also produce Korsakoff’s syndrome in adults when they compress the two mamillary bodies (Kahn and Crosby, 1972). One patient with tumor masses in both mamillary bodies and medial thalamus revealed anterograde, but no retrograde memory disturbances (Kapur et al., 1996). The lesions of Wernicke’s encephalopathy occur symmetrically, e.g. in the mamillary bodies (Figs. 29.11, 29.12 and 29.13), the hypothalamus adjacent to the third ventricle, the aqueduct and the fourth ventricle (Hazell et al., 1998). However, lesions also occur in other brain areas. The number of immunoreactive vasopressin neurons in the SON and PVN, and the volume of the SON and PVN decreases (Fig. 29.15 and 29.16) in Wernicke’s encephalopathy. This explains why alcoholics respond inappropriately, with suppressed vasopressin levels under osmotic stress (Harding et al., 1996). During a 280-day period of abstinence in alcoholics, basal vasopressin levels stayed suppressed. It is presumed that this may contribute to dysregulation of the HPA axis, mood, memory, addiction behavior and craving (Döring et al., 2003). Tau-positive granular and fibrillary inclusions are frequently present in the magnocellular neurons of the NBM in alcoholics without Wernicke’s encephalopathy. In addition, increased peroxidase activity is found in all Wernicke alcoholics in neurons of the NBM and

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in neighboring astrocytes (Cullen and Halliday, 1995). Ventricular enlargement and sulcal widening is found in 34% and 21% of cases, respectively (Harper, 1983; Jacobson and Lishman, 1990). Generalized alcoholic brain atrophy is present and cerebellar atrophy is frequently found (Torvik et al., 1982). Microscopic findings include extravasation of red blood cells (diapedesis) into the perivascular space. In some instances they extend into the parenchyma to form “ball” macrophages or hemorrhages. Acute lesions are characterized by hemorrhage, and perivascular interstitial hemorrhage underlies the petechial hemorrhages (Figs. 29.12–29.14). The endothelial cells become hypertrophic (Harper, 1983); moreover, loss of neuropil, reactive proliferation of macrophages, astrocytes, and microglia, demyelination, neuronal loss and, occasionally, spongy necrosis and hemorrhages are found (Koeppen et al., 1969; Harper, 1983; Charness and DelaPaz, 1987; Blansjaar et al. 1992; Victor, 1994). In addition, acute cases of Wernicke’s encephalopathy starting 2 weeks before death have been described, with ballooned neurons in the mamillary bodies. In one case focal necrosis was observed; the affected neurons were reactive for phosphorylated neurofilament and synaptophysin, but ubiquitin and B crystallin expression were not detected. The mamillothalamic tract appeared to be normal, while there was a marked associated microglial reaction. It is proposed that these changes reflect an early stage in the development of Wernicke’s encephalopathy (Freiesleben et al., 1997). Chronic lesions are characterized by atrophy of the mamillary bodies with brownish discoloration. This is a relatively specific macroscopic feature encountered in up to 99% of autopsies (Torvik et al., 1982; Harper, 1983; Charness and DeLaPaz, 1987; Victor, 1994). Histologically the changes vary from barely visible tissue destruction, with gliosis in the central parts of the mamillary bodies, to subtotal destruction of the tissue (Torvik et al., 1982). Shrunken mamillary bodies, the most specific macroscopic lesion of chronic Wernicke’s encephalopathy, can be identified by means of MRI imaging. The mean mamillary body volume as measured by MRI is 52–64 mm3 in controls, 40–46 mm3 in Alzheimer patients and 21–24 mm3 in Wernicke patients (Charness and DeLaPaz, 1987; Charness, 1999; Sheedy et al., 1999). Mamillary body shrinkage is related to the severity of cognitive and memory dysfunction (Sullivan et al., 1999). However, in alcoholism alone, without amnesic disorder, mamillary body atrophy also occurs. These lesions thus presumably develop before the patients 341

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Fig. 29.15. Wernicke’s encephalopathy. Upper figure: characteristic vascular disturbances in mamillary bodies. Material from a patient who died in a prisoner-of-war camp in the Far East. Frozen section. Benzidine stain,  8. Lower figure: same patient vascular lesions in floor of the third ventricle ( 50). (From Spillane and Riddock, 1947, Fig. 18 and 19, with permission.)

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A rare complication of alcoholism, defined by a degeneration of the corpus callosum and the anterior commissure is Marchiafava–Bignami disease (primary degeneration of the corpus callosum). The clinical picture shows great variation. The course may be acute, rapidly leading to death, or marked by a progressive dementia with predominantly frontal lobe signs (Moreaud et al., 1996). Neuropathologically, the typical finding is destruction of myelinated fibers in the corpus callosum and anterior commissure (Victor, 1994). 29.6. Adrenomyeloneuropathy, adrenoleukodystrophy and hypothalamic-pituitary dysfunction Adrenomyeloneuropathy is a syndrome comprising spastic paraparesis, polyneuropathy, primary adrenocortical insufficiency and variable hypogonadism. It is characterized by a degeneration of the pyramidal tracts, posterior funiculi and peripheral nerves, which follows a pattern of retrograde axonopathy. Thick cuffs of perivascular histiocytic cells are seen in all demyelinated tracts. In addition, characteristic inclusion bodies are found: these can take on an electron-lucent fusifor shape, an electron-dense, boomerang-like one, or they can be triangular. Adrenomyeloneuropathy is an hereditary X-linked disorder of peroxisomal metabolism, and is considered to be an adult variant of adrenoleucodystrophy which afflicts 5- to 15-year-old boys. The latter disorder concerns children with primary adrenocortical insufficiency and diffuse demyelination in the central nervous system, causing dementia and quadriparesis. Heterozygous carriers of adrenomyeloneuropathy may show symptoms of spastic paresis and peripheral neuropathy. Both adrenoleukodystrophy (ALD) and adrenomyeloneuropathy occur in members of the same family and are biochemically characterized by an accumulation of very long chain fatty acids in various tissues and body fluids (Probst et al., 1980; Peckham et al., 1982; Simpson et al., 1994; Van Geel et al., 1997). X-linked ALD is one of the most frequent causes of Addison’s disease in men. It is based on impaired peroxisomal -oxidation of very long chain fatty acids. Mutations have been found in the ALD gene encoding a membrane transport protein, which might be involved in the import of very long chain fatty acid coenzyme A synthetase into the peroxisome. There is a striking variability in neurological and endocrine symptoms in ALD, even within the same kindred (Korenke et al., 1997).

Fig. 29.16. Magnocellular neurons of a control (A, C, E) and an alcoholic (B, D, F). Sections are stained with cresyl violet (CV) (A, B, E, F) or immunohistochemically for vasopressin (C, D). A–D are photomicrographs of the paraventricular nucleus (PVN), while E and F are photomicrographs of magnocellular neurons in islands within the hypothalamus. There are fewer neurons present in B and D than in A and C. Note the presence of gliosis amongst the magnocellular neurons in B and F when compared with A and E. A number of normal-appearing neurons (open arrow) are present near to the pyknotic neurons (closed arrow) in B. Scale in A is the same for B–F. (From Harding et al. 1996, Fig. 1, with permission.)

develop the clinical symptoms of Wernicke–Korsakoff (Blansjaar et al., 1992). It is interesting to note that the neuropathological changes of Wernicke’s encephalopathy and subacute necrotizing encephalopathy (Leigh’s disease) are similar, except for the relative sparing of the mamillary bodies in the latter (Charness and DeLaPaz, 1987). Normal-sized corpora mamillaria also distinguish between Korsakoff (diencephalic) amnesia patients and temporal lobe amnesia (Squire et al., 1990). 343

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Some cases of adrenomyeloneuropathy accompanied by hypothalamic-pituitary dysfunction have been described. A 32-year-old man suffered from contractures, peripheral neuropathy, primary adrenocortical insufficiency and secundary hypogonadism. The low levels of gonadotropins, the minimal response of testosterone to LHRH and the diminished rise of testosterone levels in response to chorionic gonadotropins indicated hypogonadism secondary to hypothalamic or pituitary dysfunction. Other signs of this involvement were that growth hormone levels repeatedly failed to rise in response to hypoglycemia or levodopa. Prolactin levels varied from normal to slightly elevated, and, although they exhibited an exaggerated response to TRH, they showed normal suppression after levodopa. The patient’s basal TSH level was high, and there was an accentuated response to TRH, as has also been described in cases of primary adrenal cortical insufficiency (Peckham et al., 1982). He showed impressive neurological improvement after glucocorticoid replacement therapy. A 31-year-old man with an Addisonian crisis and with fever of unknown origin, followed by abrupt onset of spastic paraparesis, had peripheral neuropathy and an increase in very long chain fatty acid levels. Abnormal pituitary function, i.e. the levels of LH and TSH that had increased, returned to normal as a result of corticosteroid treatment of Addison’s disease. Two family members, who had been diagnosed with multiple sclerosis, in retrospect probably suffered from adrenomyeloneuropathy. A sibling died with the diagnosis of Schilders’s disease at the age of 8 years. It is also noteworthy that many of the family members had psychiatric problems (Simpson et al., 1994). In a series of 55 patients with ADL, adrenal insufficiency was found in 33 of them. Hypogonadism has been observed in adult ADL patients and a reduced adrenal androgen synthesis, reflected by low dehydroepiandrosterone sulfate (DHEAS) levels, is found in nearly all ADL patients. As-yet-unknown hereditary factors seem to interfere with the endocrine phenotype (Korenke et al., 1997). In a group of 26 men with ADL, 21 already had adrenoleukomyeloneuropathy. Clinical signs of gonadal dysfunction were: diminished libido (58%), failure of the testes to descend (15%), diminished body sexual hair (50%), gynecomastia (35%) and small testes (12%), low plasma testosterone (12%), insufficient increase after human chorionic gonadotropin (HCG) stimulation (88%), and increased LH (16%) and FSH (32%). The response of LH to LHRH was abnormally high in 47% and that of FSH was abnormally low in 16%. Concluding, in

20 out of 26 men, signs of hypogonadism were found. Overt or subclinical testicular insufficiency may even be the only manifestation of ADL. Generally, the high ACTH levels found in adrenomyeloneuropathy and ADL are considered to be secondary to a primary disorder in the adrenal glands (De Weerd et al., 1982). It has, however, also been proposed that ACTH – with its high molecular weight – great quantities of which are present in plasma and cerebrospinal CSF, does not seem to be the result of adrenal hypofunction, but could stem from an extrapituitary source such as the brain (Saito et al., 1987). Cerebral ADL and adrenomyeloneuropathy are frequently associated with Addison’s disease, but the adrenal insufficiency may precede, coexist or develop after neurological dysfunction (Korenke et al., 1997). A novel group of patients has recently been described. What they have in common is an unclassified form of leukodystrophy, progressive neurological deterioration, primary ovarian dysfunction and diffuse white matter disease, sometimes with frontal cortical atrophy. Some have borderline IQ. Puberty does not develop in some patients and is arrested in others, while one patient had premature ovarian failure at the age of 13 years. Pathological analysis showed ‘streak’ ovaries in one patient. The gonadal insufficiency in these patients is considered to be primary, and the hypothalamohypophysial axis normal (Schiffman et al., 1997). 29.7. Other neurodegenerative disorders (a) Frontotemporal dementia and parkinsonism linked to chromosome 17 A family has been described that is clinically characterized by a Klüver-Bucy-like desinhibition with hyper- and hyposexuality. In addition, oral tendency, alcoholism and aggressiveness, social withdrawal, depression and a schizophrenia-like picture occurs in some patients. Patients have been arrested and jailed or placed in psychiatric hospitals. Moreover, dementia, Parkinsonism, and, in one patient, amyotrophy are part of the complex. Parkinsonism and cognitive deterioration lead to a rigid, akinetic mute state; the mean duration of the disorder to death is 14 years. Immunocytochemically, no proteaseresistant prion protein is found. The neuropathological changes consist of circumscribed neuronal loss, gliosis, and spongiosis of limbic neocortical areas and frontal temporal and occipital association areas. Similar changes

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are present in the substantia nigra, ventral striatum and amygdala. The hippocampus is spared, except for degeneration of the afferent perforant tract, secondary to entorhinal nerve cell loss. Argyrophilic neuronal inclusions with a characteristic immunocytochemical profile are found in brainstem nuclei, basal ganglia

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and hypothalamus. The inclusions stain intensely with Bielchowsky’s silver impregnation and are composed of haphazardly arranged spicules. The subcortical neuronal inclusions and ballooned neurons stain positively for phosphorylated neurofilaments, variable for ubiquitin and negative for tau, -amyloid and -synuclein. In addition, oligodendroglial argyrophilic tangle-like inclusions show positive staining for ubiquitin and the microtubuleassociated protein tau. In the mamillary body, no neuronal loss or spongiosis is found, but gliosis, non-Alzheimer tangles, ballooned neurons and spheroids are present; in the ventral hypothalamus, atrophy, neuronal loss, gliosis and non-Alzheimer tangles are observed. Ultrastructurally, these inclusions have hitherto shown undescribed abnormally assembled filaments of 10–14 nm, with a lattice-like arrangement of variable periodicity. Glial cytoplasmatic inclusions were widespread in white-matter structures. These inclusions show parallel tubural structures of 14–17 nm in diameter. Linkage analysis has localized the disease on 17q21-22 (Sima et al., 1996; Spillantini et al., 1998a; Rosso et al., 2001). A number of mutations in the tau gene have subsequently been reported in this disorder (Poorkaj et al., 1998; Spillantini et al., 1998b; Rizzu et al., 1999; Van Swieten et al., 1999; Rosso et al., 2002). The circadian rest–activity rhythm of patients with frontotemporal degeneration is highly fragmented and phase-advanced, and apparently uncoupled from the rhythm of the core body temperature (Harper et al., 2001). However, so far no neuropathological information has become available on the possible degenerative changes in the SCN. In 38% of frontotemporal dementia cases, thyroid hormone abnormalities are found (Fäldt et al., 1996; Smith et al., 2002), but the TRH neurons have not been studied.

Fig. 29.17. (A) Correlation of paraventricular nucleus (PVN) (plus signs) and supraoptic nucleus (SON) (crosses) volume with maximum daily alcohol consumption. The slopes are similar, indicating that the volume reduction of these nuclei with increasing alcohol consumption is also similar. (B) The number of neurons in the PVN (squares) in CV-stained sections correlated with the duration of alcohol consumption in years. The loss of neurons in the SON (circles) is not related to duration of alcohol consumption. This implies that repeated high levels of alcohol consumption are necessary for the loss of PVN neurons. (C) The number of magnocellular hypothalamic neurons immunoreactive for vasopressin decreases with greater maximum daily alcohol consumption, forming a significant regression (solid line). (From Harding et al., 1996, Fig. 2, with permission.)

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Several multigeneration kindreds with an autosomal dominant hereditary frontotemporal dementia have been described in the Netherlands. There is also evidence of linkage to chromosome 17q21-q22. Moderate to severe atrophy of frontal and temporal cortex is found, with neuronal gliosis and spongiosis, and Pick bodies are absent. Unfortunately, the hypothalamus of these patients has not been investigated (Heutink et al., 1997). Our own observations on one subject of this family (94-003, male, 66 years of age) revealed a strong degeneration of the corpora mamillaria and fornix, while an apparently structurally intact SON, PVN, TMN, and nucleus tuberalis were found. Interestingly, the ApoE 4 genotype in a Dutch study appears to be strongly increased. The adjusted odds ratio is 5.2 (Stevens et al., 1998b). Although, in a study of other families with frontotemporal dementia and defined tau mutations, no evidence was found for an effect of ApoE genotype on the age of onset of dementia (Houlden et al., 1999), a later study of the Dutch group has shown that the ApoE 4 allele frequency is increased in the temporal variant of this disease (Rosso et al., 2002). When 13 kindred that share clinical and neuropathological features were identified with sufficient linkage to chromosome 17 and frontotemporal dementia, it was agreed that the disorder should be named “frontotemporal dementia and parkinsonism linked to chromosome 17”, instead of the terms used earlier (dementia lacking distinctive histology, Pick’s disease without Pick bodies, frontotemporal dementia, frontotemporal degeneration without Pick bodies, frontal lobe degeneration of the non-Alzheimer type, or asymetrical cortical syndrome) (Spillantini et al., 1998a, b; Stevens et al., 1998b; Wilhelmsen, 1998). The disease commonly begins insidiously, with behavioral or motor manifestations, typically in the 5th decade. The duration of the disease is usually 10 years with a range of 3–30 years. The symptoms include those described above, as well as impaired social conduct, ranging from aggressiveness to apathy and obsessive stereotyped behavior. No significant benefit is observed with L-DOPA when tried against the motor abnormalities. Changes in body weight, swallowing problems, and changes in appetite, food preference and eating habits are even more common than in Alzheimer’s disease (Ikeda et al., 2002). Increases in body weight associated with hyperphagia also occur. Neuropathologically, frontotemporal atrophy is a consistent feature, and substantia nigra depigmentation is found in most kindred (Foster et al., 1997). The microscopic alterations are described above. The lack

of attention to the hypothalamus, and in particular the pathology of the structures related to memory processes such as the corpora mamillare and fornix is remarkable in the consensus report on this disease. Vincent van Gogh’s (1853–1890) major illness during the last 2 years of his life was identified as temporal lobe epilepsy, precipitated by the use of absinthe, in the presence of an early limbic lesion, probably an injury sustained at birth (Blumer, 2002).

(b) Hippocampal sclerosis Hippocampal sclerosis is characterized by neuronal loss, with gliosis involving the hippocampus, and is often associated with intractable temporal lobe epilepsy. Temporal lobectomy is a widely accepted surgical treatment for patients with hippocampal sclerosis. Hypothalamic disorders have also been found in this disorder. MRI detection of an asymmetrically small fornix or mamillary body has been suggested as a useful presurgical, lateralizing sign of hippocampal sclerosis in patients with temporal lobe epilepsy. However, it should be noted that the majority of the fornical fibers originate from the subiculum and not from the cornu ammonis and project predominantly via the postcommissural fornix. Moreover, the subiculum is not commonly affected in hippocampal sclerosis. The remaining part of the fornical fibers arise from the cornu Ammonis, and terminate exclusively in the septal nuclei via the precommissural fornix. However, the low frequency of an asymmetrically small fornix and its association with severe hippocampal atrophy does not make the asymmetrically small fornix a sensitive diagnostic sign of hippocampal sclerosis. In addition, mamillary body asymmetry is not unique to patients with mesial temporal sclerosis, as it is also found after, e.g. a temporal infarct or a middle fossa meningeoma. However, after temporal lobectomy, an asymmetrically small fornix and mamillary body are systematically found. Apparently temporal lobectomy exaggerates the effect of neuronal degeneration as a result of massive neuronal loss in the temporal region (Kim et al., 1995; Mamourian et al., 1995). In the SCN of one of the two patients with hippocampal sclerosis, Stopa et al. (1999) found an increased astrocyte to neuron ratio. The density of vasopressin and neurotensin neurons seemed to be low in these patients, but more subjects have to be studied. Moreover, there are more indications that the seizures seen in hippocampal sclerosis will affect circadian rhythms (Quigg et al., 1999).

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-tubulin, - and -crystallin and -synuclein (Lantos, 1998). In multisystem atrophy most patients have cerebellar and extrapyramidal features, while generalized autonomic dysfunction such as orthostatic hypotension and swings in blood pressure may not appear until later in the disease process. Apart from orthostatic hypotension, urinary and rectal incontinence, loss of sweating, iris atrophy, external ocular palsies, rigidity, tremor, loss of associated movements, impotence, atonic bladder, loss of rectal sphincter tone, fasciculations, wasting of distal muscles, electromyographic evidence of involvement of anterior horn cells and neuropathic lesions in muscular biopsies are found. In contrast to Parkinson patients and normal controls, no hypothalamic -adrenoceptor response of growth hormone is present, as appears following clonidine administration. Levodopa raised growth hormone in the same way as in controls, which suggests that the hypothalamic -adrenoceptor sites may be specifically affected in multiple-system atrophy. And indeed, there seems to be a loss of catecholaminergic projections, i.e. from the locus coeruleus in the brainstem to the hypothalamus (Shy and Drager, 1960; Spokes et al., 1979; Benarroch et al., 1998; Mathias, 2002). An impairment is observed of hypothalamic responses to hemodynamic and other stresses, and baroreflex dysfunction, such as the lack of vasopressin increase in response to tilt-induced hypotension. In patients with multisystem atrophy, upright tilt elicits profound hypotension, whereas circulating levels of vasopressin only increase a little (Kaufman et al., 1992). Moreover, these patients have no thirst during saline drinking (Bevilacqua et al., 1994). Afferent and central baroreceptor and osmotic thirst pathways involved in vasopressin release thus seem to be impaired in patients with this disorder (Kaufman et al., 1992; Bevilacqua et al., 1994). In addition, patients with multisystem atrophy fail to excrete a water load while standing up, suggesting abnormal postural regulation of vasopressin release. The postural rise in vasopressin is not inhibited by a dopamine agonist or opioid antagonist, suggesting a loss of dopaminergic and opioid pathways involved in vasopressin release in this disease (Puritz et al., 1983). The patients do respond to vasopressin. A patient that later appeared to have multisystem atrophy, presented with signs of autonomic dysfunction during an operation. The initial hypertension was treated with a direct vasodilatator (hydralazine), which resulted in severe hypotension that did not respond to adrenergic agonists. The hypotension only responded to vasopressin (Vallejo et al., 2002).

(c) Progressive supranuclear palsy (PSP) Both disorders are clinically characterized by atypical Parkinsonism and cognitive disorders. PSP, also known as the Steele–Richardson–Olszewski syndrome, is a neurodegenerative disease characterized by a loss of voluntary control of vertical gaze, dysarthria, diffuse body rigidity with dystonic extension of the neck, and dementia. Histologically, the disease is characterized by extensive lesions in the midbrain, specifically cell loss, gliosis and neurofibrillary tangles. The substantia nigra, NBM, and septum, may be strongly affected by neurofibrillary tangles and neuronal loss in PSP, causing dopaminergic and cholinergic defects (Tagliavini et al., 1983; Ruberg et al., 1985). A substantial (45–85%) neural reduction is found in the subthalamic nucleus (Chapter 15a), both for parvalbumin and calretinin-containing cells. Extracellular neurofibrillary tangles and tau-positive glia cells were observed in the subthalamic nucleus (Hardman et al., 1997). In addition, there is an accumulation of hyperphosphorylated tau in this nucleus (Mattila et al., 2002). (d) Multisystem atrophy (Shy–Drager syndrome) The term “multisystem atrophy” was originally introduced to include striatonigral degeneration, olivopontocerebellar atrophy and Shy–Drager syndrome. Multisystem atrophy is characterized by a combination of cerebellar signs, parkinsonian features (see Fig. 29.12) and autonomic and urinary dysfunction (Lantos, 1998). Degeneration of the sacral horn cells (Onuf’s nucleus) in patients with multisystem atrophy has been associated with urinary, sexual and anorectal dysfunction (Vallejo et al., 2002). Orthostatic hypotension, a loss of neurons in the substantia nigra, in the preganglionic nuclei in the medulla oblongata and spinal cord, the basal ganglia, base of the pons, cerebellar nuclei and cortex is found (Shy and Drager, 1960; Saper, 1998; Mathias, 2002). Neuropathologically, multisystem atrophy is characterized by cytoplasmic inclusions that contain -synuclein (Wakabayashi et al., 1998). The definition given by Lantos (1998) is: “Multisystem atrophy is a sporadic, progressive adult onset degenerative disease of the nervous system of unknown cause, histologically characterized by glial oligodendrocytic cytoplasmic inclusions”. He goes on to say that the term “Shy–Drager syndrome” is “no longer useful”. The oligodendrocytic cytoplasmic inclusions are positive for ubiquitin, tau protein, - and 347

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Involvement of the hypothalamus in multisystem atrophy has been reported by several authors. In one case, diabetes insipidus and mild gliosis in the SON have been reported (Ozawa et al., 1993). In hypothalamic areas such as the wall of the third ventricle, in the lateral hypothalamic area, around the corpora mamillaria, and in the infundibular nucleus, recent punctate hemorrhages have been found (Schwartz, 1967). In addition, in one patient with Shy–Drager syndrome, a partial deficit in vasopressin release and neuronal loss in the supraoptic nucleus, and cluster breathing were found, an indication of pontomedullary respiratory center damage, with a normal CO2 response curve (Lockwood, 1976). Moreover, hypothalamic norepinephrine, dopamine, glutamic acid decarboxylase and choline acetyltransferase are markedly reduced in patients with multiple-system atrophy (Spokes et al., 1979). A patient with Shy–Drager syndrome exhibiting nocturnal polyuria and a reversed circadian rhythm of vasopressin has been described (Ozawa et al., 1993), suggesting that the SCN is affected in this disease. Later, evidence was indeed provided for a disorder in the SCN, the biological clock (see Chapter 4), in multisystem atrophy. The patient who exhibited nocturnal polyuria associated with decreased urinary specific gravity and decrease of nocturnal vasopressin secretion had a decreased number of vasopressin neurons and gliosis in the SCN. Moreover, the vasopressin neurons in the SCN of this patient were smaller than those of a series of controls, and gliosis was present in the SCN. Also the observation that patients with multisystem atrophy have decreased early morning cortisol levels indicates a functional alteration of the SCN (Ozawa et al., 2001). A decrease in the nightly plasma vasopressin levels has been confirmed in a sample of 13 patients with multisystem atrophy (Ozawa et al., 1998). The physiological nocturnal fall of body core temperature is blunted in multiple-system atrophy patients. The lack of decrease in body temperature in these patients distinguishes them from Parkinson patients (Pierangeli et al., 2001) and may be caused by a defect in the SCN. The SON and PVN seem to remain intact (Ozawa et al., 1998). (e) Lewy body disease Senile dementia of Lewy body type is characterized clinically by fluctuating confusion and, in the majority of cases, also by visual hallucinations (Perry et al., 1990). Orthostatic hypotension is increasingly recognized as a problem in diffuse Lewy body disease (Mathias, 2002).

Neuropathologically, Lewy bodies are especially found in archicortical areas (Perry et al., 1990). However, in the hypothalamus, including the subthalamic nucleus, -synuclein-containing Lewy bodies are also detected (Piao et al., 2000). Choline acetyltransferase activity is significantly lower in the parietal and temporal cortex of those patients with visual hallucinations (Perry et al., 1990), indicating that the NBM is especially affected. Indeed, reductions in nicotine-binding have been observed in the substantia nigra, tegmentum and striatum in demented patients with Lewy bodies (Court et al., 2000). The loss of choline acetyltransferase in the neocortex occurs much earlier in the Lewy body disease process, and is much greater than observed in Alzheimer’s disease (Tiraboschi et al., 2002). Moreover, the subthalamic nucleus (Chapter 15a) is accumulating hyperphosphorylated tau (Mattila et al., 2002). (f) Pick’s disease In Pick’s disease, the NTL (see Chapter 12) shows severe affliction, as indicated by strong staining for hyperphosphorylated tau-protein and argyrophylic Pick bodies, which have an unusual, flat shape with peripheral indentations. Small, teardrop-shaped Pick neurites emerge in varicose widenings of neuronal processes and display a much weaker argyrophilia than the Pick bodies. The large tuberomamillary neurons around the NTL usually remain uninvolved in Pick’s disease (Braak and Braak, 1998a). In the SCN of three Pick patients, Stopa et al. (1999) have found a decreased density of vasopressin and neurotensin neurons, changes that were similar to those observed in AD (see Chapters 4.3 and 29.1). (g) Miscellaneous Sporadic amyotropic lateral sclerosis (ALS) is approximately twice as prevalent in men as in women, raising the possibility of hormonal involvement. Indeed, serum free testosterone is significantly decreased in both male and female ALS patients, while no difference is found for serum levels of DHEAS, 17- estradiol and total testosterone. There is quite some experimental evidence for a putative neuroprotective role for testosterone, in particular in motorneurons (Militello et al., 2002). In a rare neurodegenerative disease that is mainly confined to Japanese patients, i.e. diffuse neurofibrillary tangles with calcification or non-Alzheimer non-Pick dementia with Fahr’s syndrome, tangles are also found

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in the NBM and in the subthalamic nucleus (Tsuchiya et al., 2002). Variant Creutzfeldt–Jakob disease is a novel human prion disease that appears to result from infection by the bovine spongioform encephalopathy agent. All cases of this disease are methionine homozygotes at codon 129

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of the protein phosphatase gene. The features comprise spongiform change, neuronal loss, astrocytic and microglial proliferation, and accumulation of the abnormal isoform of the prion protein. Spongiform changes are most abundant in the hypothalamic supraoptic and paraventricular nuclei (Ironside, 2002).

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Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2) The Human Hypothalamus: Basic and Clinical Aspects, Part II D.F. Swaab, author © 2004 Elsevier B.V. All rights reserved

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CHAPTER 30

Autonomic disorders

Finally, I want you to consider every function I attribute to this machine (the brain), such as digestion, feeding, breathing, waking and sleeping, the absorbing of light, sound, smell, the impression of ideas in the organ of perception and imagination, the holding on to these ideas in the memory, the lower movements of desires and passions, and lastly the moving of all outer limbs, I tell you I want you to consider these functions as taking place naturally in this machine exclusively as a result of the nature of its organs, in the manner of the movements of a clock. Descartes, 1596–1650.

the “ergotropic zone of the hypothalamus”. In an area more than 5 mm lateral from the wall of the third ventricle, electrical stimulation often yields parasympathetic responses such as a fall in blood pressure and bradycardia (Sano et al., 1966, 1968). Various authors have described the syndrome of ‘autonomic storm’ (paroxysmal sympathetic storm or acute hypothalamic instability). This is characterized by episodes of acute tachycardia, hyperthermia, skin vasodilatation, shivering, tachypnea, lacrimation and pupillary changes in patients with either a tumor at the level of the foramen of Monro or lesions near the third ventricle, which seem to be located in the posterior subnucleus of the PVN (Koutcherov et al., 2000) in cases of diencephalic syndrome (Connors and Sheikholislam, 1977; Chapter 19.4), or associated with closed head injury and hydrocephalus (Thorley et al., 2001). The animal experiments of W. R. Hess (1969), which have shown that cats enter a deep, normal sleep when their anterior hypothalamic-preoptic regions are stimulated, suggests the existence of a hypothalamic sleep center in this area. Destruction of this area leads to insomnia and destruction of the posterior hypothalamus to hypersomnia (Carmel, 1985; Chapter 30.7). Disorders of sleep and wakefulness are seen following hypothalamic damage, e.g. in encephalitis lethargica (Chapter 20.2), diencephalic idiopathic gliosis (Espiner et al., 1992; Chapter 32.3) and Wernicke’s encephalopathy (Chapter 29.5). Animal experiments have indicated that the caudal hypothalamus is involved in integration of respiratory output. Neurons in this region are strongly sensitive to perturbations in oxygen tension and hypercapnia (Berquin et al., 2000). In cats, respiratory responses to increases in PCO2 above the apneic threshold are modulated by neurons in the posterior hypothalamus, involving a GABAergic mechanism (Waldrop, 1991). In

Following hypothalamic lesions in patients, various vegetative or autonomic dysfunctions have been described (Carmel, 1985), which illustrates the importance of this brain structure in many autonomic processes. Moreover, autonomic disturbances are part of the signs and symptoms of many hypothalamic disorders such as idiopathic hypothalamic syndrome of childhood (Chapter 32.1), hypothalamic atrophy (Chapter 32.2) and diencephalic idiopathic gliosis (Chapter 32.3). Caloric balance may be altered with ventromedial lesions, causing hyperphagia (see Chapters 9 and 26.3) and the sympathetic nervous system has been implicated in the development and maintenance of obesity (Snitker et al., 2000). Temperature regulation may be affected by lesions in various hypothalamic areas (Chapter 30.2). In Wernicke’s encephalopathy a striking chronic hypothermia is seen that is thought to be related to the periventricular and mamillary body lesions (Chapter 29.5). Sweating may be disturbed by hypothalamic multiple sclerosis (MS) lesions (Ueno et al., 2000): a patient with a focal posterior hypothalamic stroke developed episodes of exuberant sustained sweating of the entire left side of the body (Smith, 2001). Stereotactic electrical stimulation of the posteromedian hypothalamus in patients causes a rise in blood pressure and pulse rate (Sano et al., 1968; Ramamurthi, 1988). This area is called 351

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rats, moderate hypoxia or hypercapnia cause c-FOS activation in the posterior hypothalamic area, dorsomedial hypothalamic nucleus (DMN), and ventral hypothalamic area. In addition, hypoxia activates the supraoptic nucleus (SON) whereas hypercapnia stimulates the paraventricular nucleus (PVN). The PVN exerts a facilitatory effect on ventilation, possibly mediated by direct projections to the medullary respiratory neurons and to the phrenic nucleus (Berquin et al., 2000). Oxytocin-containing projections of the PVN to the brainstem are involved in the regulation of breathing (Mack et al., 2002). In addition, the caudal hypothalamus is a major site for ‘central command’ or the parallel activation of locomotion and respiration (Horn and Waldrop, 1998). PET studies have shown that hypercapnia induces activation of a number of brain areas in human, including the hypothalamus (Brannan et al., 2001). Hypothalamic modulation of hypercapnic and hypoxic ventilatory responses is presumed to be disturbed in Prader–Willi syndrome (Menendez, 1999; Chapter 23.1), in congenital central hypoventilation syndrome and in late-onset central hypoventilation syndrome (Katz et al., 2000; see the section Autonomic syndromes, and Chapter 32.1). A decrease in plasma glucose causes prompt release of several counter-regulatory hormones, including glucagon, catecholamines, cortisol and growth hormone, which jointly act to correct hypoglycemia. The counterregulatory activation of the sympathetic nervous system consists of adrenal secretion of adrenaline, cardiac stimulation with a rise in heart rate and the development of hypoglycemic adrenergic symptoms. This reaction has its source in the hypothalamic centers, since it is impaired in patients who have undergone transcranial surgery for a craniopharyngioma extending into the hypothalamic region, and in a patient with neurosarcoidosis of the hypothalamus (Féry et al., 1999; Schöfl et al., 2002). “Cushing ulcers” are peptic ulcers of the stomach or pylorus that are found in association with intracranial events. On the basis of a patient with a duodenal ulcer and a tumor of the third ventricle, Harvey Cushing concluded that there was a parasympathetic center in the hypothalamus that was connected to the vagal center (Carmel, 1985; Dolenc, 1999). The PVN has indeed been implicated in controlling the integrity of the gastric mucosa through a combined modulation of pituitary hormones, acid secretion and gastric motility. In accordance with such observations, electrical stimulation of the PVN has been shown to produce, within 1 h, gastric ulceration through activation of cholinergic fibers of the vagus nerve (Smith

et al., 1998). In addition, oxytocin, when injected into the dorsomedial nucleus of the vagus, increases gastric acid secretion (Rogers and Hermann, 1985). Orgasm causes elevations in blood pressure, heart rate and levels of epinephrine and norepinephrine both in women and in men (Bancroft, 1999; Exton et al., 1999), as well as a release of neurohypophysial hormones (Chapter 8g), illustrating the concerted action of the hypothalamus on neuroendocrine and autonomic mechanisms during sexual behavior. Another, related example of such an integrated response is the action of the vomeronasal organ. Vomeropherins or pheromones not only stimulate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release in a sex-dependent manner, through the vomeronasal organ, but also affect the autonomic system, as appears from decreased respiratory frequency, increased cardiac frequency, event-related EEG changes and decreased skin temperature (Berliner et al., 1996; MontiBloch et al., 1994; Chapter 24.2b). Children with disruptive behavior disorders showed lower autonomic nervous system activity and hypothalamopituitary–adrenal (HPA) axis activity, although they have higher levels of emotional arousal (Van Goozen et al., 2000a). A large number of neurological and psychiatric diseases may be accompanied by autonomic disturbances that are attributed to hypothalamic disorders. Characteristic signs and symptoms are found in McCune–Albright syndrome (Chapter 24.1b), fatal familial insomnia, a prion disease (Lugaresi et al., 1998; Chapter 4), and Guamanian neurodegenerative disease (Low et al., 1997). In MS (Chapter 21.2), as well as disturbed function of the bowel, bladder, of sexual behavior and sweating, and of cardiovascular regulation, disturbed temperature regulation such as poikilothermia (Lammens et al., 1989; Kurz et al., 1998) and hypothermia (Sullivan et al., 1987; White et al., 1996) and sleep disturbances (Chapter 21.2) might be present. Depression (for hypothalamic involvement, see Chapter 26.4) is associated with altered autonomic activity in patients with coronary heart disease, as reflected by elevated resting heart rate and an exaggerated heartrate response to orthostatic challenge (Carney et al., 1999). In Alzheimer patients, especially those with symptoms of depression, an impaired response of the systolic blood pressure on standing is observed (Vitiello et al., 1993). In Parkinson’s disease a series of autonomic disturbances are found, e.g. sialorrhea, seborrhea, excessive sweating, orthostatic hypotension, a change in the relationship between blood pressure and pulse rate, and disruption of circadian control of sleep (Awerbuch and Sandyk, 1992;

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Murata et al., 1997; Mathias, 2002; Chapter 29.3). In addition, hypothalamic norepinephrine, dopamine, glutamic acid decarboxylase, and choline acetyltransferase are markedly reduced in patients with multiple-system atrophy, who characteristically have autonomic failure (Spokes et al., 1979; Mathias, 2002; Chapter 29.7d). Orthostatic hypotension is frequently a problem in diffuse Lewy body disease (Mathias, 2002; Chapter 29.7e). Penfield (1929) first applied the term “diencephalic epilepsy” to paroxysmal attacks of autonomic disturbances such as flushing, diaphoresis and temperature drop in a patient with a cholesteatoma. This tumor, however, was compressing the thalamus rather than the hypothalamus. Moreover, disorders of sweating mechanisms have been reported, but the lesions are situated immediately caudal of the hypothalamus (Carmel, 1985). Although a 38-year-old man with autonomic seizures had a hypothalamic astroblastoma, this tumor also invaded the thalamus, and it is by no means certain that the hypothalamic lesion was responsible for the symptoms (McClean, 1934). On the other hand, diencephalic autonomic seizures of Penfield’s type have also been described in patients with third-ventricle choroid plexus papillomas (Jooma and Grant, 1983) and in a 20-month-old child with an astrocytoma of the diencephalon (Solomon, 1973). Brain death may coincide with ‘autonomic storm’, which may affect donor-organ quality. The syndrome includes rapid swings in blood pressure, with eventual persistent hypotension, coagulopathies, pulmonary changes, hypothermia and electrolyte aberrations (Pratschke et al., 1999).

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PVN to the brainstem are involved in the regulation of respiratory and cardiovascular activity (Mack et al., 2002). The central actions of the stress hormone of the PVN, corticotropin-releasing hormone (CRH), on visceral organ activity are similar to those which are directly stressinduced. CRH administrated centrally elevates blood pressure and increases heart rate; CRH also produces metabolic, gastrointestinal and immune system responses. It brings about an increase in plasma glucose levels and a decrease in insulin levels (Dinan, 1994; Lehnert et al., 1998). Intranasal administration of CRH initiates, probably via central nervous system mechanisms, inhibition of gastric acid secretion and a change of mood (Kern et al., 1997; Chapter 26.4). Studies in rat have, moreover, indicated that PVN neurons participate in the regulation of breathing activity and in the coordination of cardiovascular and respiratory functions. Tracing studies have suggested the presence of a direct connection between PVN and phrenic motorneurons (Yeh et al., 1997). Thyrotropin-releasing hormone (TRH), which is produced in the PVN and transported to many intra- and extrahypothalamic brain regions (Chapter 8.6), is presumed to influence, e.g. thermoregulatory, gastrointestinal and appetitive functions (Ciosek and Guzek, 1992), and LH-releasing hormone (LHRH) neurons are involved in temperature regulation (Chapter 30.1). The human parabrachial nucleus, an important relay center for the ascending visceral projections from the nucleus tractus solitarius and area postrema, receives afferents from the PVN. It thus reflects the chemical and visceral profile of the organism. In addition, it receives nociceptive information and information about the internal milieu (Parvizi et al., 1998). This nucleus contains a large number of peptidergic fibers, such as CRH, somatostatin and vasoactive intestinal polypeptide (VIP). These fibers may originate, at least partly, from the PVN and other hypothalamic nuclei (Pammer et al., 1988; Parvizi et al., 1998). Strong neuropathological Alzheimer changes are observed in the parabrachial nucleus which may lead to autonomic dysfunctions in this disorder (Parvizi et al., 1998). On the other hand, no obvious change in the density of the vasopressin and oxytocin innervation, probably derived from the PVN, has been observed in this nucleus in Alzheimer patients (Van Zwieten et al., 1994). Furthermore, animal experiments have shown that also the suprachiasmatic nucleus (SCN) is involved in the control of the autonomous nervous system, and as such in circadian fluctuations in many functions,

Structures involved The hypothalamus is the ‘head ganglion of the autonomic nervous system”. Hess, 1969.

The PVN is a crucial central structure for many autonomous functions and disorders of the hypothalamus. In the human brain, vasopressin and oxytocin fibers of the PVN are presumed to project to, e.g. the nucleus basalis of Meynert (NBM), diagonal band of Broca (DBB), septum, bed nucleus of the stria terminalis, locus coeruleus, parabrachial nucleus, the nucleus of the solitary tract, the dorsal motor nucleus of the nervus vagus, substantia nigra, dorsal raphe nucleus and spinal cord (Sofroniew, 1980; Fliers et al., 1986; Unger and Lange, 1991; Fodor et al., 1992; Van Zwieten et al., 1994, 1996; see Chapter 8). Oxytocinergic projections from the 353

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including temperature, heart rate, blood pressure, glucose metabolism, and sleep (Nagai et al., 1996; Hall et al., 1997; Buijs and Kalsbeek, 2001). Not only SCN changes (Chapter 4), but also alterations in pineal calcification during aging have been related to disturbed circadian rhythmicity in the sleep–wake cycle and daytime tiredness in humans (Kunz et al., 1998), although the latter point is controversial (Chapter 4.5). Animal experiments have shown that brief, intermittent social stress may have a long-term influence on autonomic circadian rhythms (Tornatzky and Miczek, 1993). Similar data in humans are not available. In humans, blood pressure generally falls during the night (dippers), but in some essential hypertensives this nocturnal fall in blood pressure does not take place (nondippers) (Coca, 1994). This points to a possible involvement of the SCN in this group of hypertensives. Light influences the SCN and its output instantaneously; it also influences resting heart rate, depending on the phase of the day/night cycle and on the intensity of light (Scheer et al., 1999). Multiple-system atrophy, or Shy–Drager syndrome, is characterized by orthostatic hypotension and other autonomic disorders. The SCN has indeed been found to be affected in this disorder (Ozawa et al., 1998; Chapter 29.7). The SCN is linked to a varied range of sympathetic and parasympathetic motor pathways, as well as being involved in setting the sensitivity of endocrine organs by influencing their autonomic innervation. A polysynaptic link has been found in rat between the SCN and the intermediodorsolateral cell column in the spinal cord that may be involved in transmission of the circadian nervous signals from the SCN to the pineal gland. In a similar way, many other organs, including the adrenal glands, receive autonomic afferents that are influenced by the SCN. This concept may be extended to the heart, intestines and thyroid gland, and to other endocrine and nonendocrine organs (Vrang et al., 1997; Buijs et al., 1999; Ueyama et al., 1999; Gerendai and Halász, 2000; Kalsbeek et al., 2000b; La Fleur et al., 2000; Buijs and Kalsbeek, 2001; Scheer et al., 2001). Lesion studies in rat have shown that the SCN also controls basal glucose levels (La Fleur et al., 1999) by means of the autonomic nervous system (Buijs and Kalsbeek, 2001). The posterior hypothalamic area controls many autonomic activities such as respiration, cardiovascular activity, locomotion, antinociception, arousal/wakefulness, sweating and eating behavior (see Chapter 13.3; Smith, 2001).

Autonomic syndromes Idiopathic hypothalamic syndrome of childhood is a paraneoplastic syndrome based upon the production of antiglial and antineuronal antibodies. Diffuse infiltrates of small lymphocytes and single or paired histiocytes have been found in the hypothalamus and in other brain regions (see Chapter 32.1; Ouvrier et al., 1995). Late-onset central hypoventilation with hypothalamic dysfunction features hyperphagia with resultant obesity, hypersomnia, thermal dysregulation, emotional instability and highly variable endocrinopathies in addition to central hypoventilation after infancy (see also Chapter 32.1). The syndrome has been successfully treated by nasal, intermittent positive-pressure ventilation. The link with congenital central hypoventilation syndrome, which does not feature symptoms of hypothalamic dysfunction and which is characterized by an absent hypercapnic ventilatory response and often respiratory failure at birth, is not clear. However, their association with disorders of neural crest migration, such as Hirschsprung’s disease, and neural crest tumors, such as ganglioneuroblastoma and ganglioneuroma, is well-documented. Although three cases have revealed a histologically normal central nervous system, one case has been reported with extensive lymphocytic/histiocytic infiltrates of the hypothalamus, which is consistent with a ganglioneuroblastomaassociated paraneoplastic syndrome. A number of cases of acute pandysautonomia and acute autonomic and sensory neuropathy have been described. They originally presented as psychiatric disorders such as hysterical neurosis, epilepsy, anorexia nervosa, emotional instability and hypochondrial neurosis. However, psychiatric symptoms seem to arise from the autonomic nervous dysfunction. In addition, headache, insomnia, constipation, anhidrosis, fainting spells, vomiting, urinary incontinence, impotence, or visual difficulties may be present (Okado, 1990). The degree of involvement of the hypothalamus is, however, not clear. Pure pandysautonomia is an immunological disorder similar to the syndrome of Guillain–Barré. The symptoms comprise lethargy, decreased endurance, postural hypotension, fainting, difficulty with vision, decreased potency, decrease of tears, saliva and sweat, absence of bowel sounds and obstipation, and hypotonic bladder. There is complete sympathetic and parasympathetic denervation of the iris. In summary, there is unequivocal evidence of postganglionic denervation of the pupil and the peripheral vasculature. One patient who was treated with

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glucocorticoids indeed noted a dramatic increase in salivation and a return of a general feeling of well-being (Young et al., 1969). The site of the lesion is thought to be the postganglionic fibers of both the sympathetic and the parasympathetic nervous system, but central autonomous mechanisms have also been considered (Okada, 1990). Although some single postmortem studies have reported Lewy bodies in the brainstem of such patients (Critchley et al., 2003), no investigation of the hypothalamus seems to have been performed. Riley–Day syndrome or familial dysautonomia has an autosomal recessive means of transmission. It is characterized by pandysautonomia, including defective lacrimation, orthostatic hypotension and vomiting crisis (Kita, 1992). This disease occurs almost exclusively in descendants of the Eastern European Ashkenazi Jews (Mancini, 1990); an exception has been described by Ørbeck and Oftedal (1977). The disorder is caused by mutations of the IKBKAP gene on chromosome 9q31 (Anderson et al., 2001; Slaugenhaupt et al., 2001). From the time of birth onwards there are difficulties with feeding, episodes of unexplained fever and pneumonia, and a failure to thrive. Because of the defective lacrimation there is cornea ulceration and absent corneal reflexes. There are periods of unstable blood pressure with episodes of hypertension, unstable body temperature, profuse sweating, sialorrhea, an initial delay in mental development followed by a subsequent achievement of intellectual parity with one’s peers, and an inability to taste food. Strong emotions, whether pleasant or distressing, frequently lead to episodes of loss of consciousness. There is stunted growth and an inability to feel pain, hot or cold. There is a loss of sympathetic and parasympathetic ganglion cells and, to a lesser degree, of the nerve cells in the sensory ganglia. There is also an abnormally low concentration of serum dopamine -hydroxylase, the enzyme that converts dopamine into norepinephrine. About 25% of afflicted children are dead by the age of 10 years. Approximately 50% survive until the age of 20 years (Mancini, 1990). In the cytoplasm of the neurons of the SON and PVN unusually large vacuoles have been found (Ørbeck and Oftedal, 1977), which encourage systematic hypothalamic investigations. Congenital insensitivity to pain with anhidrosis is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, absence of sweating and of reaction to noxious stimuli, self mutilatory behavior and mental retardation. Most probably this syndrome is

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based upon mutations in the tyrosine kinase (Trk)A neurotrophin receptor (Indo et al., 1996). The hypothalamic involvement is not clear. Autonomic failure with orthostatic hypotension and nocturia has many possible causes (Mathias et al., 1986; Chapter 22.4); but it has been successfully treated with desmopressin (Kallas et al., 1999). 30.1. Temperature regulation It has been known for a long time that hypothalamic injury may cause disordered temperature regulation. Cushing (1932, p. 37) stated that “On experimental grounds, a high and abrupt thermic reaction has been occasionally seen after hypothalamic injuries of various kinds, and such studies as have been made in this direction by associates have led some of them to believe that a puncture in the region of the corpora mamillaria is more likely than any other to produce them”. The literature shows that large lesions in the posterior hypothalamus may impair heat production, which results in poikilothermia. In addition, hyperthermia, hypothermia or poikilothermia may occur when the preoptic anterior hypothalamic area (POAH) is damaged by infarction, subarachnoid hemorrhage, trauma or surgery. The anterior hypothalamus seems to contain circuits for both heat production (shivering) and heat dissipation (precapillary vasodilatation, hyperpnoea) (Rudelli and Deck, 1979). Animal experiments have shown warmth-sensitive and cold-sensitive neurons in the POAH and the DBB and that their discharge rate changes in non-REM sleep. In addition to disorders of temperature regulation, POAH lesions cause long-lasting insomnia (see Chapter 30.7a). The POAH is involved in the regulation of non-REM sleep, and the sleep regulatory and thermoregulatory mechanisms of the POAH are closely integrated. A number of factors, including monoamines, steroid hormones, glucose levels, osmotic pressure, prostoglandines, cytokines and neuropeptides, can influence the discharge of POAH temperature-sensitive neurons. The monoamines serotonin and norepinephrine seem to act as antagonists on the thermosensitive neurons (Brück and Zeisberger, 1987). Thermosensitive neurons are found in experimental animals, not only in the preoptic area, anterior hypothalamus and the DBB (Alam et al., 1995, 1996), but also in the septum, cortex, midbrain, medulla and spinal cord (Arancibia et al., 1996). LHRH can elicit

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thermoregulatory skin vasomotion by its action in the septal area. The vasodilative effect of LHRH may be related to the etiology of climacteric hot flushes (Hosono et al., 1997; see also Chapter 11f). Histamine mainly excites heat-sensitive neurons and causes hypothermia (Brown et al., 2001). This way the tuberomamillary nucleus (Chapter 13) is also involved in thermoregulation. Localization of thermosensitive areas in the human brain has only been possible by approximation. Because PVN involvement is reported to be exclusively associated with temperature elevations in bulbar poliomyelitis, the PVN is proposed to be an essential structure for lowering body temperature. In cases of hypothermia in this disease, lateral and medial hypothalamic nuclei are involved (Brown et al., 1953; Chapter 20.1). Subnormal temperature has also been reported in a sarcoidosis patient in which the ventromedial nucleus (VMN) showed the greatest involvement (Branch et al., 1971). The old concept that the PVN is exclusively involved in lowering body temperature does, however, no longer fit with the knowledge from experimental animals on the autonomous and endocrine response to a cold environment in which, e.g. TRH neurons from the PVN are stimulated to activate the thyroid axis. The old concept of a neural thermostat located in the anterior and preoptic areas should thus be replaced by one locating thermoregulation in a number of integrated neuronal systems (Arancibia et al., 1996). The PVN projections contain, moreover, e.g. oxytocin, vasopressin, CRH, TRH and somatostatin. The experimental evidence that vasopressin is an antipyretic neuropeptide involved in regulating febrile increases in body temperature by its action on the ventral septal area, the antipyretic sensitive area of the brain, has been systematically described (Kasting et al., 1989). Besides, there are direct projections from the PVN to autonomic preganglionic neurons controlling the autonomic responses. These projections convey information to peripheral targets involved in thermogenesis through the dorsal vagal complex, the spinal cord, and the nucleus tractus solitarius for parasympathetic and sympathetic neurotransmissions and sensory transmission, respectively. The sympathetic branch releases norepinephrine, which induces a rise in both metabolic rate and brown fat tissue temperature. The parasympathetic vagal stimulation not only leads to temperature changes, but also to gastric secretion and motor functions, as well as to the formation of gastric lesions, probably by TRH-containing fibers in the dorsovagal complex (Arancibia et al., 1996). In fact, it was Cushing who pointed to the similar central

effects of vasopressin, oxytocin and pilocarpine (1932, p. 72–73), stating: . . . with a sufficient dose, either of extract or drug, to give a marked reaction the contrasting colour effect in the forehead is brought out by either intraventricular pilocarpine or pituitrin (a posterior lobe extract) and also by an intramuscular injection of pilocarpine. On the other hand, the intramuscular or intravenous injection of pituitrin, as already pointed out, causes a generalized pallor which affects the skin of both sides of the forehead alike. Since the circulation of the bone flap remains intact (Fig. 30.1), this would appear to indicate that the effects both of pituitrin and pilocarpine introduced by way of the ventricle are not exerted on the sweat glands through the medium of the circulating blood or of sympathetic fibres which accompany arterial blood-vessels [sic], but must be produced by effector impulses which travel from some higher center along fibers which accompany the peripheral sensory nerves.

The SCN is responsible for the circadian fluctuations in temperature (Nagai et al., 1996). There have been a few reports regarding the thermoregulatory effects of acupuncture. It has been acknowledged to induce either hyperthermia or hypothermia, depending on the site of stimulation. Experiments in rat suggest that the reduction of fever by acupuncture may be mediated by an increased hypothalamic expression of interleukin-6 and interleukin-1 (Son et al., 2002). 30.2. Disturbed thermoregulation (Table 30.1) There are various neuropathological reports indicating that hypothalamic pathology may lead to disorders of thermoregulation. Dysthermia has been found as a result of different hypothalamic disorders, i.e.: malformations; tumors such as astrocytoma, pinealoma, craniopharyngioma, infundibuloma, angioma and plasmocytoma; meningoencephalitis; Langerhans’ cell histiocytosis; and arteriosclerotic degenerative changes (Bauer, 1954; Külleffer and Stern, 1970; Haugh and Markesbery, 1983; Kaltsas et al., 2000; Spiegel et al., 2002). Poikilothermia, i.e. fluctuations of core temperature of more than 2°C due to changes in ambient temperature, may be present in patients with hypothalamic strokes, tumors or MS (MacKenzie et al., 1991; Kurz et al., 1998). In MS patients who had chronic hypothermia and life-threatening episodes of acute hypothermia or poikilothermia, a hypothalamic preoptic defect was presumed but not shown (Sullivan et al., 1987; Kurz et al., 1998). Tourette’s syndrome patients have changes in their ambient thermal

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Fig. 30.1. Showing the vasodilator and suderific effects, sparing the bone flap of a recent operation, of 2.5 mg of pilocarpine injected into the cerebral ventricles: an intraventricular injection of 1 ml of Pituitrin in susceptible persons gives an equally marked response. (From Cushing, 1932, Fig. 25, p. 58.)

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TABLE 30.1 Neuropathological abnormalities in chronic disorders of central thermoregulation. Neoplasm

Astrocytoma Craniopharyngioma Infundibuloma Glioblastoma multiforme Neuroblastoma Angioma, third ventricle Facial hemangioma involving the hypothalamus Pinealoma

Metabolic

Wernicke’s encephalopathy

Degenerative

Glial scarring, anterior hypothalamus Parkinson’s disease with reduction and shrinkage of neurons in posterior hypothalamus Diencephalic idiopathic gliosis

Poliomyelitis Meningoencephalitis Syphilitic endarteritis Multiple sclerosis Langerhans-cell histiocytosis

Developmental

Malformations Shapiro syndrome Hydrocephalus Encephalocele

Vascular

Infarction Hemorrhage

Miscellaneous

Granulomatosis

Sarcoidosis

Postneurosurgical Head trauma Iatrogenic neuroleptic malignant syndrome Diazepam Genetic malignant hypertension

Infections and neuroimmunological disorders

Based upon Martin et al. (1997).

perception and circadian dysregulation, interpreted as being of hypothalamic origin (Kessler, 2002). A number of case histories support the central role of the hypothalamus in temperature regulation. One patient with hypothermia had hypothalamic hemorrhage caused by Nasu–Hakola disease (Kobayashi et al., 2000) and syphilitic endarteritis causing gliosis throughout the hypothalamus (Fox et al., 1970). Hypothermia has also been reported in a case of diencephalic idiopathic gliosis (Espiner et al., 1992). The reason for the extensive gliosis of the hypothalamus and other diencephalic structures is not clear. Stress-induced malignant hypothermia developed from physical and mental stress alone, e.g. during preoperative excitement, is a seldom-recognized disorder (Thorley et al., 2001). Periodic hypothermia in combination with agenesis of the corpus callosum (Shapiro syndrome) is considered to be based upon a developmental arrest of the lamina terminalis (Chapter 28.2). In addition, spontaneous periodic hypothermia has been described when hypothalamic lesions are present (Noël et al., 1973; Rehman and Atkin, 1999; Chapter

28.2). Neuroleptic malignant syndrome (Chapter 25.2) is found in psychiatric patients, possibly as a reaction to neuroleptic drug administration. It is characterized by disturbances in motor function, sometimes resulting in a state of catatonic stupor followed by a complete breakdown of autonomic functions with fatal hyperpyrexia (Kish et al., 1990). In the hypothalamus of one patient with neuroleptic malignant syndrome a clear lesion was observed (Horn et al., 1988). In addition, a decreased hypothalamic norepinephrine content and a loss of neurons in the NBM have been described in this disorder (Kish et al., 1990). Malignant hyperthermia is a genetic disease, mostly with an autosomal dominant pattern. The incidence is estimated to be 1:50,000. The onset follows exposure to inhalation anesthesia. The patient may present with hypertonicity, hyperpyrexia, tachycardia and tachypnea. The serum levels of creatine kinase are sharply elevated during attacks, probably due to prolonged muscle contraction (Guzé and Baxter, 1985). Hyperthermia has also been observed in paraneoplastic limbic encephalitis (Gultekin et al., 2000). A loss of circadian temperature

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fluctuations may occur in the case of ventricular obstruction with consequent intracranial pressure rise and/or hydrocephalus (Page et al., 1973). After administration of diazepam to mothers in labor, thermogenesis of the child is disturbed. An impaired metabolic response to cold stress has been observed in these children (Cree et al., 1973). In such cases a hypothalamic disorder may be presumed, but has not been shown. Various hypothalamic areas may be involved in disturbed temperature regulation. A patient has been described with selective infarction of the anterior hypothalamus involving the periventricular and medial zone of the preoptic hypothalamic DBB, and extending into the septum. In addition, the PVN and SON, infundibular, dorsomedial and ventromedial nucleus (VMN) were compromised. The lateral hypothalamic nuclei were only partially affected, and the mamillary nuclei were intact. The optic chiasm and tracts showed necrosis. Hypothalamic infarction in this patient occurred as a result of traumatic avulsion of part of the optic chiasm together with the anterior perforating arteries. Symptoms of hypothalamic dysfunction included altered temperature regulation, alternating diabetes insipidus and inappropriate antidiuretic hormone secretion (see Chapter 22.5), altered patterns of arousal and changing cardiac arrhythmias, including severe atrial arrhythmias with ventricular escape rhythms (Rudelli and Deck, 1979). In a young man suffering from repeated episodes of hypothermia, who revealed defects in the heat-conserving mechanisms of peripheral vasoconstriction and shivering, necropsy showed areas in the anterior hypothalamus of glial scarring with marked hypertrophy of astrocytes and fibrillary gliosis. The cause of the gliosis was not apparent. An infantry soldier who had been struck by a mortar shell fragment and who had hyperthermia, appeared to have a lesion in the preoptic region (Beaton and Herrman, 1945). In three other cases, widespread damage to the periventricular gray matter of the third ventricle was associated with persistent hypothermia. Also, lesions in the tuberal/medial part of the hypothalamus may lead to temperature disorders. In one patient there was scarring of the infundibulum and necrosis of the anterior fornix, in another, necrosis of the left side of the infundibulum and purulant ventriculitis, in a third case there was massive infarction involving the wall of the third ventricle (Treip, 1970a, b). The literature has also reported an infant with a benign facial hemangioma, which developed into a malignant hemangioendothelioma that spread rapidly into the

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intracranial cavity by way of the auditory canal to the hypothalamus and induced hypothermia. The tumor had invaded and almost completely replaced the posterior and lateral walls of the uppermost portion of the hypophysial stalk, the median eminence and the adjacent retroinfundibular part of the hypothalamic VMN. Another tumor nodule was found in the posterior part of the hypothalamus, and the tumor had also invaded the lateral hypothalamic area. The anterior part of the hypothalamus was unaffected (Sunderman and Haymaker, 1947). Familial dysautonomia, or the Riley–Day syndrome, is an autosomal hereditary disease with a dysfunction of the sensory and autonomic system. Apart from impaired temperature control, the symptoms include diminished lacrimation, hyperhydrosis, transient skin blotching and frequent vomiting. For example, in a postmortem study, subependymal granulations in the walls of the posterior hypothalamus have been found, indicating some damage to the ependymal cells. In addition, slight gliosis in the lateral parts of the hypothalamus have been observed, as well as in the ventromedial thalamic nucleus, pointing in the same direction. The striking vacuolation of the neurons of the PVN and SON is regarded as an indication of hyperactivity of these nuclei (Ørbeck and Oftedal, 1977). However, whether this is indeed the case should be studied by parameters for activation of these neurons such as vasopressin or oxytocin mRNA, the size of the nucleoli or the Golgi apparatus (see Chapters 1.5, 8). For other, related congenital dysautonomias (Alvarez et al., 1996), no studies of the hypothalamus have been performed. This also goes for congenital insensitivity to pain with anhidrosis, an autosomal-recessive disorder probably based on mutations in the TrkA receptor and characterized by unexplained episodes of fever, due to noninnervation of eccrine sweat glands (Indo et al., 1996). An interesting observation has been made in patients who, after severe traumatic brain injuries, always feel cold, while sublingual temperature and thyroid function are normal. After 4 weeks of lysine vasopressin nasal spray (Syntopressin) administration, patients have declared that they do not feel cold anymore. When administration of the vasopressin spray is discontinued, temperature perception remains normal (Eames, 1997). It is as yet not clear how such a short-term treatment can produce a lasting improvement. Although vasopressin innervation of the hypothalamus is presumed to be involved in temperature regulation, no data are present on systems involved in temperature perception. In any case, this effect should first be repeated in a double-blind experiment. 359

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In conclusion, there are a number of case histories that indicate hypothalamic pathology in disorders involving temperature regulation, but the size of the lesions and the nature of the disorders do not allow a more precise indication of which nuclei and circuits of the human hypothalamus are crucial for this function. 30.3. Cardiovascular regulation Various hypothalamic nuclei are involved in cardiovascular regulation. The SCN controls the circadian rhythm of heart rate via the sympathetic nervous system, as seen in experiments in rats (Warren et al., 1994). In addition, as shown in human subjects, light has an instantaneous effect, increasing resting heart rate, most probably via this hypothalamic structure (Scheer et al., 1999). In rats it has indeed been shown that light affects heart rate by means of the SCN, and that this effect is mediated by a multisynaptic autonomic connection from the SCN to the heart (Scheer et al., 2001). Animal experiments have also implicated the DMN and PVN in the cardiovascular response to stress. Chemical stimulation of the PVN has been reported to elicit tachycardia, to increase blood pressure and to cause hemodynamic changes resembling those observed in acute experimental stress in rats. Furthermore, electrolytic lesions of this region abolish the cardiovascular response to foot-shock stress, while inhibition of neurons in the DMN – but not in the PVN – suppresses the cardiovascular effects of stress, suggesting that the DMN is a major site for the neuronal control of the cardiovascular response to stress (Stotz-Potter et al., 1996). CRH is a crucial PVN neuropeptide involved in the central cardiovascular regulation (Lehnert et al., 1998). In rat, a decrease in mean arterial pressure activates PVN neurons that project singly and through collaterals to the nucleus tractus solitarius and caudal ventrolateral medulla. This PVN response, as shown on the basis of the expression of the immediate early gene c-FOS, plays an important role in blood pressure regulation. Neuronal nitric oxide may participate in this response (Krukoff et al., 1997). A positive correlation has been found between increased oxytocin plasma levels and increased systolic blood pressure with orgasm in human. Since oxytocin causes blood pressure rise following intracisternal administration of oxytocin in dogs, this observation supports the possibility that oxytocin from the PVN is involved in the central control of blood

pressure (Carmichael et al., 1994). Moreover, oxytocin has peripheral cardiorenal effects that are mediated by oxytocin receptors in the heart and vasculature, and by the release of atrial natriuretic peptide from the heart (Gutkowska et al., 2000). Substance P in the hypothalamus generates a pressor response and tachycardia. Since oxytocin-antisense oligonucleotide attenuated these responses in rat, oxytocin from the PVN seems to mediate the increase in blood pressure and heart rate induced by substance P (Maier et al., 1998). This pathway is thought to be part of an integrated response to nociceptive stimuli and stress. In addition, the circumventricular organs are involved in the maintenance of cardiovascular homeostasis and blood pressure (Chapter 30.5). Patients with an autonomic failure have an intact vasopressin response to osmotic stimuli, but a severely blunted response to a cardiovascular stimulus such as head-up tilt. This suggests that in man, as in rat, ascending catecholaminergic pathways are important for the mediation of the vasopressin response to cardiovascular stimuli (Lightman and Williams, 1993). In the lateral hypothalamus, cardiovascular pressor and depressor sites have been identified that have descending projections to the brain stem (Allen and Cechetto, 1992). Patients whose posterior hypothalamus is electrically stimulated show a rise in blood pressure, tachycardia and maximum pupillary dilatation. The stimulated area starts in the posterior medial hypothalamus and almost runs to the posterior commissure. The area is localized 1–5 mm lateral to the wall of the third ventricle, between the anterior border of the mamillary nucleus and the nucleus ruber. Stimulation studies in patients have delineated three zones in the posterior hypothalamus: (i) the innermost, which show parasympathetic responses; (ii) the medial zone, 1–5 mm from the wall of the third ventricle, which shows sympathetic responses; and (iii) a lateral zone, which shows parasympathetic responses in the area more than 5 mm lateral of the third ventricle, where stimulation often causes a fall in blood pressure and bradycardia (Sano et al., 1966, 1968). The tuberomamillary nucleus (Chapter 13) is also involved in cardiovascular regulation. Histamine transiently increases blood pressure and decreases heart rate (Brown et al., 2001). 30.4. Cardiovascular disturbances Various cardiac arrhythmias have been described in intracranial pathology, predominantly in subarachnoid

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hemorrhage, ischemic and hemorrhagic strokes, head trauma, meningitis and brain tumors, for which hypothalamic lesions or stimulation are at least partly held responsible (Treip, 1970a, b; Thorley et al., 2001). A patient with a hypothalamic hamartoma had epilepsy and ictal bradycardia. Monitoring with an intracranial depth electrode showed that seizures arising from the tumor were not associated with a slowing of the heart rate. It was presumed that not the hypothalamic lesion per se, but rather the fronto-orbital cortex or amygdalohippocampal complex could be responsible for the cardiac variations (Kahane et al., 1999). A case of anterior hypothalamic infarction resulted temporarily in uncontrolled triggering of vagal sinodepressive activity, which allowed secondary ectopic rhythms (Doshi and Neil-Dwyer, 1977; Rudelli and Deck, 1979). Hypertension, tachycardia and mydriasis have been described as a result of stimulation of the posterior hypothalamus, while destruction of this region leads to a tendency to decrease sympathicotonia or an increase in parasympathicotonia (Treip, 1970a, b). Such mechanisms may be part of the acute hypothalamic instability in traumatic brain injury (Thorley et al., 2001). Activation of the sympathetic nervous system is supposed to be peculiar to the essential hypertensive state (Grassi, 1998). Chronic or repetitive stressful stimuli are presumed to lead to sustained sympathetic activation and hypertension in susceptible persons (Somers and Mark, 1992). Paroxysmal hypertension with spontaneous periodic hypothermia has been described in Shapiro syndrome, in which a developmental defect of the lamina terminalis is presumed, together with an agenesis of the corpus callosum (Chapter 28.2), and in diencephalic syndrome (Chapter 19.4; Connors and Sheikholislam, 1977). Necrosis of the anterior fornix and infundibular region results in persistent bradycardia (Treip, 1970a, b), and bradycardia has been found in a patient with a hypothalamic lesion following excision of a craniopharyngioma (Rehman and Atkin, 1999). In a patient with a hypothalamic viral encephalitis, bradycardia was so severe, i.e. a heart rate of less than 30/min, that a temporary pacemaker had to be implanted (Ishikawa et al., 2001b). In patients who have died of subarachnoid hemorrhage, small, bilateral diffuse lesions are found in the hypothalamus (Doshi and Neil-Dwyer, 1977). It is proposed that increased and prolonged sympathetic activity, as appears from the high blood levels of catecholamines following subarachnoid hemorrhage, cause spasms of both blood vessels supplying the hypothalamus and the

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myocardium and thus cause lesions in these two organs. The high levels of cortisol might have potentiating effects on blood vessel constriction. Various hypothalamic nuclei are affected in this disorder. Perivascular hemorrhages and edema of the surrounding tissues have been observed in the periventricular region, including the PVN and SON. Some neurons in the PVN are shrunken and atrophic. In some cases there is distension of perforating vessels and vessels with small ball hemorrhages, similar to those described by Crompton (1963). Some patients show marked edema of the vessel wall, involving the endothelial cells, with perivascular cuffing by polymorphonuclear leucocytes in the PVN. The occurrence of microinfarcts is demonstrated by the presence of fat granule cells and polymorphonuclear leukocytes. One of the cases with severe ECG abnormalities showed almost complete infarction of the hypothalamus. In patients with other intracranial pathological changes, leading to raised intracranial pressure, this hypothalamic pathology has not been observed, so that increased intracranial pressure as such does not seem to be the cause of this disorder (Doshi and Neil-Dwyer, 1977). In the case of orthostatic hypotension, pathological changes were reported in the posterior hypothalamic area and nucleus intercallatus of the mamillary body, but also in many other brain regions (Shy and Drager, 1960). The possible contribution of vasopressin, the SON and the PVN in essential hypertension is discussed in Chapter 8.4. Whether the increased vasopressin plasma levels in essential hypertension (Zhang et al., 1999) are an essential part of the pathogenetic process or secondary to hypertension is still a matter of controversy (Padfield et al., 1976). In essential hypertension, the normal circadian rhythm, i.e. the nocturnal fall in blood pressure (“dippers”) is not always found (“nondippers”) (Pedulla et al., 1995). The period of circadian rhythmicity is disturbed in about 30% of hypertensive subjects (Abitbol et al., 1997; Chapter 8.5). The SCN of patients with primary hypertension contains about half of the normal number of vasopressin, VIP and neurotensin neurons (Goncharuk et al., 2001). These observations indicate that the SCN is seriously disturbed in its function in essential hypertension, and the contribution of this structure to the pathogenesis of hypertension is currently under investigation. The normal circadian rhythmicity of blood pressure is disrupted in patients affected by Cushing’s disease, indicating that glucocorticoids are involved in the control of this circadian mechanism by the SCN (Piovesan et al., 1990). In burn-out patients, heart rate is 361

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increased, and elevated early morning cortisol levels are observed (De Vente et al., 2003), indicating an increased amplitude of the circadian rhythm of this hormone. 30.5. Circumventricular organs: lamina terminalis, subfornical organ and autonomic regulation Brain tissue is separated from the circulating blood by the blood–brain barrier. The brain structures that are outside the blood–brain barrier because of the presence of fenestrations in the capillary endothelium act as windows through which the brain can receive information about changes in humoral factors such as circulating angiotensin II levels. The organs that have fenestrated capillaries include the median eminence (Chapter 11a), the neurohypophysis (Chapters 8 and 22.1), organum vasculosum lamina terminalis (OVLT), subfornical organ (Chapters 30.5a, c) and the area postrema. The area postrema in the brain stem mediates actions of vasopressin, which causes sympathicoinhibition and a shift in baroreflex control to lower values. These effects of vasopressin are mediated by -adrenoreceptor and glutamatergic mechanisms in the nucleus tractus solitarius. In contrast, angiotensin-II acts on this structure to blunt baroreflex control of heart rate and to cause sympathicoexcitation (Hasser et al., 2000). Others also include the pineal gland (Chapter 4.5) and choroid plexus (Chapter 17.3) in the circumventricular organs (Ganong, 2000). (a) Organum vasculosum lamina terminalis: experimental data. The lamina terminalis is an unpaired, rostral midline membrane that results from the closure of the anterior neuropore and fusion of the massive lateral plates. This area thus marks the rostral wall of the proencephalon (Sarwar, 1989). The lamina terminalis can be subdivided into a diencephalic (thin-walled) part and a telencephalic (thickened) part, the boundary between these two being the commissura anterior (Bruyn, 1977). Animal experiments have shown that circumventricular organs are essential for the normal control of hormone release (e.g. of vasopressin, oxytocin and corticotropin (ACTH)), sympathetic activation and behaviors (such as thirst and salt appetite), which collectively contribute to the maintenance of cardiovascular homeostasis, blood pressure and body fluid homeostasis. The lamina terminalis is a layer of ependymal cells that forms the rostral

end of the neural tube early in development. Three midline structures, i.e. the median preoptic nucleus (situated in the midline between the commissura anterior and the top of the third ventricle), the subfornical organ and the OVLT are adjacent to the lamina terminalis. They are implicated in fluid balance and cardiovascular functions, and are strongly interconnected. Blood-born angiotensin II acts on the subfornical organ, OVLT and periventricular preoptic nuclei to induce water intake, to stimulate vasopressin release and to give a pressor action. Angiotensin in descending projections from the lamina terminalis interacts with extracellular norepinephrine to facilitate vasopressin release from the hypothalamoneurohypophysial system (Johnson and Thurnhorst, 1996). In addition, osmoreceptors are present in neurons of the OVLT and subfornical organ that project to the SON and subserve thirst and vasopressin secretion. The relevance of these osmoreceptors, as compared to those in the SON itself, is still in debate (McKinley et al., 1996). Stimulation of central angiotensin-I receptors in the OVLT and subfornical organs elicits systemic cardiovascular, neuroendocrine and behavioral actions. Furthermore, angiotensin II may act as a neurotransmitter or neuromodulator responsible for an elevation in blood pressure and dipsinogenic control, sodium appetite, natriuresis and vasopressin release. High levels of circulating angiotensin II may cause hypertension as a result of their action on the area postrema and on the anterior portion of the ventral third ventricle, and spontaneous hypertensive rats have higher angiotensin II levels in the hypothalamus and more angiotensin II receptors in the subfornical organ. The action of angiotensin II on blood pressure may be mediated by increased salt sensitivity (Muratani et al., 1996). . . . the slightly bulging lamina terminalis extends from the divergent subcallosal gyri to the chiasm inferiorly and anteriorly. In its middle a rhomboid or better pentagonal darker part is seen, which is surrounded by a delicate frame and gives off a whitish rod projecting upward. This is the transparent part of the lamina terminalis, which I called fenestra laminae terminalis. Like most other rudimentary parts, the fenestral membrane is variably developed. It may be quite large or of moderate size. In some cases it is, however, indistinct and less transparent or reduced to a slender midline gap of variable shape closed by the fenestral membrane. Whatever its size and development, the lamina terminalis cerebri is of considerable morphological interest. Leaving aside the choroid plexus, it is one of the thinnest structures of the brain wall, but with a reinforcement on its outer aspect by the firmly attached pia mater (Retzius, 1896, p. 56, cited by De Divitiis et al., 2002).

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(b) Human data

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SON. These localizations agree with the effects of angiotensin II observed in animal experiments on fluid and electrolyte balance, cardiovascular regulation, and release of vasopressin, oxytocin, and anterior pituitary hormones (Allen et al., 1988b). Indeed, angiotensin II infusion in humans induces increased plasma levels of both vasopressin and oxytocin (Chiodera et al., 1998b). Angiotensin-converting enzyme is a peptidyl carboxypeptidase that cleaves the histidyl dipeptide from angiotensin I to form the vasoactive peptide angiotensin II. This enzyme, which is capable of local conversion of bloodborne angiotensin I to angiotensin II, is present in moderate amounts in the hypothalamus in the PVN and SON. The OVLT, infundibulum and pineal gland display the highest levels, while the choroid plexus contains only moderate amounts (Chai et al., 1990). In the neurons of the lamina terminalis of the fetus, LHRH has been found from as early as 9 weeks of gestation onwards (Bugnon et al., 1976; Paulin et al., 1977; Rance et al., 1994; Dudás et al., 2000). LHRH neurons are already present in the human OVLT of 17 to 26-week-old fetuses (Bugnon et al., 1977; Leonardelli and Tramu, 1979). Consistent with neurosecretion in the bloodstream are reports that LHRH, angiotensin-II, somatostatin and atrial natriuretic peptide-immunoreactive fibers terminate within the OVLT (McKinley and Oldfield, 1990). The OVLT contains benzodiazepinebinding sites in the human newborn and infant, showing GABA-mediated inhibitory neurotransmission (Najimi et al., 2001a); and a dense fiber network containing delta sleep-inducing peptide is found in the OVLT (Najimi et al., 2001b). LHRH is colocalized with delta sleep-inducing peptide (Vallet et al., 1990). In addition, VIP-binding sites have been observed in this structure that might well be related to innervation by the SCN. No differences are found between VIP binding in male and female individuals, nor between neonates/infants and adults (Sarrieau et al., 1994), in spite of the fact that the OVLT has been reported to play a role in the rat estrus cycle. Sporadically, enlargement, vacuolation and multiplication of nucleoli, indicating increased neuronal metabolic activity, have been observed in a man with hypogonadotropic hypogonadism (Ule and Walter, 1983).

The OVLT is almost completely situated in the human hypothalamus; it is, on average, 8.25 mm long, lying between the upper edge of the optic chiasm and the lower edge of the anterior commissure. The OVLT is a thin sheet of gray matter covered by a pial layer, which is attached as a wafer-thin membrane to the upper surface of the optic chiasm and there gives rise to the optic recess (De Divitiis et al., 2002). The ependymal cells are flattened. The OVLT contains a rich vascular plexus; it receives its arterial supply from 4 sources: (1) a superior median source branching from the anterior communicating artery, (2 and 3) two lateral sources from branches of the anterior cerebral artery, and (4) an inferior median source ascending from below the optic chiasm. These sources anastomose, and branches twig off to enter the pia mater and supply a dense, superficial capillary network. From this superficial network, a secondary deep capillary network extends into the body of the OVLT in the form of sinusoidal capillary loops and coils. The venous drainage is in a lateral direction to veins from the adjacent hypothalamus and proceeding to the anterior cerebral veins. Unlike in other species, fenestrations in the capillary endothelial cells have not been observed in the human OVLT. However, the selective entry into the OVLT and other circumventricular organs of endogenous iron deposits observed in cases of hemochromatosis and entry of imbibed silver for cosmetic purposes into the human OVLT suggest absence of the blood–brain barrier (McKinley and Oldfield, 1990). A large concentration of estrogen receptor--containing astrocytes has been observed in the OVLT and around the third ventricle (Donahue et al., 2000). Many glial cells (spongioblasts) can be seen in the deeper layer of the external zone, and primitive neurons have been described. From animal experiments it is concluded that the major input of the OVLT comes from the subfornical organ, locus coeruleus, central gray, preoptic area, lateral hypothalamic area (LHA), DMN and VMN. There are strong projections from the OVLT to the median preoptic nucleus and the SON (McKinley and Oldfield, 1990). It has been found that damage of the lamina terminalis in humans resulting from tumors, trauma or surgery, has profound effects on fluid balance (McKinley et al., 1996). In addition, autoradiographic data have shown that angiotensin II binding is not only present in the human lamina terminalis structures, i.e. the OVLT, but also in the subfornical organ and median preoptic nucleus, PVN, median eminence and

(c) Subfornical organ The subfornical organ is situated in the dorsal aspect of the midline anterior wall of the third ventricle. Bulging into the third ventricle as a rounded, pearly gray 363

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translucent nodule of about 1 mm ventral to the junction of the two fornical columns, this highly vascularized structure is concealed with the overhanging choroid plexus. It contains not only many glial cells, but also neurons and a rich vascularization with fenestrated capillary endothelium. The ependyma of the human subfornical organ is modified into flattened, squamous cells. Branches of the anterior cerebral artery and posterior choroidal artery anastomose to form the capillary network of the subfornical organ. The capillaries exhibit extensive perivascular spaces and drain laterally into a wide vein on each side of the fornix, which eventually leads to the great cerebral vein. The subfornical organ has receptors for angiotensin II, which, when stimulated induce water drinking and vasopressin secretion (McKinley and Oldfield, 1990). Membrane-bound, waterselective channel aquaporin-4, which in rat is located in astrocytes, may be involved in central osmoregulation (Wells, 1998; Badaut et al., 2000). In the rat a large majority of the subfornical organ neurons respond to changes in osmolality (Anderson et al., 2000). Animal experiments indicate, in addition, that there is release of LHRH, somatostatin or angiotensin II by neurosecretion into the bloodstream (McKinley and Oldfield, 1990). The subfornical organ may be involved in the development of hydrocephalus (Chapter 18.7). On the basis of observations in rats, it is assumed that a circuit involving V1 receptors in the subfornical organ, connecting fibers to the SCN and vasopressinergic efferents of the SCN may play a role in mediating the actions of vasopressin in the maintenance of ethanol tolerance (Lanca et al., 1999). For the subcommissural organ, see Chapter 18.7. 30.6. Micturition In experimental animals, three brain areas are specifically implicated in the control of micturition: the dorsomedial pontine tegmentum (an area that controls the motor neurons of the pelvic floor), the periaqueductal gray, and the POAH. In the cat, stimulation of, e.g. the preoptic area of the hypothalamus, bed nucleus of the stria terminalis and septal nuclei elicits bladder contractions. Brouwer (1950) has described two cases of hypothalamic lesions, one in a case of chronic encephalitis, and one in a circumscribed glioma in which involuntary micturition was one of the first symptoms of the disease. The human hypothalamus may indeed play a role in initiating micturition. Using PET scanning in right-

handed male volunteers, micturition was associated with increased blood flow in the hypothalamus, the right dorsomedial pontine tegmentum, the periaquaductal gray, and the right inferior frontal gyrus (Blok et al., 1997). 30.7. Sleep (Figs. 30A and 30B) “O sleep, o gentle sleep/Nature’s soft nurse, how have I frightened thee,/that thou no more wilt weigh my eyelids down/And steep my senses in forgetfulness?. . .” Shakespeare, Part 2, Henry IV, Act III, scene 1,4. (Fogan, 1989).

A person usually sleeps for approximately 6 h. Shorter and longer sleep and sleeping pills are associated with increased mortality. Prospective epidemiological data have disclosed that men who usually sleep less than 4 h are 2.8 times as likely to have died within 6 years of the start of the investigation than men who report 7.0–7.9 h of sleep. The ratio for women is 1.48. Men and women who report more than 10 h of sleep had about 1.8 times the mortality of those who reported 7.0–7.9 h of sleep. For those using sleeping pills, the figure is a 1.5-timeslarger mortality than in people who have never used sleeping pills (Kripke et al., 1979, 2002). Another study could not confirm the relationship between sleep patterns and survival in elderly subjects. There are, however, significant correlations between polygraphic sleep criteria and another operationalization of “successful aging”, i.e. cognitive competence. In particular potential predictive value of REM latency and REM density for cognitive functioning are observed (Spiegel et al., 1999). Insomnia is the most commonly encountered sleep disorder. It is generally reported to be associated with an overall increase in ACTH and cortisol secretion, which, however, retain a normal circadian pattern (Vgontzas et al., 2001a). In a recent study, however, cortisol secretion in primary insomniacs did not differ from controls (Riemann et al., 2002). The often-observed activation of the hypothalamopituitary–adrenal (HPA) axis is presumed to make insomniacs at risk for anxiety and depression (Chapter 26.4), hypertension (Chapter 8.5) and obesity (Chapter 23). In contrast to short or long sleeping times, insomnia is not found to be associated with an excess mortality risk (Kripke et al., 2002). (a) Hypothalamic structures involved in sleep The SCN is responsible for the circadian aspects of sleep and neuroendocrine circadian rhythms related to sleep

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Fig. 30A.

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Rustende slaapwandelaarster (resting sleepwalker) IV, 1971. Pyke Koch (1901–1991). Collectie Frisia Museum, Spanbroek.

penetrance or a multifactorial mode of inheritance (Ancoli-Israel et al., 2001). A pathogenetic mechanism of this syndrome may be the hypersensitivity of melatonin suppression in response to light in the evening (Aoki et al., 2001). A bright-light mask turned on 4 h before arising advances the circadian phase and provides clinical benefit in delayed sleep phase syndrome patients (Cole et al., 2002a). A flattening of circadian rhythms is also found in fatal familial insomnia, a prion disease (Cortelli et al., 1999). In infantile neuronal ceroid lipofuscinosis, a fragmented, diurnal sleep–wake pattern, with no distinct rhythm, is found (Kirveskari et al., 2001), pointing to impairment of the SCN. Whipple’s disease is caused by infection with Tropheryma whippelii, a gram-positive bacillus. A transient fetal abolition of the sleep–wake cycle has been found as a cerebral manifestation of this disease. Endocrine tests have revealed hypothalamic dysfunction with flattening of circadian rhythmicity of cortisol, TSH, growth hormone and melatonin. Cerebrospinal fluid

(Van Cauter and Spiegel, 1997). Hereditary circadian pacemaker properties are the biological basis for preferring morning or evening activity patterns and wake time (Duffy et al., 2001; Vink et al., 2001a). The difference between long sleepers (more than 9 h) and short sleepers (less than 6 h) is retained under constant environmental conditions and is thus a property of the circadian pacemaker (Aeschbach et al., 2002). A major sleep disorder, showing a phase advance, is present in Smith–Magenis syndrome, which is based on interstitial deletions of chromosome 17p11.2 (De Leersnyder et al., 2003; see Chapters 4, 4.5). A familial, advanced sleep-phase syndrome, a short circadian rhythm variant, has been described in humans (Jones et al., 1999) which is due to a missense mutation of the human PER2 gene (Toh et al., 2001; Chapter 4b). In patients with a delayed sleep phase syndrome, a polymorphism of the human PER3 gene was found (Ebisawa et al., 2001). The genetic transmission of this syndrome may take place both via the paternal and maternal branch and may be either of an autosomal dominant type with incomplete 365

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Fig. 30B.

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Zsuszi sleeping (Edma Balázs). Life and Work, published 1998, by Robert, Susan and John Bal*zs. (c) Robert, Susan and John Balázs, ISBN: 0-9532750-1-9. (With permission.)

hypocretin is reduced, explaining the almost complete loss of sleep (Voderholzer et al., 2002). In retinitis pigmentosa patients, a decrease in sleep quality takes place in an age-dependent manner, pointing to the degeneration of photoreceptors mediating the photic input to the SCN (Gordo et al., 2001). In addition, circadian and seasonal factors in sleep-related disorders may be related to SCN function, such as the observation that sudden infant death syndrome (SIDS) is more prevalent in the winter months and typically occurs in the early morning hours (Cornwell et al., 1998). Poor sleep is reported in 10–20% of the elderly (Asplund, 1999). During aging the function of the SCN is affected (Chapter 4.3). Since bright light has proven to be effective in the treatment of sleep maintenance insomnia in the elderly (Asplund, 1999), the SCN seems to be an important structure in the pathogenesis of this disorder. Moreover, cognitive processes are involved, since anticipation of an

early time of awakening goes together with an earlier ACTH release that may facilitate spontaneous wakening (Born et al., 1999). The physiology and pathology of the circadian timing system in relation to sleep and the effects of the pineal gland hormone melatonin on sleep are discussed in Chapter 4.5. The importance of endogenous melatonin for sleep regulation is supported by case histories of children with a pineal tumor and children that are blind and have severe sleep disorders. Oral melatonin greatly improves their sleep (Jan et al., 2001; Cavallo et al., 2002). There is an association between melatonin levels and sleep stages. Melatonin levels are at their lowest during stages 3 and 4, higher in stage 2, and at their highest in REM sleep. Modulation of melatonin secretion by increased sympathetic activity is suggested (Luboshitzky et al., 1999). Melatonin does not produce any sleep benefit in patients with primary insomnia

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(Almeida Montes et al., 2003). It has been proposed that the onset of nocturnal melatonin secretion initiates the chain of events that 2 h later leads to the opening of the sleep gate. Once secretion into the bloodstream commences, melatonin inhibits the SCN wakefulnessgenerating mechanism. This allows the somnogenic structures to take over, unopposed by the wakefulness mechanisms. Melatonin deficiency will thus interfere with the smooth transition from wake to sleep (Lavie and Luboshitzky, 1997), and altered circadian melatonin secretion patterns are accompanied by sleep disorders (Rodenbeck et al., 1998). In primary insomniacs, melatonin is reduced (Riemann et al., 2002). Changes in melatonin levels occur in many conditions in which sleep disorders have been reported. The effects of melatonin on sleep disorders are discussed in Chapter 4.5c. Melatonin did not produce any sleep benefit in patients with primary insomnia (Almeida Montes et al., 2003). It has been proposed that circadian sleeping disorders that cannot be treated with bright light and melatonin should be designated ‘sleep–wake schedule disorder disability’ (Dagan and Abadi, 2001). The circadian temperature rhythm provides an important signaling pathway for the circadian modulation of sleep and wakefulness (Van Someren, 2000b). In agreement with this idea are the observations that increased nocturnal core temperature due to sleeping under an electric blanket may disrupt sleep (Fletcher et al., 1999), and that warm feet promote the rapid onset of sleep. Dilatation of blood vessels in the skin and feet, which increases heat loss at the extremities, is the best physiological predictor for the rapid onset of sleep (Kräuchi et al., 1999). The high nocturnal body temperature and disturbed sleep in women with primary dysmenorrhea (Baker et al., 1999) also support this concept. Ascending impulses from the brainstem reticular formation that pass into the posterior hypothalamus are important for the physiology of sleep. The serotonergic and norepinephrinergic input to the hypothalamus are important wake-promoting systems. The serotonergic input is presumed to be disturbed in African trypanosomiasis, a syndrome accompanied by loss of 24-h rhythmicity in sleep (Buguet, 1999). Lesions, such as tumors (see Chapter 19.1) of the posterior hypothalamus, produce hypersomnia, even up to severe coma. On the basis of such observations, Wilder Penfield presumed in the thirties that “the indispensable substratum of consciousness lies outside the cerebral cortex, . . . probably in the diencephalon” (Anderson and Haymaker,

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1974). Sleep-generating cells are presumed to be localized in the basal forebrain and anterior hypothalamus (Culebras, 1992). Also the classic studies by Von Economo (1930), about patients dying of encephalitis lethargica (Chapter 20.2), suggest that lesions of the anterior hypothalamus and basal forebrain cause insomnia and thus contain a ‘sleep center’; whereas lesions of the posterior hypothalamus and mesencephalic tegmentum provoke lethargy and hypersomnia and thus contain a ‘wake center’. The 70-year-old hypothesis that a rostral hypothalamic area is essential for maintaining sleep has received support from the identification of a group of sleep-active neurons in the ventrolateral preoptic (VLPO) region of the rat hypothalamus, just lateral of the optic chiasm, using c-FOS (Sherin et al., 1996). The GABAergic and galanin-containing neurons of the VLPO inhibit serotonergic and norepinephrinergic wakepromoting neurons and in this way facilitate the sleep-onset process. The VLPO neurons also send descending fibers to the histaminergic neurons in the posterior hypothalamus (Salin-Pascual et al, 2001). The histaminergic neurons of the tuberomamillary nucleus promote arousal during wakefulness, become less active during slow-wave sleep and cease firing during REM sleep. The histaminergic neurons in rat are inhibited during sleep by GABAergic neurons that originate in the VLPO (Sherin et al., 1996, 1998). Antihistamines act as H1 receptor antagonists and may induce sleep and cognitive deficits by their action on these receptors in the cortex (Tashiro et al., 2002). However, the claim by Gaus et al. (2002) that the human sexually dimorphic nucleus of the preoptic area (SDN-POA) (Chapter 5) corresponds to the VPLO in the rat is very unlikely, because of its more lateral localization in the rat hypothalamus. It is likely that sleep-promoting neurons extend beyond the VLPO region in the preoptic area, and that warmthsensitive neurons in this region are essential in sleep regulation (McGinty and Szymusiak, 2000). Hypersomnia has been associated with a bilateral posterior hypothalamic lesion of unknown etiology in a 58-year-old patient (Eisensehr et al., 2003). The identification of a disorder of the orexin/hypocretin system in the lateral hypothalamus/perifornical area as the basis for narcolepsia (Chapter 14a), and for primary hypersomnia (Ebrahim et al., 2003) proves that Von Economo was correct in concluding that the posterior hypothalamus contains neurons that are important for wakefulness (Aldrich and Naylor, 1989; Salin-Pascual et al., 2001; Chapter 28.4). In contrast to the decreased CSF levels of 367

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hypocretin in narcolepsy, increased CSF hypocretin levels are found in restless legs syndrome, especially in the early-onset form of this sleep disorder (Allen et al., 2002). One study indicates that plasma orexin-A levels are decreased in sleep apnea syndrome (Nishijima et al., 2003). Animal experimental studies have confirmed that the basal forebrain nuclei are important sites of sleep–wake regulation. Arousal-related functions are mediated by this system of magnocellular cholinergic neurons, which project monosynaptically to the entire neocortex and participate not only in cognitive processes, but also in the regulation of activated EEG patterns characteristic of waking and REM sleep (see Chapter 2). Neurons that display elevated discharge rates during transitions from waking to sleep and during non-REM sleep have been recorded in basal forebrain sites, where electrical stimulation evokes sleep and experimental lesions cause insomnia. Afferents to the basal forebrain from hypothalamic and brainstem regions are functionally important for sleep–wake regulation. Inputs from thermosensitive neurons in the anterior hypothalamus modulate the activity of the basal forebrain sleep- and arousal-related cell types (Szymusiak, 1995). Slow-wave sleep requires low acetylcholine concentrations in the brain, whereas REM sleep is associated with high levels of acetylcholine (DeLecea et al., 1996), and cholinergic compounds induce REM sleep (Riemann et al., 1994). (b) Neuroendocrine changes in sleep Endocrine changes during sleep and the effects of hormones on sleep indicate the involvement of the hypothalamus in sleep. TSH, melatonin (Chapter 4.5), ACTH and cortisol (Chapter 4.1a), prolactin and growth hormone all have their typical 24-h profiles (Van Cauter and Spiegel, 1997), pointing to a role of the SCN in their regulation. Growth hormone, prolactin, LH and FSH are all secreted in large amounts during sleep, whereas TSH and cortisol secretion are reduced during the first half of the sleep period (Luboshitzky, 2000). Serum prolactin levels exhibit an episodic release pattern with 5–15 secretory episodes per day. The amplitude of these pulses increases within 60–90 min after the onset of sleep, occurring primarily during non-REM sleep periods, in both men and women. The diurnal secretion of prolactin seems to be sleep-induced, rather than induced by an inherent diurnal rhythm (Ben-Jonathan and Hnasko, 2001). HPA activity is inhibited with the first nocturnal

periods of slow-wave (deep) sleep in humans, probably under control of the SCN (Kalsbeek et al., 1992). Both CRH and cortisol stimulate arousal/wakefulness and inhibit slow-wave sleep (Vgontzas et al., 2001b). Cortisol and ACTH levels have their nadir in the early hours of nocturnal sleep. During late sleep, dominated by REM sleep, HPA secretory activity reaches high levels. Salivary free cortisol shows a marked increase following awakening, peaking at about 30 min, and subsequently declines over the remainder of the day. Those subjects who awake the earliest have higher levels of cortisol during the 45 min following awakening, as well as throughout the rest of the day. They also show a more marked decline (Edwards et al., 2001). This rhythm is supposed to primarily reflect the activity of the SCN (Chapter 4) but it is strengthened by sleep. The nocturnal inhibition of the HPA axis disappears after blockade of mineralocorticoid receptors, which suggests that sleep exerts its influence via the hippocampus or another structure that has these receptors. The mineralocorticoid-expressing cells seem to be simultaneously involved in the generation of slow-wave sleep. Dysfunction of the described neuroendocrine mode of regulation during early sleep is present in patients with Cushing’s disease, in patients with severe depression, in aged humans and in insomnia. All of these groups show insufficient inhibition of HPA secretory activity during early sleep and reduced slowwave sleep (Born et al., 1997; Born and Fehm, 1998; Rodenbeck and Hajak, 2001). Elevated cortisol secretion in the evening strongly and positively correlates with the number of nocturnal awakenings, not only in insomniacs but also in controls, indicating that elevated evening cortisol levels may be crucial in inducing and maintaining sleep disturbances (Rodenbeck and Hajak, 2001). Chronic insomnia is associated with increased activation of ACTH and cortisol secretion, which may be a risk factor for anxiety and depression (Vgontzas et al., 2001a). CRH receptor-1 antagonists have been proposed, therefore, as putative therapeutic drugs for sleep disorders (Grammatopoulos and Chrousos, 2002). Growth hormonereleasing hormone (GHRH) promotes sleep in the elderly, but, according to some studies, less efficiently so than in young subjects (Guldner et al., 1997). The balance between GHRH and CRH is said to play a key role in normal and pathological sleep regulation. In young subjects in that study, GHRH stimulates slow-wave sleep and growth hormone secretion, and inhibits cortisol release, whereas CRH has the opposite effect. The GHRH to CRH ratio changes during aging and depression, which

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may result in sleep disturbances. In another study, intranasal GHRH has had a coordinating function with respect to the regulation of sleep processes and hormone secretion, independent of the subjects’ age. GHRH reduced the cortisol nadir in the beginning of sleep, reduced sleep-induced elevations of GH during early sleep and increased REM and slow wave sleep (Perras et al., 1999b). Galanin, growth hormone-releasing peptide and neuropeptide Y also promote sleep. In elderly subjects sleep deteriorates after acute administration of somatostatin but improves after chronic treatment with vasopressin (Steiger and Holsboer, 1997). Sustained elevation of vasopressin levels are associated with a reduction in REM sleep (Luboshitzky, 2000), but slowwave sleep increases following intranasal vasopressin administration (Perras et al., 2003). VIP decelerates the non-REM/REM cycle and advances the occurrence of the cortisol nadir (Steiger and Holsboer, 1997). Growth hormone secretion increases during the first two nonREM/REM sleep cycles. Sleep pathologies such as obstructive sleep apnea syndrome, narcolepsia and trypanosomiasis alter the 24-h growth hormone profiles. Subjects with growth hormone disturbances due to isolated growth hormone deficiency or acromegalics with excess of growth hormone have abnormal REM and delta sleep. Normalization of the growth hormone levels is followed by correction of sleep stages, indicating that there is not only an effect of sleep on growth hormone release, but also an effect of growth hormone on sleep (Åström, 1995). In pubertal children the magnitude of the nocturnal pulses of LH and FSH is increased during sleep. As the child enters adulthood, the daytime pulse amplitude increases also, eliminating the diurnal rhythm in LH and FSH. In adult men, testosterone secretion reveals a marked diurnal rhythm, with maximum levels during the early morning and minimum levels in the late evening. Testosterone levels rise approximately 90 min before the first REM period, which supports the role of testosterone in REM-associated penile tumescence. In elderly men the diurnal testosterone rhythm disappears, although mean levels and pulsatile secretory patterns are unchanged (Luboshitzky, 2000). Two hormones that progressively increase in pregnancy and affect sleep are progesterone and estrogen. Progesterone has a sedative effect and induces a shortening of the latency to sleep onset and reduces wakefulness after sleep onset. Progesterone primarily affects non-REM sleep. Estrogens suppress REM sleep in rats, but enhance REM sleep in humans, increase the amount of sleep and decrease the latency to

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REM sleep. The effects of sex hormones on sleep may be responsible for at least some of the differences in sleep between genders (Manber and Armitage, 1999; Santiago et al., 2001). One of the few compounds that has fulfilled every proposed criterion as a sleep-regulatory substance is interleukin-1 (IL-1). Administration of this compound induces non-REM sleep. Interestingly, IL-1 induces a release of growth hormone via a hypothalamic mechanism, and growth hormone release is coupled to non-REM sleep (Krueger and Obál, 1997). In connection with these observations one may wonder what IL-1 – located in the hypothalamoneurohypophysial system (Huitinga et al., 2000a) – may contribute to the physiology of sleep. (c) Sleep and aging As many as 40% of elderly people complain about sleep disturbances. The relationship of these disorders to the age-related changes in the SCN is discussed in Chapter 4.3. Because of the importance of the retinohypothalamic tract for entrainment of circadian rhythms (Chapter 4b), it is understandable that older adults reporting visual impairment are also likely to report sleep complaints (Zizi et al., 2002). Elderly people spend less time in slow-wave and REM sleep (Vitiello, 1997). In elderly people a decline in slow-wave and REM sleep and a decrease in growth hormone secretion is found, while the cortisol nadir increases as a function of age (Kern et al., 1996; Cauter et al., 2000). Middle-aged men show increased vulnerability of sleep to stress hormones such as CRH and glucocorticoids, possibly resulting in impairments in the quality of sleep during periods of emotional stress (Vgontzas et al., 2001b). Age-related alterations in nocturnal wake time and daytime sleepiness are associated with elevations of both plasma interleukin-6 and cortisol concentrations, but REM sleep decline is primarily associated with cortisol increases (Vgontzas et al., 2003). Sleep-endocrine changes typically associated with major depression, namely a reduction in sleep continuity and slow-wave sleep, and an increase in REM density, are most prominent in postmenopausal women (Antonijevic et al., 2003). Although sleep disturbances in elderly people are often multifactorial, melatonin may be useful in the treatment of the circadian disturbances (Gentili and Edinger, 1999) (see Chapter 4.5). Sleep may alter the symptoms of a neurological disease. In Parkinson’s disease, for example, tremor and rigidity disappear during sleep by sleep hypotonia or REM sleep atonia (Van 369

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Someren et al., 1993; Autret, 1997). Alleviation of symptoms during sleep also occurs in migraine (see Chapter 31.2), as well as many other neurological disorders (Autret, 1997). (d) Sleep in neurological and other disorders After resection of hypothalamic/pituitary tumors, children are at risk to develop hypersomnolence. The often-severe daytime sleepiness is not the result of inappropriate hormone replacement (Snow et al., 2002). Many brain diseases are accompanied by sleep disturbances (Autret et al., 2001). Insomnia, a significant reduction in sleep duration, may be found in, e.g. neurodegenerative diseases. Patients with Parkinson’s disease run a higher risk of insomnia, parasomnias, nightmares and excessive daytime somnolence. The sleep disorders correlate with increased severity of the disease (Chapter 29.3; Larsen and Tandberg, 2001; Kumar et al., 2002). An MS patient with a hypothalamic plaque developed acute hypersomnia, accompanied by indetectable CSF hypocretin levels (Iseki et al., 2002). Patients with retinitis pigmentosa have daytime sleepiness, reduced alertness and more disturbed night-time sleep of poorer quality than normally sighted counterparts, suggesting an influence of photoreceptor degeneration on the circadian cycle (Ionescu et al., 2001). Sleep disturbances in Alzheimer patients are discussed in Chapter 4.3c; symptomatic narcolepsia is discussed in Chapter 28.4; and the circadian disturbances in sleep patterns in Chapter 4.3. Delayed-sleep disorder, which is considered to be due to alterations in the function of the circadian system, has been reported following traumatic brain injury. The sleep delay of half a day was successfully treated with melatonin (Nagtegaal et al., 1997). In addition, a lack of REM sleep has been reported in hypothalamic injury following excision of a craniopharyngioma (Rehman and Atkin, 1999). Familial fatal insomnia is an autosomal-dominant prion disease characterized by a prominent degeneration of the thalamus and involving impaired control of the sleep–wake cycle and of autonomic and endocrine function (see Chapter 4b; Autret, 1997; Parkes, 1999). A SPECT study has provided the first in vivo evidence that a reduction in serotonin transporter is present in this disorder (Klöppel et al., 2002). The claim that the hypothalamic nuclei, including the supraoptic, paraventricular, suprachiasmatic and posterior nuclei were normal (Lugaresi et al., 1986), should be investigated with modern quantitative, functional anatomical techniques.

Chronic secondary hypertension and loss of the physiological nocturnal decrease in blood pressure are found, together with hypercortisolism and abnormal secretory patterns of growth hormone, prolactin and melatonin. Advanced stages are invariably characterized by the disappearance of any circadian autonomic and neuroendocrine rhythmicity (Avoni et al., 1991; Montagna et al., 1995), indicating that the SCN is affected. One study showed that the number of serotonin-producing neurons in the medial raphe nucleus was increased, indicating that the input to the SCN may have been altered in this disorder (Wanschitz et al., 2000). The SCN appeared to be affected in primary hypertension (Goncharuk et al., 2001). Sleep disorders have been reported in approximately 80% of Tourette’s syndrome patients. Since these patients also have abnormal growth hormone release following administration of naxolone, it has been proposed that abnormalities of the hypothalamic-mediated control mechanism of sleep involving the intrinsic opioids may account for the sleep disturbances (Sandyk et al., 1987). Smith–Major syndrome is characterized by mental retardation, aggression, tantrums and serious sleep disturbances. The circadian melatonin secretion is completely inverted, showing a peak around mid-day (De Leersnyder et al., 2001, 2003). Sleep apnea is more prevalent in (neuro)endocrine diseases such as acromegaly, Cushing’s disease and syndrome, hypothyroidism and diabetes mellitus. The question whether changes in growth hormone and IGF-I levels are involved in the pathogenetic mechanism of sleep apne is unresolved. REM sleep abnormalities have been found in children at high risk for SIDS, which may be indicative of a pervasive CNS immaturity (Cornwell et al., 1998). Sleep problems are, moreover, extremely common in children with mental handicaps or learning disabilities (Quine, 1991; Wiggs and Stores, 1996; Hoban, 2000; Chapter 26.5). Some 51% of children with a mental handicap have sleeping problems and 67% have problems with waking up. These problems tend to be very persistent (Quine, 1991). Sleeping problems in children with developmental handicaps may react favorably to melatonin treatment (Gordan, 2000; Dodge and Wilson, 2001; see Chapter 4.5c). Children with attention-deficit hyperactivity disorder (ADHD) have greater difficulties with sleeping than children who develop according to the norm (Ball, 1997). Primary dysmenorrhea is characterized by painful uterine cramps near and during menstruation. Women suffering from primary dysmenorrhea have disturbed

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sleep patterns even before menstruation and in the absence of pain. In addition, nocturnal body temperature and estrogen levels are different compared with controls. When the body temperature is high, less REM sleep occurs, implying that REM sleep is sensitive to elevated body temperatures (Baker et al., 1999). Astronauts experience circadian alterations (Chapter 4) and shorter, more disturbed sleep during space flights. Also, the structure of their sleep is significantly different in that a decreased amount of delta sleep is observed. Also, the latency to the first REM period is shorter and

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slow-wave sleep redistributed from the first to the second sleep cycle (Gundel et al., 1997; Monk et al., 1998). Periodic insomnolence in Kleine–Levin syndrome (Gadoth et al., 2001) is described in Chapter 28.1. For sleep disturbances in Prader–Willi syndrome, see Chapter 23.1. Interestingly, in contrast to all the disorders that cause sleeping problems, patients with prolactinomas sleep subjectively well. These patients spend more time in slow-wave sleep (Frieboes et al., 1998). Hypersomnia has been found in patients with paraneoplastic limbic encephalitis (Gultekin et al., 2000; Chapter 32.1).

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CHAPTER 31

Pain and addiction

-endorphin and -lipotropic hormone (LPH) (Bloch et al., 1978). i(ii) The most recently discovered class of endogenous opioid peptides consists of derivates of the 256-amino acid precursor proenkephalin B (PENKB) or prodynorphin (PDYN) and coded for the pre-PDYN gene. Cleavage of PDYN yields three main opioid peptides, i.e. neoendorphin, dynorphin A, and dynorphin B, all of which contain the sequence leu-enkephalin (Sukhov et al., 1995). Leu-enkephalin regulates the gonadal axis and, in the medial preoptic area infundibular/median eminence region, leuenkephalin neurons and many leu-enkephalin fibers seem to terminate on luteinizing hormone-releasing hormone (LHRH) neurons (Dudás and Merchenthaler, 2003). Neoendorphin can exhibit two different forms, -neoendorphin and -neoendorphin, which differ by only one amino acid (Sukhov et al., 1995; Hurd, 1996). The best-known cleavage products of dynorphin A are two smaller fragments, DYN A1–8, and DYN A1–17. Processing of dynorphin B (DYNB) can produce the 29-amino acid peptide leumorphin or dymorphin B1–13 (Sukhov et al., 1995). Transcutaneous electrical nerve stimulation (TENS) induces a release of dynorphin and is very effective in ameliorating the withdrawal syndrome in heroin addicts (Wu et al., 1999). Pre-PDYN gene expression is found in neurons of the dorsomedial nucleus, ventromedial nucleus (VMN), tuberomamillary nucleus, caudal lateral hypothalamus, retrochiasmatic area and in the bed nucleus of the stria terminalis (Fig. 31.2A–F; Sukhov et al., 1995). Abe et al. (1988) have found dynorphin staining neurons mainly in the supraoptic nucleus (SON), paraventricular nucleus (PVN), supramamillary nucleus and

31.1. Opioid peptides and other addictive compounds The opiate systems are a major factor in pain perception and addiction. Moreover, these systems are involved in a wide variety of neural functions, including eating, drinking, reproduction, stress, emotions, learning and homeostasis. The opiate systems are also supposed to be involved in a number of placebo effects (Stefano et al., 2001; Chapter 31.2b). Four different classes of opioid peptides are distinguished: (i) -endorphins, (ii) dynorphins, (iii) enkephalins, and (iv) the orphanin peptide system. They are synthesized by different genes, with different precursor molecules: ii(i) Pro-opiomelanocortin (POMC) is a 267-amino acid peptide. It yields a group of opioid peptides, the -endorphins, corticotropin (ACTH)- and MSHlike peptides (Fig. 23.21). The maturation and cleavage into its various products are area-specific and post-translational processing plays a crucial role in determining the biological activity of the POMC derivates. Patients with POMC mutations leading to a lack of ACTH, -melanotropin (MSH) and -endorphin show severe early-onset obesity (Chapter 23.d), but no unusual pain sensation, which points to only a minor role of -endorphin in the modulation of pain (Krude and Grüters, 2000). Of the three opioid systems, pre-POMC neurons have the most restricted distribution and are the most numerous in the infundibular nucleus and retrochiasmatic area of the mediobasal hypothalamus (Sukhov et al., 1995; Fig. 31.1A–C). In the adult infundibular nucleus, the same neurons stain for -endorphin ACTH, MSH, MSH, 373

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lateral hypothalamus, while a few positive cells have been found in the arcuate nucleus. (iii) Enkephalins are also produced by the 267-amino acid precursor PENK. All cleavage products, including 4 metenkephalins, 2-carboxyl-extended metenkephalins and one leu-enkephalin, exhibit opioid activity. The opioid peptides are concentrated heavily in the hypothalamus (Sukhov et al., 1995). Pre-PDYN neurons are especially abundant in neurons of the tuberal and mamillary regions, with a distinct population of labeled cells in the premamillary nucleus and dorsal posterior hypothalamus (Sukhov et al., 1995). Pre-PENK neurons occur in varying numbers in all hypothalamic nuclei except the mamillary bodies. The chiasmatic area is particularly rich in pre-PENK neurons, with the highest packing density in the sexually dimorphic nucleus of the preoptic area (SDN-POA). Simerly et al. (1988) found more enkephalin neurons in the POA of the male rat. Sexual dimorphism in the number of enkephalin neurons in the human SDN-POA has yet to be elucidated. In addition, pre-PENK neurons are found in the dorsal suprachiasmatic nucleus, medial preoptic area and rostral lateral hypothalamic area. Pre-PENK neurons are numerous in the infundibular nucleus, VMN, dorsomedial nucleus, caudal parvicellular neurons of the PVN, tuberomamillary nucleus, lateral hypothalamus and retrochiasmatic area, nucleus basalis of Meynert (NBM), and in the bed nucleus of the stria terminalis (Fig. 31.3A–F) (Sukhov et al., 1995). (iv) The orphanin peptides are structurally related to the endogenous opioid family. The opioid receptor-like receptor (ORL1) binds an endogenous ligand, a heptadecapeptide, referred to as nociceptin or orphanin. Orphanin has an amino acid sequence strikingly similar to the endogenous opioid dynorphin, and may play a role in stress and pain systems. Human ORL1 and orphanin expression are observed in the hypothalamus from 16 weeks of gestation

Fig. 31.1. A–C: Computer-assisted maps of the distribution of proopiomelanocortin (POMC) cells in coronal sections of human hypothalamus arranged rostrocaudally from A to C. Each dot represents a single neuron. Numbers at the lower left correspond to sequential locations of sections from anterior to posterior. Each section is 20 m thick; hence, the distance between A and C is approx. 4.6 mm. Scale bar 5 mm. (From Sukhov et al., 1995, Fig. 1, with permission.)

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Fig. 31.2. A–F: Computer-assisted maps of the distribution of prodynorphin (PDYN) cells in coronal sections of human hypothalamus arranged rostrocaudally from A to F. The most anterior section is A, and the most posterior section is F. Numbers at the lower left correspond to sequential locations of sections from anterior to posterior. Each section is 20 m thick. Each dot represents a single neuron. Scale bar 5 mm. (From Sukhov et al., 1995, Fig. 4, with permission.)

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Fig. 31.3. A–F: Computer-assisted maps of the distribution of proenkephalin (PENK) cells in coronal sections of the human hypothalamus. The most anterior section is A, and the most posterior section is F. Each dot represents a single neuron. Numbers at the lower left correspond to sequential locations of sections from anterior to posterior. Each section is 20 m thick. Scale bar 5 mm. (From Sukhov et al., 1995, Fig. 7, with permission.)

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onwards. Prepro-orphanin mRNA is present in this fetal stage in the PVN and dorsal hypothalamic area. By 21–22 weeks it is present in the zona incerta, mamillary bodies and subthalamic nucleus. At this stage, expression of ORL1 messenger RNA (mRNA) is found in the dorsomedial and ventromedial hypothalamus, and in the PVN (Neal et al., 2001). The human opioid receptor in present in the postmortem hypothalamus and a number of other brain areas (Becker et al., 2003).

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numerous homeostatic functions and euphoria (Sukhov et al., 1995). Endogenous opioid peptides inhibit the hypothalamopituitary–adrenal (HPA) axis. This system is hyperactive in depression (see Chapter 26.4). Using an intravenous bolus injection of naloxone, a reduced endogenous opioid tone is found that may explain why some depressed patients ‘self-medicate’ with opiates (Burnett et al., 1999). The hypothalamic opiate systems are presumed to play a central role in addictive behavior (Sukhov et al., 1995; Hurd, 1996). Studies on twins, adopted children and crossfostering also indicate that, apart from environmental factors, there are also hereditary determinants for alcohol dependency. The observation that individuals from families with a high occurrence of alcohol dependency are more sensitive to naloxone seems to imply that families with a history of alcohol dependency have diminished endogenous hypothalamic opioid activity. In addition, there are differences in the HPA axis dynamics as a function of family history of alcoholism (Wand et al., 1998). At first glance, the older observations of the influence of stereotactic hypothalamotomy on alcohol and drug addiction (Dieckmann and Schneider, 1978) seem to be of interest, in connection with the possible involvement of hypothalamic systems in addiction. In a 2- to 3-year follow-up of 13 patients addicted to alcohol and drugs, the VMN was lesioned. The patients regained their selfcontrol and tended toward social stabilization. However, this was an uncontrolled study. In the case of bilateral hypothalamotomy (in 6 of 15 patients), the number of side effects was considerable, including one patient who died in a ‘vegetative crisis’. All patients experienced a reduction of their sexual drive. The practical utility of bilateral hypothalatomy is euphemistically judged to be “limited” (Dieckmann and Schneider, 1977). In a totally insufficiently documented study, Nádvornik et al. (1977) have reported that bilateral anterior hypothalectomy is quite effective in the treatment of “hedonistic manifestations” such as “toxicomania” and alcoholism. Little attention was paid to the considerable risk of this operation (Sramka and Nádvornik, 1975), and even less to its questionable ethical basis. Analgesia by electrostimulation, using deep brain electrodes, is presumed to act via the opioid system, since it is associated with elevation of enkephalin and -endorphin in the CSF of the third ventricle and because the analgesic effect could be blocked by naloxone (see Chapter 31.2). Transcutaneous cranial electric stimulation has been used for the attenuation of drug and alcohol

The POMC neurons (Fig. 31.1), located in the mediobasal hypothalamus, have an inhibitory influence on the regulation of gonadotropin secretion (Sukhov et al., 1995). There is a cyclic -endorphin release into the portal capillaries, and naloxan stimulates LHRH release. It has therefore been postulated that -endorphin is an important determinant of the menstrual cycle (Ferin et al., 1984; Gindoff and Ferin, 1987). The observation that in postmenopausal women POMC mRNA decreases in the infundibular nucleus (Abel and Rance, 1999) supports such a tonic inhibitory function of -endorphin on LHRH release. The effect of opiates on LHRH release from the adult human hypothalamus has been confirmed experimentally, using in vitro perfusion of postmortem mediobasal hypothalamic tissue. Addition of morphine to the medium reduced the frequency of LHRH pulses, whereas subsequent addition of the opioid receptor antagonist naloxone restored the frequency. Furthermore, fetal hypothalamic tissue responded to administration of naloxone with increased release of LHRH and this effect was inhibited by simultaneous administration of -endorphin (Rasmussen, 1992). Leu-enkephalin neurons are also involved in LHRH regulation, most probably by directly synaptically contacting the latter neurons (Dudás and Merchenthaler, 2003). In addition, POMC-derived peptides containing nerve fibers are found in the neural lobe of the human pituitary. These peptides comprise ACTH, -MSH, -endorphin and N-acetyl--endorphin, and may be involved in the regulation of oxytocin and vasopressin release (Manning et al., 1993; see Chapter 8d). A large number of neurons in the SON and PVN coexpress dynorphin; these neurosecretory neurons are probably the source of the dynorphin-containing nerve fibers in the neurohypophysis (Abe et al., 1988). The strikingly densely packed PDYN neurons of the premamillary nucleus may be involved in hunger, thirst, dysphoria and reproduction. PENK neurons are distributed throughout the hypothalamus and may participate in 377

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abstinence syndrome, the suppression of stress, the attenuation of postoperative pain, the potentiation of morphine analgesia for patients with chronic pain, the regulation of biorhythms disturbed by jet lag, and obstetric analgesia. Since transcutaneous cranial electric stimulation increases the level of endorphins in the CSF and plasma, while naloxone antagonizes its effects, it also seems to act via the opioid system (Limoge et al., 1999). Neuropeptide FF (NPFF) and neuropeptide AF (NPAF) are two amidated peptides, highly concentrated in the posterior pituitary and hypothalamus, but also present in other brain areas. They are derived from one precursor. These peptides may be involved in pain modulation, memory, autonomic and neuroendocrine regulation, i.e. in water balance and prolactin release. In addition, NPFF probably circulates as a hormone. The NPFF receptors are coupled to a G protein. Intracerebroventricular injection of NPFF induces a vigorous abstinence syndrome in morphine-tolerant rats (Boersma et al., 1993; Panula et al., 1996, 1999; Laemmle et al., 2003). A new hypothalamic peptide that may be involved in drug abuse is cocaine- and amphetamine-regulated transcript (CART; Kuhar and Dall Vechia, 1999). For distribution and its possible role in feeding behavior, see Chapter 23c). Marijuana (Cannabis sativa) has long been recognized as a centrally acting cannabinoid with complex cognitive, behavioral and endocrine effects. The cannabinoid receptor is found in the hippocampal complex, in the cortex of the frontal lobe, mediodorsal nucleus of the thalamus, globus pallidus and substantia nigra. In the hypothalamus the receptor has been observed in the mamillary body (Glass et al., 1997). The enzyme that degrades the ‘endocannabinoids’ is an integral membrane protein, fatty acid amidohydrolase. Its distribution resembles that of the central cannabinoid receptors. In the hypothalamus it is present in the mamillary bodies, dorsomedial nucleus and posterior hypothalamic area (Romero et al., 2002). Exposure of animals to 9-tetrahydrocannabinol (9-THC), which has effects that are similar to those of the endogenous ligand anandamide, inhibits gonadotropin, prolactin, growth hormone and thyroidstimulating hormone release, and stimulates the release of ACTH. Therefore, hypothalamic mechanisms of action are presumed (Murphy et al., 1998b). Marijuana and THC affect multiple endocrine systems. A suppressive effect is seen on the reproductive hormones, prolactin, growth hormone and the thyroid axis, while the HPA axis is activated. These effects are mediated through CB1 receptor

activation in the hypothalamus. Many of these responses are, however, lost with chronic administration (Brown and Dobs, 2002). Many epidemiological studies have shown that prenatal exposure to tobacco increases the risk of cognitive deficits, attention deficit disorder, conduct disorder and criminal behavior in adulthood (see Chapter 26.9). In addition, it has been shown that maternal smoking during pregnancy or childhood increases the risk of the children becoming smokers, possibly by a direct effect of nicotine on the developing brain of the child (Hellström-Lindahl and Nordberg, 2002). Polymorphism in the MAO genes influences smoking habits and nicotine dependency (Ito et al., 2002). The effects of ethanol abuse on the hypothalamus are described in Chapter 29.5. A functional NPY polymorphism (leu7Pro) is a risk factor for alcohol dependency (Lappalainen et al., 2002). MDMA (3,4-methylenedioxymethamphetamine, or ecstasy) causes a release of vasopressin for at least 4 h and may thus cause hyponatremia – characteristic of the syndrome of inappropriate vasopressin secretion (Henry et al., 1998; Fallon et al., 2002; Chapter 22.6). Hyperthermia, an acute and potentially life-threatening complication associated with the use of ecstasy, results from an interaction between the hypothalamopituitary– thyroid axis and the sympathetic nervous system (Sprague et al., 2003). 31.2. Pain and the hypothalamus Although pain is considered to be a necessary ingredient for survival, life without any pain occurs in a few rare, hereditary disorders, i.e. Riley–Day syndrome or familial dysautonomia (Chapter 30) and in a congenital indifference to pain (Mancini, 1990). Insensitivity to pain has been reported in idiopathic hypothalamic syndrome of childhood (Chapter 32.1), and as a congenital absence of pain in a mentally retarded child. The total CSF opioid activity was raised in this patient, but naloxone failed to reverse the analgesia (Manfredi et al., 1981). Congenital insensitivity to pain with anhydrosis is an autosomalrecessive disorder characterized by recurrent episodes of unexplained fever, absence of sweating and of reaction to noxious stimuli, and by self-mutilating behavior and mental retardation. Most probably this syndrome is based upon defects in the high-affinity neurotrophin receptor tyrosine kinase A (TrkA) (Indo et al., 1996). Since

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patients affected by POMC mutations reveal no unusual pain sensation, -endorphin seems to play only a minor role in pain modulation (Krude and Grüters, 2000). Whether the elevated pain tolerance in patients with anorexia nervosa, bulimia nervosa and binge-eating (Raymond et al., 1999) has a hypothalamic basis should be investigated. A core feature of fibromyalgia is pain, a syndrome that has many neuroendocrine characteristics (Chapter 26.8; Dessein et al., 2000).

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the processing of nociceptive signals are the dorsal noradrenergic bundle, originating in the locus coeruleus, the serotonergic fibers that arise in the dorsal and median raphe nuclei, the dopaminergic pathways of the ventral tegmentum, and the cholinergic neurons of the NBM. The dorsal noradrenergic bundle innervates the hypothalamus; and neurons in the medullary reticular formation project to the PVN of the hypothalamus via the ventral noradrenergic bundle. In the rat it has been shown that nociceptive stimuli do not reach the hypothalamus by indirect multisynaptic pathways only. Thousands of neurons throughout the length of the spinal cord send axons directly into the hypothalamus, and many of these axons carry nociceptive information. Axon collaterals of these fibers terminate in the lateral hypothalamus, VMN, periventricular and posterior nuclei. Evidence for similar connections is present in primates (Giesler et al., 1994). The long-term antinociceptive effect of massage-like stroking may be attributed, at least partly, to the oxytocinergic system, as shown in the rat; increased oxytocin plasma levels and release of oxytocin in the periaqueductal gray matter takes place. Here, the oxytocinergic fibers interact with the opiate system, where the - and -receptors especially are involved (Lund et al., 2002). The hypothalamus-mediated stress response plays a role in pain chronicity. The PVN coordinates the neuroendocrine, autonomic, emotional and behavioral responses to pain. The PVN activates the HPA axis and is responsible for the stress-induced analgesia (Chapman, 1996). Corticotropin-releasing hormone (CRH) may preferentially play a role in prolonged clinical pain (Lariviere and Melzack, 2000). Fibromyalgia is characterized by widespread muscle pain and a hypoactive CRH system (Chapter 26.8b). CRH levels in CSF are increased in chronic pain (Nemeroff, 1996), but the origin of CSF-CRH may be extrahypothalamic (Chapter 26.4). CRH is the central compound in the stress response and is also a mediator in the stress-induced analgesia. It has been shown to produce analgesia by all routes of administration, including local, systemic and central routes. The majority of the studies indicate that the pituitary or endogenous opioids are not necessary for the analgesia that occurs following intracranial or intravenous administration of CRH. In the human fetus, a potentially painful procedure such as prolonged intrauterine needling at 29–34 weeks of gestation is associated with an increase in plasma cortisol and -endorphin. The hormonal stress response to invasive procedures suggests (but does not prove) that the human fetus may feel pain in utero and may

(a) The anatomy of pain; hypothalamic structures and systems involved Pain in the brain: are hormones to blame? G. and R. Blackburn-Munro, 2003.

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage (Chapman, 1996). The distribution of the opiate systems involved in pain regulation is discussed in Chapter 31.1. The many brain structures and extensive pathways involved in pain are discussed elsewhere (Ray, 1981; May et al., 2000). Acute experimental, traumatic pain induction by intracutaneous injection of a minute amount of ethanol prominently activates the hypothalamus, periaqueductal gray, amygdala and a number of other brain areas as shown by PET studies. The circuits involving these structures are responsible for integrating the endocrine, autonomic, aggressive and defensive reactions to pain. The metabolic activation of the hypothalamus by traumatic pain implies that this structure may serve as a bridge between higher cognitive states and physiological/ emotional responsivity (Hsieh et al., 1996). Also, in a patient with chronic facial pain, the hypothalamic blood flow was increased, as was the flow in other pain-related brain structures (Kupers et al., 2000). Electrical stimulation, not only of the raphe nucleus and periaqueductal gray, but also of the hypothalamus, produces analgesia in experimental animals (Carstens, 1986), and medial hypothalamic stimulation relieves pain also in humans (see below). Nociceptive transmission engages both spinoreticular and spinothalamic pathways. A brainstem structure that is important in nociception is the parabrachial nucleus. This structure is seriously affected in Alzheimer’s disease (AD) (Parvizi et al., 1998), a disorder in which the experience of affective components of pain in particular is reduced (Scherder et al., 2003). Systems involved in 379

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benefit from analgesia or anesthesia (Giannakoulopoulos et al., 1994). Chronic pain disorder is characterized by the absence of any relevant organic pathology, and psychologial factors have consequently been suggested to have an important role in the etiology of their disorder. There are various peptides that have antinociceptive effects in experimental animals, such as angiotensin II, vasopressin, CRH, calcitonin, neurotensin, somatostatin, and some of the opiomelanocortin family. Nociceptive peptides include substance P and cholecystokinin (Carr and Lipkowski, 1990; Wahlbeck et al., 1996). Substance P effects on blood pressure and heart rate seem to be mediated by oxytocin. This is part of an integrated response to nociceptive stimuli and stress (Maier et al., 1998). In fibromyalgia, CSF levels of substance P are elevated, while met-enkephalin levels are low (Pillemer et al., 1997; see Chapter 26.8b). It has been hypothesized that incomplete degradation of nocipeptide peptides might produce the pain experienced in chronic pain disorder. However, so far only higher and not lower plasma vasopressin and serum osmolality, and an increased CRH level in CSF have been observed, possibly reflecting the chronic stress condition of these patients (Nemeroff, 1996; Wahlbeck et al., 1996). Others did not find alterations in plasma or CSF vasopressin levels (Olsson et al., 1987). Patients in a surgical emergency department complaining of pain have increased plasma vasopressin levels (Kendler et al., 1978). In addition, increased vasopressin levels are observed in women with premenstrual pain or primary dysmenorrhea (Åkerlund et al., 1979; Strömberg et al., 1984). A therapeutic effect of an orally active vasopressin V1a receptor antagonist in the prevention of dysmenorrhea has been published (Brouard et al., 2000; Paranjape and Thibonnier, 2001). However, another study has failed to show increased blood levels of vasopressin, finds no effect of a vasopressin antagonist on menstrual pain, and is thus unable to confirm the contention that vasopressin is involved in the etiology of dysmenorrhea (Valentin et al., 2000). Sex steroids are thought to be involved in pain sensitivity. In general, women are more sensitive to pain than men. Pain sensitivity peaks when estrogens are high (Blackburn-Munro and Blackburn-Munro, 2003). Melatonin has experimentally been shown to have profound analgesic effects. Hypocretins (Chapter 28.4) may also modulate nociception (Blackburn-Munro and Blackburn-Munro, 2003).

Nerve growth factor causes hyperalgesia and pain when administered either locally or systematically. In this connection it may be highly relevant that high levels of nerve growth factor are found in the CSF of patients with chronic daily headache and a previous history of migraine (Sarchielli et al., 2001). A pilot study on the treatment of Alzheimer patients with nerve growth factor, intracerebroventricularly, had to be stopped because of weight loss and pain as side effects (Chapter 2.5). Alzheimer patients experience less-intense pain and also suffer less from pain than nondemented elderly people (Scherder and Bouma, 1997, 2001; Scherder et al., 1999; Scherder, 2000; Scherder and Bouma, 2000a, b). The primary sensory areas are relatively preserved in AD (Braak and Braak, 1991). Consequently, AD patients may still be able to perceive the nature of the pain and differentiate between dull and sharp pricking pain (the sensory-discriminative aspects of pain; Treede et al., 2000). The pain threshold does not appear to be affected by AD, a suggestion which is supported by a study in which the pain threshold of AD patients was determined by the application of peripheral electrical nociceptive stimuli (Benedetti et al., 1999). Importantly, in contrast to the pain threshold, Benedetti and co-workers (1999) observed an increase in pain tolerance in the AD patients. Pain tolerance concerns the processing of the affectivemotivational aspects of pain (Treede et al., 2000). One can only speculate about the decrease in the processing of the affective aspects of pain in AD. One explanation might be the neuropathology that is present in the hypothalamus, the medial temporal lobe, the anterior cingulate gyrus and the prefrontal cortex (Chapter 29.1; Coleman and Flood, 1987; Braak and Braak, 1991). Interestingly, these areas are involved not only in cognition but also in the processing of the emotional components of pain (Scherder et al., 2003; Treede et al., 2000). An affected functioning of these areas might thus explain the increase in pain tolerance. Alternatively or additionally, a decrease in experience of the affective components of pain in AD patients may also be explained by an increase in the amount of opioid peptides in the CSF (Muhlbauer et al., 1986) and -endorphin in plasma (Franceschi et al., 1988; Rolandi et al., 1992) of AD patients. The influence of AD on -endorphin levels is, however, equivocal, since Kaiya et al. (1983) and Heilig et al. (1995) have observed a decreased CSF level of -endorphin in AD patients.

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(b) Placebo analgesia and other placebo effects

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that hypothalamic opiate and CCK systems are involved in these analgesic effects still has to be studied. It has been proposed that placebo effects can be elicited by inducing a ‘relaxation response’. This is the opposite of a ‘stress response’ (see Chapter 8.5), resulting in decreased metabolism, heart rate, blood pressure and rate of breathing. Many different methods can be used to elicit this acquired relaxation response, including progressive muscle relaxation, meditation, autogenic training, yoga and repeated physical exercise (Stefano et al., 2001). Yoga exercise was shown to be accompanied by lower serum cortisol levels (Kamei et al., 2000b); meditation is followed by increased plasma melatonin levels during the night (Tooley et al., 2000). In addition, many forms of prayer can be used to elicit the relaxation response; the method may be secular or religious, performed at rest or during exercise. The opiates and nitric oxide are hypothesized to be involved in this response. Relaxation response-based approaches have been demonstrated to be effective in chronic pain, hypertension, cardiac arrhythmias, insomnia, anxiety, depression, premenstrual syndrome and infertility (Stefano et al., 2001). It has been estimated that about 75% of the effectiveness of antidepressants derives from the placebo effect (De la Fuente-Fernández et al., 2002). In a PET study in depressed patients, the clinical improvement was comparable in both the placebo and the fluorexetine responder groups. The regions of change in the placebo group strongly overlapped with those seen in responders who were administered fluoxetine, including the decrease in metabolic activity in the hypothalamus and the increase in activity in the prefrontal cortex. This is of considerable interest in relation to the hyperactivity of a number of hypothalamic systems in depression and the hypometabolism found in the prefrontal cortex in this disorder (see Chapter 26.4). However, the fluoxetine response is associated with additional changes, which are proposed to explain the longer period of effectiveness of this compound compared with placebo (Mayberg et al., 2002). In a study using quantitative EEG, ‘effective’ placebo treatment has induced changes in brain function that are distinct from those associated with antidepressant medication (Leuchter et al., 2002). There thus appear to be similarities as well as differences between placebo and antidepressant treatment, as far as the mechanism of action is concerned. Placebo effects can thus be very specific, and the specificity seems to depend on the information available

. . . we should learn to maximize the placebo effect inherent in any active drug that we give to the patient . . . De La Fuente-Fernández et al., 2002.

The word ‘placebo’ (Latin) means ‘I shall please’ and is the first word of the church vespers sung for those who have died. In 12th century Europe the word ‘placebo’ was shorthand for those vespers. By 1300 the term had been adapted in the secular vernacular to mean ‘false consolidation’, since insincere mourners were paid to sing these placebos. In 1811 ‘placebo’ was defined as an epithet given to any medicine meant to please rather than benefit the patient. The term has kept this negative connotation in medicine as something ‘inactive’. Nevertheless, a placebo response rate of on average 35% is found in the treatment of conditions such as pain, hypertension, migraine, seasickness and mood disturbances. Even higher rates in effectiveness are found in angina pectoris, asthma, herpes simplex and duodenal ulcers. The placebo effect seems to represent an innate protective response, tapping into positive expectations and beliefs of the patient, and into the dopaminergic reward system. The placebo effect has been defined as ‘any effect attributable to a pill, potion, or procedure, but not to its pharmacodynamic or specific properties.’ Whereas the ingredients of a placebo preparation may be totally nonspecific, the effects depend on the information given to the patient and the expectations of the patient and can be very specific. The power of placebos can thus be conceptualized as the mind’s healing power (Stefano et al., 2001; De La Fuente-Fernández et al., 2002). Placebo analgesia represents a situation where the administration of a substance known to be nonanalgesic produces an analgesic response. When the subject is told that the ineffective substance is a hyperalgesic drug, an increase in pain may occur. Such a negative effect is called a nacebo effect. The effect of a placebo on pain is mediated by endogenous opioids, since naloxone can reverse placebo analgesia. The blockade of cholecystokinin (CCK) receptors potentiate the placebo analgesic response, suggesting an inhibitory role of CKK in placebo analgesia. The sites of action of the endogenous opiates and of interaction of the opiates and CCK are not exactly clear, but naloxone antagonizes analgesia induced by stimulation of the periaqueductal gray as it also antagonizes analgesia induced by TENS or acupuncture and by a placebo (Benedetti and Amanzio, 1997). The possibility

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to the recipient. PET studies have indicated that the placebo effect in Parkinson’s disease is related to the release of dopamine in the striatum, and to downregulation of the dopamine transporter. Since the nucleus accumbens is susceptible to placebo-induced dopamine release in Parkinson’s disease, placebos may activate reward mechanisms. Indeed, placebos can also be addictive and can cause withdrawal symptoms when treatment is discontinued (De la Fuente-Fernández and Stoessl, 2002). (c) Analgesia by deep brain electrostimulation, stereotactic lesions, acupuncture and TENS Brief periods of stimulation aimed at the fibers of the pro-opiomelanocortin system produces long-lasting analgesia in patients with chronic pain, e.g. from metastases, low-back pain, paraplegia, spinal arachnoiditis, spinal cord injury, thalamic pain, scoliosis, postherpetic neuralgia, phantom limb pain, arthritis and atypical face pain (Richardson and Akil. 1977; Akil et al., 1979; Hosobuchi et al., 1979; Richardson, 1982; Pilcher et al., 1988). In approximately 60% of patients who had deep brain electrodes implanted for chronic self-stimulation, this procedure caused significant relief from pain. Analgesic brain stimulation has an ‘opioid’ nature, because it is associated with elevation of enkephalin and -endorphin in the third-ventricular fluid, while the analgesic stimulation can be blocked by naloxone. However, other neurotransmitter systems might also be involved in this effect. The effects and side effects depend on the stimulation site: • Stimulation of the basal hypothalamus produces pain relief with side effects that occur at the level of effective stimulation, such as flushing, smothering, dizziness and diplopia. In addition, during stimulation, marked elevation of blood pressure and pulse rate are obtained. Endocrine side effects have not been studied. Stimulation of the inferior septal area produces pain relief with side effects obtained at hypalgesic stimulation levels, i.e. flushing, nystagmus and tingling paresthesias. • Stimulation of the superior septal area produces pain relief, while side effects, i.e. flushing, tingling, nausea and warmth or heat sensation, occur only at levels well above those producing pain reduction. • Periventricular gray stimulation in the third ventricle produces significant pain relief with vertigo, tingling,

and elevation of pulse and blood pressure at levels of stimulation above those producing pain reduction. • Superior periaqueductal gray stimulation induces pain relief, while side effects are experienced just above the level of analgesia. Side effects include oscillopsia, warmth, flushing, tingling and strabismus. • Inferior periaqueductal gray stimulation causes pain relief, with more side effects below pain-reduction levels. The periaquaductal -endorphin-containing fibers are thought to originate from the basal tuberal hypothalamus. Stimulation proves most efficacious with minimal side effects in the superior septal area and periventricular gray, at the level of the posterior third ventricle adjacent to the posterior commissure (Akil et al., 1979; Richardson, 1982; Pilcher et al., 1988). Others have reported that electrical stimulation of the posteromedial hypothalamus produces relief of pain, especially in the case of cancer. It also elevates -endorphins in the third-ventricular CSF (Sano, 1987). A thus-far underreported complication of deep brain stimulation is the development of migraine-like headaches in approximately 20–50% of the patients (Kumar et al., 1997). Stereotactic lesions of the posterior hypothalamus relieve intractable pain due to malignancies and are claimed to be either not so effective for central pain (Sano, 1987) or, on the contrary, to give a satisfactory relief of pain (Fairman, 1973). A marked increase in appetite is noted as a side effect of such operations (Fairman, 1973). Such an operation was presumed to lesion not only one of the main end-stations of the C-fibers and the slow delta-fibers, but also the portions that exert influences on the specific sensory system and thus decrease the intensity of volleys of impulses and change the pattern of impulses which can be interpreted as pain, especially pain in the case of cancer, and elevate -endorphins in the third-ventricular cerebrospinal fluid (Sano, 1987). On the other hand, the same author had claimed earlier that stimulation of the posteromedial hypothalamus produces an unpleasant feeling of fear and horror. The hypothalamus is, therefore, supposed to be important in the emotional coloring of pain sensation (Sano et al., 1975). Electroacupuncture and TENS both release dynorphin and induce analgesia at 100 Hz, and even more efficiently by alternating the stimulation between 2 Hz and 100 Hz. Different kinds of opioid peptides and receptors are implicated in these effects under different circumstances (Wu et al., 1999; Han, 2003). A 2-Hz stimulation of a

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classical analgesic acupuncture point (LI4, Hegu) on the back of the hand activated the hypothalamus as measured by PET, suggesting that this brain structure may mediate the analgesic efficacy of acupuncture (Hsieh et al., 2001). It is interesting to note that in animal experiments hypothalamic activity is enhanced by electroacupuncture (Du and Chao, 1976). The positive effects of TENS – a technique frequently used to treat chronic pain – and tactile stimulation are hypothesized to result from activation of brainstem areas such as the locus coeruleus and nucleus raphe dorsalis, with subsequent activation of the hypothalamus. In TENS, electrical pulses applied to the skin are transmitted to spinal and supraspinal areas through afferent nerve fibers of the peripheral nervous system (A- and A- fibers) (Scherder et al., 1995a, b, 1996). Histamine, produced in the tuberomamillary nucleus (Chapter 13) plays an important role in antinociception, both by naloxone-sensitive and naloxone-insensitive mechanisms. Histamine is a mediator of the stress-induced release of hormones such as ACTH and -endorphin, and the release of noradrenaline and serotonin (Brown et al., 2001).

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systemic autonomic symptoms such as alteration in blood pressure and heart rate are found. MR images show a marked dilation of the ophthalmic artery, ipsilateral to the pain (Dodick et al., 2000), while a localized narrowing of the internal carotid artery is found (Goadsby, 2002). Cluster headache has been differentiated into an upper and a lower syndrome. It is proposed that changes in hypothalamic activity may lead, posteroinferiorly, to activation of the caudal part of the spinal trigeminal nucleus by way of the hypothalamus, midbrain and trigeminal nerve fibers, and consequently to activation of the trigeminovascular system, with a different location for the two syndromes. There would be a larger and more extensive involvement of the subnucleus caudals in the lower syndrome, compared with the upper syndrome, where its ventrocaudal portions would be activated (Cademartiri et al., 2002). Cluster headache has been identified as a disorder that occurs mainly in men (maleto-female ratio of 6–7 : 1), but the clinical characteristics are very similar in both sexes (Rozen et al., 2001). The male-to-female ratio of both episodic and chronic cluster headache depends strongly on age. The sex difference is the largest between 30 and 49 years of age (7.2:1 and 11.0:1) and the lowest after 50 (2.3:1 and 0.6:1, respectively) (Ekbom et al., 2002). In addition, it should be noted that between 1960 and 1990 the male-to-female ratio decreased from 6.2:1 to 2.1:1. These changes in sex ratio are presumed to be related to changes in lifestyle and smoking (Manzoni, 1998; Ekbom et al., 2002). In 4% of patients there is a family history (Dodick et al., 2000). An autosomal dominant gene has a role in some families with cluster headache (Ekbom and Hardebo, 2002). It has been postulated that the cyclic phenomena would originate from the hypothalamic clock, i.e. the suprachiasmatic nucleus (SCN), with subsequent trigeminovascular reaction (Dodick et al., 2000; Goadsby, 2002), but there is only indirect evidence available for this presumption. The most common episodic variety of cluster headache is that 50% of the attacks occur during the night and with a circannual pattern that is similar to seasonal depression, because it increases in July and January and decreases in April and October, suggesting the involvement of the SCN in both disorders (see Chapters 4.1 and 26.4). There are, moreover, various other analogies between cluster headache, seasonal affective disorder, and bipolar mood disorders in addition to common seasonal patterns, i.e. the nature of predisposing or precipitating factors, the peculiar relationship with

31.3. Headache Various observations suggest an interplay of chronobiological, neuroendocrine and autonomic nervous systems of the hypothalamus in these disorders. Headache can be a symptom of many processes in the hypothalamic-pituitary region, including craniopharyngiomas and sometimes even Rathke’s cleft cysts (Chapter 19; Ward et al., 2001). “Suicide headache” (Dodick et al., 2000)

(a) Cluster headache Cluster headache is characterized by stereotypic, shortlasting (several minutes to several hours), severe, unilateral ‘trigeminal’ pain attacks with a highly distinctive cyclic recurrence pattern, usually located in the orbitotemporal region. An attack may be triggered by an alcoholic beverage, by increased body heat from the environment, a hot bath, central heating or from exercise (including sexual intercourse) (Peres et al., 2000). The pain is accompanied by homolateral autonomic signs, which include local symptoms such as conjunctivatial injection, lacrimation, rhinorrhea, erythema of the painful area, and occasional miosis and ptosis. In addition, 383

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sleep, such as the temporal connection between attacks and REM sleep, the neuroendocrine findings and clinical response to current treatments such as lithium and flunarizine (Morales-Asin et al., 1997; Costa et al., 1998). Some patients improve after melatonin or corticosteroid administration (Pepping, 1999; Peres et al., 2000; Peres and Rozen, 2001; Ekbom and Hardebo, 2002; Pringsheim et al., 2002). Support for the idea that the hypothalamus is the central site of origin of the pathogenesis of this disorder has emerged from four other independent observations. In the first place a significant structural difference in gray matter density has been observed by MRI. The difference consisted of an increase in gray matter volume, bilateral in the inferior posterior hypothalamus. In the second place, PET scanning has shown ipsilateral activation during cluster headache in the same hypothalamic area (May et al., 1998, 1999; Goadsby et al., 1999). The third relevant observation is that, in patients with intractable cluster headache, who underwent chronic high-frequency electric stimulation by means of an electrode implanted in the posterior inferior ipsilateral hypothalamic gray matter, the attacks were found to disappear after 48 h and to stay away during the follow-up of 2–33 months (Leone et al., 2001, 2003; Franzini et al., 2003). Lastly, during nitroglycerin-induced cluster headache attacks, the regional cerebral blood flow as measured by PET was activated in the ipsilateral inferior hypothalamic gray matter in the region of the SCN and in a number of brain areas that are involved in pain. Activation in the hypothalamus was seen solely while the patients were still in a state of pain, and not in patients who were recovering from the pain. The activation of the hypothalamus is, therefore, proposed to be the primum movens in the pathophysiology of cluster headache (May et al., 1998, 2000). In addition to the episodic occurrence, there are the neuroendocrine symptoms. The possible involvement of the circadian timing system (see Chapter 4) in this disorder is supported by the observation that the acrophase of melatonin is moved forward and the night-time peak is blunted and significantly reduced during cluster headache periods (Chazot et al., 1984; Leone and Bussone, 1993; Dodick et al., 2000). Also the growth hormone evening peak is advanced in cluster headache (Chazot et al., 1984; Leone and Bussoni, 1993), while there is an acrophase delay in testosterone release (Facchinetti et al., 1986). Some investigations have reported modifications in the diurnal plasma levels of ACTH and cortisol, consisting of an acrophase delay or advance, or an abnormal afternoon

peak of cortisol. Increased plasma levels of cortisol and ACTH are especially found in the morning and in the evening. Hypothalamic dysfunction in cluster headache also appears from changes in hormone levels (Waldenlind and Gustafson, 1987; Leone and Bussone, 1993). In addition, 24-h cortisol production is increased in the cluster period. The CRH test shows a downregulation of adrenal function in cluster headache patients, as is also found in patients receiving prolonged CRH administration. The dexamethasone suppression test results are normal in cluster headache patients, showing that the feedback control of CRH production is not altered. Factors other than pain or sleep disturbances probably explain hypercortisolemia in cluster headache, such as an alteration in the circadian rhythm of this hormone (Facchinetti et al., 1986; Leone and Bussone, 1993; Strittmatter et al., 1996b). The diurnal rhythm of prolactin has been reported as normal or altered, as in cluster headache. Blunted night peaks of prolactin are observed in men in clinical remission, suggesting an impaired neuroendocrine regulation of prolactin, also during symptom-free intervals. There are, however, great individual differences. In some patients a loss of release rhythms is found, and attacks of cluster headache are accompanied by prolactin increases, especially when the attacks take place at night. The persistence of hyperprolactinemia during cluster headache remission indicates that these increases occur independent of pain (Ferrari et al., 1983; Waldenlind and Gustafsson, 1987; Leone and Bussone, 1993). Several investigations have reported reduced thyrotropin (TSH) responses to the TRH test during the cluster headache period (Leone and Bussone, 1993). In addition, cluster headache patients demonstrate significantly decreased levels of norepinephrine, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the CSF, which concurs with a central genesis of this disorder (Strittmatter et al., 1996b). The prevalence of cluster headache in men, and the fact that it is extremely rare in the preadolescent period, indicates that sex hormones might also be involved in the pathogenetic mechanism. Testosterone levels have been reported to be normal or low during the cluster headache period (Leone and Bussoni, 1993). Total, free and carrier protein-bound testosterone levels are significantly diminished only in chronic cluster headache patients whose basal and peak FSH levels are significantly increased (Murialdo et al., 1989). In addition, a significant reduction of the 24-h integrated mean testosterone level (mesor) is found in cluster headache patients. It has been

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suggested that the stress of the attack causes elevated cortisol levels and that this, in turn, reduces testosterone levels (Facchinetti et al., 1986). Testosterone administration does not change the course of cluster headache, whereas it does enhance sexual excitement (Nicolodi et al., 1993). A recognized treatment for intractable chronic cluster headache is to section the trigeminal root proximal to the ganglion. Oxygen and verapamil treatment also work (Goadsby, 2002).

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events in the reproductive cycle. With puberty there is a marked increase in the incidence of migraine headaches, with a peak incidence occurring at menarche, and a decrease at menopause. The majority of migrainous women will have some of their attacks linked to the menstrual cycle. Menstrual migraine seems to respond very well to LHRH administration and to “add-back” therapy, i.e. a combination with continuous, transdermal estrogen–progesterone therapy (Murray and Muse, 1997). Clear examples of the periodicity of headache are weekend headaches, migraines that start during nocturnal sleep, and (pre)menstrual migraine. The primary trigger of menstrual migraine thus appears to be the withdrawal of estrogen rather than the maintenance of sustained high or low estrogen levels (Silberstein and Merriam, 1999). In migraine patients, prolactin is excreted excessively in response to stimulation (Dexter and Riley, 1975; Awaki et al., 1989; Lance, 1992). Plasma levels of metenkephalin are higher in migrainous patients, both during the attack and when there is no headache. However, individual patients consistently present with lower metenkephalin levels during the pain-free period than during the acute headache (Mosnaim et al., 1986). Vasopressin plasma levels rise during migraine attacks and are followed by a rise in endothelin-1, which exerts vasoconstrictor and vasodilator actions on cerebral vessels via endothelin A and B receptors. The elevated vasopressin levels may attribute in part to the nausea and emesis that accompany the attack (Hasselblatt et al., 1999). Another observation that connects migraine to the hypothalamus is the increased digoxin synthesis and upregulated isoprenoid pathway observed in these patients. Digoxin is an inhibitor of membrane Na–K adenosine triphosphatase (ATP-ase); it is produced by the hypothalamus and synthesized by the isoprenoid pathway (Kumar and Kurup, 2001a). In patients with chronic daily headaches, with a previous history of migraine, increased nerve growth factor levels are found in the CSF. As nerve growth factor is known for hyperalgesia when administered either locally or systematically in many species (Sarchielli et al., 2001), this observation may be of therapeutic relevance.

(b) Migraine Episodes of migraine may occur regularly, indicating the involvement of some internal clock that probably involves the hypothalamus, because premonitory symptoms such as elation, a craving for sweet food, thirst or drowsiness may precede headache by some 24 h. Hypothalamic symptoms are reported by about 25% of patients (Lance, 1992). It has even been proposed that the SCN is the site of initiation of a migraine attack (Zurak, 1997). Patients with migraine are more likely to have headaches during the bright arctic summer season. This distinguishes migraine from other headaches and suggests a role of the circadian/circannual system (Chapter 4) in the pathogenesis of this disorder (Salvesen et al., 2000). In this connection it is also of interest that melatonin secretion is reduced in patients with menstrual migraine (Dodick et al., 1998) and that melatonin may relieve migraines (Gagnier, 2001). Moreover, the circadian rhythmicity of prolactin is often disturbed in migraine (Ferrari et al., 1983). In chronic migraine, hypothalamic dysfunction appears from: (i) a decreased nocturnal prolactin peak, (ii) increased cortisol concentrations, (iii) a delayed nocturnal melatonin peak, and (iv) lower melatonin concentrations in patients with insomnia. On the basis of these findings, a chronobiological dysregulation and a possible hyperdopaminergic state are presumed to be present in patients with chronic migraine (Peres et al., 2001). Migraine occurs more often in women than in men. However, this sex difference is only present in the reproductive period of life. In children, migraine prevalence is independent of sex. It is presumed that the basis of the sexual dimorphism of migraine should be sought in hypothalamic systems related to LHRH secretion, since LHRH agonists may induce a complete relief of migraine attacks (Facchinetti et al., 2000). The prevalence of migraine headaches in women is influenced strongly by

(c) Hypnic headache syndrome The hypnic headache syndrome (“alarm clock syndrome”) is a rare, benign disorder of the elderly. It is characterized by recurrent, nocturnal bilateral headaches that awaken the patients from their sleep at a consistent time each 385

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night, usually between 1 and 3 a.m., more than 4 nights a week. The pain is moderate to extremely severe and lasts 20–180 min. The mean age of onset is 61 years. These headaches respond to treatment with lithium carbonate and in some cases to caffeine in a tablet or beverage (Newman et al., 1990; Dodick et al., 1998). One case with a good response to indomethacin has been described (Ivañez et al., 1998). The striking circadian rhythmicity and the effectiveness of lithium carbonate suggest the involvement of the SCN. The involvement of the hypothalamus in the pathogenesis of cluster headache

is supported by the reduced 24-h plasma melatonin levels during the cluster period, loss of circadian melatonin secretion in remission and reduced urinary melatonin. In addition, the levels of the melatonin metabolite 6-sulfatoxymelatonin do not differ during day and night in these patients. The observation that altered excretion of 6-sulfatoxymelatonin is also present during remission indicates that these anomalies are independent of the pain, and provide further evidence of the involvement of hypothalamic, rhythm-regulating centers in cluster headache (Leone et al., 1998).

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CHAPTER 32

Miscellaneous hypothalamic syndromes

32.1. Idiopathic hypothalamic syndrome of childhood, a paraneoplastic syndrome

improves the vegetative disorders (Gurewitz et al., 1986; Joseph et al., 1993), while naltrexone has little if any effect (Loeuille et al., 1989). Viral encephalitis cannot be excluded as a cause of idiopathic hypothalamic syndrome, since in some patients the attacks of hypothermia and somnolence follow a respiratory illness (Gurewitz et al., 1986). Moreover, in one case of a 2-year-old child who lacked thirst perception and who had inadequate temperature regulation, hyperphagia and obesity, an autopsy revealed slight dilations of the ventricles, while the floor of the third ventricle consisted only of a very thin membrane. In the hypothalamus small nests of chronic inflammatory cells were scattered throughout the hypothalamic nuclei. The white matter around the hypothalamic nuclei was not affected. The cellular components were predominantly lymphocytes, plasma cells and an occasional leukocyte. Interspersed among the inflammatory cells, predominantly degenerating neurons were seen that showed pycnosis, cellular fragmentation and neuronophagia. Although the paraventricular nucleus (PVN) exhibited the most severe degree of degeneration, the supraoptic (SON) and other hypothalamic nuclei displayed similar lesions. The inflammatory foci were apparently confined to the hypothalamus, and the neurohypophysis showed no definite alterations (Travis et al., 1967). This observation suggests that inflammation or an autoimmune process may lie at the base of hypothalamic dysfunction in these children and shows the need for the application of modern neuropathological and neurobiological techniques on postmortem tissue of such cases. The association of this syndrome with disorders of neural crest migration, such as Hirschsprung’s disease and neural crest tumors are well documented. Observations by North et al. (1994) and Ouvrier et al. (1995) have

In the literature a number of children have been described who have multiple neuroendocrine and behavioral problems due to idiopathic hypothalamic dysfunction. This syndrome, of obscure origin, is also known as congenital central hypoventilation syndrome (Katz et al., 2000). It is not homogeneous, and the symptoms may include: apneic spells; behavioral problems including hypersomnia; developmental delay; hypodipsia with bouts of hypernatremia; episodes of inappropriate vasopressin excretion; adipsia; life-threatening episodes of spontaneous hypothermia; lack of appetite control, i.e. polyphagia and obesity, anorexia and emaciation; petit mal seizures; precocious puberty that later fails to progress, probably because of decreased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels; hypercapnia with absence of respiratory response to CO2 (oxygen administration to these patients may, therefore, have catastrophic consequences); insensitivity or hyposensitivity to pain; hyperprolactinemia and galactorrhea; growth hormone deficiency; hypothyroidism; hypogonadotropism; hypocortisolism; and sleep disturbances. In addition, behavioral disturbances have been found, including personality changes, social and emotional disinhibition, irascibility and impulsivity, aggressive outbursts, impairment of concentration, outbursts of euphoria and laughing, repetitive mannerisms, hyperactivity, psychomotor retardation, flat affect, social withdrawal and lethargy (Nunn et al., 1997; Sirvent et al., 2003). CT and MRI scans and autopsy generally do not reveal any abnormality but in one case have shown a structural lesion of the lateral part of the lentiform nucleus (Joseph et al., 1993; Proulx et al., 1993). Clomipramine 387

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raised the possibility that a lymphocytic/histiocytic infiltration in the hypothalamus of children with idiopathic hypothalamic dysfunction is related to a ganglioneuroma and might thus be considered as a paraneoplastic syndrome. Seemingly idiopathic signs and symptoms involving the nervous system sometimes precede the diagnosis of a tumor outside the nervous system such as a ganglioneuroma of the posterior abdominal wall, or a neuroblastoma (Sirvent et al., 2003). Paraneoplastic syndromes have been characterized in adults, but are also thought to occur in children (North et al., 1994; Ouvrier et al., 1995; Sirvent et al., 2003). This suggestion is bolstered by the paper of Nunn et al. (1997) who describes another patient with a ganglioneuroblastoma, together with the histological picture of mild neuronal loss, marked and widespread lymphocytic infiltration with perivascular cuffing and brainstem, and thalamic and hypothalamic aggregations. The demonstration of anti-Hu antineuronal antibodies in the serum and cerebrospinal fluid (CSF) has strongly supported the autoimmune hypothesis. Hu-antigens are a class of neuron-specific, RNA-binding proteins, expressed in most neuroblastomas (Sirvent et al., 2003). On the basis of this autoimmune concept, some have reported therapeutic success with intravenous immunoglobulin, with corticosteroids, azothioprine and cyclosporine. Children presenting with this syndrome should be extensively examined for neural crest tumors. This includes MRI of the central nervous system as well as the sympathetic chain. In addition there should be a search for anti-neuronal antibodies (Nunn et al., 1997). Support for the presence of hypothalamic symptoms in paraneoplastic syndrome also comes from the study of Gultekin et al. (2000). They have found that all patients with anti-Ta (or anti-Ma-2) antibodies are young men with testicular tumors, frequent hypothalamic involvement and poor neurological outcome. In 30% of patients, treatment of the tumor results in improvement. The hypothalamic symptoms observed in that study were: diabetes insipidus, loss of libido, hypothyroidism, hypersomnia, hyperthermia and panhypopituitarism. Removal of the tumor with intensive immunotherapy may offer therapeutic hope. 32.2. Hypothalamic atrophy, Leigh’s disease and Cornelia de Lange’s syndrome (Fig. 32A) A 19-year-old female patient with progressive hypopituitarism and diabetes insipidus has been reported. She

had gross atrophy of the hypothalamus, demonstrated by pneumencephalography. Basal pituitary (TSH), prolactin, LH and FSH levels were consistently detectable and responded briskly to thyrotropin-releasing hormone (TRH) and LH-releasing hormone (LHRH) administration (Hendricks et al., 1981). Hypothalamic atrophy in the absence of systematic disease has also been described in adults. A patient who was followed for 13 years developed the first symptoms of progressive hypothalamic atrophy at the age of 39 years. Hypothalamic dysfunction manifested itself by a loss of libido, by impotence, obesity, polydipsia, somnolence and rage attacks, low serum levels of testosterone, LH, FSH, decreased basal and stimulated levels of growth hormone and progressively increasing levels of serum prolactin, and a glucose tolerance test revealed diabetes. A progressive enlargement of the third ventricle was later associated with generalized but proportionally less severe atrophy of the cerebellum and cerebral hemispheres. Following levodopa therapy, decreased somnolence and increased libido and potency were found (Kelts and Hoehn, 1978). In neither patient was any cause found for the hypothalamic atrophy. Leigh’s disease was found in a 5-year-old child whose condition had been deteriorating over a period of 6 months before death. Postmortem investigation revealed cystic and necrotic changes of the posterior hypothalamus, subthalamic nuclei, midbrain, pons and medulla. Leigh’s disease is a fatal encephalopathy that occurs in infancy or childhood. It is inherited in an autosomal recessive manner and is characterized by psychomotor regression, brainstem dysfunction, respiratory abnormalities and seizures. Neuropathology includes bilateral symmetrical foci of necrosis, which are most prominent in the diencephalon and brainstem. The lesions are characterized by necrosis, myelin destruction, astrocytosis and vascular proliferation. Although lactic acidosis, pyruvate dehydrogenase complex deficiency and cytochrome-C-oxidase deficiency have been found, they are not considered to be a sufficient explanation of Leigh’s disease. The foci of necrosis of the child with Leigh’s disease were characterized by spongious changes around blood vessels, capillary proliferation gliosis and macrophage infiltrates, with relative preservation of neurons. These changes were found in the posterior hypothalamus, while the mamillary bodies were unaffected. There was optic atrophy with loss of myelin (Heckmann et al., 1991). Cornelia de Lange’s syndrome, first described in Amsterdam in 1933 and called, by Cornelia de Lange (Fig. 32A) herself, “Typus Degenerativus Amstelodamensis”, is

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Fig. 32 A.

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Portrait of Professor Cornelia de Lange (1871–1950). First female professor at the University of Amsterdam, painted by Lizzy Ansingh (1957). Collection of University Museum “De Agnietenkapel”, Oudezijds Voorburgwal 231, 1012 EZ Amsterdam.

to the optic tract and the pituitary has also been described. The patient was an 18-year-old girl with severe mental retardation, polyuria, polydipsia, hypothyroidism, hypogonadotropism and limited response to growth hormone and cortisol after insulin-induced hypoglycemia, while the prolactin levels were normal. This case suggests a possibly causal relationship between teratogenesis and oncogenesis (Sato et al., 1986; Sugita et al., 1986; Heckmann et al., 1991). Endocrine defects are often found in Cornelia de Lange’s syndrome (Schlesinger et al., 1963; France et al., 1969), indicating a defect in the vicinity

characterized by microcephaly, a simplified pattern of cerebral convolutions, abnormal myelination and facial dysmorphic features, including synophrys (eyebrows growing together), a low-hair line on the neck and forehead, long eyelashes and a depressed bridge of the nose with upturned nostrils (Hayashi et al., 1996). Sleep disturbances are correlated with severity of mental retardation and the presence of autistic behavior (Hoban, 2000). Several studies have shown that this syndrome can be associated with hypothalamic and hypophysial lesions. A case complicated by a suprasellar germinoma extending 389

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of the median eminence (Abraham and Russell, 1968). In a 5-year-old female child with Cornelia de Lange’s syndrome, the optic systems, olfactory systems, hypothalamic nuclei, corpus callosum and cerebellar vermis were hypoplastic. The septum pellucidum, fornix and anterior commissure were present in rudimentary form. The SON in particular were not recognized, and the posterior lobe was hypoplastic. The brain had malformative features of septo-optic dysplasia combined with commissural dysplasia and cerebellar vermian hypoplasia, suggesting a relationship between Cornelia de Lange’s syndrome and midline development of the brain. Chromosomal abnormalities have been pointed out in patients with Cornelia de Lange’s syndrome, as well as in patients with De Morsier’s syndrome (Hayashi et al., 1996), and Cornelia de Lange’s syndrome is considered to be an autosomal dominant disease, with most cases reflecting a fresh mutation (Russell et al., 2001). In an adult case of Cornelia de Lange’s syndrome, no neuropathology was observed in the hypothalamus (Vuilleumier et al., 2002). 32.3. Diencephalic idiopathic gliosis A 16-year-old girl with chronic diarrhea and dermopathy had an unusual and widespread gliosis of hypothalamic and other diencephalic structures with proportionally little neural loss. The gliosis involved the hypothalamus from the anterior commissure up to and including the mamillary bodies, in particular in the medial portions of the arcuate, ventromedial (VMN), and dorsomedial nucleus, and the mamillary bodies. The lateral tuberal nucleus was also moderately involved. Likewise, the SON and PVN revealed mild gliosis and neuronal loss. The basal forebrain showed moderate gliosis, including the anterior olfactory area, the nucleus basalis of Meynert and the diagonal band of Broca. There was no sign of any inflammatory reaction or vascular proliferation. Mild to moderate gliosis was also present in the globus pallidus, subthalamic nucleus, and anterior and mid-portions of the thalamus as well as in the brainstem. The extrahypothalamic damage did not, however, cause recognized clinical features. Hypothalamic disease was suggested during life by sustained hypothermia, delayed sexual development,

altered sleep–wake cycles, abnormal cortisol diurnal rhythms and profound growth arrest from the age of 8 years onwards, despite normal growth hormone and insulin-like growth factor (IGF)-I levels. The stimulus to glial proliferation has not been identified (Espiner et al., 1992). Fox et al. (1970) have reported a case of persistent and severe hypothermia (see Chapter 30.2) in a young adult with marked gliosis, which was, however, confined to the anterior hypothalamus, while pituitary functions remained normal. The relationship of these cases of gliosis to gliomatosis cerebri (Chapter 19.4c; Peretti-Viton et al., 2002) is unknown.

32.4. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome

MELAS syndrome is due to the presence of a mixture of mutated and wild-type mitochondrial DNA. Central nervous system involvement may accompany mental retardation, epilepsia partialis continua, stroke-like episodes and neuroendocrine dysfunction, i.e. growth hormone deficiency, hypothalamopituitary hypothyroidism, primary amenorrhea, prepubertal gonadotropin levels, absence of any secondary sexual characteristics and diabetes mellitus (insulin- and noninsulin-dependent) (Balestri and Grosso, 2000). 32.5. Agenesis of the diencephalon Agenesis of the diencephalon of the fetus and neuroepithelial folding of the diencephalon has been observed following alcohol use by the mother during pregnancy (Konovalov et al., 1997). 32.6. Tourette’s syndrome Changes of the ambient thermal perception and a circadian dysregulation of the body temperature profile are present in Tourette’s syndrome probands. An ‘idiopathic hypothalamic disorder’ is presumed by the authors (Kessler, 2002).

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CHAPTER 33

Brain death and ‘dead’ neurons (Fig. 33A)

“Die, my dear doctor – that’s the last thing I shall do!” Lord Palmerston, 1784–1865. British Prime Minister.

Some studies reported that hypothalamic and anterior pituitary hormones are still detectable in peripheral plasma after the diagnosis of brain death, suggesting that hypothalamic function might, at least partly and for some time, remain intact in this condition (Sugimoto et al., 1992). In brain-dead patients, changes of the thyroid axis have been described that were considered to be a variant of euthyroid sick syndrome (= nonthyroidal sickness), characterized by a reduction of serum total T3 and free T3 levels, and a low or normal T4 (see Chapter 8.6). Thyrotropin (TSH) may be normal, lower or, sometimes, elevated, suggesting in that case the presence of intact hypothalamic thyrotropin-releasing hormone (TRH) neurons. As a result of these endocrine changes, tissue T3 also lowers. Some authors suggest treating brain-dead organ donors with T3 in order to improve the organs’ condition for transplantation, but this is a controversial subject (Keogh et al., 1988; Robertson et al., 1989; Powner et al., 1990; Novitzky, 1991; Gramm et al., 1992; Colpart et al., 1996). While the majority of brain-dead people develop diabetes insipidus (see below), anterior pituitary hormones do not decrease: corticotropin (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin levels remain within the normal range. Not only TSH, but also growth hormone levels may increase in brain death, suggesting some residual hypothalamic functions and also some perfusion of the hypothalamopituitary portal system (Howlett et al., 1989; Harms et al., 1991; Gramm et al., 1992). As an alternative explanation, one may propose that these hormones are released into the circulation as a result of necrosis of the anterior pituitary (Gramm et al., 1992). On the other hand, the observation that 1–38 days after brain death (Sugimoto et al., 1992) there was still a good

(a) The process of dying and brain death The hypothalamic clock seems to play a crucial role from the moment we are born (Chapter 4.2) to the moment we die. To a certain degree the hypothalamus determines the hour of the day at which we die, e.g. from ischemic stroke or intracerebral hemorrhage and subarachnoid hemorrhage in hypertensive patients, who show a postawakening peak (see Chapter 4d). In addition, there are circannual fluctuations in cerebral infarctions, ischemic attacks, intracerebral hemorrhage and suicides (Chapter 4.1b). During the process of dying, various neuroendocrine and autonomic changes may occur. The HPA system is strongly activated, giving rise to extremely high plasma and CSF levels of cortisol (Swaab et al., 1994c; Lamberts et al., 1997a; Chapter 1.3.iib). In severely demented patients we found even higher levels of CSF cortisol than in patients with mild Alzheimer’s and controls, while morphine in the last phase of life had no effect on these high CSF cortisol levels. ‘Physical stress’ therefore seems to cause these high cortisol levels in the moribund stage, rather than the ‘psychological stress’ of dying (Erkut et al., 2003). Prolactin in postmortem venous blood samples correlates with stress. Markedly higher blood levels of this hormone are found in postoperative deaths and in the chronically ill. However, hyperprolactinemia in cases of suicide is likely to be the result of the effects of the drugs used (Jones and Hallworth, 1999).

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Fig. 33A.

The soul that tries to overcome the religious borders of the mind.

In 1882, J.W.C. van Gorkum, a colonel in the cavalry, died and was buried next to the wall of the Protestant part of the cemetery in Roermond, the Netherlands. When his wife, Lady van Aefferden, a Roman Catholic, died six years later, she could not be buried on the Protestant side, next to her husband. She chose to be buried as close as possible to the wall on the Catholic side. The tombstones were connected to symbolize their alliance.

response to TRH in some patients favors the possibility of residual hypothalamic and pituitary functions. However, since another study showed a decrease in TSH, T3 and T4 in 80% of the brain-dead potential donors, the residual functions seem to be only partly intact (Colpart et al., 1996). In a study of 28 brain-dead patients, vasopressin plasma levels dropped a short time after the diagnosis of brain death. This manifested clinically as diabetes insipidus. Anterior pituitary hormones were initially detected in all patients, but they disappeared gradually. Morphological studies showed a partial necrosis of the anterior lobe of

the pituitary, due to a lack of circulation in the portal system that is probably caused by the rise of intracranial pressure, while preservation of the posterior lobe lasted 1 week. The zona intermedia was preserved relatively well. Some autopsy reports show that the hypothalamus becomes extensively necrotic after 3–6 days of brain death (Sugimoto et al., 1992), while a narrow outer shell of the pars distalis is usually intact (McCormick et al., 1970). On the other hand, it has also been reported that the diencephalon is less seriously affected than most other brain areas (Walker et al., 1975). In general, the supraoptic (SON) and paraventricular nuclei (PVN) are affected in

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Fig. 33B. Brain and Mind (detail) (c) Herms Romijn. Herms Romijn, who painted the water-color picture of which a detail is reproduced here, has exhibited widely and was a neurobiologist at the Netherlands Institute for Brain Research. He has published many papers on the pineal gland, neuron culture, epilepsy and the biological clock, and is the author of books (in Dutch) on sleep and mind–brain relationships. In this painting he has tried to express the essence of his view on consciousness (Romijn 2002). He sees consciousness as a manifestation of complex patterns of electric and/or magnetic fields in the brain, pointing out that virtual photons comprising these fields can therefore, in a sense, be regarded as ‘elementary carriers’ of consciousness. Because not only fields but neurons too are composed of elementary particles, he used the technique of pointillism to emphasize this feature in the painting. (Cover illustration of Journal of Consciousness Studies 8 (9–10), Sept.–Oct. 2002, with permission.)

patients with coma dépassé (irreversible coma or “respirator brain”), while the neural lobe shows a normal or even an increased amount of neurosecretory material. The mostly severe degeneration of the central portions of the anterior lobe of the pituitary and the relative infrequency of extensive necrosis of the pars nervosa in case of brain death is explained by the difference in vascularization (see Chapter 17.1). The blood supply of the pars nervosa is predominantly arterial, derived from branches of the internal carotid artery and almost completely extradural. The anterior pituitary blood supply comes largely from the low-pressure venous portal system from the pituitary

stalk and will thus be much more affected by the increased arterial pressure generally seen in the “respirator brain”. The outer rim of reasonably well preserved cells seen in the anterior lobe of the pituitary is explained by their blood supply from arterial twigs from the hypophyseal arteries derived from the carotids (McCormick and Halmi, 1970; Gramm et al., 1992). Some three-quarters of brain-dead patients develop clinical diabetes insipidus (Keogh et al., 1988; Howlett et al., 1989; Gramm et al., 1992). In about half of the cases of diabetes insipidus, this disease had already developed before the onset of brain death (Gramm et al., 1992). 393

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Fig. 33.1. Histology and viability staining of motor cortex slices after long-term culturing. (A) Overview of the cortical layers in a slice at DIV 25 (NeuN: Alzheimer patient, 99-139). (B) Detail of layer III pyramidal neurons at DIV 38 (NeuN; control patient, 00-090). (C) Astrocytes in layer III at DIV 78 (control, 00-090) stained with an antibody to GFAP (brown) and counterstained with NeuN (green). GFAP and NeuN were visualized using peroxidase (DAB) and -galactosidase (X-gal), respectively. (D) Microglial cells (HLA, brown) and neurons (NeuN, green) in layer III at DIV 78 (control, 00-090). (E) Dil tracing reveals the extensive dendritic arborizations of an upper layer III pyramidal neuron at DIV 50 (non-Alzheimer dementia patient, 99-142). Two optical CLSM sections, taken 20 m apart. (F) Electron micrograph showing axodendritic synapses at DIV 25 (AD, 99-139). (G) Viability staining of a motor cortex slice (layer III) kept in basal medium (R16) for 48 days (AD, 99139). (H) Viability staining of a motor cortex slice (layer III) kept in basal medium (R16) supplemented with NGF, BDNF, and NT-3 for 48 days (AD, 99-139). Arrows indicate viable neurons that have retained both esterase activity (green cytoplasm) and intact membranes (without red nuclei). d, dendrite; s, synaptic terminal. Roman numerals indicate the cortical layers. Scale bar 400 m (A); 20 m (B–D); 100 m (E); 35 m (G,H); 400 nm (F). (From Verwer et al., 2002, Fig. 1, with permission.)

In 76% of children with brain death, increased diuresis is present, whereas genuine diabetes insipidus is found in 38% of the patients (Fiser et al., 1987). These observations are in the first place of practical importance.

Brain-dead patients who are not given vasopressin, or only in an antidiuretic dose, demonstrate circulatory deterioration and cardiac arrest within a short time after brain death, despite administration of a large dose of

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do not even want to lose myself, because I know that I cannot come any further toward the truth and because one blunders so easily on those subjects’. Eugene Dubois, cited by Pat Shipman in The Man who Found the Missing Link.

epinephrine. All patients with a pressor dose of vasopressin, however, demonstrate stable circulation as long as vasopressin and epinephrine are administered (Iwai et al., 1989). Vasopressin substitution has therefore been recommended for brain-dead donors (Howlett et al., 1989). A more recent study on brain-dead organ donors supports the protective action of vasopressin. Organ donors often develop hypotension, due to vasodilation, which adds to the scarcity of good organ donors for transplantation. Hemodynamically unstable organ donors without clinically apparent diabetes insipidus display a defect in the baroreflex-mediated secretion of vasopressin. In these patients, a low dose of vasopressin (0.04–0.1 U/min) administered as a continuous infusion significantly increases blood pressure, with a pressor response sufficient to reduce catecholamine administration. Nonetheless, vasopressin is not widely used to improve donor stability. Instead 1-desamine-8-D-arginine vasopressin (dDAVP) is used to treat diabetes insipidus in organ donors. However, dDAVP acts selectively on the V2 receptor subtype in the renal collecting tube and has no vasopressor activity in humans, a type of activity mediated by the V1 receptors on vascular smooth muscle (Chen et al., 1999a). In addition, brain death may go together with an ‘autonomic storm’ (Chapter 30), characterized by rapid swings in blood pressure with eventual persistent hypotension, coagulopathies, hypothermia and electrolytic alterations. This syndrome may affect donor organ quality (Pratschke et al., 1999). Brain-dead patients who do not show diabetes insipidus have caused questions of a theoretical and ethical nature to be raised. When enough vasopressin is still produced to prevent diabetes insipidus, the patient does not fulfil the criterion of ‘irreversible cessation of all functions of the entire brain’ (Truog, 1997) and one may wonder what other residual brain functions are still present in such ‘brain dead’ patients. The present monography will also have made clear that the hypothalamus is involved in many ‘higher’ functions, so that it will be difficult to use ‘the higher brain criterion for death (Truog, 1997) if remnants of the hypothalamus are still functioning.

Adult and fetal postmortem hypothalamic tissue has been studied by in vitro perfusion chambers at 37°C. Oxygenated artificial CSF flowing through the chamber bathes the tissue and is then collected in intervals into sample tubes. Functional viability of fetal tissue of 21–33 weeks of gestation obtained less than 6 h after delivery and adult postmortem hypothalami within 12 h postmortem was assessed by the rapid release of LHRH in response to a depolarizing dose of KCl. Dopamine administration resulted in LHRH release in a dosedependent and dopamine-receptor-mediated fashion. Increased release of LHRH was found in response to opiate receptor blockade, supporting the inhibitory role of endogenous opioids in LHRH secretion (Chapters 24.1 and 31.1). Fetal human medial basal hypothalamus tissue releases LHRH in a pulsatile and calcium-dependent manner with a periodicity of about 1 h, and adult tissue with a periodicity of 60–100 min. These results indicate that the LHRH pulse-generating mechanism is located entirely within this brain area. Addition of morphine to the medium reduces the frequency of LHRH pulses (Rasmussen, 1992). Neurons from human fetal brain tissue of 12–16 weeks’ gestation have been isolated and cultured and induced to undergo apoptosis by serum deprivation. Apoptosis can be prevented by hormones such as 17--estradiol and transcriptionally inactive 17--estradiol, while androgens appear to induce neuroprotection directly through the androgen receptor (Hammond et al., 2001). Human neurons from craniotomies for intractable epilepsy or tumor resection have also been cultured (Brewer et al., 2001). Our group has shown that it is possible to recover at least some functions of human hypothalamic neurons up to 8 h after death in postmortem cultured brain slices. When brain slices are preincubated in modified artificial CSF at 0–4°C for 2–3 h, neuronal tracers, i.e. neurobiotin or biotinylated dextran-amine are injected into the optic nerve or hypothalamic nuclei. These tracers are taken up and transported along the axon only by ‘living’ neurons. Following 6–18 h of incubation in artificial CSF at room temperature, provided with 95% O2 and 5% CO2, the tracer appears to be transported over 0.5–1.5 cm along axons, e.g. from the optic nerve to the suprachiasmatic

(b) Postmortem perfusion of hypothalamic tissues and neuronal cultures: life after death ‘I myself speak in publications about brains, exclusively about brains – never about the psyche, let alone about the soul,’ Dubois declares defensively. ‘In the latter subjects I

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Fig. 33.2. Transgene expression in adult human postmortem brain tissue. A) Overview of a motor cortex slice from a control patient showing layers II and III with cells expressing -galactosidase (patient 99-044, infection at DIV 6; staining at DIV 13; rAAV titer; 8.3x108 tu/ml). B) Layer III pyramidal neurons of an AD patient (99-001) expressing -galactosidase at DIV 24 after infection at DIV 14 (rAAV titer: 4.6x108 tu/ml). C) -galactosidase-expressing layer III pyramidal cells in the motor cortex of a PD patient (99-069) (infection at DIV 34; staining at DIV 44l rAAV titer 8.3x108 tu/ml. D) AT-8 staining at DIV 0 in layer III of a slice from the same tissue block as in B, showing plaques (asterisks), tangles (arrows) and neuropil threads (arrowheads). D) Inset: a hyperphosphorylated tau (AT-8)-containing neuron (same patient) that also expressed -galactosidase (infection at DIV 34; staining at DIV 44; rAAV titer 2x108 tu/ml). E) Overview of another slice stained at DIV 0 with an antibody against -amyloid showing the presence of many plaques (same patient as in B). F) Large pyramidal cells of layer V in a motor cortex slice from the same experiment shown in C. Three adjacent cells suggesting that a high lipofuscin load is accompanied by low -galactosidase expression. Inset: a higher magnification of the uppermost neuron. Arrowheads indicate the location of the lipofuscin accumulations. Scale bar 400 m (E); 200 m (A); 100 m (B, D); 50 m (C, F); 25 m (F, inset), and 6 m (D, inset). (From Verwer et al., 2002, Fig. 4, with permission.)

nucleus (SCN) and from the SCN to a number of mainly hypothalamic sites of termination (Chapter 4). Axonal transport under these conditions is an active, energydependent process, since no transport is visible when oxygen, or oxygen and glucose are omitted during incu-

bation. Adding cortisol during incubation increases the neuron’s ability to transport. Neurons of patients who have been ‘dead’ for 6–8 h thus appear to be capable of recovering axonal transport with suitable in vitro treatment (Dai et al., 1998a, b, c).

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Fig. 33.3. Culture for 21 days of a slice of postmortem human hypothalamus containing the supraoptic nucleus according to the procedure of Verwer et al., 2002. The cells were stained for the Golgi apparatus with the antibody HG-130 (Ishunina et al., 2001). Patient: NHB 00-040, female, 95 years of age; postmortem delay, 4 h 45 min. Bar 100 m (preparation, T.A. Ishunina).

Subsequently, our group has shown that organotypic human brain cultures obtained by autopsy within the framework of the Netherlands Brain Bank at 2–8 h after death can be maintained in vitro for extended periods and can be manipulated experimentally. Slices in basal medium supplemented with survival promoting neurotrophic factors retain more viable cells than slices in basal medium alone. Cytochrome oxidase activity could be enhanced by the addition of pyruvate as an extra energy source to the medium. Also, we have reported for the first time that neurons in these cultures (motor cortex, hippocampus and cerebellum) can be transduced with adenoassociated viral vectors, and were able to express

the reporter genes, enhanced green fluorescent protein and LacZ, for as long as 44 days (Verwer et al., 2002; Figs. 33.1 and 33.2). In this way, we have also successfully cultured nucleus basalis of Meynert neurons (E.J.G. Dubelaar et al., unpublished observation), as well as of the supraoptic nucleus (Ishunina et al., 2001; Fig. 17.13) and other cortical areas, such as the parietal and visual cortex. These slice cultures offer new opportunities to study the cellular and molecular mechanisms of aging and neurodegenerative diseases. For instance, mutated genes involved in Alzheimer’s disease may be expressed in neurons of control patients to induce pathological alter-

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Fig. 33.4.

Het Literaire Leven. Peter van Straaten.

ations. Furthermore, putative therapeutic genes may be applied to brain slices of Alzheimer patients to enhance neuronal survival. The examples mentioned above indicate that quite a few neuronal functions may still be present when the subject as an organism is already ‘dead’. The idea that the building blocks of our personality, the neurons, can live on after death is a curious one. It is even

more curious if one realizes that the building blocks of these cells, molecules, are made of dead matter. When DNA, the building block of life, is a dead molecule, then what is life? (cf. Bert Keizer, Het Refrein is Hein. Uitgeverij SUN). In a manual nothing remains of the effort, the doubt and the despair that existed before a certain conclusion was reached. W.F. Hermans in “Nooit meer slapen”.

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Index of Volumes 79 and 80 – The Human Hypothalamus. Parts I and II

Note, underlined page numbers indicate in-depth treatment.

Acetylcholine, 45–58(I) Alzheimer’s disease, 329(II) Acetylcholinesterase islands of Calleja, 61(I) ACTH corticotropin releasing hormone, 200(I) depression, 257(II) Acute intermittent porphyria periodic disorders, 305(II) Addiction, see also Pain, and Opioid peptides behavior, 377(II) opioid peptides, 373–378(II) Addison’s disease hyponatremia, 150(II) Adipsia, 142–144(II) Adrenoleucodystrophy, 343(II) Adrenomyeloneuropathy, 343(II) Age/aging Alzheimer’s disease, 51(I), 106(I), 191–194(I), 313–330(II) androgen receptor, 143–147(I) antemortem factors, 15–17(I) circadian rhythms, 92(I), 103–107(I) corticotropin releasing hormone, 205–206(I) growth hormone, 38–44(II) hypothalamus-pituitary-gonadal system, 201–202(II) hypothyroidism, 227(I) lateral tuberal nucleus, 267(I) melatonin, 118–120(I) nucleus basalis of Meynert, 39(I), 51–52(I), 53(I) paraventricular nucleus, 191–194(I) sexually dimorphic nucleus, 131–133(I) sleep, 369(II) suprachiasmatic nucleus, 102(I) supraoptic nucleus, 191–194(I) ventromedial nucleus, 242(I) Aggression, 283–288(II) developmental factors, 283–285(II) hypothalamic structures, 285(II)

nucleus basalis of Meynert, 45(I) septum, 162(I) sex hormones, 286–287(II) stereotactic hypothalamy, 287–288(II) tuberomamillary complex, 278(I) ventromedial hypothalamic syndrome, 246–248(II) ventromedial nucleus, 239(I) Agouti-related peptide infundibular nucleus, 253(I) Prader–Willi syndrome, 172–175(II) premorbid state, 22–23(I) AIDS bed nucleus stria terminalis, 159(I) circadian rhythms, 98–99(II) growth hormone, 98(II) hypothalamus, 95–99(II) hypothalamus-pituitary-adrenal system, 97(II) hypothalamus-pituitary-gonadal system, 98(II) oxytocin, 96(II) paraventricular nucleus, 169(I) supraoptic nucleus, 169(I) vasopressin, 95(II) Alcohol consumption hypothyroidism, 227(I) vasopressin secretion, 194(I) Alcoholism Korsakoff syndrome, 339–343(II) Alström’s syndrome, 190(II) hypogonadotropic hypogonadism, 196(II) Alzheimer’s disease, 313–330(II) aggression, 284(II) bed nucleus stria terminalis, 150(I), 157(I) beta amyloid, 318–320(II) circadian disorder, 69(I), 103–107(I) conventional neuropathology, 313–315(II) corpora mamillaria, 293–294(I) corticotropin releasing hormone, 206–210(I) cytoskeletal changes, 322–324(II)

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decreased metabolism, 320–321(II) depression, 255(II) dorsomedial nucleus, 248(I) Down’s syndrome, 317–318(II) glucocorticoid cascade, 217(I), 222–223(I) Golgi apparatus, 55(I) hormones/receptors, 327–329(II) hyperphosphorylated tau, 318(II), 320(II)(II) hypothalamus reactivation, 324–325(II) hypothyroidism, 229(I) infundibular nucleus, 260–261(I) islands of Calleja, 61–62(I) lateral tuberal nucleus, 266–267(I) light/melatonin therapy, 106–107(I) melatonin, 123(I) mental deficiency, 275(II) neurofibrillary tangles, 323(II) neuronal metabolic activity, 29(I) neuropeptides, 325–327(II) nucleus basalis of Meynert, 39(I), 46(I), 49–56(I) olfactory dysfunction, 205(II) pain, 380(II) paraventricular nucleus, 191–194(I) premorbid state, 22(I) septum, 161–162(I) sex differences, 18(I), 315–317(II) sexually dimorphic nucleus, 133(I) somatostatin, 235(I) subthalamic nucleus, 287(I) supraoptic nucleus, 191–194(I) tuberomamillary complex, 276(I) ventromedial nucleus, 241(I) Amenorrhea hypogonadotropic hypogonadism, 198(II) Amines Alzheimer’s disease, 329(II) Amygdala bed nucleus stria terminalis, 149–150(I), 156(I) brain sexual differentiation, 220–226(II) Amyotropic lateral sclerosis, 348(II) Analgesia, see Pain Anatomy bed nucleus stria terminalis, 151–156(I) diagonal band of Broca, 45–48(I) hypothalamus borders, 5–9(I) hypothalamus nuclei, 41–45(I),164(I) nucleus basalis of Meynert, 45–48(I) paraventricular nucleus, 166(I) pineal gland, 112(I) tuberomamillary complex, 275–276(I) vascular supply, 3–15(II) vomeronasal organ, 206–207(II) Androgen (receptor) brain sexual differentiation, 221(II) corpora mamillaria, 291(I) corticotropin releasing hormone, 208–209(I) distribution, 140–147(I)

INDEX

islands of Calleja, 61(I) resistance syndrome, 230(II) sex differences, 138–140(I) ventromedial nucleus, 240(I), 242(I) Anencephaly brain pituitary remnants, 22–24(II) fusion failures, 21–22(II) intrauterine growth/birth, 24–25(II) transplantation, 26–28(II) Angelman’s syndrome eating disorders, 168(II) mental deficiency, 273(II) Anorexia nervosa eating disorders, 168(II), 180–189(II) genetics, 181(II) hypothalamus-pituitary-adrenal system, 214(I) hypothyroidism, 230(I) Klinefelter syndrome, 220(II) sexual dysfunction, 230(II) sociocultural factors, 182(II) symptoms, 182–186(II) therapy, 188(II) Anosmia Kallmann’s syndrome, 203–205(II), 215–218(II) Antemortem factors age, 15–17(I) circadian variation, 22(I) extracellular volume, 21–22(I) lateralization, 21(I) seasonal variation, 19–20(I) sex difference, 16–19(I) Anterior commissure sex differences, 136–137(I) Anxiety bed nucleus stria terminalis, 149(I) hypothalamus-pituitary-adrenal system, 214(I) oxytocin, 182(I) panic disorder, 278–279(II) Prader–Willi syndrome, 178(II) social anxiety, 279(II) Aphasia sex difference, 18(I) Aquaporin diabetes insipidus, 140(II) gene mutation, 140(II) Arachnoid cysts precocious puberty, 200(II) Arcuate nucleus, see Infundibular nucleus Arginine vasopressin, see also Vasopressin depression, 252(II), 263–265(II) Aromatase mutation sexual dysfunction, 230–231(II) Asperger’s syndrome autism, 299(II) Kleine–Levin syndrome, 303(II) Asthma vasopressin secretion, 198(I)

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anatomy, 151–153(I) development, 156(I), 160(I) neuron numbers, 159(I) sex differences, 150–158(I) volume, 158(I), 160(I) Behavior disorders Prader–Willi syndrome, 178–179(II) Biemond’s syndrome, 190(II) mental deficiency, 273(II) Binge eating syndrome, 190(II) Biological clock, see Circadian rhythms Blindness circadian rhythm, 67(I), 103(I) Blood pressure regulation tuberomamillary complex, 278(I) Blood supply, see Vascular supply Body weight regulation lateral hypothalamic area, 281(I) Bourneville–Pringle syndrome, see Tuberous sclerosis Brain autopsy, 12–15(I) banking, 12–15(I), 28(I) injury, 233–234(II) glucocorticoid cascade, 216–222(I) metastases, 85(II) pH, 25(I) Brain death, 391–398(II) coma, 393(II) diabetes insipidus, 393(II) dying factors agonal state, 23–24(I) illness, 22–23(I) stress, 24(I) fetal brain tissue, 395(II) motor cortex, 394(II), 396(II) postmortem perfusion, 395(II) process of dying, 391–395(II) tissue culture, 396–397(II) transgene expression, 396(II) vasopressin, 394–395(II) Breast cancer melatonin, 121(I) Bulimia nervosa borderline personality, 188(II) eating disorders, 168(II), 180–189(II) Parkinson’s disease, 187(II) sexual dysfunction, 230(II) therapy, 188(II)

Astrocytomas glioma, 64(II) radiation injury, 239(II) Atherosclerosis hypothalamus, 16(II) Atrophy nucleus basalis of Meynert, 52(I) Attention deficit hyperactivity disorder aggression, 284(II) thyroid hormone resistance, 232–233(I) Autism corpora mamillaria, 295(I) development, 297–299(II) dorsomedial nucleus, 248(I) lateral hypothalamic area, 283(I) nucleus basalis of Meynert, 57(I) septum, 162(I) tuberomamillary complex, 279(I) Autoimmunity diabetes insipidus, 135–137(II) Autonomic disorders, 351–371(II) Alzheimer’s disease, 330(II) autonomic dysfunction syndrome head/brain injury, 234(II) autonomic storm, 351(II) behavior disorder, 352(II) brain death, 353(II) cardiovascular regulation, 360–362(II) circumventricular organs, 362–364(II) hyperphagia, 351(II) hypothalamic structures, 353–354(II) micturition, 364(II) orgasm, 352(II) Parkinson’s disease, 334(II) sleep center, 351(II) sleep, 364–371(II) syndromes, 354–355(II) autonomic failure, 355(II) hypoventilation, 354(II) pandysautonomia, 354(II) Riley–Day syndrome, 355(II) sensory neuropathy, 354(II) thermoregulation, 355–360(II) Autopsy brain, 12–15(I) diagnosis, 14–15(I) hypothalamus, 15(I) Bacterial infections hypothalamus, 91–92(II) Ballism subthalamic nucleus, 286(I) Baroreception nucleus basalis of Meynert, 45(I) Bed nucleus stria terminalis, 149–162(I) AIDS, 159(I) Alzheimer’s disease, 158(I)

Cachexia eating disorders, 168(II) Calbindin paraventricular nucleus, 233(I) Cancer, see Tumors Cardiovascular regulation autonomic disorders, 360–362(II) hypertension, 361(II)

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Page 582

582 1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

orthostatic hypotension, 361(II) subarachnoid hemorrhage, 361(II) Cataplexy narcolepsy, 306(II) Catecholaminergic system dorsomedial nucleus, 248(I) infundibular nucleus, 255–256(I) paraventricular nucleus, 189–191(I) periventricular nucleus, 236(I) supraoptic nucleus, 189–191(I) Cavernous malformation hypothalamus, 17(II) Cerebrospinal fluid circadian rhythms, 81(I) melatonin, 112(I) postmortem delay, 24(I) Cerebrovascular accidents vasopressin secretion, 197(I) Chemical markers hypothalamic nuclei, 30–34(I) Chemoarchitecture corpora mamillaria, 293(I) diagonal band of Broca, 48–49(I) infundibular nucleus, 249–251(I) lateral hypothalamic area, 281–283(I) lateral tuberal nucleus, 263–266(I) nucleus basalis of Meynert, 48–49(I) ventromedial nucleus, 240(I) Choline acetyltransferase Alzheimer’s disease, 39(I) islands of Calleja, 61(I) nucleus basalis of Meynert, 59(I) Cholinergic system Alzheimer’s disease, 49(I) schizophrenia, 58(I) Chondroma, 87(II) Chordoma, 87(II) Choroid plexus third ventricle colloid cysts, 18–19(II) papilloma, 20(II) xanthogranuloma, 18(II) Chronic fatigue syndrome hypothalamus-pituitary-adrenal system, 214(I) Chronic pain disorder, 380(II) Circadian rhythms, 63–125(I) aging, 103–107(I) AIDS, 98–99(II) antemortal factors, 20–21(I) cerebrospinal fluid, 81(I) chemoarchitecture, 71–73(I) depression, 253(II), 261–265(II) development, 99–103(I) disorders, 66–71(I) dorsomedial nucleus, 243(I) headache, 384(II) melatonin, 88(I), 115–116(I) molecular genetics, 73–76(I) Parkinson’s disease, 334–335(II)

INDEX

pineal gland, 112–125(I) radiation injury, 237(II) retinohypothalamic tract, 76–80(I) thermoregulation, 356(II) timing system, 64–66(I) Circannual rhythms aggression, 286(II) aging, 103–107(I) antemortal factors, 19–20(I) hormone levels, 94(I) light therapy, 265–267(II) melatonin, 115–116(I), 261(II) seasonal affective disorder, 253(II), 261–267(II) suprachiasmatic nucleus, 93–97(I) vasoactive intestinal peptide, 110(I) Circaseptan rhythms Suprachiasmatic nucleus, 99(I) Circle of Willis vascular supply, 4–5(II), 14(II) Circumventricular organs organum vasculosum lamina terminalis, 362–363(II) subfornical organ, 363–364(II) Colloid cysts choroid plexus third ventricle, 20(II) Congenital midline defects, 29–34(II) optic nerve hypoplasia, 29(II) septo-optic dysplasia, 30–34(II) Cornelia de Lange syndrome, 388–389(II) Coronary heart disease melatonin, 121(I) Corpora mamillaria, 291–295(I) androgen receptor, 291(I) chemoarchitecture, 293(I) development, 291(I) mamillotegmental tract, 292(I) mamillothalamic tract, 292(I) neurodegenerative disorders, 294–295(I) other pathologies, 295(I) sex differences, 137–138(I), 291(I) Corticotropin releasing hormone aging, 205–206(I) Alzheimer’s disease, 206–210(I) autism, 298(II) chronic fatigue syndrome, 279–280(II) Cushing’s syndrome, 210–212(I) depression, 251(II), 256–260(II) development, 203–205(I) eating disorders, 160(II) glucocorticoid cascade, 216–222(I) hypertension, 212–213(I) infundibular nucleus, 250(I) metabolic syndrome X, 212–213(I) number of cells in PVN, 201(I) other disorders, 214–216(I) paraventricular nucleus, 171(I), 199–223(I) Parkinson’s disease, 336(II) sex difference, 205(I)

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INDEX

1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

vasopressin, 200(I) zona incerta, 288(I) Cortisol circadian rhythms, 81(I) corticotropin releasing hormone, 208–209(I) disorders, 210–216(I) feedback, 202(I) glucocorticoid cascade, 216–223(I) postmortem delay, 24(I) Craniopharyngioma, 72–75(II) chiasm 78(II) infundibulum, 72(II) MRI, 72(II) squamous papillary type, 74(II) symptoms, 74(II) third ventricle, 74(II) Creutzfeldt–Jakob’s disease nucleus basalis of Meynert, 56(I) variant, 349(II) Critical illness growth hormone deficiency, 44(II) Cushing’s syndrome circadian disorder, 69(I) corpora mamillaria, 295(I) corticotropin releasing hormone, 210–212(I) depression, 259(II) glucocorticoid cascade, 220(I) periodic disorders, 304(II)

melatonin, 122(I) menopause, 272(II) neuropeptides, 248–252(II) oxytocin, 260–261(II) Parkinson’s disease, 335(II) pathogenesis, 254–256(II) postpartum mood disorders, 272(II) premenstrual syndrome, 271(II) sex difference, 18(I) sex hormones, 270(II) sexual dysfunction, 230(II) thyroid axis, 268–270(II) thyrotropin releasing hormone, 230(I) vasopressin, 260–261(II) Dermoid/epidermoid tumors, 76–77(II) Development/growth disorders, 21–49(II), see also Fetal development Diabetes insipidus, 135–141 autoimmune, 135–137(II) brain death, 393(II) drinking disorders, 130–141(II) familial central, 131–135(II) gene mutations, 133(II) hypothalamic tumor, 85(II) Langerhans’ cell histiocytosis, 117–118(II) myeloid leukemia, 85(II) nephrogenic, 138–141(II) neurohypophysis, 167(I) other causes, 138(II) pregnancy induced, 137–138(II) vasopression administration, 198(I) Wolfram’s syndrome, 150–155(II) Diabetes mellitus vasopressin hypersecretion, 145–147(II) Wolfram’s syndrome, 150–155(II) Diagnosis autopsy, 14–15(I) Diagonal band of Broca Alzheimer’s disease, 50–52(I) anatomy, 45–48(I) androgen receptor, 49(I) chemoarchitecture, 48–49(I) Diencephalic idiopathic gliosis, 390(II) Diencephalic syndrome glioma, 65–70(II) Diencephalons agenesis, 390(II) Dopaminergic system infundibular nucleus, 253(II) Parkinson’s disease, 336(II) Dorsomedial nucleus, 243–248(I) Alzheimer’s disease, 248(I) anatomy, 244–247(I) autism, 248(I) catecholaminergic system, 248(I) eating disorders, 161(II) paraventricular nucleus, 248(I) pheromones, 243(I) sex difference, 243(I)

De Morsier’s syndrome, see Septo-optic dysplasia Deafness Wolfram’s syndrome, 150–155(II) Dehydroepiandrosterone sulfate (DHEAS) Alzheimer’s disease, 328(II) chronic fatigue syndrome, 281(II) corticotropin releasing hormone, 206(I) glucocorticoid cascade, 223(I) Dementia with argyrophilic grains, 330–332(II) Alzheimer’s disease, 332(II) bed nucleus stria terminalis, 150(I) corpora mamillaria, 293(I) lateral tuberal nucleus, 268(I), 331(II) subthalamic nucleus, 287(I) Depression amines, 252–254(II) antepartum depression, 271(II) antidepressive agents, 267(II) circadian rhythms, 253(II), 261–265(II) circannual rhythms, 96(I), 253(II), 261–267(II) corticotropin releasing hormone, 256–260(II) electric stimulation, 268(II) electroconvulsive therapy, 267(II) glucocorticoid cascade, 218–221(I) hypothalamus-pituitary-adrenal system, 214(I), 248(II) infundibular nucleus, 261(I) light therapy, 116(I), 265–267(II)

583

583

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Page 584

584 1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

Down’s syndrome Alzheimer’s disease, 317–318(II) anterior commissure, 137(I) corpora mamillaria, 294(I) infundibular nucleus, 260(I) mental deficiency, 274(II) nucleus basalis of Meynert, 57–58(I) sexual dysfunction, 230(II) tuberomamillary complex, 276(I) ventromedial nucleus, 240(I) Drinking disorders, 125–155(II) cerebral/central salt wasting, 149(II) diabetes insipidus, 130–141(II) diabetes mellitus, 145–147(II) hyponatremia, 150(II) neurohypophysis pathology, 125–130(II) nocturnal diuresis, 144–145(II) primary polydipsia/adipsia, 141–144(II) schizophrenia, 293(II) Schwartz–Bartter syndrome, 147–149(II) vasopressin hypersecretion, 145–147(II) Wolfram’s syndrome, 138(II), 150–155(II) Drosophila circadian rhythms, 74–75(I) Dying, see Brain death Eating disorders, 157–191(II), see also Feeding Alström’s syndrome, 190(II) anorexia nervosa, 180–189(II) Biemond’s syndrome, 190(II) binge eating syndrome, 190(II) bulimia nervosa, 180–189(II) epigenetic factors, 168(II) hypothalamic nuclei, 159–161(II) Laurence–Moon/Bardet–Biedl syndrome, 189–190(II) leptin, 161–162(II) mental deficiency, 274(II) molecular genetics, 167–168(II) neuropeptides/hormones, 162–167(II) night eating syndrome, 190(II) other disorders, 191(II) Prader–Willi syndrome, 168–180(II) Encephalitis lethargica eating disorders, 168(II) hypothalamus, 94(II) sexual dysfunction, 230(II) Endocrine dysfunction radiation injury, 237(II) Endodermal cyst, 89(II) Enkephalin islands of Calleja, 61(I) Epilepsy, see also Gelastic epilepsy circadian rhythm and sleep, 308(II) circannual rhythms, 95(I) hamartoma, 57(II), 310(II) hormone release, 309(II) hypothalamus pathology, 310(II)

INDEX

lateral tuberal nucleus, 268(I) laughter attacks, 244–246(II) melatonin, 118(I) thyrotropin releasing hormone, 233(I) tuberomamillary complex, 278(I) Erdheim–Chester disease diabetes insipidus, 138(II) Langerhans’ cell histiocytosis, 120(II) Estrogen receptor Alzheimer’s disease, 330(II) brain sexual differentiation, 221(II) eating disorders, 167(II) lateral tuberal nucleus, 265(I) nucleus basalis of Meynert, 49(I), 330(II) sex differences, 140–147(I) suprachiasmatic nucleus, 109(I) supraoptic nucleus, 175(I) Exophthalamus Langerhans’ cell histiocytosis, 118(II) Extracellular volume antemortal factors, 21–22(I) Familial glucocorticoid resistance hypothalamus-pituitary-adrenal system, 216(I) Fatal familial insomnia circadian disorder, 69(I) hypothalamus-pituitary-adrenal system, 214(I) nucleus basalis of Meynert, 56(I) Fatigue, 279–283(II) chronic fatigue syndrome, 279–282(II) fibromyalgic syndrome, 282–283(II) postviral fatigue syndrome, 283(II) Feeding, see also Eating disorders autonomic system, 159(II) dorsomedial nucleus, 243(I) eating behavior ventromedial nucleus, 239(I) energy storage, 158(II) food intake regulation, 158–159(II) infundibular nucleus, 249, 256–257(I) lateral hypothalamic area, 281(I) lateral tuberal nucleus, 265(I) leptin, 158(II) neuropeptides/hormones, 162–167(II) nucleus basalis of Meynert, 45(I) tuberomamillary complex, 271(I) Fetal development aggression, 284(II) brain tissue, 395(II) circadian rhythm, 100–101(I) corpora mamillaria, 291(I) corticotropin releasing hormone, 203–205(I) disorders, 21–49(II) hypothalamic nuclei, 35–38(I) lateral hypothalamic area, 283(I) melatonin, 118(I) paraventricular nucleus, 186–189(I) pituitary stalk, 241(II)

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1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

supraoptic nucleus, 186–189(I) vomeronasal organ, 207–210(II) Fibromyalgia muscle pain, 379(II) Follicle stimulating hormone brain death, 391(II) Fragile-X syndrome hypothalamus-pituitary-adrenal system, 214(I) melatonin, 120(I) Frölich’s syndrome eating disorders, 191(II) Frontotemporal dementia, 344(II) Fungal infections hypothalamus, 94(II)

Glucocorticoid receptor polymorphism eating disorders, 168(II) Glucose metabolism sex difference, 16(I) Glutamic acid decarboxylase paraventricular nucleus, 233(I) suprachiasmatic nucleus, 72(I) tuberomamillary complex, 274(I) Golgi apparatus Alzheimer’s disease, 52(I), 323(II) neuronal metabolic activity, 29(I), 171(I) nucleus basalis of Meynert, 52(I), 54–55(I) sex differences, 171(I) supraoptic nucleus, 173(I), 192(I) ventromedial nucleus, 242(I) Granular cell tumor glioma, 71(II) neurohypophysis, 127–129(II) Granular ependymitis, 122(II) Growth hormone aging, 38–44(II) AIDS, 98(II) autism, 298(II) deficiency, 40–44(II) adults, 43–44(II) Prader–Willi syndrome, 170(II) radiation injury, 236(II) development disorders, 38–44(II) Noonan syndrome, 39–41(II) Parkinson’s disease, 335(II) Growth hormone releasing hormone deficiency, 42–44(II), 255(II) depression, 255(II) eating disorders, 166(II) head/brain injury, 233(II) infundibular nucleus, 252(I) Noonan syndrome, 41(II) Prader–Willi syndrome, 172(II) septo-optic dysplasia, 31(II) Wolfram’s syndrome, 154–155(II) Guillain–Barré syndrome, 123(II) diabetes insipidus, 137(II)

Galanine bed nucleus stria terminalis, 149(I) eating disorders, 165(II) sexually dimorphic nucleus, 131(I) Gamma aminobutyric acid (GABA) corpora mamillaria, 293(I) suprachiasmatic nucleus, 72(I) zona incerta, 287(I) Gastroduodenal ulcer vasopressin secretion, 198(I) Gastrointestinal bleeding vasopression administration, 198(I) Gelastic epilepsy hamartomas, 57(II), 244(II) multiple sclerosis, 244(II) seizures, 246(II) Germ cell tumors differentiation, 78(II) germinoma, 79(II) pineal region, 77–83(II) teratoma, 79(II) yolk sac tumor, 81(II) Germinoma hypothalamic tumor 54–56(II) Germinoma, 79(II) Gestation circadian rhythm, 100(I) hypothalamic development, 35–38(I) Gitelman disease diabetes insipidus, 141(II) growth hormone deficiency, 43–44(II) Glial fibrillary acidic protein septo-optic dysplasia, 34(II) Glial neoplasms, 83(II) Glioma astrocytomas, 64(II) chiasmatic, 66(II) diencephalic syndrome, 65–70(II) optic pathway, 64–70(II) other gliomas, 70(II) Glucocorticoid cascade brain damage, 216–222(I)

Hallucinations nucleus basalis of Meynert, 56(I) Hamartoblastomas hamartoma, 64(II) Hamartoma depression, 256(II) epilepsy, 310(II) hamartoblastomas, 64(II) intrasellar gangliocytoma, 62–64(II) nodules, 62(II) pathogenesis, 60(II) precocious puberty, 200(II) symptoms, 57–60(II) therapy, 61(II)

585

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Page 586

586 1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

Hand–Schüler–Christian disease, see Langerhans’ cell histiocytosis Headache circadian disorder, 70(I) cluster headache, 383–385(II) hypnic headache syndrome, 385–386(II) melatonin, 122(I) migraine, 385(II) tuberomamillary complex, 279(I) Heart failure vasopressin secretion, 197(I) Heart frequency regulation tuberomamillary complex, 278(I) Hematoma hydrocephalus, 93(I) Hemophilia vasopression administration, 199(I) Hemorrhage hypothalamus, 15(II) Hepatorenal syndrome vasopressin secretion, 197(I) Herpes simplex encephalitis corpora mamillaria, 295(I) nucleus basalis of Meynert, 59(I) Hippocampus damage, 217(I) glucocorticoid cascade, 217–223(I) sclerosis, 346(II) Histaminergic system subthalamic nucleus, 285(I) tuberomamillary complex, 269–275(I) ventromedial nucleus, 239(I) Histidine decarboxylase tuberomamillary complex, 271–272(I) Histiocytosis-X, see Langerhans’ cell histiocytosis Histology vomeronasal organ, 206–207(II) Homosexuality brain sexual differentiation, 222(II) sex differences, 112(I) sexual orientation/behavior, 229–230(II) ventromedial nucleus, 242(I) Hunger depression, 260(II) Kleine–Levin syndrome, 301–303(II) Huntington’s disease, 337–339(II) hypothalamic changes, 338–339(II) lateral tuberal nucleus, 264(I), 266(I), 338–339(II) subthalamic nucleus, 286(I) tuberomamillary complex, 278(I) Hydrocephalus anorexia nervosa, 188(II) diabetes insipidus, 138(II) etiology, 46–47(II) hematoma, 93(I) hypothalamic symptoms, 46(II) intracerebroventricular tumor, 92(I)

INDEX

precocious puberty, 200(II) subcommissural organ, 44–46(II) 5-Hydroxytryptamine circadian variation, 21(I) seasonal variation, 19(I) Hyperandrogenemia melatonin, 121(I) Hypercortisolism glucocorticoid cascade, 216–223(I) Hyperphagia ventromedial hypothalamic syndrome, 246–248(II) Hyperphosphorylated tau Alzheimer’s disease, 318(II), 320(II) nucleus basalis of Meynert, 51(I) Hyperprolactinemia melatonin, 121(I) Hypertension circadian disorder, 69(I) corticotropin releasing hormone, 210–212(I) hypothalamus-pituitary-adrenal system, 216(I) vasopressin secretion, 195–196(I) Hypocretin lateral hypothalamic area, 283–284(I) narcolepsy, 306–308(II) Hypogonadism Klinefelter syndrome, 218–220(II) Hypogonadotropic hypogonadism gonadotropic hormone regulation disorders, 196–199(II) infundibular nucleus, 257(I) Kallmann’s syndrome, 215–218(II) lateral tuberal nucleus, 268(I) melatonin, 119(I) Hyponatremia schizophrenia, 293(II) Hypopituitarism radiation injury, 236(II) septo-optic dysplasia, 31(II) Hypotension vasopressin secretion, 195–196(I) vasopression administration, 199(I) Hypothalamoneurohypophysial system, 163–165(I) Hypothalamus adult markers, 35–38(I) aging, 143–147(I) amenorrhea, 121(I) anatomy, 5–9(I), 41–45(I), 90–91(I), 164(I), 244–247(I), 264(I), 275–276(I) atrophy, 388(II) chemical markers, 30–34(I) confounding factors, 15–29(I) corticotropin releasing hormone, 200(I) developmental/growth disorders, 21–49(II) dorsomedial nucleus, 244–247(I) fetal development, 35–38(I) infundibular nucleus, 249–261(I) lateral tuberal nucleus, 263–268(I)

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1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

other infections, 94(II) post-/parainfectious encephalitis, 93–94(II) Infundibular nucleus, 249–261(I) androgen receptor, 141(I) chemoarchitecture, 249–255(I) eating disorders, 160(II) ependyma and internal glia layer, 255(I) leptin and adipose tissue, 256(I) LHRH neurons, 257(I) neurologic/psychiatric disorders, 260–261(I) postmenopause, 257–260(I) thyroid hormone receptors, 229(I) vascular supply, 12(II) Insulae terminalis, see Islands of Calleja Intelligence growth hormone deficiency, 42(II) Intermediate hypothalamic area, 284(I) attack area, 284(I) Interstitial nucleus anterior hypothalamus sexual dimorphism, 135–136(I) Interthalamic adhesion sex differences, 137(I) Intracerebroventricular tumor hydrocephalus, 92(I) Intrasellar gangliocytoma hamartoma, 62–64(II) Islands of Calleja, 61–62(I)

lesions, 233–241(II) MRI, 6(I) nuclei representation, 8–12(I), 41–45(I) strategic research, 9–12(I) structure-function relationships, 9–12(I) thyrotropin releasing hormone, 224–225(I) tuberomamillary complex, 269–279(I) tuberous sclerosis, 84–85(II) tumors, 51–89(II) vascular lesions, 15–17(II) vascular supply, 3–6(II), 13(II) Hypothalamus-pituitary-adrenal system aggression, 284(II) AIDS, 97(II) autism, 298(II) chronic fatigue syndrome, 280(II) corticotropin releasing hormone, 199(I) depression, 248(II) development, 203–205(I) eating disorders, 165(II) glucocorticoid cascade, 216–222(I) multiple sclerosis, 108–110(II) schizophrenia, 294(II) upright position, 214(I) vasopressin, 200(I) Hypothalamus-pituitary dysfunction, 344(II) Hypothalamus-pituitary-gonadal system aging, 201–202(II) AIDS, 98(II) menopause, 201–202(II) schizophrenia, 294(II) transsexuality, 227(II) Hypothalamus-pituitary-thyroid system depression, 268–270(II) Hypothermia, 234(II) periodic disorders, 304(II) Hypothyroidism aging, 227(I) alcoholism, 227(I) Alzheimer’s disease, 229(I) hyponatremia, 150(II) mental deficiency, 275(II) Hypotonia Prader–Willi syndrome, 170(II)

Jet-lag circadian disorder, 68(I) melatonin, 118(I) Kallmann’s syndrome, 215–218(II) anosmia, 203–205(II) endocrine disorders, 218(II) functional deficits, 217(II) hypogonadotropic hypogonadism, 196(II) molecular genetics/migration, 216–217(II) pathogenesis, 217(II) sexual dysfunction, 230(II) Kennedy’s disease sexual dysfunction, 230(II) Kidney failure vasopressin secretion, 197(I) Kleine–Levin syndrome, 301–303(II) corpora mamillaria, 295(I) eating disorders, 191(II), 301(II) neuroimmunological disorders, 123(II) Prader–Willi syndrome, 179(II) sexual dysfunction, 230(II) sleep disorder, 301–303(II), 371(II) Klinefelter syndrome, 218–220(II) anorexia nervosa, 188(II) clinical aspects, 219(II) hypogonadotropic hypogonadism, 196(II) Prader–Willi syndrome, 180(II) psychosocial problems, 220(II)

Idiopathic hypothalamic syndrome childhood, 121(II), 354(II) paraneoplastic syndrome, 387–390(II) precocious puberty, 201(II) Infarction hypothalamus, 15(II) Infections, 91–99(II) acute viral meningoencephalitis, 91–93(II) AIDS, 95–99(II) bacterial, 91–92(II) encephalitis lethargica, 94–95(II) fungal, 94(II)

587

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Page 588

588 1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

schizophrenia, 291(II) sexual dysfunction, 230(II) Korsakoff syndrome alcoholism, 339–341(II) corpora mamillaria, 294(I) Kuru septum, 162(I) Lactic acidosis, 390(II) Lamina terminalis vascular supply, 13–14(II) Langerhans’ cell histiocytosis, 116–121(II) diabetes insipidus, 117–118(II), 138(II) Erdheim–Chester disease, 120(II) exophthalamus, 118(II) hypogonadotropic hypogonadism, 196(II) lytic bone disease, 118(II) pathology, 119(II) therapy, 119(II) Lateral geniculate nucleus, 288(I) Lateral hypothalamic area, 281–283(I) chemoarchitecture, 281–283(I) development, 283(I) function, 281–283(I) melanin-concentrating hormone, 282(I) Lateral tuberal nucleus, 263–268(I) Alzheimer’s disease, 323(II) chemoarchitecture, 263–265(I) function, 265(I) Huntington’s disease, 338–339(II) neurodegenerating diseases, 266–267(I) Lateralization antemortal factors, 21(I) thyrotropin releasing hormone, 230(I) Lateromamillary nucleus androgen receptor, 142(I) Laughter attacks, see Gelastic epilepsy Laurence–Moon/Bardet–Beidl syndrome, 189–190(II) diabetes insipidus, 138(II) hypogonadotropic hypogonadism, 196(II) mental deficiency, 273(II) Leigh disease, 388(II) Subthalamic nucleus, 286(I) Leptin eating disorders, 161(II) food intake regulation, 158(II) gene mutation, 167(II) infundibular nucleus, 256(I) Prader–Willi syndrome, 172(II) Lesions head/brain injury, 233–234(II) neuroleptic malignant syndrome, 234–236(II) pituitary stalk, 240–241(II) radiation injury, 236–240(II) Lewy body disease, 348(II) nucleus basalis of Meynert, 56(I) Parkinson’s disease, 336–337(II) subthalamic nucleus, 286(I)

INDEX

Life span circannual rhythms, 95(I) suprachiasmatic nucleus, 102(I) Light/melatonin therapy Alzheimer’s disease, 106–107(I) elderly, 120(I) Lipoma, 88(II) Listeriosis hypothalamus, 94(II) Liver cirrhosis melatonin, 122(I) Liver disease circadian disorder, 67(I) Lung diseases vasopressin secretion, 198(I) Luteinizing homone releasing hormone bed nucleus stria terminalis, 149(I) corpora mamillaria, 293(I) function, 194(II) hypogonadotropic hypogonadism, 196(II) infundibular nucleus, 250(I), 257(I), 259(I) Kallmann’s syndrome, 215–218(II) paraventricular nucleus, 234(I) polycystic ovary syndrome, 203(II) postmenopause, 259(I) Prader–Willi syndrome, 171(II) reproduction, 193–196(II) septo-optic dysplasia, 31(II) septum, 159–160(I) ventromedial nucleus, 240(I) vomeronasal organ, 206–215(II) Lymphoblastic leukemia radiation injury, 238(II) Lytic bone disease Langerhans’ cell histiocytosis, 118(II) Malignant lymphoma, 88(II) Malignant neuroleptic syndrome lateral tuberal nucleus, 268(I) Mamillary body androgen receptor, 142(I) Mania, 272–273(II) Marchiafava–Bignami disease, 343(II) McCune–Albright syndrome precocious puberty, 201(II) Median eminence infundibular nucleus, 249–261(I) adenohypophysis, 255(I) portal system, 254(I) catecholamines, 255–256(I) melanin, 255–256(I) vascular supply, 6–8(II) Medulloblastoma radiation injury, 238(II) Melanin infundibular nucleus, 255–256(I) Melanin-concentrating hormone eating disorders, 166(II)

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1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

Mortality circannual rhythms, 97(I) Moyamoya disease growth hormone deficiency, 42(II) MRI Alzheimer’s disease, 49(I) corpora mamillaria, 293(I) diabetes mellitus, 146(II) glioma, 69(II) hypothalamus, 6(I) Langerhans’ cell histiocytosis, 121(II) postcommissural fornix, 5(I) sarcoidosis, 103(II) Multiple endocrine neoplasia Prader–Willi syndrome, 180(II) Multiple sclerosis, 108–116 circannual rhythms, 97(I) differential diagnosis, 116(II) hypothalamic structures, 111–119(II) hypothalamic-pituitary-adrenal system, 108–110(II) inflammation/demyelination, 110–116(II) mood changes, 108(II) optic neuritis, 116(II) sexual dysfunction, 230(II) subthalamic nucleus, 286(I) symptoms, 106–108(II) Multisystem atrophy neurodegeneration, 347–348(II) nocturnal diuresis, 145(II) tuberomamillary complex, 278(I) Myeloid leukemia diabetes insipidus, 85–86(II)

lateral hypothalamic area, 282–283(I) zona incerta, 287(I) Melatonin (receptors), 112–125(I) age and sex, 118–120(I) Alzheimer’s disease, 106–107(I), 328(II) analgesic effects, 380(II) biosynthesis/metabolism, 113–115(I) circadian rhythms, 68(I), 78(I), 88(I), 115(I) circannual rhythms, 97–98(I), 115(I) development, 118(I) disorders, 120–123(I) fibromyalgic syndrome, 282(II) hypogonadotropic hypogonadism, 196(II) light intensity, 114(I) light therapy, 116(I) Parkinson’s disease, 335(II) precocious puberty, 201(II) seasonal affective disorder, 261(II) therapy, 106–107(I) side effects, 123–125(I) Memory impairment nucleus basalis of Meynert, 39–40(I) Memory loss corpora mamillaria, 294–295(I) Ménière’s disease vasopressin secretion, 198(I) Meningioma, 86(II) Meningitis vasopressin secretion, 197(I) Menopause/postmenopause aging, 115–116(I) depression, 272(II) hot flushes, 259(I) hypothalamus-pituitary-gonadal system, 201–202(II) SPECT, 50(I) subventricular nucleus, 257–260(I) suprachiasmatic nucleus, 97–99(I) vasopressin, 171(I) Menstrual cycle depression, 271(II) infundibular nucleus, 250(I) melatonin, 120(I) monthly rhythms, 97–99(I) vomeronasal organ, 215(II) Mental deficiency, 273–276(II) Metabolic syndrome X corticotropin releasing hormone, 212–213(I) Micturition autonomic disorders, 364(II) Midline developmental anomaly diabetes insipidus, 138(II) Minamata disease mental deficiency, 273(II) Mitochondrialencephalomyopathy, 390(II) Molecular genetics circadian rhythms, 73–76(I) Monthly rhythms menstrual cycle, 97–99(I)

Narcolepsy growth hormone deficiency, 42(II) Narcolepsy, 123(II) periodic disorders, 305–308(II) Nasopharyngeale carcinoma radiation injury, 238(II) Nerve growth factor receptor nucleus basalis of Meynert, 52–56(I) Neural tube defect anencephaly, 21–22(II) Neuroendocrine function oxytocin, 174–179(I) vasopressin, 174–179(I) Neurohypophysis development, 186–189(I) dystopia anterior pituitary abnormalities, 35–36(II) ectopia, 34(II) granular cell tumors, 127(II) granulomas, 127(II) metastatic carcinomas, 128(II) neurosecretion, 165–168(I) paraventricular nucleus, 164(I) pathology in drinking disorders, 125–130(II) supraoptic nucleus, 164(I)

589

589

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Page 590

590 1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

thyrotropin releasing hormone, 226(I) Wolfram’s syndrome, 150–155(II) Neuroimmunological disorders, 101–123(II) Langerhans’ cell histiocytosis, 116–121(II) multiple sclerosis, 106–116(II) other disorders, 121–123(II) sarcoidosis, 101–106(II) Neuroleptic malignant syndrome, 234–236(II) autopsy, 235(II) nucleus basalis of Meynert, 58(I) pathology, 235(II) therapy, 235(II) thermoregulation, 358(II) Neurologic disorders, see also Psychiatric disorders circannual rhythms, 95(I) glucocorticoid cascade, 216–222(I) hamartoma, 59(II) hypothalamus-pituitary-adrenal system, 214–215(I) immunologic disorders, 102–123(II) infundibular nucleus, 260–261(I) Klinefelter syndrome, 220(II) lateral tuberal nucleus, 266–267(I) melatonin, 122(I) neurodegeneration, 313–349(II) olfactory dysfunction, 205(II) Prader–Willi syndrome, 178–179(II) reset osmostat, 149(II) tuberomamillary complex, 276–278(I) Neuronal metabolic activity postmortem tissue, 29–35(I) Neuropeptide EI zona incerta, 287(I) Neuropeptide Y Alzheimer’s disease, 49(I) corticotropin releasing hormone, 202(I) eating disorders, 160–162(II) infundibular nucleus, 252(I) Prader–Willi syndrome, 174–176(II) premorbid state, 22–23(I) suprachiasmatic nucleus, 71–73(I), 79(I) thyrotropin releasing hormone, 231(I) Neuropeptides bed nucleus stria terminalis, 150(I) depression, 248–252(II) eating disorders, 162–167(II) Parkinson’s disease, 335–336(II) postmortem delay, 25(I) Neurosecretory cell cellular/molecular properties, 172(I) Neurotensin suprachiasmatic nucleus, 71–73(I), 79(I) Neurotransmittors/modulators central pathways, 179–182(I) Neurotropin receptors neuronal metabolic activity, 29(I) nucleus basalis of Meynert, 52–56(I) Night eating syndrome, 190(II)

INDEX

Nocturnal diuresis desmopressin, 144–145(II) drinking disorders, 144–145(II) Noonan syndrome growth hormone, 39–40(II) Nucleus basalis of Meynert, 45–58(I) aggression, 45(I) aging, 39(I), 51–52(I) Alzheimer’s disease, 39(I), 49–58(I), 330(II) anatomy, 45–48(I) atrophy, 29(I) baroreception, 45(I) chemoarchitecture, 48–49(I) eating disorders, 161(II) feeding, 45(I) narcolepsy, 308(II) neuroleptic malignant syndrome, 236(II) neurologic disorders, 56–58(I) neuronal loss vs. atrophy, 51–52(I) neurotropin receptors, 52–56(I) schizophrenia, 296(II) thermosensitivity, 45(I) Nucleus of Cajal, see Ventromedial nucleus Obesity eating disorders, 157(II) epigenetic factors, 168(II) melatonin, 121(I) molecular genetics, 167–168(II) Prader–Willi syndrome, 170(II) ventromedial hypothalamic syndrome, 246–248(II) Obsessive-compulsive disorder neuroendocrine changes, 277(II) therapy, 277(II) Olfaction, 203(II), see also Vomeronasal organ neurologic/psychiatric diseases, 205(II) sex, 206–215(II) structures, 204(II) Opioid peptides addiction, 373–378(II) cocaine and amphetamine regulated transcript, 378(II) enkephalins, 374(II), 376(II) marijuana, 378(II) neuropeptide AF, 378(II) neuropeptide FF, 378(II) orphanin peptides, 374(II) prodynorphin, 375(II) proenkaphelin B, 373(II) pro-opiomelanocortin, 373(II) Optic chiasm misrouting in albinism, 36–38(II) non-degussating retinal-fugal fiber syndrome, 38(II) other pathologies, 38(II) Optic chiasm Anatomy of region, 8–9(I) vascular supply, 13(II) Optic nerve hypoplasia congenital midline defects, 29(II)

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Page 591

INDEX

1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

Alzheimer’s disease, 191–194(I) anatomy, 7(I), 166(I) corticotropin releasing hormone, 199–223(I) depression, 251(II), 264(II) development, 186–189(I) dorsomedial nucleus, 248(I) eating disorders, 160–162(II) fixation, 27(I) glutamic acid decarboxylase, 233(I) hypophysectomy cell loss, 240–241(II) hypothalamoneurohypophysial system, 163–165(I) LHRH, 234(I) model, 166(I) neurohypophysis, 164(I) neurosecretory pathway, 167(I) oxytocin production/release, 168–171(I) peptides/hormones, 233–235(I) schizophrenia, 295(II) suprachiasmatic nucleus efferents, 80(I) thermoregulation, 359(II) thyroid hormone, 232(I) thyrotropin releasing hormone, 223–233(I) tyroxine hydroxylase, 189–191(I) vasoactive intestinal peptide, 88(I) vasopressin, 88(I), 164(I) production/release, 168–171(I) Parkinson dementia complex of Guam nucleus basalis of Meynert,56(I) Parkinson’s disease, 332–337(II) autonomic symptoms, 334(II) bed nucleus stria terminalis, 150(I) bulimia nervosa, 187(II) circadian disorder, 70(I) circadian rhythms, 334–335(II) depression, 335(II) hormones/neuropeptides, 335–336(II) Kleine–Levin syndrome, 303(II) lateral tuberal nucleus, 268(I) levodopa therapy, 332(II) Lewy bodies, 336–337(II) nucleus basalis of Meynert, 56–57(I) olfactory dysfunction, 205(II) periventricular nucleus, 237(I) sexual dysfunction, 230(II) sleep, 334(II) subthalamic nucleus, 285(I) tuberomamillary complex, 277(I), 279(I) Parkinsonism linked to chromosome 17, 344(II) Pars distalis vascular supply, 12(II) Perifornical area, 283–284 (I) feeding, 283(I) hypocretin, 283–284(I) Periodic disorders, 301–311 acute intermittent porphyria, 305(II) Cushing’s syndrome, 305(II) epilepsy, 308–311(II)

Optic neuritis differential diagnosis, 116(II) Optic pathway glioma, 64–70(II) radiation injury, 238(II) Oral contraception melatonin, 121(I) Osmoregulation drinking disorders, 143–144(II) pregnancy, 184–185(I) Oxytocin AIDS, 96(II) central pathways, 179–182(I) depression, 260–261(II) development, 186–189(I) infundibular nucleus, 250(I) neuroendocrien function, 174–179(I) neurohypophysis, 164(I) osmoregulation in pregnancy, 184–185(I) paraventricular nucleus, 164, 170(I) Prader–Willi syndrome, 176–178(II) pre-ecclampsia, 185–186(I) preterm labor, 178(I) production/release, 168–171(I) reproduction, 182–184(I) schizophrenia, 292(II) supraoptic nucleus, 164–(I) thyrotropin releasing hormone, 226(I) tyroxine hydroxylase, 189–191(I) Pain, 379–383(II), see also Addiction acupuncture, 382–383(II) analgesia, 382–383(II) anatomy, 379(II) chronic, 380(II) deep brain electrostimulation, 382(II) headache, 383–386(II) hereditary disorders, 378(II) hypothalamic structures, 379–380(II) infundibular nucleus, 249(I) nociceptive signals, 379(II) placebo analgesia, 381(II) sex steroids, 380(II) stereotactic lesions, 382–383(II) symptoms vasopressin secretion, 198(I) Pallister–Hall syndrome hamartoma, 64(II) Papilloma choroid plexus third ventricle, 20(II) Parabrachial nucleus oxytocin, 182(I) vasopressin, 182(I) Paraneoplastic encephalitis hypothalamic tumor 54(II) neuroimmunological disorders, 123(II) Paraventricular nucleus aging, 191–194(I) alcoholism, 345(II)

591

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Page 592

592 1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

fever, 303–304(II) hypothermia, 304(II) Kleine–Levin syndrome, 301–303(II) narcolepsy, 305–308(II) Shapiro’s syndrome, 304(II) Periventricular nucleus Alzheimer’s disease, 235(I) Parkinson’s disease, 237(I) peptides/hormones, 235–237(I) Pheromones dorsomedial nucleus, 243(I) ventromedial nucleus, 239(I) Pick’s disease, 348(II) lateral tuberal nucleus, 268(I) nucleus basalis of Meynert, 56(I) tuberomamillary complex, 278(I) Pineal gland, see also Melatonin circannual rhythms, 97(I) depression, 264(II) germ cell tumors, 77–83(II) glial neoplasms, 83(II) innervation, 114(I) lipoma, 83(II) malignant melanoma, 84(II) malignant rhabdoid tumor, 84(II) melatonin (receptors), 112–125(I) myeloblastoma, 84(II) neural pathways, 112(I) pineal cysts, 83(II) pineoblastoma, 83(II) pineocytoma, 83(II) suprachiasmatic nucleus, 112–115(I) tumor symptoms, 84(II) Pineoblastoma, 83(II) Pineocytoma, 83(II) Pituitary gland deficiencies, 40–42(II) failure, 85(II) neurohypophysis, dystopia, 35–36(II) radiation injury, 239(II) thyrotropin releasing hormone, 226(I) vascular supply, 7–8(II) Pituitary stalk hypophysectomy lesion, 240–241(II) Pituitary tumors adenoma, 89(II) corticotropin releasing hormone, 210(I) vasopressin secretion, 198(I) Polycystic ovary syndrome hypothalamus-pituitary-adrenal system, 202(II), 216(I) LHRH, 203(II) Polydipsia primary, 141–142(II) psychogenic, 142(II) Portal system vascular supply, 8–12(II) Post-/parainfectious encephalitis hypothalamus, 93–94(II)

INDEX

Postcommissural fornix MRI, 5(I) Posterior fossa tumors radiation injury, 238(II) Postmortem factors/tissue archival brain tissue, 28(I) cooling, 26(I) culture conditions, 28(I) delay, 24–26(I) freezing, fixation, storage, 26–28(I) neuronal metabolic activity, 29–35(I) Postoperative delirium melatonin, 121(I) Post-traumatic stress disorder hypothalamus-pituitary-adrenal system, 214(I), 220–221(I) Prader–Willi syndrome comorbidity, 179–180(II) eating disorders, 168–180(II) hypogonadotropic hypogonadism, 196(II) hypothalamic abnormalities, 170–178(II) mental deficiency, 273(II) molecular genetics, 169(II) obesity, 170(II) premorbid state, 23(I) sexual dysfunction, 230(II) sleep disorder, 371(II) symptoms, 168–169(II) Precocious puberty hamartoma, 59(II) Pregnancy corticotropin releasing hormone, 203–205(I) infundibular nucleus, 253(I) labor/birth, 186–189(I) aggression, 284(II) Prader–Willi syndrome, 170(II) pre-ecclampsia, 185–186(I) suprachiasmatic nucleus, 103(I) vasopressin/oxytocin, 182–184(I) Primary empty sella syndrome cerebrospinal fluid pressure, 28(II) growth hormone deficiency, 42(II) hypothyroidism, 233(I) Progesterone receptor suprachiasmatic nucleus, 109(I) Progressive supranuclear palsy nucleus basalis of Meynert, 56(I) subthalamic nucleus, 286(I), 347(II) Prolactin infundibular nucleus, 254(I) Pro-opiomelanocortin protein sequence, 164(II) Psychiatric disorders, 246–297, see also Neurologic disorders aggression, 246–248(II), 283–288(II) anxiety, 278–279(II) depression, 248–272(II) eating disorders, 157–191(II) fatigue syndromes, 279(II)283(II)

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1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

infundibular nucleus, 261(I) Klinefelter syndrome, 220(II) lateral tuberal nucleus, 268(I) melatonin, 122(I) neurotransmitters/-modulators/-hormones, 292–297(II) nucleus basalis of Meynert, 58(I) sex difference, 17(I) third ventricle tumor symptoms, 243(II) tuberomamillary complex, 278(I) Schwartz–Bartter syndrome head/brain injury, 233(II) vasopressin secretion, 147–149(II) Seasonal variation, see Circannual rhythms Seizures, see Epilepsy Septic shock vasopression administration, 199(I) Septo-optic dysplasia congenital midline defects, 30–34(II) Septum, 158–162 (I) aggression, 162(I) Alzheimer’s disease, 161(I) autism, 161(I) development, 160(I) Kuru, 162(I) nuclei, 161(I) pelludidum abnormalities, 47–49(II) structure, 158–159(I) tumors, 49(II) Serotonin autism, 298(II) eating disorders, 166(II) Sex difference/dimorphism aggression, 286–287(II) aging, 143–147(I) Alzheimer’s disease, 50(I), 315–317(II) androgen receptors, 138–147(I) antemortem factors, 15–19(I) anterior commissure, 136–137(I) bed nucleus stria terminalis, 150–158(I) brain sexual differentiation, 220–231(II) hypothalamus/amygdala, 224–226(II) mechanism, 220–224(II) circannual rhythms, 97(I) depression, 254(II) dorsomedial nucleus, 243(I) homosexuality, 112(I) interstitial nucleus ant. hypothalamus, 135–136(I) interthalamic adhesion, 137(I) melatonin, 119(I) neurologic diseases, 19(I) sexually dimorphic nucleus, 130–132(I) sleep, 107–109(I) smelling, 215(II) suprachiasmatic nucleus, 107–109(I) vasopressin, 171–174(I) Sex hormone receptors postmortem delay, 26(I) Sexual behavior/orientation

laughter attacks/gelastic epilepsy, 244–246(II) mania, 272–273(II) mental deficiency, 273–276(II) obsessive-compulsive disorder, 276–278(II) schizophrenia, 289–297(II) third ventricle tumor symptoms, 243(II) ventromedial hypothalamus syndrome, 246–248(II) Puberty disorders, 199–201(II) delayed, 199(II) precocious, 199(II) Pulmonary hemorrhage vasopression administration, 199(I) Radiation injury hypothalamic symptoms, 236–238(II) other complications, 239–241(II) postradiation tumors, 239(II) tumors, 238(II) vascular complications, 239(II) Yttrium–90 in pituitary, 239(II) Rathke’s cleft cysts, 75–76(II) REM sleep circadian rhythm, 104(I), 117(I) nucleus basalis of Meynert, 40(I) tuberomamillary complex, 271(I) Reproduction aging, 201–202(II) dorsomedial nucleus, 243(I) hypogonadotropic hypogonadism, 196–199(II) infundibular nucleus, 249(I) LHRH, 193–196(II) menopause, 201–202(II) polycystic ovary syndrome, 202–203(II) puberty disorders,199–201(II) sexual arousal, 195(II) suprachiasmatic nucleus, 110(I) vasopressin/oxytocin, 182–184(I) Retinitis pigmentosa circadian disorder, 69(I) Rett syndrome circadian disorder, 69(I) mental deficiency, 275(II) nucleus basalis of Meynert, 57(I) Salla disease mental deficiency, 276(II) Sarcoidosis clinical aspects, 101–102(II) endocrine changes, 104–105(II) hypogonadotropic hypogonadism, 196(II) pathology, 102(II) therapy, 106(II) Schizophrenia bed nucleus stria terminalis, 150(I) brain structures, 290(II) corpora mamillaria, 295(I) developmental abnormalities, 289–292(II) hypothalamus, 292–297(II)

593

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Page 594

594 1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

bed nucleus stria terminalis, 149(I) brain sexual differentiation, 220–231(II) depression, 270–272(II) gender identity, 226–228(II) homosexuality, 229–230(II) pedophiles, 231(II) preoptic area, 127(I) reproduction, 193–196(II) septum, 225(II) sexually dimorphic nucleus, 129(I) suprachiasmatic nucleus, 110–112(I) transsexualism, 226–229(II) vasopressin/oxytocin, 182–184(I) ventromedial nucleus hypothalamus, 226(II) ventromedial nucleus, 239(I), 242(I) violent sexual offender, 231(II) vomeronasal organ, 206–215(II) Sexual dysfunction epilepsy, 309(II) hypothalamopituitary disorders, 230–231(II) Sexually dimorphic nucleus (preoptic area), 123–133(I) aging, 15, 131–133(I) Alzheimer’s disease, 133(I) brain sexual differentiation, 222(II) development, 130(I) LHRH neurons, 206–215(II) nomenclature, 129(I) rat homology, 129–130(I) topography, 128(I) volume, 111(I) Shapiro’s syndrome periodic disorders, 304(II) Shy–Drager syndrome, see Multisystem atrophy Sick euthyroid syndrome hypothyroidism, 230–231(I) Sleep disorder, 364–371(II) Alzheimer’s disease, 370(II) autism, 299(II) circadian disorder, 67–68(I), 104(I), 117–118(I) familial fatal insomnia, 370(II) head/brain injury, 234(II) Kleine–Levin syndrome, 123(II), 301–303(II), 371(II) melatonin, 117–118(I) narcolepsy, 123(II), 305–308(II), 370(II) neurological disorders, 370–371(II) Parkinson’s disease, 335(II), 370(II) Prader–Willi syndrome, 179(II) retinitis pigmentosa, 370(II) Smith–Magenis syndrome, 365(II) Wipple’s disease, 365(II) Sleep–wake regulation aging, 369(II) basal forebrain nuclei, 368(II) circadian rhythm, 104(I) hypothalamic structures, 364–368(II) melatonin, 117(I), 367(II)

INDEX

neuroendocrine changes, 368(II) nucleus basalis of Meynert, 40(I) sex differences, 107–109(I) tuberomamillary complex, 271(I) ventrolateral preoptic region, 367(II) Smelling, see Olfaction Smith–Magenis syndrome melatonin, 120(I) mental deficiency, 276(II) sleep disorder, 365(II) Smith–Major syndrome sleep disorder, 370(II) Somatostatin Alzheimer’s disease, 235(I) bed nucleus stria terminalis, 155(I) depression, 252(II) islands of Calleja, 61(I) lateral tuberal nucleus, 263–264(I) periventricular nucleus, 235–236(I) ventromedial nucleus, 240(I) SPECT hippocampus, 223(I) postmenopause, 50(I) Stalk vascular supply, 6–8(II) Stress bed nucleus stria terminalis, 149(I) corticotropin releasing hormone, 200(I) dorsomedial nucleus, 243(I) dying, 24(I) glucocorticoid cascade, 217(I), 222(I) lateral hypothalamic area, 282(I) Stria terminalis, see Bed nucleus stria terminalis Stroke hypothalamus-pituitary-adrenal system, 215(I) Stroke-like episodes, 390(II) Structure-function hypothalamus, 9–12(I) Subarachnoid cysts, 87(II) Subarachnoïdale aneurysm hypothalamus, 15(II) Subcommissural organ hydrocephalus, 44–46(II) Substance P fibromyalgic syndrome, 283(II) islands of Calleja, 61(I) paraventricular nucleus, 234(I) ventromedial nucleus, 242(I) Substantia innominata Alzheimer’s disease, 49(I) corpora amylacia, 58(I) Subthalamic nucleus, 285–287(I) disorders, 285–287(I) emotion regulation, 286(I) Subventricular nucleus infundibular nucleus, 249–261(I) postmenopause, 257–260(I) Sudden infant death syndrome

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INDEX

1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

vasopressin, 88(I), 164(I) production/release, 168–171(I) Sympathetic system tuberomamillary complex, 278(I)

circadian disorder, 70(I) LHRH, 236(I) melatonin, 120(I) nucleus basalis of Meynert, 57(I) Suicide circadian rhythms, 89(I) circannual rhythms, 96(I) hypothalamus-pituitary-adrenal system, 215(I) subthalamic nucleus, 286(I) Suprachiasmatic nucleus, 63–125(I) afferents, 79–80(I) aggression, 284(II) aging, 15(I) Alzheimer’s disease, 106–107(I), 325–326(II) cardiovascular regulation, 360(II) chemoarchitecture, 71–73(I) circadian system, see Circadian rhythms circannual rhythms, 93–97(I) circaseptan rhythms, 99(I) depression, 251(II), 263–264(II) development, 99–103(I) distribution of fibers, 90–91(I) eating disorders, 161(II) efferents, 80–81(I) fixation, 28(I) melatonin receptors, 123(I) monthly rhythms, 97–99(I) multisystem atrophy, 348(II) neuronal metabolic activity, 29(I) pineal gland, 112(I) retinohypothalamic tract, 76–80(I) schizophrenia, 295(II) sex/reproduction, 107–112(I) sleep, 364–366(II) stimulation, 65(I) volume, 111(I) Supraoptic nucleus aging, 15(I), 191–194(I) alcoholism, 345(II) Alzheimer’s disease, 191–194(I), 321–322(II) development, 186–189(I) diabetes insipidus, 134(II) eating disorders, 162(II) hypophysectomy cell loss, 240–241(II) hypothalamoneurohypophysial system, 163–165(I) LHRH, 234(I) NADPH diaphorase, 233(I) neurohypophysis, 164(I) neuronal metabolic activity, 35(I) neurosecretory pathway, 167(I) nitric oxide synthase, 233(I) oxytocin production/release, 168–171(I) peptides/hormones, 233–235(I) sex differences, 174(I) suprachiasmatic nucleus efferents, 80(I) thermoregulation, 359(II) tyroxine hydroxylase, 189–191(I)

Teratoma, 79–80(II) hypothalamus tumor, 56–57(II) Testicular dysgenesis, see Klinefelter syndrome Testosterone brain sexual differentiation, 223(II) Thermoregulation, 355–360(II) circadian rhythms, 356(II) climacterium, 356(II) malignant hypothermia, 358(II) Nasu-Hakola disease, 358(II) neuroleptic malignant syndrome, 358(II) pilocarpine, 356(II) preoptic anterior hypothalamic area, 355(II) Thermosensitivity nucleus basalis of Meynert, 45(I) suprachiasmatic nucleus, 65(I) Thirst, see Drinking disorders Thyroid hormone (receptors) depression, 268–270(II) hypothalamus, 228(I) infundibular nucleus, 229(I), 251(I) thyrotropin releasing hormone, 226–227(I) zona incerta, 289(I) Thyroid stimulating hormone brain death, 391(II) depression, 268–270(II) disorders, 227–233(I) thyrotropin releasing hormone, 226(I) Thyrotropin releasing hormone brain death, 391(II) depression, 268–270(II) disorders, 227–233(I) paraventricular nucleus, 223–233(I) sexually dimorphic nucleus, 131(I) suprachiasmatic nucleus, 71–73(I) thyroid hormone receptors, 226–227(I) vasopressin, 225(I) ventromedial nucleus, 240(I) Tourette syndrome circadian disorder, 69(I), 390(II) sleep disorder, 370(II) Trabecula vascular supply, 12(II) Transsexuality bed nucleus stria terminalis, 150–158(I) brain sexual differentiation, 222(II) sexual orientation/behavior, 226–229(II) Transsphenoidal encephalocele, 28(II) Tremor circadian disorder, 70(I) Triple H syndrome hypothalamus-pituitary-adrenal system, 216(I) Trypanosomiasis

595

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Page 596

596 1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

circadian disorder, 68(I) Tuberculosis hypothalamus, 92(II) Tuberomamillary complex, 269–279(I) anatomy, 275–276(I) functions, 269(I) histaminergic system, 269–275(I) neurodegenerative diseases, 276–278(I) posterior hypothalamic area, 278–279(I) schizophrenia, 296(II) Tuberous sclerosis hypothalamus, 84–85(II) Tumors anorexia nervosa, 188(II) breast cancer, 121(I) craniopharyngioma, 72–75(II) dermoid/epidermoid, 76–77(II) eating disorders, 168(II) germinoma, 54–56(II) glioma, 64–72(II) hamartoma, 57–64(II) hypothalamus, 51–89(II) idiopathic hypothalamic syndrome, 387–388(II) melatonin, 121(I) metastases, 85–86(II) pineal region, 77–84(II) Rathke’s cleft cysts, 75–76(II) symptoms cognitive/behavior, 53–54(II) endocrine/autonomic, 51–52(II) teratoma, 56–57(II) third ventricle tumor symptoms, 243(II) tuberous sclerosis, 84–85(II) ventromedial hypothalamic syndrome, 246–248(II) xanthogranuloma, 76(II) Tyrosine hydroxylase islands of Calleja, 61(I) vasopressin/oxytocin, 189–191(I) zona incerta, 288(I) Tyrosine receptor kinases nucleus basalis of Meynert, 52–56(I) Vascular lesions choroid plexus third ventricle, 17–20(II) hypothalamus, 15–17(II) Vascular supply infundibular process, 12(II) trabecula, 12(II) pars distalis, 12(II) optic chiasm, 13(II) lamina terminalis, 13–14(II) hypothalamus, 3–6(II), 13(II) stalk/median eminence, 6–8(II) pituitary, 7–8(II) portal system, 8–12(II) Vasoactive intestinal peptide

INDEX

Alzheimer’s disease, 325–327(II) anterior hypothalamus innervation, 88(I) bed nucleus stria terminalis, 150(I), 154(I) circadian rhythms, 76 (I) circannual rhythms, 93–97(I), 110(I) development, 101(I) dorsomedial nucleus hypothalamus, 89(I) hypothalamus, 82(I) paraventricular nucleus, 88(I) sex differences, 107–109(I) suprachiasmatic nucleus, 71–73(I) Vasopressin adipsia, 143(II) administration in disorders, 198–199(I) aggression, 286(II) aging, 105(I) AIDS, 95(II) Alzheimer’s disease, 325–327(II) anterior hypothalamus innervation, 88(I) autoimmunity , 136(II) bed nucleus stria terminalis, 161(I) brain death, 392(II), 394–395(II) central pathways, 179–182(I) cerebral/central salt wasting, 149(II) circadian rhythms, 67(I), 176(I) circannual rhythms, 93–97(I), 178(I) corticotropin releasing hormone, 200(I) depression, 251(II), 260–261(II) development, 101(I), 186–189(I) diabetes insipidus, 132–134(II), 139(II) diabetes mellitus, 145–147(II) dorsomedial nucleus hypothalamus, 89(I) gene mutation, 139(II) hyponatremia, 150(II) hypothalamus, 82(I) infundibular nucleus, 250(I) neuroendocrien function, 174–179(I) neurohypophysis, 164(I) nocturnal diuresis, 145(II) osmoregulation in pregnancy, 184–185(I) paraventricular nucleus, 88(I), 164(I), 170(I) Parkinson’s disease, 336(II) Prader–Willi syndrome, 176–178(II) pre-ecclampsia, 185–186(I) production/release, 168–171(I) reproduction, 182–184(I) schizophrenia, 292(II) Schwartz–Bartter syndrome, 147–149(II) secretion in disorders, 194–198(I) septum, 161(I) sex differences, 171–174(I) suprachiasmatic nucleus, 65(I), 105(I) supraoptic nucleus, 22(I), 164(I) thyrotropin releasing hormone, 225(I) tyroxine hydroxylase, 189–191(I) water regulation, 177(I)

2014 Index

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INDEX

1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911

Weil’s disease hypothalamus, 94(II) Wernicke’s encephalopathy, 339–343(II) corpora mamillaria, 294(I) hormone/neurotransmitter disturbances, 339(II) nucleus basalis of Meynert, 56(I) thiamine deficiency, 340(II) West’s syndrome laughter attacks, 246(II) Whiplash injury head/brain injury, 234(II) Whipple’s disease hypothalamus, 94(II) sleep disorder, 365(II) Wolfram’s syndrome, 150–155(II) anorexia nervosa, 188(II) clinical symptoms, 150(II) diabetes insipidus, 138(II) differential diagnosis, 152(II) hypothalamoneurohypophysial system, 153–155(II) molecular genetics, 151–152(II) psychiatric symptoms, 152(II) sexual dysfunction, 230(II)

Wolfram’s syndrome, 153(II) Ventromedial hypothalamic syndrome aggression, 246–248(II) eating disorders, 191(II) psychiatric disorder, 246–248(II) Ventromedial nucleus, 239–242(I) aggression, 239(I), 246–248(II), 284(II) androgen receptor, 141(I), 242(I) chemoarchitecture, 240(I) eating disorders, 159–162(II), 239(I) sexual behavior, 226(II), 242(I) sexually dimorphic functions, 239–240(I) thermoregulation, 359(II) Viral infections meningoencephalitis, 91–93(II) postviral fatigue syndrome, 283(II) Visual system anterior commissure, 137(I) hypothalamus tumor, 85(II) pineal gland, 114(I) Wolfram’s syndrome, 150–155(II) Vomeronasal organ, see also Olfaction anatomy/histology, 206(II) embryology, 207–208(II) LHRH neurons preoptic area, 206–215(II) menstrual cycle, 215(II) sexuality, 206–215(II) vomeropherins, 211(II) Von Eeconomo’s encephalitis, see Encephalitis lethargica Von Willebrand’s disease vasopression administration, 199(I)

Xanthogranuloma, 76(II) choroid plexus third ventricle, 18(II) Yolk sac tumor, 81(II) Zona incerta, 287–289(I) corticotropin releasing hormone, 288(I) GABA, 287(I) tyrosine hydroxylase, 288(I)

597

597