Neurology Volume 72(10) March 10, 2009

This week in Neurology® Highlights of the March 10 issue

Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood The risk of CNS demyelination associated with hepatitis B vaccine is debated. This paper found that hepatitis B vaccination does not generally increase the risk of a first ever CNS inflammatory demyelination in childhood and suggests that further studies of the effects of different brand types could be of interest.

Apathy: A major symptom in CADASIL The authors assessed the frequency, clinical, neuropsychological, and imaging correlates of apathy in a large cohort of patients with CADASIL. The results suggest that apathy is common in CADASIL; appears in association with cognitive impairment, global functional disability, and severe neuropsychiatric symptoms during the course of the disease; and can occur separately from depression. See p. 905

See p. 873; Editorial, p. 870

Pediatric optic neuritis: Brain MRI abnormalities and risk of multiple sclerosis

Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use

It has not been established whether MRIs are as predictive of future multiple sclerosis in children with optic neuritis as they are in adults. This study shows that children with white matter lesions on brain MRI at the time of the diagnosis of optic neuritis have an increased risk of multiple sclerosis.

This paper investigates the combined oral contraceptive use and how it affects serum levels of valproate and lamotrigine. The authors found that oral contraceptives may adversely impact seizure control by lowering the serum levels of the glucuronidated antiepileptic drugs lamotrigine and valproate.

See p. 881

See p. 911

A controlled trial of antidepressants in patients with Parkinson disease and depression

Acute ischemic stroke: Imaging-guided tenecteplase treatment in an extended time window

In a double-blind, randomized, NIH-supported trial of nortriptyline, paroxetine, and placebo in patients with depression and PD, nortriptyline outperformed paroxetine and placebo. This suggests that

This study showed improved outcomes in acute ischemic stroke patients, selected with penumbral/angiographic imaging, and treated with the modified plasminogen activator tenecteplase, compared to the standard IV thrombolytic alteplase. These findings encourage further tenecteplase stroke trials and also support dual-target (penumbra plus vessel occlusion) imaging selection for stroke thrombolysis. See p. 915

dual reuptake antidepressants may be the preferred first-line drugs for these patients. See p. 886; Editorial, p. 868

ACGME competencies in neurology: Web-based objective simulated computerized clinical encounters The Accreditation Council for Graduate Medical Education (ACGME) Outcome Project was designed to ensure and improve the quality of graduate medical education. This paper shows that this program improves neurology residents’ success in meeting the ACGME competencies in headache

Mild cognitive impairment: Loss of linguistic task-induced changes in motor cortex excitability This paper demonstrates that physiologic enhancement of hand motor cortex excitability during specific linguistic tasks is lost in patients with amnestic mild cognitive impairment, even if linguistic skills are preserved. The transcranial magnetic stimulation protocol used here represents a potential tool to investigate neural connectivity in a clinical setting of patients at risk for Alzheimer disease. See p. 928

care. See p. 893

Podcasts can be accessed at www.neurology.org

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867

EDITORIAL

Will tricyclic antidepressants make a comeback for depressed Parkinson disease patients? Michael S. Okun, MD Hubert H. Fernandez, MD

Address correspondence and reprint requests to Dr. Michael S. Okun, University of Florida Movement Disorders Center, McKnight Brain Institute, Neurology, 3rd floor, 100 S. Newell Dr., Rm. L3-101, Gainesville, FL 32611 [email protected]

Neurology® 2009;72:868–869

Neurologists and psychiatrists were willing to embrace the revolution of the serotonin reuptake inhibitor (SSRI) which in most offices replaced the standard tricyclic antidepressants (TCA) for treatment of depression in patients with Parkinson disease (PD). It is not hard to imagine how such a drastic transition occurred so rapidly, as there was a desire for a more refined and targeted therapy with fewer side effects (such as dry mouth, dry eyes, constipation, and confusion). The switch occurred, however, in the absence of a prospective, randomized, head-to-head comparison between SSRIs and TCAs. Menza et al.1 offer a true evidence-based comparison in this issue of Neurology®. With depression reported to occur in 40% or more of patients with PD,2,3 this is an important clinical study. The authors presented a simple study design that compared paroxetine CR, nortriptyline, and placebo in a 52-patient randomized trial. The doses were escalated up to three times, based on the clinician’s discretion, up to a top dose of 75 mg of nortriptyline, 37.5 mg of paroxetine CR, or three pills of placebo. The mean daily doses were 48.5 mg of nortriptyline and 28.4 mg of paroxetine CR. The authors chose a primary outcome of a change in Hamilton Depression Rating Scale (HAM-D) and a percentage of depression responders following 8 weeks of treatment. An intention-to-treat study design was employed with the last observation carried forward (LOCF) for all subjects during the 4- and 8-week timepoints. Eleven of 18 subjects on paroxetine, 12 of 17 on nortriptyline, and 11 of 17 on placebo completed the 8-week trial. Nortriptyline outperformed placebo on HAM-D, while paroxetine CR did not. Response rates also favored nortriptyline (53% vs 11%), as did sleep, anxiety, and social functioning.1 This report is in contrast to the results of a similar double-blind, placebo-controlled study by Devos et al.4 comparing desipramine (a TCA) vs citalopram (an SSRI) in 48 depressed subjects with PD. While

desipramine showed rapid improvement of depressive symptoms at the early timepoint, both drugs were equally efficacious at the study’s primary endpoint, with slightly more side effects in the desipramine group. Only 1 of 17 subjects on desipramine and 1 of 15 subjects on citalopram prematurely discontinued therapy.4 Thus, more subjects finished the trial in the Devos et al. study compared to Menza et al.’s experience.1 Comparing these two studies and critically analyzing the Menza et al. data offers us some potential explanations for the findings: 1. Extending the study by 4 more weeks may have yielded different results (slower acting paroxetine CR). 2. The sample size was small and a significant number of subjects prematurely discontinued the study. Utilizing the LOCF method among the dropouts in the Menza et al. study could have biased the results. 3. TCAs had an inherent advantage over SSRIs in improving sleep, which may have had little to do with improving depression (3 of 17 items in HAM-D). 4. Two items probed anxiety (psychic and somatic), which were also improved by TCAs over SSRIs. We wonder if the difference would have been less dramatic if sleep with or without anxiety items were discarded and only intrinsic symptoms of depression were used for the analysis. Despite the relatively clean study design, it is not inconceivable that when considering the small sample size, short study duration, high dropout rate, the “sprinting to efficacy” ability of TCAs (in contrast to SSRIs), and the LOCF methodology, in combination produced a type II error scenario. When a type II error occurs, a potentially good drug is missed (false-negative results). The other minor limitations of this study were the bias to include early age patients with PD (61– 63 years), shorter disease duration (4 – 8 years), and lesser disease severity (mean Hoehn and Yahr 2.2;

See page 886 e-Pub ahead of print on December 17, 2008, at www.neurology.org. From the Departments of Neurology, Neurosurgery, and Psychiatry, Movement Disorders Center, McKnight Brain Institute, Gainesville, FL. Disclosure: The authors report no disclosures. 868

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Unified Parkinson’s Disease Rating Scale numbers not reported). These variables limited the generalizability of this study. Nevertheless, depression is a common disabling feature in the early stages of PD. The safety issues of older subjects with PD with longer disease durations, greater cognitive difficulties, and those on higher doses of levodopa will need to be carefully factored into future trials, since more advanced and cognitively challenged patients with PD may be more susceptible to TCA-induced mental status problems, cardiac issues, and orthostatic hypotension.5,6 What we can conclude from this study is that cumulative data on PD depression are limited and conflicting.1,4,7–10 This study reminds us that TCAs are not necessarily less tolerated, and SSRIs may not be as efficacious as currently perceived by practice patterns. A larger and perhaps a longer duration clinical trial, taking into consideration the lessons learned from this important study, will be important. Such trials may demonstrate that, for a subpopulation of patients with non-motor PD symptoms, a TCA may be the right choice. REFERENCES 1. Menza M, DeFronzo Dobkin R, Marin H, et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology 2009;72:886–892. 2. Miller KM, Okun MS, Fernandez HF, Jacobson CET, Rodriguez RL, Bowers D. Depression symptoms in move-

3.

4.

5. 6.

7.

8.

9.

10.

ment disorders: comparing Parkinson’s disease, dystonia, and essential tremor. Mov Disord 2007;22:666–672. Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leentjens AF. A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord 2008;23:183–189. Quiz 313. Devos D, Dujardin K, Poirot I, et al. Comparison of desipramine and citalopram treatments for depression in Parkinson’s disease: a double-blind, randomized, placebo-controlled study. Mov Disord 2008;23:850–857. Papakostas GI. Tolerability of modern antidepressants. J Clin Psychiatry 2008;69suppl e1:8–13. Sala M, Coppa F, Cappucciati C, et al. Antidepressants: their effects on cardiac channels, QT prolongation and Torsade de Pointes. Curr Opin Investig Drugs 2006;7: 256–263. Avila A, Cardona X, Martin-Baranera M, Maho P, Sastre F, Bello J. Does nefazodone improve both depression and Parkinson disease? A pilot randomized trial. J Clin Psychopharmacol 2003;23:509–513. Chen P, Kales HC, Weintraub D, Blow FC, Jiang L, Mellow AM. Antidepressant treatment of veterans with Parkinson’s disease and depression: analysis of a national sample. J Geriatr Psychiatry Neurol 2007;20: 161–165. Tesei S, Antonini A, Canesi M, Zecchinelli A, Mariani CB, Pezzoli G. Tolerability of paroxetine in Parkinson’s disease: a prospective study. Mov Disord 2000;15:986– 989. Weintraub D, Taraborelli D, Morales KH, Duda JE, Katz IR, Stern MB. Escitalopram for major depression in Parkinson’s disease: an open-label, flexible-dosage study. J Neuropsychiatry Clin Neurosci 2006;18:377–383.

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869

EDITORIAL

Hepatitis vaccines and pediatric multiple sclerosis Does timing or type matter?

Jayne M. Ness, MD, PhD James F. Bale, Jr., MD

Address correspondence and reprint requests to Dr. Jayne M. Ness, University of Alabama at Birmingham, Children’s Hospital of Alabama, 1600 7th Avenue South, CHB 314, Birmingham, AL 35233-1711 [email protected]

Neurology® 2009;72:870–871

Pediatric multiple sclerosis (MS) accounts for fewer than 5% of MS cases. Nevertheless, these young patients with MS may provide invaluable insights regarding the pathogenesis of the disorder. Children with MS are closest to the onset of their disease, enabling detailed examination of potential environmental, viral, and genetic triggers. An ongoing controversy well-suited for study in a pediatric MS population is whether immunizations, particularly hepatitis B (HB) virus vaccine, increase the risk of MS and other forms of CNS demyelinating disease. In this issue of Neurology®, Mikaeloff et al.1 examine the timing and type of HB vaccine with respect to pediatric MS risk. Despite the benefits of HB prevention, implementation of universal HB immunization has been controversial. Case reports raising the concern of CNS demyelinating disease following HB vaccination emerged in the mid-1990s, but no association between HB vaccination and MS was found in a retrospective cohort study.2 Subsequent case– control studies also failed to identify an association between recent HB immunization and MS3-5 or subsequent relapse.6 Several review panels supported “rejection of a causal relationship between HB vaccine and MS.”7 Is the case settled? Not quite. In 2004, Neurology® published a study8 which analyzed MS and HB vaccine exposure in the General Practice Research Database of the United Kingdom. Eleven of 163 (6.7%) patients with MS had symptom onset within 3 years of HB vaccine compared to 39 of 1,604 (2.4%) case controls with no vaccination, resulting in an odds ratio (OR) of 3.1 (95% confidence interval [CI] 1.5, 6.3). These findings prompted others to reanalyze their populations in a similar manner, but these analyses did not alter the original conclusions that there was no association between HB vaccine and MS. The debate continues.9 Now a pediatric study of demyelinating disorders enters the fray. The French Kid Scle´rose en Plaque

(KIDSEP) follows 400⫹ patients who experienced an initial CNS demyelinating event ⬍age 16 between 1994 and 2003. Detailed immunization records are available for ⬎85% of patients. Approximately 40% of the patients have experienced recurrent demyelination which the authors define as MS. In December 2007, the KIDSEP investigators reported no difference in HB vaccine exposure of pediatric patients with MS compared to controls matched by age, sex, and region of France.10 However, further stratification by HB vaccine brand and time from last HB immunization to disease onset (index date) suggested a slight increased risk of MS in patients who received Engerix-B ⬎3 years prior to initial symptoms (OR 1.68; CI 0.92–3.04), although it did not reach significance. In their current report, Mikaeloff and KIDSEP investigators examined HB vaccine exposure in the 50% of demyelinating patients and controls who were compliant with vaccination (defined by receiving BCG, one MMR, and three of the diphtheria-tetanus-poliomyelitis series). No effect of HB brand or timing was observed in patients with a single demyelinating event, but in the 72 vaccine-compliant subjects with MS, 19 (31%) had Engerix-B exposure ⬎3 years prior to the index date (adjusted OR 1.74; 95% CI 1.03– 2.95). Although the increased MS risk observed in vaccine-compliant patients appears related to remote exposure to Engerix-B, twice as many pediatric subjects with MS were immunized with Engerix-B (n ⫽ 30) as the other formulations combined (GenHevacB, HevacB, Recombivax HB, Twinrix). Is this a spurious observation due to multiple comparisons, in which the likelihood of identifying a significant association increases with each subanalysis? Or is there really an increased risk of pediatric MS in vaccine-compliant children ⬎3 years after exposure to a specific brand of HB vaccine? Engerix-B and Recombivax HB, the only single antigen HB vaccines available in the United States and Canada,

See page 873 e-Pub ahead of print on December 17, 2008, at www.neurology.org. From the Department of Neurology (J.M.N.), University of Alabama at Birmingham, Children’s Hospital of Alabama; and Departments of Pediatrics and Neurology (J.F.B.), University of Utah School of Medicine, Primary Children’s Medical Center, Salt Lake City. Dr. Ness has funding from NIH and National Multiple Sclerosis Society. Dr. Bale has funding from the NIH. Disclosure: The authors report no disclosures. 870

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both contain the recombinant 226-amino acid S gene product of the HB major surface antigen generated in cultures of Saccharomyces cerevisiae (baker’s yeast). GenHevac B (not licensed in the United States or Canada) contains both PreS2 and S recombinant proteins generated in a mammalian cell line. The KIDSEP findings emphasize the importance of examining both the type and timing of immunization with respect to disease risk. A pediatric cohort is well-suited for this analysis as many countries require detailed immunization records for school attendance. This carefully performed case– control analysis of a well-defined population of pediatric demyelinating patients suggests a small increased risk of pediatric MS in a vaccine-compliant group following remote exposure to a specific HB vaccine. Before concluding that there may be a link between HB immunization and MS, however, other adult and pediatric MS populations must be studied in similar detail. If the association of MS with specific HB vaccines is substantiated, this finding may enable identification of triggers that may or may not have structural or antigenic similarities to the vaccine-associated HB antigens. In the meantime, current recommendations for widespread HB vaccination should be supported as the real risk of HB infection still outweighs the theoretical risk of developing MS.

REFERENCES 1. Mikaeloff Y, Caridade G, Suissa S, Tardieu M. Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood. Neurology 2009;72:873–880. 2. Zipp F, Weil JG, Einhaupl KM. No increase in demyelinating diseases after hepatitis B vaccination. Nat Med 1999;5:964–965. 3. Asherio A, Zhang S, Herna´n M, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 2001; 344:327–332. 4. Touze E, Fourrier A, Rue-Fenouche C, et al. Hepatitis B vaccination and first central nervous system demyelinating event: a case-control study. Neuroepidemiology 2002;21:180–186. 5. DeStefano F, Verstraeten T, Jackson LA, et al. Vaccinations and risk of central nervous system demyelinating diseases in adults. Arch Neurol 2003;60:504–509. 6. Confavreux C, Suissa S, Saddier P, Bourdes V, Vukusic S. Vaccinations and the risk of relapse in multiple sclerosis. N Engl J Med 2001;344:319–326. 7. DeStefano F, Verstraeten T, Chen RT. Hepatitis B vaccine and risk of multiple sclerosis. Exp Rev Vaccines 2002;1:461–466. 8. Herna´n MA, Jick SS, Olek MJ, Jick H. Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study. Neurology 2004;63:838–842. 9. Destefano F, Weintraub ES, Chen RT. Hepatitis B vaccine and risk of multiple sclerosis. Pharmacoepidemiol Drug Saf 2007;16:705–707. 10. Mikaeloff Y, Caridade G, Rossier M, Suissa S, Tardieu M. Hepatitis B vaccination and the risk of childhood-onset multiple sclerosis. Arch Pediatr Adolesc Med 2007;161: 1176–1182.

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IN MEMORIAM

Julius Korein, MD (1928 –2008)

Calixto Machado, MD, PhD

Julius Korein, MD

The global neurology and neuroscience communities mourn the passing of Professor Emeritus of Neurology Julius Korein, MD, on November 12, 2008, at age 80. Dr. Korein graduated from the New York College of Medicine in 1953 and from the neurology residency program in the NYU-Bellevue Hospital Center in 1955. Dr. Korein spent most of his professional life as Professor of Neurology at NYU and as a research physician at Bellevue Hospital. He was Director of the EEG laboratories at Bellevue Hospital for 34 years. He published more than 100 articles and book chapters and had been a member of the American Academy of Neurology since 1954. Dr. Korein was best known for his work on brain death. In 1978, he chaired a memorable conference, “Brain Death: Interrelated Medical and Social Issues,” attended by the outstanding scholars in the field at the time, the proceedings of which were subsequently published. In the preface of the book, Dr. Korein remarked, “In my early training in medicine, I encountered this problem and formed a philosophy which I expressed in a poem that ended with the line, ‘Death is the closing of an eye of God.’” He was a strong defender of the thesis that an individual is

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dead when the brain is dead. Dr. Korein had participated as a primary researcher in the Collaborative Study of several US institutions to set the criteria of so-called cerebral death in the 1970s. He achieved recent notoriety as an authority on the persistent vegetative state. His testimony on the Karen Ann Quinlan case was known worldwide when he stated: “Karen is not in a ‘locked-in’ syndrome, i.e., a state in which she sees, hears, or understands but cannot communicate. She is a vegetable.” Dr. Korein attended the Second International Symposium on Brain Death held in Havana in 1996. In the opening lecture, he presented his pioneering views and thoughts about human death. When asked about consciousness, the brain, and brain death, he would likely discuss quantum physics, and theories concerning the origin of the universe. He had an enduring vision that we cannot understand brain function and human consciousness without discovering the scientific laws that govern the interrelationships between the brain, the mind, and the universe. He was an early defender of using computers for biologic signal processing and compilation of medical data. He also performed extensive research in biofeedback, including treatment of torticollis, dystonia, and other diseases. Outside neurology, he was a major coin collector, creating the most complete collection of Gobrecht Dollars on the globe, which he donated to the American Numismatic Society. He loved nature and was a passionate scuba diver, exploring reefs around the world. He chaired the Korein Foundation, a charitable organization to support scientific, environmental, and educational projects. He is survived by his significant other Gillian Hee, sister Elysabeth, children James, Jonathan, and Beth, nine grandchildren, and a greatgranddaughter. Dr. Julius Korein is a symbol to present and future generations of an exceptional neuroscientist and human being and he will be deeply missed.

ARTICLES

Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood

Yann Mikaeloff, MD, PhD Guillaume Caridade, MSc Samy Suissa, PhD Marc Tardieu, MD, PhD

Address correspondence and reprint requests to Dr. Yann Mikaeloff, Service de Neurologie Pe´diatrique, CHU Biceˆtre, Assistance Publique-Hoˆpitaux de Paris, 78 Avenue du Ge´ne´ral Leclerc, 94275 Le KremlinBiceˆtre Cedex, France [email protected]

ABSTRACT

Background: The risk of CNS inflammatory demyelination associated with hepatitis B (HB) vaccine is debated, with studies reporting conflicting findings.

Methods: We conducted a population-based case-control study where the cases were children with a first episode of acute CNS inflammatory demyelination in France (1994 –2003). Each case was matched on age, sex, and geographic location to up to 12 controls, randomly selected from the general population. Information on vaccinations was confirmed by a copy of the vaccination certificate. The odds ratios (ORs) of CNS inflammatory demyelination associated with HB vaccination were estimated using conditional logistic regression.

Results: The rates of HB vaccination in the 3 years before the index date were 24.4% for the 349 cases and 27.3% for their 2,941 matched controls. HB vaccination within this period was not associated with an increase in the rate of CNS inflammatory demyelination (adjusted OR, 0.74; 0.54 –1.02), neither ⬎3 years nor as a function of the number of injections or brand type. When the analysis was restricted to subjects compliant with vaccination, HB vaccine exposure ⬎3 years before index date was associated with an increased trend (1.50; 0.93–2.43), essentially from the Engerix B vaccine (1.74; 1.03–2.95). The OR was particularly elevated for this brand in patients with confirmed multiple sclerosis (2.77; 1.23– 6.24).

Conclusions: Hepatitis B vaccination does not generally increase the risk of CNS inflammatory demyelination in childhood. However, the Engerix B vaccine appears to increase this risk, particularly for confirmed multiple sclerosis, in the longer term. Our results require confirmation in future studies. Neurology® 2009;72:873–880 GLOSSARY ADEM ⫽ acute disseminated encephalomyelitis; BCG ⫽ Bacille Calmette–Gue `rin; HB ⫽ hepatitis B; MS ⫽ multiple sclerosis; OR ⫽ odds ratio.

The first reports of an association between recombinant hepatitis B (HB) vaccine exposure and cases of CNS inflammatory demyelination involved not only multiple sclerosis (MS) but also clinically isolated syndromes such as acute disseminated encephalomyelitis (ADEM) or transverse myelitis.1 The later conditions are in fact considered to be more likely than MS a consequence of acute exposure to viral or vaccine antigen stimulation.2-4 However, most epidemiologic studies were performed in adult patients and evaluated the association between HB vaccine and an increase in confirmed MS. They demonstrated for most of them no increase in risk after immunization but methodologic limitations were raised by some authors.5-9 Only one database nested case-control study reported a significant increase in the risk of adult-onset MS within the first 3 years of vaccination.10 In a recent population-based case-control study,

Editorial, page 870 e-Pub ahead of print on October 8, 2008, at www.neurology.org. From Assistance Publique-Hoˆpitaux de Paris, Service de Neurologie Pe´diatrique and Centre de Re´fe´rence National des Maladies Inflammatoires du Cerveau de l’Enfant (Y.M., G.C., M.T.), INSERM U822 (Y.M., G.C.), and INSERM U802 (M.T.), Hoˆpital Biceˆtre, Universite´ Paris Sud 11, Le Kremlin Biceˆtre, France; and Division of Clinical Epidemiology (S.S.), McGill University and Royal Victoria Hospital, Montreal, Canada. Funded by grants from the “Agence Franc¸aise de Se´curite´ Sanitaire des Produits de Sante´” (AFSSAPS), the “Agence Nationale de Recherche sur le SIDA et les hépatites” (ANRS), and the French Ministry of Health by a grant from the “Projet Hospitalier de Recherche Clinique” and by the “Direction Ge´ne´rale de la Sante´.” S. Suissa holds a Distinguished Scientist award from the Canadian Institutes of Health Research (CIHR). Disclosure: The authors report no disclosures. Copyright © 2009 by AAN Enterprises, Inc.

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we found no increase in the risk of incident MS, even within prolonged risk periods after vaccination.11 However, we observed a trend toward an increased risk over the long term and a slight difference between HB vaccine brand types. We performed a population-based casecontrol study to investigate whether exposure to the HB vaccine in childhood increases the risk of a first ever episode of acute CNS inflammatory demyelination. METHODS This study is a part of a research program evaluating the impact of environmental risk factors on acute CNS inflammatory demyelinations in childhood. A first study assessed the risk of childhood-onset MS and found no association with HB vaccine exposure.11 The present study addresses the risk of a first ever episode of acute CNS inflammatory demyelination in childhood, whatever the course of the disease after the first attack.

Cases definition and controls selection. The case series for this study was selected from patients enrolled in the French neuropediatric “KIDSEP” cohort.12-15 Cases were all patients with a first episode of acute CNS inflammatory demyelination occurring between January 1, 1994, and December 31, 2003, before the age of 16 years, and born in France. Thus, the case definition includes patients with single episodes without relapse during the follow-up, as well as patients who went on to relapse and were diagnosed with MS. The last group of patients was included in the previous study with a similar design that tested specifically confirmed MS.11 The procedure of population-based selection of controls was previously described in detail.11 In short, we aimed to individually match each case with up to 12 controls selected from the French general population on the basis of age (⫾6 months), sex, and current area of residence. Controls were selected by random telephone dialing in the geographic area of residence of each case. Households including an eligible subject were sent an information letter and questionnaire after consent. Each matched control was assigned the index date of the case (the date of onset of the symptoms of the first episode) for the evaluation of previous vaccinations.

Data collection and exposure confirmation. An information letter and a questionnaire were sent to all cases and controls, as previously described.11 In summary, a copy of the child’s vaccination certificate (carnet de sante´), that includes all recordings of vaccinations and particularly for HB, was requested as well as information on familial autoimmune history (in siblings or parents) and parental smoking at home before index date. Statistical analysis and ethical considerations. Conditional logistic regression for matched case-control data was used to estimate odds ratios (ORs) of first ever episodes of acute CNS inflammatory demyelination associated with HB vaccine exposure. Subjects not exposed to HB vaccine, between birth and the index date, were used as the reference group. In addition to the intrinsic confounder adjustment for the matching factors, the regression model was used to perform further adjustment for family history of MS or of other autoimmune diseases, occupation of the head of the family, and parental smoking at home.16 874

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Various exposure time windows were used. Our primary hypothesis was the time window of effect within or more than the last 3 years before index date. The study was determined to have sufficient power to detect an OR of 1.5, with a minimal number of four controls per case, considering a frequency of exposure of 20% for 3 years in the controls. In addition, we studied ever use (defined by the entire exposure period spanned from birth to index date), the number of doses, and the major brand type of vaccine (last injection before index date). Different sensitivity analyses were also realized. Analyses were restricted to cases without a family history of MS or another autoimmune disease, or with a low socioprofessional status of head of family, or with an age at index date ⱖ3 years (to eliminate possible biases from younger children not exposed for the full 3-year exposure period), or with an age at index date ⱖ10 years, or belonging to one or the other group of severity among MS cases. We also considered the year period just before the index date as an unexposed period to assess the theoretical possibility of a prescription bias in cases related to unrecognized symptoms during this period and performed another analysis excluding the controls recruited from the same household. To control for a potential selection bias from subjects who agreed to participate in the study, we performed an analysis restricted to cases and controls compliant with vaccinations guidelines. We considered the distribution of vaccine coverage in children in France in the study period to develop the definition.17 Compliant subjects were defined as receiving at least one Bacille Calmette–Gue`rin (BCG) vaccine, one mumps-rubellameasles vaccine, and four diphtheria-tetanus-poliomyelitis vaccine during the first 2 years of life. BCG vaccine is an obligation to be accepted in community care structures (day-nursery, nursery school) in France but could also be realized voluntarily. Mumps-rubella-measles is recommended by Health Authorities but is not an obligation. Diphtheria-tetanus-poliomyelitis vaccine is an obligation (three injections at 2, 3, and 4 months of age and a booster before 18 months of age). Other less restricted definitions of compliance were also used: 1) four diphtheriatetanus-poliomyelitis vaccine and one mumps-rubella-measles during the first 2 years of life, and 2) one mumps-rubella-measles during the first 2 years of life. These sensitivity analyses were not performed in our previous study11 and, accordingly, we also reanalyzed cases with a relapsing course (confirmed MS). The study was approved by the Comite´ National Informatique et Liberte´ (the French data protection agency). All patients gave informed consent for their inclusion in the study. The study was supported by the Socie´te´ Franc¸aise de Neurope´diatrie and the French Ministry of Health (Direction Ge´ne´rale de la Sante´). The study was overseen by a scientific committee and advisory board composed of independent experts who approved the protocol, conduct, analysis, interpretation, and publication of the study.

The initial case series amounted to 403 cases, of which 86.6% agreed to participate, including 349 cases who provided a copy of their vaccination certificate and who were retained for analysis. These were not significantly different baseline characteristics from the 54 patients who did not participate (data not shown). Among the 349 cases included in the study, the diagnosis confirmed by the course of disease was 1) single episodes without relapse for 198 cases including ADEM (n ⫽ 79,

RESULTS

Table 1

Characteristics of cases with a first episode of acute CNS inflammatory demyelination and matched population-based controls All case patients (n ⴝ 349)

Variable Male

156 (44.7)

Age, y, mean ⴞ SD

9.3 ⫾ 4.6

Residence in Paris or suburbs Familial MS history Other familial autoimmune disease history Low socioprofessional status of head of family (unemployed people, laborers, and low-income employees) Infection during the month before disease onset

All matched controls* (n ⴝ 2,941) 1,349 (45.9) 9.0 ⫾ 4.5

109 (31.2)

898 (30.5)

8† (2.3)

31 (1.1)

18 (5.2)

210 (7.1)

166† (47.6)

1,606 (54.6)

149 (43)

Symptoms at disease onset Multiple

219 (64)

Transverse myelitis

49 (14)

Optic neuritis

86 (25)

Severe mental status change

121 (35)

Brainstem dysfunction

127 (36)

CSF Oligoclonal bands Cells >10/␮L Proteins >0.5 g/dL

89 (26) 157 (45) 88 (25)

MRI Child-MS MRI criteria‡

124 (36)

Three Barkhof MRI criteria§

124 (36)

*Matched on age (⫾6 months), sex, geographic location (place of residence). †p ⬍ 0.05 (␹2 test for comparison of proportions or t test for comparison of means). ‡Corpus callosum long axis perpendicular lesions or sole presence of well-defined lesions.13 § Three criteria among four: at least one gadolinium-enhancing T1 lesion or ⱖ9 T2 lesions, at least one infratentorial T2 lesion, at least one juxtacortical T2 lesion, ⱖ3 periventricular lesions.31

39.9%), isolated optic neuritis (n ⫽ 19, 9.6%), isolated transverse myelitis (n ⫽ 18, 9.1%), and brainstem dysfunction (n ⫽ 8, 4.0%), and other episodes (n ⫽ 74, 37.4%); 2) MS (confirmed by at least one other episode) for 151, including 90 (59.6%) with a higher initial index of early severity.14 A total of 371,996 households were contacted for the recruitment of controls. Among the 5,838 eligible households contacted, 1,666 refused to participate in the study at first contact. We identified 4,172 eligible controls who accepted and could be matched to the case on age, sex, and geographic location; 2,941 of them provided vaccination information (response rate 70.5%). The reasons for a lack of vaccination information for 1,231 recruited controls, despite initial consent, were no response despite a full recall procedure (n ⫽ 807, 65.6%), refusal at first recall (n ⫽ 208, 16.9%), lost vaccination certificate (n ⫽ 98, 8.0%), never reached by phone or incorrect telephone number or address given (n ⫽ 118, 9.5%).

Our analyses therefore included 349 cases of first episode of acute CNS inflammatory demyelination and 2,941 matched controls (n ⫽ 207, 7.0) were recruited from the same household) (table 1). Vaccination information was provided in the form of a copy of the vaccination records for 97.7% (n ⫽ 2,873) of controls; the others had a standardized telephone interview. However, all these data were used for analysis. The median number of controls per case was 9 (mean: 8.4): 60 (17.2%) had 11 to 12 controls, 232 (66.5%) had 7 to 10 controls, 50 (14.3%) had 4 to 6 controls, and only 7 cases (2.0%) had 1 to 3 controls. The frequency of family heads with a low socioprofessional status was lower for cases than for controls (table 1). The frequency of family history of MS was higher in cases, but the frequency of familial autoimmune diseases was similar in the two groups. The rates of any HB vaccination in the 3 years before the index date were 24.4% for the 349 cases and 27.3% for their 2,941 matched controls. The adjusted OR of such episode occurrence associated with any HB vaccination during a risk period of 3 years was 0.74 (95% CI: 0.54 –1.02). Other results of analyses in all study subjects are presented in table 2. Similar results were obtained for more detailed risk periods within 3 years, ever use, number of HB immunizations, and last brand type used. ORs were similarly not significantly different from 1 in analyses restricted to cases without a family history of MS or another autoimmune disease, or with a low socioprofessional status of head of family, or with an age at index date ⱖ3 years, or with an age at index date ⱖ10 years, or belonging to one or the other group of severity among MS cases. Similar results were found in considering the 1-year period just before the index date as an unexposed period or excluding the controls recruited from the same household. When cases compliant with vaccination guidelines were compared with noncompliant according to variables of table 1, there were no significant differences except for location in Paris and suburbs for cases with a CNS inflammatory demyelination (42.9% in compliant vs 21% in noncompliant) and for the detection of oligoclonal bands in CSF (36.1% in compliant vs 58.2% in noncompliant) for confirmed MS. There was no differential compliance between cases and their matched controls because, before exclusions of cases without controls and of controls without cases required by the analysis method, 166/349 (47.6%) cases with a CNS inflammatory demyelination and 1,612/2,941 (54.8%) of their controls were compliant. It was the same for cases with confirmed MS: before exclusions required by the analysis method, 74/151 (49.0%) cases and 615/1,192 (51.6%) of their controls were compliant. Neurology 72

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Table 2

Crude and adjusted OR of acute CNS inflammatory demyelination associated with timing, number, and brand of hepatitis B vaccine

Hepatitis B (HB) vaccine exposure

Case patients (n ⴝ 349), n (%)

Matched controls* (n ⴝ 2,941), n (%)

Crude OR†

Adjusted OR (95% CI)‡

No HB vaccination

195 (55.9)

1,543 (52.5)

1

Reference

Ever use

154 (44.1)

1,398 (47.5)

0.80

0.81 (0.62–1.05)

0–1 y

30 (8.6)

317 (10.8)

0.64

0.65 (0.42–1.02)

>1–2 y

25 (7.2)

247 (8.4)

0.67

0.70 (0.43–1.16)

>2–3 y

30 (8.6)

239 (8.1)

0.93

0.94 (0.58–1.51)

>3 y

69 (19.8)

595 (20.2)

0.92

0.93 (0.65–1.31)

1–2

23 (6.6)

187 (6.4)

0.79

0.80 (0.48–1.32)

>3

131 (37.5)

1,211 (41.2)

0.80

0.81 (0.62–1.06)

Engerix B ever use

84 (24.1)

724 (24.6)

0.85

0.86 (0.63–1.16)

Engerix B 0–3 y

45 (12.9)

409 (13.9)

0.75

0.76 (0.52–1.12)

Engerix B >3 y

39 (11.2)

315 (10.7)

0.98

0.98 (0.65–1.48)

47 (13.5)

415 (14.1)

0.77

0.78 (0.52–1.16)

GenHevac B 0–3 y

24 (6.9)

229 (7.8)

0.65

0.68 (0.40–1.14)

GenHevac B >3 y

23 (6.6)

186 (6.3)

0.92

0.91 (0.54–1.54)

23 (6.6)

259 (8.8)

0.70

0.71 (0.45–1.14)

16 (4.6)

165 (5.6)

0.77

0.79 (0.46–1.38)

7 (2.0)

94 (3.2)

0.58

0.59 (0.26–1.32)

HB vaccination before index date

No. of HB immunizations before index date

Last brand type used before index date

GenHevac B ever use

Other HB vaccine ever use

§

Other HB vaccine 0–3 y Other HB vaccine >3 y

*Matched on age (⫾6 months), sex, geographic location (current place of residence). †No HB vaccine exposure is the reference group. ‡Adjusted on covariates: familial multiple sclerosis history, family history of another autoimmune disease, parental smoking at home before index date, socioprofessional status of the head of the family. § HBVax, Hevac B, Twinrix, or Recombivax.

As shown in table 3, when the analysis was restricted to compliant cases and their matched compliant controls, HB vaccine exposure ⬎3 years before index date was associated with an increased trend for acute CNS inflammatory demyelination, essentially from the Engerix B vaccine. The OR was particularly elevated for this major brand type in patients with confirmed MS (table 4). Similar results were found with other less restricted definition of compliance to vaccination (four diphtheria-tetanuspoliomyelitis vaccine and one mumps-rubellameasles during the first 2 years of life). Engerix B exposure ⬎3 years before index date was associated with an adjusted OR of 1.50 (0.92–2.45) for CNS inflammatory demyelination and 2.40 (1.16 – 4.94) for confirmed MS. GenHevac B was associated with ORs of 1.36 (0.69 –2.70) for CNS inflammatory demyelination and 1.21 (0.43–3.44) for confirmed MS. Similar results were also found with a third definition of compliance to vaccination (recommended but not obligated: one mumps-rubella-measles during the first 2 years of life). Engerix B exposure ⬎3 years before index date was associated with an ad876

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justed OR of 1.29 (0.82–2.03) for CNS inflammatory demyelination and 1.96 (1.00 –3.82) for confirmed MS. GenHevac B was associated with ORs of 1.48 (0.80 –2.71) for CNS inflammatory demyelination and 1.18 (0.46 –3.06) for confirmed MS. DISCUSSION This study is the second part of a research program evaluating the impact of vaccinations on acute CNS inflammatory demyelination in childhood. We evaluate the risk associated with HB vaccine exposure of any first episode of acute CNS inflammatory demyelination in childhood and report of a lack of increase in risk within a risk period of 3 years or more or considering the number of injections. However, in the subgroup analysis restricted to subjects compliant with vaccinations guidelines, Engerix B exposure ⬎3 years before index date was associated with an increased risk that was significant in patients who went on to develop MS. Our new results suggesting a possible association of HB vaccine with pediatric MS (albeit HB vaccine of a specific manufacturer and only in vaccine-compliant

Table 3

Crude and adjusted OR of acute CNS inflammatory demyelination associated with timing, number, and brand of hepatitis B vaccine, restricted to subjects compliant with vaccination*

Hepatitis B (HB) vaccine exposure

Case patients (n ⴝ 163) , n (%)

Matched controls† (n ⴝ 892) , n (%)

Crude OR‡

Adjusted OR (95% CI)§

Unvaccinated

78 (47.9)

435 (48.8)

1

Reference

85 (52.1)

457 (51.2)

0.96

1.03 (0.70–1.51)

Vaccinated against HB before index date Ever use 0–1 y

13 (8.0)

78 (8.7)

0.78

0.81 (0.40–1.63)

>1–2 y

11 (6.7)

87 (9.8)

0.42

0.45 (0.20–1.01)

>2–3 y

14 (8.6)

>3 y

47 (28.8)

79 (8.9)

0.82

0.89 (0.43–1.84)

213 (23.8)

1.40

1.50 (0.93–2.43)

54 (6.1)

0.93

0.99 (0.46–2.15)

No. of HB immunizations before index date 1–2

11 (6.7)

>3

74 (45.4)

403 (45.2)

0.96

1.03 (0.70–1.53)

Engerix B ever use

51 (31.3)

236 (26.5)

1.11

1.17 (0.76–1.79)

Engerix B 0–3 y

20 (12.3)

121 (13.6)

0.68

0.71 (0.39–1.29)

Engerix B >3 y

31 (19.0)

115 (12.9)

1.63

1.74 (1.03–2.95)

22 (13.5)

121 (13.6)

0.91

1.03 (0.56–1.89)

Last brand type used for vaccination before index date

GenHevac B ever use GenHevac B 0–3 y

10 (6.1)

63 (7.1)

0.61

0.68 (0.28–1.65)

GenHevac B >3 y

12 (7.4)

58 (6.5)

1.34

1.50 (0.71–3.17)

12 (7.4)

Other HB vaccine ever use


100 (11.2)

0.65

0.70 (0.35–1.41)

Other HB vaccine 0–3 y

8 (4.9)

60 (6.7)

0.69

0.75 (0.32–1.77)

Other HB vaccine >3 y

2 (2.5)

40 (4.5)

0.59

0.63 (0.20–2.00)

*Defined as at least one BCG vaccine, one mumps-rubella-measles vaccine, and four diphtheria-tetanus-poliomyelitis vaccine during the first 2 years of life. †Matched on age (⫾6 months), sex, geographic location (current place of residence). ‡No HB vaccine exposure is the reference group. § Adjusted on covariates: familial multiple sclerosis history, family history of another autoimmune disease, parental smoking at home before index date, socioprofessional status of the head of the family.
HBVax, Hevac B, Twinrix, or Recombivax.

cases) are not in contradiction with prior results. Indeed, in this new study, we enlarged the analysis to all first episodes of CNS inflammatory demyelination and tried to address the potential selection bias from the partial answer of subjects who could participate, using different definitions of compliance to vaccination guidelines. The first case reports in adults of a possible association between recombinant HB vaccine exposure and CNS inflammatory demyelination involved any first episodes of acute CNS inflammatory demyelination.1,18-25 A French case-control study included 236 adult cases (193 with an initial episode of definite or probable MS according to follow-up data) and 355 matched controls recruited in hospital.26 The adjusted ORs for CNS inflammatory demyelination within a 2-month risk period was 1.8 (95% CI: 0.7– 4.6) in the whole group and 1.4 (95% CI: 0.4 – 4.5) in the subgroup of subjects referring to vaccination certificates during the phone interview. In a retrospective cohort study on 134,698 individuals (children and adults) enrolled in the US healthcare

database (integrated pharmacy and medical claims from six health maintenance organizations plans) from 1988 to 1995, authors found no association between CNS inflammatory demyelination and HB vaccine (comparison to nonvaccinated individuals matched on age and sex) in the 3 years after vaccination and over.27 However, the accuracy of validation of MS status was debated.9 Two case-control studies in adults focused on recombinant HB vaccine with a systematic validation procedure for case status and ascertainment of information on vaccinations from computerized records. The first, in three American health maintenance organizations, involved 108 cases of isolated optic neuritis and 332 of MS, matched to 950 controls, and found no increase in risk of both diseases combined or analyzed separately, associated with HB vaccine in the short or the long term (⬍1 year, 1–5 years, ⬎5 years, and within 3 years after HB vaccination).6,7 The second, a large database nested case-control study with patients issued from the General Practice Research Database in UK, involved 163 cases of MS, Neurology 72

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877

Table 4

Crude and adjusted OR of confirmed multiple sclerosis associated with timing, number, and brand of hepatitis B vaccine, restricted to subjects compliant with vaccination*

Hepatitis B (HB) vaccine exposure

Case patients (n ⴝ 72), n (%)

Matched controls† (n ⴝ 347), n (%)

Crude OR‡

Adjusted OR (95% CI)§

Unvaccinated

27 (37.5)

153 (44.1)

1

Reference

Ever use

45 (62.5)

194 (55.9)

1.26

1.35 (0.72–2.56)

0–1 y

6 (8.3)

29 (8.4)

0.98

0.88 (0.28–2.79)

>1–2 y

6 (8.3)

41 (11.7)

0.42

0.45 (0.12–1.71)

8 (11.1)

36 (10.4)

1.10

1.20 (0.38–3.74)

25 (34.6)

88 (25.4)

1.86

2.12 (1.00–4.48)

Vaccinated against HB before index date

>2–3 y >3 y No. of HB immunizations before index date 1–2

5 (6.9)

27 (7.8)

0.78

0.75 (0.21–2.61)

>3

40 (55.6)

167 (48.1)

1.34

1.48 (0.78–2.82)

Engerix B ever use

30 (41.7)

91 (26.2)

1.71

1.92 (0.96–3.85)

Engerix B 0–3 y

11 (15.3)

43 (12.4)

1.05

1.11 (0.43–2.90)

Engerix B >3 y

Last brand type used for vaccination before index date

19 (26.4)

48 (13.8)

2.38

2.77 (1.23–6.24)

GenHevac B ever use

11 (15.3)

68 (19.6)

0.82

0.96 (0.38–2.46)

GenHevac B 0–3 y

6 (8.3)

35 (10.1)

0.69

0.82 (0.22–3.00)

GenHevac B >3 y

5 (6.8)

33 (9.5)

0.98

1.13 (0.36–3.55)

Other HB vaccine ever use


4 (5.6)

35 (10.1)

0.60

0.55 (0.14–2.07)

Other HB vaccine 0–3 y

3 (4.2)

28 (8.1)

0.51

0.45 (0.09–2.21)

Other HB vaccine >3 y

1 (1.4)

7 (2.0)

0.90

0.88 (0.07–10.54)

*Defined as at least one BCG vaccine, one mumps-rubella-measles vaccine, and four diphtheria-tetanus-poliomyelitis vaccine during the first 2 years of life. †Matched on age (⫾6 months), sex, geographic location (current place of residence). ‡No HB vaccine exposure is the reference group. § Adjusted on covariates: familial multiple sclerosis history, family history of another autoimmune disease, parental smoking at home before index date, socioprofessional status of the head of the family.
HBVax, Hevac B, Twinrix, or Recombivax.

matched to 1,604 controls, and reported a significant increase in the risk of adult-onset MS within the first 3 years of vaccination for adult MS (OR 3.1; 95% CI: 1.5– 6.3).10 The brand types used were not specified in all these studies. The strengths of our study include the accurate ascertainment of the first episode of acute CNS inflammatory demyelination, the validation of the vaccination status by a copy of the vaccination certificates, and the inclusion of the vast majority of incident pediatric cases in France.11 Another was the population-based nature of the selection of controls by random sampling for controls among the French population, with matching on age, sex, and geographic area of living of the corresponding case. It was tempered by the partial response rate of controls. Indeed, 1,666 eligible households contacted refused to participate in the study. Although these controls were replaced by others who were also individually matched with cases and agreed to participate at initial contact, this could have introduced a selection bias. However, it is a constant limitation of case-control 878

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studies on vaccine safety and the level of participation we obtained was satisfying compared to previous population-based case-control field studies, as discussed previously.11,16,28,29 To address this bias, we restricted the analysis to subjects who were compliant with vaccinations guidelines. We deemed that the actual response rate to our requests among compliant subjects would be higher than in less compliant subjects. The rates of exposure to vaccines in controls were consistent with that previously described for the general childhood population in France, considering the study period.17 In compliant subjects, the OR was particularly elevated for Engerix B vaccine, the major brand type, in patients with confirmed MS. This analysis was not performed in our previous study in patients with MS that already indicated a nonsignificant trend toward a higher risk in subjects having received Engerix B ⬎3 years before the index date. Considering the relatively small number of exposed subjects, the results concerning GenHevac B vaccine should be considered inconclusive. A clinically relevant risk associated with this vaccine cannot

be ruled out by this study. Our significant results concerning Engerix B vaccine were obtained from subgroup analyses, and were thus subject to false significance from multiple comparisons. Nevertheless, the risk magnitude we observed in patients with MS for Engerix B vaccine exposure is close to the one using the General Practice Research Database in United Kingdom, for exposure to any HB vaccine within 3 years before index date.10 However, this latter study did not present analysis according to the brand. Further studies would be needed to assess the brand influence among the UK population of adults in this study period and to confirm our results in children. Differences between children and adults in susceptibility to immune stimulation must be considered to interpret the results.3,30 Two possible explanations for the differences between brands could be as follows: 1) each vaccine uses a different section of the HBs antigen and some protein fragments produced by yeasts may induce molecular mimicry while others do not; 2) the production process varies by brand and differences in yeast protein content may be crucial if yeast protein may trigger autoimmune reactions: it is stated in the description of Engerix B manufacturing process that the vaccine has no more than 5% of yeast proteins, whereas it is no more than 1% for GenHevac B. ACKNOWLEDGMENT Professional organization specializing in population-based opinion polls and case-control studies on health topics responsible for the populationbased selection of controls: CSA Institute (Paris, France). The authors thank Me´lanie Rossier and Chittima Tilavanh for assistance in the collection of questionnaires.

APPENDIX Members of the Scientific Committee and Advisory Board: Dr. Annick Alperovitch (Epidemiologist, Paris, France), Prof. Jacques Benichou (Biostatistician, INSERM U 657, Rouen, France), Prof. Ge´rard Bre´art (Epidemiologist, INSERM U149, Paris, France), Prof. Bertrand Fontaine (Neurologist, Pitie´-Salpe´trie`re Hospital, Paris, France), Prof. Edeltraut Garbe (Pharmacologist/epidemiologist, Berlin, Germany), Prof. Miguel Hernan (Epidemiologist, Boston, MA). Participants of the KIDSEP-VAC study group: Pediatric neurology departments (France): D. Amsallem (Besanc¸on); P. Aubourg (Hoˆpital SaintVincent de Paul, Paris); M.A. Barthez, P. Castelnau (Tours); P. Berquin (Amiens); O. Boespflug (Clermont-Ferrand); J.C. Carrie`re, C. Cances, Y. Chaix (Toulouse); J.M. Cuisset, J.C. Cuvelier, L. Valle´e (Lille); A. de Saint-Martin (Strasbourg); I. Desguerre, O. Dulac (Necker-Enfants Malades, Paris); V. Des Portes, C. Rousselle, D. Ville (Lyon); B. Echenne, F. Rivier (Montpellier); P. Evrard (Hoˆpital Robert Debre´, Paris); A. Joannard (Grenoble); P. Landrieu, Y. Mikaeloff, M. Tardieu (Biceˆtre); M.O. Livet (Aix en Provence); J. Mancini, B. Chabrol (Marseilles); J. Motte, N. Bednarek, P. Sabouraud (Reims); S. Napuri, L. Lazaro (Rennes); S. Nguyen (Nantes); S. Peudenier (Brest); F. Pouplard (Angers); J.M. Pedespan (Bordeaux); S. Perelman, C. Richelme (Nice); N. Perez (Belfort); D. Rodriguez, T. Billette de Villemeur, M.L. Moutard, G. Ponsot (Hoˆpital Trousseau, Paris); M.C. Routon (Orsay); H. Testard (Annemasse), C. Van Hulle (Rouen). Clinical epidemiology department (Canada): A. Kezouh, S. Suissa (McGill University and Royal Victoria Hospital, Montreal).

Received March 21, 2008. Accepted in final form August 6, 2008.

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Pediatric optic neuritis Brain MRI abnormalities and risk of multiple sclerosis

G.R. Bonhomme, MD* A.T. Waldman, MD* L.J. Balcer, MD, MSCE A.B. Daniels, MD, MSc G.I. Tennekoon, MBBS S. Forman, MD S.L. Galetta, MD G.T. Liu, MD

Address correspondence and reprint requests to Dr. Liu, Division of Neuro-ophthalmology, Department of Neurology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104 [email protected]

ABSTRACT

Background: Optic neuritis is often the initial presentation of multiple sclerosis (MS). As established by the Optic Neuritis Treatment Trial, an abnormal baseline brain MRI is a strong predictor of MS after isolated optic neuritis in adults. However, the rate of conversion to MS after optic neuritis in children based upon brain MRI findings is unknown.

Methods: We reviewed the medical records of children (⬍18 years) presenting with optic neuritis between 1993 and 2004 at the Children’s Hospital of Philadelphia. Children with a history of demyelinating disease or prior optic neuritis were excluded. Symptoms, ophthalmologic findings, MRI findings, and clinical outcomes were recorded.

Results: We identified 29 consecutive children with idiopathic optic neuritis. Eleven patients (38%) had white matter T2/FLAIR lesions in the brain (not including the optic nerves). Eighteen patients were followed for more than 24 months, and 3 of the 18 (17%) developed MS. All 3 patients had an abnormal brain MRI scan at their initial presentation of optic neuritis. None of the patients with a normal brain MRI scan at presentation developed MS over an average follow-up of 88.5 months. Patients with one or more white matter lesions on MRI were more likely to develop MS (3/7 vs 0/11, p ⫽ 0.04, Fisher exact test).

Conclusions: Children with brain MRI abnormalities at the time of the diagnosis of optic neuritis have an increased risk of multiple sclerosis. Larger collaborative studies are needed to further define the prognosis for childhood optic neuritis. Neurology® 2009;72:881–885 GLOSSARY CHOP ⫽ Children’s Hospital of Philadelphia; FLAIR ⫽ fluid-attenuated inversion recovery; MS ⫽ multiple sclerosis; NMO ⫽ neuromyelitis optica; ONTT ⫽ Optic Neuritis Treatment Trial.

Optic neuritis is often the initial manifestation of multiple sclerosis (MS) in children and adults. After acute unilateral optic neuritis, adults have a 38% chance of developing MS within 10 years.1 The risk of MS is further increased (56%) in adult patients with an abnormal brain MRI scan at the time of the presentation with optic neuritis.1 In contrast, the conversion rate to MS in children is unclear, perhaps due to the variability in study methodologies in published reports. One pediatric study reported a low conversion rate to MS (4%); however, the mean follow-up was 13 months (range 1– 41 months).2 Another study reported a 10-year risk of developing MS after childhood optic neuritis of 13% using life-table analysis,3 whereas a different study reported a 2-year risk of 36%.4 A fourth study reported 16% of their patients with optic neuritis had MS; however, the purpose of that study was to define the presentation and visual prognosis in children, and children with a prior history of demyelinating disease were not excluded.5 Although MRI data are reported in many studies, few have examined the role of brain MRI in predicting the development of MS in children. The purpose of our study was to examine the Supplemental data at www.neurology.org *These authors contributed equally. From the Division of Neuro-ophthalmology (G.R.B., L.J.B., A.B.D., S.L.G., G.T.L.), Departments of Neurology and Ophthalmology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia; Division of Child Neurology (A.T.W., G.I.T.) and Neuro-ophthalmology Service (G.T.L.), Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia; and Department of Ophthalmology (S.F.), Westchester Medical Center, Valhalla, NY. Disclosure: The authors report no disclosures. Copyright © 2009 by AAN Enterprises, Inc.

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association of brain MRI findings at presentation with the development of MS in children after a first episode of optic neuritis. Our secondary aim was to determine whether children with recurrent optic neuritis have a greater risk of MS than children with isolated optic neuritis. METHODS Since 1993, the neuro-ophthalmology service at the Children’s Hospital of Philadelphia (CHOP) has maintained a database to record the names and diagnoses of all patients seen with a neuro-ophthalmologic disorder. The database was queried for all patients with a diagnosis of optic neuritis. For further review, those patients seen between 1993 and 2004 with a first attack of optic neuritis who were less than 18 years of age at presentation were selected. Patients with a known diagnosis of MS or other demyelinating, infectious, vasculitic, neoplastic, or rheumatologic disorder were not included in this study. To ascertain whether the neuroophthalmology service captured all patients throughout the hospital with a diagnosis of optic neuritis, a search of CHOP coding records for additional patients with ICD-9 code 377.3 (optic neuritis) from any visit within the CHOP system was also performed. The study protocol was approved by the Institutional Review Board at the Children’s Hospital of Philadelphia, and written consent was obtained from all participants. When patients with optic neuritis are seen by the neuroophthalmology service, a standard neuro-ophthalmologic examination is attempted in all cases. This includes visual acuity (using age-appropriate methods, such as Lea vs HOTV vs Snellen), color vision, visual fields (using confrontation and formal methods), and dilated fundus examination. Because in our experience the majority of children under the age of 10 are unable to cooperate successfully with formal automated or kinetic visual field testing, we did not require our patients to undergo these tests. Acute optic neuritis was diagnosed based on standard clinical criteria, including the presence of subacute visual loss, dyschromatopsia, pain on eye movement, visual field defects, and a relative afferent pupillary defect (in unilateral cases).6,7 The presence or absence of optic disc swelling was recorded. New patients with optic neuritis are also seen by the neurology service, which routinely obtains brain MRI scans in such patients. Optic nerve enhancement on MRI was not a uniform inclusion criterion since not all patients had dedicated MRI scans of the orbits with fat saturation and gadolinium. The diagnosis of MS before 2005 was made using published criteria available at the time of the patient’s presentation; from 2005 on, the diagnosis of MS was made using the 2005 revisions of the McDonald criteria.8 These criteria for MS are consistent with the working definitions for demyelinating diseases in children established by the International Pediatric MS Study Group.9 Relapsing optic neuritis affecting the opposite eye without involvement of an additional clinical or radiographic site affecting the CNS was not considered sufficient for a diagnosis of MS. Neuromyelitis optica (NMO) antibody testing was not included as data were collected before this testing was routinely available. Patients were grouped according to whether they had bilateral simultaneous, unilateral, or bilateral sequential optic neuritis. Bilateral simultaneous optic neuritis was defined according to symptoms, ophthalmoscopic appearance, and radiographic features as affecting both eyes within 2 weeks of each other. Bilateral sequential optic neuritis was defined as having both eyes affected between 2 weeks and 3 months of each other. Recurrent 882

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disease was defined as relapses of either unilateral or bilateral simultaneous optic neuritis separated by at least 3 months. Descriptive statistics were calculated to characterize the cohort of patients with pediatric optic neuritis. Percentages of patients with and without brain MRI abnormalities at the time of the optic neuritis diagnosis who developed MS or new neurologic symptoms were expressed as binomial proportions. The association between baseline MRI abnormalities and subsequent diagnosis of MS was examined using a two-sided Fisher exact test. Similar calculations were performed examining the association between recurrent optic neuritis and MS as well as the association between presentation (bilateral simultaneous, unilateral, or bilateral sequential) and MS. Statistical analyses were performed using Stata 10.0 statistical software (Stata Corp, College Station, TX).

We identified 46 consecutive children with optic neuritis through our neuro-ophthalmology database. Of this cohort, 17 patients were excluded when additional workup revealed another diagnosis, such as Sjo¨gren disease or Lyme disease. Of the 29 remaining children, 8 (28%) were boys and 21 (72%) were girls (table). The mean age was 9.7 years ⫾ 3.4 years, with a range of 4.3 to 16 years. The median age was also 9.7 years. Subjects had been followed for a mean of 50.4 months (median 36 months, range ⬍1–161 months). Review of all CHOP inpatient and outpatient ICD-9 coding records for optic neuritis (377.3) from every subspecialty, including general pediatrics, did not reveal any additional patients who met inclusion criteria for this study. At initial presentation, 89% of affected eyes (40 out of 45 eyes) exhibited impaired distance visual acuities, quantified by Snellen, HOTV, or Lea testing, of worse than 20/25 (table e-1 on the Neurology® Web site at www.neurology.org). Sixty-two percent of affected eyes (28 eyes) exhibited visual field defects on initial examination. The most common visual field defect was a central scotoma. Ophthalmoscopic examination of the RESULTS

Table

Demographics and clinical findings

Description

Value

No. of patients enrolled

29

Age, y, mean ⴞ SD (range)

9.7 ⫾ 3.4 (4.3–16)

Sex, n (%) female

21 (72)

Follow-up duration, all patients, mo (range)

50.4 (⬍1–161)

No. of patients followed >2 years, n (%)

18 (62)

Bilateral simultaneous optic neuritis, n (%)

16 (55)

Bilateral sequential optic neuritis, n (%)

3 (10)

Unilateral optic neuritis, n (%)

10 (39)

Brain MRI (baseline) abnormal, n (%)

11 (38)

Recurrent optic neuritis, n (%)

9 (31)

affected eyes on initial presentation revealed disc edema in 69% (31 eyes) and hemorrhage in 4% (2 eyes). None of the patients had a macular exudate. At the time of the last follow-up examination, 96% of affected eyes (47 out of 49 eyes, including 4 initially normal eyes affected by optic neuritis during the study period) had visual acuities that were 20/40 or better. Optic neuritis was bilateral and simultaneous in 16 (55%) of the children. Three additional patients met criteria for bilateral sequential optic neuritis (10%). The remaining 10 patients presented with unilateral optic neuritis (34%). Eleven patients (38%) had one or more white matter lesions in the brain (excluding the optic nerves) on baseline MRI. None of the patients met the McDonald MRI criteria for dissemination in space8 at presentation. Six of the 11 patients with an abnormal brain MRI at presentation had a follow-up brain MRI performed; in two patients the subsequent examination showed resolution of the lesions. Six of the 18 patients with a normal baseline brain MRI had subsequent imaging performed; none of these patients developed new lesions. Eighteen patients were followed for 24 months or longer; 11 patients had more than 5 years of follow-up data. These 18 patients comprised the cohort with long-term follow-up for which conversion rate to MS was determined. Of the 18 patients followed for more than 2 years, none of the patients with a normal brain MRI at presentation (n ⫽ 11) developed MS (table e-1). Four patients had an abnormal brain MRI at presentation and did not develop MS. The remaining 3 patients (17%) who had white matter lesions on their initial brain MRI scans developed MS (risk difference 0.43 using two-sided Fisher exact, p ⫽ 0.04). Patients with one or more white matter lesions on MRI at presentation were more likely to develop MS (3/7 vs 0/11, p ⫽ 0.04, Fisher exact test) than patients with a normal MRI at baseline. The patient histories follow. CASE REPORTS Patient 8. Patient 8 (table e-1) presented at age 7.3 years with bilateral optic neuritis. Visual acuity was counting fingers at 6 inches on the right and 1 foot on the left. Bilateral disc swelling was present, left greater than right. Her initial lumbar puncture was notable for 40 leukocytes, and a brain MRI revealed increased T2 signal intensity within the posterior aspect of the right thalamus as well as multiple bilateral foci in the cortical gray matter and subcortical white matter. Over the next 2 years, she developed multiple relapses of optic neuritis, as well as a right sixth nerve palsy, ataxia, paresthesias, and urinary difficulties. Repeated neuroimaging revealed new lesions in the pons, posterior left thalamus, and left parietal subcortical white matter. She was diagnosed with MS and treated with a disease-modifying drug. She is now clinically stable.

Patient 24. Patient 24 (table e-1) presented at 6.8 years with left optic neuritis and periventricular white matter abnormalities. Visual acuity was 20/20⫺2 on the right with a normal disc. She had no light perception from her left eye, a left relative afferent

pupillary defect, and disc swelling in the left eye. Her initial lumbar puncture revealed the following: leukocytes 1, erythrocytes 0, protein 17, glucose 60. Oligoclonal bands and immunoglobulin G synthesis were not sent. Two months after her initial presentation, she developed right optic neuritis, thereby meeting criteria for bilateral sequential optic neuritis. She had no light perception from her right eye, but recovered vision in her left eye (20/25⫺1). She had a relative afferent pupillary defect on the right, and disc swelling in the right eye only. Her brain MRI was unchanged from her initial study. Another 2 months later, she relapsed again with right optic neuritis. A subsequent brain MRI performed 5 months after her initial presentation revealed enhancing foci of abnormal long repetition time sequence signal abnormality within the left corpus callosum and periventricular white matter as well as the right parietal subcortical white matter. With the development of additional periventricular lesions, one of which enhanced, as well as a juxtacortical lesion, she met McDonald criteria for dissemination in space and was diagnosed with MS.

Patient 1. Patient 1 (table e-1) presented at the age of 10.7 years with left optic neuritis. Visual acuity was 20/25 on the right and 20/80 on the left. A left relative afferent pupillary defect was present. Fundus examination revealed slight hyperemia of the left disc. Her initial brain MRI revealed increased signal intensity within the right optic radiation, extending into the right retrocapsular region, as well as lesions in the periventricular white matter of the right temporal horn, peritrigonal white matter on the right, and along the roof of the right corpus callosum. A follow-up study was not performed. More than 3 years later, she developed a left sixth nerve palsy. Another brain MRI was recommended but was not obtained, and the patient was lost to follow-up. Relationship between recurrent optic neuritis and development of MS. Our secondary aim was to examine

the relationship between recurrent optic neuritis and the development of MS. Nine patients (31%) had relapses of optic neuritis during the study period; five patients had more than one relapse (table e-1). Three patients who initially presented with bilateral optic neuritis had unilateral relapses. The remaining six patients presented with unilateral optic neuritis; half of these patients ultimately met criteria for bilateral sequential optic neuritis and the other half developed relapses more than 3 months after their initial unilateral presentation. Two of the three patients with unilateral involvement initially had a relapse in the opposite eye. Of the nine patients who developed relapses, two patients developed MS. The relative risk of developing MS among patients with optic neuritis recurrence was 4.0 (p ⫽ 0.25). Patients with bilateral simultaneous or sequential optic neuritis did not have a greater risk of MS compared to patients presenting with unilateral disease (p ⫽ 0.53). The baseline characteristics of the group followed for more than 24 months were compared with those of the group followed for less than 24 months. The patients followed for less than 24 months were older (mean 12.4 ⫾ 2.2 years) than the patients followed for more than 24 months (mean 8.1 ⫾ 2.9 years). Neurology 72

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There was no difference in the presence of lesions on their initial brain MRI scans or optic neuritis laterality at presentation. Our data demonstrate the utility of brain MRI in predicting development of MS in a cohort of pediatric patients presenting with optic neuritis. The Optic Neuritis Treatment Trial (ONTT) has had a substantial impact on defining the prognosis for MS after isolated optic neuritis in adults. Prospective follow-up of the trial’s original cohort concluded that the risk of developing MS was 7.5% at 2 years in the IV methylprednisolone group and 16.7% in the placebo group.10 Two of our 18 patients developed MS within 2 years (11%). The third patient developed MS by 3 years. The remaining 15 patients did not develop MS over a mean of 76.2 months. A follow-up study from the ONTT also stratified the risk by the number of T2 lesions found on the initial MRI. After 10 years, the risk of MS in adults was further increased (56%) by the presence of at least one typical T2 lesion on the baseline brain MRI compared to no lesions on the initial scan (22%).1 In our cohort, all three patients with a diagnosis of MS had abnormalities on their baseline brain MRI scans using T2 and fluid-attenuated inversion recovery (FLAIR) images. FLAIR images were not included in the ONTT; therefore, direct comparisons between the imaging of our pediatric patients and adult patients in the ONTT must be made carefully. Our data differ from another pediatric optic neuritis study which reported a higher rate of conversion to MS than seen in adults (the 2-year risk of developing MS after optic neuritis in children was 36%4). Our population was derived from a neuro-ophthalmology practice in a tertiary pediatric hospital whereas the patients enrolled in the other study were identified from a demyelinating disease clinic.4 Also, the baseline MRI characteristics between the two groups were different. In our study, none of the 11 patients with an abnormal baseline brain MRI met the McDonald criteria for dissemination in space8; only one patient met these criteria during the follow-up period. In contrast, in the other study, 10 out of 13 children met the criteria for dissemination in space on their initial brain MRI scans performed at the time of their presentation of optic neuritis.4 The difference in the number and location of MRI lesions on baseline neuroimaging may explain the difference in conversion rates to MS between our cohorts. Another pediatric study reported a significantly increased risk of progression to MS in children who experienced recurrent episodes of optic neuritis.3 In our study, 9 patients (31%) had relapses of optic DISCUSSION

884

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neuritis; 3 patients presented with bilateral simultaneous optic neuritis and 6 patients presented with unilateral optic neuritis. Of the latter group, 5 patients ultimately developed optic neuritis in the opposite eye; one of these 5 patients met criteria for MS. The remaining 4 patients did not present with or develop brain MRI abnormalities outside the optic nerves. Since dissemination in space outside the visual system was not met by clinical or radiographic criteria, these patients did not meet our criteria for MS. In our cohort, the relationship between recurrence and conversion to MS did not reach significance, and larger sample sizes are needed to explore this relationship. Optic neuritis in children is diagnosed using the same clinical criteria used in adults, including some combination of subacute vision loss, pain with eye movements, visual field defects, and a relative afferent pupillary defect. However, in contrast to adults, children with optic neuritis often present with bilateral involvement, profound vision loss, and prominent disc swelling. In adults with a normal MRI scan of the brain at the initial presentation, patients with optic disc swelling have a lower risk of MS.1 Of the 18 patients with a normal MRI at presentation in our study, 16 (89%) also had disc edema on initial examination, and none of these patients developed MS during the follow-up period. Despite the poor vision at presentation, most children recover quite well. Visual acuity improved to 20/40 or better at the time of the last follow-up examination in 96% of affected eyes. Our data suggest that the risk of MS after a first episode of optic neuritis in children is increased in patients with one or more white matter lesions on their baseline brain MRI scans. In addition, we confirmed that a normal brain MRI at presentation is prognostically favorable. None of the patients with a negative brain MRI at presentation have been diagnosed with MS to date. Prospective research studies incorporating MRI data and longer follow-up intervals are under way to further explore the risk factors associated with the development of MS after pediatric optic neuritis. AUTHOR CONTRIBUTIONS Statistical analysis was performed by L.J. Balcer, MD, MSCE.

ACKNOWLEDGMENT The authors thank Drs. Valerie Biousse, Robert Egan, and Nancy Newman for their helpful hints and suggestions.

Received April 18, 2008. Accepted in final form December 12, 2008. REFERENCES 1. Beck RW, Trobe JD, Moke PS, et al., for the Optic Neuritis Study Group. High- and low-risk profiles for the de-

2.

3.

4.

5.

velopment of multiple sclerosis within 10 years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 2003;121:944–949. Lana-Peixoto MA, de Andrade GC. The clinical profile of childhood optic neuritis. Arq Neuropsiquiatr 2001;59: 311–317. Lucchinetti CF, Kiers L, O’Duffy A, et al. Risk factors for developing multiple sclerosis after childhood optic neuritis. Neurology 1997;49:1413–1418. Wilejto M, Shroff M, Buncic JR, Kennedy J, Goia C, Banwell B. The clinical features, MRI findings, and outcome of optic neuritis in children. Neurology 2006;67:258–262. Brady KM, Brar AS, Lee AG, Coats DK, Paysse EA, Steinkuller PG. Optic neuritis in children: clinical features and visual outcomes. J AAPOS 1999;3:98–103.

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Atkins EJ, Biousse V, Newman NJ. The natural history of optic neuritis. Rev Neurol Dis 2006;3:45–56. 7. Liu GT, Volpe NJ, Galetta SL. Neuro-ophthalmology: Diagnosis and Management. Philadelphia: Saunders; 2001. 8. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005;58:840–846. 9. Krupp LB, Banwell B, Tenembaum S. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology 2007;68:S7–12. 10. Beck RW, Cleary PA, Trobe JD, et al., for the Optic Neuritis Study Group. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med 1993;329:1764–1769.

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Announcement of Winner 2009 Resident and Fellow Section Writing Award Neurology® is delighted to announce that Megan Alcauskas, MD, a resident at Mount Sinai Hospital in New York City, is the recipient of the first Annual Resident and Fellow Section Writing Award. The Resident and Fellow Section editorial team gave the award for the article “Right Brain: Reading, writing, and reflecting: Making a case for narrative medicine in neurology” (Neurology® 2008;70:891– 894), which was co-authored by Rita Charon, MD, PhD. The Resident and Fellow Section Writing Award is intended to recognize the extraordinary writing abilities of those currently training in neurology. The 2010 award will be announced early next year, and eligible articles will include any submission published during 2009 in the Resident and Fellow Section. No formal submission process is required. For questions, contact Kathy Pieper, Editorial Office, [email protected].

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A controlled trial of antidepressants in patients with Parkinson disease and depression M. Menza, MD R.D. Dobkin, PhD H. Marin, MD M.H. Mark, MD M. Gara, PhD S. Buyske, PhD K. Bienfait, PhD A. Dicke

Address correspondence and reprint requests to Dr. Matthew Menza, Robert Wood Johnson Medical School, D207A, 671 Hoes Lane, Piscataway, NJ 08854 [email protected]

ABSTRACT

Background: Parkinson disease (PD) is a common neurodegenerative disease affecting up to 1 million individuals in the United States. Depression affects up to 50% of these patients and is associated with a variety of poor outcomes for patients and their families. Despite this, there are few evidence-based data to guide clinical care.

Methods: An NIH-funded, randomized, controlled trial of paroxetine CR, nortriptyline, and placebo in 52 patients with PD and depression. The primary outcomes were the change in the Hamilton Depression Rating Scale (HAM-D) and the percentage of depression responders at 8 weeks.

Results: Nortriptyline was superior to placebo for the change in HAM-D (p ⬍ 0.002); paroxetine CR was not. There was a trend for superiority of nortriptyline over paroxetine CR at 8 weeks (p ⬍ 0.079). Response rates favored nortriptyline (p ⫽ 0.024): nortriptyline 53%, paroxetine CR 11%, placebo 24%. In planned contrasts of response rates, nortriptyline was superior to paroxetine CR (p ⫽ 0.034). Nortriptyline was also superior to placebo in many of the secondary outcomes, including sleep, anxiety, and social functioning, while paroxetine CR was not. Both active drug treatments were well tolerated. Conclusions: Though relatively modest in size, this is the largest placebo-controlled trial done to date in patients with Parkinson disease (PD) and depression. Nortriptyline was efficacious in the treatment of depression and paroxetine CR was not. When compared directly, nortriptyline produced significantly more responders than did paroxetine CR. The trial suggests that depression in patients with PD is responsive to treatment and raises questions about the relative efficacy of dual reuptake inhibitors and selective serotonin reuptake inhibitors. Neurology® 2009;72:886–892 GLOSSARY ARR ⫽ absolute risk reduction; DSM-IV ⫽ Diagnostic and Statistical Manual of Mental Disorders, 4th edition; HAM-A ⫽ Hamilton Anxiety Scale; HAM-D ⫽ Hamilton Depression Rating Scale; MMSE ⫽ Mini-Mental State Examination; NNT ⫽ number needed to treat; PD ⫽ Parkinson disease; PDQ ⫽ Parkinson’s Disease Questionnaire; PSQI ⫽ Pittsburgh Sleep Quality Index; SCID ⫽ Structured Clinical Interview; SSRI ⫽ selective serotonin reuptake inhibitor; TCA ⫽ tricyclic antidepressant; UPDRS ⫽ Unified Parkinson’s Disease Rating Scale.

Parkinson disease (PD) is the second most prevalent neurodegenerative illness in the United States, affecting approximately 1 million individuals. While the illness is defined by the motor triad of tremor, rigidity, and bradykinesia, non-motor features are both common and functionally important. Depression, dementia, drug-induced psychosis, impulsivity, and sleep disturbances may all complicate the course and management of PD and are associated with a variety of poor short and long-term outcomes.1 Editorial, page 868 e-Pub ahead of print on December 17, 2008, at www.neurology.org. From the Departments of Psychiatry (M.M., R.D.D., H.M., M.H.M., M.G., K.B., A.D.) and Neurology (M.M., M.H.M.) at the Robert Wood Johnson Medical School, UMDNJ-University Behavioral HealthCare (M.M., H.M., M.G.), and the Department of Statistics at Rutgers University (S.B.), Piscataway, NJ. Supported by a grant from the National Institute of Neurological Disorders and Stroke (NINDS) RO1NS043144. GlaxoSmithKline provided free paroxetine CR and matching placebo. Disclosure: Matthew Menza, MD—research support: National Institutes of Health (NINDS), Astra-Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Forest Laboratories, GlaxoSmithKline, Lilly, Pfizer, Sanofi-Aventis, Sepracor, Takeda Wyeth. Consultant: National Institutes of Health (NIMH, NINDS), GlaxoSmithKline, Kyowa, Lilly Research Laboratories, Pfizer, Sepracor, Takeda. Speaker: Sanofi-Aventis. Stocks: none. Other financial: none; Roseanne DeFronzo Dobkin, PhD—research support: National Institutes of Health (NINDS); Humberto Marin, MD—research support: National Institutes of Health (NINDS), GlaxoSmithKline, Lilly, Sanofi-Aventis, Sepracor, Takeda. Consultant: Lilly Research Laboratories; Margery Mark, MD: research support: Kyowa, Cephalon. Speaker: Allergan, Boehringer Ingelheim, GlaxoSmithKline, Valeant; Michael Gara, PhD— none; Steven Buyske, PhD—research support: National Institutes of Health (NIAAA); Karina Bienfait, PhD—none; Allison Dicke—none. 886

Copyright © 2009 by AAN Enterprises, Inc.

Depression is one of the most common nonmotor aspects of PD, with a reported prevalence of approximately 40% to 50%.2 It is of particular importance to these patients because, in addition to personal suffering, depression is associated with a faster progression of physical symptoms, a greater decline in cognitive skills and ability to care for oneself, poorer treatment compliance and quality of life, as well as greater caregiver distress.3-5 In fact, depression appears to be more predictive of distress than motor disability.6 Despite the prevalence and importance of depression in PD, there are few well-designed studies that inform treatment.7 There are a variety of open label trials and some older, methodologically flawed controlled trials, but a recent Cochrane Review concluded that there are insufficient data on the effectiveness and safety of any antidepressant therapies in PD to allow recommendations for their use.8 Nevertheless, antidepressants are apparently widely used for these patients, with selective serotonin reuptake inhibitors (SSRIs) being the most commonly used medications. A survey of physicians in the Parkinson Study Group found that 26% of the patients with PD were on antidepressants for depression and 51% of the physicians used SSRIs as their first line therapy.9 A more recent Veterans Affairs database study found that 63% of patients with PD and depression were taking SSRIs, while only 7% were taking tricyclic antidepressants (TCAs).10 In order to begin to provide clinical guidance for these patients, we conducted an NIH-funded, controlled trial of nortriptyline, paroxetine CR, and placebo in patients with PD and depression. The primary outcomes were the change in the Hamilton Depression Rating Scale (HAM-D), from baseline to endpoint, and the percent responders to each treatment. METHODS Study design. Clintrials.gov identifier: NCT 00062738. Dr. Buyske, Department of Statistics at Rutgers University, carried out the statistical analysis. Fifty-two patients were enrolled in this 8-week, randomized, double-blind trial of nortriptyline, paroxetine CR, or placebo. The primary hypothesis was that patients on active drug would have a significantly greater decrease in the baseline to endpoint

HAM-D scores and that there would be significantly more responders in the active drug groups.

Consent procedures and data collection. All procedures used were approved by the University of Medicine and Dentistry of New Jersey’s Institutional Review Board. All patients were evaluated between October 2003 and July 2007. Patients. Patients were included if they were between the ages of 35 and 80, had a confirmed diagnosis of PD by research criteria,11 and had a diagnosis on the Structured Clinical Interview12 (SCID) for the Diagnostic and Statistical Manual of Mental Disorders 4th ed. (DSM-IV)13 of major depression or dysthymia. Patients were excluded if they had cognitive impairment (Mini-Mental State Examination [MMSE]14 less than 26), were “off” for greater than 50% of the day, or had any current DSM-IV Axis I diagnosis other than a depressive or anxiety disorder. Patients were not allowed to take any psychotropic medications other than the study medication during the trial. Patients who had been nonresponsive to more than one trial of an adequate dose and length of an approved antidepressant were excluded. Patients were required to maintain a stable dose of the PD medication that they were on at the start of the trial and all evaluations were done in the “on” state.

Dosing. Patients were randomized, in variable length blocks, to equivalent-appearing nortriptyline, paroxetine CR, or placebo. Dosing was flexible with decisions on dose being made at each visit (or between visits if the patient was having troublesome side effects) based on efficacy and tolerability. Paroxetine CR was started at 12.5 mg and could be increased up to 37.5 mg. Nortriptyline was started at 25 mg and could be increased up to 75 mg. Placebo was started at one pill and could be increased up to three pills.

Assessments. The primary outcomes were the HAM-D 17item15 change from baseline and the percent responders. Responders were defined as patients who had a 50% or greater decrease in their baseline HAM-D at last observation. All patients and study personnel were blind to drug assignment. Patients were assessed on primary outcomes at 2, 4, and 8 weeks. Secondary outcomes included quality of life, which was assessed using the Parkinson’s Disease Questionnaire (PDQ-8)16 and the Medical Outcome Study Short Form (SF 36),17 the Clinical Global Impression Scale,18 the Hamilton Anxiety Scale (HAM-A),19 The Pittsburgh Sleep Quality Index (PSQI),20 and the Unified Parkinson’s Disease Rating Scale (UPDRS).21 We also administered a battery of cognitive tests including the MMSE,14 forward and backward digit span of the Wechsler Adult Intelligent Test–Third Edition,22 the Boston Naming Test,23 the word list recall and recognition subtests of the Wechsler Memory Scale–Third Edition24 verbal category fluency, and the Stroop color-word test.25 All secondary outcomes were assessed at baseline and at week 8 or at the last visit for those who terminated early. Data analyses. An intent-to-treat approach was used in all analyses and included all 52 patients. The primary outcome of HAM-D change was evaluated at baseline, 2, 4, and 8 weeks using a mixed-model repeated measures analysis of variance as implemented in the MIXED procedure of SAS Version 9.1 with restricted maximum likelihood estimation.26 This analysis assumes that the data that are missing, most of which are attributed to patient dropout, are missing at random. Fixed effects were treatment (placebo, nortriptyline, paroxetine CR), time of Neurology 72

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Figure 1

Patient flow diagram

assessment (baseline, 2, 4, and 8 weeks), and the treatment by time interaction. Random subject intercepts were included in the model. In modeling covariance structure for all analyses, we chose a continuous AR1 structure as a function of the square root of days from baseline that a given assessment occurred for a given patient. This model yielded the lowest AIC among all covariate structures examined. The interaction between treatment and time in the mixed model was of most interest, since a time effect alone would only indicate improvement over time across all three groups, whereas a treatment by time interaction indicates differential improvement over time, depending on treatment. For the responder analysis, an LOCF approach was used in which a clinical response was operationally defined as at least a 50% reduction in the HAM-D score from baseline to 8 weeks. Clinical response was cross-tabulated with treatment and Fisher

Table 1

Clinical information on patients Overall (SD)

Nortriptyline (SD)

Paroxetine CR (SD)

Placebo (SD)

Age, y

62.2 (8.7)

62.9 (9.3)

62.8 (8.1)

61.4 (9.2)

Age at onset, y

56.1 (9.5)

56.8 (10.0)

54.2 (7.8)

57.2 (10.8)

Women

25

11

5

9

Men

27

6

13

8

Daily dose, mg Nortriptyline

48.5 (5.0)

Paroxetine CR

28.4 (2.0)

Placebo

2.7 pills (0.14)

Hoehn-Yahr

888

2.2

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exact test was used to distinguish differences among these groups. Mixed models analyses were used to analyze secondary variables. Nominal p values are given for secondary outcomes. RESULTS Sixty-seven patients signed informed consent and 15 were screened out for a variety of reasons (figure 1). Thus, 52 patients, 27 men and 25 women, entered the trial. Fifty of the patients had major depression, two had dysthymia in addition to major depression, and two had only dysthymia. The mean age was 62.8 and the mean duration of PD was 6.6 years. The average dose of medication was 28.4 mg for paroxetine CR, 48.5 mg for nortriptyline, and 2.7 pills for placebo. Other clinical information on the sample is found in table 1.

Primary outcomes. HAM-D. The mixed effects analysis of the primary outcome measure, the HAM-D, resulted in a significant effect for treatment by time interaction [F(6,119) ⫽ 2.99, p ⫽ 0.009], using repeated measures collected at baseline and all available follow-up assessments for all 52 subjects. We then examined this treatment by time interaction for three distinct slices of the data set: 2 weeks vs baseline, 4 weeks vs baseline, and 8 weeks vs baseline (table 2). Table 2 shows the nominal significance level of treatment at each of these three slices (p values are 0.028, 0.022, and 0.005). Table 2 also shows, for each study group, least-squares means adjusting for other pa-

Table 2

Hamilton Depression Rating Scale (HAM-D) changes Nortriptyline

Paroxetine

Placebo

Nominal p values

HAM-D

Mean

SD

Mean

SD

Mean

SD

Baseline

21.12

5.64

18.82

5.60

19.29

5.64

2 Weeks

15.33

5.64

17.41

5.60

17.61

4 Weeks

13.00

6.04

15.77

6.07

14.56

8 Weeks

10.84

6.20

12.45

6.36

15.81

Nortriptyline vs placebo

Paroxetine vs placebo

Nortriptyline vs paroxetine

Group difference

5.60

0.029

0.905

0.018

0.028

5.62

0.100

0.413

0.016

0.022

5.78

0.002

0.165

0.079

0.005

1.20

0.51

1.02

Effect size

rameters in the model, standard deviations, and significance levels for three planned contrasts (nortriptyline vs placebo, paroxetine CR vs placebo, and nortriptyline vs paroxetine CR). In planned contrasts, nortriptyline was superior to placebo at 2 weeks (p ⬍ 0.029) and at 8 weeks (p ⬍ 0.002). The 8-week comparison of nortriptyline and placebo remained significant (p ⬍ 0.05) after a Bonferroni correction for multiple comparisons. Paroxetine CR was not superior to placebo at any point. Nortriptyline was (nominally) superior to paroxetine CR at 2 weeks (p ⬍ 0.018) and 4 weeks (p ⬍ 0.016) but not 8 weeks (p ⬍ 0.079). Table 2 also lists the Cohen’s effect sizes, which are 1.2 for nortriptyline vs placebo, 1.02 for nortriptyline vs paroxetine CR, and 0.51 for paroxetine CR vs placebo. The change in the HAM-D scores is shown graphically in figure 2. Covariates. We examined the effect of patient age, gender, and length of illness by adding these data to the mixed model. There were no significant effects (all p values ⬎0.30) for any of these variables. Responders. The response rates at endpoint, based on a 50% change in the HAM-D total score, also significantly favored nortriptyline: nortriptyline 53%, paroxetine CR 11%, placebo 24% (Fisher exact p ⫽ 0.024). In planned contrasts, adjusted for multiple comparisons, nortriptyline was superior to paroxetine CR (p ⫽ 0.034). While not an a priori outcome, we did examine

Figure 2

Change in Hamilton Depression Rating Scale

remitter rates, using a HAM-D of 7 or less as a definition of remitter. The remitter rates were different (nortriptyline 41%, paroxetine CR 17%, placebo 12%) but they did not differ statistically (p ⫽ 0.154). Number needed to treat. The number needed to treat (NNT), based on responders, for nortriptyline compared to placebo is 3.5, with an absolute risk reduction (ARR) of 29%. NNT for nortriptyline compared to paroxetine CR is 2.4 with an ARR of 42%. Secondary outcomes. Quality of life. The total SF36 score was not different between groups; however, patients on nortriptyline reported better social functioning at endpoint (drug by time interaction p ⫽ 0.0142; planned contrast nortriptyline vs placebo p ⫽ 0.016). No differences between groups were found on the PDQ 8. Disease measures. There were no significant differences between groups found on the UPDRS. Sleep. Patients taking nortriptyline reported significant improvements in sleep (PSQI) compared to placebo (drug by time interaction, p ⫽ 0.0021; planned contrast nortriptyline vs placebo, p ⫽ 0.008). Anxiety. A significant time by drug interaction was noted on the HAM-A (p ⬍ 0.0001). In the planned contrasts, nortriptyline was significantly better than paroxetine CR (p ⬍ 0.007) and placebo (p ⬍ 0.0001) in alleviating anxiety. Paroxetine CR showed a trend advantage over placebo (p ⫽ 0.0740). Overall improvement. There was a significant effect between treatment arms in the Clinical Global Improvement scale (Fisher exact, p ⫽ 0.0297). Cognition. There was no significant time by drug interaction on the neuropsychological measures. Integrity of the blind. To test the integrity of the blind-

ing we asked both the patient and the rater to guess what treatment the patient was taking. There was no indication that the blinding was compromised. Tolerability. There were no differences in the dropout rates among the three arms of the trial: nortriptyline 29%, paroxetine CR 39%, and placebo 35%. Side effects of the treatments were generally mild or Neurology 72

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889

Table 3

Side effects

Placebo (%)

Nortriptyline (%)

Paroxetine CR (%)

Constipation

6

35

6

Dry mouth

0

41

6

Insomnia

24

12

0

Fatigue

12

0

17

Orthostatic hypotension

12

12

11

Dizziness

12

12

0

moderate. There was a significantly higher average number of side effects in the paroxetine CR group compared to placebo (Tukey contrasts, p ⫽ 0.0281) but no significant differences between nortriptyline and placebo. The most common side effects are listed in table 3. Safety. Safety measures in the trial included measure-

ment of the QTc interval in patients on nortriptyline, nortriptyline levels, vital signs, and serious adverse events. The QTc of patients on nortriptyline decreased nonsignificantly from baseline (423 msec) to endpoint (422 msec). There was one patient with a QTc of greater than 450 msec at baseline and two at endpoint. No patient had a QTc above 500 msec. Nortriptyline levels ranged between 32 and 138 with an average of 74.88. There were no significant baseline to endpoint changes in vital signs in any of the groups. Six patients developed orthostatic hypotension at at least one visit in the trial: two on placebo, two on paroxetine CR, and two on nortriptyline. None of these patients had falls and none stopped the trial because of this side effect. There were three serious adverse events: one patient on paroxetine CR was hospitalized for fainting—no cause was discovered—and one patient on placebo had a severe worsening of rigidity due to a Parkinson medication change and another patient on placebo had delirium. DISCUSSION This is the largest placebo-controlled medication trial to date in depressed patients with PD, and the first to compare a dual reuptake inhibitor (nortriptyline) and an SSRI (paroxetine CR). It is also the largest controlled trial to show that depression in patients with PD responds to antidepressant treatment. Nonetheless, it is not large by clinical trial standards and must be seen as preliminary. While preliminary, this trial yielded results that are perhaps surprising and may have significant clinical implications. The treatment effect of nortriptyline was significant for both the overall change in the HAM-D and in the percent responders, while paroxetine CR was not. Furthermore, nortriptyline, when 890

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compared directly to paroxetine CR, produced significantly more responders. Nortriptyline was also superior to placebo on many of the secondary outcomes while paroxetine CR was not. The effect size of nortriptyline was large (1.20, based on HAM-D) and the number needed to treat for nortriptyline was 3.5 based on response status. Both active treatments were well tolerated, although paroxetine CR did have significantly more side effects than placebo and nortriptyline did not. Nortriptyline has been widely used in treatment of depression in the elderly27 and was found in one study to be superior to an SSRI in patients with poststroke depression.28 The one previous study done with nortriptyline in depressed patients with PD, a small crossover study which used an outcome instrument that is not widely validated, did suggest that the drug is efficacious.29 The etiology of depression in patients with PD is unclear and any explanation of the apparent superiority of nortriptyline would be speculative. While there are significant psychosocial stressors intrinsic to the illness, there are also numerous studies that point to a neurobiological etiology. There is evidence implicating dopaminergic, serotonergic, noradrenergic, and cholinergic dysfunction.30 In addition, changes in trophic and inflammatory factors, such as nerve growth factor and cytokines, which seem to play a role in clinical depression, have also been associated with PD.31 A 2005 PET study30 provided evidence of a loss of noradrenergic neurons in the limbic system in patients with PD and depression, perhaps providing a possible way of understanding these results. Nortriptyline is a dual reuptake inhibitor, that is, it inhibits reuptake of both serotonin and norepinephrine, whereas paroxetine CR, an SSRI, inhibits the reuptake of only serotonin. Thus, it is possible that the mechanism of the apparent superiority of nortriptyline is its effect on norepinephrine. Another, admittedly speculative, explanation for these results may lie in the role of norepinephrine transporters in the prefrontal cortex. The norepinephrine reuptake transporter is responsible for removing dopamine from the synapse in this area of the brain.32 Blockade of these transporters by agents such nortriptyline can acutely increase dopamine levels in the frontal cortex,33 facilitating dopaminergic function. At present, it appears that the SSRIs are the firstline choice for depression in PD in clinical practice and that the TCAs are not commonly used.9,10 This study, however, suggests that the SSRI paroxetine CR is not superior to placebo in patients with PD and depression and may be inferior to nortriptyline.

The effect size for paroxetine CR on the HAM-D was medium (0.51); a study with a larger sample size or of longer duration might have found a significant effect on this outcome, although paroxetine produced fewer responders than did placebo. These results are consistent with the two previous controlled trials with SSRIs34,35 (sertraline and paroxetine) in PD which, while admittedly methodologically flawed, did not support the efficacy of these compounds. However, there are also numerous open-label studies of paroxetine (non CR)36 and other SSRIs7 in this population that have shown good efficacy and low dropout rates. While only an 8-week trial, the improvement in the secondary outcomes in this trial is noteworthy. Patients on nortriptyline had significant improvements in physician-rated overall improvement, social functioning, sleep, and anxiety. These improvements are consistent with the descriptive literature in depression that suggests that depression negatively affects these aspects of the patient’s condition. Furthermore, sleep and anxiety are strongly correlated with overall quality of life5 and improvements in these symptoms may be, by themselves, valuable outcomes. The tolerability and safety assessment included in the trial indicated that both drugs were well tolerated. Both drug treatment arms had similar dropout rates and, although dropout rates of this size are not unusual in psychopharmacologic trials, their size may limit the generalizability of the trial. The side effects were consistent with side effects seen in non-PD populations. Nortriptyline can increase the P–R interval, QRS duration, and Q–Tc interval and has been associated with cardiac arrhythmias.37 There were, however, no significant effects of nortriptyline on cardiac conduction in this trial. There were also no significant changes in vital signs in any of the groups and neither active drug had negative effects on cognition. While nortriptyline, given its potential for cardiac conduction delay, needs to be used cautiously, the emerging evidence suggests that its benefits are substantial. The two non-TCA dual reuptake inhibitors that do not have significant cardiac effects, venlafaxine and duloxetine, have not been extensively evaluated in depression in PD. There are ongoing trials evaluating some of these compounds in PD, so we await, with interest, the results of these trials. Further studies, with larger numbers of patients, broader entrance criteria, and antidepressants that effect neurotransmitters other than serotonin, are needed. Received March 31, 2008. Accepted in final form August 22, 2008.

REFERENCES 1. Menza M, Marsh L, eds. Psychiatric Issues in Parkinson’s Disease: A Practical Guide. London: Taylor & Francis; 2006. 2. Reijnders MA, Ehrt U, Weber WEJ, Aarsland D, Leentjens AFG. A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord Epub 2007 Nov 6. 3. Ravina B, Camicioli R, Como PG, Marsh L, Jankovic J, Weintraub D, Elm J. The impact of depressive symptoms in early Parkinson disease. Neurology 2007;69:342–347. 4. Whetten-Goldstein K, Sloan F, Kulas E, Cutson T, Schenkman M. The burden of Parkinson’s disease on society, family, and the individual. J Am Geriatr Soc 1997;45: 844–849. 5. Schrag A. Quality of life and depression in Parkinson’s disease. J Neurol Sci 2006;248:151–157. 6. Global Parkinson’s Disease Steering Committee. Factors impacting on quality of life in Parkinson’s disease: results from an international survey. Mov Disord 2002;17:60–67. 7. Weintraub D, Morales KH, Moberg PJ, et al. Antidepressant studies in Parkinson’s disease: a review and metaanalysis. Mov Disord 2005;20:1161–1169. 8. Ghaxi-Noori S, Chung TH, Deane KHO, Rickards H, Clarke CE. Therapies for depression in Parkinson’s disease. Cochrane Database Syst Rev 2003;3:CD003465. 9. Richard IH, Kurlan R. A survey of antidepressant drug use in Parkinson’s disease. Neurology 1997;49:1168–1170. 10. Chen P, Kales HC, Weintraub D, Blow FC, Jiang L, Mellow AM. Antidepressant treatment of veterans with Parkinson’s disease and depression: Analysis of a national sample. J Geriatr Psychiatry Neurol 2007;20:161–165. 11. Ward CD, Gibb WR. Research diagnostic criteria for Parkinson’s disease. Adv Neurol 1990;53:245–249. 12. First MB, Spritzer RL, Gibbon M. Structured Clinical Interview for DSM-IV Axis I Disorders: Patient Edition, Biometrics Research Department. New York: New York State Psychiatric Institute; 1995. 13. American Psychiatric Association. DSM-IV: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994. 14. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189– 198. 15. Hamilton M. Hamilton Depression Scale. In: ECDEU Assessment Manual for Psychopharmacology, revised edition. Rockville, MD: National Institute of Mental Health; 1976: 179–192. 16. Jenkinson CR. The PDQ-8: development and validation of a short-form Parkinson’s disease questionnaire. Psychol Health 1997;12:805–814. 17. Jenkinson C, Coulter A, Wright L. Short Form 36 (SF 36) Health Survey Questionnaire; normative data for adults of working age. BMJ 1993;306:1437–1440. 18. Guy W. ECDEU assessment manual for psychopharmacology. Washington, DC: U.S. Department of Health, Education, and Welfare; 1976. 19. Hamilton M. The assessment of anxiety status by rating. Br J Med Psychol 1959;32:50–55. 20. Carpenter JS, Andrykowski MA. Psychometric evaluation of the Pittsburgh Sleep Quality Index. J Psychosom Res 1998;45(1 Spec No):5–13. Neurology 72

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21.

22. 23. 24. 25. 26. 27.

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Fahn S, Elton RL, Members of the UPDRS Development Committee. Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson’s Disease, Vol. 2. Florham Park, NJ: Macmillan Health Care Information; 1987: 153–164. Wechsler D. Wechsler Adult Intelligence Test (Third Edition). New York: Psychological Corporation; 1997. Kaplan EF, Goodglass H, Weintraub S. Boston Naming Test. Philadelphia: Lee & Febiger; 1983. Wechsler D. Wechsler Memory Scale (Third Edition). New York: Psychological Corporation; 1997. Golden CJ. Stroop Color and Word Test. Wood Dale, IL: Stoelting Co.; 1978:1–32. Verbeke G, Molenberghs G. Linear Mixed Models for Longitudinal Data. New York: Springer; 2000. Bump GM, Mulsant BH, Pollock BG, et al. Paroxetine versus nortriptyline in the continuation and maintenance treatment of depression in the elderly. Depress Anxiety 2001;13:38–44. Robinson RG, Schultz SK, Castillo C, et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. Am J Psychiatry 2000;157:351–359. Anderson J, Aabro E, Gulmann AE, Hjelmsted A, Pedersen HE. Anti-depressive treatment in Parkinson’s disease: a controlled trial of the effect of nortriptyline in patients with Parkinson’s disease treated with L-dopa. Acta Neurol Scand 1980;62:210–219. Remy P, Doder M, Lees A, Turjanki N, Brooks D. Depression in Parkinson’s disease: loss of dopamine and nor-

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adrenaline innervation in the limbic system. Brain 2005; 128:1314–1322. Nagatsu T, Sawada M. Inflammatory process in Parkinson’s disease: role for cytokines. Current Pharma Des 2005;11:999–1016. Moro´n JA, Brockington A, Wise RA, Rocha BA, Hope BT. Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci 2002;22:389–395. Valentini V, Frau R, Di Chiara G. Noradrenaline transporter blockers raise extracellular dopamine in medial prefrontal but not parietal and occipital cortex: differences with mianserin and clozapine. J Neurochem 2004;88: 917–927. Wermuth L, Sorensen PS, Timm S, et al. Depression in idiopathic Parkinson’s disease treated with paroxetine: a placebo-controlled trial. Nord J Psychiatry 1998;52:163– 169. Leentjens AFG, Vreeling FW, Luijckx GJ, Berhey FRJ. SSRIs in the treatment of depression in Parkinson’s disease. Int J Geriatric Psychiatry 2003;18:552–554. Ceravolo R, Nuti A, Piccinni A, et al. Paroxetine in Parkinson’s disease: effects on motor and depressive symptoms. Neurology 2000;55:1216–1218. Glassman AH, Bigger JT Jr. Cardiovascular effects of therapeutic doses of tricyclic antidepressants: a review. Arch Gen Psychiatry 1981;38:815–820.

Learn. Earn. Network. 2009 AAN Annual Meeting: An Excellent Value • Learn about the latest scientific advances in neurology • Earn valuable CME credit and fulfill Maintenance of Certification requirements • Network with your peers at exciting social events all week long • Enjoy the convenience and value of all this and more—in just one meeting Early registration and hotel deadline is March 20, 2009. Register today at www.am.com/AM2009.

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ACGME competencies in neurology Web-based objective simulated computerized clinical encounters

K.M. Kash, PhD B.F. Leas, MS, MA J. Clough, MD, MBA D.W. Dodick, MD D.J. Capobianco, MD D.B. Nash, MD, MBA L. Bance

ABSTRACT

Objective: The American Headache Society developed an innovative Web-based neurology resident educational program to 1) meet the objectives of the Accreditation Council for Graduate Medical Education Outcomes Project; 2) provide measurable improvement of a neurology resident’s understanding of headache and the performance within each core competency; 3) assist residents and program directors in identifying knowledge gaps; and, ultimately, 4) improve the quality of patient care through enhanced educational initiatives.

Methods: Quantitative analysis focused on pretest and post-test results, level attainment on Address correspondence and reprint requests to Dr. Kathryn M. Kash, Jefferson School of Population Health, Thomas Jefferson University, 1015 Walnut St., Suite 115, Philadelphia, PA 19107 [email protected]

case-based simulations, competency achievement, and interactions between cases. One of four validated global scores was related to each resident response on all competency learning opportunities and was measured, from one case to another, to determine improvement and understanding. The pretest and post-test each consisted of 50 randomized questions that tested baseline and improvement on specific core competencies and understanding of headache.

Results: The pretest mean score was 30.08, and the post-test mean score was 34.79. A paired sample t test analysis showed a significant difference from pretest to post-test scores (M ⫽ ⫺4.72, SD ⫽ 4.88, t[91] ⫽ ⫺9.269, p ⬍ 0.001). There was significant improvement in the competencies as the residents moved through the cases as well as in each of the competencies from the pretest to the post-test. Results showed that residents increased their knowledge and performance by synthesizing the content. Conclusions: This outcomes analysis demonstrates the effectiveness of the American Headache Society Neurology Resident’s Program in improving the resident’s knowledge of headache medicine and Accreditation Council for Graduate Medical Education core competencies. Neurology® 2009;72:893–898 GLOSSARY ACGME ⫽ Accreditation Council for Graduate Medical Education; AHS ⫽ American Headache Society; GME ⫽ graduate medical education; NS ⫽ not significant; OSCCE ⫽ objective simulated computerized clinical encounter; PGY ⫽ postgraduate year.

The Accreditation Council for Graduate Medical Education (ACGME) Outcome Project was designed to ensure and improve the quality of graduate medical education (GME). The ACGME requires that GME programs teach and evaluate residents on six core competencies and 27 subcompetencies.1 It is a requirement for all accredited residency programs that the ACGME core competencies be embedded into the curriculum. In addition, residency programs are required to develop objective measurements of resident performance in each of these competencies for accreditation review and as a basis for improvement in curricula.2 Residency programs must also begin to validate their data with external measures. Traditionally, GME programs evaluated residents’ medical knowledge, a content-based competency, using in-service examination percentile scores and pass rates on the American Board of Psychiatry and Neurology board examination. However, assessing the other competencies has proven more challenging. A recent study demonstrated that the systems-based

From Thomas Jefferson University/Jefferson School of Population Health (K.M.K., B.F.L., J.C., D.B.N.), Philadelphia PA; Mayo Clinic (D.W.D.), Scottsdale AZ; Mayo Clinic (D.J.C.), Jacksonville FL; and RedActive Inc. (L.B.), Philadelphia PA. Disclosure: The authors report no disclosures. Copyright © 2009 by AAN Enterprises, Inc.

893

practice and practice-based learning competencies are particularly challenging for program directors to assess quantitatively.3 Although the ACGME Toolkit provides assessment methods such as multisource (360°) evaluations and performance global ratings from attending physicians, educators, and other healthcare professionals,4 there is little consensus as to how to measure the non– content-based competencies, demonstrating a clear need for validated outcome measures.5-19 In response to the need for validated outcome measures of resident performance within each of the core competencies, program directors David W. Dodick, MD, and David J. Capobianco, MD, collaborated with the American Headache Society (AHS) to create the Neurology Resident Program to enhance headache education and simultaneously embed the ACGME six core competencies into the Web-based modules. Headache was chosen as the subject area for several reasons. Migraine alone affects approximately 12% of the world’s population; is one of the 20 most disabling medical illnesses worldwide; and, together with other causes for headache, represents the most common reason for outpatient neurology consultation.20,21 Unfortunately, migraine continues to be misdiagnosed, and undertreated in a substantial proportion of patients.22 One reason for this headache care gap is the underrepresentation of migraine and headache education programs in undergraduate and postgraduate medical training programs. One study revealed that 34% of US neurology residents receive less than 5 hours of structured headache education during a typical 3-year residency program.23 This article quantitatively analyzes and describes the development of this initiative, the validation of the pretest and post-test questions, and the quantitative outcomes for enhanced resident knowledge in headache medicine and performance in each of the core competencies. METHODS Program design. The Neurology Resident Program’s interactive Web-based module consists of five interactive headache cases that simultaneously teach, test, and reinforce residents’ knowledge through objective simulated computerized clinical encounters (OSCCEs). Each case is structured into practice areas (e.g., history, diagnosis, management) that are designed to mimic real-life patient encounters. The program includes a standardized and validated 50-question pretest and post-test. Each of the interac894

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tive cases includes an extensive, downloadable reference and slide library that reinforces self-directed learning opportunities. The curriculum and resources are embedded in an innovative Consequence-Based Learning software application. This patentpending software generates a myriad of customized learning pathways, qualitative and quantitative feedback, and resident and program director reports, which are linked to the six core competency domains. Depending on the decision point at which the resident determines the correct tests, he or she achieves one of four levels, with level 1 having the resident demonstrate knowledge and understanding of the learning objective at the first decision point and level 4 representing that the resident did not demonstrate knowledge or complete understanding of the learning objective at any decision point. For level 4, the resident is given feedback with the correct information. If a resident achieves level 2, he or she is provided with references online to review the patient’s problems. A level 3 would reflect that the resident has reviewed the literature successfully and has knowledge and understanding of the learning objective. Within each case, the resident responds to each question by selecting an answer to indicate what he or she thinks is the correct action to take (e.g., proper introduction to the patient, tests to be ordered, treatment prescribed, preliminary or final diagnosis). If the resident succeeds in getting the right answer(s) on the first try, a level 1 is achieved.

Cases and competencies. There are five cases covering thunderclap headache (reversible cerebral vasoconstriction), trigeminal autonomic cephalalgia (cluster headache), episodic headache (migraine), headache associated with white matter hyperintensities on MRI (CADASIL; cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and chronic daily headache (medication overuse headache). In the pretest and post-test, there were 11 to 16 skill sets that encompassed the six competencies. Some examples of these skill sets for the six competencies are as follows: 1. Patient care: caring and respectful behaviors, informed decision making, and work within a team 2. Medical knowledge: investigatory and analytic thinking and knowledge and application of basic sciences 3. Practice-based learning and improvement: analyze own practice for needed improvements, use of evidence from scientific studies, and application of research and statistical methods 4. Interpersonal and communication skills: creation of therapeutic relationship with patients and listening skills 5. Professionalism: ethically sound practice and sensitive to cultural, age, sex, and disability issues 6. Systems-based practice: understands interaction of their practices within the larger system and practice cost-effective care In the case vignettes, 22 to 25 learning opportunities were linked to each of the six competencies. Some examples of the learning opportunities are as follows: 1. 2. 3. 4. 5. 6. 7. 8.

Proper introduction to the patient Correct preliminary diagnosis Necessary interview questions Ordering the correct examinations, tests, or imaging Correct acute or preventive treatment Using the correct management strategy Correct final diagnosis Correct presentation of diagnosis and treatment plan to the patient

Each of the five cases strived to incorporate learning and assessment on all competencies within all learning opportunities.

Table 1

case, online resources linked to the specific competencies are provided for further learning.

Lowest and highest scores by postgraduate year Minimum score

Maximum score

Mean

SD

PGY 2

13

37

29.75

3.60

PGY 3

13

37

30.36

4.58

PGY 4

21

35

30.11

3.64

13

37

30.08

3.95

PGY 2

11

42

34.44

5.84

PGY 3

13

45

34.97

6.17

PGY 4

28

45

35.00

3.77

11

45

34.79

5.40

Pretest

Overall range Post-test

Overall range

PGY ⫽ postgraduate year.

The interactive module includes a standardized pretest and posttest, consisting of 50 validated questions, each of which was generated to relate to one or two competencies and one or more of the five cases. The final test questions were generated from a pool of 73 questions, which were completed and evaluated by nine residents in the testing phase. The final 50 questions had a Cronbach ␣ of 0.86, indicating strong internal consistency.

Resident performance. The five interactive cases incorporate 21 of the 27 subcompetencies. The program’s pretest and posttest measure 16 of the subcompetencies. Each interactive case provides residents a simulated clinical encounter. The resident selects a question for the patient. Next, the patient’s response appears on the screen. The robustness of the patient’s response and the usefulness of the feedback vary depending on the appropriateness and timing of the resident’s question. As such, the resident’s score on the question and the progression of the test questions vary. This interactive process mimics real-life patient encounters, specifically history taking, providing reinforcement of the interpersonal and communication competency. The simulated patient encounter continues until the resident has acquired all the necessary information to make an appropriate clinical decision regarding diagnosis, testing, and treatment. Residents receive ongoing feedback that teach and reinforce the core competencies throughout each of the cases. If a knowledge gap is identified during the resident’s progression through the

Table 2

Total case scores by each competency on the pretest and post-test Pretest

Post-test

Competency

No. of items Mean

Patient care

6

Medical knowledge

26

Interpersonal and communication skills

3

1.82 0.81

1.75 0.91 0.339 (NS)

Professionalism

8

6.09 1.18

6.65 1.45 0.001

SD

3.91 1.29

Mean

SD

p Value

4.40 1.20 0.001

14.76 2.57 17.20 3.33 0.001

Practice-based learning and improvement 3

2.01 0.75

2.34 0.57 0.001

Systems-based practice

7.17 1.56

8.64 1.86 0.001

12

Number of items is greater than 50 because some questions relate to more than one case and more than one competency. NS ⫽ not significant.

RESULTS The 92 resident participants represented 40 neurology training programs across the United States. The sample represents postgraduate year (PGY) residents in the second, third, and fourth years of training, including 32 PGY2s, 33 PGY3s, and 27 PGY4s. There were 33 women and 54 men (no sex available for 5 individuals). There were 11 women in each PGY, 20 men in PGY2 and PGY3, and 14 men in PGY4. The principal objective of the program was to demonstrate improvement in knowledge and performance of the competencies from pretest to post-test as the residents progressed through the Web-based, interactive case vignettes. The pretest and post-test measures were highly reliable, with a Cronbach ␣ of 0.74, indicating strong reliability. Improvement was evident in all PGY cohorts (table 1). There were no significant differences among the PGY cohorts or sex. Data from table 1 indicate that there were significant differences found between the pretest and post-test (M ⫽ ⫺4.72, SD ⫽ 4.88, t[91] ⫽ ⫺9.269, p ⬍ 0.001). Although the PGY4 residents had higher minimum scores on the pretest, there were no significant differences between this cohort and the PGY2 and PGY3 residents. Table 2 summarizes the residents’ scores for each competency on the pretest and post-test, for all the five cases. The research question was: Is there significant measurable and quantifiable improvement in the learners’ knowledge and skills in each of the competencies, from pretest to post-test? In table 2, it is clear there are significant improvements in five of the six core competencies across the cases. Overall, there were significant increases from pretest to post-test for five of the six competencies. The only core competency that did not significantly improve was interpersonal and communication skills. The competency based analysis demonstrated significant improvement from the first case to the second case (M ⫽ 4.55, SD ⫽ 5.07, t[91], p ⬍ 0.001) and from the third case to the fourth case (M ⫽ 2.38, SD ⫽ 5.94, t[91], p ⬍ 0.001). These findings indicate that the residents learned and improved in the competencies as they moved through the cases. The two figures highlight the differences between pretest scores and post-test scores for two of the competencies shown in table 2: professionalism (figure 1) and systems-based practice (figure 2). The data demonstrated significant improvement for these two competencies, highlighting the shift from lower scores on the pretest to higher scores on the post-test. Eight questions tested the professional competency Neurology 72

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Figure 1

Number of residents who scored from 0 to 8 on professionalism

domain. Thirty-four residents answered seven or eight items correctly in the pretest, and 64 residents answered seven or eight items correctly in the posttest, demonstrating improved competency (figure 1). For systems-based practice, the improvement was more robust in a total of 12 items. None of the residents answered either 11 or 12 items correctly in the pretest, but 15 residents answered 11 or 12 items correctly in the post-test (figure 2). Overall, significant improvement was seen on the outcome measure from pretest to post-test as well as progressing through the cases in terms of demonstrated improvement in their knowledge of the competencies. Until recently, little progress has been made toward developing a strategy that simultaneously allows the transfer of a core body of medical knowledge while using validated outcome endpoints for assessing residents’ knowledge and growth in each of the six core competencies. The results of this analysis of the AHS program revealed significant improvement using validated outcome measures in each of the six core competencies across neurology PGY cohorts. Further, this assessment demonstrated the program’s potential to supplement residency headache curricula and reinforce the core knowledge and skills required to evaluate and manage patients with primary and secondary headache disorders. Neurologists recognize that headache is a major healthcare issue and accounts for a significant per-

DISCUSSION

Figure 2

896

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Number of residents who scored from 2 to 12 on systems-based practice

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cent of patients in their clinical practice. However, only 20% feel adequately trained to treat headache and acknowledge the need for additional resident training in this area. A survey of 95 institutions (including 75 neurology department chairs and 44 neurology residency program directors), found that only 55 institutions had a headache clinic. Thirty-two percent offer headache electives to medical students, and 57% offer headache electives to residents.24 Because headache education is not systematically embedded into all medical schools and residency programs, initiatives such as the AHS neurology resident program may help close the knowledge gap in the area of headache medicine and provide a benchmark for comparing residents within and across programs in each of the six core competency domains. Residents may appreciate the self-directed nature and interactive features of the program. Residency program directors will appreciate having an objective tool for measuring resident performance within each competency domain and having a benchmark for comparing residents within and across programs. Systems-based practice and practice-based learning are particularly challenging competencies to assess. Residents are unlikely to have meaningful exposure to these concepts, and few programs have a formal, objective, and validated method of evaluating the resident’s performance in these competencies. The AHS program represents a unique opportunity to identify and measure systems-based practice and practice-based learning opportunities within the context of the five cases. The results demonstrate that the neurology resident’s performance in these two competencies improved as they progressed through the case vignettes. The outcome “report cards,” which each resident (table 3) and program director receive after completion of the program, provide valuable feedback on the resident and program performance compared with all corresponding PGY level trainees and programs across the country. The outcomes also facilitate the identification of competency areas of strength for each resident, and those where improvement is needed for both the resident and the program. In addition, the report cards are a resource for illustrating measures being taken to fulfill the program requirements for the ACGME outcome project. There are several limitations of this preliminary analysis. The results reflect residents’ performance with this tool during one calendar year (2007), so it is not yet possible to assess the OSCCE’s impact on the residents’ performance longitudinally or within a larger cohort of residents. However, because no outcomes data from similar OSCCE programs have been published in any specialty, there is no benchmark for comparing the results. The absence of a significant difference between the PGY2 cohort and

Table 3

Sample of resident report

ACGME Competencies Achievement

Ratio correct answers achieved by resident

Competency and learning objective

Percent correct answers achieved by resident

Percent correct answers achieved by all residents XYZ Institution*

Percent global answers achieved by all residents in all participating neurology GMEs†

1. Patient care a. Caring and respectful behaviors

3/4

75

80

81

b. Interviewing

2/3

67

71

79

c. Informed decision making

4/6

67

75

73

e. Counsel and educate patients and families

0/1

75

67

70

a. Investigatory and analytic thinking

3/3

100

94

92

b. Knowledge and application of basic sciences

2/2

100

87

88

a. Creation of therapeutic relationship with patient

2/2

100

75

69

b. Listening skills

0/1

80

82

74

2/2

100

81

69

1/1

87

87

88

1/1

67

70

50

2. Medical knowledge

3. Interpersonal and communication skills

4. Professionalism b. Ethically sound practice 5. Practice-based learning and improvement b. Use of evidence from scientific studies 6. Systems-based practice b. Knowledge of practice and delivery systems

*The resident’s individual institution. †All residents in all participating institutions. ACGME ⫽ Accreditation Council for Graduate Medical Education; GME ⫽ graduate medical education.

their more senior colleagues is of interest, although explanatory factors cannot yet be inferred from the analysis. This finding, however, at least suggests and perhaps confirms the lack of and need for a formal headache education curriculum in postgraduate neurology residency programs. The absence of a formal curriculum and faculty members with expertise in the field of headache medicine may yield a suboptimal clinical environment in which a rich knowledge base with sharp clinical instincts in the broad field of headache medicine may not develop adequately. An important objective of this program will be to determine whether the improved outcomes from this project are sustained over time by comparing residents’ performance over the course of their residency. A second limitation is that some competencies are more heavily represented in the pretest and post-test, as well as in the case vignettes. Finding creative ways to test knowledge and skills on the underrepresented competencies would strengthen the program’s overall capacity to comprehensively assess each resident’s performance. In fact, the program has been updated and enhanced and now includes equal numbers of items for each of the six competencies in the case vignettes and the pretest and post-test. The authors acknowledge that Webbased programs do not and cannot replace the value of

and insights gained from direct faculty oversight and supervision of resident–patient encounters, nor the faculty member’s ability to evaluate certain competencies, especially interpersonal and communication skills. The program also cannot ensure that improvement within individual competency areas will translate into improved clinical efficiency and enhanced patient outcomes. However, enriched Web-based programs such as the AHS program can identify competencies where individual attention may be warranted. Finally, the interpersonal and communication skills competency is particularly difficult to assess in a Web-based format. The cases contained substantial attention to communication issues, but it was not possible to adequately assess the resident’s performance on the competency with the pretest and posttest. Perhaps the revised pretest and post-test will show significant differences in the new version. This innovative program is the first Web-based, simulated clinical encounters teaching, learning, and assessment tool to integrate the six core competencies and provide a quantifiable, objective benchmark for assessing resident performance within and across residency programs. As such, it is reflective of the importance of using Internet-based learning as an effective way for health professionals to obtain the knowledge and skills Neurology 72

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needed during their education.25 The technology used in the AHS Neurology Resident’s Program of Webbased case vignettes could be extrapolated to and developed for other diseases within neurology (e.g., multiple sclerosis, Parkinson disease, epilepsy) as well as other specialties, such as pediatrics, surgery, or psychiatry. In addition, the approach described here could easily be adapted for use in recertification or maintenance of certification programs as well as continuing medical education programs in headache and other areas of neurology. Future research should address how residents and resident program directors should use feedback and incorporate the knowledge gained into their clinical practice to improve patient care. Program data could provide an opportunity to review resident and programmatic performance and help identify methods to close the knowledge gaps, but it is unknown whether, how, or to what extent program directors will use the data. Future studies should focus on how residents and resident program directors use the data and longitudinal retention of the clinical knowledge gained.

7.

8.

9.

10.

11.

12.

13.

14. AUTHOR CONTRIBUTIONS K.M.K. conducted statistical analyses.

15. ACKNOWLEDGMENT

898

The authors thank the curriculum team: Drs. Jonathan Gladstone, Elizabeth Loder, Allen Purdy, Nabih Ramadan, and Steven Silberstein. The authors also thank Katherine Purcell for preparation of the manuscript.

16.

Received August 12, 2008. Accepted in final form November 18, 2008.

17.

REFERENCES 1. Accreditation Council for Graduate Medical Education. Common program requirements: general competencies. Available at: http://www.acgme.org/outcome/comp/ GeneralCompetenciesStandards21307.pdf. Accessed May 27, 2008. 2. Accreditation Council for Graduate Medical Education. Timeline—working guidelines. Available at: http://www. acgme.org/outcome/project/timeline/TIMELINE_index_ frame.htm. Accessed May 27, 2008. 3. Moskowitz EJ, Nash DB. Accreditation Council for Graduate Medical Education competencies: practice-based learning and systems-based practice. Am J Med Qual 2007;22:351–382. 4. Accreditation Council for Graduate Medical Education. Toolbox of assessment methods. Available at: http://www. acgme.org/Outcome/assess/Toolbox.pdf. Accessed May 27, 2008. 5. Accreditation Council for Graduate Medical Education. References: assessment general. Available at: http://www. acgme.org/outcome/assess/refs_general805.pdf. Accessed May 27, 2008. 6. Williams RG, Verhulst S, Colliver JA, Dunnington GL. Assuring the reliability of resident performance appraisals: more items or more observations? Surgery 2005;137:141–147.

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Massagli TL, Carline JD. Reliability of a 360-degree evaluation to assess resident competence. Am J Phys Med Rehabil 2007;86:845–852. Whitson BA, Hoang CD, Jie T, Maddaus MA. Technologyenhanced interactive surgical education. J Surg Res 2006;136: 13–18. Sadosty AT, Stead LG, Boie ET, Goyal DG, Weaver AL, Decker WW. Evaluation of the educational utility of patient follow-up. Acad Emerg Med 2004;11:715–719. Staton LJ, Kraemer SM, Patel S, Talente GM, Estrada CA. Correction: Peer chart audits—a tool to meet Accreditation Council on Graduate Medical Education (ACGME) competency in practice-based learning and improvement. Implement Sci 2007;2:24. Panek RC, Deloney LA, Park J, Goodwin W, Klein S, Ferris EJ. Interdepartmental problem-solving as a method for teaching and learning systems-based practice. Acad Radiol 2006;13:1150–1154. Adams KE, O’Reilly M, Romm J, James K. Effect of Balint training on resident professionalism. Am J Obstet Gynecol 2006;195:1431–1437. Berman EM, Heru AM, Grunebaum H, Rolland J, Wood B, Bruty H. Family skills for general psychiatry residents: meeting ACGME core competency requirements. Acad Psychiatry 2006;30:69–78. Greenberg JA, Irani JL, Greenberg CC, et al. The ACGME competencies in the operating room. Surgery 2007;142:180–184. Horwitz IB, Horwitz SK, Brandt ML, Brunicardi FC, Scott BG, Awad SS. Assessment of communication skills of surgical residents using the Social Skills Inventory. Am J Surg 2007;194:401–405. Lee AG, Beaver HA, Boldt HC, et al. Teaching and assessing professionalism in ophthalmology residency training programs. Surv Ophthalmol 2007;52:300–314. Watling CJ, Brown JB. Education research: communication skills for neurology residents—structured teaching and reflective practice. Neurology 2007;69:E20–E26. Johnston KC. Responding to the ACGME’s competency requirements: an innovative instrument from the University of Virginia’s neurology residency. Acad Med 2003;78:1217–1220. Peltier WL. Core competencies in neurology resident education: a review and tips for implementation. Neurologist 2004;10:97–101. Lipton RB, Scher AI, Kolodner K, Liberman J, Steiner TJ, Stewart WF. Migraine in the United States: epidemiology and patterns of health care use. Neurology 2002;58:885–894. Finkel AG. Academic headache medicine in America: report of academic membership survey of the American Headache Society special interest section on academic affairs. Headache 2003;43:266–271. Lipton RB, Diamond S, Reed M, Diamond ML, Stewart WF. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache 2001;41:638–645. Gallagher RM, Alam R, Shah S, Mueller L, Rogers JJ. Headache in medical education: medical schools, neurology and family practice residencies. Headache 2005;45:866–873. Kommineni M, Finkel AG. Teaching headache in America: survey of neurology chairs and residency directors. Headache 2005;45:862–865. Cook DA, Levinson AJ, Garside S, et al. Internet-based learning in the health professions: a meta-analysis. JAMA 2008;300:1181–1196.

Prevalence of nephroangiosclerosis in patients with fatal stroke

H. Abboud, MD J. Labreuche, BS C. Duyckaerts, MD, PhD J.-J. Hauw, MD P. Amarenco, MD

ABSTRACT

Background: Glomerular filtration rate and decline in renal function can be improved by global cardiovascular prevention. However, the prevalence of nephroangiosclerosis in patients with stroke is unknown.

Methods: Using an autopsy data bank, we studied the prevalence of nephroangiosclerosis in 820 consecutive autopsies of neurologic patients.

Address correspondence and reprint requests to Professor Pierre Amarenco, Department of Neurology and Stroke Centre, Bichat University Hospital, 46 rue Henri Huchard, 75018 Paris, France [email protected]

Results: Among the 820 autopsies, 354 had pathologic evidence of stroke and 466 had other neurologic diseases. Nephroangiosclerosis was found in 39.8% (95% confidence interval [CI], 34.7– 44.9) of patients with stroke vs 9.0% (95% CI, 6.4 –11.6) in patients with other neurologic diseases. The odds ratio (OR) for nephroangiosclerosis, adjusted for age and sex, was 4.37 (95% CI, 2.92– 6.52), and was 2.94 (95% CI, 1.83– 4.74) after further adjustment for cardiovascular risk factors. Among the 354 stroke patients, the prevalence of nephroangiosclerosis was similar in patients with brain infarction and in those with brain hemorrhage, in patients with or without parenchymal abnormalities related to small-vessel disease, and across ischemic stroke subtypes except for those with coexisting causes. After multivariable analysis, nephroangiosclerosis was independently associated with age and history of hypertension in patients with stroke, and with age in those with other neurologic diseases.

Conclusions: Nephroangiosclerosis is common in patients with fatal stroke. The association is independent of age, sex, and other cardiovascular risk factors. Impaired renal function should be monitored and prevented in stroke patients with high blood pressure. Neurology® 2009;72:899–904 GLOSSARY CI ⫽ confidence interval; OND ⫽ neurologic diseases other than stroke; OR ⫽ odds ratio; SVD ⫽ small-vessel disease.

Hypertension and increasing age are the most powerful risk factors for cardiovascular disease including stroke and coronary heart disease.1,2 Since the kidney is an integral part of the cardiovascular system, the development of renovascular and cardiovascular diseases is part of a continuum. Both the renal and systemic vasculatures are target organs for damage caused by diabetes and hypertension.3,4 Hypertensive nephrosclerosis causes 25% of end-stage renal disease in the United States and 8% in Europe.5,6 Because most cases of nephroangiosclerosis are clinically silent, information about the prevalence and incidence of this condition in stroke patients is limited. The only available data are from histology tissue obtained from biopsy or autopsy. Addressing risk factors for nephroangiosclerosis in patients with stroke should help to prevent renal insufficiency in this population. Recent findings from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, that 5 years of statin therapy in patients with stroke or TIA can be nephroprotective by improving renal function (glomerular filtration rate) and significantly reducing the

From the Assistance Publique-Hoˆpitaux de Paris (H.A., C.D., J.-J.H., P.A.), the Department of Neuropathology Raymond Escourolle (C.D., J.-J.H., P.A.), La Salpeˆtrie`re Hospital; and INSERM U-698 and Denis Diderot University–Paris VII, the Department of Neurology and Stroke Centre (H.A., J.L., P.A.), Bichat-Claude Bernard University Hospital, Paris, France. Supported by SOS-ATTAQUE Cerebrale Association. Disclosure: The authors report no disclosures. Copyright © 2009 by AAN Enterprises, Inc.

899

decline of renal function in diabetic patients, reinforces the need to explore the relationship between stroke and renal disease of vascular origin.7 In the Multiple Atherosclerosis Site in Stroke (MASS) study, a comprehensive autopsy study of patients who died from neurologic diseases or stroke, we evaluated the prevalence of nephroangiosclerosis in relation to hypertension and other risk factors. METHODS From the pathology database of La Salpeˆtrie`re Hospital, Paris, France, we studied all patients with neurologic diseases who were autopsied over a 7-year period (November 1982 to February 1989), during which time the autopsy rate was 73%. Of the 886 autopsies, 381 were from patients with stroke, including 83 with brain hemorrhage, 288 with brain infarction, and 10 with both brain hemorrhage and infarction. A total of 505 patients had neurologic diseases other than stroke, such as degenerative and demyelinating diseases (n ⫽ 152), brain tumors (n ⫽ 202), infections (n ⫽ 92), trauma (n ⫽ 4), and other neurologic disorders with normal brain tissue (n ⫽ 55). Causes of death fulfilled WHO criteria for underlying cause of death from stroke or other neurologic diseases. Subclassification of ischemic stroke was determined according to the Etude du Profil Ge´ne´tique de l’Infarctus Ce´re´bral (GENIC)8 classification as follows: lacunar, atherothrombotic, cardioembolic, rare causes (such as disseminated intravascular coagulation and other hematologic causes, vasculitis, or dissection), coexisting causes (two or more possible etiologies as defined previously), and unknown causes (when no identifiable cause was found). The patients’ baseline characteristics, risk factors, and premortem clinical diagnoses were examined from their medical records. Among the risk factors, hypertension was defined as blood pressure ⱖ140/90 mm Hg or if the patient was taking antihypertensive medication. Diabetes mellitus was defined as the use of oral hypoglycemic drugs or insulin or a fasting blood glucose level ⱖ140 mg/dL. Smoking habits were registered. None of our patients was under dialysis for end stage renal disease. Blood creatinine levels were not available in the database. According to French regulation, there is no need to have ethic committee approval for analysis of an autopsy database.

Autopsy study. The methods have been reported previously.9 Autopsies were performed according to a standardized protocol from our pathology department and French legislation. Briefly, extensive macroscopic examinations of the abdominal viscera, brain, and proximal part of the arterial system were performed in each case. Significant stenosis of the renal artery, coronary artery, and extracranial and intracranial arteries was defined as ⬎50% luminal narrowing. Small-vessel disease (SVD) was defined as the presence of sclerosis and hyalinosis (replacement of the smooth muscle cells of small arteries by fibroblasts and collagen, leading to hyaline thickening of the media), lipohyalinosis (wherein additional fibrinoid necrosis and sometimes lipid deposits were present), and isolated fibrinoid necrosis noted on microscopic examination.10 Kidneys were included in the systematic macroscopic and microscopic analyses. 900

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Whatever the blood pressure levels, the histologic diagnosis of hypertensive nephrosclerosis was made as follows, after large postmortem sampling including cortex, medulla, and proximal urinary tract: inclusion criteria included combined sclerosis of vessels, extensive global glomerulosclerosis, and proportional tubulointerstitial fibrosis. Exclusion criteria included primary focal segmental glomerulosclerosis without severe vascular lesions, or reflux nephropathy indicated either by urinary tract infection or by pyelonephritis induced patchy, geographical areas of fibrosis with major tubulointerstitial injury.11

Statistical analysis. Data are presented as the mean (SD) for continuous variables and the percentage (count) for binary variables. We compared the prevalence of nephroangiosclerosis between patients with and without pathologic evidence of stroke using the ␹2 test. We also used the ␹2 test to compare the prevalence of nephroangiosclerosis between the brain-infarction and brain-hemorrhage groups, and between the main braininfarction subtypes; a level of significance of 0.0125 (0.05/4) was used for the post hoc pairwise comparisons of brain infarction classified as coexisting causes with each of the four other braininfarction subtypes. Comparison of the prevalence of nephroangiosclerosis between patients with stroke and other neurologic diseases was adjusted for age, sex, and other conventional cardiovascular risk factors including heart weight (reflecting the presence of arterial hypertension) using logistic regression analysis. Crude and adjusted odds ratios (ORs) of stroke associated with the presence of nephroangiosclerosis were calculated with their 95% confidence intervals (CIs). Sensitivity analyses were restricted to 565 patients without a history of hypertension, and to 224 pairs of patients with or without stroke matched by age (⫾1 year) and gender. Sensitivity analysis on matched groups was performed using conditional logistic regression analysis. We studied the cardiovascular risk factors associated with the presence of nephroangiosclerosis in patients with stroke or other neurologic diseases using Student t test for continuous factors and the ␹2 test for binary factors; Fisher exact test was used when the expected cell frequency was ⬍5. Multivariate analyses were performed by including age, sex, and other vascular risk factors associated with nephroangiosclerosis in univariate analysis. In exploratory post hoc analysis, we investigated the associations between nephroangiosclerosis and atherosclerosis at different sites (cerebral, coronary, aortic, and renal arteries), and parenchymal abnormalities related to SVD among stroke patients. These associations were tested in a multiple logistic regression model including age, sex, and other vascular risk factors associated with nephroangiosclerosis. Statistical testing was done at the two-tailed ␣ level of 0.05. Data were analyzed using the SAS package, release 9.1 (SAS Institute, Cary, NC). RESULTS Among 886 consecutive autopsies, 92.6% (n ⫽ 820) underwent macroscopic autopsy examination of the kidneys and had complete clinical data and heart weight (figure). Of these, 354 patients had pathologic evidence of stroke (median time between event and death, 13 days; interquartile range, 6 to 33 days) and 466 had other neurologic diseases. The proportion of patients with missing data who were excluded from the statistical analysis was similar in both groups (7.1% vs 7.7%; p ⫽ 0.72). Patients with stroke were older, had more cardiovascular risk

Figure

Flow chart of study population

OND ⫽ neurologic diseases other than stroke.

factors, and more frequently had a cardiovascular history (i.e., any symptomatic vascular event) than patients with other neurologic diseases (data not shown). Prevalence of nephroangiosclerosis. Nephroangiosclerosis was found in 39.8% (95% CI, 34.7– 44.9) of patients with stroke vs 9.0% (95% CI, 6.4 –11.6) in those with other neurologic diseases (crude OR, 6.68; 95% CI, 4.56 –9.79). After adjustment for age and sex, this difference was attenuated but remained significant, with an adjusted OR of 4.37 (95% CI, 2.92– 6.52). This difference persisted after additional adjustment for cardiovascular risk factors (OR, 2.94; 95% CI, 1.83– 4.74). Similar results were found in sensitivity analysis restricted to patients with no history of hypertension (adjusted OR, 2.35; 95% CI, 1.29 – 4.27) and to age-matched and gendermatched groups (adjusted OR, 2.54, 95% CI, 1.24 – 5.23). Among the 354 patients with stroke, the prevalence of nephroangiosclerosis was similar in patients with brain infarction and in those with brain hemorrhage (p ⫽ 0.76). However, there was a significant difference between the main brain-infarction subtypes resulting from the higher prevalence of nephroangiosclerosis in patients with brain infarction due to coexisting causes (table 1). Similar results were found after adjustment for age and sex. Nephroangiosclerosis and vascular risk factors. In both stroke patients and those with other neurologic diseases, univariate analysis showed that nephroangiosclerosis was associated with age, history of hypertension (with a nonsignificant difference in patients with other neurologic diseases), heart weight, and cardiovascular history (table 2). In multivariable analysis, the presence of nephroangiosclerosis appeared independently associated with age (OR per 10-year increase, 1.41; 95% CI, 1.13–1.76) and his-

Table 1

Prevalence of nephroangiosclerosisin 820 consecutive autopsies of patients with neurologic diseases

Patients, n

Patients with nephroangiosclerosis, n (%)

Cerebrovascular disease

354

141 (39.8)

Brain infarction

263

106 (40.3)

Atherothrombotic

62

25 (40.3)*

Cardioembolic

93

34 (36.6)*

Lacunar

25

11 (44.0)

Coexisting causes

37

25 (67.6)

Unknown cause

34

11 (32.4)*

Brain hemorrhage†

91

35 (38.5)

Other neurologic diseases

466

42 (9.0)‡

*p ⬍ 0.01 for comparison with brain infarction of coexisting cause. †Including 10 brain infarctions. ‡p ⬍ 0.001 for comparison with cerebrovascular disease.

tory of hypertension (OR, 1.84; 95% CI, 1.14 – 2.95) in stroke patients, and only with age in patients with other neurologic diseases (OR per 10-year increase, 2.51; 95% CI, 1.78 –3.55). Nephroangiosclerosis, widespread atherosclerosis, and SVD. Table 3 shows the prevalence of atherosclerosis

at different sites, the presence of myocardial infarction at autopsy, and small-vessel lesions according to the presence or absence of nephroangiosclerosis in patients with stroke. No association was found between nephroangiosclerosis and cerebral atherosclerosis except for a borderline association with the presence of stenosis in the cerebral artery. Compared to stroke patients without nephroangiosclerosis, stroke patients with nephroangiosclerosis had a significantly higher frequency of plaques in the coronary arteries (84% vs 65%), pathologic evidence of myocardial infarction (49% vs 34%), and stenosis in renal arteries (9% vs 3%). However, there was no difference in the prevalence of coronary artery stenosis and in ulcerated plaques in the aortic arch and abdominal and thoracic aorta. Parenchymal abnormalities related to SVD (e.g., white matter changes, e´tat crible´, or Virchow-Robin dilatation of perivascular spaces) were not associated with the presence of nephroangiosclerosis. This autopsy study describes the epidemiology of nephroangiosclerosis in patients with stroke. The main finding is that nephroangiosclerosis was substantially more common in patients with fatal stroke than in those with other neurologic diseases. Among stroke patients, nephroangiosclerosis was DISCUSSION

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Table 2

Association between nephroangiosclerosis and cardiovascular risk factors according to pathologic evidence of stroke Patients with stroke

Patients with other neurologic diseases

Characteristic

Nephroangiosclerosis (ⴙ) (n ⴝ 141)

Nephroangiosclerosis (ⴚ) (n ⴝ 213)

Nephroangiosclerosis (ⴙ) (n ⴝ 42)

Nephroangiosclerosis (ⴚ) (n ⴝ 424)

Age, mean ⴞ SD, y

75.1 ⫾ 9.8

71.1 ⫾ 12.9

p

0.001

74.9 ⫾ 11.2

59.0 ⫾ 16.0

⬍0.001

Men, n (%)

86 (61.0)

Hypertension, n (%)

95 (67.4)

109 (51.2)

0.07

27 (64.3)

250 (59.0)

0.50

111 (52.1)

0.004

8 (19.1)

41 (9.7)

0.07*

Diabetes, n (%) Smoking, n (%)

20 (14.2)

27 (12.7)

0.68

3 (7.1)

19 (4.5)

0.44*

20 (14.2)

35 (16.4)

0.57

3 (7.1)

28 (6.6)

0.75*

Dyslipidemia, n (%)

7 (5.0)

19 (8.9)

0.16

0 (0.0)

5 (1.2)

Atrial fibrillation, n (%)

40 (28.4)

55 (25.8)

0.60

3 (7.1)

9 (2.1)

Cardiovascular history, n (%)

38 (27.0)

36 (16.9)

Heart weight, mean ⴞ SD, g

444 ⫾ 98

406 ⫾ 106

p

0.02 ⬍0.001

— 0.08

6 (14.3)

14 (3.3)

0.006*

387 ⫾ 84

343 ⫾ 84

0.001

Proportions and continuous variables were compared using the ␹2 (or *Fisher exact) test and Student t test, respectively.

strongly associated with a history of hypertension. Increasing age was also an important risk factor for nephroangiosclerosis. Nephroangiosclerosis was present in 40% of stroke patients. This percentage was much higher than that in patients with other neurologic disease (9%) and in those reported from several national renal biopsy registries from Europe12 and other countries.13,14 A higher frequency of nephroangiosclerosis in stroke patients was expected based on the link with cardiovascular disease risk factors. However, it is rather difficult to report definitive epidemiologic data on the frequency of nephroangiosclerosis in the general population because a renal biopsy procedure Table 3

is usually only performed when the likelihood of therapeutic consequences is high.15 Since renal function and particularly glomerular filtration rate can be improved in patients with stroke, and even decline in renal function can be reduced in diabetic patients, our present results may have an important impact on clinical practice.7 Since preventive treatments such as antihypertensive drugs and statin therapy may provide renoprotection, and as nephroangiosclerosis is present in 40% of fatal strokes, improving renal function should be part of secondary stroke prevention. Nephroangiosclerosis commonly represents a silent disease entity, and is considered a consequence

Association of nephroangiosclerosis with atherosclerosis, myocardial infarction, and small-vessel disease among 354 stroke patients Nephroangiosclerosis (ⴙ) (n ⴝ 141)

Nephroangiosclerosis (ⴚ) (n ⴝ 213)

Odds ratio (95% confidence interval)*

p*

Cerebral artery plaques

111 (81.6)

153 (77.3)

1.09 (0.61–1.93)

0.78

Cerebral artery stenosis

86 (63.2)

99 (50.0)

1.50 (0.94–2.38)

0.09

Coronary artery plaques

117 (83.6)

129 (64.5)

2.17 (1.24–3.82)

0.007

Coronary artery stenosis

58 (41.4)

69 (34.5)

1.07 (0.67–1.70)

0.79

Ulcerated plaques in aortic arch

37 (26.2)

43 (20.2)

1.09 (0.64–1.84)

0.75

Ulcerated plaques in abdominal or thoracic aorta

33 (23.4)

33 (15.5)

1.47 (0.85–2.56)

0.17

Silent or clinical myocardial infarction

69 (48.9)

73 (34.3)

1.63 (1.04–2.55)

0.03

Renal artery stenosis

13 (9.2)

7 (3.3)

2.75 (1.04–7.26)

0.04

Small-vessel disease†

19 (17.3)

29 (16.1)

0.91 (0.47–1.77)

0.79

Lacunar infarction

47 (33.3)

55 (25.8)

1.13 (0.69–1.84)

0.63

Multilacunes

27 (19.2)

34 (16.0)

0.98 (0.55–1.75)

0.94

´ tat crible E ´

16 (12.8)

23 (11.9)

0.87 (0.43–1.77)

0.69

Widespread atherosclerosis, n (%)

Parenchymal abnormalities related to small-vessel disease, n (%)

*Logistic regression analysis adjusted for age, sex, and history of hypertension. †Sclerosis, hyalinosis, or lipohyalinosis of small arteries ⬍300 ␮m and arterioles. 902

Neurology 72

March 10, 2009

of high blood pressure or aging.16 However, hypertension first causes damage to the heart and brain and later to the kidneys. Left ventricular hypertrophy is strongly related to blood pressure levels, is a frequent complication of even mild hypertension,17 and accounts for most of the increase in heart weight.18 In our study, it is thus possible that heart weight was associated with nephroangiosclerosis in univariate analysis because of their relationship with blood pressure. However, the mechanisms by which hypertension could cause renal injury are incompletely understood and may include glomerular ischemia secondary to vascular narrowing,19 glomerulosclerosis due to intracapillary hypertension,20 and interstitial fibrosis.21 Since high blood pressure is a frequent risk factor for both cerebral SVD and nephroangiosclerosis, and because both have some small-vessel histology changes in common (e.g., hyaline changes, sclerosis and fibrinoid necrosis in arteriolar wall), we expected an association between these two conditions, which is supported by the finding of an association between renal function and MRI markers of cerebral SVD.22 In the present series, the lack of an association between nephroangiosclerosis and SVD can be in part explained by insufficient statistical power due to the small number of patients who died after a lacunar stroke. Another explanation is that hypertension was similarly frequent across stroke subtypes, and this likely explains why nephroangiosclerosis was equally distributed among stroke subtypes.20-22 Several cardiovascular risk factors were also examined in relation to nephroangiosclerosis in this study. In keeping with previous studies, age was significantly related to nephroangiosclerosis.23 Although an association between diabetes and arteriolar hyalinosis is frequent,24 we did not find any association between nephroangiosclerosis and diabetes among stroke patients. However, we caution that some association could be overlooked due to inadequate statistical power, especially in our control group. Based on our sample sizes, we could detect an OR for nephroangiosclerosis of 2.2 in stroke patients and of 2.9 in patients with other neurologic diseases, with an 80% power and a 5% ␣ level (two-tailed), assuming an exposure frequency of 0.15 in the group without nephroangiosclerosis. A potential limitation of this study was the relatively small number of patients in each stroke subtype, particularly in the lacunar stroke group. Another limitation is that we could not associate nephroangiosclerosis with serum creatinine values or to glomerular filtration rate before death because these values were not recorded in the database. Finally, this cohort was collected in the 1980s. Since

then, antihypertensive treatment has been widely used and global cardiovascular risk is better controlled, including lipid-lowering therapy and smoking cessation. Consequently, nephroangiosclerosis in stroke patients might be less frequent nowadays than in our study. However, while treatment and outcomes for atherothrombosis-related diseases have evolved greatly since then, the pathophysiology, epidemiology, and associations between the various conditions are likely to remain stable. Nowadays and because of the general decline in autopsy rates, large autopsy studies are very rare, and as a consequence, our large autopsy database appears unique. AUTHOR CONTRIBUTIONS Julien Labreuche, BS, conducted the statistical analysis.

ACKNOWLEDGMENT Dr. Sophie Rushton-Smith provided editorial assistance in the preparation of the final draft of this manuscript and was funded by SOSATTAQUE Cerebrale Association. Dr. Rushton-Smith was not involved in drafting of the paper or answering to the reviewer, and did not have other technical involvement.

Received July 30, 2008. Accepted in final form December 17, 2008. REFERENCES 1. Bonita R. Epidemiology of stroke. Lancet 1992;339:342– 344. 2. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease: part 1: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335:765–774. 3. Brosius FC 3rd, Hostetter TH, Kelepouris E, et al. Detection of chronic kidney disease in patients with or at increased risk of cardiovascular disease: a science advisory from the American Heart Association Kidney and Cardiovascular Disease Council; the Councils on High Blood Pressure Research, Cardiovascular Disease in the Young, and Epidemiology and Prevention; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: developed in collaboration with the National Kidney Foundation. Circulation 2006;114:1083–1087. 4. Zanchetti A. Evidence-based medicine in hypertension: what type of evidence? J Hypertens 2005;23:1113–1120. 5. US Renal Data System. USRDS 2007 Annual Data Report. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2007. 6. Kincaid-Smith P. Renal pathology in hypertension and the effects of treatment. Br J Clin Pharmacol 1982;13:107– 115. 7. Campese VM, Callahan A III, Rudolph A, et al., on behalf of the SPARCL Investigators. Effect of high-dose atorvastatin on changes in renal function: a secondary analysis of the Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial. Circulation 2007;116:II-471. Abstract. 8. Touboul PJ, Elbaz A, Koller C, et al. Common carotid artery intima-media thickness and brain infarction: The Etude du Profil Genetique de l’Infarctus Cerebral (Genic) Neurology 72

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Case-control study: The Genic Investigators. Circulation 2000;102:313–318. 9. Jaramilo A, Gongora-Rivera F, Labreuche J, Hauw J-J, Amarenco P. Anatomic and vascular predictors for malignant middle cerebral artery infarctions: a post-mortem analysis. Neurology 2006;66:815–820. 10. Lammie GA. Hypertensive cerebral small vessel disease and stroke. Brain Pathol 2002;12:358–370. 11. Luke RG. Hypertensive nephrosclerosis: pathogenesis and prevalence: essential hypertension is an important cause of end-stage renal disease. Nephrol Dial Transplant 1999;14: 2271–2278. 12. Simon P, Ramee MP, Autuly V, et al. Epidemiology of primary glomerular diseases in a french region: variations according to period and age. Kidney Int 1994;46:1192– 1198. 13. Nationwide and long-term survey of primary glomerulonephritis in japan as observed in 1,850 biopsied cases: Research group on progressive chronic renal disease. Nephron 1999;82:205–213. 14. Briganti EM, Dowling J, Finlay M, et al. The incidence of biopsy-proven glomerulonephritis in Australia. Nephrol Dial Transplant 2001;16:1364–1367. 15. Meyrier A, Simon P. Nephroangiosclerosis and hypertension: things are not as simple as you might think. Nephrol Dial Transplant 1996;11:2116–2120.

16.

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Vikse BE, Aasarod K, Bostad L, Iversen BM. Clinical prognostic factors in biopsy-proven benign nephrosclerosis. Nephrol Dial Transplant 2003;18:517–523. Kannel WB. Blood pressure as a cardiovascular risk factor: Prevention and treatment. JAMA 1996;275:1571–1576. Reiner L, Mazzoleni A, Rodriguez FL, Freudenthal RR. The weight of the human heart: II: hypertensive cases. Arch Pathol 1961;71:180–201. Ritz E, Fliser D, Siebels M. Pathophysiology of hypertensive renal damage. Am J Hypertens 1993;6:241S–244S. Harvey JM, Howie AJ, Lee SJ, et al. Renal biopsy findings in hypertensive patients with proteinuria. Lancet 1992; 340:1435–1436. Bohle A, Muller GA, Wehrmann M, Mackensen-Haen S, Xiao JC. Pathogenesis of chronic renal failure in the primary glomerulopathies, renal vasculopathies, and chronic interstitial nephritides. Kidney Int Suppl 1996;54:S2–9. Ikram MA, Vernooij MW, Hofman A, Niessen WJ, van der Lugt A, Breteler MM. Kidney function is related to cerebral small vessel disease. Stroke 2008;39:55–61. Tracy RE, Berenson G, Wattigney W, Barrett TJ. The evolution of benign arterionephrosclerosis from age 6 to 70 years. Am J Pathol 1990;136:429–439. Tracy RE. Blood pressure related separately to parenchymal fibrosis and vasculopathy of the kidney. Am J Kidney Dis 1992;20:124–131.

Support Research at the AAN Foundation Wine Tasting & Auction You are cordially invited to sample some of the finest wines in the Pacific Northwest. Enjoy an array of food, music, and fun. This exclusive 2009 Annual Meeting event takes place Wednesday, April 29, from 7:00 p.m. to 9:30 p.m. in the Grand Ballroom at the Sheraton Hotel in Seattle. Bid on a variety of silent auction prizes including exquisite wine, entertainment, gifts, and more. The evening culminates with a live auction of exciting prizes. Bid high and often to support research. Proceeds benefit the AAN Foundation Research Program. Tickets are $100 per guest. Tickets are limited, so go to www.aan.com/wine and register now!

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Neurology 72

March 10, 2009

Apathy A major symptom in CADASIL

S. Reyes, MSc A. Viswanathan, MD, PhD O. Godin, MSC C. Dufouil, PhD S. Benisty, MD K. Hernandez, MSc A. Kurtz, MSc E. Jouvent, MD M. O’Sullivan, MD, PhD V. Czernecki, PhD M.G. Bousser, MD M. Dichgans, MD, PhD H. Chabriat, MD, PhD

ABSTRACT

Objective: The frequency and impact of apathy in subcortical ischemic vascular dementia (SIVD) remain undetermined. The frequency, clinical, neuropsychological, and imaging correlates of apathy were assessed in a large cohort of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a genetic model of SIVD.

Methods: Apathy was diagnosed based on Neuropsychiatric Inventory assessment. Degree of disability was assessed by modified Rankin scale, cognitive impairment by Mattis Dementia Rating Scale (MDRS) and Mini-Mental State Examination (MMSE), autonomy by the Instrumental Activities of Daily Living (IADL) scale, and quality of life by SEP-59 self-questionnaire. Validated imaging methods were used to determine the total burden of cerebral lesions.

Results: Among 132 patients, 54 (41%) were apathetic. Apathetic patients were older than nonapathetic subjects, had a lower MMSE and MDRS score, had more global disability, and were more limited in IADL. Apathetic patients were more frequently depressed compared to nonapathetic patients and more frequently presented additional neuropsychiatric symptoms. Multiple regression modeling showed a significant and independent association between apathy and a lower score of overall quality of life and between apathy and a higher load of white matter and lacunar lesions.

Conclusions: The results suggest that apathy is common in cerebral autosomal dominant arteriAddress correspondence and reprint requests to Pr. Hugues Chabriat, Service de Neurologie, Hoˆpital Lariboisiere, 2 rue Ambroise Pare´, 75010 Paris, France [email protected]

opathy with subcortical infarcts and leukoencephalopathy (CADASIL), appears in association with cognitive impairment, global functional disability, and severe neuropsychiatric symptoms during the course of the disease, and can occur separately from depression. Apathy has an independent impact on the overall quality of life in CADASIL. Neurology® 2009;72:905–910 GLOSSARY CADASIL ⫽ cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; DSM-IV ⫽ Diagnostic and Statistical Manual of Mental Disorders, 4th edition; IADL ⫽ Instrumental Activities of Daily Living; ICC ⫽ intracranial cavity; LL ⫽ lacunar lesions; MDRS ⫽ Mattis Dementia Rating Scale; MMSE ⫽ Mini-Mental State Examination; mRS ⫽ modified Rankin scale; NA ⫽ not applicable because of insufficient observations; nCM ⫽ number of cerebral microhemorrhages; nLL ⫽ normalized volume of lacunar lesions; NPI ⫽ Neuropsychiatric Inventory; nWMH ⫽ normalized volume of white matter hyperintensities; QOL ⫽ quality of life; SIVD ⫽ subcortical ischemic vascular dementia; TIA ⫽ transient ischemic attack; WMH ⫽ white matter hyperintensities.

Apathy is reported as a frequent clinical feature of vascular dementia1,2 and is also recognized as a prominent manifestation of neurodegenerative disorders.3,4 Apathy has been classically defined as a lack of motivation5,6 but it can be defined in a more operational way as a quantitative reduction of voluntary (or goal-directed) behavior.7 Apathetic patients can also present with reduced interest in their environment, indifference, flattening of affect, or lack of emotional reactivity.8 Apathy may result from alterations in the cerebral networks that generate and control goaldirected actions mostly represented within the prefrontal cortex connected to basal ganglia, thala-

From the Departments of Neurology (S.R., A.V., K.H., A.K., E.J.) and Geriatry (S.B.), CHU Lariboisie`re, Assistance Publique des Hoˆpitaux de Paris, and INSERM U740 (M.G.B., H.C.), France; Department of Neurology and Clinical Trials Unit (A.V.), Massachusetts General Hospital and Harvard Medical School, Boston; INSERM U708 (O.G., C.D.), Universite´ Pierre et Marie Curie, Paris, France; Department of Neurology (M.O.), Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany; and INSERM U610 (V.C., M.D.), Hoˆpital de la Pitie´-Salpeˆtrie`re, Paris, France. Supported by PHRC grant AOR 02-001 (DRC/APHP) and performed with the help of ARNEVA (Association de Recherche en Neurologie Vasculaire), Hopital Lariboisie`re, France, with a sponsorship of the Company Bouygues. Disclosure: The authors report no disclosures. Copyright © 2009 by AAN Enterprises, Inc.

905

mus, and structures involving the limbic system.7,9 It has been reported in Parkinson disease,3,10 progressive supranuclear palsy,11 Huntington disease,12 or in presence of frontal subcortical lesions.7 In patients with stroke or vascular dementia, the frequency of apathy was found to vary between 15% and 93%.1,13,14 However, studies of apathy in cerebrovascular diseases have been hampered by methodologic problems related to 1) heterogeneity of populations with vascular dementia, 2) multiple definitions and methods for assessing apathy, and 3) lack of controlling for potential confounding factors such as depression. To better understand the frequency and clinical impact of apathy in patients with cerebrovascular diseases, we chose to evaluate this clinical symptom in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic model of SIVD.15,16 METHODS Subjects. A total of 132 subjects were drawn from an ongoing prospective cohort study of patients with CADASIL. Subjects were recruited among patients with CADASIL evaluated at Lariboisie`re Hospital, Paris, France, between April 2006 and December 2007. All patients who had an informative caregiver or relative were invited to participate and agreed to be included in this study. In all cases, diagnosis was confirmed by identification of a typical mutation in the Notch3 gene (mutations within epidermal growth factor–like repeats, in the extracellular domain of Notch3 and leading to an unpaired number of cysteine residues).17 Clinical and demographic data were collected by study investigators and included age, sex, number of years of education, the presence of vascular risk factors (i.e., hypertension, diabetes, history of smoking, and hypercholesterolemia), history of psychiatric disorders, presence of migraine with aura, history of transient ischemic attacks (TIA) or stroke, presence of seizures, gait disorders, and dementia (defined by DSM - IV criteria). The study was approved by an independent ethics committee.

Neurologic and neuropsychological evaluation. All enrolled subjects underwent a detailed neurologic and neuropsychological examination preceding an MRI examination. Global cognitive function was evaluated with the Mini-Mental State Examination (MMSE)18 and Mattis Dementia Rating Scale (MDRS).19,20 Functional abilities were assessed using the Instrumental Activities of Daily Living scale (IADL)21 (this score ranges from 0 [severe functional impairment] to 8 [no functional impairment]) and disability was assessed using the modified Rankin scale (mRS). As in previous studies, we defined poor outcome or functional dependence as a mRS score ⱖ3.22 The SEP-59, a French self-questionnaire derived from the Short Form–3623 and validated in multiple sclerosis, was used to assess quality of life (QOL).24 The SEP-59 was sent to each patient by mail, to be filled out and sent back to the hospital. To assess apathy and other neuropsychiatric symptoms, a neuropsycholo906

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gist (S.R.) interviewed relatives by telephone using the French version of the Neuropsychiatric Inventory (NPI).25-27 NPI and SEP-59 assessments were obtained less than 6 months after the initial hospital visit in each patient. Consent was obtained from all patients, relatives, or caregivers for these evaluations. The NPI consists of 12 screening questions assessing different neuropsychiatric symptoms: delusions, hallucinations, agitation, apathy, anxiety, depression, euphoria, irritability, disinhibition, aberrant motor behavior, change in appetite, and nighttime behavior disturbances.26 If the screening question was answered positively, then the symptom was explored with scripted questions that focused on the specific feature of the neuropsychiatric symptom. Patients were considered apathetic if they had a NPI score of apathy ⱖ1. We also checked that all these patients fulfilled the current diagnostic criteria of apathy proposed by Starkstein and Leentjens.8 For this purpose, we verified that the caregiver’s version of the Apathy Scale (appendix) was always superior or equal to the cutoff value of 14.28 The Apathy Scale is an abridged and modified version of the Marin Apathy Scale already used in stroke patients.13 Patients were considered depressed if they had NPI depression score ⱖ1 and fulfilled more than five of the nine DSM-IV diagnostic criteria of depression at their previous clinical examination.25 The SEP-5924 explores 16 dimensions of QOL. This questionnaire was chosen due to similar QOL issues between CADASIL and multiple sclerosis (both chronic and progressive conditions with similar progressive motor and cognitive disability due, primarily, to damage to subcortical structures) and lack of a specific validated QOL questionnaire for CADASIL. We chose not to use standard stroke QOL questionnaires in this study since disability is mainly related to the chronic progression of cerebral lesions in CADASIL rather than to the occurrence of single strokes, making the stroke QOL scales less relevant. In the SEP-59, each of 16 dimensions of quality of life is rated from 0 (worst) to 100 (best).

Image processing and analysis. Lesions were quantified as previously described.22 Briefly, white matter hyperintensities (WMH) were measured on all axial fluid-attenuated inversion recovery slices from the base of the cerebellum to the vertex. Volume of lacunar lesions (LL) was determined on T1-weighted sequences. The total volumes of WMH and LL were normalized to the intracranial cavity (ICC) in each patient (normalized volume ⫽ [volume/ICC] ⫻ 100, nWMH and nLL). The number of cerebral microhemorrhages (nCM), defined as rounded foci ⱕ5 mm in diameter hypointense on gradient-echo sequences and distinct from vascular flow voids, leptomeningeal hemosiderosis, or nonhemorrhagic subcortical mineralization, was recorded.

Statistical analyses. To evaluate the associations between demographic, clinical, and MRI variables and the prevalence of apathy, analysis of variance was used for continuous variables and ␹2 for categorical variables. To evaluate the relationship between MRI markers (nWMH, nLL, nCM) and apathy, analysis of covariance (independent variable ⫽ MRI marker volume) and logistic regression (independent variable ⫽ apathy [yes/no]) were performed. Analyses were systematically adjusted for sex, age, educational level, disability, cognition, and depression. All p values were two-tailed and criterion for significance was p ⬍ 0.05. Statistical analysis were performed with SAS (release 9.1; SAS Statistical Institute, Cary, NC).

Table 1

Comparison of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy with and without apathy

Demographic and clinical characteristics

Apathetic (n ⴝ 54)

Nonapathetic (n ⴝ 78)

p

p*

Age, y, mean (SD)

58.7 (9.9)

50.5 (11.8)

⬍0.0001

—

34–77

25–74

Men, % (n)

66.7 (36)

34.6 (27)

0.0004

—

Years of school, mean (SD)

9.2 (0.5)

11 (0.4)

0.0038

—

MMSE/30, mean (SD)

23.0 (0.6)

28.4 (0.5)

⬍0.0001

⬍0.0001

MDRS/144, mean (SD)

119.7 (2.4)

139.9 (1.9)

⬍0.0001

⬍0.0001

Modified Rankin Scale >3, % (n)

42.6 (23)

7.7 (6)

⬍0.0001

0.008

IADL/8, mean (SD)

3.9 (0.3)

7.6 (0.3)

⬍0.0001

⬍0.0001

Presence of vascular risk factors, % (n)

77.4 (41)

75.3 (58)

0.8367

0.07

History of psychiatric disorders, % (n)

55.6 (30)

40.3 (31)

0.1094

0.27

Migraine with aura, % (n)

40.0 (20)

46.6 (34)

0.5793

0.79

History of TIA or stroke, % (n)

79.6 (43)

57.4 (44)

0.0086

0.46

Presence of seizures, % (n)

16.7 (9)

5.2 (4)

0.0393

0.62

Presence of gait disorders, % (n)

51.9 (28)

9.1 (7)

⬍0.0001

Dementia, % (n)

35.2 (19)

0.0 (0)

⬍0.0001

⬍0.0001

MRI markers

(n ⴝ 48)

(n ⴝ 76)

p

p†

nWMH, mean ⴛ 10ⴚ2 (SD)

9.00 (0.5)

7.00 (0.4)

0.00–22

0.00–22

0.24 (0.05)

0.05 (0.08)

0–3

0–0.5

52.1 (25)

24.0 (18)

Range

Range nLL, mean ⴛ 10ⴚ2 (SD) Range nCM (n) >1, % (n)

0.008

0.002

0.03

0.002

0.01

0.0014

0.21

*Results adjusted for sex, age, education level, Rankin Scale score (no correction of Rankin score in row 6), and depression. †Results adjusted for sex, age, education level, and depression. For MRI analyses, the sample size varies from 132 to 124 because of missing data. MMSE ⫽ Mini-Mental State Examination; MDRS ⫽ Mattis Dementia Rating Scale; IADL ⫽ Instrumental Activities of Daily Living scale; TIA ⫽ transient ischemic attack; nWMH ⫽ normalized volume of white matter hyperintensities; nLL ⫽ normalized volume of lacunar lesions; nCM ⫽ number of cerebral microhemorrhages.

RESULTS Frequency of apathy and associated symp-

toms. Fifty-four of the 132 evaluated patients (41%) had apathy. Apathetic patients were older on average. They were significantly more frequently men and had a lower level of education than nonapathetic patients (table 1). The frequency of vascular risk factors, history of psychiatric disorders, migraine with aura, TIA, or completed stroke and seizures did not differ between apathetic and nonapathetic patients when adjusting for age, sex, and educational level. In contrast, apathetic patients had lower MMSE and MDRS global cognitive scores, had more global disability (assessed using mRS), and were more limited in IADL. In addition, apathetic patients more frequently had gait disorders and dementia vs nonapathetic patients. MRI markers. In multivariate analysis, apathetic pa-

tients had on average a significantly higher nWMH volume and a higher nLL volume than nonapathetic patients (table 1). This was observed independently of

age, sex, educational level, and depression. In contrast, the number of CM did not differ between apathetic and nonapathetic patients, although a trend for a larger frequency of apathetic patients with more than one CM was observed (52% vs 24% in nonapathetic patients). Apathy and other behavioral symptoms. Apathy was the fourth most frequent behavioral disturbance observed in patients with CADASIL after depression, disturbed sleep, and irritability/lability (table 2). Ninety-four percent of apathetic patients presented with at least one behavioral disturbance. Apathetic patients presented more frequently than nonapathetic patients with the following behavioral disturbances after adjusting for potential confounding factors (i.e., age, sex, educational level, degree of disability, degree of global cognitive abilities, and depression): irritability/ lability, agitation/aggression, disturbed appetite, disinhibition, and aberrant motor behavior. Apathy and depression. Apathy and depression were also observed in association after adjusting for potential confounding factors including the degree of disability and of global cognitive abilities (table 2). We observed that apathy was more frequent in depressed compared to nondepressed patients (54.1% vs 45.9%; p ⫽ 0.0048). Finally, 25.0% (n ⫽ 33) of subjects in the whole sample were both apathetic and depressed; 15.9% (n ⫽ 21) were apathetic but not depressed. Clinical and demographic variables did not differ between apathetic patients with depression and those without depression, except the frequency of dementia, which was higher in apathetic subjects without depression (52.4% [n ⫽ 11] vs 24.2% [n ⫽ 8], p ⫽ 0.0448). Quality of life. Apathetic patients showed a lower mean score in almost all of the 16 dimensions of QOL except for emotional well-being, perception of their sleep quality, and social support dimensions (table 3). Only 2 of these 16 dimensions were significantly lower in apathetic patients independently of age, sex, educational level, degree of disability, degree of global cognitive abilities, and depression: limitations in their usual role and activities because of emotional problems and overall QOL. DISCUSSION The major findings of this large cohort study are that apathy is common and seems to be associated with the clinical severity and load of subcortical tissue lesions in CADASIL, a model of subcortical ischemic vascular dementia. The 41% frequency of apathy exceeds that of other classic hallmarks of the disease, such as migraine with aura, reported in 20 –30% of symptomatic subjects.16,29 The frequency of apathy in CADASIL is close to that reNeurology 72

March 10, 2009

907

Table 2

Frequency of behavioral disturbances (Neuropsychiatric Inventory [NPI]) in the whole cohort and in patients with and without apathy

Behavioral disturbance

Cohort (n ⴝ 132)

Apathetic (n ⴝ 54)

Nonapathetic (n ⴝ 78) p

Total NPI score, mean (SD)

15.3 (16.0) 29.0 (14.9) 5.8 (7.6)

⬍0.0001 —

At least one behavioral disturbance, % (n)

75 (99)

94.4 (51)

61.5 (48)

⬍0.0001

Depression/dysphoria, % (n)

46.2 (61)

61.1 (33)

35.9 (28)

0.0048

0.02

Disturbed sleep, % (n)

44.7 (59)

64.8 (35)

30.8 (24)

0.0001

0.31

Irritability/lability, % (n)

43.1 (57)

64.8 (35)

28.2 (22)

⬍0.0001

Anxiety, % (n)

37.1 (49)

40.7 (22)

34.6 (27)

0.47

Apathy, % (n)

41.0 (54)

—

—

—

Agitation/aggression, % (n)

26.6 (35)

53.7 (29)

7.7 (6)

⬍0.0001 ⬍0.0001

Disturbed appetite, % (n)

16.0 (21)

31.5 (17)

5.1 (4)

⬍0.0001

0.003

Disinhibition, % (n)

13.7 (18)

27.8 (15)

3.9 (3)

⬍0.0001

0.008

Euphoria, % (n)

7.5 (10)

p*

0.0003 0.71 —

14.8 (8)

2.6 (2)

0.009

0.20

Aberrant motor behavior, % (n) 6.0 (8)

14.8 (8)

0.0 (0)

0.0005

0.0007

Delusion, % (n)

2.2 (3)

3.7 (2)

1.3 (1)

0.36

NA

Hallucination, % (n)

0.7 (1)

1.9 (1)

0.0 (0)

0.23

NA

Comparisons between apathetic and nonapathetic patients. Results adjusted for sex, age, educational level, modified Rankin scale score, Mattis Dementia Rating Scale score, and depression (no correction for depression in raw 2). *Results adjusted for sex, age, education level, Rankin Scale score (no correction of Rankin score in row 6), and depression. NA ⫽ not applicable because of insufficient observations.

ported in other subcortical disorders also involving the basal ganglia such as Parkinson disease or Huntington disease.12,30 This frequency appears also in Table 3

Comparison of the 16 dimensions of quality of life between nonapathetic and apathetic patients before and *after correction for age, sex, educational level, modified Rankin Scale score, Mattis Dementia Rating Scale score, and depression

SEP-59 dimensions

Apathetic (n ⴝ 54)

Nonapathetic (n ⴝ 78)

p

Overall quality of life

50.5 (19.3)

69.2 (19.3)

⬍0.0001

0.05

Role limitation, emotional

30.3 (41.2)

62.1 (40.4)

0.0001

0.04

Physical function

42.8 (35.1)

77.3 (28.0)

⬍0.0001

0.06

Role limitation, physical

31.3 (41.8)

63.6 (43.2)

0.0002

0.12

Pain

55.2 (31.3)

76.6 (26.3)

0.0002

0.13

Emotional well-being

44.5 (10.0)

42.0 (9.4)

0.19

0.58

Energy

43.5 (11.8)

48.3 (10.6)

0.0238

0.47

Social function

53.2 (28.4)

72.2 (22.1)

0.0001

0.16

Alterations of sphincter control

65.4 (35.4)

82.6 (31.3)

0.009

0.53

Cognition

37.2 (23.0)

55.1 (20.2)

⬍0.0001

0.12

Health distress

39.7 (22.9)

56.5 (21.9)

0.0002

0.15

Health perception

39.3 (24.3)

56.6 (22.4)

0.0010

0.14

Sleep

51.4 (14.2)

49.3 (11.5)

0.39

0.64

Social support

72.6 (23.2)

70.1 (26.2)

0.62

0.74

Sexual satisfaction

39.0 (32.6)

57.9 (29.3)

0.0036

0.17

Sexual function

52.0 (29.5)

67.4 (25.3)

0.0064

0.09

Values are mean (SD). 908

Neurology 72

March 10, 2009

p*

the range of that observed in patients with Alzheimer disease from 29 to 72%.9 The results of the study also suggest that the presence of apathy can result in a reduction of QOL independently of cognitive status and depression during the course of the disease. In the present series, apathy was found to be more frequent in patients with CADASIL with cognitive impairment and dementia than in patients without dementia. Men, older patients, and those with abnormal gait were also found more likely to be apathetic. In contrast, apathy was not associated with other manifestations of the disorder such as migraine with aura, seizures, stroke, or with vascular risk factors. These findings are consistent with previous observations of apathy in patients with various subtypes of stroke and with studies in neurodegenerative diseases which have shown apathy to be mostly associated with older age, cognitive impairment, and deficits in activities of daily living.13,14,31 In our study, the burden of subcortical MRI lesions was found to be higher in apathetic patients compared to nonapathetic patients, independently of age, which suggests that the accumulation of subcortical lesions may actually promote the occurrence of apathy in CADASIL, as previously observed for cognitive impairment.32 Apathy was found to be frequently associated with other neuropsychiatric symptoms in CADASIL. In this study, 94% of apathetic patients had at least one other behavioral disturbance. Irritability and depression were detected using NPI in two thirds of apathetic patients while agitation or aggressive behavior were observed in half of them. A significant association was detected between irritability and apathy as previously reported in Huntington disease. 33 The frequent association of depression with apathy is not surprising since apathy is also considered as a possible clinical manifestation of depression. Indeed, depressed patients can show a loss of motivation to engage in enjoyable behavior, lack of goals and perspectives, and may even have anhedonia (insensitivity to pleasure). Nevertheless, in several studies, apathy has been shown to also occur independently of sadness, negative thoughts, or other signs and symptoms of depression. 34 The difference between apathy and depression is important because of their likely disparate underlying mechanisms and potentially different treatments.7 In the present study, 38.9% of apathetic patients with CADASIL were found without depression, in agreement with distinct mechanisms underlying depression and apathy.7 Apathy has been reported in neurodegenerative diseases affecting the gray matter of basal ganglia.35 In CADASIL, lacunar lesions most commonly occur in

basal ganglia, thalamus, brainstem, and frontal and parietal white matter regions.22 Thus, damage of striatocortical circuits linking such gray matter areas to frontal cortical regions can be secondary to white matter tract damage or to ischemic infarction in this disorder.36 Interestingly, although apathy was associated with a large burden of subcortical ischemic lesions in our patients, apathy was also detected in some cases in the presence of few subcortical lesions and at early stages of the disease. These data suggest that not only lesion burden but also location of lesions may play a key role in the occurrence of this symptom in CADASIL. Further localization studies are thus needed to determine which pathways are mostly affected and associated with apathy seen in the disease. Finally, the results of this study suggest that apathy plays an independent role on the reduction of quality of life in patients with CADASIL. We observed that apathetic patients perceived a significant reduction of their overall quality of life. In particular, they perceived a reduction and limitation of their usual role in activities because of “emotional problems.” In the self-questionnaire used in the study, this characteristic can be interpreted as a decrease in the motivation to accomplish daily activities. These results further emphasize that apathy is indeed a major symptom of CADASIL and should be considered separately from the other clinical manifestations due to its strong and independent impact on QOL. The impact of apathy has been rarely differentiated from the impact of depression on QOL in neurodegenerative or vascular brain diseases. Since a large number of apathetic patients in our study also had some clinical features of depression, an additive

APPENDIX

effect of both neuropsychiatric symptoms is likely to be involved in some patients’ perception of QOL. Our study has limitations. We did not control for psychotropic medications in the current analyses. However, this would tend to underestimate the prevalence of apathy and depression in this population. The fact that strong associations with apathy were found also attests to the strength of the observed associations in the current study. Because our study was cross-sectional in nature, it is unclear whether the effect of lacunar lesions on apathy in CADASIL represents an association or is in fact a causative phenomenon. Furthermore, prospective studies will help to correlate the clinical manifestations of apathy with disease progression and the severity of cognitive impairment in CADASIL. Finally, additional studies are needed to determine whether apathy is qualitatively different in CADASIL compared to that observed in Alzheimer disease, and how the neural circuitry underlying apathy may differ between the two disorders. AUTHOR CONTRIBUTIONS O. Godin and C. Dufouil performed the statistical analysis.

ACKNOWLEDGMENT Jocelyne Ruffie´ and Solange Hello contributed to the organization of the study. Dr. Jean Pierre Guichard, Daniel Reizine, and Monique Boukobza contributed to the acquisition of MRI data.

Received August 27, 2008. Accepted in final form December 17, 2008. REFERENCES 1. Fuh JL, Wang SJ, Cummings JL. Neuropsychiatric profiles in patients with Alzheimer’s disease and vascular dementia. J Neurol Neurosurg Psychiatry 2005;76:1337– 1341.

Apathy Scale, caregiver version28

1. Is he/she interested in learning new things?

Not at all

Slightly

Some

A lot

2. Does anything interest him/her?

Not at all

Slightly

Some

A lot

3. Does someone have to tell him/her what to do each day?

Not at all

Slightly

Some

A lot

4. Is he/she concerned about his/her condition?

Not at all

Slightly

Some

A lot

5. Is he/she indifferent to things?

Not at all

Slightly

Some

A lot

6. Does he/she put much effort into things?

Not at all

Slightly

Some

A lot

7. Is he/she always looking for something to do?

Not at all

Slightly

Some

A lot

8. Does he/she have plans and goals for the future?

Not at all

Slightly

Some

A lot

9. Does he/she have motivation?

Not at all

Slightly

Some

A lot

10. Does he/she have energy for daily activities?

Not at all

Slightly

Some

A lot

11. Is he/she unconcerned with many things?

Not at all

Slightly

Some

A lot

12. Does he/she need a push to get started on things?

Not at all

Slightly

Some

A lot

13. Is he/she neither happy nor sad, just in between, no matter what happens?

Not at all

Slightly

Some

A lot

14. Would you consider him/her to be apathetic?

Not at all

Slightly

Some

A lot

Neurology 72

March 10, 2009

909

2.

3. 4.

5. 6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

910

Aharon-Peretz J, Kliot D, Tomer R. Behavioral differences between white matter lacunar dementia and Alzheimer’s disease: a comparison on the neuropsychiatric inventory. Dement Geriatr Cogn Disord 2000;11:294–298. Pluck GC, Brown RG. Apathy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2002;73:636–642. Craig D, Mirakhur A, Hart DJ, McIlroy SP, Passmore AP. A cross-sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer’s disease. Am J Geriatr Psychiatry 2005;13:460–468. Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991;3:243–254. Marin RS. Apathy: concept, syndrome, neural mechanisms, and treatment. Semin Clin Neuropsychiatry 1996; 1:304–314. Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb Cortex 2006;16:916–928. Starkstein SE, Leentjens AF. The nosological position of apathy in clinical practice. J Neurol Neurosurg Psychiatry 2008;79:1088–1092. Marshall GA, Monserratt L, Harwood D, Mandelkern M, Cummings JL, Sultzer DL. Positron emission tomography metabolic correlates of apathy in Alzheimer disease. Arch Neurol 2007;64:1015–1020. Isella V, Melzi P, Grimaldi M, et al. Clinical, neuropsychological, and morphometric correlates of apathy in Parkinson’s disease. Mov Disord 2002;17:366–371. Aarsland D, Litvan I, Larsen JP. Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001;13:42–49. Paulsen JS, Ready RE, Hamilton JM, Mega MS, Cummings JL. Neuropsychiatric aspects of Huntington’s disease. J Neurol Neurosurg Psychiatry 2001;71:310–314. Starkstein SE, Fedoroff JP, Price TR, Leiguarda R, Robinson RG. Apathy following cerebrovascular lesions. Stroke 1993;24:1625–1630. Brodaty H, Sachdev PS, Withall A, Altendorf A, Valenzuela MJ, Lorentz L. Frequency and clinical, neuropsychological and neuroimaging correlates of apathy following stroke: the Sydney Stroke Study. Psychol Med 2005;35:1707– 1716. Chabriat H, Bousser MG, Pappata S. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a positron emission tomography study in two affected family members. Stroke 1995;26:1729– 1730. Dichgans M, Mayer M, Uttner I, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 1998;44:731–739. Joutel A, Vahedi K, Corpechot C, et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 1997;350:1511–1515. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198. Schmidt R, Freidl W, Fazekas F, et al. The Mattis Dementia Rating Scale: normative data from 1,001 healthy volunteers. Neurology 1994;44:964–966. Mattis S. Mini-Mental Status Examination for organic mental syndrome in the elderly patients. In: Geriatric Psychiatry:

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36.

A Handbook for Psychiatrists and Primary Care Physicians. New York, NY: Grune & Stratton; 1976:77–121. Lawton MP, Brody EM. Assessment of older people: selfmaintaining and instrumental activities of daily living. Gerontologist 1969;9:179–186. Viswanathan A, Guichard JP, Gschwendtner A, et al. Blood pressure and haemoglobin A1c are associated with microhaemorrhage in CADASIL: a two-centre cohort study. Brain 2006;129:2375–2383. Hays RD, Sherbourne CD, Mazel RM. The RAND 36Item Health Survey 1.0. Health Econ 1993;2:217–227. Vernay D, Gerbaud L, Biolay S, et al. [Quality of life and multiple sclerosis: validation of the french version of the self-questionnaire (SEP-59).] Rev Neurol (Paris) 2000; 156:247–263. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308–2314. Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 1997; 48:S10–16. Robert P, Medecin I, Vincent S, Staccini P, Cattelin F, Goni S. The Neuropsychiatric Inventory: validation of the French version of an instrument to assess behavioral disturbances in demented patients. L’Anne´e Ge´rontologique 1998;5:63–87. Chatterjee A, Anderson KE, Moskowitz CB, Hauser WA, Marder KS. A comparison of self-report and caregiver assessment of depression, apathy, and irritability in Huntington’s disease. J Neuropsychiatry Clin Neurosci 2005; 17:378–383. Chabriat H, Vahedi K, Iba-Zizen MT, et al. Clinical spectrum of CADASIL: a study of 7 families. Lancet 1995;346: 934–939. Aarsland D, Larsen JP, Lim NG, et al. Range of neuropsychiatric disturbances in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999;67:492–496. Zawacki TM, Grace J, Paul R, et al. Behavioral problems as predictors of functional abilities of vascular dementia patients. J Neuropsychiatry Clin Neurosci 2002;14:296–302. Buffon F, Porcher R, Hernandez K, et al. Cognitive profile in CADASIL. J Neurol Neurosurg Psychiatry 2006;77: 175–180. Thompson JC, Snowden JS, Craufurd D, Neary D. Behavior in Huntington’s disease: dissociating cognitionbased and mood-based changes. J Neuropsychiatry Clin Neurosci 2002;14:37–43. Andersson S, Krogstad JM, Finset A. Apathy and depressed mood in acquired brain damage: relationship to lesion localization and psychophysiological reactivity. Psychol Med 1999;29:447–456. Starkstein SE, Mayberg HS, Preziosi TJ, Andrezejewski P, Leiguarda R, Robinson RG. Reliability, validity, and clinical correlates of apathy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1992;4:134–139. O’Sullivan M, Singhal S, Charlton R, Markus HS. Diffusion tensor imaging of thalamus correlates with cognition in CADASIL without dementia. Neurology 2004;62:702– 707.

Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use A.G. Herzog, MD, MSc A.S. Blum, MD, PhD E.L. Farina, RN X.E. Maestri, RN J. Newman, RNP E. Garcia, MD K.B. Krishnamurthy, MD D.B. Hoch, MD S. Replansky K.M. Fowler, MA S.D. Smithson, BA B.A. Dworetzky, MD E.B. Bromfield, MD

Address correspondence and reprint requests to Dr. Andrew G. Herzog, Harvard Neuroendocrine Unit, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215 [email protected]

ABSTRACT

Objective: To determine whether 1) combined oral contraceptive (COC) use affects serum levels of valproate (VPA) as well as lamotrigine (LTG) and 2) the naturally occurring high (mid-luteal) and low (early-mid follicular) reproductive steroid level phases of the menstrual cycle might affect antiepileptic drug levels as well.

Methods: This investigation compared serum antiepileptic drug levels at two timepoints during a single menstrual cycle in four groups of women with epilepsy: 12 on VPA, 12 on VPA plus COC (VPA-COC), 12 on LTG, and 12 on LTG plus COC (LTG-COC).

Results: Both VPA and LTG levels were lower (p ⬍ 0.01) on active COC than on inactive pill with median declines of 23.4% for the VPA-COC group and 32.6% for the LTG-COC group. Serum LTG levels showed a notable but not significant 31.3% median decline during the mid-luteal phase compared to the early-mid follicular phase in the non-COC group. The non-COC valproate group showed the least change of any group between the two measured timepoints with a decline of 8.3% (p ⫽ NS).

Conclusions: The findings suggest that valproate (VPA), like lamotrigine (LTG), has substantially and significantly lower serum levels while women take active combined oral contraceptives as compared to inactive pills. Larger sample sizes will be required to determine whether LTG levels may drop significantly also during the luteal (high steroid) phase of natural menstrual cycles and whether VPA levels may show greater stability in levels across the phases of the menstrual cycle. Neurology® 2009;72:911–914 GLOSSARY AED ⫽ antiepileptic drug; BMI ⫽ basal metabolic index; COC ⫽ combined oral contraceptive; EIAED ⫽ enzyme-inducing antiepileptic drug; IGE ⫽ idiopathic generalized epilepsy; LRE ⫽ localization-related epilepsy; LTG ⫽ lamotrigine; VPA ⫽ valproate.

Birth control is an important issue for women of reproductive age.1 Combined oral contraceptives (COCs) are considered to be the most convenient and widely used form of birth control.1 Therefore, thorough characterization of the interactions between COCs and antiepileptic drugs (AEDs) is important for optimal management of seizures and reproductive health in women with epilepsy. Clinically important unidirectional or bidirectional interactions between COCs and AEDs have been described for the older enzyme-inducing AEDs (barbiturates, phenytoin, and carbamazepine),2-4 some newer enzyme-inducing AEDs (topiramate, felbamate),5,6 and for the non enzyme-inducing AED lamotrigine (LTG).7-9 Estrogen-induced hepatic glucuronidation has been implicated in the drop of LTG levels during the active pill phase of COC use.7-10 The possibility of a similar effect of COC on valproate (VPA) serum levels has been raised by the involvement of glucuronidation in VPA metabolism and by the report of a single case in which cyclic seizure flares occurred in relation to substantial decreases in serum VPA levels on active COC as compared to inactive pill.11 If estrogen in COCs can impact the serum levels of

From the Harvard Neuroendocrine Unit (A.G.H., E.L.F., K.B.K., K.M.F., S.D.S.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Neurology (A.S.B., X.E.M., J.N.), Rhode Island Hospital, Providence; Department of Neurology (E.G.), Newton Wellesley Hospital; Massachusetts General Hospital (D.B.H.), Boston; and Department of Neurology (S.R., B.A.D., E.B.B.), Brigham & Women’s Hospital, Boston, MA. Disclosure: Supported by an investigator-initiated grant from Abbott Laboratories. Copyright © 2009 by AAN Enterprises, Inc.

911

glucuronidated AEDs, it would also be important to determine whether the natural variations in estradiol levels across the phases of the menstrual cycle, i.e., high levels during the mid-luteal phase and low levels during the early-mid follicular phase, might be associated with changes in serum AED levels as well. The purpose of this investigation was to determine whether 1) COC use affects serum levels of VPA as well as LTG and 2) the naturally occurring high (mid-luteal) vs low (early-mid follicular) reproductive steroid level phases of the menstrual cycle affect AED levels as well.6,7 METHODS Experimental design. This was a crosssectional, observational, pilot investigation of serum AED levels at two timepoints during a single menstrual cycle in four groups of women with epilepsy: 12 on VPA, 12 on VPA plus COC (VPACOC), 12 on LTG, and 12 on LTG plus COC (LTG-COC). The two timepoints for each group are selected to compare the effects of active vs inactive COC use and high (mid-luteal) vs low (early-mid follicular) reproductive steroid (estrogen) level phases of the menstrual cycle on AED levels.

Subjects. This investigation was approved by the Investigational Review Board of the Beth Israel Deaconess Medical Center and each subject was consented before participation. The women were enrolled from hospital outpatient epilepsy clinics. They were 13 to 45 years of age and documented clinically and by EEG to have idiopathic generalized epilepsy (IGE) or localization-related epilepsy (LRE). All entered on stable VPA or LTG monotherapy with or without concomitant standard commercially marketed COC use for at least 1 month on both. These medications were continued during the investigational cycle. All subjects on valproate took brand name Depakote or Depakote ER and all subjects on lamotrigine took brand name Lamictal. The COCs were monophasic in 22 subjects and triphasic in 2 subjects. COC estrogenic content in the monophasic pills was exclusively ethinyl estradiol in dosages of 20 –30 ␮g; the progestin was either norethindrone 1 mg or levonorgestrel 150 –300 ␮g. The triphasic pill contained 25 ␮g of ethinyl estradiol and of 100 –250 ␮g of norgestimate. COC use involved 3 weeks of active pills and 1 week of inactive pills in all cases of COC users. Exclusionary criteria included the use of enzymeinducing or enzyme-inhibiting drugs, other than their AED monotherapy and COCs, and the use of reproductive hormones other than COCs.

Procedures. Morning trough VPA and LTG levels were measured during the third week of active pill use and at the end of the week of inactive pill use in women on COCs. Women not on COCs had two levels measured at comparable high and low reproductive steroid level times of the cycle, i.e., during the mid-luteal phase between days 20 and 24 and during the early-mid follicular phase between days 3 and 7. Serum samples were stored in a freezer at ⫺20°C. Samples were processed using batched assays at the conclusion of the investigation in order to minimize intrasubject and intersubject assay differences.

Assay methods. Serum level determinations for each AED and hormone were run in batched assays to minimize interassay variability. Serum VPA levels were measured using a fluorescence 912

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polarization immunoassay. LTG serum levels were determined using high performance liquid chromatography. Estradiol and progesterone serum levels were determined using chemiluminescent assays. Interassay and intra-assay variabilities (% coefficient of variation) were determined for all assays and were less than 10% and 5%.

Statistical analysis. Statistical analysis was carried out using SPSS version 12. Women served as their own controls in analyses that compared data between the two hormonal phases. This was done to minimize the effects of differences in past medication, especially AED, exposure. Since the Shapiro-Wilks, Kolmogorov-Smirnov, and Levene tests showed that some of the distributions of grouped data differed significantly from normality and from each other, nonparametric statistical analysis was used. Comparisons of serum AED levels between high and low reproductive steroid phases were carried out using the Wilcoxon matched-pairs test. The changes in serum AED levels were correlated, using Spearman correlational analyses, with age, basal metabolic index, type of epilepsy, duration of epilepsy, and, in the non-COC groups, serum estradiol levels. Comparisons were made among the four groups for the ratios of changes in AED levels in relation to menstrual cycle phase and active vs inactive COC use using the Kruskal-Wallis and Mann-Whitney tests.

The four treatment groups did not differ significantly in age, basal metabolic index, duration of epilepsy, or percentage with past enzyme-inducing AED use (table 1). Idiopathic generalized epilepsy was more common in the VPA groups than in the LTG groups among both COC users and nonusers (COC users: ␹2 ⫽ 10.74; p ⫽ 0.001; COC nonusers: ␹2 ⫽ 9.19; p ⫽ 0.002). RESULTS Demographics.

Comparisons within treatment groups. Both VPA and LTG serum levels were substantially and significantly lower on active COC than on inactive pill with median declines of 23.4% for the VPA-COC group and 32.6% for the LTG-COC group (table 2). Serum LTG levels also showed a notable 31.3%, albeit not significant, median decline during the mid-luteal phase compared to the early-mid follicular phase in the non-COC group. The non-COC VPA group showed the least change of any group between the two measured timepoints with a decline of 8.3% (p ⫽ NS) during the mid-luteal phase compared to the early-mid follicular phase. The changes in AED levels did not show any significant correlation with serum estradiol levels, changes in estradiol levels, or proportional changes in estradiol levels in the non-COC groups. Groups of COC users were not compared because synthetic estrogen levels were not assayed. Likewise, no significant correlations could be demonstrated between changes in AED levels and progesterone levels for non-COC users. There were no significant correlations between serum AED level changes and age, basal metabolic index, epilepsy type, epilepsy duration, and past enzyme-inducing AED use. Changes

Table 1

Demographic and epilepsy characteristics of the four treatment groups VPA-COC

LTG-COC

VPA

LTG

Age, y

30.5 (25.0, 36.3)

29.5 (25.3, 38.3)

34.0 (30.3, 40.0)

32.5 (26.0, 36.3)

BMI

28.3 (22.5, 30.6)

29.8 (23.3, 32.2)

25.0 (21.4, 27.7)

22.7 (22.5, 24.9)

IGE/LRE

11/1*

2/10*

Seizure frequency/mo

1.5 (0, 3)/0.5

0.5 (0, 1)/0 (0, 1)

8/4†

0/12†

1 (0, 2)/1 (0, 1)

0/1 (1, 2)

Epilepsy duration, y

19.0 (12.6, 24.8)

11.0 (6.3, 15.8)

19.5 (9.3, 27.5)

15.0 (8.0, 22.3)

Past EIAED use, %

58.3

41.7

58.3

33.3

N/A

N/A

COC duration, y

2.5 (1.0, 8.0)

2.0 (1.0, 5.0)

Values are median (quartiles). *p ⫽ 0.001 For comparisons of COC groups. †p ⫽ 0.002 For comparisons of non-COC groups. VPA ⫽ valproate; COC ⫽ combined oral contraceptive; LTG ⫽ lamotrigine; BMI ⫽ basal metabolic index; IGE ⫽ idiopathic generalized epilepsy; LRE ⫽ localization-related epilepsy; EIAED ⫽ enzyme-inducing antiepileptic drug.

in valproate level did not differ significantly between specific brands of valproate, i.e., Depakote vs Depakote ER, nor between subjects with IGE vs LRE, but the numbers are small for these comparisons. The findings of this prospective study suggest that VPA as well as LTG produce substantially and significantly lower serum AED levels while women take active COCs as compared to inactive COCs. The findings also suggest that lamotrigine, but not valproate, might show a substantial drop in serum levels during the luteal phase as compared to the follicular phase, albeit not at a significant level. A larger sample size (n ⫽ 35 for a comparison to show a 25.4% difference between luteal and follicular phase values with ␣ ⫽ 0.05, ␤ ⫽ 0.20) will be required to determine whether LTG levels may drop significantly during the luteal (high steroid) phase of the natural menstrual cycle since the sample size of 12 is powered only for a change of 31% for the demonstrated 25.4% difference in lamotrigine level. The finding that VPA levels may drop substantially during active COC use in this investigation as well as in a previously published case report11 raises the possibility that the COC-related drop might be DISCUSSION

Table 2

Antiepileptic drug (AED) levels in relation to menstrual cycle phase and oral contraceptive use

AED group

Follicular or inactive COC

Luteal or active COC

% Change

VPA-COC (mg/L), n ⴝ 12

83.6 (67.2, 98.3)

62.7 (50.0, 71.8)

23.4%† (16.0%, 36.4%)

LTG-COC (␮g/mL), n ⴝ 12 VPA (mg/L), n ⴝ 12 LTG (␮g/mL), n ⴝ 12

6.7 (5.0, 11.2) 72.5 (49.9, 84.3) 8.0 (3.0, 12.2)

4.5 (3.1, 7.7) 60.9 (53.4, 78.4) 5.5 (2.3, 8.5)

32.6%† (4.8%, 47.2%) 8.3% (5.3%, 22.4%) 25.4% (13.9%, 38.2%)

Values are median (quartiles). *p ⱕ 0.05, †p ⱕ 0.01 For comparisons within groups of AED levels between active vs inactive COC or luteal vs follicular phases of the cycle. COC ⫽ combined oral contraceptive; VPA ⫽ valproate; LTG ⫽ lamotrigine.

of some clinical significance in the form of seizure exacerbation, not unlike that found in reports for LTG.7-10 Seizure exacerbation with a drop in VPA level was found in the single case report10 and remains to be investigated further in larger prospective series. The statistical and clinical significance of the luteal phase drop in LTG levels remains to be investigated further as well. In contrast, VPA did not show substantial changes in levels between luteal and follicular phases in the non-COC group. In contrast to enzyme-inducing AEDs and lamotrigine, a study of six women has suggested that VPA may not lower COC hormone levels.12 By way of mechanism, it has been suggested that estrogen-induced glucuronidation might be responsible for the drop in AED levels during active COC use and the restoration of AED levels over a few days off active pill.7-10 Different types of estrogen vary in their enzyme induction potential.12,13 Several forms of estrogens that are used in COCs are more enzyme inducing than estradiol, which might possibly account for the apparently greater effect of COCs than the cyclic variation of estradiol during the natural menstrual cycle.13,14 Any difference between LTG and VPA might also relate to the greater extent to which LTG is glucuronidated15-17 and to the possible inhibition of enzyme induction by valproate.16,17 Catamenial epilepsy refers to the cyclic exacerbation of seizures in relation to the menstrual cycle.18,19 Approximately 70% of women with epilepsy are estimated to show some variation of seizure frequency in relation to the menstrual cycle and approximately 1/3 show an approximately twofold or greater increase during certain phases of the cycle.18,20 While cyclic fluctuations in neuroactive reproductive steroid levels have been implicated pathophysiologically,18-20 the lowering of enzymeinducing AED levels premenstrually has also been identified as a potential contributory factor.3,4 The posNeurology 72

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913

sibility that non-enzyme-inducing AEDs may behave differently, i.e., increase or remain more stable rather than decrease in serum concentration premenstrually, might alter patterns of seizure occurrence and might have some relevance for the management of women with epilepsy, especially those with catamenial epilepsy. The findings of this prospective investigation suggest that VPA, as well as LTG, has substantially lower serum levels while women take active COCs as compared to inactive pills. For naturally cycling women, larger sample sizes will be required to determine whether LTG levels may drop significantly also during the luteal (high steroid) phase of natural menstrual cycles and whether, in comparison, VPA levels may show greater stability across the phases of the menstrual cycle.

8.

9.

10.

11.

12.

13.

Received July 2, 2008. Accepted in final form December 1, 2008. 14. REFERENCES 1. Mosher WD, Martinez GM, Chandra A, Abma JC, Willson SJ. Use of contraception and use of family planning services in the United States: 1982–2002. Adv Data 2004; 350:1–36. 2. Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs 2002;16:263–272. 3. Shavit G, Lerman P, Korczyn AD, Kivity S, Bechar M, Gitter S. Phenytoin pharmacokinetics in catamenial epilepsy. Neurology 1984;34:959–961. 4. Rosciszewska D, Buntner B, Guz I, Zawisza L. Ovarian hormones, anticonvulsant drugs and seizures during the menstrual cycle in women with epilepsy. J Neurol Neurosurg Psychiatry 1986;49:47–51. 5. Rosenfeld WE, Doose DR, Walker SA, Nayak RK. Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia 1997;38:317–323. 6. Saano V, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive. Clin Pharmacol Ther 1995;58:523–531. 7. Sabers A, Buchholt JM, Udall P, Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Research 2001;47:151–154.

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Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce lamotrigine plasma levels. Neurol 2003; 61:570–571. Sidhu J, Bulsara S, Job S, et al. A bi-directional pharmacokinetic interaction study of lamotrigine and the combined oral contraceptive pill in healthy subjects. Epilepsia 2004; 45(suppl 7):330. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial. Epilepsia 2007;48: 484–489. Herzog AG, Farina EL, Blum AS. Fluctuation in serum valproate levels with oral contraceptive use. Epilepsia 2005;46:970–971. Crawford P, Chadwick D, Cleland P, et al. The lack of effect of sodium valproate on the pharmacokinetics of oral contraceptive steroids. Contraception 1986;33:23–29. Mashchak CA, Lobo RA, Dozono-Takano R, et al. Comparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet Gynecol 1982;144: 511–518. Wiegratz I, Kutschera E, Lee JH, et al. Effect of four different oral contraceptives on various sex hormones and serum-binding globulins. Contraception 2003;67:25–32. Dickins M, Chen C. Lamotrigine: chemistry, biotransformation, and pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, Perucca E, eds. Antiepileptic Drugs (5th ed.). Philadelphia: Lippincott Williams & Wilkins; 2002:370–379. Levy RH, Shen DD, Abbott FS, Riggs KW, Hachad H. Valproic acid: chemistry, biotransformation, and pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, Perucca E, eds. Antiepileptic Drugs (5th ed.). Philadelphia: Lippincott Williams & Wilkins; 2002:780–800. Tomson T, Luef G, Sabers A, Pittschieler S, Ohman I. Valproate effects on kinetics of lamotrigine in pregnancy and treatment with oral contraceptives. Neurology 2006; 67:1297–1299. Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia 1997;38:1082–1088. Quigg M, Fowler KM, Herzog AG, and the Progesterone Trial Study Group. Circalunar and ultralunar periodicities in women with partial seizures. Epilepsia 2008;49:1081– 1085. Herzog AG, Harden CL, Liporace J, et al. Frequency of catamenial seizure exacerbation in women with localization-related epilepsy. Ann Neurol 2004;56:431– 434.

Acute ischemic stroke Imaging-guided tenecteplase treatment in an extended time window

M.W. Parsons, PhD, FRACP F. Miteff, FRACP G.A. Bateman, FRANZCR N. Spratt, PhD, FRACP A. Loiselle, FRACP J. Attia, PhD, FRACP C.R. Levi, FRACP

Address correspondence and reprint requests to Dr. Mark W. Parsons, Department of Neurology, John Hunter Hospital, Locked Bag No. 1, Hunter Region Mail Centre, New South Wales, Australia 2310 [email protected]

ABSTRACT

Background: Tenecteplase is a modified tissue plasminogen activator with a longer half-life and higher fibrin specificity than alteplase.

Methods: We conducted a prospective, nonrandomized, pilot study of 0.1 mg/kg IV tenecteplase given 3 to 6 hours after ischemic stroke onset. For a control group, we used patients contemporaneously treated with sub–3-hour 0.9 mg/kg IV alteplase following standard selection criteria. All patients underwent pretreatment and 24-hour perfusion/angiographic imaging with CT or MRI. Eligibility criteria for tenecteplase (but not alteplase) treatment included a perfusion lesion at least 20% greater than the infarct core, with an associated vessel occlusion. Primary outcomes, assessed blind to treatment group, were reperfusion (reduction in baseline–24-hour mean transit time lesion) and major vessel recanalization.

Results: Fifteen patients received tenecteplase, and 35 patients received alteplase. The tenecteplase group had greater reperfusion (mean 74% vs 44% in the alteplase group, p ⫽ 0.01) and major vessel recanalization (10/15 tenecteplase vs 7/29 alteplase, p ⫽ 0.01). Despite later time to treatment, more tenecteplase patients (10/15 vs 7/35 alteplase, p ⫽ 0.001) had major neurologic improvement at 24 hours (NIH Stroke Scale reduction ⱖ8). Four of the alteplase patients and none of the tenecteplase patients had parenchymal hematoma at 24 hours.

Conclusions: Tenecteplase 0.1 mg/kg, using advanced imaging guidance in an extended time window, may have significant biologic efficacy in acute ischemic stroke. The imaging selection differences between the tenecteplase and alteplase groups prevent a conclusive efficacy comparison. Nonetheless, these results lend support for randomized trials comparing tenecteplase with alteplase, preferably incorporating penumbral/angiographic imaging selection. Neurology® 2009;72:915–921 GLOSSARY CBV ⫽ cerebral blood volume; CTA ⫽ CT angiography; CTP ⫽ perfusion CT; DWI ⫽ diffusion-weighted echo-planar spin-echo sequence; ICH ⫽ intracranial hemorrhage; MNI ⫽ major neurologic improvement; MR ⫽ magnetic resonance; mRS ⫽ modified Rankin Scale; MTT ⫽ mean transit time; NCCT ⫽ noncontrast CT; NIHSS ⫽ NIH Stroke Scale; PH ⫽ parenchymal hematoma; TIMI ⫽ Thrombolysis in Myocardial Infarction.

There is substantial overall benefit from alteplase in appropriately selected ischemic stroke patients.1-3 However, IV alteplase has its limitations; there is a risk of intracranial hemorrhage (ICH), and less than half of patients treated have substantial reperfusion by 24 hours.4-6 Tenecteplase, a genetically engineered mutant tissue plasminogen activator, has a longer half-life, is more fibrin specific, produces less systemic depletion of circulating fibrinogen, and is more resistant to plasminogen activator inhibitor 1 than alteplase.7 These pharmacodynamic differences result in more rapid coronary reperfusion, with tenecteplase now the first-line IV thrombolytic for myocardial infarction.8-10 In animal stroke models, tenecteplase leads to more rapid and complete reperfusion than alteplase, with reduced ICH.11,12 A pilot dose-escalation study of tenecteplase in human stroke showed that clinical outcomes with the lowest dose of tenecteplase (0.1 mg/kg) were Supplemental data at www.neurology.org From the Departments of Neurology, Radiology, and Centre for Clinical Epidemiology and Biostatistics, John Hunter Hospital/Hunter Medical Research Institute, University of Newcastle, Australia. Disclosure: M.W.P. and C.R.L. have received honoraria to speak at educational symposia sponsored by Boehringer-Ingelheim (who market alteplase and tenecteplase in Australia). All remaining authors have no disclosures. Copyright © 2009 by AAN Enterprises, Inc.

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equivalent to higher doses of tenecteplase.13 This study did not have an alteplase control group, and measures of biologic efficacy, such as tissue reperfusion or vessel recanalization, were not assessed.13,14 To help plan future randomized doseranging studies of tenecteplase, we performed a pilot study assessing the biologic efficacy of the lowest dose of tenecteplase (0.1 mg/kg) used in human and animal stroke. We did not wish to deny sub–3-hour stroke patients proven therapy with alteplase; therefore, we used the 3- to 6-hour time window to test tenecteplase. For a comparator group, we used sub–3-hour patients contemporaneously treated with alteplase. All patients underwent pretreatment and post-treatment multimodal CT or MRI to assess tissue reperfusion and vessel recanalization. METHODS Patients. Between January 2006 and July 2007, we prospectively conducted a pilot, open-label, nonrandomized, controlled study of 0.1 mg/kg tenecteplase vs 0.9 mg/kg alteplase for patients with acute ischemic stroke. The tenecteplase group was selected from patients presenting with hemispheric ischemic stroke in the 3- to 6-hour time window. We prespecified that significant penumbral tissue, without a large infarct core, on baseline perfusion CT (CTP) or MRI was required for tenecteplase treatment. This was because we were testing an agent with limited safety/efficacy data in human stroke, and advanced imaging selection does show promise in identifying patients more likely to benefit from thrombolytic treatment in the not yet definitively proven 3- to 6-hour time window.16,17 Thus, in addition to standard thrombolysis eligibility criteria, the following imaging inclusion criteria were prespecified: 1) a hemispheric perfusion lesion at least 20% greater than the infarct core on baseline CTP or MRI and 2) an infarct core on CTP or MRI less than one-third of the middle cerebral artery territory.21,22 Because the primary outcomes of this study were reperfusion and recanalization, we also prespecified the following imaging exclusion criteria for tenecteplase treatment: 1) patients with absent or small perfusion lesions (⬍10 cm3) and 2) absence of visible intracranial vessel occlusion on CT or magnetic resonance (MR) angiography.23 Tenecteplase (0.1 mg/kg) was given as a single IV bolus. The control group consisted of all patients treated with IV alteplase (0.9 mg/kg) within 3 hours of hemispheric stroke onset during this period. These patients were selected for alteplase treatment following standard National Institute of Neurological Disorders and Stroke eligibility criteria.20 Although these patients also routinely underwent penumbral/angiographic imaging pretreatment, we do not deny sub–3-hour patients alteplase based on this imaging.18,19 The imaging protocol consisted of multimodal CT at baseline followed by MRI at 24 hours, unless there were contraindications to MRI, in which case multimodal CT was repeated at 24 hours. We also included patients who underwent baseline MRI rather than CT. The NIH Stroke Scale (NIHSS) was performed immediately before baseline imaging and at 24 hours. 916

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The modified Rankin Scale (mRS) was performed at day 90. The 24-hour and 90-day clinical assessments were performed by a trained observer not involved in the patients’ clinical care and blind to thrombolytic agent received. This study was approved by our institutional Ethics Committee, and individual patient consent was obtained.

Imaging. Multimodal CT was obtained with a multidetector scanner (16-slice Philips Mx8000).19 Whole-brain noncontrast CT (NCCT) was followed by perfusion CT, comprising two 45-second series. Each perfusion series covered a 24-mm axial section acquired as four adjacent 6-mm slices. The first section was at the level of the basal ganglia/internal capsule, and the second was placed 6 mm above, toward the vertex.19 CT angiography (CTA) was performed after CTP with acquisition from the base of the skull to the top of the lateral ventricles. MRI used was a 1.5-tesla MRI (Siemens Avanto).2 The stroke MRI protocol included an axial gradient-echo T2*weighted series, an axial isotropic diffusion-weighted echoplanar spin-echo sequence (DWI), time of flight MR angiography (MRA), bolus-tracking perfusion-weighted imaging with an axial T2*-weighted sequence, and a fluid-attenuated inversion recovery sequence.2 Image review before tenecteplase treatment. Baseline CTP and MR images were assessed by the treating stroke neurologist and neuroradiologist to determine whether the imaging criteria for tenecteplase treatment were met. The CTP assessment used the proprietary Philips brain perfusion software to generate maps of cerebral perfusion by deconvolution analysis, including mean transit time (MTT) and cerebral blood volume (CBV). Infarct core and penumbra maps were automatically calculated by the software using validated MTT and CBV thresholds (penumbra: MTT ⬎145% of contralateral side values, CBV ⬎2.0 mL/100 g; infarct core: MTT ⬎145% of contralateral side values, CBV ⬍2.0 mL/100 g).24 The software also provides automated volume measurements, based on these thresholds, for infarct core and penumbra.16 For those undergoing baseline MRI, high-intensity lesions on DWI (b ⫽ 1,000) maps were used to assess infarct core, and MTT maps generated by deconvolution analysis were used to assess perfusion lesion volume.19 The same selection criteria for tenecteplase treatment were applied to MRI as to CTP, but had to be judged qualitatively because the proprietary MR software does not provide quantitative lesion volumes.16,17 Baseline CTA or MRA circle of Willis maximum intensity projection source images and reconstructions were also reviewed to determine the presence of an intracranial vessel occlusion associated with the perfusion lesion. Imaging outcomes assessment: CTP/MR. Deidentified perfusion CT or MR data were analyzed with commercial software using an identical deconvolution algorithm to generate both CTP and MR perfusion maps (MIStar, Apollo Medical Imaging, Melbourne, Australia).18,19 For those that had baseline CTP and 24-hour MR, the MR-MTT maps were coregistered so that MR-MTT volumes were obtained from the same spatial position and axis orientation as the CTPMTT maps. Lesions were outlined on MR and CTP-MTT maps, and the same automated threshold (MTT delay of ⬎2 seconds) compared with the contralateral hemisphere (as previously validated) was used to calculate MR and CTP-MTT lesion volumes.19 Baseline infarct core volume was determined from CBV maps using an automated threshold of ⬍2.0 mL/100 g, or

from baseline DWI maps using an automated threshold based on increased signal intensity.2 Penumbral volume was determined from the difference between the coregistered baseline MTT lesion and CBV (or DWI) infarct core lesions. All lesion volumes were obtained from the average of measurements taken on separate occasions by a stroke neurologist and stroke fellow.

Imaging outcomes assessment: Recanalization. Deidentified baseline and 24-hour CTA or MRA circle of Willis maximum intensity projection reconstructions were reviewed by a stroke neurologist and neuroradiologist using adapted Thrombolysis in Myocardial Infarction (TIMI) criteria.4 Vessel occlusion status was classified as complete occlusion (TIMI 0), minimal flow (TIMI 1), partial flow (TIMI 2), or normal flow (TIMI 3).

Imaging outcomes assessment: ICH. Deidentified 24hour gradient-echo MR or NCCT was reviewed and graded by a stroke neurologist and neuroradiologist, based on the European Cooperative Acute Stroke Study definitions as hemorrhagic infarction type 1 or 2, or parenchymal hematoma (PH) type 1 (PH1) or 2 (PH2).25,26

Table 1

Comparisons between baseline and outcome variables for patients in the tenecteplase and alteplase groups Tenecteplase group

Alteplase group

Age, mean ⴞ SD, y

73.0 ⫾ 9.5

69.4 ⫾ 13.5

0.35*

Baseline NIHSS, median (IQR)

14 (13 to 17)

15 (11 to 18)

0.66§

Time to treatment, mean ⴞ SD, h

3.4 ⫾ 0.4

2.3 ⫾ 0.4

⬍0.001*

Baseline glucose, mean ⴞ SD, mmol/L

6.7 ⫾ 1.4

6.9 ⫾ 3.6

0.83*

Variable

p Value

Baseline variables

3

Baseline infarct core, mean ⴞ SD, cm

18.7 ⫾ 12.4

30.8 ⫾ 24.4

0.19*

Baseline penumbra, mean ⴞ SD, cm3

120.7 ⫾ 22.2

83.7 ⫾ 51.0

0.01*

Percent penumbra, mean ⴞ SD

84.1 ⫾ 12.0

69.4 ⫾ 27.3

0.05*

Total perfusion lesion, mean ⴞ SD, cm3

139.4 ⫾ 16.3

114.5 ⫾ 56.5

0.10*

Proportion with baseline vessel occlusion

15/15

30/35

0.12†

Proportion with baseline TIMI grade 0

6/15

12/35

0.70†

Percent reperfusion, mean ⴞ SD

73.8 ⫾ 23.3

44.4 ⫾ 30.5

0.01*

Proportion with 24-h reperfusion >80%

9/15

7/30

0.02†

Proportion with 24-h reperfusion >50%

11/15

11/30

0.02†

TIMI >2/complete recanalization

10/15

7/29

0.01†

Any (TIMI >1) recanalization

13/15

15/29

0.02†

NIHSS improvement, median (IQR)

9 (5 to 10)

1 (⫺2 to 4)

NIHSS improvement >8

10/15

7/35

0.001‡

Parenchymal hematoma

0/15

4/35

0.30‡

Hemorrhagic infarction

5/15

8/35

0.44‡

Independent (mRS 0, 1)

9/15

12/35

0.09†

Outcome variables

Statistical analysis. The following were compared between the tenecteplase and alteplase patients using STATA (version 7, College Station, TX 2001): 1. Baseline demographics and imaging volumes. 2. Baseline–24-hour reperfusion, expressed as the percentage reduction in the baseline–24-hour MTT lesion. We prespecified ⬎80% reperfusion as “major reperfusion” because this has been shown to be associated with substantially better imaging and clinical outcomes, and thus compared the proportion of patients in each group achieving this.2,18,27 To test for a consistent treatment difference on reperfusion, we also compared the proportion of patients in each group with “partial” reperfusion (⬎50%). Patients in the alteplase group with absent/small perfusion lesions were excluded from these analyses.23 3. Proportion with “major” vessel recanalization, defined as improvement in baseline–24-hour TIMI score of ⱖ2, or complete recanalization. To test for a consistent treatment difference, the proportion in each group with any recanalization (improvement in TIMI score of ⱖ1) was also examined. Patients in the alteplase group without a vessel occlusion were excluded from this analysis. 4. Baseline–24-hour improvement in NIHSS. We also compared the proportion of patients in each group with early major neurologic improvement (MNI, an NIHSS improvement of ⱖ8).13,14 5. Proportion with PH, because this is more common than symptomatic ICH but is strongly associated with adverse clinical outcome.26 6. Proportion achieving independence at 3 months (mRS 0 –1). We then used logistic regression analysis to assess the effects of the various baseline variables on the main imaging outcomes (reperfusion and recanalization), as well as on early (MNI) and late clinical outcomes (mRS 0 –1). The main baseline variable tested was treatment group (tenecteplase or alteplase); other potential predictor baseline variables were age, NIHSS, serum glucose, infarct core volume, penumbra volume, percent penumbra, and complete vessel occlusion. Time to treatment was not used in the regressions as it had colinearity with treatment group because all tenecteplase patients were treated ⬎3 hours and all alteplase patients were treated ⬍3 hours. First, univariate analysis was used to identify predictive baseline variables. All variables with a univariate p value (⬍0.2) were then included in a multivariate model.

During the study period, 15 patients received 0.1 mg/kg IV tenecteplase between 3 and 6 hours after onset of hemispheric ischemic stroke, and 35 patients received 0.9 mg/kg IV alteplase within 3 hours of hemispheric stroke onset. These patients all had baseline and 24-hour perfusion/angiographic imaging. One alteplase-treated and two tenecteplasetreated patients had baseline MRI instead of CTP/ CTA, and two tenecteplase-treated and three alteplase-treated patients had 24-hour CTP/CTA rather than MRI. During the study period, there were a further 12 ischemic stroke patients who underwent perfusion/ angiographic imaging 3 to 6 hours after symptom onset. These patients fulfilled standard clinical criteria for thrombolytic treatment (apart from time), but they did not fulfill the prespecified imaging criteria

RESULTS

⬍0.001§

*Two-sample t test. †Pearson ␹2 test. ‡Fisher exact test. § Mann–Whitney rank sum test. NIHSS ⫽ NIH Stroke Scale; IQR ⫽ interquartile range; TIMI ⫽ Thrombolysis in Myocardial Infarction; mRS ⫽ modified Rankin Scale.

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917

Table 2

Logistic regression with baseline variables: Outcome variable, >80% reperfusion Univariate

Multivariate

Baseline variable

Odds ratio (95% CI)

p Value

Odds ratio (95% CI)

p Value

Age

1.00 (0.95–1.05)

0.930

—

NIHSS

0.81 (0.65–1.01)

0.061

0.88 (0.64–1.22)

Serum glucose

1.10 (0.90–1.34)

0.353

—

TIMI grade 0

0.56 (0.15–2.02)

0.376

—

Core volume

0.95 (0.91–1.00)

0.057

0.94 (0.84–1.04)

Penumbra volume

1.01 (0.99–1.03)

0.307

—

% Penumbra

9.95 (0.42–28.66)

0.156

0.10 (0.01–61.67)

0.517

Tenecteplase

4.93 (1.30–18.73)

0.019

4.73 (1.07–20.98)

0.041

0.440

0.225

With multivariate regression, only tenecteplase remained significant. When ⬎50% reperfusion was assessed as the outcome variable, tenecteplase was again the only significant baseline predictor in multivariate analysis (odds ratio 4.5, 95% confidence interval [CI] 1.1– 18.8, p ⫽ 0.04). NIHSS ⫽ NIH Stroke Scale; TIMI ⫽ Thrombolysis in Myocardial Infarction.

for treatment with tenecteplase and thus did not receive thrombolytic therapy. Four patients had a large infarct core, and another two patients without large infarct cores were nonpenumbral. Four patients had small/absent acute perfusion lesions, and two had acute perfusion lesions ⬎10 cm3 but with no visible vessel occlusion. Baseline comparisons between tenecteplase and alteplase groups. Demographic variables were similar be-

tween the tenecteplase and alteplase groups, apart from an earlier time to treatment in the alteplase group (table 1). Penumbral volumes were higher in the tenecteplase group. There were six patients withTable 3

Logistic regression with baseline variables: Outcome variable, TIMI >2/complete recanalization Univariate

Baseline variable

Odds ratio (95% CI)

Multivariate p Value

Odds ratio (95% CI)

Age

1.00 (0.95–1.05)

0.947

—

NIHSS

0.90 (0.74–1.11)

0.332

—

Serum glucose

1.07 (0.88–1.30)

0.481

—

TIMI grade 0

0.68 (0.20–2.38)

0.549

—

Core volume

0.95 (0.90–1.00)

0.048

0.96 (0.88–1.04)

Penumbra volume

1.02 (0.99–1.03)

0.212

—

p Value

0.336

% Penumbra

10.75 (1.21–106.93)

0.041

2.03 (0.01–171.17)

0.850

Tenecteplase

6.29 (1.60–24.72)

0.009

4.81 (1.13–20.55)

0.034

With multivariate regression, only tenecteplase remained significant. When any (Thrombolysis in Myocardial Infarction [TIMI] ⱖ1) recanalization was assessed as the outcome variable, univariate baseline predictors (p ⬍ 0.2) were treatment with tenecteplase, baseline TIMI grade ⬎0, acute infarct core volume, and percent penumbra. In multiple regression analysis using these four baseline variables, treatment with tenecteplase (odds ratio 7.31, 95% confidence interval [CI] 1.04 –51.35, p ⫽ 0.045) and baseline TIMI grade 0 (odds ratio 0.10, 95% CI 0.02– 0.49, p ⫽ 0.005) remained independent predictors of TIMI ⱖ1 recanalization. NIHSS ⫽ NIH Stroke Scale. 918

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out a baseline vessel occlusion (all in the alteplase group), and five of these also had small baseline perfusion lesions (⬍10 cm3). Two of these five had lacunar stroke, and the other three had small cortical perfusion lesions. All 15 tenecteplase patients had acute perfusion lesions ⬎10 cm3 and an associated vessel occlusion. There were no differences in the proportion of patients with complete vessel occlusion at baseline. Outcome comparisons between tenecteplase and alteplase groups. There were significant differences be-

tween the two groups with respect to the major imaging outcome variables (table 1). The tenecteplase group overall had a higher extent of reperfusion, and consequently a higher proportion of tenecteplase-treated patients achieved both ⬎80% and ⬎50% reperfusion at 24 hours (figure e-1 on the Neurology® Web site at www.neurology.org). Similarly, the tenecteplase group had higher rates of both major and any vessel recanalization (table 1). Major vessel recanalization and reperfusion were closely linked; 8 of 10 tenecteplase and 5 of 7 alteplase patients with major recanalization also had ⬎80% reperfusion. Similarly, greater improvements in baseline–24hour NIHSS were seen in the tenecteplase group, translating into a higher proportion of tenecteplasetreated patients with early MNI (table 1). Major reperfusion occurred in 9 of 10 tenecteplase patients and 5 of 6 alteplase patients with early MNI, and major vessel recanalization occurred in all but one patient with early MNI. There was also a trend toward better 3-month functional outcomes in the tenecteplase group (figure e-2). Again, better functional outcomes were closely linked to the occurrence of major reperfusion and vessel recanalization, although, notably, four of five alteplase patients with small baseline perfusion lesions also had an excellent functional outcome. Parenchymal hematoma occurred in four patients, all in the alteplase group (table 1). Two patients had PH1 and two had PH2, none of these four had an improvement in 24-hour NIHSS, and one of the PH2 patients had a symptomatic deterioration of four points on 24-hour NIHSS. Regression analysis of outcome variables. Univariate

baseline predictors (p ⬍ 0.2) of major reperfusion were treatment with tenecteplase, (lower) acute NIHSS, (smaller) acute infarct core volume, and (greater) percent penumbra. In multiple regression analysis using these four baseline variables, treatment with tenecteplase remained the only significant predictor of ⬎80% reperfusion (table 2). Univariate baseline predictors of major recanalization were

Table 4

Logistic regression with baseline variables: Outcome variable, early major neurologic improvement Univariate

Baseline variable

Odds ratio (95% CI)

Multivariate p Value

Odds ratio (95% CI)

p Value

Age

0.98 (0.94–1.04)

0.497

—

NIHSS

1.03 (0.89–1.19)

0.697

—

Serum glucose

1.11 (0.91–1.34)

0.306

—

TIMI grade 0

1.10 (0.32–3.77)

0.880

—

Core volume

0.95 (0.91–0.99)

0.037

0.94 (0.84–1.05)

0.252

Penumbra volume

1.03 (0.99–1.03)

0.057

1.01 (0.98–1.04)

0.618

0.027

0.73 (0.01–998.9)

0.952

0.001

6.85 (1.42–33.06)

0.017

% Penumbra

32.88 (1.93–560.17)

Tenecteplase

9.7 (2.41–38.71)

CI ⫽ confidence interval; NIHSS ⫽ NIH Stroke Scale; TIMI ⫽ Thrombolysis in Myocardial Infarction.

treatment with tenecteplase, acute infarct core volume, and percent penumbra. In multiple regression analysis using these three baseline variables, treatment with tenecteplase remained the only significant predictor of major recanalization (table 3). Univariate baseline predictors of early MNI were treatment with tenecteplase, acute infarct core volume, acute penumbral volume, and percent penumbra. In multiple regression analysis using these four baseline variables, treatment with tenecteplase remained the only significant predictor of early MNI (table 4). Univariate baseline predictors of excellent 3-month functional outcome were treatment with tenecteplase, age, acute NIHSS, acute infarct core volume, and percent penumbra. In multiple regression analysis, treatment with tenecteplase, age, and acute infarct core volume remained significant predictors of excellent long-term outcome (table 5). Thus, treatment with tenecteplase was the only baseline variable that independently predicted all imaging and clinical outcomes in multiple regression analysis. Table 5

Logistic regression with baseline variables: Outcome variable, excellent 3-month functional outcome (mRS 0 –1) Univariate

Baseline variable

p Value

Odds ratio (95% CI)

p Value

Age

0.94 (0.89–0.99)

0.028

0.93 (0.87–0.99)

0.037

NIHSS

0.81 (0.69–0.96)

0.015

0.90 (0.67–1.21)

0.493

Serum glucose

1.08 (0.89–1.30)

0.458

—

TIMI grade 0

0.57 (0.17–1.88)

0.354

—

Core volume

0.92 (0.87–0.97)

0.003

0.88 (0.78–0.98)

Penumbra volume

Odds ratio (95% CI)

Multivariate

0.99 (0.98–1.01)

0.041

0.916

—

% Penumbra

81.74 (1.36–489.34)

0.035

0.05 (0.01–221.85)

0.495

Tenecteplase

2.88 (0.83–10.01)

0.097

6.99 (1.03–44.69)

0.045

mRS ⫽ modified Rankin Scale; CI ⫽ confidence interval; NIHSS ⫽ NIH Stroke Scale; TIMI ⫽ Thrombolysis in Myocardial Infarction.

This nonrandomized pilot study in acute ischemic stroke patients showed greater early reperfusion and recanalization in the 0.1-mg/kg tenecteplase group compared with the 0.9-mg/kg alteplase group. The greater reperfusion seen in the tenecteplase group clearly was also biologically significant because it translated into greater early clinical improvement, despite later time to treatment. This enhanced reperfusion also did not seem to come at the cost of increased ICH, with no incidences of PH in the 15 tenecteplase patients compared with four in the alteplase group. The previously reported strong association of PH with adverse outcome was also supported in this study.26 None of the four patients with PH in our study improved clinically at 24 hours (which contributed to the lower proportion of alteplase patients with early MNI) or was independent at 3 months. One potential explanation for the differences seen between the two groups is the pharmacokinetic profile that makes tenecteplase a faster acting and more potent thrombolytic than alteplase.28 However, another possible explanation for the better outcomes in the tenecteplase group is that these patients were selected with penumbral/angiographic imaging guidance, whereas patients in the alteplase group were selected by standard criteria using NCCT. Better patient selection almost certainly contributed to the higher rate of early MNI in our tenecteplase group compared with that in the previous human tenecteplase stroke study, which only used NCCT in the pretreatment assessment.13 Indeed, our data support the concept of a “dual-target” imaging selection approach, where patients with a large penumbra and a coexistent intracranial arterial occlusion seem most likely to benefit from major reperfusion.13,22,29 It is also notable that a smaller baseline infarct core was independently predictive of 3-month outcome (table 5). Thus, it is not possible to determine the individual contributions of better patient selection vs the effects of tenecteplase treatment itself toward the improved clinical outcomes seen in the tenecteplase group compared with the alteplase group in our study. However, tenecteplase treatment remained a significant predictor of improved clinical outcome even when controlling for baseline imaging volumes, and the significant difference in time to treatment would have been expected to favor alteplase if there was no efficacy difference between these agents.14,30 It is also less plausible that the reperfusion and recanalization outcomes were affected by imaging selection, because only patients with vessel occlusion and large perfusion lesions were included in these comparisons. Our findings suggest that 0.1 mg/kg tenecteplase treatment using advanced imaging guidance in an exDISCUSSION

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tended time window may have significant biologic efficacy, but the imaging selection differences also mean that we cannot conclude that tenecteplase has an enhanced therapeutic margin compared with 0.9 mg/kg alteplase. The results of this study also do not allow us to determine whether 0.1 mg/kg tenecteplase is the optimal dose for stroke, although we suggest that is a reasonable dose at which to commence dose-ranging trials. Indeed, a recent nonrandomized human study showed that 0.4 mg/kg tenecteplase had superior early recanalization rates on transcranial ultrasound compared with 0.9 mg/kg alteplase, albeit with similar ICH rates.15 We believe that randomized (alteplase-controlled) dose-ranging phase 2 studies with tenecteplase in stroke are required before a phase 3 trial is contemplated. As demonstrated in the current study, the use of a dualtarget imaging selection approach, with reperfusion/ recanalization as a primary outcome, might allow for relatively small sample sizes in such proof-of-concept studies.31 AUTHOR CONTRIBUTIONS Statistical analysis was conducted by J.A.

ACKNOWLEDGMENT The authors thank their stroke research nurses and CT and MR radiographers.

Received April 16, 2008. Accepted in final form December 12, 2008.

REFERENCES 1. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768–774. 2. Parsons MW, Barber PA, Chalk J, et al. Diffusion- and perfusion-weighted MRI response to thrombolysis in stroke. Ann Neurol 2002;51:28–37. 3. Davis SM, Donnan GA, Butcher KS, Parsons M. Selection of thrombolytic therapy beyond 3 h using magnetic resonance imaging. Curr Opin Neurol 2005;18:47–52. 4. Neumann-Haefelin T, du Mesnil de Rochemont R, Fiebach JB, et al. Effect of incomplete (spontaneous and postthrombolytic) recanalization after middle cerebral artery occlusion: a magnetic resonance imaging study. Stroke 2004;35:109–114. 5. Liberatore GT, Samson A, Bladin C, Schleuning WD, Medcalf RL. Vampire bat salivary plasminogen activator (desmoteplase): a unique fibrinolytic enzyme that does not promote neurodegeneration. Stroke 2003;34:537–543. 6. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 2007;38: 967–973. 7. Tanswell P, Modi N, Combs D, Danays T. Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmacokinet 2002;41:1229–1245. 920

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Van De Werf F, Adgey J, Ardissino D, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 1999;354:716–722. 9. Al-Shwafi KA, de Meester A, Pirenne B, Col JJ. Comparative fibrinolytic activity of front-loaded alteplase and the single-bolus mutants tenecteplase and lanoteplase during treatment of acute myocardial infarction. Am Heart J 2003;145:217–225. 10. Binbrek AS, Rao NS, Neimane D, Hatou E, Abdulali S, Sobel BE. Comparison of rapidity of coronary recanalization in men with tenecteplase versus alteplase in acute myocardial infarction. Am J Cardiol 2004;93:1465–1468. 11. Benedict CR, Refino CJ, Keyt BA, et al. New variant of human tissue plasminogen activator (TPA) with enhanced efficacy and lower incidence of bleeding compared with recombinant human TPA. Circulation 1995;92:3032– 3040. 12. Thomas GR, Thibodeaux H, Errett CJ, et al. A long-halflife and fibrin-specific form of tissue plasminogen activator in rabbit models of embolic stroke and peripheral bleeding. Stroke 1994;25:2072–2078. 13. Haley EC Jr, Lyden PD, Johnston KC, Hemmen TM. A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke. Stroke 2005;36:607–612. 14. Brown DL, Johnston KC, Wagner DP, Haley EC. Predicting major neurological improvement with intravenous recombinant tissue plasminogen activator treatment of stroke. Stroke 2004;35:147–150. 15. Molina CA, Ribo M, Rubiera M, et al. TNK induces faster MCA recanalization and leads to better short and long term clinical outcome than native tPA. Stroke 2008;39: 527. Abstract. 16. Wintermark M, Meuli R, Browaeys P, et al. Comparison of CT perfusion and angiography and MRI in selecting stroke patients for acute treatment. Neurology 2007;68: 694–697. 17. Kohrmann M, Juttler E, Fiebach JB, et al. MRI versus CT-based thrombolysis treatment within and beyond the 3 h time window after stroke onset: a cohort study. Lancet Neurol 2006;5:661–667. 18. Parsons MW, Pepper EM, Chan V, et al. Perfusion computed tomography: prediction of final infarct extent and stroke outcome. Ann Neurol 2005;58:672–679. 19. Parsons MW, Pepper EM, Bateman GA, Wang Y, Levi CR. Identification of penumbra and infarct core on hyperacute non-contrast and perfusion CT. Neurology 2007;68: 730–736. 20. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333:1581–1587. 21. Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005;36:66–73. 22. Hacke K-A, Furlan A, investigators ftD. Results from the phase III study of desmoteplase in acute ischemic stroke trial (DIAS2). Cerebrovasc Dis 2007;23 (suppl 2):54. 23. Albers GW, Thijs VN, Wechsler L, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60:508–517.

24. Wintermark M, Flanders AE, Velthuis B, et al. Perfusion-CT assessment of infarct core and penumbra: receiver operating characteristic curve analysis in 130 patients suspected of acute hemispheric stroke. Stroke 2006; 37:979–985. 25. Hacke W, Kaste M, Fieschi C. Randomised double-blind placebo controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998;352:1245–1251. 26. Trouillas P, von Kummer R. Classification and pathogenesis of cerebral hemorrhages after thrombolysis in ischemic stroke. Stroke 2006;37:556–561. 27. Butcher K, Parsons M, Baird T, et al. Perfusion thresholds in acute stroke thrombolysis. Stroke 2003;34:2159–2164.

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Keyt BA, Paoni NF, Refino CJ, et al. A faster-acting and more potent form of tissue plasminogen activator. Proc Natl Acad Sci USA 1994;91:3670–3674. Davis SM, Donnan GA, Parsons MW, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 2008; 7:299–309. Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study. Neurology 2000;55:1649–1655. Barber PA, Parsons MW, Desmond PM, et al. Use of PWI and DWI measures in the design of “proof of concept” stroke trials. J Neuroimaging 2004;14:123–132.

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Weather and air pollution as triggers of severe headaches

Kenneth J. Mukamal, MD Gregory A. Wellenius, ScD Helen H. Suh, ScD Murray A. Mittleman, MD, DrPH

Address correspondence and reprint requests to Dr. Kenneth J. Mukamal, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215 [email protected]

ABSTRACT

Background: The roles of weather conditions and air pollution as triggers of headache have been inconsistent in previous, generally small studies.

Methods: We performed a case-crossover study of 7,054 patients seen in a single emergency department between May 2000 and December 2007 with a primary discharge diagnosis of headache. We compared levels of temperature, barometric pressure, humidity, fine particulate matter, black carbon, and nitrogen and sulfur dioxides during the three 24-hour periods preceding presentation with corresponding levels on the remaining occurrences of that day of the week in a given month, using local meteorologic and pollutant monitors.

Results: Higher mean ambient temperature in the 24 hours preceding hospital presentation positively and linearly increased the acute risk of headache (odds ratio [OR] for a 5°C increment 1.075; 95% confidence interval [CI], 1.021–1.033; p ⫽ 0.006). Higher risk was observed for cases with and without a discharge diagnosis of migraine and for cases between October and March or between April and September. Lower barometric pressure also increased the risk of nonmigraine cases in the 48 to 72 hours before hospitalization (OR 0.939 per 5 mm Hg; 95% CI, 0.902– 0.978; p ⫽ 0.002). Current levels of pollutants did not influence the risk of headache.

Conclusions: Higher ambient temperature and, to a lesser degree, lower barometric pressure led to a transient increase in risk of headache requiring emergency department evaluation. We did not find clear association of air pollutants with risk, but cannot exclude effects of air pollution of the magnitude previously observed for stroke and other cardiovascular events. Neurology® 2009;72:922–927 GLOSSARY BC ⫽ black carbon; BIDMC ⫽ Beth Israel Deaconess Medical Center; CI ⫽ confidence interval; OR ⫽ odds ratio; PM2.5 ⫽ fine particulate matter with aerodynamic diameter ⱕ2.5 ␮m.

Migraine and other headache syndromes represent an enormous source of morbidity, especially among young and middle-aged adults.1 Approximately 18% of women and 6% of men in the United States report migraines,2 and annual costs attributable to migraines have been estimated to approximate $17 billion.3 Among the most widely cited yet poorly documented triggers of headache are weatherrelated variables, such as temperature, humidity, and barometric pressure. Although numerous reports link headache with weather conditions,4,5 large, well-controlled studies have been mixed in this regard. One large study in Montreal found an association solely with barometric pressure,6 but this was not confirmed in a case-crossover study in Ottawa.7 There is increasing evidence that air pollution, and particularly small particulate pollutants, can induce transient increases in the risk— or triggering— of myocardial infarction,8 stroke,9 congestive heart failure,10 ventricular arrhythmias,11 asthma,12 and respiratory infections.13 A few small studies have suggested that various forms of air pollution may be linked to headache,14-17

From the Department of Medicine (K.J.M., G.A.W., M.A.M.), Beth Israel Deaconess Medical Center, Boston; and Departments of Environmental Health (H.H.S.) and Epidemiology (M.A.M.), Harvard School of Public Health, Boston, MA. Supported in part by grants ES015774 and ES009825 from the National Institute of Environmental Health Sciences and R827353 and R832416 from the US Environmental Protection Agency. Disclosure: The authors report no disclosures. 922

Copyright © 2009 by AAN Enterprises, Inc.

as have two Canadian studies that compared trends in hospital visits for headaches and pollutant levels.6,18 To our knowledge, no studies have evaluated whether ambient air pollution— and particularly fine particulate matter—triggers migraines or other headache syndromes using case-crossover methodology,19 which directly compares levels of pollutants and meteorologic variables at the time of presentation for headaches to corresponding levels on preceding and subsequent weeks. To evaluate whether weather conditions and ambient air pollution transiently increase the risk of severe headaches, we conducted a casecrossover analysis of approximately 7,000 patients presenting for emergency care with headache, using levels of ambient air pollution measured continuously at a local site monitor. METHODS This study was conducted at Beth Israel Deaconess Medical Center (BIDMC), an academic hospital providing primary and tertiary care in Boston, Massachusetts. The hospital uses an entirely electronic medical record in both the inpatient and outpatient settings. The BIDMC emergency department accounts for approximately 52,000 visits annually. The BIDMC Committee on Clinical Investigations approved the protocol with a waiver of informed consent. No participants were contacted as part of these analyses.

Study participants. Using administrative data, we identified all 8,235 individuals seen and discharged from the BIDMC emergency department between May 26, 2000 (when an administrative dashboard was instituted), and December 31, 2007, with a primary discharge diagnosis of headache (ICD-9 code 784.0), migraine (codes 346.xx), or tension headache (code 307.81). To minimize exposure misclassification, we excluded individuals who lived greater than 40 km from the hospital (based upon zip code of residence), leaving 7,054 participants eligible for analysis. Exposure assessment. Exposure to particulate air pollution was based on measurements made at our Boston stationary ambient monitoring site, located on the roof of the Countway Library of Medicine, located less than a half-mile from BIDMC. Daily air pollution concentrations have been measured at this site since 1999 and used in a number of studies.20-23 Fine particulate matter with aerodynamic diameter ⱕ2.5 ␮m (PM2.5) was measured continuously using a TEOM (Model 1400A, Rupprecht & Patashnick; Albany, NY). PM2.5 measured at this central site monitor have been shown to be strong proxies for personal exposure to particles of ambient origin in communities surrounding Boston.24,25 Black carbon (BC) was measured continuously using an aethalometer (AE-14, Magee Scientific Inc., Berkeley, CA). Where missing data occurred (⬃10% of hourly measurements), levels were imputed based on values of adjoining hours and concurrent measurements of correlated pollutants and atmospheric conditions. Hourly nitrogen dioxide (NO2) and sulfur dioxide (SO2) were obtained from local monitoring sites operated by the Massachusetts Department of Environmental Protection. Meteorologic data (temperature, relative

humidity, and barometric pressure) were obtained from the hourly surface observations of the National Weather Service First Order Station at Logan Airport (East Boston).

Statistical analyses. We used case-crossover analyses to compare measures of weather and ambient air pollution on the day of presentation and control days for each patient. The hallmark of case-crossover studies is self-matching, in which each individual provides his or her own control information and hence confounding by factors that are constant within individuals over the sampling period (e.g., personal medical history) is completely controlled.26 We selected control periods according to the time-stratified approach proposed by Lumley and Levy27 to minimize potential biases due to season and long-term time trends. In this approach, exposure during the 24 hours immediately preceding presentation (or the comparable periods 1–2 days beforehand) was compared to exposure on the three or four other occurrences of that day of the week in a single calendar month. We used conditional logistic regression models, in which the individual patient was the conditioning factor. We present odds ratios (OR) and 95% confidence intervals (CI) associated with an increment of one interquartile range in 24-hour mean levels of exposure; for interpretability, we also present results for temperature in units of 5°C and pressure in units of 5 mm Hg. We used all headaches as the primary outcome of interest, and tested those with and without a specific discharge diagnosis of migraine in secondary analyses. In all cases, we employed distributed lag models, in which we examined the associations of exposure in the 0 –24 hour (lag 0 days), 24 – 48 hour (lag 1 day), and 48 –72 hour (lag 2 days) periods preceding hospitalization simultaneously. We first examined the associations of meteorologic variables with headaches. We modeled mean apparent temperature at lag 0 with linear and quadratic terms and mean apparent temperature at lags 1 and 2, mean barometric pressure at lags 0 –2, and relative humidity at lags 0 –2 as linear functions of continuous variables. We next examined the effects of ambient air pollutants in single pollutant models, with lags of 0 –2, also as continuous variables. In these models, we adjusted for mean temperature and barometric pressure, using the same lag structure. Given the strong association of season with temperature, we also repeated analyses separately for emergency visits between October and March (cooler) and between April and September (warmer).

Among the 7,054 patients, there were 2,250 with a primary discharge diagnosis of migraine and 4,803 with tension or unspecified headache. In the 7 full years of data collection, the number of participants ranged from 815 in 2004 to 1,033 in 2002. A total of 5,292 (75%) were women. The panel was multiethnic, with 48% white, 23% African American, and 10% Latino; 15% did not have ethnicity recorded. The mean age (⫾SD) was 42 ⫾ 16 years. Table 1 summarizes ambient levels of meteorologic variables, PM2.5, BC, and gaseous pollutants during the time period of the study. Table 2 indicates the pairwise Pearson correlation coefficients among these variables. Among meteorologic variables, temperature correlated moderately with relative humidity but weakly with barometric pressure; relative humidity was inversely correlated with pressure. Lev-

RESULTS

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Table 1

Summary of 24-hour averages of air pollutants in Boston, Massachusetts, May 26, 2000 –December 31, 2007 Median

Temperature (°C) Barometric pressure (mm Hg) Relative humidity (%)

75th Percentile

3.6

19.2

761.0

757.0

764.9

68.1

55.7

80.3

3

PM2.5 (␮g/m ) Nitrogen dioxide (ppm)

25th Percentile

11.3

8.6

6.1

12.8

18.1

14.4

22.5

Sulfur dioxide (ppm)

3.6

2.3

5.5

Black carbon (␮g/m3)

0.64

0.41

0.92

PM2.5 ⫽ fine particulate matter with aerodynamic diameter ⱕ2.5 ␮m.

els of pollutants tended to correlate at least moderately with each other, particularly for the pairs of NO2 with SO2 and PM2.5 with BC. Meteorologic variables. In multivariable models (table 3), higher mean ambient temperature in the 24 hours preceding hospital presentation increased the acute risk of headache (OR for a 5°C increment 1.075; 95% CI, 1.021–1.033; p ⫽ 0.006). There was no evidence of a nonlinear effect (p quadratic ⫽ 0.53), nor were there effects of temperature in the preceding lag periods (p ⫽ 0.71 for lag 1; p ⫽ 0.34 for lag 2). Higher temperature increased the risk of cases with both a discharge diagnosis of migraine (OR for a 5°C increment 1.111; 95% CI, 1.013–1.218; p ⫽ 0.03) and other headache (OR 1.059; 95% CI, 0.994 –1.128; p ⫽ 0.08), and for headaches that occurred in colder months (OR 1.089; 95% CI, 1.016 –1.167; p ⫽ 0.02) or warmer months (OR 1.118; 95% CI, 1.021–1.225; p ⫽ 0.02). Results were also positive when minimum (rather than mean) temperature in the preceding 24 hours (OR 1.068; 95% CI, 1.014 –1.125; p ⫽ 0.01) or maximum temperature (OR 1.039; 95% CI, 1.014 – 1.081; p ⫽ 0.05) were considered. After adjusting for temperature on the 24 hours before hospitalization, there was also no effect of change in temperature in

Table 2

Temperature Pressure

Pearson correlation coefficients among meteorologic variables and pollutants in Boston, Massachusetts, May 26, 2000 – December 31, 2007 Temperature

Pressure

Humidity

PM2.5

BC

NO2

SO2

1.00

⫺0.08

0.94

0.27

0.34

⫺0.23

⫺0.55

1.00

⫺0.15

0.01

0.05

0.13

0.14

1.00

0.23

0.42

0.01

⫺0.17

1.00

0.70

0.53

0.28

1.00

0.58

0.21

Humidity PM2.5 BC NO2

1.00

0.61 1.00

SO2

PM2.5 ⫽ fine particulate matter with aerodynamic diameter ⱕ2.5 ␮m; BC ⫽ black carbon. 924

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the preceding 24 hours, either in colder or warmer months. Lower barometric pressure increased the acute risk of headache, but only on a lag 2 scale (i.e., in the 48- to 72-hour period before hospitalization), with an adjusted OR of 0.939 per 5 mm Hg (95% CI, 0.902– 0.978; p ⫽ 0.002). In contrast with temperature, barometric pressure only increased the risk of nonmigraine cases (OR 0.923; 95% CI, 0.880 – 0.969; p ⫽ 0.001), and tended to be greater in colder months (OR 0.928; 95% CI, 0.884 – 0.974; p ⫽ 0.002). Change in pressure between the 24 and 48 hours before hospitalization did not influence risk in warmer or colder months. There was no association of relative humidity with headache at any lag. Ambient air pollutants. Table 3 also presents the risks associated with an increment of one interquartile range in mean levels of ambient air pollutants in the 24 hours before presentation, adjusting for temperature and barometric pressure. Pollutant levels did not influence the acute risk of headache at lag 0 days, either overall or with migraine and nonmigraine cases separately. There was also no significant association of any pollutant with headache on the lag 1 or 2 scales, although NO2 had a borderline effect on nonmigraine cases on the lag 1 scale (OR for an increment of an interquartile range 1.067; 95% CI, 1.001–1.138; p ⫽ 0.05). The trend toward higher risk with greater ambient concentration of NO2 on the lag 1 scale was numerically similar in both colder (OR 1.053; 95% CI, 0.984 –1.128; p ⫽ 0.14) and warmer months (OR 1.062, 95% CI, 0.975–1.157; p ⫽ 0.17); there were no associations of headache with other pollutants in analyses of warmer or colder months.

In this analysis of over 7,000 patients, we found that higher ambient temperature transiently increased the risk of headache requiring emergency department evaluation, with approximate 7.5% higher risk for each 5°C increment in temperature. There was also some evidence for higher risk with lower barometric pressure in the 48 to 72 hours before hospital presentation for cases not diagnosed as migraine. We did not find clear association of ambient air pollutants with risk. Migraine and other headache syndromes have long been linked to weather conditions, particularly with changes in barometric pressure.4,5 In fact, an association with weather conditions has been suggested as a diagnostic symptom specific to migraine relative to other forms of headache.28 However, this association was not borne out in a large casecrossover study of migraines in Ottawa,7 and a large study of headaches not coded as migraines in Montreal also found an association solely with barometric DISCUSSION

Table 3

Odds ratios (95% confidence intervals) for total, migraine, and nonmigraine headache requiring emergency department evaluation associated with an increment of one interquartile range in mean exposure level during the 24 hours before presentation Interquartile range

Total

Migraine

Nonmigraine

15.6

1.255 (1.066–1.477)

1.389 (1.042–1.852)

1.195 (0.980–1.456)

7.9

1.000 (0.946–1.058)

1.075 (0.973–1.188)

0.965 (0.902–1.034)

24.6

0.972 (0.912–1.036)

1.018 (0.910–1.139)

0.949 (0.878–1.025)

6.7

1.005 (0.967–1.045)

1.021 (0.956–1.090)

0.997 (0.951–1.045)

Black carbon (␮g/m )

0.51

0.995 (0.955–1.036)

1.001 (0.934–1.074)

0.992 (0.944–1.042)

Nitrogen dioxide (ppm)

8.1

0.983 (0.936–1.032)

0.973 (0.892–1.061)

0.988 (0.931–1.049)

Sulfur dioxide (ppm)

3.3

0.975 (0.933–1.018)

0.988 (0.916–1.065)

0.968 (0.917–1.022)

Temperature (°C) Barometric pressure (mm Hg) Relative humidity (%) PM2.5 (␮g/m3) 3

PM2.5 ⫽ fine particulate matter with aerodynamic diameter ⱕ2.5 ␮m.

pressure.6 These results together with ours suggest that the association of headache with barometric pressure is unlikely to be a useful diagnostic marker specific for migraine. We also found a strong association of headache with ambient temperature, regardless of the discharge diagnosis coded. The one previous large casecrossover study of migraines did not find such an association but examined only a single temperature cutpoint of 19.6°C.7 However, other studies have found generally higher rates of migraine in warmer seasons,29-31 despite an association of higher temperature with lower blood pressure.32,33 Whether higher temperature is also associated with a greater likelihood of triggering the more common headaches that do not result in emergency department evaluation will require additional study. There is growing interest in air pollution as a trigger of a variety of acute health conditions. Air pollution represents a complex mix of pollutants, including both coarse and fine particles and gaseous constituents. Two common pollutant gases, sulfur and nitrogen dioxides, were positively associated with emergency visits for nonmigraine headache in similar time-series studies in Ottawa and Montreal, with higher risks seen across multiple lag scales.6,18 Our results tend to support the higher risk associated with NO2 exposure, where higher risk was seen specifically for headaches not diagnosed as migraine. We anticipated that PM2.5 might have the strongest association with headache, as they appear to induce sympathetic nervous system activation (best studied in relation to heart rate variability34), pulmonary and subsequently systemic inflammation,35,36 and vascular endothelial injury.37,38 They have also been most closely associated with triggering cardiovascular events.39 In the one previous large-scale study of headaches, PM2.5 only increased risk on a lag 2 scale, with a generally weaker effect than observed for gaseous pollutants.6 Given the marked effects of fine particulate matter observed in

previous studies of cardiovascular disease, the role of these particles as a trigger of headache clearly merits additional study. It is also important to recognize the expected magnitude of effect when considering the lack of statistical association between pollutants and risk in our study. In general, previous case-crossover studies of fine particulate air pollution and cardiovascular conditions such as ischemic stroke9 have demonstrated approximately 1% higher risk (i.e., relative risk of 1.01) with an interquartile range increment similar to that used here. The precision of our estimates was generally insufficient to exclude an effect of that magnitude, and hence we cannot rule out an association that, albeit small in magnitude, could have farreaching public health implications. The clinical and public health implications of our findings even for temperature may differ to some degree. Our results suggest that an increase in temperature of 5°C would confer a short-term 7.5% increase in risk. This magnitude of excess risk is obviously modest and may not be an important factor in the clinical management of individual patients, given the many other potential triggers of migraine that patients may face. At the same time, every member of a given geographic region is repeatedly exposed to this excess risk, and hence the public health impact of triggering migraine by rising ambient temperatures may be greater than exposures that confer a higher relative risk but to a much smaller number of potentially exposed patients. This study has several potential limitations, most of which were likely to have potentially biased our results toward the null. First, we relied upon headaches classified by emergency department physicians, and hence misclassification of some admissions— and particularly for comparisons of cases coded as migraine or not40—is likely. Second, we relied upon use of a central ambient monitor rather than personal exposure measures, although levels of SO2 and Neurology 72

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PM2.5 in particular tend to be spatially homogenous within our region of study. Third, we had highly accurate information on the time of hospital presentation but not about the timing of actual symptom onset, and hence could not account for the variable duration of time that patients experienced headaches before evaluation. Finally, because this study relied upon patients seen for headaches requiring emergency evaluation, we cannot distinguish whether observed increases in risk related to temperature or barometric pressure reflect changes in the incidence of headaches or in their severity.

16.

17.

18.

Received October 9, 2008. Accepted in final form December 15, 2008. 19. REFERENCES 1. Carson AL, Rose KM, Sanford CP, et al. Lifetime prevalence of migraine and other headaches lasting 4 or more hours: the Atherosclerosis Risk in Communities (ARIC) study. Headache 2004;44:20–28. 2. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001;41:646–657. 3. Goldberg LD. The cost of migraine and its treatment. Am J Manag Care 2005;11:S62–67. 4. Prince PB, Rapoport AM, Sheftell FD, Tepper SJ, Bigal ME. The effect of weather on headache. Headache 2004; 44:596–602. 5. Osterman PO, Lundberg PO, Lundquist S, Lovstrand KG, Muhr C. Weekly periodicity of headache and the effect of changes in weather on headache. Ups J Med Sci Suppl 1980;31:23–26. 6. Szyszkowicz M. Air pollution and daily emergency department visits for headache in Montreal, Canada. Headache 2008;48:417–423. 7. Villeneuve PJ, Szyszkowicz M, Stieb D, Bourque DA. Weather and emergency room visits for migraine headaches in Ottawa, Canada. Headache 2006;46:64–72. 8. Peters A, Dockery DW, Muller JE, Mittleman MA. Increased particulate air pollution and the triggering of myocardial infarction. Circulation 2001;103:2810–2815. 9. Wellenius GA, Schwartz J, Mittleman MA. Air pollution and hospital admissions for ischemic and hemorrhagic stroke among medicare beneficiaries. Stroke 2005;36:2549–2553. 10. Wellenius GA, Schwartz J, Mittleman MA. Particulate air pollution and hospital admissions for congestive heart failure in seven United States cities. Am J Cardiol 2006;97: 404–408. 11. Rich DQ, Schwartz J, Mittleman MA, et al. Association of short-term ambient air pollution concentrations and ventricular arrhythmias. Am J Epidemiol 2005;161:1123–1132. 12. von Klot S, Wolke G, Tuch T, et al. Increased asthma medication use in association with ambient fine and ultrafine particles. Eur Respir J 2002;20:691–702. 13. Dominici F, Peng RD, Bell ML, et al. Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases. JAMA 2006;295:1127–1134. 14. Nattero G, Enrico A. Outdoor pollution and headache. Headache 1996;36:243–245. 15. Medina S, Le Tertre A, Quenel P, et al. Air pollution and doctors’ house calls: results from the ERPURS system for 926

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monitoring the effects of air pollution on public health in Greater Paris, France, 1991–1995: Evaluation des Risques de la Pollution Urbaine pour la Sante. Environ Res 1997; 75:73–84. Segala C, Poizeau D, Neukirch F, Aubier M, Samson J, Gehanno P. Air pollution, passive smoking, and respiratory symptoms in adults. Arch Environ Health 2004;59: 669–676. Diaz E, Smith-Sivertsen T, Pope D, et al. Eye discomfort, headache and back pain among Mayan Guatemalan women taking part in a randomised stove intervention trial. J Epidemiol Community Health 2007;61:74–79. Szyszkowicz M. Ambient air pollution and daily emergency department visits for headache in Ottawa, Canada. Headache 2008;48:417–423. Mittleman MA. Optimal referent selection strategies in case-crossover studies: a settled issue. Epidemiology 2005; 16:715–716. Peters A, Dockery DW, Muller JE, Mittleman MA. Increased particulate air pollution and the triggering of myocardial infarction. Circulation 2001;103:2810–2815. Gold DR, Litonjua A, Schwartz J, et al. Ambient pollution and heart rate variability. Circulation 2000;101:1267– 1273. Zanobetti A, Canner MJ, Stone PH, et al. Ambient pollution and blood pressure in cardiac rehabilitation patients. Circulation 2004;110:2184–2189. Rich DQ, Mittleman MA, Link MS, et al. Increased risk of paroxysmal atrial fibrillation episodes associated with acute increases in ambient air pollution. Environ Health Perspect 2006;114:120–123. Sarnat JA, Brown KW, Schwartz J, Coull BA, Koutrakis P. Ambient gas concentrations and personal particulate matter exposures: implications for studying the health effects of particles. Epidemiology 2005;16:385–395. Sarnat SE, Coull BA, Schwartz J, Gold DR, Suh HH. Factors affecting the association between ambient concentrations and personal exposures to particles and gases. Environ Health Perspect 2006;114:649–654. Maclure M, Mittleman MA. Should we use a casecrossover design? Annu Rev Public Health 2000;21:193– 221. Lumley T, Levy D. Bias in the case-crossover design: implications for studies of air pollution. Environmetrics 2000;11:689–704. Spierings EL, Ranke AH, Honkoop PC. Precipitating and aggravating factors of migraine versus tension-type headache. Headache 2001;41:554–558. Brewerton TD, George MS. A study of the seasonal variation of migraine. Headache 1990;30:511–513. Salvesen R, Bekkelund SI. Migraine, as compared to other headaches, is worse during midnight-sun summer than during polar night: a questionnaire study in an Arctic population. Headache 2000;40:824–829. Alstadhaug KB, Salvesen R, Bekkelund SI. Seasonal variation in migraine. Cephalalgia 2005;25:811–816. Woodhouse PR, Khaw KT, Plummer M. Seasonal variation of blood pressure and its relationship to ambient temperature in an elderly population. J Hypertens 1993;11: 1267–1274. Chifamba J, Mufunda J, Sigola LB, Matenga JA, Sparks HV. Effect of variation in environmental temperature

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Mild cognitive impairment Loss of linguistic task-induced changes in motor cortex excitability

L. Bracco, MD F. Giovannelli, PsyD V. Bessi, MD A. Borgheresi, MD A. Di Tullio, RhD S. Sorbi, MD G. Zaccara, MD M. Cincotta, MD

Address correspondence and reprint requests to Dr. Massimo Cincotta, U.O. di Neurologia, Azienda Sanitaria di Firenze, Ospedale Piero Palagi, Viale Michelangiolo, 41, 50125 Firenze, Italy [email protected]

ABSTRACT

Background: In amnestic mild cognitive impairment (aMCI), functional neuronal connectivity may be altered, as suggested by quantitative EEG and neuroimaging data. In young healthy humans, the execution of linguistic tasks modifies the excitability of the hand area of the dominant primary motor cortex (M1hand), as tested by transcranial magnetic stimulation (TMS). We used TMS to investigate functional connectivity between language-related cortical areas and M1hand in aMCI.

Methods: Ten elderly women with aMCI and 10 age-matched women were recruited. All participants were right handed and underwent a neuropsychological evaluation. In the first TMS experiment, participants performed three different tasks: reading aloud, viewing of non-letter strings (baseline), and nonverbal oral movements. The second experiment included the baseline condition and three visual searching/matching tasks using letters, geometric shapes, or digits as target stimuli. Results: In controls, motor evoked potentials (MEP) elicited by suprathreshold TMS of the left M1hand were significantly larger during reading aloud (170% baseline) than during nonverbal oral movements, whereas no difference was seen for right M1hand stimulation. Similarly, MEP elicited by left M1hand stimulation during letter and shape searching/matching tasks were significantly larger compared to digit task. In contrast, linguistic task performance did not produce any significant MEP modulation in patients with aMCI, although neuropsychological evaluation showed normal language abilities.

Conclusions: Findings suggest that functional connectivity between the language-related brain regions and the dominant M1hand may be altered in amnestic mild cognitive impairment. Follow-up studies will reveal whether transcranial magnetic stimulation application during linguistic tasks may contribute to characterize the risk of conversion to Alzheimer disease. Neurology® 2009;72:928–934 GLOSSARY AD ⫽ Alzheimer disease; aMCI ⫽ amnestic mild cognitive impairment; ANOVA ⫽ analysis of variance; FDI ⫽ first dorsal interosseous; M1 ⫽ primary motor cortex; MEP ⫽ motor evoked potentials; MMSE ⫽ Mini-Mental State Examination; pvIQ ⫽ premorbid verbal intelligence; RMT ⫽ resting motor threshold; TMS ⫽ transcranial magnetic stimulation.

In amnestic mild cognitive impairment (aMCI), conversion rate to Alzheimer disease (AD) is markedly increased compared to healthy subjects, although some patients never progress to dementia.1 Neuropathologic2 and EEG data3 support the hypothesis that aMCI may represent preclinical AD. Accordingly, ApoE ␧4 allele frequency is similar in aMCI and AD.4 There is growing evidence that AD includes a cortical disconnection syndrome.5 Although it is an open question whether neocortical disconnection is a feature of early neurodegenerative processes preceding AD, recent EEG3,6 and neuroimaging data7-10 suggest that abnormal functional connectivity can be present even in aMCI . Transcranial magnetic stimulation (TMS) allows multiparametric evaluation of primary motor cortex (M1) excitability in normally and pathologically aging brain.3,11 Resting motor

From the Department of Neurological and Psychiatric Sciences (L.B., V.B., A.D.T., S.S.), University of Florence; and the Unit of Neurology (F.G., A.B., G.Z., M.C.), Florence Health Authority, Florence, Italy. The Department of Neurological and Psychiatric Sciences, University of Florence, was supported by a grant from Regione Toscana (grant no. 734). The Unit of Neurology of the Florence Health Authority was supported by a grant from Ente Cassa di Risparmio di Firenze, Florence, Italy. Disclosure: The authors report no disclosures. 928

Copyright © 2009 by AAN Enterprises, Inc.

Table

Demographic and neuropsychological data Control group (n ⴝ 10)

MCI patients (n ⴝ 10)

p

Age, y

68 ⫾ 6.8

70.0 ⫾ 4.4

NS

Education, y

9.4 ⫾ 4.7

8.0 ⫾ 3.4

NS

104.9 ⫾ 6.3

NS

related modulation of corticomotoneuronal excitability was evaluated in a group of women with aMCI and in age- matched and sex-matched healthy controls.

Digit Span

3.8 ⫾ 1.4

3.4 ⫾ 0.6

NS

Corsi Tapping Test

5.1 ⫾ 1.3

4.5 ⫾ 1.2

NS

METHODS Subjects. Ten right-handed women with aMCI and 10 right-handed, age-matched, and education-matched women were recruited (table). We enrolled only women to prevent gender-related factors from influencing findings. The women had no history of implanted metal devices and gave written informed consent to the study, which was approved by the local ethics committee. aMCI diagnosis was based on unanimously adopted criteria: 1) memory complaint usually corroborated by an informant, 2) objective memory impairment for age, that is a score below the cutoff in at least one task exploring episodic memory, 3) normal scores in the other neuropsychological tests, 4) largely intact functional activities, and 5) absence of dementia.1 Handedness was assessed by the Edinburgh inventory.19 All subjects received a thorough clinical history, neurologic examination, laboratory tests, and brain MRI to exclude hydrocephalus, intracranial mass, infarcts, and moderate to severe nonspecific white matter disease. ApoE genotype20 was tested in all patients and 7 out of 10 healthy volunteers. No subject was on cholinesterase inhibitor or anticholinergic treatment.

Copy Drawing

15.5 ⫾ 0.5

13.9 ⫾ 2.1

NS

Neuropsychological measures. Neuropsychological evalua-

Token Test

34.1 ⫾ 1.4

31.9 ⫾ 2.6

NS

105.5 ⫾ 11.0

Premorbid verbal intelligence

29.4 ⫾ 1.1

27.4 ⫾ 1.9

Information Memory Concentration Test

32.5 ⫾ 2.3

31.7 ⫾ 1.8

NS

Five Words Acquisition

13.3 ⫾ 1.6

11 ⫾ 3.4

NS

Mini-Mental State Examination

0.02

Five Words 10’ Recall

19.3 ⫾ 1.1

18.1 ⫾ 2.5

NS

24-Hour Delayed Five Words Recall

16.5 ⫾ 2.1

14.3 ⫾ 3.2

NS NS

Paired Words Acquisition

15.9 ⫾ 3.2

12.1 ⫾ 4.5

Paired Words 10’ Recall

23.9 ⫾ 0.4

20.9 ⫾ 2.9

24-Hour Delayed Paired Words Recall

22.4 ⫾ 1.2

19.2 ⫾ 3.5

Short Story Immediate Recall

10.6 ⫾ 4.8

6.5 ⫾ 3.7

Short Story Delayed Recall

13.9 ⫾ 3.5

7.5 ⫾ 5.0

33 ⫾ 4.5

30.0 ⫾ 5.1

24.3 ⫾ 5.5

12.9 ⫾ 2.8

9.7 ⫾ 0.8

8.3 ⫾ 3.1

Rey-Osterrieth Complex Figure (copy) Rey-Osterrieth Complex Figure (recall) Rivermead Behavioural Memory Test

0.01 0.03 NS 0.007 NS ⬍0.01 NS

Category Fluency Test

39.8 ⫾ 0.7

40.0 ⫾ 0.0

NS

Phonemic Fluency

40.9 ⫾ 6.3

34.8 ⫾ 8.0

NS

Dual Task

87.7 ⫾ 6.7

92.5 ⫾ 7.0

NS

Trail Making Test (B-A)

22.5 ⫾ 73.2

64.7 ⫾ 57.1

NS

Values are expressed as mean ⫾ SD. All test scores were adjusted for each subject’s age and education level. MCI ⫽ mild cognitive impairment.

threshold (RMT) and afferent inhibition of motor evoked potentials (MEP) by peripheral nerve inputs at short intervals (SAI) were reduced in AD.12-14 However, neither RMT nor SAI were significantly altered in MCI.15 In healthy young subjects, reading aloud and movement-free letter and geometric shape recognition increased MEP size in the dominant hand.16-18 Lack of spinal excitability changes suggested that linguistic task-induced MEP facilitation occurred at the cortical level.16 Therefore, TMS represents a potential tool to test functional connections between language-related cortical areas and the dominant hand area of M1 (M1hand). We speculated that, if aMCI is associated with altered cortical connectivity, TMS could contribute to reveal this functional derangement. To test this hypothesis, linguistic task-

tion (table) included an extensive battery testing global cognitive functions, verbal and spatial short- and long-term memory, language, and visuomotor functions.21 Visuospatial long-term memory was evaluated by the Rey-Osterrieth Complex Figure22 and everyday memory by the Rivermead Behavioral Memory Test.23 Attention/executive functions were assessed by Stroop Test,24 Dual Task,25 Phonemic Fluency test,26 and Trail Making A-B Test.27 Premorbid verbal intelligence (pvIQ) was estimated by a reading task representing an Italian version of the National Adult Reading Test.28

Recordings and stimulation. Subjects were seated in a comfortable chair with their arms fully supported. Surface EMG was recorded from both first dorsal interosseous (FDI) muscles, amplified, analog filtered (20 –2,000 Hz), and digitized (A/D rate 5,000 Hz) by a micro 1401 unit and signal 2 software (Cambridge Electronic Design, UK). Focal TMS of either M1hand was delivered using a Magstim 200 stimulator (Magstim Co., UK) connected to an eight-shaped coil placed at the optimal position to elicit MEP in the contralateral FDI, with the handle pointing backwards and 45° away from the midline. The resting motor threshold (RMT), defined as the minimum stimulus intensity producing MEP ⬎50 ␮V in peak-to-peak amplitude in 50% of 10 trials at rest, was measured in either FDI. Then, for either M1hand, TMS intensity was adjusted to elicit MEP of about 0.5–1 mV in peak-to-peak amplitude in the relaxed contralateral FDI when the subject performed no linguistic task. This stimulus intensity (110 –120% individual RMT) was used in each condition. Throughout recordings, FDI relaxation was monitored online by acoustic feedback from high-gain EMG. Procedures of TMS experiments. In each subject, the excitability of either M1hand was evaluated during two different experimental paradigms: a reading aloud protocol (adapted from Meister et al.17) and a visual searching-matching protocol (adapted from Papathanasiou et al.18). Neurology 72

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The reading aloud protocol consisted of three tasks: main task, baseline, and control condition. In the main task (reading aloud), high-frequency Italian bisyllabic concrete nouns (e.g., “casa,” c.f. English, “house”) were displayed separately on a computer screen. The subject was requested to read aloud each word as soon as it appeared. As a baseline condition, meaningless figures matching the word letters in font size were presented. The subjects were instructed to view each string of non-letter figures passively. In the control condition (nonverbal oral movement), the subject was requested to purse the lips repetitively without vocalization as soon as a black circle appeared on the screen. A magnetic pulse was applied to the right or left M1hand 600 msec after the onset of word, non-letter figure, or black circle presentation. The visual searching-matching protocol consisted of four conditions. At the baseline, the subject was requested to remain fully relaxed without performing linguistic tasks. In the three searching-matching tasks, the items were the capital letters of the Italian alphabet (letters), digits ranging from 0 to 9 (digits), and geometric shapes (squares, circles, triangles, and diamonds) (shapes). In each task, items were randomly mixed and printed on a sheet of A4 size paper in 10 rows with 14 graphemes each. The sheet was fixed 40 cm from subjects. Subjects were instructed to scan each row as during usual reading, and to identify a predefined target item for each task (A, 8, or triangle). Once a target item was recognized, scanning has to be continued for recognition of further targets. In both protocols, the interval between two consecutive magnetic pulses was ⱖ5 s. In each experimental condition, 12 traces were recorded for each FDI. The largest and the smallest MEP were discarded and the mean MEP peak-to-peak amplitude was calculated from the remaining traces. The order of experimental conditions and right or left M1hand stimulation was randomized and counterbalanced across subjects, except for the baseline condition in the searching-matching protocol. In this protocol, the baseline evaluation was performed before and after the searching-matching tasks to test stability of baseline M1hand excitability.18 As paired t test revealed no difference between the measures obtained in the two baseline blocks, data were pooled for further analysis.

Data analysis. Neuropsychological test scores were compared between with MCI and controls using a two-tailed unpaired t test. The reading aloud and the visual searching-matching protocol data were analyzed separately. To confirm the homogeneity of test stimulus intensity, RMT and baseline MEP amplitude values were entered in mixed analyses of variance (ANOVA) with group (controls and patients) as between-subjects factor and hemisphere as within-subject factor. Then, the mean amplitude of the MEP recorded during each active condition was expressed as percentage of the baseline and used as primary measure. To test whether the excitability of either M1hand was differentially modulated by linguistic tasks, data obtained in each group were entered in a two-way repeated-measures ANOVA with hemisphere and condition as within-subject factors. To evaluate whether the modulation of left M1hand excitability produced by linguistic tasks in controls was significantly altered in patients with MCI, data were analyzed by a mixed ANOVA design with group as between-subjects factor and condition as within-subject factor. Finally, to test whether the effects of linguistic tasks on left M1hand excitability were influenced by the ApoE ␧4 status, data obtained in patients with MCI were analyzed by a mixed ANOVA design with group (ApoE ␧4-positive 930

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and ApoE ␧4-negative patients) as between-subjects factor and condition as within-subject factor. Post hoc tests were performed using Tukey test. For graphical presentation of individual MEP sizes, values were z-transformed relative to the baseline.18 In experimental conditions modulating the M1hand excitability, the Pearson correlation coefficient was used to investigate the relationships between individual neuropsychological task scores and MEP size and between RMT and MEP size. Significance was set at p ⬍ 0.05. RESULTS Clinical and neuropsychological data. Demographic and neuropsychological data are reported in the table. Patients with MCI presented a mean memory impairment duration of 6.8 ⫾ 4.3 (SD) years (range 2–17 years) and have been followed for 3.9 ⫾ 2.0 years. Brain MRI showed mild ventricular and sulcal enlargement in four patients with MCI, whereas no brain atrophy was seen in the other six patients. Patients with MCI scored significantly lower than controls only on Mini-Mental State Examination (MMSE), and delayed recall of both verbal (Paired Words Recall after 10= and 24-hour, Short Story Delayed Recall) and visuospatial (Rey-Osterrieth Complex Figure Recall) memory tasks. No difference emerged on semantic and phonemic verbal fluency and on verbal comprehension as evaluated by Token Test. The pvIQ did not differ between groups, indicating preserved general intelligence and reading capacity in patients with MCI. In the MCI group, the proportion of ApoE ␧4 carriers (50%) was larger than in controls (29%).

TMS experiments. None of the participants reported

adverse reactions during or after the experiments. Mixed ANOVA showed no significant main effect or interaction of group and hemisphere on RMT, test stimulus intensity, or baseline MEP amplitude. Reading aloud protocol. In healthy volunteers, there

was a significant interaction between condition and hemisphere on MEP size (F1,9 ⫽ 5.609, p ⫽ 0.042). The main effects of condition or hemisphere were not significant, although a strong trend toward significance was seen for condition (F1,9 ⫽ 5.032, p ⫽ 0.052). Post hoc tests revealed that, for left M1hand stimulation, MEP size during reading aloud (170% baseline) was significantly larger than during nonverbal oral movements (117% baseline), whereas no significant difference between main and control conditions was seen for TMS of the right M1hand (figure 1A). During reading aloud, the MEP elicited by TMS of the left M1hand was larger than the MEP evoked by right M1hand stimulation (figure 1A), although this difference did not reach significance. In patients with MCI, repeated-measures ANOVA showed no significant main effect or interaction of

Figure 1

Effects of linguistic tasks on motor cortex excitability

(A) Reading aloud protocol: amplitude of the motor evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS) of either the left or right M1hand during the main task (reading aloud) and in the control condition (nonverbal oral movements). Values are expressed as a percentage of the baseline (passive viewing of non-letter figures). Each column corresponds to the mean and the bars to the SE values. Asterisk indicates a significant difference between experimental conditions (p ⬍ 0.05, two-way repeated-measures analysis of variance and post hoc Tukey tests). In the control group, the size of the MEP evoked by left M1hand stimulation was larger during reading aloud than during nonverbal oral movements, whereas no difference was seen for TMS of the right M1hand. In contrast, no significant MEP size modulation was observed in patients with mild cognitive impairment (MCI). (B) Visual searching-matching protocol: amplitude of the MEP elicited by TMS of either the left or right M1hand during letters, digits, and shapes tasks. Values are expressed as a percentage of the baseline condition. For further arrangement and conventions, see (A). In the control group, the size of the MEP evoked by left M1hand stimulation during letters and shapes tasks was significantly larger than in digits condition, whereas no difference was seen for TMS of the right M1hand. In contrast, no MEP size modulation was observed in patients with MCI.

condition and hemisphere (figure 1A). Mixed ANOVA showed a significant interaction between condition and group (F2,36 ⫽ 10.570, p ⫽ 0.004), whereas the main factors were not significant. Post hoc tests revealed that, during reading aloud, the amplitude of the MEP elicited by left M1hand stimulation was significantly lower in patients with MCI (107% baseline) than in controls. Mixed ANOVA showed no significant difference in MEP size between ApoE ␧4-positive and ApoE ␧4-negative patients with MCI. Visual searching-matching protocol. In controls, the main effect of condition on MEP amplitude and the interaction between condition and hemisphere were significant (F2,18 ⫽ 5.462, p ⫽ 0.014 and F2,18 ⫽ 5.326, p ⫽ 0.015), whereas no main effect of hemi-

sphere was seen. Post hoc tests revealed that, for left M1hand stimulation, MEP amplitudes during letters and shapes tasks (166% and 156% baseline) were significantly larger compared to digits task (102% baseline), whereas no significant difference between letters, shapes, and digits was seen for right M1hand stimulation (figure 1B). During letters and shapes tasks, the MEP elicited by TMS of the left M1HAND was larger than the MEP evoked by right M1hand stimulation (figure 1B). This difference was significant for letters, but not for shapes. In patients with MCI, no significant main effect or interaction of condition and hemisphere was observed (figure 1B). Mixed ANOVA showed that the main effect of condition and group, and the interaction between these two factors, were significant (F1,18 ⫽ 5.571, p ⫽ 0.008; F1,18 ⫽ 5.279, p ⫽ 0.034; F1,18 ⫽ 5.152, p ⫽ 0.011). Post hoc tests revealed that, for left M1hand stimulation, the MEP size during letters and shapes tasks was significantly lower in patients with MCI (88% and 105% baseline) than in the control group. Mixed ANOVA did not show any significant difference in MEP size between ApoE ␧4-positive and ApoE ␧4-negative patients with MCI. In either patients with MCI or healthy volunteers, no significant correlation was seen between the RMT and the size of MEP recorded during linguistic tasks modulating left M1hand excitability in controls (reading aloud and letters and shapes). In 7 out of 10 controls, MEP amplitude was above the mean baseline size during each one of the three tasks, producing significant effects on M1hand excitability (figure 2). In contrast, the unique patient with MEP size above the baseline in each experimental condition (P1) was the one with the longest history of MCI (17 years) without conversion to dementia (figure 2). Relationship between TMS and neuropsychological data. In patients with MCI, no significant correlation

was seen between the size of MEP recorded during linguistic tasks normally modulating left M1hand excitability in controls and the altered neuropsychological measures (i.e., MMSE and delayed recall of memory tasks) or the normal scores obtained in neuropsychological tests exploring linguistic functions. The novel finding is that the enhancement of dominant M1hand excitability during specific linguistic tasks, as tested by TMS procedures already adopted in healthy young humans,17,18 is preserved in normal elderly group but is suppressed in patients with aMCI. In healthy elderly, MEP size enhancement during reading aloud and movement-free recognition of letter and geometric shapes does not reflect a nonspecific arousal effect because it was not seen during DISCUSSION

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Figure 2

Individual values of motor evoked potential (MEP) size obtained in the right first dorsal interosseous muscle during tasks producing a significant modulation of the left M1hand excitability in either the reading aloud or the visual searching-matching protocol (reading aloud, letters, and shapes tasks)

In each control subject (A) and patient with mild cognitive impairment (MCI) (B), values are expressed as z-scores relative to the baseline using the formula z ⫽ (A ⫺ B)/SD B , where A and B are the individual amplitudes in the active and baseline conditions, while SD B is the SD of baseline amplitude.

nonverbal oral movements or digit recognition. All patients with aMCI and age-matched healthy volunteers were right-handed women. Hence, different TMS findings between aMCI and control groups cannot be due to manual dominance-related or gender-related differences in hemispheric asymmetry or language abilities. Computer-based human brain model data suggest that prominent cortical atrophy may alter the site and population of neural elements stimulated by TMS.29 However, in our aMCI group, only four patients had minimal brain atrophy. In addition, neither RMT and baseline MEP amplitude nor test stimulus intensity differed between patients with aMCI and controls or between the dominant and nondominant M1hand. Therefore, it is very unlikely that these results depended on the effects of atrophy on TMS or on altered corticomotoneuronal excitability in patients with aMCI. Linguistic skills, as evaluated by Category and Phonemic Fluency and by Token Test, were similar in patients and controls. Furthermore, no difference emerged in pvIQ as tested by a reading task,28 confirming preserved reading abilities in our aMCI group. Accordingly, in patients with aMCI, individual MEP amplitudes 932

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during linguistic tasks were not related to the neuropsychological measures of language functions. Hence, it is unlikely that, in our patients with aMCI, the loss of linguistic task-induced MEP size modulation depended on a relevant direct derangement of Broca and Wernicke areas, which are the crucial nodes of language processing.30 In summary, these data suggest that in aMCI, the lack of the enhancement of dominant M1hand excitability normally induced by certain linguistic tasks likely reflects altered functional connectivity. This interpretation does not exclude the possibility that an increased effort to perform cognitive tasks in aMCI may have influenced our findings. One possibility is that in aMCI, functional connections between the language-related brain regions and the dominant M1hand are impaired because a compensatory reallocation of brain resources is required to maintain basic linguistic skills. Further investigation using linguistic tasks of different difficulties could help to resolve this issue. Abnormal brain connectivity is thought to be a prominent feature of AD.3,5,6,31,32 MCI is considered a transitional stage between normal elderly and AD1 and recent data support the view that disconnection be-

tween cerebral areas is already present in this early stage of neurodegeneration. Namely, fMRI studies suggest an impaired connectivity between hippocampal-based memory system and neocortex9,10 and MRI show reduced white matter volume in the parahippocampal gyrus.8 Furthermore, in aMCI, fMRI data document changes in the frontoparietal network subserving divided attention7 and quantitative EEG studies show altered global synchronization6 and frontoparietal coherence.3 Finally, MCI converters to AD show metabolic changes in the inferoparietal cortex,33 which is involved in the distributed neural network connecting Broca and Wernicke areas.34 The present TMS findings expand our knowledge about functional disconnection in prodromal stages of AD by suggesting an abnormal integration between the language-related cortical areas and the dominant M1hand in aMCI, although no direct information is provided about the anatomic circuitry underlying this process. The influence of co-speech gestures in understanding spoken language provides evidence for tight functional links between the brain areas mediating language processes and the M1hand.35 In deaf people using signing to communicate, manual language activates cortical areas that are similar, although not identical, to those recruited during spoken language in hearing subjects.36 In the ventral premotor cortex of nonhuman primates, a class of neurons (mirror neurons) discharge both when a monkey observes or executes an action.37 The mirror system is considered a neural substrate for the development of interindividual communication and, in an evolutionary scenario, has led to the theory of “gestural origin of language.”37 Neuroimaging and TMS studies suggest that a mirror neuron system also exists in humans and involves the Broca area.38 In keeping with this view, an articulation task may facilitate imitation of finger movements.39 The putative role of gesture in the development of spoken language highlights the neurobiological relevance of impaired functional connectivity between the language-related cortical areas and the M1hand in aMCI. Our results suggest that TMS could be a reliable noninvasive instrument to investigate neural connectivity in patients at risk for AD. Our aMCI group presented an increased proportion of ApoE ␧4 carriers with respect to controls, suggesting a higher probability of progression to AD. However, in the five ApoE ␧4-positive patients, the effect of linguistic tasks on M1hand excitability did not differ from that observed in the five ApoE ␧4-negative patients. Nevertheless, the unique patient with a more than 10-year history of aMCI without conversion to dementia was the only one showing a normal pattern of MEP modulation during each linguistic task. It has

been shown that EEG coherence analysis3 and fluorodeoxyglucose PET33 may help to distinguish patients with MCI who progress into AD from stable patients with MCI at the group level. Further follow-up studies are needed to verify whether the evaluation of linguistic task-related modulation of corticomotoneuronal excitability may represent a complimentary tool to characterize the risk of conversion to dementia in clinical settings. AUTHOR CONTRIBUTIONS Statistical analysis was conducted by F. Giovannelli and M. Cincotta.

Received September 18, 2008. Accepted in final form December 16, 2008. REFERENCES 1. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256:183–194. 2. Bennett DA, Schneider JA, Bienias JL, Evans DA, Wilson RS. Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology 2005; 64:834–841. 3. Rossini PM, Rossi S, Babiloni C, Polich J. Clinical neurophysiology of aging brain: from normal aging to neurodegeneration. Prog Neurobiol 2007;83:375–400. 4. Orsitto G, Seripa D, Panza F, et al. Apolipoprotein E genotypes in mild cognitive impairment subtypes. J Am Geriatr Soc 2006;54:1965–1966. 5. Delbeuck X, Van der Linden M, Collette F. Alzheimer’s disease as a disconnection syndrome? Neuropsychol Rev 2003;13:79–92. 6. Koenig T, Prichep L, Dierks T, et al. Decreased EEG synchronization in Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 2005;26:165–171. 7. Dannhauser TM, Walker Z, Stevens T, Lee L, Seal M, Shergill SS. The functional anatomy of divided attention in amnestic mild cognitive impairment. Brain 2005;128: 1418–1427. 8. Stoub TR, DeToledo-Morrell L, Stebbins GT, Leurgans S, Bennett DA, Shah RC. Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer’s disease. Proc Natl Acad Sci USA 2006;103: 10041–10045. 9. Celone KA, Calhoun VD, Dickerson BC, et al. Alterations in memory networks in mild cognitive impairment and Alzheimer’s disease: an independent component analysis. J Neurosci 2006;26:10222–10231. 10. Sorg C, Riedl V, Mu¨hlau M, et al. Selective changes of resting-state networks in individuals at risk for Alzheimer’s disease. Proc Natl Acad Sci USA 2007;104:18760–18765. 11. Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol 2003;2:145–156. 12. Ferreri F, Pauri F, Pasqualetti P, Fini R, Dal Forno G, Rossini PM. Motor cortex excitability in Alzheimer’s disease: a transcranial magnetic stimulation study. Ann Neurol 2003;53:102–108. 13. Di Lazzaro V, Oliviero A, Pilato F, et al. Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004; 75:555–559. 14. Di Lazzaro V, Oliviero A, Tonali PA, et al. Noninvasive in vivo assessment of cholinergic cortical circuits in AD using Neurology 72

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transcranial magnetic stimulation. Neurology 2002;59: 392–397. Sakuma K, Murakami T, Nakashima K. Short latency afferent inhibition is not impaired in mild cognitive impairment. Clin Neurophysiol 2007;118:1460–1463. Tokimura H, Tokimura Y, Oliviero A, Asakura T, Rothwell JC. Speech-induced changes in corticospinal excitability. Ann Neurol 1996;40:628–634. Meister IG, Boroojerdi B, Foltys H, Sparing R, Huber W, Topper R. Motor cortex hand area and speech: implications for the development of language. Neuropsychologia 2003;4:401–406. Papathanasiou I, Filipovic SR, Whurr R, Rothwell JC, Jahanshahi M. Changes in corticospinal motor excitability induced by non-motor linguistic tasks. Exp Brain Res 2004;154:218–225. Oldfield RC. The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychology 1971;9:97–113. Sorbi S, Nacmias B, Forleo P, et al. ApoE allele frequencies in Italian sporadic and familial Alzheimer’s disease. Neurosci Lett 1994;177:100–102. Bracco L, Amaducci L, Pedone D, et al. Italian Multicentre Study on Dementia (SMID): a neuropsychological test battery for assessing Alzheimer’s disease. J Psychiatr Res 1990;24:213–226. Rey A. L’examen psychologique dans les cas d’encephalopathie traumatique. Arch Psychol 1941;28:286–340. Wilson B, Cockburn J, Baddeley A, Hiorns R. The development and validation of a test battery for detecting and monitoring everyday memory problems. J Clin Exp Neuropsychol 1989;11:855–870. Stroop JR. Studies of interference in serial verbal reaction. J Exp Psychol 1935;18:643–662. Baddeley A, Della Sala S, Papagno C, Spinnler H. Dualtask performance in dysexecutive and nondysexecutive patients with a frontal lesion. Neuropsychology 1997;11: 187–194. Novelli G, Pagano C, Capitani E. Tre test di ricerca e produzione lessicale. Archiv Psicol Neurol Psichiatr 1986; 47:477–506.

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Giovagnoli AR, Del Pesce M, Mascheroni S, Simoncelli M, Laiacona M, Capitani E. Trail making test: normative values from 287 normal adult controls. Ital J Neurol Sci 1996;17:305–309. Colombo L, Sartori G, Brivio C. Stima del quoziente intellettivo tramite l’applicazione del TIB (test breve di Intelligenza). Giornale Italiano Psicologia 2002;3:613–637. Wagner T, Eden U, Fregni F, et al. Transcranial magnetic stimulation and brain atrophy: a computer-based human brain model study. Exp Brain Res 2008;186:539–550. Mesulam M. Imaging connectivity in the human cerebral cortex: the next frontier? Ann Neurol 2005;57:5–7. Schro¨der J, Buchsbaum MS, Shihabuddin L, et al. Patterns of cortical activity and memory performance in Alzheimer’s disease. Biol Psychiatry 2001;49:426–436. Grady CL, Furey ML, Pietrini P, Horwitz B, Rapoport SI. Altered brain functional connectivity and impaired shortterm memory in Alzheimer’s disease. Brain 2001;124: 739–756. Che´telat G, Desgranges B, de la Sayette, V Viader F, Eustache F, Baron JC. Mild cognitive impairment: can FDG-PET predict who is to rapidly convert to Alzheimer’s disease? Neurology 2003;60:1374–1377. Catani M, Jones DK, ffytche DH. Perisylvian language networks of the human brain. Ann Neurol 2005;57: 8–16. Willems RM, Hagoort P. Neural evidence for the interplay between language, gesture, and action: a review. Brain Lang 2007;101:278–289. Leva¨nen S, Uutela K, Salenius S, Hari R. Cortical representation of sign language: comparison of deaf signers and hearing non-signers. Cerebral Cortex 2001;11:506–512. Rizzolatti G, Arbib MA. Language within our grasp. Trends Neurosci 1998;21:188–194. Rizzolatti G, Craighero L. The mirror-neuron system. Annu Rev Neurosci 2004;27:169–192. Ku¨hn S, Brass M. Testing the connection of the mirror system and speech: how articulation affects imitation in a simple response task. Neuropsychologia 2008;46:1513– 1521.

Buy a Brain: Support Research in Neurology Make a donation to brain research and make a difference in lives of neurology patients. For each $5 donation to the AAN Foundation’s Brain Fund from now through the 2009 AAN Annual Meeting, you will receive a brain certificate. Add your name or the name of someone special to your certificate. Certificates will be displayed onsite at the Annual Meeting and donors/honorees will be recognized online. Buy a brain to invest in the future of neurology to support careers in research and better outcomes for patients. Buy a brain today at www.aan.com/buybrain!

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Neurology 72

March 10, 2009

Clinical/Scientific Notes

C. Del Borgo, MD S. Zaniratti, MD C. Minosse, MD A. Vetica, MD A. Bellini, MD F. Soscia, MD P. Missori, MD F. Pierelli, MD A. Curra`, MD, PhD

A CASE OF ACUTE POLYRADICULONEUROPATHY, DRUG-INDUCED HYPERSENSITIVITY, AND HHV-6 INFECTION

A 35-year-old man from India with a history of heavy alcohol abuse was admitted with jaundice, abdominal right quadrant pain, and mild fever. The physical examination showed enlarged liver and spleen, but normal peristalsis. Clinical and laboratory data (table) suggested cholangitis, treated with ceftriaxone, omeprazole, albumin, and vitamin K. CT documented liver steatosis and gallbladder sludge. Cholangio MRI and esophagogastroduodenoscopy showed normal findings. Two weeks later, because the mild fever persisted, ceftriaxone was switched to meropenem. At neurologic examination, the patient was awake, alert, and oriented. Cranial nerve function, muscle strength, sensory examination findings, motor coordination, muscle tone, and deep tendon and plantar reflexes were normal. Six days after the antibiotic switch, a diffuse rash developed, indicating a drug-induced hypersensitivity reaction. Meropenem was discontinued, and methylprednisolone plus antihistamine was started. Although corticosteroids resolved the rash, muscle strength diminished in the legs, and neurologic examination showed a rapidly evolving gait disturbance and areflexia, but normal cranial nerve function. A CSF sample contained no cells, protein 29 mg/dL, and glucose 61 mg/dL. Electrodiagnostic findings suggested acute inflammatory demyelinating sensorimotor polyradiculoneuropathy (AIDP). Sensory action potentials were absent in the lower limbs (left sural, right superficial peroneal), and severely reduced in the upper limbs (left and right ulnar). Conduction velocity was severely reduced on motor (left median, right peroneal) and sensory nerves (left and right ulnar). Motor conduction studies documented a right peroneal nerve block. Upper and lower limb compound motor action potentials were chronodispersed (slightly for left median nerve stimulation, markedly for left plantar medial nerve stimulation). Distal latencies were prolonged diffusely, and F-waves were absent (right peroneal), abnormally excitable, or severely delayed (left plantar medial 87 msec, right median 37 msec). Nee-

dle EMG showed no denervation, but did show a severely reduced lower limb recruitment pattern. CSF PCR assay was negative for cytomegalovirus (CMV), Epstein-Barr virus, varicella zoster virus, mumps virus, enterovirus, human T-lymphotrophic virus-I (HTLV-I), and JC virus but detected human herpesvirus 6 (HHV-6) DNA (3,480 copies/mL). Antibody assay in the undiluted CSF sample detected HHV-6 immunoglobulin M (IgM) and immunoglobulin G (IgG), but no HTLV-I IgM or IgG. Serum assays showed HHV-6 IgM and IgG titers (1:20 and ⱖ1.20), indicating active viral replication. MRI excluded brain or spinal cord abnormalities. Two days after the muscle weakness developed, the patient’s limbs became flaccid and swallowing became difficult. IV immunoglobulins reversed the neurologic deficit, and the patient was transferred for rehabilitation care. A positive CSF PCR HHV-6 assay in an adult immunocompetent patient with rapidly progressing polyradiculoneuropathy is a previously unreported finding raising interesting questions on the viral causes of peripheral nervous system (PNS) diseases. In our patient, the polyradiculoneuropathy developed after a rash induced by antibiotic therapy for acute liver disease. HHV-6 is a ubiquitous virus associated with various clinical conditions1 (exanthem infantum, fulminant hepatitis) that also participates in the drug-induced hypersensitivity syndrome.2 HHV-6 involving the nervous system usually affects the CNS3 (seizures, encephalitis/meningitis, and multiple sclerosis), and only recently has a primary childhood HHV-6 infection been proposed as a cause of acute inflammatory PNS diseases.4 Establishing the relationship between our adult patient’s infection and neuropathogenesis meant distinguishing whether the viral DNA in the CSF sample indicated viral reactivation or chromosomal HHV-6 integration.5 Several findings in our patient suggest viral reactivation rather than chromosomal integration. First, his CSF sample was acellular, and when the CSF cell count is less than 1 cell/mm3, only half the samples from subjects with chromosomally integrated virus contain detectable HHV-6 DNA. Second, the CSF sample contained HHV-6 IgM and Neurology 72

March 10, 2009

935

Table

Laboratory values at admission

Hematologic and chemical values

Serum virology

Analyte

Value

Results

Hematocrit

25%

HIV negative

Mean corpuscular volume

102 ␮m3

HTLV-I negative 3

White cell count

18,300/mm

Neutrophils

77%

HBsAg negative

Lymphocytes

9.2%

EBV negative

Eosinophils

4%

Platelet count

232,000/mm

Fibrinogen

390 mg/dL

Prothrombin time

31 s

Urea nitrogen

19 mg/dL

Creatinine

1.1 mg/dL

Ammonia

42 mmol/mL

Glucose

86 mg/dL

Total bilirubin

12.8 mg/dL

Conjugated bilirubin

8.1 mg/dL

Aspartate aminotransferase

161 U/L

Alanine aminotransferase

64 U/L

HCV negative

CMV negative 3

HSV-1 negative HSV-2 negative

HTLV ⫽ human T-cell lymphotrophic virus; HCV ⫽ hepatitis C virus; EBV ⫽ Epstein-Barr virus; CMV ⫽ cytomegalovirus; HSV ⫽ herpes simplex virus.

IgG. Third, serum contained increased HHV-6 IgM. Remarkably, HHV-6 is closely related to CMV, the second most commonly found infection preceding Guillain-Barre´ syndrome, and its most common viral trigger.6 The normal CSF protein content in our patient seemingly contrasts with evidence that about 80% of patients with AIDP have raised CSF protein concentrations. One explanation is that we collected our patient’s CSF sample in the early days of illness, a time when protein content is often normal.7 Measurement of potassium, phosphate, and porphyrin metabolism products helped to exclude alternative diagnoses. Stool sample cultures excluded Campylobacter jejuni enteritis. In addition, the neurologic examination on admission failed to disclose the cognitive disturbances typical of some alcohol-related

Christopher M. DeGiorgio, MD Diana Murray Daniela Markovic, MS Todd Whitehurst, MD

936

acute reactions, thus arguing against a history of alcohol abuse, and lacked the signs of distal symmetric axonal polyneuropathy typically found in heavy chronic alcohol users. Viral reactivation of a latent HHV-6 infection may be among the causative or precipitating factors of acute inflammatory PNS diseases. From the Infectious Disease Unit (C.D.B., A.V., F.S.) and Neurology Unit (A.B.), Ospedale S. Maria Goretti, Latina; Virology (S.Z., C.M.), Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, Rome; Department of Neurological Sciences, Neurosurgical Unit, Ospedale S. Maria Goretti (P.M.), Department of ENT and Neurology, Neurorehabilitation Unit, ICOT (F.P.), and Department of Neurological Sciences, Neurology Unit, Ospedale A. Fiorini Terracina (A.C.), Sapienza University of Rome, Polo Pontino, Italy. Disclosure: The authors report no disclosures. Received August 19, 2008. Accepted in final form November 10, 2008. Address correspondence and reprint requests to Dr. Antonio Curra`, Department of Neurological Sciences, Neurology Unit, Ospedale A. Fiorini Terracina, LT, Sapienza University of Rome, Polo Pontino, Italy; [email protected] Copyright © 2009 by AAN Enterprises, Inc. 1. 2.

3.

4.

5.

6.

7.

Levy JA. Three new human herpesviruses (HHV6, 7, and 8). Lancet 1997;349:558–563. Morimoto T, Sato T, Matsuoka A, et al. Trimethoprimsulfamethoxazole-induced hypersensitivity syndrome associated with reactivation of human herpesvirus-6. Intern Med 2006;45:101–105. Gilden DH, Mahalingam R, Cohrs RJ, Tyler KL. Herpesvirus infections of the nervous system. Nat Clin Pract Neurol 2007;3:82–94. Miyake F, Yoshikawa T, Suzuki K, Ohashi M, Suga S, Asano Y. Guillain-Barre´ syndrome after exanthem subitum. Pediatr Infect Dis J 2002;21:569–570. Ward KN, Leong HN, Thiruchelvam AD, Atkinson CE, Clark DA. Human herpesvirus 6 DNA levels in cerebrospinal fluid due to primary infection differ from those due to chromosomal viral integration and have implications for diagnosis of encephalitis. J Clin Microbiol 2007;45:1298–1304. Hadden RD, Karch H, Hartung HP, et al. Preceding infections, immune factors, and outcome in Guillain-Barre syndrome. Neurology 2001;56:758–765. Paradiso G, Tripoli J, Galicchio S, Fejerman N. Epidemiological, clinical, and electrodiagnostic findings in childhood Guillain-Barre´ syndrome: a reappraisal. Ann Neurol 1999;46:701–707.

TRIGEMINAL NERVE STIMULATION FOR EPILEPSY: LONG-TERM FEASIBILITY AND EFFICACY

of external TNS for epilepsy.

Neurostimulation has emerged as a viable alternative for intractable epilepsy. Trigeminal nerve stimulation (TNS), a novel form of neurostimulation, has an antiepileptic effect in a rodent model.1 The superficial location of trigeminal branches allows for minimally invasive approaches, allowing assessment of response prior to a permanent device.2 We report the long-term safety and efficacy

Methods. Research committee approval was obtained for an open study of external TNS in epilepsy. Informed consent was obtained before enrollment. Inclusion/exclusion criteria were age 18 – 65 years, ⱖ3 complex-partial/generalized tonic-clonic seizures/month, no progressive medical conditions, and exposure to ⱖ2 antiepileptic drugs (AEDs). Subjects enrolled in a 4-week pretreatment baseline, and were

Neurology 72

March 10, 2009

Figure

Adjusted mean daily seizure rate across time

Bars indicate standard error ⫽ 0.64.

evaluated at 1, 2, 3, 6, and 12 months. AEDs remained unchanged unless essential for patient safety. Neurostimulation was initially supplied using the analog EMS Model 400, and later a digital EMS model 7500.2 Stimulation settings were as follows: frequency 120 Hz, 250 ␮s, ⱕ30 seconds on, ⱕ30 seconds off for 12–24 hours/day, and 1.25-inch disposable, silver-gel, adhesive electrodes were utilized, spaced 2 inches apart. Subjects 1–3 were initiated with infraorbital stimulation (V2), but subjects found this awkward for chronic use. Since then, we have stimulated the ophthalmic nerve (V1) in all subjects, which allows bilateral stimulation and can be concealed by a cap. See figure e-1 on the Neurology® Web site at www.neurology.org for a diagram of the device and electrode placement. Statistical analysis. We compared mean seizure rates over time using a repeated measure analysis of variance (ANOVA) model. After confirming that missing data were missing at random, we used multiple imputation to replace missing values for daily seizure rate with a set of imputed values in patients who did not complete the study. The imputation was carried out under the repeated measure ANOVA model. The resulting variances of the means reflect not only the variation in the observed data but also the added uncertainty of using partially imputed information. It is preferable to impute missing values rather than omit patients with incomplete data entirely. Four imputed values were generated for each missing value. All analyses were carried out using SAS version 9.1. A p value of 0.05 was chosen for significance. Supplemental data at www.neurology.org

Results. Thirteen subjects completed the 4-week prospective baseline. Twelve completed 3 months, 10 completed 6 months, and 7 completed 12 months (table e-1). Short-term results from the first seven subjects reported previously are included in this analysis.2 The fig-

ure shows results at 3, 6, and 12 months. At 3 months, mean seizure frequency was reduced from a baseline of 2.1 seizures/day to 0.71 seizures/day (66% reduction, p ⫽ 0.034, standard error 0.64). At 6 months, mean seizure frequency was 0.92 seizures/day (56% reduction, p ⫽ 0.073, standard error 0.64). At 12 months, mean seizure frequency was 0.86 seizures/day (59% reduction, p ⫽ 0.058, standard error 0.64). Five subjects experienced greater than 50% reduction at 6 and 12 months; one subject had ⬎90% reduction at 12 months. TNS was well tolerated. Side effects included skin irritation in five subjects, which improved by reducing stimulation to 12–16 hours/day, or with hydrocortisone 1% cream. Tingling, forehead pressure, and headache were reported, but improved with reduction of current. No effect on pulse, blood pressure, or ECG was detected. Discussion. External stimulation of the trigeminal nerve (V1 and V2) was well tolerated, with a mean reduction in seizure frequency of 59% at 12 months. The results of this study build upon data in an animal model, and our short-term report in humans.1,2 Why stimulate the trigeminal nerve for epilepsy? The trigeminal nerve has three bilateral cutaneous branches.3 These afferent branches (V1–V3) exit foramen 1.25–1.5 inches lateral of the midline, and project to the trigeminal ganglion and the trigeminal nucleus, which projects to the nucleus tractus solitarius and locus ceruleus, all of which play a role in inhibition of seizures.4-7 The antiepileptic effect of the trigeminal nerve and related structures has been confirmed in animal models.1,4,5 Stimulation of the locus ceruleus suppresses epileptic discharges induced by cobalt and penicillin, and plays a central role in the mechanism of VNS.6,7 In a pentylenetetrazole model, high-frequency stimulation of the trigeminal nerve significantly reduced seizure severity and frequency.1 Bilateral stimulation was more effective than unilateral stimulation, and high frequency stimulation was more effective than low frequency stimulation.1 The data provide a foundation for future randomized studies of TNS in humans. Based on the longterm feasibility and efficacy of this study, we have embarked on a randomized controlled study of high vs low frequency stimulation of the ophthalmic branch (V1) of the trigeminal nerve for intractable epilepsy. From the Departments of Neurology (C.M.D.) and Biomathematics (D. Markovic), David Geffen School of Medicine at UCLA, Los Angeles; Olive View/UCLA Medical Center (D. Murray), Sylmar; and Boston Scientific (T.W.), Valencia, CA. Neurology 72

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937

Supported by an investigator-initiated grant from Advanced Bionics and Boston Scientific and grants from Mr. James Peters, the Salter, Brill, Jacoby, Lagermeier, Lester, and Johnson Families, AMDG. Disclosure: C.M.D. has received grant support from Advanced Bionics/Boston Scientific for this investigator-initiated study. T.W. is an employee of Boston Scientific, Inc. Received August 29, 2008. Accepted in final form November 18, 2008. Address correspondence and reprint requests to Dr. Christopher M. DeGiorgio, 710 Westwood Plaza AMDG, UCLA, Los Angeles, CA 90095; [email protected] Copyright © 2009 by AAN Enterprises, Inc.

2.

3. 4.

5.

AUTHOR CONTRIBUTIONS Daniela Markovic performed the statistical analysis.

6.

ACKNOWLEDGMENT The authors thank Dr. Alan Shewmon for his support and assistance.

7. 1.

938

Fanselow EE, Reid A, Nicolelis AL. Reduction of pentylenetetrazole induced seizure activity in awake rats by

Neurology 72

March 10, 2009

seizure-triggered trigeminal nerve stimulation. J Neurosci 2000;20:8160–8168. DeGiorgio CM, Shewmon DA, Whitehurst T. Pilot study of trigeminal nerve stimulation (TNS) for epilepsy: a proof-of-concept trial. Epilepsia 2006;47:1213–1215. Clemente C. Anatomy: A Regional Atlas of the Human Body, 4th ed. Baltimore: Williams & Wilkins; 1997. Magdaleno-Madrigal VM, Valdes Cruz A, Martinez Vargas, et al. Effect of electrical stimulation of the nucleus of the solitary tract on the development of electrical amygdaloid kindling in the cat. Epilepsia 2002;43:964–969. Walker BR, Easton A, Gale K. Regulation of limbic motor seizures by GABA and glutamate transmission in nucleus tractus solitarius. Epilepsia 1999;40:1051–1057. Weiss GK, Lewis J, Jimenez-Rivera C, Vigil A, Corcoran ME. Anti-kindling effects of locus coeruleus stimulation: mediation by ascending noradrenergic projections. Exp Neurol 1990;108:136–140. Krahl SE, Clark K, Smith D, et al. Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation Epilepsia 1998;39:709–714.

Clinical/Scientific Notes

C. Del Borgo, MD S. Zaniratti, MD C. Minosse, MD A. Vetica, MD A. Bellini, MD F. Soscia, MD P. Missori, MD F. Pierelli, MD A. Curra`, MD, PhD

A CASE OF ACUTE POLYRADICULONEUROPATHY, DRUG-INDUCED HYPERSENSITIVITY, AND HHV-6 INFECTION

A 35-year-old man from India with a history of heavy alcohol abuse was admitted with jaundice, abdominal right quadrant pain, and mild fever. The physical examination showed enlarged liver and spleen, but normal peristalsis. Clinical and laboratory data (table) suggested cholangitis, treated with ceftriaxone, omeprazole, albumin, and vitamin K. CT documented liver steatosis and gallbladder sludge. Cholangio MRI and esophagogastroduodenoscopy showed normal findings. Two weeks later, because the mild fever persisted, ceftriaxone was switched to meropenem. At neurologic examination, the patient was awake, alert, and oriented. Cranial nerve function, muscle strength, sensory examination findings, motor coordination, muscle tone, and deep tendon and plantar reflexes were normal. Six days after the antibiotic switch, a diffuse rash developed, indicating a drug-induced hypersensitivity reaction. Meropenem was discontinued, and methylprednisolone plus antihistamine was started. Although corticosteroids resolved the rash, muscle strength diminished in the legs, and neurologic examination showed a rapidly evolving gait disturbance and areflexia, but normal cranial nerve function. A CSF sample contained no cells, protein 29 mg/dL, and glucose 61 mg/dL. Electrodiagnostic findings suggested acute inflammatory demyelinating sensorimotor polyradiculoneuropathy (AIDP). Sensory action potentials were absent in the lower limbs (left sural, right superficial peroneal), and severely reduced in the upper limbs (left and right ulnar). Conduction velocity was severely reduced on motor (left median, right peroneal) and sensory nerves (left and right ulnar). Motor conduction studies documented a right peroneal nerve block. Upper and lower limb compound motor action potentials were chronodispersed (slightly for left median nerve stimulation, markedly for left plantar medial nerve stimulation). Distal latencies were prolonged diffusely, and F-waves were absent (right peroneal), abnormally excitable, or severely delayed (left plantar medial 87 msec, right median 37 msec). Nee-

dle EMG showed no denervation, but did show a severely reduced lower limb recruitment pattern. CSF PCR assay was negative for cytomegalovirus (CMV), Epstein-Barr virus, varicella zoster virus, mumps virus, enterovirus, human T-lymphotrophic virus-I (HTLV-I), and JC virus but detected human herpesvirus 6 (HHV-6) DNA (3,480 copies/mL). Antibody assay in the undiluted CSF sample detected HHV-6 immunoglobulin M (IgM) and immunoglobulin G (IgG), but no HTLV-I IgM or IgG. Serum assays showed HHV-6 IgM and IgG titers (1:20 and ⱖ1.20), indicating active viral replication. MRI excluded brain or spinal cord abnormalities. Two days after the muscle weakness developed, the patient’s limbs became flaccid and swallowing became difficult. IV immunoglobulins reversed the neurologic deficit, and the patient was transferred for rehabilitation care. A positive CSF PCR HHV-6 assay in an adult immunocompetent patient with rapidly progressing polyradiculoneuropathy is a previously unreported finding raising interesting questions on the viral causes of peripheral nervous system (PNS) diseases. In our patient, the polyradiculoneuropathy developed after a rash induced by antibiotic therapy for acute liver disease. HHV-6 is a ubiquitous virus associated with various clinical conditions1 (exanthem infantum, fulminant hepatitis) that also participates in the drug-induced hypersensitivity syndrome.2 HHV-6 involving the nervous system usually affects the CNS3 (seizures, encephalitis/meningitis, and multiple sclerosis), and only recently has a primary childhood HHV-6 infection been proposed as a cause of acute inflammatory PNS diseases.4 Establishing the relationship between our adult patient’s infection and neuropathogenesis meant distinguishing whether the viral DNA in the CSF sample indicated viral reactivation or chromosomal HHV-6 integration.5 Several findings in our patient suggest viral reactivation rather than chromosomal integration. First, his CSF sample was acellular, and when the CSF cell count is less than 1 cell/mm3, only half the samples from subjects with chromosomally integrated virus contain detectable HHV-6 DNA. Second, the CSF sample contained HHV-6 IgM and Neurology 72

March 10, 2009

935

Table

Laboratory values at admission

Hematologic and chemical values

Serum virology

Analyte

Value

Results

Hematocrit

25%

HIV negative

Mean corpuscular volume

102 ␮m3

HTLV-I negative 3

White cell count

18,300/mm

Neutrophils

77%

HBsAg negative

Lymphocytes

9.2%

EBV negative

Eosinophils

4%

Platelet count

232,000/mm

Fibrinogen

390 mg/dL

Prothrombin time

31 s

Urea nitrogen

19 mg/dL

Creatinine

1.1 mg/dL

Ammonia

42 mmol/mL

Glucose

86 mg/dL

Total bilirubin

12.8 mg/dL

Conjugated bilirubin

8.1 mg/dL

Aspartate aminotransferase

161 U/L

Alanine aminotransferase

64 U/L

HCV negative

CMV negative 3

HSV-1 negative HSV-2 negative

HTLV ⫽ human T-cell lymphotrophic virus; HCV ⫽ hepatitis C virus; EBV ⫽ Epstein-Barr virus; CMV ⫽ cytomegalovirus; HSV ⫽ herpes simplex virus.

IgG. Third, serum contained increased HHV-6 IgM. Remarkably, HHV-6 is closely related to CMV, the second most commonly found infection preceding Guillain-Barre´ syndrome, and its most common viral trigger.6 The normal CSF protein content in our patient seemingly contrasts with evidence that about 80% of patients with AIDP have raised CSF protein concentrations. One explanation is that we collected our patient’s CSF sample in the early days of illness, a time when protein content is often normal.7 Measurement of potassium, phosphate, and porphyrin metabolism products helped to exclude alternative diagnoses. Stool sample cultures excluded Campylobacter jejuni enteritis. In addition, the neurologic examination on admission failed to disclose the cognitive disturbances typical of some alcohol-related

Christopher M. DeGiorgio, MD Diana Murray Daniela Markovic, MS Todd Whitehurst, MD

936

acute reactions, thus arguing against a history of alcohol abuse, and lacked the signs of distal symmetric axonal polyneuropathy typically found in heavy chronic alcohol users. Viral reactivation of a latent HHV-6 infection may be among the causative or precipitating factors of acute inflammatory PNS diseases. From the Infectious Disease Unit (C.D.B., A.V., F.S.) and Neurology Unit (A.B.), Ospedale S. Maria Goretti, Latina; Virology (S.Z., C.M.), Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, Rome; Department of Neurological Sciences, Neurosurgical Unit, Ospedale S. Maria Goretti (P.M.), Department of ENT and Neurology, Neurorehabilitation Unit, ICOT (F.P.), and Department of Neurological Sciences, Neurology Unit, Ospedale A. Fiorini Terracina (A.C.), Sapienza University of Rome, Polo Pontino, Italy. Disclosure: The authors report no disclosures. Received August 19, 2008. Accepted in final form November 10, 2008. Address correspondence and reprint requests to Dr. Antonio Curra`, Department of Neurological Sciences, Neurology Unit, Ospedale A. Fiorini Terracina, LT, Sapienza University of Rome, Polo Pontino, Italy; [email protected] Copyright © 2009 by AAN Enterprises, Inc. 1. 2.

3.

4.

5.

6.

7.

Levy JA. Three new human herpesviruses (HHV6, 7, and 8). Lancet 1997;349:558–563. Morimoto T, Sato T, Matsuoka A, et al. Trimethoprimsulfamethoxazole-induced hypersensitivity syndrome associated with reactivation of human herpesvirus-6. Intern Med 2006;45:101–105. Gilden DH, Mahalingam R, Cohrs RJ, Tyler KL. Herpesvirus infections of the nervous system. Nat Clin Pract Neurol 2007;3:82–94. Miyake F, Yoshikawa T, Suzuki K, Ohashi M, Suga S, Asano Y. Guillain-Barre´ syndrome after exanthem subitum. Pediatr Infect Dis J 2002;21:569–570. Ward KN, Leong HN, Thiruchelvam AD, Atkinson CE, Clark DA. Human herpesvirus 6 DNA levels in cerebrospinal fluid due to primary infection differ from those due to chromosomal viral integration and have implications for diagnosis of encephalitis. J Clin Microbiol 2007;45:1298–1304. Hadden RD, Karch H, Hartung HP, et al. Preceding infections, immune factors, and outcome in Guillain-Barre syndrome. Neurology 2001;56:758–765. Paradiso G, Tripoli J, Galicchio S, Fejerman N. Epidemiological, clinical, and electrodiagnostic findings in childhood Guillain-Barre´ syndrome: a reappraisal. Ann Neurol 1999;46:701–707.

TRIGEMINAL NERVE STIMULATION FOR EPILEPSY: LONG-TERM FEASIBILITY AND EFFICACY

of external TNS for epilepsy.

Neurostimulation has emerged as a viable alternative for intractable epilepsy. Trigeminal nerve stimulation (TNS), a novel form of neurostimulation, has an antiepileptic effect in a rodent model.1 The superficial location of trigeminal branches allows for minimally invasive approaches, allowing assessment of response prior to a permanent device.2 We report the long-term safety and efficacy

Methods. Research committee approval was obtained for an open study of external TNS in epilepsy. Informed consent was obtained before enrollment. Inclusion/exclusion criteria were age 18 – 65 years, ⱖ3 complex-partial/generalized tonic-clonic seizures/month, no progressive medical conditions, and exposure to ⱖ2 antiepileptic drugs (AEDs). Subjects enrolled in a 4-week pretreatment baseline, and were

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Figure

Adjusted mean daily seizure rate across time

Bars indicate standard error ⫽ 0.64.

evaluated at 1, 2, 3, 6, and 12 months. AEDs remained unchanged unless essential for patient safety. Neurostimulation was initially supplied using the analog EMS Model 400, and later a digital EMS model 7500.2 Stimulation settings were as follows: frequency 120 Hz, 250 ␮s, ⱕ30 seconds on, ⱕ30 seconds off for 12–24 hours/day, and 1.25-inch disposable, silver-gel, adhesive electrodes were utilized, spaced 2 inches apart. Subjects 1–3 were initiated with infraorbital stimulation (V2), but subjects found this awkward for chronic use. Since then, we have stimulated the ophthalmic nerve (V1) in all subjects, which allows bilateral stimulation and can be concealed by a cap. See figure e-1 on the Neurology® Web site at www.neurology.org for a diagram of the device and electrode placement. Statistical analysis. We compared mean seizure rates over time using a repeated measure analysis of variance (ANOVA) model. After confirming that missing data were missing at random, we used multiple imputation to replace missing values for daily seizure rate with a set of imputed values in patients who did not complete the study. The imputation was carried out under the repeated measure ANOVA model. The resulting variances of the means reflect not only the variation in the observed data but also the added uncertainty of using partially imputed information. It is preferable to impute missing values rather than omit patients with incomplete data entirely. Four imputed values were generated for each missing value. All analyses were carried out using SAS version 9.1. A p value of 0.05 was chosen for significance. Supplemental data at www.neurology.org

Results. Thirteen subjects completed the 4-week prospective baseline. Twelve completed 3 months, 10 completed 6 months, and 7 completed 12 months (table e-1). Short-term results from the first seven subjects reported previously are included in this analysis.2 The fig-

ure shows results at 3, 6, and 12 months. At 3 months, mean seizure frequency was reduced from a baseline of 2.1 seizures/day to 0.71 seizures/day (66% reduction, p ⫽ 0.034, standard error 0.64). At 6 months, mean seizure frequency was 0.92 seizures/day (56% reduction, p ⫽ 0.073, standard error 0.64). At 12 months, mean seizure frequency was 0.86 seizures/day (59% reduction, p ⫽ 0.058, standard error 0.64). Five subjects experienced greater than 50% reduction at 6 and 12 months; one subject had ⬎90% reduction at 12 months. TNS was well tolerated. Side effects included skin irritation in five subjects, which improved by reducing stimulation to 12–16 hours/day, or with hydrocortisone 1% cream. Tingling, forehead pressure, and headache were reported, but improved with reduction of current. No effect on pulse, blood pressure, or ECG was detected. Discussion. External stimulation of the trigeminal nerve (V1 and V2) was well tolerated, with a mean reduction in seizure frequency of 59% at 12 months. The results of this study build upon data in an animal model, and our short-term report in humans.1,2 Why stimulate the trigeminal nerve for epilepsy? The trigeminal nerve has three bilateral cutaneous branches.3 These afferent branches (V1–V3) exit foramen 1.25–1.5 inches lateral of the midline, and project to the trigeminal ganglion and the trigeminal nucleus, which projects to the nucleus tractus solitarius and locus ceruleus, all of which play a role in inhibition of seizures.4-7 The antiepileptic effect of the trigeminal nerve and related structures has been confirmed in animal models.1,4,5 Stimulation of the locus ceruleus suppresses epileptic discharges induced by cobalt and penicillin, and plays a central role in the mechanism of VNS.6,7 In a pentylenetetrazole model, high-frequency stimulation of the trigeminal nerve significantly reduced seizure severity and frequency.1 Bilateral stimulation was more effective than unilateral stimulation, and high frequency stimulation was more effective than low frequency stimulation.1 The data provide a foundation for future randomized studies of TNS in humans. Based on the longterm feasibility and efficacy of this study, we have embarked on a randomized controlled study of high vs low frequency stimulation of the ophthalmic branch (V1) of the trigeminal nerve for intractable epilepsy. From the Departments of Neurology (C.M.D.) and Biomathematics (D. Markovic), David Geffen School of Medicine at UCLA, Los Angeles; Olive View/UCLA Medical Center (D. Murray), Sylmar; and Boston Scientific (T.W.), Valencia, CA. Neurology 72

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Supported by an investigator-initiated grant from Advanced Bionics and Boston Scientific and grants from Mr. James Peters, the Salter, Brill, Jacoby, Lagermeier, Lester, and Johnson Families, AMDG. Disclosure: C.M.D. has received grant support from Advanced Bionics/Boston Scientific for this investigator-initiated study. T.W. is an employee of Boston Scientific, Inc. Received August 29, 2008. Accepted in final form November 18, 2008. Address correspondence and reprint requests to Dr. Christopher M. DeGiorgio, 710 Westwood Plaza AMDG, UCLA, Los Angeles, CA 90095; [email protected] Copyright © 2009 by AAN Enterprises, Inc.

2.

3. 4.

5.

AUTHOR CONTRIBUTIONS Daniela Markovic performed the statistical analysis.

6.

ACKNOWLEDGMENT The authors thank Dr. Alan Shewmon for his support and assistance.

7. 1.

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Fanselow EE, Reid A, Nicolelis AL. Reduction of pentylenetetrazole induced seizure activity in awake rats by

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seizure-triggered trigeminal nerve stimulation. J Neurosci 2000;20:8160–8168. DeGiorgio CM, Shewmon DA, Whitehurst T. Pilot study of trigeminal nerve stimulation (TNS) for epilepsy: a proof-of-concept trial. Epilepsia 2006;47:1213–1215. Clemente C. Anatomy: A Regional Atlas of the Human Body, 4th ed. Baltimore: Williams & Wilkins; 1997. Magdaleno-Madrigal VM, Valdes Cruz A, Martinez Vargas, et al. Effect of electrical stimulation of the nucleus of the solitary tract on the development of electrical amygdaloid kindling in the cat. Epilepsia 2002;43:964–969. Walker BR, Easton A, Gale K. Regulation of limbic motor seizures by GABA and glutamate transmission in nucleus tractus solitarius. Epilepsia 1999;40:1051–1057. Weiss GK, Lewis J, Jimenez-Rivera C, Vigil A, Corcoran ME. Anti-kindling effects of locus coeruleus stimulation: mediation by ascending noradrenergic projections. Exp Neurol 1990;108:136–140. Krahl SE, Clark K, Smith D, et al. Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation Epilepsia 1998;39:709–714.

REFLECTIONS: NEUROLOGY AND THE HUMANITIES

Guns in the Afternoon

Section Editor Michael H. Brooke, MD

Ludwig Gutmann, MD

Address correspondence and reprint requests to Dr. Ludwig Gutmann, Robert C. Byrd Health Sciences Center, P.O. Box 9180, West Virginia University, Morgantown, WV 26506-9180 [email protected]

Sam sat in the far corner of the bar, his sweat-marked Stetson hanging on a wooden peg above his head. The whiteness of his forehead ended abruptly just above his eyebrows. His face was wrinkled and dark from years in the prairie sunshine. He sat motionless, leaning against the timbered wall behind him, his chair angled so he could see across the whole room. Only his eyes were moving as he watched men playing card games at several tables, noisily arguing every hand, four miners drinking whiskey in complete silence at the other end of the long mahogany bar, and the women in tight skimpy dresses serving whiskey to the men at the tables. People who didn’t know him sometimes had trouble meeting Sam’s gaze— blue eyes washed out from the blazing prairie sun. Sam glanced at a distant corner of the barroom where a man played a piano. The man was old, with the beginnings of a beard that probably wouldn’t turn into anything. He wasn’t much of a piano player, either. The Irish tune he played was barely audible above the complaints of the crowd. He had taken off his hat and upended it on the upright some time before, but no coins gleamed inside the black crown. Sam’s eyes kept coming back to a young man playing cards with some of the older cowhands. That kid, Sam thought, he still seemed a kid even though he was grown up now. That kid had a moustache, it was thin and scraggly and looked new and he wore a Colt 45 in a holster. The revolver was well cared for; the pearl handle gleamed in a shaft of sunlight that raked across the room. Matthew, Sam thought. Matthew’s life hasn’t been easy. He had always lived with his mother in an old shack a few miles out of town. The night the boy was born, Sam had to go out to arrest the boy’s father—at least, Mattie said he was the father—for threatening to kill the baby. Sam was a new deputy and that was his first arrest. The man he took into custody was drunk, as were most of the men who hung out at Mattie’s place. “I don’t know what it is about me,” she’d told Sam years later. “Every time I find a nice fella,’ he turns out to be a drunk. Talk about bad luck.” Mattie was a woman whose smile was an attraction for men. She liked sitting on her front porch in a

rocker, always waiting—so Sam thought—for some man to show up. She had three horses, eight head of cattle, and a goat that wandered about the open range surrounding the house, and she expected her boyfriends to feed and water them. When there was no one else to help, Matthew had to pitch in. Matthew was her only son. “He’s more than enough,” she’d tell anyone who’d ask. “He’s always in trouble. You’d think the sheriff and his deputies lived out here, the many times they have to come out.” Matthew often skipped school and, when he was there, he spent more time fighting than studying. Sam usually got to ride him home and not without some wrestling. Sometimes, though, they would talk. When Matthew turned ten, Sam taught him how to shoot a gun. Sometimes the kid seemed to be coming around and, at times like that, Sam figured he was the closest anyone got to being a father to the boy. But the older Matthew got, the more irascible he became. He was getting to be as much trouble for Sam as his mother’s drunken friends. Sam had told Mattie again and again that she needed to be firmer with the boy, but she would just laugh. “There’s no meanness in him— he’s really a good boy,” Mattie tried to assure him. At the rate things were going, Sam worried he would have to take the boy on when he got to be a man or even before. “He’s just as independent as his grandpap was,” Mattie said. Yea, Sam thought when she said that, and what happened to that old man? He got shot in a bank holdup and ended up in the penitentiary. Sam drank his beer slowly, rubbing his thigh, and watching Matthew playing cards. A woman leaned against his back, her breasts touching him lightly. Unlike the other women, she wore makeup like an actress. She gently messaged his back muscles, her hands moving to the rhythm of the Irish tune. The kid is certainly a handsome fellow except for that moustache he’s tryin’ to grow, Sam thought. Doesn’t look like Mattie, he’s lean and trim and she’s getting’ fat. In fact, it’s hard to believe Mattie is his mother. What’s she going to do when she gets old? That kid’s all she has. Matthew worked as a cowhand for Chet Holcombe on a cattle ranch out in the county. Chet emCopyright © 2009 by AAN Enterprises, Inc.

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ployed a dozen cowboys to take care of the spread. He said Matt was a good worker, always full of energy and enthusiasm. He could lose his temper easily but, so far, it hadn’t been a problem. Sam looked down at his right leg and rubbed it again. The outside of his thigh burned so fiercely, he thought it might ignite his pants. It had been going on for a year and was just getting worse. It was now keeping him up at night. He was never much of a drinking man but he’d begun taking a shot of whiskey at night to help with sleep. He had finally gone to see Doc Sloan about it. “It’s all numb and burning in one spot,” Sam said, pointing. “It’s about the size of a one-egg frying pan. I can put up with the numbness but the burning is tough to take.” Doctors in the early west had the same difficulty all doctors had then—there weren’t many drugs to help with problems and the problems, except for the simple ones, were often not understood. Setting a broken bone by touch alone, prescribing laudanum for pain, a few stomachache remedies of dubious merit, these few were the arsenal. But Doc Sloan had something else in his kit. He was a canny observer— he could come up with answers even when he didn’t fully understand the questions. The Doc had seen Sam approaching all the way across the street. By the walk he could tell Sam was in pain, and he knew why. “I’ve seen that before,” Doc said after the exam, “especially in them lean gunslingers.” Sam’s forehead wrinkled into a frown. “Ain’t never been a gunfighter,” he said. “I know sheriffs ain’t gunfighters even though you’re pretty quick with that iron of yours.” Doc ran his hand through his hair and stood up from his chair as he always did when he was about to say something serious. He looked down at Sam. “I think what’s happened is that that gun belt of yours with that pistol and ammo weighing it down is what’s giving you the trouble.” He picked it up from the back of the chair and hefted it. “You ain’t got enough fat on you to hold up such a weight. Leather’s heavy and that holster alone weighs a lot. The boys with more meat on’ em don’t have the problem you have, I seen it over and over again.” “Can you fix it, Doc?” Sam asked. “It’ll get better by itself if you quit wearing that gun belt of yours.” “How do I do that and keep being sheriff?” Sam asked. “Well, you can carry your gun on the other leg for a while, but you better learn to shoot with your left hand,” Doc said, and sat down, turning the chair 940

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around so he was facing his desk. Sam knew it was time to leave. Doc had spoken and there wasn’t any other answer. As Sam sat in the bar he reflected on Doc’s analysis. Smart old coot, he thought, sees a lot of stuff and talks with a lot of people and sometimes figures it out. He’d visited Doc the week before and had been working on shooting with his left hand ever since. He’d always been able to use his left hand pretty fine, so he was accurate with his shots— his aim was as good as ever— but he couldn’t draw the gun out quite fast enough. Without that instant reflex, he knew he’d come out second best in a gunfight. Matthew concentrated on the card game. The woman standing behind him kept filling up his whiskey glass. He would occasionally reach back and pat her—she might go to bed with him tonight— but the real business right now was winning at poker. Sam’s gun belt lay next to his beer on the polished bar. He’d gotten in the habit of taking it off whenever he could. He didn’t want to end up hurting his left leg same as the right one. Sam took a swallow of beer and touched his holster. The leather had gotten soft after years of rubbing and use. I’m getting’ soft with age too, Sam thought. The burning in his leg was no better but Doc Sloan had said to give it time. Sam finished his beer, slung the gun belt over his shoulder, and pushed his way out through the swinging doors. There had been no rain for weeks— even the horse droppings on the street were dried up. His boots kicked up miniature clouds of dust as he stepped off the boardwalk and walked across the sunbaked dirt street to his office. Posters announced a cattle auction coming the next month to be held there, in the wide unpaved town square. Can’t have cattle and unshod range horses on cobblestone streets like in the city, Sam thought, but I sure hope it rains by auction time. Paperwork was done quickly and Sam, bored, must have been dozing at his desk. For a brief instant, he thought the gunshot was part of his dream. At the second shot, loud and clear, he was out of his chair. He knew it was from the saloon. One of his deputies was running across the street. The frightened look on the deputy was enough for Sam— he knew someone was hurt, if not killed. Sam strapped on his gun belt as he ran and headed for the door. “Get over to Doc Sloan’s office,” he yelled. “Tell him to get over here pronto.” The saloon was as quiet as the church down the street on Sunday during the silent prayer. Everyone watched Sam as he strode through the entryway. The only sounds were the soft squeak of the swinging doors and his heels clicking on the wooden floor. Matthew stood in the middle of the room behind the

overturned card table, still holding his gun, a wisp of smoke rising from its barrel. “Put the gun down, Matthew,” Sam said. A man he didn’t recognize was lying on the floor, holding his knee. Blood was seeping from two holes in his pant legs. “He couldn’t keep his hands off Tina,” Matthew said, his speech slightly slurred. Matthew’s girlfriend of the afternoon stood right behind him. “I told him to let it be. I gave him three chances and then I’d had enough.” “Put down the gun, Matthew,” Sam repeated. Matthew dropped it into his holster and stood still, watching. Doc Sloan came through the doorway carrying his black medical bag, the deputy right behind him. The doctor stepped to one side and so did the deputy. They both knew the game was not over yet. “OK,” Sam said to Matthew, “Let’s walk over to my office while Doc takes care of things here.” Matthew swayed gently, his hands dangling loosely at his side. “I ain’t coming with you, sheriff. If you want me, you’ll have to take me.” Looking at Tina, he added, “You better move away.” The center of the big room suddenly emptied out as people backed away, crowding themselves against the bar and the opposite wall. The piano player, hat in hand, disappeared into a back room. Two women slipped out through the swinging doors. Sam groaned silently to himself. That boy can outdraw

me even if he is full of liquor, he thought. The late afternoon sunlight streaming through the open window gave Sam’s dusty boots a shimmering brightness. A look of patience seemed painted on his immobile face. The stillness of the afternoon was broken by a whimper from the man on the floor. “We got one person hurt, Matthew,” Sam said, his voice just above a whisper. “We don’t need two. Let’s go across the street.” “Sheriff, you’ve always been good to me and my Mom,” Matthew said. His arms hung loose at his sides. “I’m sorry it’s come to this.” Matthew’s index finger twitched. Sam knew the moment had arrived. Both men drew. The young man’s gun was already pointed straight at Sam’s chest while the older man’s had just cleared his holster. The explosion never came. Matthew’s gun stayed frozen in midair. “I can’t do it, Sher . . .,” Matthew began to say. Sam lowered his gun as it went off. Matthew slumped into a chair, blood oozing from the top of his boot. “I shouldn’t have drawn on you, Sheriff . . .” He trailed off, tears streaming down his face. Sam walked over toward him, still holding the gun in his left hand. Matthew was as fast as ever but Mattie was right, there was no meanness in him. Sam patted the young man’s shoulder. “Doc’ll fix it up.” There was a faint smile on Sam’s face. He was proud of the kid.

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NEUROIMAGES

Corpus callosum dysgenesis limits MRI changes to one hemisphere in status epilepticus Figure 1

Unilateral seizure activity

Figure 2

Dysgenesis of the corpus callosum

Bipolar longitudinal EEG montage demonstrates unilateral ictal activity in C4 and P4. Complete bipolar montage (figure e-1) and prolonged EEG recording (figure e-2) are available on the Neurology姞 Web site at www.neurology.org.

Axial T2 (A) and sagittal T1 (B) images demonstrate the dysgenesis of the corpus callosum. Diffusion-weighted imaging (C) and apparent diffusion coefficient (D) images show cytotoxic edema throughout the complete right cortex, corresponding with electroencephalographic status epilepticus.

A 46-year-old man with cerebral palsy presented with complex partial seizures and left sided clonic movements. EEG showed right hemispheric seizures (figure 1). MRI demonstrated dysgenesis of the corpus callosum (figure 2, A and B) with hyperintense signal throughout the right cortex in diffusion-weighted imaging (DWI) (figure 2C) corresponding with decreased apparent diffusion coefficient signal (figure 2D). Gyriform cortical hyperintensities on DWI may occur during status epilepticus that do not respect vascular distributions.1,2 We suggest that DWI changes are restricted to one hemisphere because dysgenesis of the corpus callosum prohibits the spread of ictal activity to the contralateral hemisphere. Supplemental data at www.neurology.org

Christian Grommes, MD, Roger Oghlakian, MD, Kristina A. Blackham, MD, and Michael A. De Georgia, MD, Cleveland, OH Disclosure: The authors report no disclosures. Address correspondence and reprint requests to Dr. Michael A. De Georgia, Department of Neurology, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106; [email protected] 1. 2.

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Wieshmann UC, Symms MR, Shorvon SD. Diffusion changes in status epilepticus. Lancet 1997;16:493–494. Lansberg MG, O’Brien MW, Norbash AM, Moseley ME, Morrell M, Albers GW. MRI abnormalities associated with partial status epilepticus. Neurology 1999;52:1021–1027.

Copyright © 2009 by AAN Enterprises, Inc.

RESIDENT & FELLOW SECTION Section Editor Mitchell S.V. Elkind, MD, MS

Aleksandra Pikula, MD Jorge L. Almodovar, MD Thanh N. Nguyen, MD

Teaching NeuroImages: Cerebral arteriovenous malformation in hereditary hemorrhagic telangiectasia Figure 1

Skin telangiectasias (A) and lip telangiectasias (B)

Address correspondence and reprint requests to Dr. Aleksandra Pikula, Boston University School of Medicine, Department of Neurology, 715 Albany Street, C-329, Boston, MA 02118 [email protected]

A 41-year-old woman with a history of recurrent epistaxis presented with left hemiplegia, right gaze deviation, and dysarthria. Physical examination confirmed skin and lip telangiectasia (figure 1). Her son had pulmonary arteriovenous malformation (AVM). Her head CT and cerebral angiography revealed right parietal hemorrhage with parasagittal AVM (figure 2). Hereditary hemorrhagic telangiectasia (HHT, OslerWeber-Rendu syndrome) is a disorder characterized by recurrent epistaxis, skin and mucosal telangiectasias, visceral and cerebral AVMs, and positive family history. Diagnosis Figure 2

is made when three of the above criteria are present.1 Cerebral AVMs affect 10% of patients with HHT. Routine screening for cerebral AVMs in asymptomatic patients with HHT remains controversial.1,2 REFERENCES 1. Begbie ME, Wallace GMF, Shovlin CL. Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st century. Postgrad Med J 2003;79:18–24. 2. Willemse RB, Mager JJ, Westermann CJJ, et al. Bleeding risk of cerebrovascular malformations in hereditary hemorrhagic telangiectasia. J Neurosurg 2000;92:779–784.

CT (A), cerebral angiography (B), and magnified view of AVM nidus (C)

(A) CT: right parietal hemorrhage. (B) Cerebral angiography: right parasagittal arteriovenous malformation (AVM) supplied by the right distal anterior cerebral artery (white arrowhead), draining to superior sagittal sinus. (C) Microcatheter injection: magnified view of AVM nidus with aneurysmal appearance.

From the Departments of Neurology (A.P., J.L.A., T.N.N.) and Neurosurgery and Radiology (T.N.N.), Boston University Medical Center, Boston, MA. Disclosure: The authors report no disclosures.

Copyright © 2009 by AAN Enterprises, Inc.

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RESIDENT & FELLOW SECTION Section Editor Mitchell S.V. Elkind, MD, MS

T. Munsat, MD J. Aarli, MD M. Medina, MD G. Birbeck, MD A. Weiss, MA

Address correspondence and reprint requests to Dr. Theodore Munsat, 3515 Fletcher Hill, South Woodstock, VT 05071 [email protected]

International Issues: Educational programs of the World Federation of Neurology During the past few years, several publications have documented the striking lack of neurologic health care givers in countries with limited resources.1-3 Neurologic care is particularly deficient in those developing countries where health problems are most severe. Even in those countries where a small number of neurologists practice, care is often fragmented and the neurologic community poorly organized. Educational programs for neurologic health care givers and neurologic patients are typically seriously deficient. The problem has been defined. The challenge is reasonably clear. A resolution is required. In North America and Western Europe, effective organizations exist that serve the organizational and educational needs of its neurologic community. However, no such meaningful process exists to provide these services for resource-deficient countries. During the past decade, the World Federation of Neurology (WFN) has attempted to fill this void. The WFN (www.wfneurology.org) was organized as a federation of national neurologic societies 50 years ago. Its secretariat is located in London, and it is registered as a Charity Corporation in the United Kingdom. Each country has one vote in its deliberations. A primary goal of the WFN is to assist low-resource countries in providing meaningful education for its neurologic health care providers and thus improve the neurologic health of its citizens. We hope that this brief review of the educational activities of the WFN will be informative for residents and fellows who are interested in working with and helping colleagues living in low resource environments. GENERAL PRINCIPLES The WFN’s educational programs have been operating under several principles.

1. The successful education of neurologic health care providers, and their patients, is a major strategy in achieving improvement in health care in developing countries.

2. In order to strengthen the effectiveness of this educational process, each country should develop a cohesive neurologic society with specific individuals identified as leading that society’s educational activities. 3. The WFN will provide educational assistance in response to a specific request from a member country. It does not advocate seeking out or proactively identifying a country’s educational needs. These needs should be identified by the participating society, not the WFN. 4. To counteract the destructive effects of the emigration of trained basic and clinical neuroscientists to countries with more resources (“brain drain”), the WFN strongly supports the principle of training neurologists in their native countries. Its primary strategy is to help countries develop their own training programs. We believe that, in most situations, this can be accomplished without compromise to the educational process and within a reasonable period of time. 5. The educational material used should be of the highest quality and both problem (case) and evidence based. 6. Although the WFN believes that the best care of patients with a neurologic illness should be given by a trained neurologist, it recognizes the need for non-neurologist caregivers as an interim measure. However, developing a cadre of well-trained nonneurologist caregivers requires a core of experienced neurologists resident in that country to provide adequate training. 7. The WFN supports the principle of establishing small, pilot studies when new educational programs are being considered. 8. Periodic follow-up evaluation and feedback of a program’s effectiveness is essential. 9. The education of an effective neurologist should be a seamless and integrated process from medical school to residency training and then to lifelong continuing education.

From South Woodstock (T.M.), VT; University of Bergen (J.A.), Norway; Autonomous University of Honduras (M.M.); Michigan State University (G.B.), East Lansing; and American Academy of Neurology (A.W.), St. Paul, MN. Disclosure: The authors report no disclosures.

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Copyright © 2009 by AAN Enterprises, Inc.

CONTINUING MEDICAL EDUCATION: LIFEThis proLONG LEARNING IN NEUROLOGY

gram, now 10 years old, is a partnership between the WFN and the American Academy of Neurology (AAN). It provides six specially designed educational courses each year of the AAN’s premier continuing medical education journal Continuum: Lifelong Learning in Neurology, by hard copy or online. Forty-two developing countries currently participate, including Argentina, Bangladesh, Brazil, Bulgaria, Cameroon, Chile, Columbia, Congo, Croatia, Cuba, Cypress, Czech Republic, Egypt, Ethiopia, Guatemala, Honduras, Hungary, India, Iraq, Jordan, Kenya, Lebanon, Lithuania, Macedonia, Mexico, Mongolia, Nigeria, Panama, Peru, Romania, Russia, Serbia, Slovenia, Sri Lanka, Syria, Tunisia, Uganda, Uruguay, Vietnam, Venezuela, Yemen, and Zambia. Current WFN Coordinator contact information is available at www.wfneurology.org. Each country has a WFN Education Coordinator appointed by that society’s President. The coordinator is in charge of receiving and distributing the courses and arranging for discussion groups, which are an integral part of the program. Upon completion of a course, each participant fills out an evaluation form, and certificates of participation are provided. Typically, these programs begin in the capital city of a country. In larger countries, secondary participating centers, each with a coordinator, have been established in smaller cities. This has occurred in Russia, Turkey, Cuba, Honduras, Argentina, and Hungary. The effectiveness of these programs depends in great part on the skills, dedication, and active involvement of the WFN Education Coordinator in that country. This program is now being used increasingly for certification purposes, grand round presentations, educational retreats, and the education of non-neurologists. The WFN and AAN are currently gradually moving from hard copy to online distribution, which will significantly reduce shipping costs and delays. Future plans include an online chat group wherein participants can communicate with the authors of the courses. SUPPORT FOR NEUROLOGIC TRAINING The WFN provides assistance in estabPROGRAMS

lishing neurology training programs where there are none, and helping further develop existing programs. We have worked with programs in Ethiopia, Honduras, two in Guatemala, Nicaragua, and Mexico. The request for such assistance must come from the national neurologic society and chairman of the neurology department and have the support of the neurologic society members. After a request is received, the WFN carries out a preliminary site visit to answer the following questions: 1) Is the need for help shared by most members of the neurologic community and are they prepared to make a long-term commitment?

2) Are there adequate resources, both human and infrastructural, to establish a program? 3) Are university and hospital administrators, the national minister of health, and the chiefs of related departments, such as medicine and neurosurgery, supportive? 4) Above all, is the chief of the proposed department adequately committed and capable of assuming this most important leadership position? Following this visit, a report is presented to the requesting society and the WFN Trustees with specific recommendations. Follow-up visits are arranged according to need. An early experience in Honduras has been very informative.4,5 A collaboration between the WFN and the Neurologic Society of Honduras began in 1997 when the WFN was asked to help the society establish a training program for neurologists. The Director, Prof. Marco T. Medina, is a dynamic, capable leader dedicated to improving the neurologic health of the citizens of his country. Prior to the WFN’s site visit, he had collected sound epidemiologic data showing that the health of citizens living in Honduras was being adversely affected by the lack of good neurologic care.6 In addition, it was demonstrated that an improvement in neurologic care would result in significant economic benefits to the country. Armed with these data, a meeting was held with the Minister of Health, who agreed to fund four resident positions at each level of a 3-year training program. The WFN continued to monitor the progress of the first several resident training classes. This training program is now about to celebrate its 10-year anniversary. The results have been dramatic. The Neurology Department has become recognized as one of the best departments in the medical center and in Central America. A neuroscience PhD program is being developed. Importantly, every graduate of the neurology training program has stayed in Honduras. The program is attracting the better medical school graduates. Cities of secondary size are getting well-trained neurologists for the first time. Outcome assessment has shown, for example, a dramatic reduction of deaths from status epilepticus. A vigorous stroke prevention program has been initiated. Preventive programs for neurocysticercosis, a scourge of the country, are beginning to show results. Importantly, neighboring countries have begun to ask for similar help from the WFN. The WFN has recently provided a program certification process for programs that wish to have an external review. This has been carried out in Honduras, Guatemala, Mexico, and Ethiopia. If a program meets certain predetermined criteria for an effective training program, it receives a certificate. This process is very effective not

WFN CERTIFICATION

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only in confirming that the program is functioning effectively, but also in notifying other members of the hospital and university communities that the program meets international criteria of performance. Several countries have requested that the WFN provide a process of external evaluation of their residents at time of graduation. A logical extension of that process may lead to a more formal certification and recertification process. The WFN has responded to requests for resident evaluations and has begun discussions of a certification and recertification process. In carrying out these regulatory functions, the WFN is providing a service that is available internally in most, if not all, developed countries but not in countries with limited resources and fewer neurologists. What, then, are adequate criteria for a training program in a developing country—for example, in a country of 20 million people with no CT scans, MRIs, or adequate electrophysiologic capabilities and 10 or fewer well-trained neurologists? There is general agreement that the goals of a training program should be goals that are appropriate for the needs of that country,4 as determined in great part by individuals practicing in that or a similar environment. How are those goals defined in the context of what constitutes adequate modern neurologic care? Can there be criteria that are internationally appropriate? THE WFN AFRICA INITIATIVE Because of the special and relatively unaddressed neurologic health issues in sub-Saharan Africa, the WFN has mounted a special effort. A special task force has been established and several meetings held in an effort to define the best way to approach the immense needs in that region. Currently, six sub-Saharan countries are participating in the WFN Continuing Education program: Cameroon, Uganda, Zambia, Nigeria, Ethiopia, and Kenya. The WFN has recently formed a partnership with the People to People Foundation, which has made major contributions to neurologic care in Ethiopia. Under this arrangement, a site visit of the neurology training program at Addis Ababa University was recently carried out by a team from the WFN. A recent conference for non-neurologists was held under the auspices of People to People, the Mayo Clinic, and the Ethiopian government in Addis Ababa. The European Federation of Neurologic Societies (EFNS), one of our component regional societies, has a long experience in organizing training courses in neurology in developing countries. EFNS will soon arrange a teaching course in neurology in Dakar, Senegal. Most participants will come from French-speaking countries and the course will follow standards given at teaching courses at EFNS congresses. EFNS also has a long experience with e48

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department-to-department exchange programs, which will be utilized in the future. The WFN is in the process of designating a small number of African Centers of Neurologic Excellence for regional training. There is need for training activities in both English-speaking and French-speaking African countries. Some neurologists from other African countries are already in training positions in South Africa. South Africa has offered to accommodate others for training in neurology. NEUROLOGIC CARE NO NEUROLOGIST

WHERE

THERE

IS

In our discussions with health ministers, deans, and other senior medical officials, it is often pointed out that in a country with threadbare health services, especially in rural areas, major problems, such as HIV/AIDS, malnutrition, and parasitic infestation, must take precedence over neurologic diseases, which are still considered esoteric and untreatable. They often express the view that it is much more reasonable to train clinical assistants, nurses, and primary care physicians.7 However, it is often overlooked that in order to train nonneurologists properly, appropriate training materials and a core group of clinically experienced academic neurologists are necessary. Thus, in addition to focusing on training neurologists, the WFN has developed training materials for nonphysician healthcare providers8 and established a program for nonphysician/neurologist clinical officers in Zambia. Under the direction of Gretchen Birbeck, MD, this increasingly effective training program for clinical officers in Zambia now involves Malawi as well.9 In Ethiopia, the WFN plans to train an existing cadre of psychiatric nurses to diagnose and manage neurologic problems. Such training is particularly urgent in resource-poor regions, where nonphysician healthcare workers provide clinical services without recourse to physician-level referral.10 However, the two educational tracks—neurologist and non-neurologist—need not and should not be mutually exclusive. Both approaches are needed and clearly reinforce each other. ADDITIONAL PROGRAMS Because of the lack of educational material specifically designed and directed to neurology health care givers practicing in lowresource environments, the WFN has initiated a series of books produced by neurologists with experience in these issues. This series, published by Demos, Inc., is edited by Jerome Engel, MD, and is available in hard copy or online. Other related and more traditional programs offered by the WFN, when resources permit, include a book sharing program by which over 8,000 books and journals have been provided by individual donors and publishing companies. Approximately 150 visiting professorships have been sponsored or cospon-

sored. Ten traveling fellowships have been supported and several small equipment grants have been made. Preliminary experience with providing assistance to our neurologic colleagues in developing countries has led the WFN to conclude that effective help in improving neurologic care can be provided with modest resource investment in a relatively short period of time. The effective elements of the WFN’s programs include a detailed needs assessment by the recipient country, local dedicated and committed leadership, the production of relevant evidence-based educational material, periodic feedback, and periodic reevaluation of goals and strategies. DISCUSSION

3.

4.

5. 6.

7. 8. 9.

REFERENCES 1. World Health Organization, World Federation of Neurology. Atlas: Country Resources for Neurological Disorders 2004. Geneva, Switzerland: WHO Press; 2004. 2. World Health Organization. Neurological Disorders: Public Health Challenges. Geneva, Switzerland: WHO Press; 2007.

10.

Aarli JA, Diop AG, Lochmu¨ller H. Neurology in subSaharan Africa: a challenge for World Federation of Neurology. Neurology 2007;69:1715–1718. Medina MT, Munsat T, Portera-Sanchez A, et al. Developing a neurology training program in Honduras: a joint project of neurologists in Honduras and the World Federation of Neurology. J Neurol Sci 2007;253:7–17. Medina MT, Munsat T. Continuing medical education in developing countries. J Neurol Sci 2001;190:1–2. Medina MT, Duro´n RM, Martı´nez L, et al. Prevalence, incidence, and etiology of epilepsies in rural Honduras: the Salama´ study. Epilepsia 2005;46:124–131. Mullan F, Frehywot S. Non-physician clinicians in 47 subSaharan African countries. Lancet 2008;370:2158–2163. Birbeck G. Where there is no neurologist: 2002. Available at: www.wfneurology.org. Chomba EN, Haworth A, Atadzhanove M, et al. Zambian health care workers’ knowledge, attitudes, beliefs, and practices regarding epilepsy. Epilepsy Behav 2007;10:111– 119. Birbeck GL, Kalichi EM. Primary healthcare workers’ perceptions about barriers to health services in Zambia. Trop Doct 2004;34:84–86.

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Correspondence

EPILEPSY-ASSOCIATED BONE MINERAL DENSITY LOSS SHOULD BE PREVENTED

To the Editor: We read with interest Dr. Trevathan’s1 editorial commenting on the study by Sheth et al.2 We agree with Sheth et al.’s conclusions and compare them to our findings. In addition, we would advocate for specific additional interventions based on current evidence.3,4 Problems in bone metabolism in patients on antiepileptic drugs (AEDs) are well known.3,4 Sheth et al. found that bone mineral density (BMD) was low in children on AEDs and that epilepsy duration was negatively correlated with BMD. We found that vitamin D levels were low in both adults and children on AEDs. Polytherapy in children and therapy duration and enzyme-inducing AEDs in adults were negatively correlated with BMD.3,4 In his editorial, Dr. Trevathan advocates early screening and intervention.1 We propose additional interventions.5,6 1) Measurement of BMD at the start of treatment and periodically on an individualized basis at followup. Although the International Society for Clinical Densitometry (ISCD) did not specify epilepsy in its recent position development statement as an indication for BMD measurements in children, special considerations in children with decreased mobility were provided. 2) Monitoring of vitamin D (25-OHD) levels to help adjust the vitamin D dosing on an individualized basis. 3) Enforcement of adequate calcium intake and vitamin D supplementation at each clinic visit. 4) Vitamin D replacement at doses of 400 –2,000 IU/day as prophylaxis at the start of therapy.6 In addition, we recommend the following: higher doses in patients with low baseline vitamin D levels, 2,000 IU/day in children, and 4,000 IU/day in adults. We have shown such doses to be safe; and doses of 5,000 –15,000 IU/day in patients with osteomalacia.5 Our recommendations are based on two randomized trials where we investigated the effect of vitamin D supplementation on BMD in adults and children on AEDs. We found that 4,000 IU/day was more effective than 400 IU/day in adults, and that 2,000 and 400 IU/day in children had similar effects.5 Our

experience supports Drezner’s recommendation of supplementation with vitamin D using higher doses. However, when he made his recommendation, evidence for the effectiveness of these guidelines was not available.6 Our study provided level I evidence according to the American Academy of Neurology guidelines and level II evidence according to the International League Against Epilepsy guidelines in support of these recommendations.5 Mohamad A. Mikati, Nour Ataya, Ghada El-Hajj Fuleihan, Beirut, Lebanon Disclosure: The authors report no disclosures.

Reply from the Author: I thank Dr. Mikati for providing some specific proposals regarding the screening for and treatment of BMD loss among children with epilepsy consistent with published data. Unfortunately, the risk of BMD loss among children treated with antiseizure drugs occurs in a population of children who often do not receive adequate calcium intake. The American Academy of Pediatrics (AAP) has provided specific recommendations for increasing physical activity and increasing intake of fruits, vegetables, and low fat milk products in order to optimize bone health.7 Neurologists should familiarize themselves with these AAP recommendations and incorporate them into their counseling of patients and their families consistent with Dr. Mikati’s suggestions. The ISCD, as pointed out by Dr. Mikati, recommended standards for laboratories performing studies to diagnose and monitor BMD loss in a variety of populations, including some recommendations for children and for those with motor impairment (e.g., cerebral palsy). However, the ISCD guidelines note the need for further studies among children. Furthermore, the ISCD guidelines state that the diagnosis of osteoporosis should not be made based upon densitometric criteria alone, and that therapeutic interventions should not be based upon a single DXA measurement. ISCD guidelines recommend that prior to treatment, when technically feasible, all children have spine and total body less head bone mineral content and bone mineral density (BMD) measurements.8 Neurology 72

March 10, 2009

943

The AAP recommends that all children receive 200 IU of vitamin D supplements as infants and continue through adolescence, but the AAP has not recommended vitamin D doses specifically for children on antiseizure drugs.9 Dr. Mikati mentions his study on vitamin D therapy and significant increases in BMD among children with epilepsy treated with antiseizure drugs.5 In the absence of other clinical trials of vitamin D therapy among children with epilepsy, Dr. Mikati’s proposal that children with epilepsy be treated with 2,000 IU/day of vitamin D is consistent with other authors’ recommendations,6 but additional clinical trials of vitamin D supplementation among children on antiseizure drugs have not been published. Dr. Mikati’s recommended approach is important and is a starting point for further discussion on preventing BMD loss among children treated with antiseizure drugs. Additional studies are needed and this issue deserves the attention of organizations and committees that develop treatment guidelines for these specific patient populations. Edwin Trevathan, MD, MPH, Atlanta, GA Disclosure: The author reports no disclosures. Copyright © 2009 by AAN Enterprises, Inc. 1. 2. 3.

4.

5.

6. 7.

8.

9.

Trevathan E. Epilepsy-associated bone mineral density loss should be prevented. Neurology 2008;70:166 –167. Sheth RD, Binkley N, Hermann BP. Progressive bone deficit in epilepsy. Neurology 2008;70:170 –176. Farhat G, Yamout B, Mikati MA, Demirjian S, Sawaya R, El-Hajj Fuleihan G. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology 2002;58:1348 – 1353. El-Hajj Fuleihan G, Dib L, Yamout B, Sawaya R, Mikati M. Predictors of bone density in ambulatory patients on antiepileptic drugs. Bone 2008;43:149 –155. Mikati MA, Dib L, Yamout B, Sawaya R, Rahi AC, Fuleihan G. Two randomized vitamin D trials in ambulatory patients on anticonvulsants: Impact on bone. Neurology 2006;67:2005–2014. Drezner MK. Treatment of anticonvulsant drug-induced bone disease. Epilepsy Behav 2004;5:S41– 47. Greer FR, Krebs NF, Committee on Nutrition. Optimizing bone health and calcium intakes of infants, children, and adolescents. Pediatrics 2006;117:578 –585. Official Positions and Official Pediatric Positions of the International Society for Clinical Densitometry. Available at: at www.ISCD.org. Gartner LM, Greer FR, the Section on Breastfeeding and Committee on Nutrition. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics 2003;111:908 –910.

DYSLIPIDEMIA IS A PROTECTIVE FACTOR IN AMYOTROPHIC LATERAL SCLEROSIS

To the Editor: We read the article by Dupuis et al.1 with interest. The authors caution clinicians treating patients with amyotrophic lateral sclerosis (ALS) 944

Neurology 72

March 10, 2009

with dyslipidemia with lipid lowering drugs since dyslipidemia is a protective factor in ALS. We recently performed a study using wobbler mice treated with 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors (statin). The results showed that the statin group had significantly increased duration of normal functioning of the forelimbs yet the contraction of forelimbs was delayed. The wobbler mouse carries a mutation in the Vps54 gene coding for a protein2 involved in the retrograde transport of late endosomes from the periphery to the Golgi apparatus.3 This type of mouse has long been used to test the efficacy of novel treatments for human motor neuron disease.4 Since statin has a pleiotropic effect including anti-inflammatory effect on Alzheimer disease (AD) and possible neuroprotective effect on Parkinson disease (PD), we investigated the neuroprotective effect of statin on the wobbler mouse. Atorvastatin was mixed with feed at 0.01% (10 mg/kg) and randomly given to symptomatic wobbler mice (3– 4 weeks of age). Control group mice were given normal feed. Motor function was evaluated with the degree of contraction (five stages: normal to severe contraction) of forelimbs and muscle strength using a dynamometer. Symptomatic evaluation was performed until bilateral forelimbs changed to moderate contracture. Atorvastatin group significantly increased the duration until the loss of function of forelimbs (average 4.7 weeks). Progression of muscle weakness was significantly delayed in the atorvastatin group. Based on these data, we concluded that statin has a neuroprotective effect on the wobbler mouse. We also confirmed that atorvastatin has a neuroprotective effect against glutamate-induced sliced spinal cord cultures. Although an unfavorable relationship between ALS and statin has been reported,5 we contend that dyslipidemia brings a toxic effect to neurons and statin has a positive effect on ALS. Y. Yoshii, K. Ikeda, K. Iwamoto, Y. Kawase, Y. Iwasaki, Tokyo, Japan Disclosure: The authors report no disclosures.

Reply from the Authors: We thank Dr Yoshii et al. for providing their unpublished results suggesting a protective effect of atorvastatin in the wobbler mouse. However, we have several concerns about their findings and subsequent conclusions. First, the relevance of the wobbler mouse as a model for human treatments strategies with regard to ALS is unclear. To our knowledge, there is no known

mutation of the Vps54 gene in ALS cases and the symptoms developed by the wobbler mouse are closer to spinal muscular atrophy than ALS. Second, Yoshii and colleagues based the rationale of their studies on the neuroprotective effect of statins in other neurodegenerative diseases (AD and PD) and their results show that the wobbler mouse is similarly protected. We do not claim that statins are devoid of neuroprotective or anti-inflammatory properties that could make them useful in some neurodegenerative conditions. However, we and others have suggested that statins might be detrimental in ALS because of their systemic and widely documented hypolipemic effect that would obscure a potential neuroprotection. Our assumption is based on our own results showing the probable “protective” effect of hyperlipemia in patients with ALS and also on results5 suggesting that statin intake could accelerate the ALS disease process. Yoshii et al.’s commentary illustrates that, as suggested by numerous recent studies, there are a number of steps between preclinical studies in mice and clinical trials in patients with ALS. Our studies have consistently shown profound differences between mSOD1 mice energy metabolism and patients with ALS.

Murine metabolism is strikingly different between mice and men and we therefore think that the discrepancy between our results and those of Yoshii et al. may be due to interspecies differences. Vincent Meininger, Jean-Philippe Loeffler, Luc Dupuis, Paris, France Disclosure: The authors report no disclosures. Copyright © 2009 by AAN Enterprises, Inc. 1.

2.

3.

4.

5.

Dupuis L, Corcia P, Fergani A, et al. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 2008;70:1004 –1009. Schmitt-John T, Drepper C, Mussmann A, et al. Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse. Nat Genet 2005;37: 1213–1215. Liewen H, Meinhold-Heerlein I, Oliveira V, et al. Characterization of the human GARP (Golgi associated retrograde protein) complex. Exp Cell Res 2005;306: 24 –34. Duchen LW, Strich SJ. An hereditary motor neurone disease with progressive denervation of muscle in the mouse: the mutant ‘wobbler.’ J Neurol Neurosurg Psychiatry 1968;31:535–542. Edwards IR, Star K, Kiuru A. Statins, neuromuscular degenerative disease and an amyotrophic lateral sclerosis-like syndrome: an analysis of individual case safety reports from vigibase. Drug Saf 2007;30:515–525.

Neurology 72

March 10, 2009

945

Correspondence

EPILEPSY-ASSOCIATED BONE MINERAL DENSITY LOSS SHOULD BE PREVENTED

To the Editor: We read with interest Dr. Trevathan’s1 editorial commenting on the study by Sheth et al.2 We agree with Sheth et al.’s conclusions and compare them to our findings. In addition, we would advocate for specific additional interventions based on current evidence.3,4 Problems in bone metabolism in patients on antiepileptic drugs (AEDs) are well known.3,4 Sheth et al. found that bone mineral density (BMD) was low in children on AEDs and that epilepsy duration was negatively correlated with BMD. We found that vitamin D levels were low in both adults and children on AEDs. Polytherapy in children and therapy duration and enzyme-inducing AEDs in adults were negatively correlated with BMD.3,4 In his editorial, Dr. Trevathan advocates early screening and intervention.1 We propose additional interventions.5,6 1) Measurement of BMD at the start of treatment and periodically on an individualized basis at followup. Although the International Society for Clinical Densitometry (ISCD) did not specify epilepsy in its recent position development statement as an indication for BMD measurements in children, special considerations in children with decreased mobility were provided. 2) Monitoring of vitamin D (25-OHD) levels to help adjust the vitamin D dosing on an individualized basis. 3) Enforcement of adequate calcium intake and vitamin D supplementation at each clinic visit. 4) Vitamin D replacement at doses of 400 –2,000 IU/day as prophylaxis at the start of therapy.6 In addition, we recommend the following: higher doses in patients with low baseline vitamin D levels, 2,000 IU/day in children, and 4,000 IU/day in adults. We have shown such doses to be safe; and doses of 5,000 –15,000 IU/day in patients with osteomalacia.5 Our recommendations are based on two randomized trials where we investigated the effect of vitamin D supplementation on BMD in adults and children on AEDs. We found that 4,000 IU/day was more effective than 400 IU/day in adults, and that 2,000 and 400 IU/day in children had similar effects.5 Our

experience supports Drezner’s recommendation of supplementation with vitamin D using higher doses. However, when he made his recommendation, evidence for the effectiveness of these guidelines was not available.6 Our study provided level I evidence according to the American Academy of Neurology guidelines and level II evidence according to the International League Against Epilepsy guidelines in support of these recommendations.5 Mohamad A. Mikati, Nour Ataya, Ghada El-Hajj Fuleihan, Beirut, Lebanon Disclosure: The authors report no disclosures.

Reply from the Author: I thank Dr. Mikati for providing some specific proposals regarding the screening for and treatment of BMD loss among children with epilepsy consistent with published data. Unfortunately, the risk of BMD loss among children treated with antiseizure drugs occurs in a population of children who often do not receive adequate calcium intake. The American Academy of Pediatrics (AAP) has provided specific recommendations for increasing physical activity and increasing intake of fruits, vegetables, and low fat milk products in order to optimize bone health.7 Neurologists should familiarize themselves with these AAP recommendations and incorporate them into their counseling of patients and their families consistent with Dr. Mikati’s suggestions. The ISCD, as pointed out by Dr. Mikati, recommended standards for laboratories performing studies to diagnose and monitor BMD loss in a variety of populations, including some recommendations for children and for those with motor impairment (e.g., cerebral palsy). However, the ISCD guidelines note the need for further studies among children. Furthermore, the ISCD guidelines state that the diagnosis of osteoporosis should not be made based upon densitometric criteria alone, and that therapeutic interventions should not be based upon a single DXA measurement. ISCD guidelines recommend that prior to treatment, when technically feasible, all children have spine and total body less head bone mineral content and bone mineral density (BMD) measurements.8 Neurology 72

March 10, 2009

943

The AAP recommends that all children receive 200 IU of vitamin D supplements as infants and continue through adolescence, but the AAP has not recommended vitamin D doses specifically for children on antiseizure drugs.9 Dr. Mikati mentions his study on vitamin D therapy and significant increases in BMD among children with epilepsy treated with antiseizure drugs.5 In the absence of other clinical trials of vitamin D therapy among children with epilepsy, Dr. Mikati’s proposal that children with epilepsy be treated with 2,000 IU/day of vitamin D is consistent with other authors’ recommendations,6 but additional clinical trials of vitamin D supplementation among children on antiseizure drugs have not been published. Dr. Mikati’s recommended approach is important and is a starting point for further discussion on preventing BMD loss among children treated with antiseizure drugs. Additional studies are needed and this issue deserves the attention of organizations and committees that develop treatment guidelines for these specific patient populations. Edwin Trevathan, MD, MPH, Atlanta, GA Disclosure: The author reports no disclosures. Copyright © 2009 by AAN Enterprises, Inc. 1. 2. 3.

4.

5.

6. 7.

8.

9.

Trevathan E. Epilepsy-associated bone mineral density loss should be prevented. Neurology 2008;70:166 –167. Sheth RD, Binkley N, Hermann BP. Progressive bone deficit in epilepsy. Neurology 2008;70:170 –176. Farhat G, Yamout B, Mikati MA, Demirjian S, Sawaya R, El-Hajj Fuleihan G. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology 2002;58:1348 – 1353. El-Hajj Fuleihan G, Dib L, Yamout B, Sawaya R, Mikati M. Predictors of bone density in ambulatory patients on antiepileptic drugs. Bone 2008;43:149 –155. Mikati MA, Dib L, Yamout B, Sawaya R, Rahi AC, Fuleihan G. Two randomized vitamin D trials in ambulatory patients on anticonvulsants: Impact on bone. Neurology 2006;67:2005–2014. Drezner MK. Treatment of anticonvulsant drug-induced bone disease. Epilepsy Behav 2004;5:S41– 47. Greer FR, Krebs NF, Committee on Nutrition. Optimizing bone health and calcium intakes of infants, children, and adolescents. Pediatrics 2006;117:578 –585. Official Positions and Official Pediatric Positions of the International Society for Clinical Densitometry. Available at: at www.ISCD.org. Gartner LM, Greer FR, the Section on Breastfeeding and Committee on Nutrition. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics 2003;111:908 –910.

DYSLIPIDEMIA IS A PROTECTIVE FACTOR IN AMYOTROPHIC LATERAL SCLEROSIS

To the Editor: We read the article by Dupuis et al.1 with interest. The authors caution clinicians treating patients with amyotrophic lateral sclerosis (ALS) 944

Neurology 72

March 10, 2009

with dyslipidemia with lipid lowering drugs since dyslipidemia is a protective factor in ALS. We recently performed a study using wobbler mice treated with 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors (statin). The results showed that the statin group had significantly increased duration of normal functioning of the forelimbs yet the contraction of forelimbs was delayed. The wobbler mouse carries a mutation in the Vps54 gene coding for a protein2 involved in the retrograde transport of late endosomes from the periphery to the Golgi apparatus.3 This type of mouse has long been used to test the efficacy of novel treatments for human motor neuron disease.4 Since statin has a pleiotropic effect including anti-inflammatory effect on Alzheimer disease (AD) and possible neuroprotective effect on Parkinson disease (PD), we investigated the neuroprotective effect of statin on the wobbler mouse. Atorvastatin was mixed with feed at 0.01% (10 mg/kg) and randomly given to symptomatic wobbler mice (3– 4 weeks of age). Control group mice were given normal feed. Motor function was evaluated with the degree of contraction (five stages: normal to severe contraction) of forelimbs and muscle strength using a dynamometer. Symptomatic evaluation was performed until bilateral forelimbs changed to moderate contracture. Atorvastatin group significantly increased the duration until the loss of function of forelimbs (average 4.7 weeks). Progression of muscle weakness was significantly delayed in the atorvastatin group. Based on these data, we concluded that statin has a neuroprotective effect on the wobbler mouse. We also confirmed that atorvastatin has a neuroprotective effect against glutamate-induced sliced spinal cord cultures. Although an unfavorable relationship between ALS and statin has been reported,5 we contend that dyslipidemia brings a toxic effect to neurons and statin has a positive effect on ALS. Y. Yoshii, K. Ikeda, K. Iwamoto, Y. Kawase, Y. Iwasaki, Tokyo, Japan Disclosure: The authors report no disclosures.

Reply from the Authors: We thank Dr Yoshii et al. for providing their unpublished results suggesting a protective effect of atorvastatin in the wobbler mouse. However, we have several concerns about their findings and subsequent conclusions. First, the relevance of the wobbler mouse as a model for human treatments strategies with regard to ALS is unclear. To our knowledge, there is no known

mutation of the Vps54 gene in ALS cases and the symptoms developed by the wobbler mouse are closer to spinal muscular atrophy than ALS. Second, Yoshii and colleagues based the rationale of their studies on the neuroprotective effect of statins in other neurodegenerative diseases (AD and PD) and their results show that the wobbler mouse is similarly protected. We do not claim that statins are devoid of neuroprotective or anti-inflammatory properties that could make them useful in some neurodegenerative conditions. However, we and others have suggested that statins might be detrimental in ALS because of their systemic and widely documented hypolipemic effect that would obscure a potential neuroprotection. Our assumption is based on our own results showing the probable “protective” effect of hyperlipemia in patients with ALS and also on results5 suggesting that statin intake could accelerate the ALS disease process. Yoshii et al.’s commentary illustrates that, as suggested by numerous recent studies, there are a number of steps between preclinical studies in mice and clinical trials in patients with ALS. Our studies have consistently shown profound differences between mSOD1 mice energy metabolism and patients with ALS.

Murine metabolism is strikingly different between mice and men and we therefore think that the discrepancy between our results and those of Yoshii et al. may be due to interspecies differences. Vincent Meininger, Jean-Philippe Loeffler, Luc Dupuis, Paris, France Disclosure: The authors report no disclosures. Copyright © 2009 by AAN Enterprises, Inc. 1.

2.

3.

4.

5.

Dupuis L, Corcia P, Fergani A, et al. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 2008;70:1004 –1009. Schmitt-John T, Drepper C, Mussmann A, et al. Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse. Nat Genet 2005;37: 1213–1215. Liewen H, Meinhold-Heerlein I, Oliveira V, et al. Characterization of the human GARP (Golgi associated retrograde protein) complex. Exp Cell Res 2005;306: 24 –34. Duchen LW, Strich SJ. An hereditary motor neurone disease with progressive denervation of muscle in the mouse: the mutant ‘wobbler.’ J Neurol Neurosurg Psychiatry 1968;31:535–542. Edwards IR, Star K, Kiuru A. Statins, neuromuscular degenerative disease and an amyotrophic lateral sclerosis-like syndrome: an analysis of individual case safety reports from vigibase. Drug Saf 2007;30:515–525.

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Calendar

Neurology® publishes short announcements of meetings and courses related to the field. Items must be received at least 6 weeks before the first day of the month in which the initial notice is to appear. Send Calendar submissions to Calendar, Editorial Office, Neurology®, Suite 214, 20 SW 2nd Ave., P.O. Box 178, Rochester, MN 55903 [email protected]

2009 MAR. 26 –27 The International Scientific Symposium, Epilepsy & Sleep Update, will be held in Kempenhaeghe, Netherlands. The central theme is diagnostics: differential diagnosis of epilepsy, seizures, and sleep disorders. For more information about the scientific symposium, visit www.kempenhaeghe.nl. APR. 2– 4 The Innsbruck Colloquium on Status Epilepticus 2009 will be held at the Congress Innsbruck, Austria. [email protected]; www.innsbruck-SE2009.eu. APR. 3 5th Annual Contemporary Issues in Pituitary: Casebase Management Update will be held at the Cleveland Clinic Lerner Research Institute in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details. APR. 20 –22 Leksell Gamma Knife® Perfexion™ Upgrade Course will be held at the Gamma Knife Center in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 2232273, ext 53449, or at [email protected] for seminar details. APR. 25–MAY 2 AAN Annual Meeting will be held in Seattle, Washington State Convention & Trade Center, WA. American Academy of Neurology: tel (800) 879-1960; www.aan.com/am. st

APR. 26 The 21 Annual Symposium on the Treatment of Headaches and Facial Pain will be held at the New York Marriott East Side Hotel, New York, NY. For further details please contact: Alexander Mauskop, MD; tel (212) 794-3550; fax (212) 794-0591; [email protected]. MAY 3– 6 2nd International Epilepsy Colloquium, Pediatric Epilepsy Surgery Cite´ Internationale will be held in Lyon, France. http://epilepsycolloquium2009ams.fr. MAY 6 –10 International SFEMG Course and Xth Quantitative EMG conference will be held in Venice, Italy. tel 39041-951112; [email protected]; www.congressvenezia.it. MAY 8 The Office of Continuing Medical Education at the University of Michigan Medical School is sponsoring a CME conference entitled: Movement Disorders: A Practical Approach. It is located at The Inn at St. John’s in Plymouth, Michigan. tel (734) 763-1400; fax (734) 936-1641. MAY 11–12 Music and the Brain will be held at the InterContinental Hotel & Bank of America Conference Center in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details. 946

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MAY 15–17 The Fifth International Conference on Alzheimer’s Disease and Related Disorders in the Middle East will be held in Limassol, Cyprus. www.worldeventsforum.com/alz. MAY 28 –30 6th International Headache Seminary. Focus on Headaches: New Frontier in Mechanisms and Management will be held at the Grand Hotel des Iles Borromees in Stresa (Italy); tel/fax 02 7063 8067; [email protected]. JUN. 8 –12 Leksell Gamma Knife® Perfexion™ Introductory Course will be held at the Gamma Knife Center in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details. JUN. 12 Mellen Center Regional Symposium on Multiple Sclerosis will be held at the InterContinental Hotel & Bank of America Conference Center in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details. JUN. 16 –20 14th Annual meeting of the International Society for the History of the Neurosciences, including special sessions on Darwin and ‘Neurology and War,’ will be held at Charleston, South Carolina. For information, visit www.ishn.org or e-mail [email protected]. JUN. 19 –24 Epileptology Symposium will be held at the InterContinental Hotel & Bank of America Conference Center, in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details. JUL. 7–10 SickKids Centre for Brain & Behaviour International Symposium. [email protected]; www.sickkids.ca/ learninginstitute. JUL. 16 –18 Mayo Clinic Neurology in Clinical Practice2009 will be held at the InterContinental Hotel, Chicago, IL. Mayo CME: tel (800) 323-2688; [email protected]; http:// www.mayo.edu/cme/neurology-neurologic-surgery.html. JUL. 21–27 Cleveland Spine Review 2009 will be held at the Embassy Suites Cleveland–Rockside Hotel in Independence, OH. Contact Martha Tobin at (216) 445-3449 or (800) 2232273, ext 53449, or at [email protected] for seminar details. AUG. 17–19 Leksell Gamma Knife® Perfexion™ Upgrade Course will be held at the Gamma Knife Center in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details.

SEP. 12–15 13th Congress of the European Federation of Neurological Societies will be held in Florence, Italy. For more information: tel ⫹41 22 908 0488; http://www.kenes.com/efns2009/ index.asp; [email protected]. SEP. 16 –19 Annual Conference of the German Genetics Society will be held at Cologne, Germany; tel 49(0)3641-3-5332-22; [email protected]. SEP. 25 Practical Pearls in Neuro-Ophthalmology–International Symposium in Honour of Dr. James Sharpe will be held on September 25, 2009 at the University of Toronto Conference Centre, Toronto, Ontario. For further information contact the Office of Continuing Education & Professional Development, Faculty of Medicine, University of Toronto: tel (416) 978-2719; (888) 512-8173; fax (416) 9467028; [email protected]; http://events.cmetoronto. ca/website/index/OPT0907. OCT. 8 –11 The Third World Congress on Controversies in Neurology. Full information is available at: ComtecMed - Medical Congresses, PO Box 68, Tel-Aviv, 61000 Israel; tel ⫹972– 3-5666166; fax ⫹972–3-5666177; [email protected]; www.comtecmed.com/cony. OCT. 11 Symposium on Etiology, Pathogenesis, and Treatment of Parkinson’s Disease and Other Movement Disorders will be held at the Baltimore Marriott Waterfront Hotel, in Baltimore, Maryland. www.Parkinson-Study-Group.org.

OCT. 24 –30 19th World Congress of Neurology, WCN 2009, will be held in Bangkok, Thailand. www.wcn2009bangkok.com. OCT. 29 –30 Clinical Trials on Alzheimer’s Disease will be held in Las Vegas at the Lou Ruvo Brain Institute. For more information, please visit www.ctad.fr. NOV. 19 –22 The Sixth International Congress on Vascular Dementia will be held Barcelona, Spain. For further details, please contact: Kenes International 17 Rue du Cendrier, P.O. Box 1726, CH-1211, Geneva 1, Switzerland; tel ⫹41 22 908 0488; fax ⫹41 22 732 2850; [email protected]; http://www.kenes.com/vascular. DEC. 3– 6 Neuromodulation 2009 Encore will be held at Wynn Las Vegas in NV. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details. DEC. 7–11 Leksell Gamma Knife® Perfexion™ Introductory Course will be held at the Gamma Knife Center in Cleveland, OH. Contact Martha Tobin at (216) 445-3449 or (800) 223-2273, ext 53449, or at [email protected] for seminar details.

2010 MAY 2–7 11th International Child Neurology Congress will be held in Cairo, Egypt; http://www.icnc2010.com/.

Save These Dates for AAN CME Opportunities! Mark these upcoming dates on your calendar for these exciting continuing education opportunities, where you can catch up on the latest neurology information. AAN Annual Meetings ● April 25—May 2, 2009, Seattle, Washington State Convention & Trade Center ● April 10 –17, 2010, Toronto, Ontario, Canada, Toronto Convention Centre

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In the next issue of Neurology® Volume 72, Number 11, March 17, 2009 www.neurology.org THE MOST WIDELY READ AND HIGHLY CITED PEER-REVIEWED NEUROLOGY JOURNAL

THIS WEEK IN Neurology®

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Highlights of the March 17 issue

EDITORIALS

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The numb and the restless: Peripheral neuropathy and RLS Michael Pourfar and Andrew Feigin Sensitivity vs specificity: Progress and pitfalls in defining MRI criteria for pediatric MS Tanuja Chitnis and Istvan Pirko

VIEWS & REVIEWS

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George A. Schumacher, MD, FAAN (1912–2008) Robert W. Hamill and John F. Kurtzke

ARTICLES

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MRI in the diagnosis of pediatric multiple sclerosis D.J.A. Callen, M.M. Shroff, H.M. Branson, et al.

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Role of MRI in the differentiation of ADEM from MS in children D.J.A. Callen, M.M. Shroff, H.M. Branson, et al.

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A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures K. Schlachter, U. Gruber-Sedlmayr, et al. High-frequency oscillations mirror disease activity in patients with epilepsy M. Zijlmans, J. Jacobs, R. Zelmann, F. Dubeau, et al.

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Suicidality, depression screening, and antiepileptic drugs: Reaction to the FDA alert B.F. Shneker, J.S. Cios, and J.O. Elliott

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HIV DNA and cognition in a Thai longitudinal HAART initiation cohort: The SEARCH 001 Cohort Study V.G. Valcour, et al., for the Southeast Asia Research Collaboration with the University of Hawaii (SEARCH) 001 protocol team

Neuropeptide Y: Its multiple effects in the CNS and potential clinical significance Eduardo E. Benarroch

CLINICAL/SCIENTIFIC NOTES

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Sarcoidosis presenting as brainstem ischemic stroke Babak B. Navi and Lisa M. DeAngelis

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Hemorrhaging focal encephalitis under fingolimod (FTY720) treatment F. Leypoldt, A. Mu ¨nchau, F. Moeller, M. Bester, et al.

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Serum VEGF levels in POEMS syndrome and in immune-mediated neuropathies E. Nobile-Orazio, F. Terenghi, C. Giannotta, et al.

Is there a higher risk of restless legs syndrome in peripheral neuropathy? E. Hattan, C. Chalk, and R.B. Postuma

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Multiple sclerosis therapeutics: Unexpected outcomes clouding undisputed successes Heinz Wiendl and Reinhard Hohlfeld

CLINICAL IMPLICATIONS OF NEUROSCIENCE RESEARCH

IN MEMORIAM

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Hippocampal atrophy rates in Alzheimer disease: Added value over whole brain volume measures W.J.P. Henneman, J.D. Sluimer, J. Barnes, et al.

VIDEO NEUROIMAGES

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Postinfectious ocular flutter Michael Waisbourd and Anat Kesler

RESIDENT & FELLOW SECTION

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Teaching NeuroImages: Face of the giant panda and her cub: MRI correlates of Wilson disease Shivakumar R and Sanjeev V. Thomas

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Emerging Subspecialties in Neurology: Neuro-oncology: A developing subspecialty with many opportunities B. Vaillant, S.-H. Kuo, and J. de Groot

CORRESPONDENCE

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Neuropathology of brain death Varicella zoster virus vasculopathies Central obesity and increased risk of dementia

FUTURE ISSUES

Subject to change.

Abstracts In the Next Issue of Neurology®

THE OFFICIAL JOURNAL OF THE AMERICAN ACADEMY OF NEUROLOGY