537 References 1. Rosenberg DR, Keshavan MS, Dick EL, et al: Corpus callosal mor2. phology in treatment naive pediatric obsessive compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 1997;21:1269-1283. MacMaster FP, Dick EL, Keshavan MS, Rosenberg DR: Corpus callosal signal intensity in treatment naive pediatric obsessive compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 1999;23: 601-612. 3. deLacoste MC, Kirkpatrick JB, Ross ED: Topography of the human cor- Acute disseminated encephalomyelitis is an acute inflammatory demyelinating disease of the central nervous system, typically characterized by onset of neurologic deficits days to weeks after an episode of viral illness or vaccinations Although the lesions are predominantly located in the periventricular, deep, and subcortical white matter, other whole-brain lesions involving the cortical gray matter, brain stem, basal ganglia, and thalami are frequently pus callosum. J Neuropathol Exp Neurol 1985;44:578-591. observed .2,3 4. Seltzer B, Pandya DN: The topography of commissural fibers, in Jasper HH, Lepore F, Ptito M (eds): Two He~nispheres, One Brain. Functions of the Corpus Callosum. New York, Liss, 1986, 47-73. 5. Giedd JN, Rumsey JM, Castellanos FX, et al: A quantitative MRI study of the corpus callosum in children and adolescents. Dev Brain Res Hypocretin (also known as orexin) has recently been recognized as a neuropeptide, and hypocretin deficiency is responsible for idiopathic human narcolepsy,4 a condition characterized by excessive daytime sleepiness. Narcolepsy or hypersomnia has been reported in demyelinating diseases such as multiple sclerosis5 and acute disseminated encephalomyelitis,6 although the pre- ’ , 6. 7. 8. 1996;91:274-280. Rajapaske JC, Giedd JN, Rumsey JM, et al: Regional MRI measurements of the corpus callosum: A methodological and developmental study. Brain Dev 1996;18:379-388. Schaefer GB, Thompson JN, Bodensteiner JB, et al: Quantitative morphometric analysis of brain growth utilizing quantitative analysis of magnetic resonance imaging. J Child Neurol 1990;5:127-130. Schaefer GB, Bodensteiner JB, Thompson JN Jr, Wilson DA: Clinical and morphometric analysis of the hypoplastic corpus callosum. Arch cise mechanism remains unknown. We report a case of acute disseminated encephalomyelitis manifesting hypersomnia, hyperintense lesions in the hypothalamus on magnetic resonance imag- ing (MRI), and decreased hypocretin level in cerebrospinal fluid. Neurol 1991;48:933-936. 9. 10. Filteau MJ, Pourcher E, Bouchard RH, et al: Corpus callosum agenesis and psychosis in Andermann syndrome. Arch Neurol 1991;48: 1275-1280. Taylor M, David AS: Agenesis of the corpus callosum: A United Kingdom series of 56 cases. JNeurol Neurosurg Psychiatry 1998;64: 131-134. 11. 12. 13. 14. Myrianthopolous NC: Epidemiology of CNS malformations, in Myrianthopolous NC (ed): Handbook of Clinical Neurology. Amsterdam, Elsevier, 1987, 49-70. Bodensteiner J, Schafer GB, Breeding L, Cowan L: Hypoplasia of the corpus callosum: A study of 445 consecutive MRI scans. J Child Neurol 1994;9:47-49. Milner D: Neuropsychological studies of callosal agenesis. Psychol Med 1983;13:721-725. Baxter LR, Schwartz JM, Bergman KS, et al: Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessivecompulsive disorder. Arch Gen Psychiatry 1992;49:681-689. Case Report A 12-year-old previously healthy girl started to complain of drowsiness several days after an episode of rhinorrhea and low-grade fever. Within a few days, she fell asleep easily even during the daytime, although she was capable of taking a meal by herself and communicating properly with her family. A consulting doctor diagnosed her as having acute disseminated encephalomyelitis from neurologic and brain MRI findings. A T2-weighted MRI showed multiple foci of high-intensity signal in the midbrain, caudate, putamen, periventricular white matter, and subcortical white matter, and the hypothalamus was also involved (Figures 1 to 3). Her family history was unremarkable, and she had no recent vaccination. On admission, she could sit in the chair, talk with the examiner, and obey some verbal commands, but she frequently closed her eyes and was nodding off during physical examination. She had no cataplexy and no change of appetite. Her body temperature was 36.6°C, and heart rate and respiratory state were normal. Physical examination revealed no abnor- A Case of Acute Disseminated Encephalomyelitis Presenting Hypersomnia With Decreased Hypocretin Level in Cerebrospinal Fluid ABSTRACT A 12-year-old girl was diagnosed as having acute disseminated encephalomyelitis and manifested hypersomnia as the main clinical feature. Magnetic resonance imaging (MRI) revealed lesions in the bilateral hypothalamus in addition to other multifocal brain lesions involving the cerebral white matter, brain stem, and basal ganglia. The level of hypocretin in cerebrospinal fluid was decreased in this patient. Corticosteroid treatment resulted in improvement of the hypersomnia and resolution of MRI lesions in the hypothalamus and other regions. This case suggests that the arousal state control mechanism related to the hypocretin peptide/receptor system may be impaired in some patients with acute disseminated encephalomyelitis. (J Child Neurol 2002;17:537-539). Figure 1. Magnetic resonance T 2-weighted parasagittal image shows high-intensity signal in the posterior hypothalamus (arrowhead) in a addition to lesions in the anterior thalamus. Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 8, 2015 538 Figure 2. Axial T2-weighted image shows high signal intensity in the right midbrain. Figure 3. Axial T 2-weighted image shows high signal intensity in the white matter (large arrowhead), the bilateral basal ganglia (arrow), and the hypothalamus (small arrowhead). The high signal intensities in the frontal lobe cortexes are artifacts. malities. Neurologic evaluation showed hyperactive deep tendon reflexes bilaterally in lower extremities and a positive left extensor response but no abnormalities in cranial nerves and other motor and sensory systems and no symptoms of ataxia and vesicorectal disturbance. Blood examination showed a white blood cell count of 12 x 10’/L, C-reactive protein of 0.5 mg/dL, and erythrocyte sedimentation rate of 4 mm/hr. Cerebrospinal fluid analysis revealed a white blood cell count of 33 x 106/L (100% lymphocytes), protein and glucose concentrations of 28 mg/dL and 60 mg/dL, respectively, a myelin basic protein level of 57.2 pg/mL (normal < 102 pg/mL), an IgG index of 0.73, and no oligoclonal IgG band. Bacterial and viral cultures of cerebrospinal fluid were negative. Other blood tests were unremarkable, including complete blood cell count, biochemistry, electrolytes, coagulation system, complements, lactic acid, amino acids, blood gas analysis, and antinuclear and anti-DNA antibodies. Serum antiviral antibodies to varicella-zoster virus, cytomegalovirus, EpsteinBarr virus, and human herpesvirus 6 and antibacterial antibody to Mycoplasma pneumoniae indicated no recent infection by these organisms. Human leukocyte antigen typing of this patient was negative for DQB1*0602. An electroencephalogram (EEG) showed normal basic activity with no slow wave in the waking recordings. She was therefore judged to have no consciousness disturbance. Throughout EEG examination, she could not keep awake without being stimulated verbally. Multiple sleep latency tests revealed a mean sleep latency of 4.5 minutes with no sleep-onset rapid eye movement (REM) periods. The hypocretin-1 level in cerebrospinal fluid was measured with a 125I hypocretin-1 radioimmunoassay kit (Phoenix Pharmaceuticals, Mountain View, CA). The hypocretin level was decreased (102 pg/mL) compared with the values of age-matched control subjects (238-376 pg/mL). From the second hospital day, high-dose intravenous methylprednisolone (30 mg/kg) was given for 3 consecutive days followed by oral prednisolone therapy. Her drowsiness gradually decreased from around the initiation of oral prednisolone, and she began to read books or draw her favorite pictures. She no longer noticed drowsiness when she was discharged on the twelfth hospital day. An MRI examination repeated 3 weeks after discharge showed complete resolution of hypothalamic and other lesions, except faintly increased intensity in the bilateral basal ganglia on TZ weighted images. She remained symptom free during the follow-up period of 1 year. A cerebrospinal fluid examination was not repeated because of complete symptomatic recovery. The cerebrospinal fluid hypocretin-1 levels were measured in four other patients with acute disseminated encephalomyelitis but no hypothalamic lesions and were found to be within normal limits (data not shown). Of these four patients, two showed consciousness disturbance with abnormal EEGs but did not show hypersomnia, as in the present case. Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 8, 2015 539 Discussion Acute disseminated encephalomyelitis is a monophasic inflam- Department of Neuropsychiatry matory demyelinating disease of the central nervous system pre- Akita University School of Medicine senting multifocal neurologic disturbances and an altered consciousness state. Variable degrees of consciousness disturbance were observed in about 70% of patients in large series of acute disseminated encephalomyelitis2~3; however, there was no description of hypersomnia in these series. Although the frequency of hypothalamic lesions detected by MRI has not been reported, thalamic involvement was found in up to 40% of patients in previous reports.2,3 The present case indicates that a patient with acute disseminated encephalomyelitis manifesting hypersomnia might be misdiagnosed as consciousness disturbance owing to cerebral cortex Akita, Japan Yuzo Tanabe, MD Division of Neurology Chiba Children’s Hospital Jun-ichi Takanashi, MD Yoichi Kohno, MD Department of Pediatrics Graduate School of Medicine Chiba University Chiba, Japan Takashi Kanbayashi, MD involvement. Recently, hypocretin cells relating to sleep and arousal regulation have been demonstrated in the posterior thalamus and rostral mid- brain, and these regions have been speculated to constitute the &dquo;waking center&dquo;7 because many hypersomnolent or narcoleptic patients associated with lesions of the diencephalon have been reported. In the present case, it is reasonable to consider that hypersomnia could have resulted from impaired control of the arousal state, judging from the normal EEG in the waking state and the posterior hypothalamic lesion on MRI. We speculate that the acute disseminated encephalomyelitis lesions can injure the hypocretin cells in the posterior hypothalamus, resulting in dysfunction of the hypocretin system and decreased cerebrospinal fluid hypocretin level. To our knowledge, this is the first report of a decreased hypocretin level in a demyelinating disease manifesting hypersomnia. Recent studies have demonstrated that genetic alterations in the preprohypocretin or hypocretin receptor 2 gene induce narcolepsy in animals .8, Although the involvement of hypocretinrelated genes is rare in human narcolepsy, a series of studies that measured hypocretin contents in cerebrospinal fluid and brain suggest that a deficit in hypocretin neurotransmission is involved in most cases .4,10 Since a reduction of hypocretin in the cerebrospinal fluid is likely to reflect the major pathophysiology of the disease in humans, measuring cerebrospinal fluid hypocretin levels may thus become a standard diagnostic tool for narcolepsy.&dquo;l Decreased cerebrospinal fluid hypocretin levels have also been recognized in symptomatic narcolepsy after a diencephalic strokel2 and hypersomnolence after removal of a hypothalamic tumor.l3 However, a decreased hypocretin level has not been described in inflammatory demyelinating disorders. 14 Further, our four other patients with acute disseminated encephalomyelitis also had normal hypocretin levels. However, the evaluation of the cerebrospinal fluid hypocretin levels in patients with acute disseminated encephalomyelitis has just begun; further investigations will elucidate the significance of hypocretin in the pathophysiology of acute disseminated encephalomyelitis. Received Feb 5, 2002. Received revised April 8, 2002. Accepted for publication April 16, 2002. Address correspondence to Dr Hiroald Kubota, Division of Neurology, Chiba Children’s Hospital, 579-1 Heta-chou, Midori-ku, Chiba, 266-0007, Japan. Tel: +8143 292 2111; fax: +8143 292 3815; e-mail: h-kubota@ta2.so-net.ne.jp. References 1. Alvord EC Jr: Disseminated encephalomyelitis: Its variations in form and their relationships to other diseases of the nervous system, in Vinken PJ, Bruyn GW, Klawans HL (eds): Handbook of Clinical Neurology, vol 47, series 3. Amsterdam, Elsevier Science Publishers, 1985; 467-502. 2. 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Sleep Med 2000;2: 13. 14. von Economo C: Sleep as a problem of localization. J Nerv Ment Dis 1930;71:249-259. Chemelli RM, Willie JT, Sinton CM, et al: Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation. Cell 1999;98:437-451. Lin L, Faraco J, Li R, et al: The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999;98:365-376. Peyron C, Faraco J, Rogers W, et al: A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000;6:991-997. Nishino S, Ripley B, Overeem S, et al: Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 2001;50:381-388. Scammell TE, Nishino S, Mignot E, Saper CB: Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke. Neurology 2001;56:1751-1753. Arii J, Kanbayashi T, Tanabe Y, et al: A hypersomnolent girl with decreased CSF hypocretin level after removal of a hypothalamic tumor. Neurology 2001;56:1775-1776. Ripley B, Overeem S, Fujiki N, et al: CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 2001;57: 2253-2258. Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 8, 2015