Narcolepsy Caused by Acute Disseminated Encephalomyelitis

OBSERVATION Narcolepsy Caused by Acute Disseminated Encephalomyelitis

Richard F. Gledhill, MD, MRCP; Peter R. Bartel, PhD; Yasushi Yoshida, MD, PhD; Seiji Nishino, MD, PhD; Thomas E. Scammell, MD

Background: Narcolepsy with cataplexy is caused by ueduct, which are consistent with acute disseminated a selective loss of hypocretin-producing neurons, but nar- encephalomyelitis. colepsy can also result from hypothalamic and rostral brainstem lesions. Results: After treatment with steroids, this patient’s subjective sleepiness, hypersomnia, and hypocretin defi- Patient: We describe a 38-year-old woman with severe ciency partially improved. daytime sleepiness, internuclear ophthalmoplegia, and bilateral delayed visual evoked potentials. Her multiple Conclusions: Autoimmune diseases such as acute dis- sleep latency test results demonstrated short sleep laten- seminated encephalomyelitis can produce narcolepsy. cies and 4 sleep-onset rapid eye movement sleep peri- Most likely, this narcolepsy is a consequence of demy- ods, and her cerebrospinal fluid contained a low con- elination and dysfunction of hypocretin pathways, but centration of hypocretin. Magnetic resonance imaging direct injury to the hypocretin neurons may also occur. showed T2 and fluid-attenuated inversion recovery hyperintensity along the walls of the third ventricle and aq- Arch Neurol. 2004;61:758-760

ARCOLEPSY IS CHARAC- REPORT OF A CASE terized by excessive daytime sleepiness and rapid eye movement A previously healthy, 38-year-old, black, (REM) sleep-related South African woman was admitted to Ga- symptomsN such as cataplexy. More than Rankuwa Hospital, Pretoria, Republic of 90% of people with narcolepsy with cata- South Africa, with 6 weeks of severe day- plexy have no detectable hypocretin/ time sleepiness and hypersomnia (total orexin in their cerebrospinal fluid sleep time about 16 of every 24 h). She re- (CSF),1,2 most likely because of a loss of ported forgetfulness and impaired vision but hypocretin-producing neurons.3,4 denied cataplexy, sleep paralysis, hypna- Because narcolepsy usually occurs spo- gogic hallucinations, a preceding viral in- radically in individuals positive for fection, fever, rash, or vaccination. Her body From the Department of human leukocyte antigen DQB1*0602, mass index was increased at 32.3 kg/m2. She Neurology, Medical University of Southern Africa, an autoimmune process is hypothesized was disoriented to time and place, and she Ga-Rankuwa Hospital, to injure the hypocretin neurons. was inattentive and had impaired memory. Pretoria, Republic of South Although the evidence for an inflamma- Visual acuity was 20/300 OD and 20/150 Africa (Dr Gledhill); the tory process is sparse, many have won- OS, and the pupils were 4 mm, with a weak Department of Neurology, dered whether autoimmune disorders reaction to light. She had bilateral inter- University of Pretoria and such as multiple sclerosis or acute dis- nuclear ophthalmoplegia with poor up- Pretoria Academic Hospital, seminated encephalomyelitis (ADEM) gaze and convergence. Cerebrospinal fluid Pretoria (Dr Bartel); the Center could cause narcolepsy.5-9 had no white blood cells, a normal glu- for Narcolepsy, Department of We describe an unusual patient with cose level, 44 mg/dL protein, and a nor- Psychiatry, Stanford secondary narcolepsy due to ADEM whose mal IgG index. Her morning cortisol level University, Stanford, Calif (Drs Yoshida and Nishino); and sleepiness was associated with sleep- was 8 µg/dL (221 nmol/L; normal range, the Department of Neurology, onset REM (SOREM) periods and a low 9-22 µg/dL [248-607 nmol/L]). Beth Israel Deaconess Medical CSF concentration of hypocretin that par- Electroencephalography performed Center, Boston, Mass tially improved along with her subjective while the patient was awake showed fron- (Dr Scammell). sleepiness. tal intermittent delta activity, a slow al-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 pha rhythm, and excessive theta activity. Magnetic reso- A nance imaging revealed multiple areas of T2 and fluid- attenuated inversion recovery hyperintensity involving the corona radiata and deep periventricular gray matter. This region of increased signal intensity was especially prominent around the third ventricle and aqueduct, involving most of the hypothalamus (Figure) and extend- ing rostrally to the basal forebrain. Scattered regions of contrast enhancement were evident throughout the hypothalamus, especially near the fornix. Rapid plasma re- agin, serum angiotensin-converting enzyme, human im- munodeficiency virus antibodies, autoantibody panel, and liver and thyroid function test results were all normal. She was positive for human leukocyte antigens DR2 and DQB1*0602. The unextracted hypocretin-1 level in CSF was low (87 pg/mL [24.4 pmol/L]; normal, Ͼ200 pg/mL [56.1 pmol/L]).1 On the basis of these laboratory results and her monophasic onset of symptoms, ADEM was diagnosed, and the patient was treated with high-dose steroids. Magnetic resonance imaging 1 month later showed B smaller, fewer lesions. Six months after her initial examination, the patient’s subjective sleepiness was partially improved, but she still took 3 to 4 nonrefreshing naps per day, each last- ing as long as an hour. Although she continued to have mildly impaired memory and visual acuity, with slight slowing of visual evoked potentials, her extraocular move- ments and attention were normal. Her multiple sleep latency test results demonstrated an average sleep latency of 4.4 minutes and SOREM periods in all 4 naps. The CSF hypocretin-1 level (148 pg/mL [41.5 pmol/L]) had increased to the intermediate range.1 On the basis of these test results and her persistent sleepiness, narcolepsy without cataplexy was diagnosed. The patient’s sleepiness partially responded to methylphenidate hydrochloride. One year after her initial examination, some sleepiness persisted, with a total daily sleep time of 12 hours without methylphenidate hydrochloride. Overnight poly- somnography results showed 7.6 hours of sleep with a sleep efficiency of 95%, REM latency of 52 minutes, 20% Coronal fluid-attenuated inversion recovery magnetic resonance images stage 1 sleep, normal proportions of all other stages, and demonstrate increased signal intensity in the hypothalamus, particularly near no sleep-disordered breathing. The multiple sleep la- the walls of the third ventricle (A) and in the corona radiata, floor of the tency test results were essentially unchanged, with an av- aqueduct, and raphe nuclei (B). erage sleep latency of 2.6 minutes and SOREM periods in 4 of 5 naps. cess of white blood cells, as in this case. The patient’s Peptides are most stable when frozen, but samples monophasic onset of symptoms with bilateral delayed vi- could be maintained only at ambient temperature dur- sual evoked potentials, internuclear ophthalmoplegia, and ing the 9 days of shipping from the Republic of South periventricular T2 hyperintensity makes ADEM the most Africa to the United States. Therefore, CSF also was ana- likely diagnosis, especially because multiple sclerosis is lyzed from 3 patients with other neurologic diseases (2 extremely rare among black South Africans. with motor neuron disease and 1 with spastic dysphonia). Because demyelinating diseases and narcolepsy may These specimens were collected within a few weeks of be caused by an autoimmune or neurodegenerative pro- our patient’s first lumbar puncture and shipped to- cess, many clinicians have taken a special interest in cases gether with this first sample. Hypocretin levels for the of narcolepsy associated with multiple sclerosis or ADEM. control subjects were all in the normal range (241-290 Hypersomnia and low hypocretin levels were reported pg/mL [67.6-81.4 pmol/L).1 in a girl with ADEM and a young woman with multiple sclerosis, but neither had SOREM periods or cata- 10,11 COMMENT plexy. In other cases of multiple sclerosis with narcolepsy, it is usually unclear whether the narcolepsy was We describe a patient with narcolepsy and low hypocre- caused by a focal lesion.5-9 The inflammatory lesions in tin levels due to ADEM. Although most patients with our patient clearly involved the hypothalamic regions in ADEM have CSF lymphocytosis, a few may have no ex- which hypocretin neurons are found and extended into

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 state-regulatory, hypocretin-responsive areas in the mid- Nishino, and Scammell); obtained funding (Drs Nishino brain and pons such as the raphe nuclei. In addition, her and Scammell); administrative, technical, and material sup- sleepiness was coincident with her ADEM. Thus, we think port (Drs Bartel, Yoshida, Nishino, and Scammell); study it is most likely that ADEM caused her narcolepsy, es- supervision (Drs Gledhill and Scammell). pecially because her hypocretin level and subjective sleepi- This study was supported by grants MH62589 and ness partially improved after treatment with steroids. MH01507 from the National Institutes of Health, Bethesda, Unlike previous patients with hypersomnia due to Md. ADEM, our patient had SOREM periods, possibly be- Corresponding author: Thomas E. Scammell, MD, De- cause she is DQB1*0602 positive, and these individuals partment of Neurology, Beth Israel Deaconess Medical Cen- enter REM sleep more quickly.12 More likely, it is be- ter, Harvard Institutes of Medicine, 77 Ave Louis Pasteur, cause her lesions involved REM-regulating pathways. The Boston, MA 02115 (e-mail: [email protected]). hypocretin neurons probably suppress REM sleep by in- creasing the activity of the locus coeruleus and dorsal raphe neurons via projections through the periaqueductal REFERENCES gray and midbrain tectum. Impaired hypocretin signal- ing along these pathways probably contributed to our pa- 1. Mignot E, Lammers G, Ripley B, et al. The role of cerebrospinal fluid hypocretin tient’s SOREM periods. measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neu- Low levels of hypocretin are specific for narcolepsy rol. 2002;59:1553-1562. 2. Krahn L, Pankratz V, Oliver L, Boeve B, Silber M. 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