First Attack of Kleine-Levin Syndrome Triggered by Influenza B Mimicking Influenza-Associated Encephalopathy

□ CASE REPORT □

First Attack of Kleine-Levin Syndrome Triggered by Influenza B Mimicking Influenza-associated Encephalopathy

Minori Kodaira and Kanji Yamamoto

Abstract

Six days after the onset of influenza B symptoms, a 14-year-old Japanese boy presented with encephalopathy-like symptoms, somnolence, irritability, and childishness, which we first considered was an atypical type of influenza-associated encephalopathy because the infection symptoms disappeared by day 4. His encephalopathy-like symptoms gradually improved, although he had repetitive hypersomnia attacks. Ow- ing to the patient’s clinical presentation and normal interleukin-6 levels in the cerebrospinal fluid during the first period of hypersomnia, we diagnosed him with Kleine-Levin syndrome (KLS) triggered by influenza B. The preceding influenza infection was not only a diagnostic clue of KLS but also a diagnostic confounding factor.

Key words: Kleine-Levin syndrome, recurrent hypersomnia, preceding infection, influenza, influenza- associated encephalopathy

(Intern Med 51: 1605-1608, 2012) (DOI: 10.2169/internalmedicine.51.7051)

with influenza-associated encephalopathy. Introduction Case Report Recurrent hypersomnia, which is a rare disorder that causes recurring periodic episodes of hypersomnia, has a A previously healthy 14-year-old Japanese boy who had male predominance with a typical age of onset in the teen- no family history of hypersomnia presented with high-grade age years (1). Kleine-Levin syndrome (KLS) is a disorder fever, cough, and general fatigue in March 2011. He was di- that is classified as a subtype of recurrent hypersomnia and agnosed with influenza B by a rapid antigen test that was that presents with recurrent hypersomnia plus binge eating, performed the following day, and he was treated with hypersexuality, cognitive disturbances, and/or odd behav- zanamivir inhalation (10 mg, twice daily). His symptoms ior (1, 2). Various infections often precede the onset and re- disappeared on day 4, but he was somnolent all day after occurrence of KLS (2, 3), although the infectious agents day 6. He exhibited disturbed concentration, cried, and on have rarely been identified (4-8). Patients with KLS often day 7, said, “I cannot concentrate on studying.” Brain com- present with cognitive disturbances, mood disorders, and ir- puted tomography (CT) and magnetic resonance imaging ritability (1, 2), and, thus, they are sometimes misdiagnosed (MRI) scans that were performed at another hospital de- as psychiatric disorders or encephalopathy (9). In this paper, tected no abnormal findings on day 8. Influenza-associated we report on a 14-year-old Japanese boy who presented encephalopathy was suspected, and he was transferred to our with normal interleukin-6 (IL-6) levels and slightly de- hospital for intensive care on day 9. creased levels of hypocretin in the cerebrospinal fluid (CSF) Upon admission, findings from a physical examination during the first attack of KLS, which occurred just after an showed a temperature of 36.0℃, a pulse of 70 beats/min, influenza B infection, and, thus, his disorder was confused and a blood pressure of 116/66 mmHg. No abnormal find-

Department of Neurology, Nagano Municipal Hospital, Japan Received for publication December 5, 2011; Accepted for publication March 12, 2012 Correspondence to Dr. Minori Kodaira, [email protected]

1605 Intern Med 51: 1605-1608, 2012 DOI: 10.2169/internalmedicine.51.7051

Fp1-A1 findings, including in the hypothalamus, and the EEG again Fp2-A2 showed a slightly diffuse slowing of basic activity. Encepha-

F3-A1 lopathy of unknown origin was suspected, but his somno-

F4-A2 lence, irritability, and childishness gradually decreased, and he was alert on day 51 without any therapy. However, a C3-A1 third somnolent attack occurred 1 month later. We diagnosed C4-A2 him with KLS due to his clinical presentation, recurrent hy- O1-A1 persomnia, cognitive disturbances, irritability, and childish O2-A2 behavior according to the diagnostic criteria of the Interna- F7-A1 tional Classification of Sleep Disorders II (ICSD-2) for re-

F8-A2 current hypersomnia, and his disorder was believed to be

T3-A1 triggered by influenza B (1). In the analysis of the CSF that

T4-A2 was performed during the first attack of KLS (day 9), IL-6 50μV 1sec levels were not elevated (0.7 pg/mL), and tests for the oligoclonal band and anti-influenza B antibody were negative. Figure 1. Results from the electroencephalogram (EEG) Hypocretin levels in the CSF during the first attack of KLS that was performed during the first hypersomnia attack that were 189 pg/mL (normal, 200 pg/mL or more; intermediate, was triggered by influenza B (day 9). The EEG shows a slight- 110-200 pg/mL; low/undetectable, 110 pg/mL or less). We ly diffuse slowing of basic activity without epileptic abnormal- could not reexamine the CSF hypocretin levels during the ities. other symptomatic and asymptomatic periods because of his and his family’s refusal. The symptoms of KLS disappeared about 1 week later, and the EEG findings were normal dur- ings were detected in the chest or abdomen. He was somno- ing the asymptomatic period. He had the fourth attack of lent most of the day and was sleeping while speaking. In KLS on day 98, and he was treated with methylphenidate addition, he was irritable and cried like a preschool-aged (18 mg once daily). Methylphenidate slightly decreased the child during the physical and clinical examination. The cra- degree of sleepiness, but he has had repetitive hypersomnia nial nerves were intact. Paresis, sensory disturbances, ataxia, attacks monthly for 6 months. and meningeal and myelopathic signs were not detected. Findings from laboratory examinations, including blood Discussion counts, electrolytes, and liver and kidney function tests, were all within normal limits. The levels of C-reactive pro- KLS is a rare disorder that consists of recurring periodic tein were 0.02 mg/dL; blood sugar, 98 mg/dL; and ammo- hypersomnia episodes that last more than 2 days and less nia, 22 μg/dL. Thyroid function, antithyroid antibodies, anti- than 4 weeks, binge eating, hypersexuality, cognitive distur- nuclear antibody, anti-DNA antibody, and complement activ- bances, and/or odd behavior (1). Theoretically, it is possible ity were negative and normal. An analysis of the CSF dem- to diagnose recurrently hypersomnic patients with KLS from onstrated white blood cell counts of 2 cells/mm3 (mono- the second hypersomnia attack onward, although they are cytes), a protein concentration of 36 mg/dL, an IgG concen- sometimes misdiagnosed as psychiatric disorders or en- tration of 3.5 mg/dL, and a sugar concentration of 61 mg/dL cephalopathy due to the rarity of KLS and the psychiatric with normal pressure. Chest X-ray showed normal findings. and encephalopathy-like symptoms (9). About one-quarter of An electroencephalogram (EEG) showed a slightly diffuse patients with KLS experience a precipitating flu-like fever slowing of basic activity without epileptic abnormalities before the onset and reoccurrence of the hypersomnia at- (Fig. 1). We diagnosed him with atypical influenza- tack (2). A strong relationship between an upper respiratory associated encephalopathy because he was afebrile, and the infection and the first attack of KLS has recently been re- acute phase of influenza was terminated. A 3-day regimen ported (3), although identification of the infectious agents of high-dose intravenous methylprednisolone (1 g/day) was has been very rare (4-8). The clinical profiles of 5 patients initiated from the day of admission. A single intravenous in- who were reported to have KLS that was triggered by iden- jection of 600 mg of peramivir was also administered. His tified infectious agents are summarized in Table 1. All of somnolence, irritability, and childishness gradually im- them were male and teenagers, which was consistent with proved, and he was alert on day 12 and said, “I felt like I typical KLS patients. Infections of streptococci and various was dreaming and do not have any memory of the state of viruses preceded the onset and recurrence of KLS. Except somnolence.” He was discharged on day 14, although he for 1 patient of the 5, infection preceded the first attack of was somnolent again from day 42 and readmitted on day KLS. The symptoms of KLS occurred between 3 and 7 days 47. Upon physical and neurological examinations, no abnor- after the onset of infection symptoms. Patients presented mal findings were detected except for somnolence, irritabil- with various cognitive and psychiatric symptoms in addition ity, and childishness. Blood tests were normal, including tu- to hypersomnia. Therefore, 1 patient was misdiagnosed with mor marker levels. Brain CT and MRI detected no abnormal viral meningitis at first (7), and 2 patients were diagnosed

1606 Intern Med 51: 1605-1608, 2012 DOI: 10.2169/internalmedicine.51.7051

Table 1. Clinical Profiles of the Patients with Kleine-Levin Syndrome Triggered by Identified Infectious Agents

Author Onset age/ Triggered Agents/Method to Duration from onset of KLS symptoms CSF hypocretin Sex attack of KLS identify agents infection to onset of KLS concentration Garland et al. 4 15/M First attack Asian influenza virus/ NA hypersomnia, hypersexuality, NE (1965) NA binge eating, odd behavior Gallinek 5 18/M First attack Streptococci septicemia/ NA hypersomnia, depression, NE (1967) NA irritability Smolik and Roth 6 14/M First attack Scarlet fever/ NA hypersomnia, hypersexuality, NE (1988) NA aggression, binge eating Fernandez et al. 7 17/M First attack Enterovirus/ 3 days hypersomnia, hypersexuality, NE (1990) serum antibody test irritability, delusion, incoherent speech Salter and White 8 12/M Second attack Epstein-Barr virus/ 7 days hypersomnia, hypersexuality, NE (1993) serum antibody test irritability, perplexity, Fourth attack Varicella-Zoster NA mood alternation NE virus/serum antibody test Our patient 14/M First attack Influenza B virus/ 6 days hypersomnia, irritability, slightly rapid antigen test cognitive disturbance, decreased childish behavior CSF: cerebrospinal fluid, KLS: Kleine-Levin syndrome, NA: not apparent, NE: not examined with KLS after 5 and about 40 attacks of KLS (4, 6). The patient. Steroid pulse therapy was given during the first at- current patient presented with typical KLS symptoms 6 days tack of KLS, but we could not determine the effects of the after the onset of infection symptoms, as did other patients steroid therapy. with KLS that were triggered by identified infectious agents, Dysfunction of the hypothalamus has also been suggested although we could not discriminate the first attack of KLS as one of the sites of pathophysiology in KLS (6). Hypocre- from influenza-associated encephalopathy because of the tin, which is a neuropeptide that is generated by hypotha- encephalopathy-like symptoms and EEG findings. Patients lamic neurons, regulates sleep-wake rhythms and feed- with influenza-associated encephalopathy present with al- ing (14). A marked decrease of CSF hypocretin levels is the tered or loss of consciousness and sometimes abnormal be- hallmark of narcolepsy (15). The measurement of CSF hy- havior (10). However, the timing of the onset and his age pocretin levels in other types of hypersomnia has been at- were different from that seen in typical influenza-associated tempted, but studies of patients with KLS are limited, espe- encephalopathy. Influenza-associated encephalopathy usually cially during the symptomatic period. Hypocretin levels occurs 1 or 2 days after the onset of fever in children under were normal during asymptomatic intervals in patients with the age of 5 years old (10). Typical KLS occurs between 3 KLS (16) and during symptomatic periods in some pa- and 5 days after the onset of fever in teenagers (2), and this tients (17). However, hypocretin levels during symptomatic was consistent with the clinical presentation of the current periods in 2 patients with KLS were relatively low com- patient. The main pathology of influenza-associated en- pared to the levels during the asymptomatic period, which cephalopathy is increased levels of cytokines, including IL- were within normal or intermediate levels (18, 19). We 6, in the CSF and serum (11). There have been no examina- measured hypocretin levels during the first attack of KLS, tions of the levels of cytokines, including IL-6, in patients which occurred just after the influenza B infection, and the with KLS, although white cell counts and protein levels in levels were intermediate. Although the meaning of the the CSF are normal (2). The fact that IL-6 levels in the CSF slightly decreased levels of hypocretin during the first attack were not increased in our patient even 1 week after the in- of KLS was limited because we could not reexamine the hy- fluenza B infection suggested that his pathophysiology was pocretin levels during subsequent symptomatic and asympto- different from that of influenza-associated encephalopathy. matic periods, the slightly decreased hypocretin levels may Narcolepsy is another representative hypersomnia disor- contribute to the onset of KLS. Further investigation is der, which is characterized by irresistible bouts of sleep in needed to elucidate the pathophysiology of KLS. the daytime, cataplexy, sleep attacks, and hypnagogic hallu- In this paper, we report a 14-year-old Japanese boy who cinations. An association with a preceding influenza infec- was affected by KLS just after an influenza B infection. At tion, especially the 2009 H1N1 influenza, and narcolepsy the third hypersomnia attack, KLS was suspected for the was recently reported in China (12). The onset of narcolepsy first time. The preceding influenza infection was not only a is assumed to be delayed by about 6 months after the influ- diagnostic clue of KLS, but also one of the diagnostic con- enza infection, suggesting that the preceding influenza infec- founding factors. A first attack of KLS that is triggered by tion initiates and activates an immune response that induces influenza should be considered in patients presenting with the onset of narcolepsy (12). Autoimmune mechanisms have atypical features of influenza-associated encephalopathy, also been postulated as one of the causes of KLS (13), but such as delayed onset and no findings of inflammation. the tests for oligoclonal band and anti-influenza antibody in Slightly decreased levels of hypocretin may play a part in the CSF were negative at the onset of KLS in the present the onset of KLS, and, thus, the measurement of the levels

1607 Intern Med 51: 1605-1608, 2012 DOI: 10.2169/internalmedicine.51.7051 of IL-6 and hypocretin in the CSF may help in the early dif- 9. Ramdurg S. Kleine-Levin syndrome: etiology, diagnosis, and treat- ferential diagnosis of KLS from influenza-associated en- ment. Ann Indian Acad Neurol 13: 241-246, 2010. 10. Morishima T, Togashi T, Yokota S, et al; Collaborative Study cephalopathy. Group on Influenza-Associated Encephalopathy in Japan. En- cephalitis and encephalopathy associated with an influenza epi- The authors state that they have no Conflict of Interest (COI). demic in Japan. Clin Infect Dis 35: 512-517, 2002. 11. Ichiyama T, Isumi H, Ozawa H, Matsubara T, Morishima T, Fu- Acknowledgement rukawa S. Cerebrospinal fluid and serum levels of cytokines and We are grateful to Dr. Takashi Kanbayashi (Akita University) soluble tumor necrosis factor receptor in influenza virus-associated encephalopathy. Scand J Infect Dis 35: 59-61, 2003. for examining the hypocretin levels in the CSF. 12. Han F, Lin L, Warby SC, et al. Narcolepsy onset is seasonal and References increased following the 2009 H1N1 pandemic in China. Ann Neu- rol 70: 410-417, 2011. 1. American Academy of Sleep Medicine. International Classification 13. Dauvilliers Y, Mayer G, Lecendreux M, et al. Kleine-Levin syn- of Sleep Disorders: Diagnostic and Coding Manual. 2nd ed. drome: an autoimmune hypothesis based on clinical and genetic American Academy of Sleep Medicine, Westchester, IL, 2005. analyses. Neurology 59: 1739-1745, 2002. 2. Arnulf I, Zeitzer JM, File J, Farber N, Mignot E. Kleine-Levin 14. Willie JT, Chemelli RM, Sinton CM, Yanagisawa M. To eat or to syndrome: a systematic review of 186 cases in the literature. Brain sleep? Orexin in the regulation of feeding and wakefulness. Annu 128: 2763-2776, 2005. Rev Neurosci 24: 429-458, 2001. 3. Huang YS, Guilleminault C, Lin KL, Hwang FM, Liu FY, Kung 15. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hy- YP. Relationship between Kleine-Levin syndrome and upper respi- pocretin (orexin) deficiency in human narcolepsy. Lancet 355: 39- ratory infection in Taiwan. Sleep 35: 123-129, 2012. 40, 2000. 4. Garland H, Sumner D, Fourman P. The Kleine-Levin syndrome. 16. Bourgin P, Zeitzer JM, Mignot E. CSF hypocretin-1 assessment in Some further observations. Neurology 15: 1161-1167, 1965. sleep and neurological disorders. Lancet Neurol 7: 649-662, 2008. 5. Gallinek A. The Kleine-Levin syndrome. Dis Nerv Syst 28: 448- 17. Katz JD, Ropper AH. Familial Kleine-Levin syndrome: two sib- 451, 1967. lings with unusually long hypersomnic spells. Arch Neurol 59: 6. Smolík P, Roth B. Kleine-Levin syndrome ethiopathogenesis and 1959-1961, 2002. treatment. Acta Univ Carol Med Monogr 128: 5-94, 1988. 18. Dauvilliers Y, Baumann CR, Carlander B, et al. CSF hypocretin-1 7. Fernández JM, Lara I, Gila L, O’Neill of Tyrone A, Tovar J, Gi- levels in narcolepsy, Kleine-Levin syndrome, and other hypersom- meno A. Disturbed hypothalamic-pituitary axis in idiopathic recur- nias and neurological conditions. J Neurol Neurosurg Psychiatry ring hypersomnia syndrome. Acta Neurol Scand 82: 361-363, 74: 1667-1673, 2003. 1990. 19. Podestá C, Ferreras M, Mozzi M, Bassetti C, Dauvilliers Y, Bil- 8. Salter MS, White PD. A variant of the Kleine-Levin syndrome liard M. Kleine-Levin syndrome in a 14-year-old girl: CSF precipitated by both Epstein-Barr and varicella-zoster virus infec- hypocretin-1 measurements. Sleep Med 7: 649-651, 2006. tions. Biol Psychiatry 33: 388-390, 1993.

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