Pediatrics International (2017) 59, 929–931
doi: 10.1111/ped.13326
Patient Report
Kleine–Levin syndrome elicited by encephalopathy with reversible splenial lesion Masaru Takayanagi,1 Shinichi Okabe,2 Katsuya Yamamoto,3 Juri Komatsu,1 Rikio Suzuki,1 Taro Kitamura1 and Toshihiro Ohura1 1 Division of Pediatrics, Sendai City Hospital, 2Okabe Clinic and 3Nankodai Yamamoto Children’s Clinic, Sendai, Miyagi, Japan Abstract
Kleine–Levin syndrome is a rare sleep disorder of unknown etiology characterized by repetitive episodes of hypersomnia between asymptomatic periods. We report the case of a 13-year-old girl who presented with drowsiness triggered by influenza A as the first episode. Magnetic resonance imaging (MRI) on day 6 showed transient reduction of diffusion in the corpus callosum splenium. The patient was diagnosed with encephalopathy with a reversible splenial lesion. The symptoms resolved after 10 days, but additional episodes of hypersomnia lasting 5– 10 days occurred 1, 5, 6, 11, 13, and 25 months after the first episode. MRI during hypersomnia indicated no lesions, and sleep duration and cognition were normal between episodes. The patient was diagnosed with Kleine– Levin syndrome. Electroencephalographic and clinical findings during the first episode were similar to those during the other episodes. Encephalopathy with a splenial lesion and Kleine–Levin syndrome may have similar pathological mechanisms causing a disturbance in consciousness.
Key words clinically mild encephalitis/encephalopathy with a reversible splenial lesion, corpus callosum, influenza encephalopathy, periodic hypersomnolence, recurrent hypersomnia. The International Classification of Sleep Disorders, third edition, defines Kleine–Levin syndrome (KLS) as a type of central hypersomnolence disorder that manifests as recurrent episodes of excessive sleepiness, lasting for a median of 10 days, separated by intervening periods of normal brain function.1 Although well-defined symptomatically, the pathogenesis and etiology of KLS remain unclear.2 Here, we present a case of KLS elicited by mild encephalitis/encephalopathy with a reversible splenial lesion, secondary to influenza A infection. The appearance of both KLS and this type of encephalopathy suggests that these disorders have a common underlying pathology.
Case report The patient was a 13-year-old girl with KLS elicited by influenza A encephalopathy with a reversible splenial lesion that showed decreased diffusion on initial magnetic resonance imaging (MRI). She had no significant family medical history or previous illnesses. The clinical course is summarized in Table 1.
Correspondence: Masaru Takayanagi, MD PhD, Division of Pediatrics, Sendai City Hospital, 1-1-1 Asutonagamachi, Taihaku-ku, Sendai, Miyagi 982-8502, Japan. Email: takayanagi-mas@ hospital.city.sendai.jp Received 17 December 2015; revised 8 December 2016; accepted 17 May 2017. © 2017 Japan Pediatric Society
First episode
The patient visited a clinic with a 2 day history of fever. Rapid diagnostic testing confirmed influenza A antigens, and treatment with laninamivir was initiated. Fever resolved the following day, but she remained drowsy. Electroencephalography (EEG) on day 6 of the illness showed intermittent rhythmic delta activity during wakefulness, and she was admitted to hospital. The patient had a mild consciousness disturbance on admission (Glasgow coma scale, 13–14; E2–3, V5, and M6), but otherwise normal neurological signs. Body temperature was 37.2°C, and cardiopulmonary function was normal. Complete blood count and blood chemistry were normal, including normal serum sodium (140 mEq/L). No pathogens besides influenza A were detected. Brain MRI indicated decreased diffusion in the splenium of the corpus callosum (Fig. 1). The patient was diagnosed with influenza encephalopathy, and dexamethasone (2 mg) was given four times daily for 4 days. Level of consciousness improved gradually, beginning the day after admission, and appetite recovered on day 9. Somnolence resolved by day 11, with no obvious sequelae. No convulsive seizures occurred during the course of the illness. The splenial lesion resolved completely by day 16, according to diffusion-weighted MRI. The patient was therefore diagnosed with mild encephalitis/ encephalopathy with a reversible splenial lesion, secondary to influenza A infection.
930 M Takayanagi et al. Table 1 Clinical features of the present hypersomnia episodes Episode ID no.
Time from episode 1 (months)
Duration of hypersomnia (days)
Duration of anorexia (days)
Brain MRI (on episode day)
Electroencephalography (on episode day)
Treatment
1
–
10
8
Diffuse IRDA (6, 9)
DI + DEXA
2
1
8
5
Splenial lesion (6) Normal (16) Normal (3)
DI
3 4 5 6 7
5 6 11 13 25
8 5 10 5 8
6 0 7 5 0
Normal (4) NA NA Normal (2) NA
Diffuse IRDA (3) Normal (5) Diffuse IRDA (4) NA NA Diffuse IRDA (2) NA
DI ND DI DI ND
DEXA, dexamethasone; DI, i.v. drip infusion; IRDA, intermittent rhythmic delta activity; MRI, magnetic resonance imaging; NA, not available; ND, not done.
a
c
b
d
Fig. 1 (a) T1-weighted imaging (T1WI); (b) T2-weighted imaging (T2WI); (c) diffusion-weighted imaging (DWI); and (d) apparent diffusion coefficient (ADC) map in the first episode of hypersomnia (day 6). (c) DWI shows a high-intensity signal in the splenium of the corpus callosum, as does the (d) lower ADC map. (b) T2WI also shows a mild high-intensity signal in the same region. No other abnormal signals were detected in the brain. Magnetic resonance angiography showed no abnormalities in the major cephalic arteries (data not shown). Second episode
The patient recovered completely from encephalopathy, but exactly 1 month after the onset of the initial illness, she developed pharyngitis and somnolence. EEG on day 3 showed intermittent rhythmic delta activity during wakefulness. The patient experienced intense somnolence throughout the day, with reduced appetite even after forced awakening. She was © 2017 Japan Pediatric Society
readmitted to hospital on day 4, and an i.v. infusion commenced. Brain MRI showed no abnormalities. Appetite improved on day 6, and somnolence resolved spontaneously on day 9. Five additional episodes (5, 6, 11, 13, and 25 months after the initial presentation) are described in Table 1. The hypersomnia in all episodes resolved spontaneously after 5–10 days. Polysomnography on day 3 of the fourth episode indicated a long sleep latency (27 min) and an increase in the arousal index (25.8/h). Polysomnography was negative for sleep apnea, periodic limb movement, and narcolepsy. Actigraphy (non-invasive activity pattern monitoring) showed KLScompatible sleep patterns, including long sleep patterns during episodes and short sleep patterns during recovery periods. An ictal study using single-photon emission computed tomography with 99mTc-hexamethylpropylene amine oxime during the sixth episode showed no demonstrably abnormal findings. Neither hyperphagia nor hypersexuality was observed during the hypersomnia episodes, although the patient did not speak voluntarily and exhibited altered environmental perception and apathy. No relationship was observed between hypersomnia and menstruation. Intelligence quotient (IQ), evaluated between episodes, was 95 (total IQ on the Wechsler Intelligence Scale for Children, third edition). All examinations were negative for mood disturbances, other sleep disorders, brain structural disorders, tumors, multiple sclerosis, drug intoxication, inborn metabolic disturbances, viral infection, and psychological disorders. Cerebrospinal fluid level of hypocretin-1 was not measured. No other injuries, intoxication, hypoglycemia, types of encephalitis, epileptic status, or degenerative diseases were observed, except the splenial lesion. The patient was given 7.5 g/day of hospital-grade hochuekkito extract, a traditional Japanese herbal medicine, when admitted for the sixth episode. No further episodes have been observed for more than 3 years since the seventh episode.
Discussion The present case demonstrates two important clinical features. First, KLS was triggered by acute encephalopathy and an
KLS elicited by encephalopathy 931 influenza A infection. This is the first reported case of KLS induced by acute encephalopathy associated with MRI abnormalities. Second, the clinical features of the first episode (diagnosed as mild encephalitis/encephalopathy with a reversible splenial lesion) and those of episodes 2–7 (diagnosed as KLS) were strongly similar (Table 1). The main symptom in all episodes was somnolence for several days, without convulsions or cranial nerve signs, and complete recovery with no sequelae. EEG findings were also similar, demonstrating intermittent high-voltage rhythmic delta activity during wakefulness in all episodes. Slowing of background activity and a mixture of paroxysmal slow waves on EEG during KLS episodes, as seen here, have been described previously.2 Thalamic and hypothalamic lesions have been implicated in KLS.3 As was the case here, the typical imaging findings for mild encephalitis/encephalopathy with a reversible splenial lesion include reduced diffusion in the splenium of the corpus callosum.4 Neither the pathology underlying the consciousness disturbances nor the neuroanatomical relationship between mild encephalitis/encephalopathy with a reversible splenial lesion and somnolence, however, are well understood. The symptoms of mild encephalitis/encephalopathy with a reversible splenial lesion cannot always be explained by MRI abnormalities, and the mechanisms regarding site specificity remain unclear.5 Various brain lesions have been identified in KLS.2,6 Similar localization of the lesions in the two conditions may reflect one component of the pathophysiology. Thus, the present first episode could be considered the first episode of KLS. Because the abnormal MRI findings in mild encephalitis/encephalopathy with a reversible splenial lesion are transient, they can be missed if MRI is not performed at the critical time. Thus, mild encephalitis/encephalopathy with a reversible splenial lesion-like MRI lesion might have been overlooked in some of the cases reported previously as KLS. Ideally, patients with KLS should undergo serial MRI, particularly with diffusion-weighted MRI. Notably, during episodes 2–7, which were defined as KLS, the patient had symptoms similar to those associated with acute encephalopathy, suggesting a possible common pathology. Several studies have reported patients with recurrent acute encephalopathy,7,8 but most of these patients had underlying inborn metabolic disturbances. No evidence of underlying disease was found in the present case, and episodes 2–7 were more typical of KLS than encephalopathy. Additional investigation is warranted in future similar cases, including identification of common biomarkers and genes for acute encephalopathy and KLS. No evidence-based treatments have been established for KLS. This disease typically resolves after a median of 14 years.1 Many drugs have been investigated for the treatment of KLS, most with little success, except lithium.2,9
Although lithium is effective in some cases (benefit reported in 25–62% of patients), notable risks are thyroid and kidney insufficiency.2 In the present case, the hochuekkito extract, a traditional Japanese herbal medicine, may have prevented relapse of hypersomnia without any adverse effects or the illness may have run its natural course. Nevertheless, clarification of the pathophysiology of KLS should lead to the development of appropriate therapy.
Acknowledgments We thank the patient and her family for their participation in this study. We also thank Kiyoshi Ishii, MD (Division of Radiology, Sendai City Hospital), for constructive comments.
Disclosure The authors declare no conflict of interest.
Author contributions M.T. contributed to the concept and design of this study; M.T. and S.O. drafted the manuscript; K.Y., J.K., R.S., T.K., and T.O. critically reviewed the manuscript and supervised the study. All authors read and approved the final version of the manuscript.
References 1 American Academy of Seep Medicine. International Classification of Sleep Disorders, 3rd edn. American Academy of Sleep Medicine, Darien, IL, 2014. 2 Arnulf I, Rico TJ, Mignot E. Diagnosis, disease course, and management of patients with Kleine-Levin syndrome. Lancet Neurol. 2012; 11: 918–28. 3 Lo YC, Chou YH, Yu HY. PET finding in Kleine-Levin syndrome. Sleep Med. 2012; 13: 771–2. 4 Tada H, Takanashi J, Barkovich AJ et al. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology 2004; 63: 1854–8. 5 Takanashi J. Two newly proposed infectious encephalitis/ encephalopathy syndromes. Brain Dev. 2009; 31: 521–8. 6 Miglis MG, Guilleminault C. Kleine-Levin syndrome: a review. Nat. Sci. Sleep 2014; 6: 19–26. 7 Sakai E, Yamanaka G, Kawashima H et al. A case of recurrent acute encephalopathy with febrile convulsive status epilepticus with carnitine palmitoyltransferase II variation. Neuropediatrics 2013; 44: 218–21. 8 Cartagena A, Prasad AN, Rupar CA et al. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Can. J. Neurol. Sci. 2013; 40: 3–9. 9 Sveinsson O. A striking response to lithium in Kleine-Levin syndrome. Front. Neurol. 2014; 5: 33.
© 2017 Japan Pediatric Society
doi: 10.1111/ped.13326
Patient Report
Kleine–Levin syndrome elicited by encephalopathy with reversible splenial lesion Masaru Takayanagi,1 Shinichi Okabe,2 Katsuya Yamamoto,3 Juri Komatsu,1 Rikio Suzuki,1 Taro Kitamura1 and Toshihiro Ohura1 1 Division of Pediatrics, Sendai City Hospital, 2Okabe Clinic and 3Nankodai Yamamoto Children’s Clinic, Sendai, Miyagi, Japan Abstract
Kleine–Levin syndrome is a rare sleep disorder of unknown etiology characterized by repetitive episodes of hypersomnia between asymptomatic periods. We report the case of a 13-year-old girl who presented with drowsiness triggered by influenza A as the first episode. Magnetic resonance imaging (MRI) on day 6 showed transient reduction of diffusion in the corpus callosum splenium. The patient was diagnosed with encephalopathy with a reversible splenial lesion. The symptoms resolved after 10 days, but additional episodes of hypersomnia lasting 5– 10 days occurred 1, 5, 6, 11, 13, and 25 months after the first episode. MRI during hypersomnia indicated no lesions, and sleep duration and cognition were normal between episodes. The patient was diagnosed with Kleine– Levin syndrome. Electroencephalographic and clinical findings during the first episode were similar to those during the other episodes. Encephalopathy with a splenial lesion and Kleine–Levin syndrome may have similar pathological mechanisms causing a disturbance in consciousness.
Key words clinically mild encephalitis/encephalopathy with a reversible splenial lesion, corpus callosum, influenza encephalopathy, periodic hypersomnolence, recurrent hypersomnia. The International Classification of Sleep Disorders, third edition, defines Kleine–Levin syndrome (KLS) as a type of central hypersomnolence disorder that manifests as recurrent episodes of excessive sleepiness, lasting for a median of 10 days, separated by intervening periods of normal brain function.1 Although well-defined symptomatically, the pathogenesis and etiology of KLS remain unclear.2 Here, we present a case of KLS elicited by mild encephalitis/encephalopathy with a reversible splenial lesion, secondary to influenza A infection. The appearance of both KLS and this type of encephalopathy suggests that these disorders have a common underlying pathology.
Case report The patient was a 13-year-old girl with KLS elicited by influenza A encephalopathy with a reversible splenial lesion that showed decreased diffusion on initial magnetic resonance imaging (MRI). She had no significant family medical history or previous illnesses. The clinical course is summarized in Table 1.
Correspondence: Masaru Takayanagi, MD PhD, Division of Pediatrics, Sendai City Hospital, 1-1-1 Asutonagamachi, Taihaku-ku, Sendai, Miyagi 982-8502, Japan. Email: takayanagi-mas@ hospital.city.sendai.jp Received 17 December 2015; revised 8 December 2016; accepted 17 May 2017. © 2017 Japan Pediatric Society
First episode
The patient visited a clinic with a 2 day history of fever. Rapid diagnostic testing confirmed influenza A antigens, and treatment with laninamivir was initiated. Fever resolved the following day, but she remained drowsy. Electroencephalography (EEG) on day 6 of the illness showed intermittent rhythmic delta activity during wakefulness, and she was admitted to hospital. The patient had a mild consciousness disturbance on admission (Glasgow coma scale, 13–14; E2–3, V5, and M6), but otherwise normal neurological signs. Body temperature was 37.2°C, and cardiopulmonary function was normal. Complete blood count and blood chemistry were normal, including normal serum sodium (140 mEq/L). No pathogens besides influenza A were detected. Brain MRI indicated decreased diffusion in the splenium of the corpus callosum (Fig. 1). The patient was diagnosed with influenza encephalopathy, and dexamethasone (2 mg) was given four times daily for 4 days. Level of consciousness improved gradually, beginning the day after admission, and appetite recovered on day 9. Somnolence resolved by day 11, with no obvious sequelae. No convulsive seizures occurred during the course of the illness. The splenial lesion resolved completely by day 16, according to diffusion-weighted MRI. The patient was therefore diagnosed with mild encephalitis/ encephalopathy with a reversible splenial lesion, secondary to influenza A infection.
930 M Takayanagi et al. Table 1 Clinical features of the present hypersomnia episodes Episode ID no.
Time from episode 1 (months)
Duration of hypersomnia (days)
Duration of anorexia (days)
Brain MRI (on episode day)
Electroencephalography (on episode day)
Treatment
1
–
10
8
Diffuse IRDA (6, 9)
DI + DEXA
2
1
8
5
Splenial lesion (6) Normal (16) Normal (3)
DI
3 4 5 6 7
5 6 11 13 25
8 5 10 5 8
6 0 7 5 0
Normal (4) NA NA Normal (2) NA
Diffuse IRDA (3) Normal (5) Diffuse IRDA (4) NA NA Diffuse IRDA (2) NA
DI ND DI DI ND
DEXA, dexamethasone; DI, i.v. drip infusion; IRDA, intermittent rhythmic delta activity; MRI, magnetic resonance imaging; NA, not available; ND, not done.
a
c
b
d
Fig. 1 (a) T1-weighted imaging (T1WI); (b) T2-weighted imaging (T2WI); (c) diffusion-weighted imaging (DWI); and (d) apparent diffusion coefficient (ADC) map in the first episode of hypersomnia (day 6). (c) DWI shows a high-intensity signal in the splenium of the corpus callosum, as does the (d) lower ADC map. (b) T2WI also shows a mild high-intensity signal in the same region. No other abnormal signals were detected in the brain. Magnetic resonance angiography showed no abnormalities in the major cephalic arteries (data not shown). Second episode
The patient recovered completely from encephalopathy, but exactly 1 month after the onset of the initial illness, she developed pharyngitis and somnolence. EEG on day 3 showed intermittent rhythmic delta activity during wakefulness. The patient experienced intense somnolence throughout the day, with reduced appetite even after forced awakening. She was © 2017 Japan Pediatric Society
readmitted to hospital on day 4, and an i.v. infusion commenced. Brain MRI showed no abnormalities. Appetite improved on day 6, and somnolence resolved spontaneously on day 9. Five additional episodes (5, 6, 11, 13, and 25 months after the initial presentation) are described in Table 1. The hypersomnia in all episodes resolved spontaneously after 5–10 days. Polysomnography on day 3 of the fourth episode indicated a long sleep latency (27 min) and an increase in the arousal index (25.8/h). Polysomnography was negative for sleep apnea, periodic limb movement, and narcolepsy. Actigraphy (non-invasive activity pattern monitoring) showed KLScompatible sleep patterns, including long sleep patterns during episodes and short sleep patterns during recovery periods. An ictal study using single-photon emission computed tomography with 99mTc-hexamethylpropylene amine oxime during the sixth episode showed no demonstrably abnormal findings. Neither hyperphagia nor hypersexuality was observed during the hypersomnia episodes, although the patient did not speak voluntarily and exhibited altered environmental perception and apathy. No relationship was observed between hypersomnia and menstruation. Intelligence quotient (IQ), evaluated between episodes, was 95 (total IQ on the Wechsler Intelligence Scale for Children, third edition). All examinations were negative for mood disturbances, other sleep disorders, brain structural disorders, tumors, multiple sclerosis, drug intoxication, inborn metabolic disturbances, viral infection, and psychological disorders. Cerebrospinal fluid level of hypocretin-1 was not measured. No other injuries, intoxication, hypoglycemia, types of encephalitis, epileptic status, or degenerative diseases were observed, except the splenial lesion. The patient was given 7.5 g/day of hospital-grade hochuekkito extract, a traditional Japanese herbal medicine, when admitted for the sixth episode. No further episodes have been observed for more than 3 years since the seventh episode.
Discussion The present case demonstrates two important clinical features. First, KLS was triggered by acute encephalopathy and an
KLS elicited by encephalopathy 931 influenza A infection. This is the first reported case of KLS induced by acute encephalopathy associated with MRI abnormalities. Second, the clinical features of the first episode (diagnosed as mild encephalitis/encephalopathy with a reversible splenial lesion) and those of episodes 2–7 (diagnosed as KLS) were strongly similar (Table 1). The main symptom in all episodes was somnolence for several days, without convulsions or cranial nerve signs, and complete recovery with no sequelae. EEG findings were also similar, demonstrating intermittent high-voltage rhythmic delta activity during wakefulness in all episodes. Slowing of background activity and a mixture of paroxysmal slow waves on EEG during KLS episodes, as seen here, have been described previously.2 Thalamic and hypothalamic lesions have been implicated in KLS.3 As was the case here, the typical imaging findings for mild encephalitis/encephalopathy with a reversible splenial lesion include reduced diffusion in the splenium of the corpus callosum.4 Neither the pathology underlying the consciousness disturbances nor the neuroanatomical relationship between mild encephalitis/encephalopathy with a reversible splenial lesion and somnolence, however, are well understood. The symptoms of mild encephalitis/encephalopathy with a reversible splenial lesion cannot always be explained by MRI abnormalities, and the mechanisms regarding site specificity remain unclear.5 Various brain lesions have been identified in KLS.2,6 Similar localization of the lesions in the two conditions may reflect one component of the pathophysiology. Thus, the present first episode could be considered the first episode of KLS. Because the abnormal MRI findings in mild encephalitis/encephalopathy with a reversible splenial lesion are transient, they can be missed if MRI is not performed at the critical time. Thus, mild encephalitis/encephalopathy with a reversible splenial lesion-like MRI lesion might have been overlooked in some of the cases reported previously as KLS. Ideally, patients with KLS should undergo serial MRI, particularly with diffusion-weighted MRI. Notably, during episodes 2–7, which were defined as KLS, the patient had symptoms similar to those associated with acute encephalopathy, suggesting a possible common pathology. Several studies have reported patients with recurrent acute encephalopathy,7,8 but most of these patients had underlying inborn metabolic disturbances. No evidence of underlying disease was found in the present case, and episodes 2–7 were more typical of KLS than encephalopathy. Additional investigation is warranted in future similar cases, including identification of common biomarkers and genes for acute encephalopathy and KLS. No evidence-based treatments have been established for KLS. This disease typically resolves after a median of 14 years.1 Many drugs have been investigated for the treatment of KLS, most with little success, except lithium.2,9
Although lithium is effective in some cases (benefit reported in 25–62% of patients), notable risks are thyroid and kidney insufficiency.2 In the present case, the hochuekkito extract, a traditional Japanese herbal medicine, may have prevented relapse of hypersomnia without any adverse effects or the illness may have run its natural course. Nevertheless, clarification of the pathophysiology of KLS should lead to the development of appropriate therapy.
Acknowledgments We thank the patient and her family for their participation in this study. We also thank Kiyoshi Ishii, MD (Division of Radiology, Sendai City Hospital), for constructive comments.
Disclosure The authors declare no conflict of interest.
Author contributions M.T. contributed to the concept and design of this study; M.T. and S.O. drafted the manuscript; K.Y., J.K., R.S., T.K., and T.O. critically reviewed the manuscript and supervised the study. All authors read and approved the final version of the manuscript.
References 1 American Academy of Seep Medicine. International Classification of Sleep Disorders, 3rd edn. American Academy of Sleep Medicine, Darien, IL, 2014. 2 Arnulf I, Rico TJ, Mignot E. Diagnosis, disease course, and management of patients with Kleine-Levin syndrome. Lancet Neurol. 2012; 11: 918–28. 3 Lo YC, Chou YH, Yu HY. PET finding in Kleine-Levin syndrome. Sleep Med. 2012; 13: 771–2. 4 Tada H, Takanashi J, Barkovich AJ et al. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology 2004; 63: 1854–8. 5 Takanashi J. Two newly proposed infectious encephalitis/ encephalopathy syndromes. Brain Dev. 2009; 31: 521–8. 6 Miglis MG, Guilleminault C. Kleine-Levin syndrome: a review. Nat. Sci. Sleep 2014; 6: 19–26. 7 Sakai E, Yamanaka G, Kawashima H et al. A case of recurrent acute encephalopathy with febrile convulsive status epilepticus with carnitine palmitoyltransferase II variation. Neuropediatrics 2013; 44: 218–21. 8 Cartagena A, Prasad AN, Rupar CA et al. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Can. J. Neurol. Sci. 2013; 40: 3–9. 9 Sveinsson O. A striking response to lithium in Kleine-Levin syndrome. Front. Neurol. 2014; 5: 33.
© 2017 Japan Pediatric Society
