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Objective: Functional hearing loss (FHL) is a disorder in which there are abnormal values on a hearing test, despite the absence of organic abnormalities in the peripheral and central auditory pathways. Here, we examined the developmental characteristics of FHL and the importance of intervention by analyzing the clinical characteristics of children with this disorder., Methods: We retrospectively examined 16 patients assessed under a diagnosis of FHL. After interventions such as psychological counseling by our pediatrics and psychiatry departments, we compared the clinical profiles of patients in which hearing was "improved/normalized" and "unimproved"., Results: Fourteen patients visited a pediatrician and two chose not to do so. A discrepancy between the maximum and minimum values of the four index scores was observed in all patients in which WISC-IV (the fourth version of the Wechsler Intelligence Scale for Children) was performed (n = 12). The discrepancy between the verbal comprehension index (VCI) and perceptual reasoning index (PRI) was significantly greater in "unimproved" patients than in "improved/normalized" patients. Hearing improved, or was normalized, after intervention in six of 16 patients., Conclusions: Developmental imbalances were suspected in all 12 children who visited a pediatrician and completed the WISC-IV. Cooperation with pediatricians, psychiatrists, and other health professionals is desirable in supporting patients diagnosed with FHL., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: A few case reports have described patients with myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated demyelinating syndrome who presented with symptoms of aseptic meningitis. All such patients required immunotherapy. We report a patient with MOG-Ab-associated disorder (MOGAD) who presented with symptoms of aseptic meningitis and improved without treatment., Case: A 13-year-old girl presented with fever, headache, decreased appetite, and neck stiffness. Cerebrospinal fluid (CSF) analysis revealed pleocytosis and magnetic resonance imaging (MRI) showed leptomeningeal enhancement. The patient was diagnosed with aseptic meningitis at admission. However, there were no signs of recovery 4 days after admission (i.e., 8 days after disease onset). Therefore, we performed extensive investigations to identify the cause of the underlying infection and inflammation. On day 14 after admission, the serum MOG-Ab test performed at admission came back positive (1:128) and she was diagnosed with MOGAD. She was discharged on day 18 after admission, because her symptoms, CSF pleocytosis, and MRI findings had improved. About 6 weeks after discharge, MRI revealed hyperintensity without gadolinium enhancement. However, her serum MOG-Ab test was negative. We did follow-ups for 11 months but found no new neurological symptoms., Discussion and Conclusion: To the best of our knowledge, this is the first ever report of a pediatric patient with MOGAD experiencing spontaneous remission with no demyelinating symptoms during an extended follow-up period., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: The clinical severity of Sandhoff disease is known to vary widely. Furthermore, long-term follow-up report is very limited in the literature., Case Presentation: We present a long-term follow-up report of a patient with juvenile-onset Sandhoff disease with a motor neuron disease phenotype. The patient had compound heterozygous variants of HEXB (p.Trp460Arg, p. Arg533His); the Trp460Arg was a novel variant. Long-term follow-up revealed no intellectual deterioration, swallowing dysfunction, or respiratory muscle dysfunction despite progressive weakness of the extremities and sensory disturbances., Conclusion: We need to be aware of Sandhoff disease in patients with juvenile-onset motor neuron disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objectives: Long-term adrenocorticotropic therapy (LT-ACTH), which consisted of 2-4 weeks of daily injections of adrenocorticotropic hormone (ACTH) and subsequent months of weekly injections, was tried for relapsed West syndrome (WS) or other intractable epilepsies in small case reports. Our aim was to explore the efficacy of LT-ACTH for preventing WS relapse, as well as the prevalence of its adverse events., Methods: This is a retrospective, nationwide, multicenter case series of patients with WS who underwent LT-ACTH. Clinical information of the patients and protocol of LT-ACTH were collected from participating institutes in this study. We defined clinical response to ACTH as achievement of hypsarrhythmia and epileptic spasms resolution. Patients who responded to daily ACTH injections were identified and assessed whether they experienced WS relapse during/after the weekly ACTH injection period. The outcome was measured by the nonrelapse rate at 24 months after daily ACTH injections using the Kaplan-Meier method., Results: Clinical information of 16 children with WS was analyzed. The median age at LT-ACTH initiation was 14.5 months (range: 7-68 months). Thirteen (81%) patients had previously undergone conventional ACTH treatment. The LT-ACTH regimens comprised a median of 16 days of daily injections (range: 11-28 days) and 10 months of weekly injections (range: 3-22 months). Seven patients experienced WS relapse during/after subsequent weekly ACTH period, and the nonrelapse rate at 24 months after daily injections was estimated at 60.6% (95% confidence interval: 32.3%-80.0%). Height stagnation, hypertension, and irritability were observed; lethal adverse events were not reported., Significance: Our study firstly explored the efficacy of LT-ACTH for preventing WS relapse. LT-ACTH might be a treatment option for patients with relapsed or intractable WS; however, we note that our study is limited by its small sample size and the lack of an appropriate control group., Competing Interests: None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues regarding ethical publication and affirm that this report is consistent with those guidelines., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

We report a patient with a 6q22.1 deletion, who presented with a rare syndrome of generalized epilepsy, myoclonic tremor, and intellectual disability. There was no clinical progression after follow-up for more than 10 years. Our report presents the genetic basis for a phenotype involving a non-progressive generalized epilepsy with tremor. The efficacy of valproic acid for seizure control and the partial efficacy of deep brain stimulation with propranolol for myoclonic tremor is detailed., (© 2020 The Author(s).)

Introduction: There is increasing evidence that immunosuppressive therapy is essential for reducing disease activity and avoiding further attacks in patients positive for anti-myelin-oligodendrocyte glycoprotein (MOG) antibodies. However, to date, no placebo-controlled trial has been published., Objective: We aimed to evaluate the long-term outcome and anti-MOG antibody titers of seropositive Japanese pediatric patients without long-term immunosuppressive therapy., Methods: Of 11 consecutive patients positive for anti-MOG antibodies seen at Tohoku University Hospital from 1992 to 2013, 5 patients did not receive preventive long-term immunosuppressive treatment and had been followed up longitudinally (more than 60 months)., Results: The follow-up periods were 68-322 months (median, 150 months). The expanded disability status scale scores of all patients were 0 at the last observation. Three patients were negative for the antibody at the last follow-up, and the titers of the two patients whose anti-MOG antibodies were positive at the last follow-up were lower than at the first examinations. The interval to the second attack in three patients was 1-124 months (median, 33 months). Acute attacks were treated with methylprednisolone pulse therapy (four patients) or intravenous immunoglobulin (one patient). All patients achieved full recovery after acute therapy. Oral corticosteroid was tapered over a period of 6-26 weeks (median, 17 weeks)., Conclusions: We reported our experience with very long-term follow-up of 5 Japanese pediatric patients with anti-MOG antibody-positive disease who did not receive long-term immunosuppressive therapy. Persistent positivity to anti-MOG antibody in some patients suggests the necessity for long-term follow up despite infrequent relapse., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation., Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations., Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge., Conclusion: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To understand cerebral brain dysfunction in patients with Dravet syndrome (DS), we conducted a [ 18 F]fluorodeoxyglucose-positron emission tomography (FDG-PET) study in patients with DS whose SCN1A gene variant was confirmed., Methods: FDG-PET was performed on eight patients with DS. A SCN1A mutation analysis revealed missense variants in four patients and truncation variants in four patients. The patients' ages at the time of the PET study were 2, 2, 2, 3, 6, 13, 20, and 29 years old, respectively. The patients' developmental/intelligence quotient at the time of the PET study were 62, 52, 64, 35, 30, 15, and <25, respectively. The mean standardized uptake value (SUV) was calculated in four segments (frontal, temporal, parietal, and occipital) for the semi-quantitative analysis of 18 F-FDG uptake. This value represents the average of the regions of interest in each lobe and was divided by the average SUV of the cerebellar hemisphere of each patient and compared between the patients with DS and the diseased controls., Results: Glucose uptake in patients with DS decreased significantly, particularly in those ≥6 years old. Importantly, a comparison between the younger and older patients with DS revealed that glucose uptake was normal in patients who were ≤3 years (2, 2, 2, and 3 years), whereas a profound reduction in glucose uptake in the fronto-temporo-parietal-occipital cortices was observed in patients ≥ 6 years (6, 13, 20, and 29 years). Magnetic resonance imaging revealed no detectable atrophic legions or other changes in the cerebral cortices of patients ≥ 6 years of age., Significance: The present study showed a remarkable reduction in cerebral glucose metabolism in multiple lobes for the first time, which became obvious after the late infantile period. These findings may indicate a functional neuroimaging aspect of epileptic encephalopathy of DS or a feature of the SCN1A variant itself., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Caveolinopathies, caused by CAV3 mutations, can include several phenotypes such as rippling muscle disease, limb-girdle muscular dystrophy type 1C, distal myopathy, familial hypertrophic cardiomyopathy, and idiopathic hyperCKemia. Here we present characteristic skeletal muscle imaging findings in four patients with genetically defined childhood-onset RMD caused by CAV3 mutations and in one patient with congenital generalized lipodystrophy type 4 with muscular dystrophy due to polymerase I and transcript release factor (PTRF) mutations, which may have caused secondary deficiency of caveolin-3. Muscle MRI revealed that the rectus femoris and semitendinosus muscles were most commonly affected in the rippling muscle disease patients. Peripheral changes in the rectus femoris were specific and observed even in one of the younger patients in this study. Furthermore, muscle involvement extended to the semitendinosus muscles, biceps femoris, and gracilis with disease progression or increase in its severity. Similar patterns of involvement were observed on reviewing skeletal muscle images of various previously reported phenotypes of caveolinopathy; interestingly, patients with secondary deficiency of caveolin due to PTRF mutations revealed the same pattern. Thus, primary caveolinopathies and secondary deficiency of caveolin demonstrated specific findings on skeletal muscle imaging, regardless of the broad phenotypic spectrum of these two conditions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Long-term outcome of West syndrome with a NR2F1 mutation., (Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

We describe the first case of a successful functional hemispherectomy in a patient with epileptic encephalopathy and a de novo collagen type IV alpha 1 (COL4A1) mutation. A 4-year-old girl was COL4A1 mutation-positive and suffered from drug-resistant epilepsy, hemiplegia, and developmental delay. Magnetic resonance imaging detected no porencephaly, and she had no cataract or renal abnormality. Following a presurgical evaluation for epilepsy, she underwent a functional hemispherectomy. She has been seizure free with no intracranial hemorrhage or other perioperative complications. Patients with a COL4A1 mutation have an increased risk for intracranial hemorrhage because of disrupted integrity in the vascular basement membrane due to the mutation. After weighing the risks and benefits to these patients, epilepsy surgery may not be absolutely contraindicated. Furthermore, pediatric neurologists should be aware of an undiagnosed COL4A1 mutation when a patient presents with an unexplained neurological phenotype, such as mild hemiparesis, even in the absence of porencephaly., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the effects and tolerability of vigabatrin (VGB) in children with tuberous sclerosis (TS) with infantile spasms or tonic seizures. Methods: We examined the impact of VGB on a series of 17 children with TS visiting Tohoku University Hospital in Japan during April 2010 and May 2015. To minimize potential adverse effects, VGB was given to the patients for limited 6 months with titration from 30 mg/kg/day as an initial dose. Results: Main seizure types were classified into spasms (n=10) or tonic seizures (n=7). Seizure reduction was positively associated with seizure type of infantile spasms, lower maximum dosage, younger age on VGB administration, and earlier VGB treatment after the diagnosis. Seizure type of infantile spasm was an independent favorable predictor and also associated with long-term seizure reduction. Major adverse events included psychiatric symptoms (n=7) and electroretinogram (ERG) abnormalities (n=2). All symptoms were recovered by reducing the dosage of VGB. Conclusion: VGB is effective and well tolerated as first-line treatment for TS children with infantile spasms. Our “low dosage and limited period” protocol is efficient for improving seizure control as well as minimizing the potential risks of VGB.

Background: Congenital cytomegalovirus (CMV) infection causes various neurological sequelae. However, most infected infants are asymptomatic at birth, and retrospective diagnosis is difficult beyond the neonatal period., Objective: This study aimed to investigate the aspects of neurological sequelae associated with asymptomatic congenital CMV infection., Methods: We retrospectively analyzed 182 patients who were suspected of having asymptomatic congenital CMV infection with neurological symptoms in Japan. Congenital CMV infection was diagnosed by quantitative polymerase chain reaction amplification of CMV from dried umbilical cord DNA., Results: Fifty-nine patients (32.4%) who tested positive for CMV were confirmed as having congenital CMV infection. Among 54 congenital CMV patients, major neurological symptoms included intellectual disability (n=51, 94.4%), hearing impairment (n=36, 66.7%) and cerebral palsy (n=21, 38.9%), while microcephaly (n=16, 29.6%) and epilepsy (n=14, 25.9%) were less common. In a brain magnetic resonance imaging (MRI) study, cortical dysplasia was observed in 27 CMV-positive patients (50.0%), and all patients (100%) had cerebral white matter (WM) abnormality. Intracranial calcification was detected by CT in 16 (48.5%) of 33 CMV-positive patients. Cerebral palsy, cortical dysplasia and a WM abnormality with a diffuse pattern were associated with marked intellectual disability., Conclusions: Brain MRI investigations are important for making a diagnosis and formulating an intellectual prognosis. Analysis of umbilical cord tissue represents a unique and useful way to retrospectively diagnose congenital CMV infection., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is characterized by prolonged severe seizures and a high-grade fever. We experienced a boy with severe AERRPS with frequent partial seizures that exhibited right-side predominance. The patient required the continuous intravenous administration of many antiepileptic drugs and respirator management for several months. Methylprednisolone pulse therapy and intravenous immunoglobulin administration were only temporarily effective. The MRI and EEG showed the abnormality in the left occipital lobe. Although occipital lobectomy was performed, his seizures continued. His cerebrospinal fluid exhibited elevated protein and proinflammatory cytokine levels, and was positive for anti-glutamate receptor ε2 antibodies. Pathological examination showed infiltration of many neutrophilic leukocytes, T cells, and microglia in the area exhibiting severe spongiosis. We thought that the exaggerated microglia and T-cell responses were related to the pathogenesis of the patient's seizures, and we therefore initiated treatment with tacrolimus. As a result, many of the daily seizure clusters were ameliorated, and the patient was discharged. We attempted to discontinue the tacrolimus twice, but the patient's seizure clusters recurred each time. This is the first case report of the pathological findings of AERRPS and showing an effective therapeutic approach using tacrolimus. Tacrolimus may be an effective immunosuppressant, especially for patients with severe AERRPS., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations., Methods: In total, 526 and 145 patients with infantile epilepsy were analyzed by whole-exome sequencing and GABRA1-targeted resequencing, respectively., Results: We identified five de novo missense GABRA1 mutations in six unrelated patients. A p.R112Q mutation in the long extracellular N-terminus was identified in a patient with infantile epilepsy; p.P260L, p.M263T, and p.M263I in transmembrane spanning domain 1 (TM1) were identified in three unrelated patients with West syndrome and a patient with Ohtahara syndrome, respectively; and p.V287L in TM2 was identified in a patient with unclassified early onset epileptic encephalopathy. Four of these mutations have not been observed previously., Significance: Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

We conducted a [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) study in five patients (median age 11 (range 4-13) years) with Leigh syndrome to evaluate its usefulness for understanding the functional brain dysfunction in this disease and in future drug trials. Four patients were found to have reported mitochondrial DNA gene mutations. The brain T2-weighted magnetic resonance imaging (MRI) showed high-intensity areas in the putamen bilaterally in five patients, caudate bilaterally in four, thalamus bilaterally in two, and brainstem in one. Cerebellar atrophy was observed in older two patients. For disease control, seven age-matched epilepsy patients who had normal MRI and FDG-PET studies were selected. For semiquantitative analysis of the lesions with decreased (18)F-FDG uptake, the mean standard uptake value (SUV) was calculated in regions of interest (ROIs) placed in each brain structure. We compared the SUV of nine segments (the frontal, temporal, parietal, and occipital lobes, thalami, basal ganglia, mid-brain, pons, and cerebellum) between patients with Leigh syndrome and controls. The glucose uptake was decreased significantly in the cerebellum and basal ganglia, which could explain the ataxia and dystonia in patients with Leigh syndrome. Although this study had some limitations, FDG-PET might be useful for evaluating the brain dysfunction and treatment efficacy of new drugs in patients with Leigh syndrome. Further study with more patients using advanced methods to quantify glucose uptake is needed before drawing a conclusion., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Neuronal ceroid lipofuscinoses (NCLs) are clinically and genetically heterogeneous neurodegenerative lysosomal diseases. Fourteen distinct NCL subtypes (CLN1-CLN14) are known, and they are caused by mutations in different genes. CLN8 was first identified in Finnish patients, and the phenotype was subsequently found in Turkish, Italian, and Pakistani patients. We report a 6-year-old Japanese boy with NCL with a novel missense mutation in CLN8. At the age of 3years, he manifested frequent drop seizures, and then progressively developed motor difficulties with an ataxic gait, myoclonus, left conjugate deviation, and rotational nystagmus. At age 5, he developed profound visual difficulty and dysphagia, and he has now lost his mobility. A bone marrow examination at age 5 showed sea-blue histiocytes. An electroretinogram was non-recordable. No giant somatosensory evoked potentials were found. Brain magnetic resonance imaging revealed bilateral diffuse hyperintensities in the white matter around the lateral ventricles and cerebellar and pontine atrophy on T2-weighted images. In a lysosomal enzyme study, the palmitoyl-protein-thioesterase and pepinase activity was within normal limits. Whole-exome sequencing revealed a homozygous CLN8 mutation: c.620T>G (p.L207R). His parents were both heterozygous for this mutation. To our knowledge, this is the first report of a CLN8 mutation in late infantile NCL in Japan., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

We described clinical course of a 24-year-old woman with 3p deletion syndrome associated with cerebellar hemangioblastoma at the age of 16 years old. She presented dysmorphic facial features, growth retardation and severe psychomotor retardation associated with 3p deletion syndrome. We identified de novo 3p deletion encompassing p25 by using array-based comparative genomic hybridization, where causative gene of von Hippel-Lindau (VHL) disease located. Surgical therapy for cerebellar hemangioblastoma was performed, and histological examination was consistent in cerebellar hemangioblastoma. She showed no other tumors associated VHL disease till 24 years old. This is the first case report of a patient with 3p deletion syndrome whose cerebellar hemangioblastoma may be associated with VHL disease. Repeat imaging studies were recommended for the patients with 3p deletion syndrome., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: No population-based surveys of porencephaly, schizencephaly, and hydranencephaly have been conducted in Japan or other Asian countries. We performed a neuroepidemiologic analysis to elucidate the incidence of porencephaly, schizencephaly, and hydranencephaly in Miyagi prefecture, Japan, during 2007-2011., Methods: We sent inquiry forms in February 2012 to three neonatal intensive care units, 25 divisions of orthopedic surgery in municipal hospitals, 33 divisions of pediatrics including one university hospital, municipal hospitals, pediatric practitioners, and institutions for physically handicapped children located in Miyagi prefecture. These covered all clinics related to pediatric neurology and orthopedic surgery in Miyagi prefecture. In the inquiry, diagnostic criteria for porencephaly, schizencephaly, and hydranencephaly were described and representative images of magnetic resonance imaging were shown. We obtained an 82% (27 of 33) response rate from the divisions of pediatrics, a 100% (3 of 3) response rate from the neonatal intensive care units, and a 68% (17 of 25) response rate from orthopedic surgery clinics. The magnetic resonance imaging scans of each patient were retrieved and inspected., Results: Five, one, and two individuals developed porencephaly, schizencephaly, and hydranencephaly, respectively. The estimated incidence rates of porencephaly, schizencephaly, and hydranencephaly were 5.2 (95% confidence interval [CI], 0.6-9.8), 1.0 (95% CI, 0.0-3.1), and 2.1 (95% CI, 0.0-5.0) per 100,000 live births, respectively., Conclusions: The prevalence rates of porencephaly, schizencephaly, and hydranencephaly at birth reported herein are compatible with results reported previously in the United States and European countries. The overall prevalence rate of these three diseases was 8.3 (95% CI, 2.6-14.1) per 100,000 live births., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: This study was aimed to determine what preoperative profiles were associated with seizure remission after corpus callosotomy and whether such seizure outcome was associated with the postoperative developmental outcome., Methods: This retrospective study included 26 consecutive patients with childhood onset epilepsy who underwent one-stage total corpus callosotomy at our institution and were followed up for a minimum of 1 year. The age at surgery ranged from 13 months to 32 years (median 6 years). The association between postoperative seizure freedom and preoperative profiles, post-operative developmental gains was examined., Results: Five patients achieved seizure freedom (Engel class I), and 10 patients achieved worthwhile reduction of seizures (class III), whereas the remaining patients had a class IV outcome. All five seizure-free patients had "lack of abnormal magnetic resonance imaging findings", "lack of proven etiology of seizures", and underwent "surgery at age 6 years or younger". These three factors were associated with seizure freedom (p<0.05, Fisher exact test). Post-operative gains in developmental quotient were significantly better in patients with seizure freedom than in those without (p<0.05, Mann Whitney U test)., Conclusion: Our study replicated the notion that seizure remission can be achieved after total corpus callosotomy in subsets of patients with medically-uncontrolled epilepsy, and suggested that a better developmental outcome can be expected in patients benefiting from seizure freedom., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

T2 hyperintensity of brain white matter lesions detected by magnetic resonance imaging (MRI) are characteristic of a heterogeneous group of diseases. Persistent T2 high intensity in combination with T1 iso- or high intensity of white matter in infants indicates a lack of normal myelination, that is, hypomyelination. However, the precise diagnosis of hypomyelinating leukodystrophy based solely on MRI findings can be difficult, especially in the early stage of the disease. We studied 26 patients who were diagnosed with hypomyelinating leukodystrophy according to MRI findings and clinical features to uncover their genetic etiology through chromosomal analyses, targeted gene analyses, and an array comparative genomic hybridization (aCGH) assay. Then, for the 17 patients with unexplained hypomyelination by traditional analyses, whole-exome sequencing (WES) was performed. The presumptive diagnoses were confirmed in 58 % of the enrolled patients (15/26) and involved 9 different genetic backgrounds. The most frequent backgrounds were 18q deletion syndrome and Pelizaeus-Merzbacher disease, with an incidence of 12 % (3/26) for both. The diagnostic rate of chromosomal analyses, targeted gene analyses, and aCGH was 31 % (8/26), and one patient was clinically diagnosed with Cockayne syndrome. Using WES, the following causative genes of hypomyelination were identified in six individuals (35 %, 6/17): TUBB4A, POLR3B, KCNT1, and MCOLN1, and some of those genes were pathogenic for not only hypomyelination but also dysmyelination or delayed myelination. Our findings suggested heterogeneous genetic backgrounds in patients with persistent white matter lesions. These data also indicate that WES may be a rapid and useful tool for identifying the underlying genetic causes of undiagnosed leukodystrophies.

Background: Myelin-oligodendrocyte glycoprotein and aquaporin-4 have been extensively analyzed as targets for humoral immune reactions in central nervous system (CNS) demyelinating diseases, and the results indicated a possible role of these antibodies in the pathogenesis of various demyelinating diseases., Objective: To investigate the antibody titer levels against myelin-oligodendrocyte glycoprotein and aquaporin-4 in pediatric patients with inflammatory CNS disorders, and to evaluate clinical significance to study anti-myelin-oligodendrocyte glycoprotein antibodies., Methods: Sera at onset from patients with acute disseminated encephalomyelitis (ADEM) in 7, optic neuritis (ON) in 5, pediatric MS in 4 and neuromyelitis optica in one were tested for myelin-oligodendrocyte glycoprotein and aquaporin-4 antibodies using cell-based assays with live transfected cells. The duration of the observation periods ranged from 1 to 21 years (median, 10 years). We also described clinical course of patients with positive anti-myelin-oligodendrocyte glycoprotein antibodies., Results: Among 17 patients diagnosed with inflammatory CNS demyelinating diseases nine (52%) were positive to anti-myelin-oligodendrocyte glycoprotein antibodies. Of note, all cases with positive anti-myelin-oligodendrocyte glycoprotein antibodies showed seronegativity against anti-aquaporin-4 antibodies and had a favorable prognosis., Conclusions: This preliminary report showed that anti-myelin-oligodendrocyte glycoprotein antibodies testing at onset could be a useful tool predicting clinical outcome of children with ADEM, ON, and MS., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

West syndrome, which is narrowly defined as infantile spasms that occur in clusters and hypsarrhythmia on EEG, is the most common early-onset epileptic encephalopathy (EOEE). Patients with West syndrome may have clear etiologies, including perinatal events, infections, gross chromosomal abnormalities, or cases followed by other EOEEs. However, the genetic etiology of most cases of West syndrome remains unexplained. DNA from 18 patients with unexplained West syndrome was subjected to microarray-based comparative genomic hybridization (array CGH), followed by trio-based whole-exome sequencing in 14 unsolved families. We identified candidate pathogenic variants in 50% of the patients (n = 9/18). The array CGH revealed candidate pathogenic copy number variations in four cases (22%, 4/18), including an Xq28 duplication, a 16p11.2 deletion, a 16p13.1 deletion and a 19p13.2 deletion disrupting CACNA1A. Whole-exome sequencing identified candidate mutations in known epilepsy genes in five cases (36%, 5/14). Three candidate de novo mutations were identified in three cases, with two mutations occurring in two new candidate genes (NR2F1 and CACNA2D1) (21%, 3/14). Hemizygous candidate mutations in ALG13 and BRWD3 were identified in the other two cases (14%, 2/14). Evaluating a panel of 67 known EOEE genes failed to identify significant mutations. Despite the heterogeneity of unexplained West syndrome, the combination of array CGH and whole-exome sequencing is an effective means of evaluating the genetic background in unexplained West syndrome. We provide additional evidence for NR2F1 as a causative gene and for CACNA2D1 and BRWD3 as candidate genes for West syndrome.

Background: Ataxia telangiectasia (A-T) is a common inherited cause of early childhood-onset ataxia, distinguished by progressive cerebellum malfunction, capillary vessel extension, and immunodeficiency. The diagnosis of A-T is sometimes difficult to establish in patients with atypical clinical evolution., Case Report: We experienced a pediatric 12-years-old female patient, who was finally diagnosed with classic A-T, demonstrating progressive dystonic-myoclonic axial jerks with ataxia as a predominant clinical feature. Oculocutaneous telangiectasias and immune status were unremarkable. Her myoclonic jerks were spontaneous or stimulus-sensitive, and partially ameliorated by levodopa treatment, but the ataxia was slowly progressive. A laboratory examination showed moderate atrophy of the vermis and cerebellum on brain magnetic resonance imaging, elevated serum alpha fetoprotein (AFP) levels, and total absence of A-T mutated (ATM) protein activity. We subsequently confirmed compound heterozygous truncating mutations of the ATM gene in this patient., Conclusion: Our findings highlight the importance of recognizing dystonic-myoclonic jerks as one of the extrapyramidal signs of classic A-T. Measurement of AFP levels should be considered in patients with unexplained myoclonic jerk movements with ataxia in whom definitive diagnoses are not identified. Physicians should be aware that there are cases where typical findings of A-T may not be fulfilled., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

We examined serum levels of various cytokines, chemokines, growth factors, and adhesion molecules in patients with uncomplicated influenza (n=20) and influenza virus-associated encephalopathy (IE) (n=18) to understand the underlying mechanism of IE. We found that IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, G-CSF, GM-CSF, TNF-α, TIMP-1, MMP-9, sE-selectin, and neutrophil elastase were elevated significantly in sera from patients with uncomplicated influenza and those with IE, compared with normal controls (n=20). Of note, neutrophil elastase, sE-selectin, IL-8, and IL-13 were elevated significantly in IE as compared with uncomplicated influenza. In the present study, for the first time, we found that serum levels of neutrophil elastase were increased in patients with IE compared with uncomplicated influenza, which suggested that cerebral endothelial damage in the development of IE was mediated by neutrophil elastase. The present study implied that anti-elastase agents are possibly an effective therapeutic protocol for IE, but this needs further elucidation., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease with a poor prognosis that is characterized by inflammatory optic neuritis and myelitis. Although it is commonly misdiagnosed as multiple sclerosis (MS), distinguishing NMO from MS is important, as therapeutic approaches approved for MS are ineffective in patients with NMO. The aquaporin-4 (AQP4) antibody is a pathogenic and diagnostic biomarker for NMO. We report an AQP4 antibody-positive 9-year-old female with intractable hiccups and nausea (IHN). Brain imaging revealed lesions in the brainstem, thalami, and hypothalamus. Nevertheless, she had no clinical or radiological signs referable to the optic nerve or spinal cord. We propose that in patients with characteristic IHN associated lesions involving the brainstem or hypothalamus, measurement of AQP4 antibody should be considered for selectivity of treatment, even if the patient has no optic nerve or spinal cord lesions., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Idiopathic stabbing headache is a primary headache defined as "transient stabs of pain in the head that occur spontaneously in the absence of underlying organic disease." Although its variant form, stabbing pain with extracephalic distribution, has been reported in rare adult cases, pediatric presentation is extremely rare. We report an 8-year-old boy suffering from severe stabbing pain in the left side of the chest, right side of the abdomen, and right knee lasting 2 to 3 minutes with increasing frequency. He was completely normal between attacks. The attack was not accompanied with headache initially. Investigation showed no abnormality. A diagnosis of extracephalic stabbing pain was made. The patient's symptoms were ameliorated by administration of valproic acid. This report illustrates that extracephalic stabbing pain can occur in pediatric patients. It is important to be aware of this peculiar condition because the pain is so severe, and it can be treatable with medication., (© The Author(s) 2013.)

Proximal 4p deletion syndrome is characterized clinically by mental retardation, minor dysmorphic facial features, and is occasionally complicated with epilepsy. More than 20 cases of proximal 4p deletion syndrome have been reported, but the causative gene(s) remain elusive. We describe here a 2-year-old female patient with a common manifestation of proximal 4p deletion syndrome and infantile epileptic encephalopathy possessing a de novo balanced translocation t(4;13)(p15.2;q12.13). The patient was diagnosed as infantile spasms at 9 months of age. She presented with dysmorphic facial features and global developmental delay, compatible with proximal 4p deletion syndrome. Using fluorescence in situ hybridization, we determined the translocation breakpoint at 4p15.2 to be within RBPJ. RBPJ is a transcription factor in the Notch/RBPJ signaling pathway, playing a crucial role in the developing human brain, and particularly telencephalon development. Our findings, combined with those of previous studies, strongly suggest that RBPJ is causative for proximal 4p deletion syndrome and epilepsy in this case., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Autosomal recessive guanosine triphosphate cyclohydrolase I (GTPCH) deficiency is an inborn error of tetrahydrobiopterin (BH4) synthesis from GTP. GTPCH deficiency causes severe reduction of BH4, resulting in hyperphenylalaninemia (HPA) and decreased dopamine and serotonin synthesis. Without treatment, a patient with GTPCH deficiency develops complex neurological dysfunctions, including dystonia and developmental delays. The first Japanese patient with GTPCH deficiency was discovered by HPA during asymptomatic newborn screening. The phenylalanine level at the age of 5days was 1273μmol/L (cutoff value, 180.0μmol/L). The high serum phenylalanine level was decreased to normal after adequate BH4 oral supplementation. Serum and urinary pteridine examination revealed very low levels of neopterin and biopterin. Sequence analysis of GCH1 revealed compound heterozygous point mutations, including a novel point mutation (p.R235W). Replacement therapy with BH4 and L-dopa/carbidopa were started at the age of 1month, and 5-hydroxytryptophan (5-HTP) was started at the age of 5months. At 10months of age, the patient showed slight dystonia but no obvious developmental delay. Cerebrospinal fluid should be examined to determine the appropriate dosage of supplement drugs. In conclusion, it is important to control the serum phenylalanine level and perform early replacement of neurotransmitters to prevent neurological dysfunction., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: during the eastern Japan earthquake in 2011 and the following prolonged blackout, pediatric patients with home medical devices sought electricity at the pediatric department. We retrospectively studied the effect of this earthquake and the following blackout., Methods: we hand-reviewed pediatric admission records in Tohoku University Hospital for new inpatients attributed to the earthquake from March 11, 2011 to April 12, 2011. A survey by questionnaire regarding the situation during the earthquake was performed for parents of technology-assisted patients., Results: during the study period, 24 pediatric patients were admitted to the pediatric department. Eighteen technology-assisted pediatric patients, including those with home respirators, accounted for 75% of new pediatric admissions. Patients who were admitted for electricity shortage stayed in the hospital for a mean of 11.0days (3-25days). The questionnaire survey showed that 55% of technology-assisted patients were admitted to medical centers for evacuation. The majority of patients (89%) with ventilators were eventually admitted to medical centers during the earthquake. Most of the parents of technology-assisted patients experienced a prolonged petrol shortage and difficulty in communications with medical centers., Conclusion: the current study suggests that technology-assisted pediatric patients with neurological disorders as the primary disease can overwhelm the capacity of hospital inpatient facilities in certain situations. Disaster preparedness should consider assuring power requirements in healthcare facilities and preparing backup power generators lasting for at least 24h for these patients. Preparing alternative measures for emergent electricity and communications could remedy serious conditions during a disaster., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Idiopathic stabbing headache (ISH) is a primary headache syndrome characterized by transient, sharp, stabbing pains located in the first division of the trigeminal nerve. Reports of pediatric ISH are rare, and extracephalic pain in pediatric ISH is extremely rare. Here we report the case of a 7-year-old male patient suffering from frequent, short, stabbing headache, which was occasionally associated with abdominal and lower back pain. Various investigations were normal. He was diagnosed with ISH, and valproic acid was administered to relieve his headache and accompanying symptoms. Our case demonstrates that abdominal and lower back pain may occur in pediatric ISH. This case may provide new evidence linking ISH and migraine by showing that extracephalic symptoms accompanying ISH are similar to those of migraine. We hypothesize that the mechanism underlying the headache and abdominal and lower back pain associated with ISH may be similar to that of a migraine headache. Accumulating additional cases by asking specific questions regarding the presence of the unusual symptoms presented in our case may help to establish a detailed clinical profile of these unfamiliar and peculiar symptoms in the pediatric ISH population.

The recent findings on subtraction ictal SPECT and ictal near-infrared spectroscopic topography in patients with West syndrome were summarized and its availability for presurgical evaluation was discussed. The subtraction ictal SPECT study in patients with West syndrome demonstrated the cortical epileptic region and subcortical involvement, which may consist of epilepsy networks related to the spasms. Moreover, subtraction ictal SPECT may have predictive power for short-term seizure outcome. Patients with a symmetric hyperperfusion pattern are predicted to have a better seizure outcome, whereas patients with asymmetric hyperperfusion pattern may develop poor seizure control. Importantly, asymmetric MRI findings had no predictive power for seizure outcome. Multichannel near-infrared spectroscopic topography applied to the patients with West syndrome detected an increase in regional cerebral blood volume in multiple areas which were activated either simultaneously or sequentially during spasms. Topographic changes in cerebral blood volume were closely correlated with spasm phenotype, suggesting that the cortex is involved in the generation of spasms. In conclusion, subtraction ictal SPECT may be considered as a useful tool for presurgical evaluation of patients with West syndrome and investigation of the pathophysiology of spasms. The ictal near-infrared spectroscopic topography should be more investigated to see if this is useful tool for presurgical evaluation., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

In addition to the typical infantile spasm symptoms, several other symptoms, such as eye movements, have been reported to be associated with infantile spasms, although the relationship between the typical spasms and these other events is not fully understood. Here we present a case with West syndrome. We observed the appearance of periodic eye movements followed by the onset of typical spasms and the appearance/disappearance of periodic eye movements during withdrawal/increases of vigabatrin. We believe that the case strongly supports the notion that periodic eye movements and typical spasms represent a spectrum of symptoms related to the same phenomenon of West syndrome.

Purpose: To elucidate the benefit of corpus callosotmy in terms of parental satisfaction and seizure outcome., Method: This study included 16 consecutive patients with infantile or early childhood onset epilepsy who underwent total corpus callosotomy for alleviation of seizures. Questionnaires were sent anonymously to the parents asking about relative changes in seizures and about parental satisfaction for the post-operative outcome., Results: The improvements in frequency, intensity, and duration of seizures were correlated with the level of satisfaction (Spearman's rank-order correlation coefficient, ρ=0.87, 0.93, and 0.75, respectively). The highest level of satisfaction was only seen in patients who achieved freedom from all seizures or drop attacks., Conclusion: Complete seizure freedom and freedom from drop attacks are important goals of corpus callosotomy for parental satisfaction. These factors should be considered in assessing post-operative outcome after corpus callosotomy., (Copyright © 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)