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Background: Most cases of spinal muscular atrophy (SMA) can be diagnosed by copy number analysis of survival motor neuron (SMN) 1. However, a small number of cases of SMA can only be diagnosed by sequencing analysis. We present a case of SMA diagnosed 7 years after the onset of symptoms., Case Report: She was a 12-year-old girl of Sri Lankan origin. At age 5, she began to fall easily. She had normal intellectual development, and electromyography suggested a neurogenic disorder. Copy number analysis of SMN1 exons 7 and 8 via polymerase chain reaction revealed at least one copy of SMN1. Exome sequence analysis for neuromuscular disorders panel could not detect the pathogenic mutation. She moved to Japan at the age of 12 years. Sequencing analysis later identified a novel mutation in SMN1 at the same locus as previously reported (c.284G>A: p.Gly95Glu). Multiple ligation-dependent probe amplification indicated she had two copies of SMN2. She was diagnosed with SMA type 3b and treated with nusinersen., Discussion: In patients with SMA, 2-5 % have a point mutation or a small insertion/deletion in SMN1. Since copy number analysis cannot detect such mutations, sequencing analysis is required. Two copies of SMN2 often result in SMA type 1 or 2, but her mild symptoms of SMA type 3b may be due to a combination of a point mutation and a deletion in SMN1., Conclusion: Even if genetic testing has been performed at previous institutions, sequencing analysis should be considered if the patient's symptoms are consistent with SMA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HI received honoraria for 4 lectures and 2 manuscript writings (2022: 157,500 yen; 2023: 300,417 yen; 2024: 110,833 yen). The other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Background: As there have been no comprehensive reports of human metapneumovirus-associated encephalopathy (hMPVE), this study examined the clinical features of hMPVE in children in Japan., Method: A nationwide survey of children with hMPVE was conducted using a structured research form. An initial survey asked pediatricians about children with hMPVE treated between 2014 and 2018. A second survey obtained patient information from hospitals that responded to the initial survey and those identified as having treated cases from a literature search. We collected demographic data, symptoms of hMPV infection, neurological symptoms, laboratory data, treatment, and outcomes. Outcomes were determined using the Pediatric Cerebral Performance Category Score., Result: Clinical information was available for 16 children. Their median age was 37 months. Six had preexisting neurological disorders. The interval between the onsets of infection and hMPVE was 4 days. Outcomes were good in 11 patients and poor in 5. There were no significant differences in demographic data, neurological symptoms, or laboratory data between the patients with good and poor outcomes. The encephalopathy subtypes were acute encephalopathy with biphasic seizures and late reduced diffusion in 3, clinically mild encephalitis/encephalopathy with a reversible splenial lesion in 3, hemorrhagic shock and encephalopathy syndrome in 2, and others in 8., Conclusion: The outcomes of children with hMPVE were not very different from those of acute encephalopathy due to other viruses. We found no factors associated with poor outcomes., 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.)

Backgrounds: The efficacy of nusinersen and its evaluation in patients with spinal muscular atrophy (SMA) has been established in clinical trials only for pediatric patients, not for adolescent and adult patients who developed SMA in infancy or early childhood. We report a long-term follow-up in adolescent and adult patients with SMA types 1 and 2., Methods: Nusinersen-treated patients with SMA types 1 and 2 between 2017 and 2022 were retrospectively reviewed. We compared baseline motor function tests with those after the final treatment. Physical and occupational therapists performed Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Hammersmith Functional Motor Scale-Expanded (HFMSE), and Revised Upper Limb Module (RULM). The Landau and Galant reflexes were not performed in CHOP-INTEND. Meaningful improvement was defined as CHOP-INTEND, 4; HFSME, 3; and RULM, 2., Results: Seven patients with SMA (type 1, 1; type 2, 6) with a median age of 23 (range, 12-40)years were treated with nusinersen for 3.55 (1.78-4.53)years. Improvement was detected in CHOP-INTEND (pre, 5 [0-31]; post, 21 [0-39]; difference, 5 [0-26]; p = 0.100) without significance, although not in HFMSE (pre, 0 [0-3]; post, 0 [0-5]; difference, 0 [0-2]; p = 0.346) and RULM (pre, 1 [0-20]; post, 3 [0-21]; difference, 1 [0-2]; p = 0.089). Owing to prolonged treatment intervals with the COVID-19 pandemic, RULM worsened in two patients., Conclusion: Nusinersen was effective in long-term follow-up. Only CHOP-INTEND showed meaningful improvement. The interval between doses of nusinersen should not be prolonged even with the COVID-19 pandemic., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HI received honoraria for 5 lectures (2019: 400,376 yen; 2020: 192,367 yen), and 2 manuscript writings (2019: 175,307 yen). AO received honoraria for 1 speakers bureau (2019: 47,080 yen). The other authors declare no competing interests., (Copyright © 2022 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: In a study using a mouse model of CDKL5 deficiency disorder (CDD), seizures are specific to female mice heterozygous for Cdkl5 mutations and not observed in hemizygous knockout males or homozygous knockout females. The aim of this study was to examine whether the clinical phenotype of patients with CDD can be impacted by the type of genetic variant., Methods: Eleven CDD patients (six females and five males) were included in this study. The molecular diagnosis of hemizygous male patients was performed using digital PCR and their clinical phenotypes were compared with those of patients with mosaic or heterozygous CDKL5 variants. The severity of clinical phenotypes was graded by using CDKL5 Developmental Score and the adapted version of the CDKL5 Clinical Severity Assessment. The effect of cellular mosaicism on the severity of CDD was studied by comparing the clinical characteristics and comorbidities between individuals with hemizygous and mosaic or heterozygous CDKL5 variants., Results: One of the five male patients was mosaic for the CDKL5 variant. All patients developed seizures irrespective of their genetic status of the pathogenic variant. However, cellular mosaicism of CDKL5 deficiency was associated with lesser severity of other comorbidities such as feeding, respiratory, and visual functional impairments., Significance: This study provided evidence that cellular mosaicism of CDKL5 deficiency was not necessarily required for developing epilepsy. CDD patients not only exhibited clinical features of epilepsy but also exhibited the developmental consequences arising directly from the effect of the CDKL5 pathogenic variant., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To examine the efficacy and tolerance of the antiseizure medications lacosamide (LCM) and levetiracetam (LEV) in patients with benign infantile epilepsy (BIE)., Methods: The clinical data of 24 children with BIE seen between 2014 and 2020 were collected retrospectively, and treatment, effectiveness, and adverse effects were examined. PRRT2 gene analysis was performed using Sanger sequencing., Results: Of the 24 children with BIE, 14 were treated with antiseizure medications. PRRT2 gene analysis was performed in 14 children, and mutations were identified in 4, including a pair of siblings. All five children treated with LCM became seizure-free, similar to those treated with carbamazepine. The LCM does was 2 mg/kg/day in all cases. There were no adverse effects in any patient treated with LCM. By contrast, both patients treated with LEV had seizure recurrence. In one patient, LEV was replaced with CBZ, resulting in seizure freedom., Conclusions: Low-dose LCM was effective and well tolerated in patients with BIE, whereas LEV was insufficiently effective., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: The current study aimed to identify and compare the clinical characteristics of human parechovirus type 3 (HPeV3)-associated acute encephalitis/encephalopathy (HPeV3E/E) between infants with abnormal brain magnetic resonance imaging (MRI) findings (typical, or MRI-positive HPeV3E/E) and those with MRI-negative findings (MRI-negative HPeV3E/E)., Methods: This is a retrospective study on patients with HPeV3 infection, and a two-step questionnaire survey performed on 837 hospitals in Japan between 2014 and 2016., Results: We identified 240 infants with HPeV3 infection, of which 34 had been clinically-diagnosed HPeV3E/E (cHPeV3E/E). However, detailed clinical data were provided by 32 of the 34 patients. Among these 32, 23 had undergone MRI and were categorized into two groups, MRI-positive (n = 17) and -negative (n = 6). There were no significant intergroup differences in clinical lab results or symptoms, except for gastrointestinal symptoms that were only present in the MRI-negative patients. The MRI-positive group showed white matter involvement on brain MRI during the acute phase, and 8 patients presented with lesions on follow-up MRI. Furthermore, 4 (50%) of the 8 patients had neurological sequelae., Conclusion: Clinical characteristics of cHPeV3E/E patients with and without lesions on brain MRI showed no significant differences. Therefore, considering the difficulty in distinguishing febrile infants with cHPeV3E/E from those with a sepsis-like illness, during an HPeV3 infection epidemic, it is imperative to frequently perform brain MRI in febrile infants presenting with severe disease for the early diagnosis of HPeV3E/E presenting with brain lesions., 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 © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the success rate, procedure time, and adverse events of intrathecal administration of nusinersen via the paramedian approach in adolescents and adults with spinal muscular atrophy (SMA) associated with scoliosis., Methods: Seven patients with genetically confirmed SMA (age, 12-40 years) were included. Intrathecal administration of nusinersen was performed via paramedian approach using fluoroscopy after determination of the largest interlaminal foramen among L2-L3, L3-L4, or L4-L5 by three-dimensional computed tomography. We measured the times for preparation, positioning, and puncture, and the total time of stay. Adverse effects of intrathecal administration were noted., Results: Intrathecal administration via paramedian approach was successful for all 38 opportunities. The median total time of stay was 44.0 min (interquartile range, 37.3-50.0 min). The total time of stay was significantly longer in patients with SMA type 1 than in those with SMA type 2, but was not different according to the severity of scoliosis. Adverse effects included oxygen supplementation, headache, and back pain. Sedation was correlated with oxygen supplementation and headache., Conclusions: Intrathecal administration of nusinersen via the paramedian approach had the advantages of a high success rate and short procedure time with fewer adverse events in SMA patients associated with scoliosis., 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 © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Benign convulsions with gastroenteritis are characterized by a cluster of seizures. Sodium channel blockers are efficacious. We prescribed lacosamide, a new channel blocker, for five patients. Patient age ranged from 17 to 33 months; all five experienced 1-4 generalized convulsions persisting for 30-120 s. One patient exhibited a transient splenial lesion on head magnetic resonance imaging. All received one dose (2 mg/kg) of lacosamide. The convulsions ceased, and no adverse drug effect was noted. A single dose of lacosamide was effective and well-tolerated in five patients with benign convulsions with gastroenteritis., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Recently, many genes related to neurodevelopmental disorders have been identified by high-throughput genomic analysis; however, a comprehensive understanding of the mechanism underlying neurodevelopmental disorders remains to be established. To further understand these underlying mechanisms, we performed a comprehensive genomic analysis of patients with undiagnosed neurodevelopmental disorders., Methods: Genomic analysis using next-generation sequencing with a targeted panel was performed for a total of 133 Japanese patients (male/female, 81/52) with previously undiagnosed neurodevelopmental disorders, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. Genomic copy numbers were also analyzed using the eXome Hidden Markov Model (XHMM)., Results: Thirty-nine patients (29.3%) exhibited pathogenic or likely pathogenic findings with single-gene variants or chromosomal aberrations. Among them, 20 patients were presented here. Pathogenic or likely pathogenic variants were identified in 18 genes, including ACTG1, CACNA1A, CHD2, CDKL5, DNMT3A, EHMT1, GABRB3, GABRG2, GRIN2B, KCNQ3, KDM5C, MED13L, SCN2A, SHANK3, SMARCA2, STXBP1, SYNGAP1, and TBL1XR1., Conclusion: A diagnostic yield of 29.3% in this study was nearly the same as that previously reported from other countries. Thus, we suggest that there is no difference in genomic backgrounds in Japanese patients with undiagnosed neurodevelopmental disabilities. Although most of the patients possessed de novo variants, one of the patients showed an X-linked inheritance pattern. As X-linked recessive disorders exhibit the possibility of recurrent occurrence in the family, comprehensive molecular diagnosis is important for genetic counseling., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Purpose: This study was performed to clarify the clinical features of Japanese patients with PRRT2 mutations., Methods: The PRRT2 gene was analyzed in 135 patients with benign infantile epilepsy (BIE) or paroxysmal kinesigenic dyskinesia (PKD) using a direct sequencing method: 92 patients had BIE alone, 25 had both BIE and PKD, and 18 had PKD alone. Of the cases, 105 were familial, and 30 were sporadic. Clinical information was collected using a structured questionnaire., Results: PRRT2 mutations were identified in 104 patients. Among the familial cases, PRRT2 mutations were found in at least one individual in 21 of 28 families with BIE alone, in 26 of 27 families with infantile convulsions and choreoathetosis, and in 2 of 3 families with PKD alone. Among the sporadic cases, PRRT2 mutations were observed in 7 of 25 patients with BIE alone, in 1 of 1 patient with BIE and PKD, and in 3 of 4 patients with PKD alone. The c.649dupC mutation was the most frequent, followed by the c.981C > G mutation. Among the patients with epilepsy, the median age at BIE onset was 5 months, the median age at the last seizure was 6 months, and the median number of seizures was 5., Conclusion: PRRT2 mutations were found in 68% of Japanese probands with BIE or PKD. The phenotypes of BIE associated with PRRT2 mutations were consistent with those of BIE diagnosed clinically., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: This study measured the serum carnitine levels in patients with epilepsy and determined the factors contributing to low carnitine levels., Methods: We measured the serum carnitine levels in 94 consecutive patients with epilepsy, including the free carnitine (FC) and acylcarnitine fractions, using an enzyme cycling method. We defined a low FC as a serum FC level < 36 μmol/L. Age, body mass index (BMI), standard deviation score of BMI (BMI-SDS), use of valproate, cognitive disorder, and feeding problems differed between patients with low and normal FC. In patients taking valproate, the associations of the serum FC level with the platelet count and serum ammonia and amylase levels were analyzed., Results: Univariate analysis showed that a low BMI and BMI-SDS, the use of valproate, and cognitive disorder were more frequent in patients with a low FC. Logistic regression analysis revealed that a low BMI-SDS and cognitive disorders were independently associated with a low FC. Among the patients taking valproate, a low BMI-SDS and age were associated with a low FC. The serum FC and ammonia levels were inversely correlated, whereas no correlation was observed between the serum FC level and platelet count or serum amylase level., Conclusion: A low BMI and cognitive disorders were related to a low FC in patients with epilepsy and the serum carnitine levels should be monitored in these patients., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Norovirus is a major pathogen of gastroenteritis and is known to cause encephalitis/encephalopathy. The aim of this national survey was to clarify the clinical features of norovirus-associated encephalitis/encephalopathy (NoVE) among children in Japan., Methods: A nationwide survey of children with NoVE was conducted using a structured research form. The initial survey asked pediatricians about children with NoVE treated between January 2011 and March 2016. The second survey obtained patient information from two sources: hospitals that responded to the initial survey and those identified as having treated cases from a literature search., Results: Clinical information was available for 29 children. Their median age was 2 y 8 m. The outcome was good in 13 patients and poor in 15. The interval between the onset of gastrointestinal symptoms and that of encephalitis/encephalopathy was significantly shorter in those with a poor outcome. At the onset of an elevated serum creatinine level and an abnormal blood glucose level were correlated with a poor outcome. Regarding the subtypes of encephalitis/encephalopathy, acute encephalopathy with biphasic seizures and late reduced diffusion and hemorrhagic shock and encephalopathy syndrome were frequent., Conclusion: The outcome of children with NoVE was poor. Early onset of neurological symptoms, an elevated serum creatinine level, and an abnormal blood glucose level were associated with a poor outcome. No effective treatment was identified and this should be the subject of future studies., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to clarify the effects of antihistamines on the semiology of febrile seizures., Methods: The manifestations of febrile seizures were recorded using a structured questionnaire immediately after patients arrived at the hospital. We focused on events at seizure commencement, including changes in behavior and facial expression, and ocular and oral symptoms. The presence or absence of focal and limbic features was determined for each patient. Drugs taken within 6 h prior to seizure were noted. Seizure manifestations were compared between children who did not take antihistamines and those who took antihistamines., Results: Seizures lasting ≥5 min were relatively more frequent in children who did not take antihistamines, although the difference was not statistically significant. One or more focal features were present in 60 of 78 children with no antihistamines and 17 of 23 children with antihistamines. One or more limbic features were present in 32 of 78 children with no antihistamines and 9 of 23 children with antihistamines. No significant difference in the numbers of focal or limbic features was apparent between children who did not take antihistamines and those who took antihistamines., Conclusion: Antihistamines did not significantly affect the semiology of febrile seizures., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

We report on a 4-year-old girl with a de novo GNAO1 mutation who had neurological findings, including decreased spontaneous movements, hypotonia, and dystonic features. She was referred to our hospital because of delayed psychomotor development. She showed hypotonia and decreased spontaneous movements. Voluntary movements of the limbs were more frequent in the lower extremities than in the upper extremities. Occasional dyskinetic features, such as awkward hand/foot posturing and grimacing, were seen during the voluntary movements. Serum metabolic screening, head magnetic resonance imaging, and electroencephalography were unremarkable. Whole-exome sequencing revealed a de novo mutation in the patient's GNAO1 gene, c.709 G > A (p.E237K). We calculated the free-energy change using the FoldX Suite to evaluate the impact of the E237K mutation. The FoldX calculations showed an increased free-energy change in the active state of the GNAO1 protein, indicating that the E237K mutation destabilizes the active state complexes. No seizures, chorea, tremor, or myoclonia, which are frequently reported in patients with GNAO1 mutations, were observed as of the last follow up. Our patient will improve the understanding of early neurological features in patients with GNAO1 mutations., (Copyright © 2018. Published by Elsevier B.V.)

Background: The characteristics of epilepsy in patients with Kabuki syndrome with KMT2D mutations (KABUK1) have not yet been well documented. This is the first review to explore this., Materials & Methods: We enrolled 14 patients with KABUK1, whose median age was 13.6years (range=4.1-21.3years). Their medical records from October 1981 to May 2016 were retrospectively analyzed., Results: Epilepsy was present in 5 (36%) patients. Four of these patients presented with nonsense mutations and one with missense mutations. None presented with brain abnormalities. Four patients presented with annual or monthly focal seizures, of which three evolved to bilateral convulsive seizures. Median onset age of focal epilepsy was 11.8years (range=9.5-12.8years). One presented with monthly myoclonic seizures from age 11.2, whose mother with no other KABUK1 features, had focal epilepsy. The cumulative incidence of epilepsy related to KABUK1 up until age 13 was 45%. Interictal electroencephalogram revealed focal paroxysmal epileptiform discharges (in frontal, central, and parietal regions) in three patients, diffuse high-voltage spike-and-waves in one patient, and normal sleep record in one patient. Myoclonic seizures were rapidly controlled by levetiracetam. In contrast, focal seizures were not controlled in the early period of antiepileptic therapy., Conclusion: This long-term follow-up of patients with KABUK1 revealed a higher prevalence of epilepsy than previously reported. The age of epilepsy onset and rate of focal seizures evolving to bilateral convulsive seizures in KABUK1 were also higher than previously reported in patients with clinically diagnosed Kabuki syndrome. Although seizure outcome is reported to be favorable in Kabuki syndrome, focal seizures in patients with KABUK1 were not immediately responsive to medication., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Fournier's gangrene is an infectious necrotizing fasciitis of the perineal, genital, or perianal regions and is uncommon in children. Adrenocorticotropic hormone (ACTH) is effective for the treatment of infantile spasms; however, suppression of immune function is one of the major adverse effects of this approach. We encountered a 2-month-old boy with infantile spasms that had been treated with ACTH and had developed complicating Fournier's gangrene. Strangulation of a right inguinal hernia was observed after ACTH treatment. Although surgical repair was successful and no intestinal injuries were detected, swelling and discoloration of the right scrotum developed in association with pyrexia and a severe inflammatory response. A scrotal incision revealed pus with a putrid smell. The patient was subsequently diagnosed with Fournier's gangrene complicated by septic shock and disseminated intravascular coagulation. Extensive debridement and intensive care was performed. Enterobactor aerogenes, methicillin-resistant Staphylococcus aureus, and Enterococcus faecalis were isolated from the pus. Meropenem, teicoplanin, and clindamycin were administered to control the bacterial infection. The patient was discharged from the intensive care unit without any obvious neurological sequelae. Suppression of immune function associated with ACTH therapy may have been related to the development of Fournier's gangrene in this case., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The outcome of mild encephalitis/encephalopathy with reversible splenial lesion (MERS) is favorable whether or not specific treatment is performed. We report a patient with MERS treated with methylprednisolone, complicated by gastric perforation followed by critical illness polyneuropathy. The patient was a 14-year-old male with mildly impaired consciousness and hyponatremia who was treated with methylprednisolone pulse therapy. High fever appeared after methylprednisolone pulse therapy and free air was recognized on an abdomen roentgenogram. Gastric perforation was recognized on emergent endoscopic surgery and omental implantation repair was performed. His consciousness was fully recovered after surgery, whereas he was noted to have motor and sensory impairment of the lower extremities and vesico-rectal disturbance. Nerve conduction studies revealed decreased compound muscle action potentials with preserved motor conduction velocity and decreased sensory nerve action potentials. He was diagnosed as having critical illness polyneuropathy, and bedside physical rehabilitation was initiated. His neurological symptoms resolved within 6months. Our patient highlighted possible serious adverse events associated with steroid treatment for children with MERS., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Purpose: Although it has been reported that some antiepileptic drugs have inducing or inhibiting effects on lamotrigine (LTG) clearance, whether they have the same effects in Asian epilepsy patients as in those in other countries has not been clarified, especially in children. The aim of this study was to determine the effects of co-medications on LTG clearance in Japanese children with epilepsy., Methods: A total of 342 routine serum concentration measurements of LTG in 102 Japanese epilepsy patients under 20years of age were reviewed. The dose-corrected concentration (DCC) of LTG was calculated as [concentration]/[dose/(body weight)], and the DCC of LTG was compared by co-medication. The difference in the DCC of LTG was compared between patients with and without valproic acid (VPA) and between those with and without drugs inducing glucuronic acid conjugation (phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB))., Results: The DCC of LTG was significantly higher in patients on VPA and significantly lower in patients on drugs inducing glucuronic acid conjugation than in patients on LTG monotherapy. The DCC of LTG was significantly higher in patients on CBZ than in patients on PHT or PB. There was no correlation between the DCC of LTG and the concentration of VPA or metabolic inducers within the therapeutic range. Other antiepileptic drugs including clobazam, clonazepam, zonisamide, and levetiracetam had little effect on LTG concentration., Conclusion: LTG concentration changes dramatically with concomitant antiepileptic drugs in Japanese children, as previously reported from other countries, and special attention is required. Although the dose of LTG should be adjusted when starting or discontinuing VPA or metabolic inducers, no adjustment is needed when changing the dose of VPA or metabolic inducers in the therapeutic range., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Purpose: We retrospectively evaluated the imaging spectrum of Pelizaeus-Merzbacher disease (PMD) in correlation with the clinical course and genetic abnormality., Methods: We collected the magnetic resonance imaging (MRI) findings of 19 genetically proven PMD patients (all males, aged 0-29years old) using our integrated web-based MRI data collection system from 14 hospitals. The patterns of hypomyelination were determined mainly by the signals of the cerebrum, corticospinal tract, and brainstem on T2-weighted images (T2WI). We assessed the degree of myelination age on T1-weighted images (T1WI) and T2WI independently, and we evaluated cerebellar and callosal atrophy. The clinical severity and genetic abnormalities (causal mutations of the proteolipid protein gene PLP1) were analyzed together with the imaging findings., Results: The clinical stage tended to be more severe when the whole brainstem, or corticospinal tract in the internal capsule showed abnormally high intensity on T2WI. Diffuse T2-high signal of brainstem was observed only in the patients with PLP1 point mutation. Myelination age "before birth" on T1WI is a second manifestation correlated with the clinically severe phenotypes. On the other hand, eight patients whose myelination ages were > 4months on T1WI were associated with mild clinical phenotypes. Four of them showed almost complete myelination on T1WI with a discrepancy in myelination age between T1WI and T2WI. A random and patchy pattern of myelination on T2WI was noted in one patient with PLP1 point mutation. Advanced myelination was observed in three of the seven followed-up patients. Four patients had atrophy of the cerebellum, and 17 patients had atrophy of the corpus callosum., Conclusion: Our multicenter study has demonstrated a wide variety of imaging findings of PMD. Signal intensity of brainstem and corticospinal tract of internal capsule would be the points to presume clinical severity in PMD patients. The spectrum of MRI findings should be kept in mind to diagnose PMD and to differentiate from other demyelinating leukodystrophies., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: This study used quantitative analysis to determine whether increased variability in fetal heart rate (FHR) is related to the risk of developing periventricular leukomalacia (PVL)., Methods: We analyzed 124 FHR traces of neonates delivered preterm at 27-33 weeks' gestation to 105 mothers. FHR traces 1-3h before delivery were translated into power-spectrum curves using a fast Fourier transformation. The total power (the area under the curve of 1-10 cycles per minute), segmental power of every cycle per minute, peak power, and frequency edges were calculated, and their relationship with the subsequent development of PVL was examined., Results: Total power was significantly higher in the PVL group (n=9, median 1813, range 1064-2426) compared to the non-PVL group (n=114, median 1383, range 381-3324, p=0.029). Infants in the PVL group had greater segmental power in segments with 1-2, 2-3, and 9-10 cycles per minute, than those in the non-PVL group. Total power of ⩾1550 was significantly correlated with the subsequent development of PVL and premature rupture of membranes. Furthermore, the frequency of pregnancy-induced hypertension was significantly reduced in the fetuses with a total power of ⩾1550., Conclusion: Our study suggests that a fetus with increased FHR variability is at risk of developing PVL. This study provides additional evidence supporting the contribution of antenatal factors to the subsequent development of PVL., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: Evaluation of the efficacy of antiepileptic drugs (AEDs) used in the treatment of Dravet syndrome (DS) with different genotypes., Methods: Patients with DS were recruited from different tertiary hospitals. Using a direct sequencing method and Multiplex Ligation-Dependent Probe Amplification (MLPA), genetic abnormalities were assessed within the exons and flanking introns of SCN1A gene, which encodes the α1 subunit of neuronal sodium channels. Patients were divided into SCN1A-positive and SCN1A-negative groups according to the results of genetic tests. Medical records, including detailed treatment information, were surveyed to compare the effect of different AEDs on clonic or tonic-clonic seizures (GTCS). Efficacy variable was responder rate with regard to seizure reduction., Results: One hundred and sixty of 276 (57.97%) patients had mutation in SCN1A gene (only 128 of them had provided detailed medical records). Among the 116 patients without SCN1A mutations, 87 had provided detailed medical records. Both older AEDs (valproate, phenobarbital, bromide, carbamazepine, clonazepam, and clobazam) and newer AEDs such as zonisamide were used in these patients. Valproate was the most frequently used AED (86.72% in the SCN1A-positive group, 78.16% in the SCN1A-negative group), with 52.25% and 41.18% responder rates in SCN1A-positive and SCN1A-negative patients, respectively (P=0.15). Bromide was used in 40.63% of the SCN1A-positive patients and 20.69% of the SCN1A-negative patients, and its responder rates were 71.15% and 94.44% in SCN1A-positive and SCN1A-negative patients, respectively (P=0.05). Efficacy rates of clonazepam, clobazam, phenobarbital, and zonisamide ranged from 30% to 50%, and these rates were not correlated with different genotypes (P>0.05). Carbamazepine had either no effect or aggravated seizures in all SCN1A-positive patients., Significance: Bromide is most effective and is a well-tolerated drug among DS patients, especially among SCN1A-negative patients. Carbamazepine should be avoided in patients with SCN1A mutations., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

This study examines whether microdeletions and duplications of the gene encoding α1 subunit of the sodium channel (SCN1A) are underlying causes in Dravet syndrome (DS) with SCN1A missense mutation. Multiple exonic deletions were identified in 8/84 patients without mutation and 0/41 patients with missense mutations. Our findings indicate that while microdeletions are not rare in SCN1A-negative patients, they are not likely to be present simultaneously with other SCN1A mutations., (Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Mutations in SCN2A, the gene encoding α2 subunit of the neuronal sodium channel, are associated with a variety of epilepsies: benign familial neonatal-infantile seizures (BFNIS); genetic epilepsy with febrile seizures plus (GEFS+); Dravet syndrome (DS); and some intractable childhood epilepsies. More than 10 new mutations have been identified in BFNIS, all of them are missense. To date, only one nonsense mutation has been found in a patient with intractable childhood epilepsy and severe mental decline. Recently, microduplication of chromosome 2q24.3 (containing eight genes including SCN2A, SCN3A, and the 3' end of SCN1A) was reported in a family with dominantly inherited neonatal seizures and intellectual disability. Functional studies of SCN2A mutations show that they can cause divergent biophysical defects in Na(V)1.2 and impair cell surface expressions. There is no consistent relationship between genotype and phenotype., (Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Many types of spinocerebellar ataxias (SCAs) manifest as progressive disorders with cerebellar involvement. SCA type 27 (SCA27) is a rare type of SCA caused by mutations in the fibroblast growth factor 14 gene (FGF14). FGF14 disruption caused by a de novo reciprocal chromosomal translocation between chromosomes 13 and 21 was identified in a patient with the phenotype of paroxysmal non-kinesigenic dyskinesia (PNKD). This indicated genetic heterogeneity of PNKD, since 60% of the patients with PNKD exhibit mutations in another gene responsible for PNKD, the myofibrillogenesis regulator 1 gene (MR-1). We hypothesized that the remaining 40% of patients with PNKD may have FGF14 mutations; therefore, the nucleotide sequences of MR-1 and FGF14 were analyzed in another six patients with PNKD, but no nucleotide alterations were observed in these genes for these patients. Further studies should be conducted on the phenotypic heterogeneity of FGF14 mutations and/or haploinsufficiency in SCA27 and PNKD., (Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: To examine the relation between outcome and treatment with steroids and gammaglobulin in children with acute necrotizing encephalopathy., Methods: We retrospectively evaluated the clinical course and outcome of 34 children with acute necrotizing encephalopathy. They were divided into two groups; 17 patients with brainstem lesion and 17 patients without brainstem lesion. Early steroid use was defined as when steroids were administered within 24h after the onset. The outcome was judged as good when a patient had no or mild cognitive impairment and poor when a patient had more severe sequelae, or died., Results: Among patients without brainstem lesions, the outcome was good in 7 of 12 with early steroid, whereas it was poor in all 5 patients without early steroid. There was no significant difference in sex, age, and laboratory data between patients with and without early steroid. The outcome was not correlated with gammaglobulin treatment. As to patients without brainstem lesions, the outcome was not correlated with early steroid or gammaglobulin treatment., Conclusions: Steroid within 24 h after the onset was related to better outcome of children with acute necrotizing encephalopathy without brainstem lesions. Early steroid treatment will be an important option of the treatment for acute necrotizing encephalopathy.

This report describes a 4-year-old male patient experienced prolonged febrile seizures after 1 year of age, multiple febrile seizures and complex partial seizures with secondary generalization. The gene encoding voltage-gated sodium channel alpha1-subunit: SCN1A analysis revealed a heterozygous de novo one-point mutation (IVS16+2 T>C) at a splice-acceptor site. This mutation was inferred to cause truncation of the alpha1-subunit molecule and, thereby, a loss of channel function. To date, truncation mutation has been found exclusively in patients with severe myoclonic epilepsy in infancy (SMEI), although only missense mutations have been found in generalized epilepsy with febrile seizures plus (GEFS+), partial epilepsy with FS+, FS+, and FS. The patient's phenotype is consistent with that of partial epilepsy with FS+, rather than SMEI, including borderline SMEI (SMEB). We present the first case report of partial epilepsy with FS+ associated with a truncation mutation of SCN1A. The possibility exists for concomitant involvement of multiple genes other than SCN1A for seizure phenotypes.

Although posterior reversible encephalopathy syndrome (PRES) is caused by various conditions, there have been no reports on PRES associated with bronchial asthma. We report a case with PRES during the treatment for severe asthmatic attack. A 4-year-old girl was treated for asthmatic attack with steroids. From the 10th hospital day, hypertension, pulmonary edema, and cardiomegaly were observed. In spite of treatment with furosemide, she became lethargic and had a generalized convulsion on the 23rd hospital day. CT showed low density areas in the bilateral occipital white matter and MRI on the 28th hospital day demonstrated high intensity areas in the same regions on T2-weighted and FLAIR images. After discontinuation of corticosteroid and further antihypertensive therapy, her consciousness improved. MRI on the 67th hospital day had no abnormalities and no neurological sequelae were seen at 2 years after the event. We should be aware that PRES is a rare but important adverse event related to steroid therapy, because hypertension and water retention are major adverse effects of steroids.