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A 49-year-old Japanese man had shown developmental delay, learning difficulties, epilepsy, and slowly progressive gait disturbance in elementary school. At 46 years old, he experienced repeated drowsiness with or without generalized convulsions, and hyperammonemia was detected. Brain magnetic resonance imaging detected multiple cerebral white matter lesions. An electroencephalogram showed diffuse slow basic activities with 2- to 3-Hz δ waves. Genetic tests confirmed a diagnosis of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Leukoencephalopathy was resolved following the administration of L-arginine and lactulose with a decrease in plasma ammonia levels and glutamine-glutamate peak on magnetic resonance spectroscopy. Leukoencephalopathy in HHH syndrome may be reversible with the resolution of hyperammonemia-induced glutamine toxicity.

To examine the current medical and psychosocial status of patients with epilepsy, aiming to facilitate appropriate application of the Intractable/Rare Diseases Act of Japan.By analysing the cross-sectional data of patients registered in the tertiary hospital-based Epilepsy Syndrome Registry of Japan, we investigated the proportion of patients who met the severity criteria as defined by the Act (seizure frequency of at least once a month, or presence of intellectual/neurological/psychiatric symptoms, or both) and whether there are candidate syndrome/diseases to be added to the existing list in the Act.In total, 2,209 patients were registered. After excluding self-limited/idiopathic epilepsies, 1,851 of 2,110 patients (87.7%) met the severity criteria. The patients were classified into eight main epilepsy syndromes (594 patients), 20 groups based on aetiology (1,078 patients), and three groups without known aetiology (427 patients). Most of the groups classified by syndrome or aetiology had high proportions of patients satisfying the severity criteria (90%), but some groups had relatively low proportions (80%) resulting from favourable outcome of surgical therapy. Several small groups with known syndrome/aetiology await detailed analysis based on a sufficiently large enough number of patients registered, some of whom may potentially be added to the list of the Act.The registry provides data to examine the usefulness of the severity criteria and list of diseases that are operationally defined by the Act. Most epilepsy patients with various syndromes/diseases and aetiology groups are covered by the Act but some are not, and the list of designated syndromes/diseases should be complemented by further amendments, as suggested by future research.

We summarize the long-term motor outcome and disability level in a cluster of pediatric patients with acute flaccid myelitis (AFM) associated with the enterovirus D68 outbreak in 2015.This is a nationwide follow-up questionnaire analysis study. Clinical data including the motor function (manual muscle strength test) and other neurological symptoms were collected at the acute (nadir), recovery (six months), and chronic (three years) stages. We use the Barthel index, which measures 10 variables describing activity of daily living and mobility to assess the disability level.Clinical data of 33 patients with AFM (13 females, 20 males; median age = 4.1 years) were available. Among patients with tetraplegia or triplegia, paraplegia, and monoplegia at the acute stage, two of seven, four of thirteen, and two of thirteen exhibited complete recovery without paralysis; of those five of seven, eight of thirteen, and two of thirteen showed improvement with lesser limb involvement at the chronic stage, respectively. Nine patients (27%) demonstrated improvement at the recovery-to-chronic period. All six patients with positive isolation of enterovirus D68 from biological samples at the acute stage showed persistent motor deficits. Other neurological findings had better prognosis than motor weakness. Better Barthel index score at the chronic stage was observed (P 0.001; median difference [95% confidence interval], 53 [40 to 63]), implying an improved disability level even in patients with persistent motor deficits.AFM has a high rate of persistent motor deficits showing one- to two-limb paralysis. Disability level of patients with AFM, however, generally improved at the three-year time point.

Background We aimed to demonstrate the biochemical characteristics of vitamin B6–dependent epilepsy, with a particular focus on pyridoxal 5′-phosphate and pyridoxal in the cerebrospinal fluid. Methods Using our laboratory database, we identified patients with vitamin B6–dependent epilepsy and extracted their data on the concentrations of pyridoxal 5′-phosphate, pyridoxal, pipecolic acid, α-aminoadipic semialdehyde, and monoamine neurotransmitters. We compared the biochemical characteristics of these patients with those of other epilepsy patients with low pyridoxal 5′-phosphate concentrations. Results We identified seven patients with pyridoxine-dependent epilepsy caused by an ALDH7A1 gene abnormality, two patients with pyridoxal 5′-phosphate homeostasis protein deficiency, and 28 patients with other epilepsies with low cerebrospinal fluid pyridoxal 5′-phosphate concentrations. Cerebrospinal fluid pyridoxal and pyridoxal 5′-phosphate concentrations were low in patients with vitamin B6–dependent epilepsy but cerebrospinal fluid pyridoxal concentrations were not reduced in most patients with other epilepsies with low cerebrospinal fluid pyridoxal 5′-phosphate concentrations. Increase in 3-O-methyldopa and 5-hydroxytryptophan was demonstrated in some patients with vitamin B6–dependent epilepsy, suggestive of pyridoxal 5′-phosphate deficiency in the brain. Conclusions Low cerebrospinal fluid pyridoxal concentrations may be a better indicator of pyridoxal 5′-phosphate deficiency in the brain in vitamin B6–dependent epilepsy than low cerebrospinal fluid pyridoxal 5′-phosphate concentrations. This finding is especially helpful in individuals with suspected pyridoxal 5′-phosphate homeostasis protein deficiency, which does not have known biomarkers.

BackgroundVariants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear.MethodsWe examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.ResultsPathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.ConclusionsPrenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

Background Febrile neonates and young infants presenting with seizure require immediate evaluation and treatment. Herein we experienced two young infants with parechovirus-A3 (PeV-A3) encephalitis, initially presented with focal seizure suspecting herpes simplex virus (HSV) encephalitis. Cases We have experienced 2 infantile cases, initially presented with focal seizure. At presentation, HSV encephalitis was strongly suspected and empiric acyclovir therapy was started; however, serum and/or cerebrospinal fluid (CSF) PCR for HSV were negative. Instead, serum and/or CSF PCR for parechovirus-A was positive. PeV-A3 infection was confirmed by genetic sequence analyses. Both cases required multiple anticonvulsant therapy and intensive care for intractable seizure. Diffusion-weighted imaging of brain magnetic resonance imaging (MRI) showed distinct findings; high-intensity lesions in the gray matter of parietal and occipital lobes in Case 1, and bilateral decreased diffusion of the deep white matter and corpus callosum in Case 2. We have followed two cases more than four years; Case 1 developed epilepsy, has been on an anticonvulsant to control her seizure. Case 2 has significant neurodevelopmental delay, unable to stand or communicate with language. Conclusions PeV-A3 encephalitis needs to be in differential diagnosis when neonates and young infants present with focal seizure, mimicking HSV encephalitis. Special attention may be necessary in patients with PeV-A3 encephalitis given it could present with intractable seizure with high morbidity in a long-term.

Dystrophinopathy is caused by alterations in DMD. Approximately 1% of patients remain genetically undiagnosed because intronic variations are not detected by standard methods. Here, we combined laboratory and in silico analyses to identify disease-causing genomic variants in genetically undiagnosed patients and determine the regulatory mechanisms underlying abnormal DMD transcript generation. DMD transcripts from 20 genetically undiagnosed dystrophinopathy patients in whom no exon variants were identified, despite dystrophin deficiency on muscle biopsy, were analyzed by transcriptome sequencing. Genome sequencing captured intronic variants and their effects were interpreted using in silico tools. Targeted long-read sequencing was applied in cases with suspected structural genomic abnormalities. Abnormal DMD transcripts were detected in all cases analyzed. Exonization of intronic sequences was observed in 15 cases and exon skipping in one case; 13 single nucleotide variants and three structural rearrangements were identified as causal genomic variations. DMD transcripts were aberrantly spliced and polyadenylated in two cases in which chromosome rearrangements were detected. In one case, DMD transcripts were terminated due to nucleotide repeat expansion. Our combined analysis approach successfully identified pathogenic events. Detection of diseasing-causing mechanisms in DMD transcripts could inform the therapeutic options for patients with dystrophinopathy.

Dystrophinopathy is caused by alterations in DMD. Approximately 1% of patients remain genetically undiagnosed, because intronic variations are not detected by standard methods. Here, we combined laboratory and in silico analyses to identify disease-causing genomic variants in genetically undiagnosed patients and determine the regulatory mechanisms underlying abnormal DMD transcript generation. DMD transcripts from 20 genetically undiagnosed dystrophinopathy patients in whom no exon variants were identified, despite dystrophin deficiency on muscle biopsy, were analyzed by transcriptome sequencing. Genome sequencing captured intronic variants and their effects were interpreted using in silico tools. Targeted long-read sequencing was applied in cases with suspected structural genomic abnormalities. Abnormal DMD transcripts were detected in 19 of 20 cases; Exonization of intronic sequences in 15 cases, exon skipping in one case, aberrantly spliced and polyadenylated transcripts in two cases and transcription termination in one case. Intronic single nucleotide variants, chromosomal rearrangements and nucleotide repeat expansion were identified in DMD gene as pathogenic causes of transcript alteration. Our combined analysis approach successfully identified pathogenic events. Detection of diseasing-causing mechanisms in DMD transcripts could inform the therapeutic options for patients with dystrophinopathy.

Sepiapterin reductase deficiency (SRD) causes central nervous system symptoms due to dopamine and serotonin depletion because sepiapterin reductase plays an important role in tetrahydrobiopterin biosynthesis. SRD cannot be detected by newborn screening because of the absent hyperphenylalaninemia. To diagnose SRD biochemically, confirmation of reduced monoamine metabolites and elevated sepiapterin in the cerebrospinal fluid (CSF) has been considered necessary, because a past study showed no elevation of urine sepiapterin. Recently, however, the elevation of urine sepiapterin in SRD was reported.We developed a fast method to measure sepiapterin and creatinine simultaneously using high-performance liquid chromatography with fluorescence and ultraviolet detection. Urine sepiapterin and creatinine were measured in three SRD patients, two SRD carriers, four SRD siblings, and 103 non-SRD patients.In the three SRD cases, concentrations of urine sepiapterin were 1086, 914, and 575 µmol/mol creatinine (upper limit: 101.7 µmol/mol creatinine), and were markedly higher than those in other groups. CSF sepiapterin concentration was also measured in one SRD case and it was 4.1 nmol/L (upper limit: 0.5 nmol/L).The simultaneous determination of urine sepiapterin and creatinine appears helpful for the diagnosis of SRD. This assay system can also be used to measure sepiapterin in the CSF.

Objective To unveil current medical and psychosocial conditions of patients with West syndrome in Japan. Methods A cross-sectional analysis was performed in patients with West syndrome registered in the Rare Epilepsy Syndrome Registry (RES-R) of Japan. Furthermore, new-onset patients registered in the RES-R were observed prospectively and their outcomes after one and two years of follow-up were compared with data at onset. Results For the cross-sectional study, 303 patients with West syndrome were included. Seizures (such as spasms, tonic seizures and focal seizures) occurred daily in 69.3% of the patients at registration. Seizure frequency of less than one per year was observed in cases of unknown etiology (22.6%), genetic etiology (23.8%) and malformation of cortical development (MCD; 19.1%). Neurological findings were absent in 37.0%, but a high rate of abnormality was seen in patients with Aicardi syndrome, hypoxic-ischemic encephalopathy (HIE), genetic etiology and MCD other than focal cortical dysplasia, accompanied by a >50% rate of bedridden patients. Abnormal EEG was found in 96.7%, and CT/MRI was abnormal in 62.7%. Treatments included antiepileptic drug therapy (94.3%), hormonal therapy (72.6%), diet therapy (8.3%) and surgery (15.8%). Intellectual/developmental delay was present in 88.4%, and was more severe in patients with Aicardi syndrome, genetic etiology and HIE. Autism spectrum disorder was found in 13.5%. For the longitudinal study, 27 new-onset West syndrome patients were included. The follow-up study revealed improved seizure status after two years in 66.7%, but worsened developmental status in 55.6%, with overall improvement in 51.9%. Significance The study reveals the challenging neurological, physical and developmental aspects, as well as intractable seizures, in patients with West syndrome. More than a half of the children showed developmental delay after onset, even though seizures were reduced during the course of the disease.

ObjectiveWe examined the clinical manifestations of acute encephalopathy (AE) and identify risk factors for AE in children with tuberous sclerosis complex (TSC).MethodsThe clinical data of 11 children with clinically diagnosed TSC associated with AE and 109 children with clinically diagnosed TSC alone aged 4 years or older were collected from 13 hospitals.ResultsOf the 11 children with AE, 5 had histories of febrile seizures (FS), and all had histories of febrile status epilepticus (FSE). AE developed within 24 h after fever onset in all children with seizures lasting 30 min or longer. All children developed coma after seizure cessation. Head magnetic resonance imaging (MRI) revealed widespread abnormalities in the cerebral cortex, subcortical white matter, corpus callosum, basal ganglia, and thalamus. One child died; seven had severe neurological sequelae; and the other three, mild sequelae. Logistic regression analysis revealed that a history of FSE was correlated with the development of AE.SignificanceAE in children with TSC was characterized by sudden onset after fever, followed by coma, widespread brain edema evident on MRI, and poor outcomes. A history of FSE was a risk factor for the development of AE.

A pentanucleotide TTTCA repeat insertion into a polymorphic TTTTA repeat element in SAMD12 causes benign adult familial myoclonic epilepsy. Although the precise determination of the entire SAMD12 repeat sequence is important for molecular diagnosis and research, obtaining this sequence remains challenging when using conventional genomic/genetic methods, and even short-read and long-read next-generation sequencing technologies have been insufficient. Incomplete information regarding expanded repeat sequences may hamper our understanding of the pathogenic roles played by varying numbers of repeat units, genotype–phenotype correlations, and mutational mechanisms. Here, we report a new approach for the precise determination of the entire expanded repeat sequence and present a workflow designed to improve the diagnostic rates in various repeat expansion diseases. We examined 34 clinically diagnosed benign adult familial myoclonic epilepsy patients, from 29 families using repeat-primed PCR, Southern blot, and long-read sequencing with Cas9-mediated enrichment. Two cases with questionable results from repeat-primed PCR and/or Southern blot were confirmed as pathogenic using long-read sequencing with Cas9-mediated enrichment, resulting in the identification of pathogenic SAMD12 repeat expansions in 76% of examined families (22/29). Importantly, long-read sequencing with Cas9-mediated enrichment was able to provide detailed information regarding the sizes, configurations, and compositions of the expanded repeats. The inserted TTTCA repeat size and the proportion of TTTCA sequences among the overall repeat sequences were highly variable, and a novel repeat configuration was identified. A genotype–phenotype correlation study suggested that the insertion of even short (TTTCA)14 repeats contributed to the development of benign adult familial myoclonic epilepsy. However, the sizes of the overall TTTTA and TTTCA repeat units are also likely to be involved in the pathology of benign adult familial myoclonic epilepsy. Seven unsolved SAMD12-negative cases were investigated using whole-genome long-read sequencing, and infrequent, disease-associated, repeat expansions were identified in two cases. The strategic workflow resolved two questionable SAMD12-positive cases and two previously SAMD12-negative cases, increasing the diagnostic yield from 69% (20/29 families) to 83% (24/29 families). This study indicates the significant utility of long-read sequencing technologies to explore the pathogenic contributions made by various repeat units in complex repeat expansions and to improve the overall diagnostic rate.

Objective The aim of this study was to determine the prognostic factors for acute encephalopathy with reduced diffusion (AED) during the acute phase through retrospective case evaluation. Methods The participants included 23 patients with AED. The diagnosis of AED was based on their clinical course and radiological findings. We divided the patients into severe and non-severe groups based on the neurodevelopmental outcome. The severe group included seven patients (median age, 21 months; range, 6–87 months) and the non-severe group included 16 patients (19 months, 9–58 months). Clinical symptoms, laboratory data and electroencephalogram (EEG) findings within 48 h from the initial seizure onset were compared between the two groups to identify neurological outcome predictors. Results The incidence of coma 12–24 h after onset, serum creatinine (Cr) levels within 2 h after onset, maximum aspartate aminotransferase (AST) levels within 24 h after onset, and the rate of electrographic seizures in EEG were significantly higher in the severe group (Coma, 80%; Cr, 0.40 mg/dl, 0.37–0.73; AST, 363 IU/L, 104–662; electrographic seizures, 80%) than the non-severe group (Coma, 0%; Cr, 0.29 mg/dL, 0.19–0.45; AST, 58.5 IU/L, 30–386; electrographic seizures, 0%). Conclusions Coma 12–24 h after onset, elevation of Cr levels within 2 h after onset, elevation of AST levels within 24 h after onset, and non-convulsive status epileptics (NCSE) in comatose patients were early predictors of severe AED. Patients in a coma after a febrile seizure should be checked for NCSE signs in EEG to terminate NCSE without delay.

Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) (OMIM #617481) is an autosomal recessive disease characterized by progressive microcephaly, plagiocephaly, hypotonia, spastic quadriparesis, global developmental delay, intellectual disability, optic features and abnormal brain magnetic resonance imaging (MRI). NMIHBA was recently reported to be caused by PRUNE1 mutations. Eight mutations have been reported in 13 unrelated families. Here, we report 3 PRUNE1 mutations in 1 Caucasian and 3 Japanese families. One recurrent missense mutation (p.Asp106Asn) was previously reported in Turkish and Italian families, while the other 2 mutations (p.Leu18Serfs*8 and p.Cys180*) are novel. We also show that mutant PRUNE1 mRNA can be subject to nonsense-mediated mRNA decay. The patients presented in this study showed atypical NMIHBA phenotypes with no progressive microcephaly. Furthermore, one Caucasian case had significant macrocephaly; therefore, patients with PRUNE1 mutations can exhibit a broad and heterogeneous spectrum of phenotypes.

Purpose For a diagnosis of Rasmussen syndrome (RS), clinical course together with electroencephalography (EEG) and magnetic resonance imaging (MRI) findings are considered important, but there are few reports on functional neuroimaging. This study investigated cerebral blood flow (CBF)-single photon emission computed tomography (SPECT), central benzodiazepine receptor (BZR)-SPECT, and fluorine-18 fluorodeoxy glucose-positron emission tomography (FDG-PET) in RS patients, and correlated neuroimaging results with MRI and pathological findings. Methods Twenty-three patients diagnosed with RS according to Bien’s (2005) diagnostic criteria (including 12 patients with a histological diagnosis) were studied. CBF-SPECT, BZR-SPECT and FDG-PET images were visually evaluated, and the findings correlated with MRI and histological findings. Results Hypoperfusion areas were observed in 16 of 22 patients by interictal CBF-SPECT. Hyperperfusion areas were observed in 10 of 12 patients by ictal CBF-SPECT, which correlated with ictal onset area by ictal EEG (IOAE). In the limited data of BZR-SPECT in nine patients, lowered uptake was detected in all nine patients, including two with no MRI abnormalities. Lowered glucose metabolism was observed in affected areas in all five patients by FDG-PET. Histological examination revealed findings of chronic encephalitis in all 12 patients examined, concomitant with focal cortical dysplasia in five patients. Conclusion In RS patients, functional neuroimaging reveals clear abnormal findings, even before the appearance of MRI abnormalities. BZR-SPECT and FDG-PET could detect the IOAE efficiently even in the absence of MRI abnormalities, while interictal CBF-SPECT occasionally failed to detect IOAE if MRI was normal. Based on BZR-SPECT, refractory epileptic seizures in RS may suggest possible impairment of inhibitory neurons.

We report a one-year-old boy with early-onset myoclonic epilepsy, developmental arrest, and hyperekplexia during early infancy. He presented with refractory myoclonic/tonic seizures since birth. Electroencephalography revealed multifocal spikes, and rhythmic activities that occurred simultaneous with aggravation of myoclonus accompanied by tonic upper limb elevation. Brain magnetic resonance imaging revealed progressive cerebral atrophy with periventricular signal change and thin corpus callosum at one year of age. A de novo heterozygous missense mutation in the CACNA1A gene was confirmed. This patient was the most severe phenotype of CACNA1A-related early-onset encephalopathy among previous reports.

Variants in the type IV collagen gene (We examinedPathogenicPrenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and

Objective Clinically mild encephalitis/encephalopathy with a reversible lesion (MERS) is characterized by reversible lesions with transiently-reduced diffusion in the splenium of the corpus callosum on magnetic resonance imaging. Recently, cases of MERS with accompanying acute focal bacterial nephritis (AFBN) have been reported in children. This study aimed to clarify the clinical features of MERS with AFBN. Methods A retrospective study of patients with MERS was conducted at Nagano Children’s Hospital, Japan, from April 2013 to March 2018. The clinical signs and laboratory findings of MERS patients with AFBN (AFBN group) and without AFBN (non-AFBN group) were measured and compared. Results Of 12 patients diagnosed as having MERS, 3 were also found to have AFBN. Seven of the 9 patients without AFBN were associated with infectious agents, including rotavirus and influenza viruses. No patient received steroids or intravenous immunoglobulin therapy, and none displayed neurological sequelae. Serum C-reactive protein (CRP) levels were significantly higher in the AFBN group than in the non-AFBN group (14.7 mg/dL versus 0.8 mg/dL, P = 0.009). AFBN group patients were also significantly older (97 months versus 27 months, P = 0.018) and experienced significantly less frequent seizures (33% versus 100%, P = 0.045). The mean duration of neurological symptoms was significantly longer in the AFBN group than in the non-AFBN group (4 days versus 1.7 days, P = 0.013). Conclusions Pediatric patients with AFBN often present with non-specific findings, such as fever and abdominal pain. Pediatricians should be aware of the possibility of AFBN in the clinical setting of MERS, particularly when the patient exhibits inexplicably high CRP.

We report a 12-year-old female citrin-deficient patient presenting with severe anorexia and body weight loss, mimicking the restricting type of anorexia nervosa (AN). She showed normal development until age 10 years when she started to play volleyball at school. She then became gradually anorexic, and her growth was stunted. At age 12, she was admitted to hospital because of severe anorexia and thinness. She was first thought to have AN, and drip infusion of glucose solution and high-calorie drinks were given, but her condition deteriorated further. She had a history of neonatal hepatitis and was therefore suspected to have citrin deficiency (CD). Genetic analysis of SLC25A13 revealed that she was compound heterozygous for 851del4 and IVS16ins3kb, and a diagnosis of CD was made. A low-carbohydrate diet with oral intake of arginine and ursodeoxycholic acid was started, and her condition gradually improved. The clinical features in our patient were similar to those of AN, and therefore AN may also be an important clinical sign in adolescent patients with CD.

We report a pediatric case of critical illness polyneuropathy and myopathy caused by Bacillus cereus sepsis during acute lymphoblastic leukemia therapy. A 15-year-old boy developed B. cereus sepsis and multiple organ failure on the 19th day after initiation of chemotherapy, and multidisciplinary treatment was started. Treatment was effective and septic shock with multiple organ failure remitted. He was weaned from a respirator on day 23 after the onset of sepsis, but complete flaccid paralysis of the 4 extremities occurred. His compound muscle action potential and F-wave occurrence were reduced on a nerve conduction test. The number of motor units was markedly decreased, and the amplitude and duration of individual motor units were low and short, respectively, on electromyography. Cerebrospinal fluid was normal. On the basis of these findings, he was diagnosed with critical illness polyneuropathy/myopathy. He underwent intensive rehabilitation and recovered the ability to walk 3 months after onset. He was discharged 1 year after the initiation of chemotherapy, and remission has been maintained without inconvenience to daily living activities for 3 years since disease onset.

We report a six-year-old girl with seizures induced by both micturition and defecation. Several days after unprovoked generalised tonic-clonic seizures, she developed reflex seizures characterised by the extension of both arms and rhythmic jerking of her upper body. No abnormal findings were noted on brain magnetic resonance imaging. Interictal electroencephalography (EEG) showed spike-and-wave activity on central electrode recording, and rhythmic fast activity was recorded by central electrodes during the ictal EEG upon micturition. The combination of clobazam and phenytoin was effective for both unprovoked and reflex seizures. Although some previous reports have described reflex seizures triggered by either micturition or defecation, this is the first case report of reflex seizures induced by both micturition and defecation in the same patient. Based on a comparison with previous cases of reflex seizures induced either by micturition or defecation, the neuronal pathway from the pelvic base musculature to the supplementary motor area may be responsible for the condition in our patient.

Fukuyama T, Tanaka M, Nakazawa Y, Motoki N, Inaba Y, Higuchi T, Koike K. Prophylactic treatment for hypertension and seizure in a case of allogeneic hematopoietic stem cell transplantation after posterior reversible encephalopathy syndrome. Pediatr Transplantation 2011: 15: E169–E173. © 2010 John Wiley & Sons A/S. Abstract: A six-yr-old boy developed PRES after induction chemotherapy for the relapse of acute lymphoblastic leukemia. Two months after PRES, he underwent BMT from an unrelated HLA-mismatched donor. There were many risk factors for PRES in the BMT including the long-term use of FK506 and methylprednisolone, grade III graft-versus-host disease, thrombotic microangiopathy, and sepsis. Prophylactic treatment for hypertension with nicardipine in conjunction with close monitoring of the magnesium level and the use of valproic acid might be an effective management approach to prevent post-transplant PRES.

Background In rare cases, patients with Langerhans cell histiocytosis (LCH) develop neurodegenerative CNS disease (ND-CNS-LCH). Management of ND-CNS-LCH has not been established. Methods We treated five pediatric patients with a combination of intravenous immunoglobulin (IVIG) and chemotherapy (steroid ± vinblastine ± 6-mercaptopurine ± methotrexate). Prior to the therapy, three of the five patients had cerebellar ataxia while the remaining two had abnormal MRI findings without apparent neurological deficits. IVIG was given monthly or twice monthly at the dosage of 250–400 mg/kg/dose. Results The four patients administered more than 23 doses of IVIG and chemotherapy remained in a stable condition and did not show significant progression signs in neurological deficits or brain MRI findings during the 30-month follow-up period (median; range: 19+ to 38+) following the initiation of therapy for ND-CNS-LCH. Conclusion The IVIG-containing treatment may be promising for ND-CNS-LCH; however, its effectiveness remains to be further tested in more patients as well as in a randomized trial. Pediatr Blood Cancer 2008;50:308–311. © 2007 Wiley-Liss, Inc.

The hypoglossal (XII) nerve is made up of functionally different nerve branches: the medial branch related to protrusion of the tongue and the lateral branch related to its retraction. The present study was performed to determine the effects of facial (VII) and XII nerve injuries on the survival and growth of rats in which the unilateral or bilateral VII and XII nerve components (main trunk, XII-trunk; medial branch, XII-med; lateral branch, XII-lat) had been resected at different developmental stages. In the suckling period, unilateral as well as bilateral injuries in the XII-trunk or XII-med nerve produced disturbed milk intake, lower survival rates and growth retardation in the nerve-injured rats. In the transition and mastication periods, only bilateral injury in the XII-trunk or XII-med nerve produced disturbed food intake followed by lower survival rates and growth retardation in those animals. The unilateral XII-lat nerve injury did not have significant effects on milk and food intake, whereas the bilateral injury caused disturbance in milk intake especially at the early neonatal stage. The unilateral VII nerve injury at the early neonatal stage caused deteriorating effects on food intake resulting in lower survival rate and severe growth retardation in the nerve-injured rats. The results indicate that the survival and growth of XII and VII nerve-resected rats differ considerably depending on the nerves injured and the developmental ages of the animals at the time of nerve insult.

Functional roles of the perioral anatomical structures involved in breastfeeding were examined in newborn rat pups in which the hypoglossal (XII) and facial (VII) nerves had been resected at the neonatal stage. The XII nerve controls tongue movement and is comprised of two functionally distinct branches: the medial branch related to protrusion of the tongue and the lateral branch related to its retraction. Newborn rat pups with bilateral resection of either of the XII nerve components (main trunk: XII-trunk; medial branch: XII-med; lateral branch: XII-lat) failed to suckle milk and did not survive. Unilateral XII nerve-resected neonates showed different milk-suckling capabilities, which thus resulted in differences in survival rate (XII-trunk: 38%; XII-med: 24%; XII-lat: 92%) and postnatal growth during the postnatal 3 weeks until P21. Unilateral and bilateral resections of the VII nerve innervating the buccolabial musculature produced lowered suckling capabilities and retarded postnatal growth, although all pups showed 100% survival. The results indicate a crucial role of the tongue, especially of protruding muscular elements innervated by the XII-med nerve, in breastfeeding. The results also indicate differential effects of the VII and XII nerve components on suckling capability, survival, and postnatal growth of newborn rat pups.

In Rasmussen syndrome (RS), in addition to the predominant involvement of cytotoxic T cells, heterogeneous autoantibodies against neural molecules are also found, but their function has not been elucidated. We examined antibodies to N-methyl-d-aspartate (NMDA) type glutamate receptor (GluR) subunits (GluN2BGluN1) semi-quantitatively in cerebrospinal fluid (CSF) samples from RS patients, and evaluated their changes over time and their roles in immunopathogenesis.Autoantibodies against N-terminal and C-terminal of GluN2B and GluN1 were examined in 40 CSF samples collected from 18 RS patients 5 to 180 months after the onset of RS. Epileptic patients without infectious etiology or progressive clinical course served as disease controls (n=23). Synthesized peptides encoding the extracellular and intracellular domains of human GluN2B and GluN1 subunits were used as antigens in ELISA. We defined the cut-off for these antibodies as mean +2 standard deviations (optimal density) of the disease controls. MRI were evaluated according to the MRI staging proposed by Bien et al. (2002b, Neurology 58, 250).CSF levels of antibodies against N-terminal and C-terminal of GluN2B were higher in RS patients than in disease controls (p0.01). Likewise, CSF levels of antibodies against N-terminal and C-terminal of GluN1 were also higher in RS patients than in disease controls (p0.01). All four antibodies tested were below cut-off levels in almost all CSF samples collected within one year from epilepsy onset. The proportions of CSF samples with these antibodies above cut-off levels were highest from 12 to 23 months after epilepsy onset, and declined after 24 months. CSF levels of these antibodies were higher when seizure occurred daily than when seizure occurred less frequently (p0.01), and were higher at MRI stage 3 than at MRI stages 0, 2 and 4 (p0.05), except for anti-GluN1-CT antibody at stage 2.Broad epitope recognition spectrum and delayed production of autoantibodies to NMDA type GluR in CSF of RS patients suggest that the autoantibodies are produced against NMDA type GluR antigens derived from cytotoxic T cell-mediated neuronal damages. These antibodies may impact the pathophysiology of RS in the most active stage, and could be a marker for active inflammation in the clinical course of RS. Further studies including passive transfer of the antibodies to mice may reveal the pivotal roles of the antibodies in RS.

A boy with spastic paraplegia type 2 (SPG2) due to a novel splice site mutation of PLP1 presented with progressive spasticity of lower limbs, which was first observed during late infancy, when he gained the ability to walk with support. His speech was slow and he had dysarthria. The patient showed mildly delayed intellectual development. Subtotal dysmyelination in the central nervous system was revealed, which was especially prominent in structures known to be myelinated during earlier period, whereas structures that are myelinated later were better myelinated. These findings on the brain magnetic resonance imaging were unusual for subjects with PLP1 mutations. Peaks I and II of the auditory brainstem response (ABR) were normally provoked, but peaks III-V were not clearly demarcated, similarly to the findings in Pelizaeus-Merzbacher disease. These findings of brain MRI and ABR may be characteristic for a subtype of SPG2 patients.

Health examination programs for five-year-old children are aimed at effectively detecting developmental disorders, such as attention deficit/hyperactivity disorders (AD/HD), learning disorders (LD), higher functioning autistic spectrum disorders (HFASD), and other abnormalities. Tests usually include a questionnaire and observation of group playing, verbal communication, and soft neurological signs; however, it is often difficult to detect children who have LD with visual cognitive dysfunctions through such conventional examination techniques. Here, we analyzed the efficacy of using a battery of visual cognitive function tests to identify such cases.We employed four simple tests to evaluate visual cognitive function in addition to a standard health examination for five-year-old between April 2008 and March 2010. To analyze visual cognitive function tests, the results were scored and the applicability of these tests was verified by comparisons with established tests.A total of 653 five-year-old children underwent health examinations, and 48 children were referred to the hospital for further examinations. As a result, 34 children were newly diagnosed with developmental disorders, including HFASD, AD/HD, LD, and mild intellectual disturbances. Strong correlations were seen between the scores of these four examinations and those of other established tests, such as the performance intelligence score, the perceptual organization index of WISC-III, and the Frostig visual development test score. An additional benefit of our method was that parents could easily recognize developmental disorders in their children through direct observation of these examinations.We concluded that the battery of visual cognitive function tests was simple and useful for detecting developmental disorders in the health examinations of five-year-old children.

Fulminant Wilson's disease (WD) is life-threatening. The revised WD prognostic index (RWPI) has been used to predict the severity of the disease, with a score ≥11 indicating fatal outcome without liver transplantation (LTx). We here report the case of a 10-year-old female patient with fulminant WD (RWPI, 16) who recovered fully after plasma exchange and continuous hemodiafiltration, followed by treatment with copper chelate agents. To the best of our knowledge, there have been five fulminant WD patients with RWPI ≥ 11 including the present patient, in whom LTx was not done. Based on the therapeutic modalities in these five cases, non-surgical treatment (blood purification and copper chelate agents) may be able to avoid LTx in fulminant WD even with very high RWPI, although preparation for LTx is necessary.

Several immune mechanisms are suspected in the unknown etiology of West syndrome (WS). We report a male infant who suffered from WS and X-linked T-B+NK- severe combined immunodeficiency (X-SCID) with a missense mutation of the IL2RG gene (c.202G>A, p.Glu68Lys). He promptly began vitamin B6 and valproic acid treatment, but infantile spasms (IS) and hypsarrhythmia persisted. Administration of intravenous immunoglobulin and the change to topiramate (TPM) at 7 months of age resulted in the rapid resolution of IS. The CD4/8 ratio in his peripheral blood increased from 0.04-0.09 to 0.20-1.95 following unrelated cord blood transplantation (UCBT). In vitro lymphocyte proliferation in response to phytohemagglutinin or concanavalin A and the ability of B lymphocytes to produce antibodies improved as well. Electroencephalogram findings became normal 1 month after UCBT. Thus, we consider that T-cell dysfunction and/or impairments in T-B cell interactions due to X-SCID may have played important roles in the onset of WS. Immune-modulating therapies along with the administration of TPM effectively treated this severe epileptic syndrome in our patient.

Background: Myoclonic astatic epilepsy (MAE) is an idiopathic and generalized childhood epileptic syndrome. Although several studies have reported on cognitive function and intellectual outcome in MAE, little is known about the behavioral problems associated with this disease. The aim of this study was to clarify behavior and cognitive function in children with MAE. Methods: Four children who were diagnosed as having MAE using the proposed criteria of the International Classification of Epilepsies were retrospectively analyzed using patient records with regard to clinical and neuropsychological findings such as age of seizure onset, semiology and severity of seizures, treatment course, behavioral problems, EEG findings, and WISC-III and Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores that indicate the tendency of autistic behaviors. Results: Disease onset in our cohort ranged from 9 to 35 months of age. Seizures were controlled within 3-8 months over a follow-up period of 4-12 years. All patients had borderline normal intelligence (mean IQ: 75.8 at 5-7 years of age) and exhibited impaired coordination, clumsiness, hyperactivity or impulsivity, and impaired social interaction after improvement of seizures. Though these autistic social problems manifested gradually, the children were able to adapt to school life with appropriate support. Interestingly, the behaviors of impaired social interaction and hyperactivity or impulsivity had already been observed before the onset of MAE in most patients, whose PARS scores were all higher than reference values (

Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is a peculiar form of encephalitis mainly affecting children. Although not usually lethal, we report a case of sudden unexpected death in epilepsy (SUDEP) 3 years after the onset of AERRPS. A 6-year-old boy was admitted to our hospital because of fever and extremely refractory partial and secondary generalized seizures with delirium and psychiatric change. The seizures were highly resistant to anticonvulsants and suppressed only by large dose intravenous administration of midazolam. Seven months after the onset, the seizures were ameliorated by treatment with potassium bromide and clorazepate. After the acute phase, the patient developed complex partial seizures that tended to present with cyanosis. At the age of 10, he was found lying prone in respiratory arrest with facial pallor. Although he regained cardiac function after being taken to our emergency room, the patient died 12 days later. Six SUDEP cases after the onset of AERRPS, including this one, have been reported to date. Since epilepsy following AERRPS is one of the risk factors of SUDEP, clinicians should consider SUDEP to be a rare but high risk syndrome in AERRPS-afflicted children.

We report two cases of symptomatic West syndrome with severe respiratory syncytial virus (RSV)-induced bronchiolitis: one was a 9-month-old boy who was hospitalized for shock, and the other was a 15-month-old boy in pre-shock condition. Both cases needed mechanical ventilation for approximately 2 weeks. Seizures from the primary disease worsened in both patients during the infection, and both needed long periods of hospitalization, which resulted in a considerable reduction in their quality of life and that of their families. According to a one-year epidemiological survey of RSV infection conducted in 2004-2005 in Nagano prefecture, 7 of 238 hospitalized RSV cases were found to have basic neuromuscular disorders. Compared to patients with chronic lung disease or other primary diseases, they were older, had higher incidence of mechanical ventilation, and required longer hospitalization. Neuromuscular disorders may thus be an important risk factor for severe forms of RSV infection. Although children with such disorders should be protected from RSV, they are currently excluded from the indication for palivizumab administration as passive immunization against RSV in Japan.

A six-yr-old boy developed PRES after induction chemotherapy for the relapse of acute lymphoblastic leukemia. Two months after PRES, he underwent BMT from an unrelated HLA-mismatched donor. There were many risk factors for PRES in the BMT including the long-term use of FK506 and methylprednisolone, grade III graft-versus-host disease, thrombotic microangiopathy, and sepsis. Prophylactic treatment for hypertension with nicardipine in conjunction with close monitoring of the magnesium level and the use of valproic acid might be an effective management approach to prevent post-transplant PRES.

We report a case of multiple organ failure caused by the Bacillus cereus infection during acute lymphoblastic leukemia therapy, who was treated successfully. A 15-year-old male developed (B. cereus) sepsis on the 19th day after chemotherapy initiation. Polymyxin-direct hemoperfusion for septic shock was started, followed by continuous hemodiafiltration. His condition improved after starting the hemoperfusion. At the onset of sepsis, elevated levels of serum inflammatory cytokines, anti-inflammatory cytokines, and plasminogen-activator inhibitor complex-1 were observed. Serum levels of these cytokines and bioactive substances decreased after blood purification therapy, which correlated with the improvement of clinical symptoms. Pediatr Blood Cancer 2010;55:202–205. © 2010 Wiley-Liss, Inc.

A nine-yr-old girl developed AdV-associated HC after bone marrow transplantation. Intravenous GCV markedly reduced urinary AdV DNA loads and improved clinical findings. This appeared to result partly from a high concentration of GCV in urine. GCV may be effective for AdV-induced HC without definitive disseminated infection.

Functional role of lingual nerve in breastfeeding was investigated in rat pups during the suckling period. DiI, a postmortem neuronal tracer, was used to confirm the immature lingual nerve (LN) responsible for tongue sensation and resulted in successful fiber labeling anterogradely to the tongue, which showed different distribution patterns from fiber labeling derived from the hypoglossal nerve. Unilaterally LN-injured pups did not show suckling disturbance with absence of any shortening (P11 pups: 559 ± 16 s; 105% of the control value) in nipple attachment time and the survival rate remained high (P11: 100%). Bilaterally LN-injured pups showed suckling disturbance with marked shortening (P11 pups: 220 ± 54 s; 42% of the control value) in nipple attachment time and a low survival rate (P1: 33%; P11: 41%). Bilaterally infraorbital nerve-injured or bilaterally bulbectomized pups did not show any nipple attachment at all and there were no survivors, confirming the crucial roles of upper lip sensation and olfaction in suckling. Based on these findings, we conclude that tongue sensation is very important, but not essential for suckling.

The present study was aimed to determine neuronal population essential for normal motor function in young adult rats receiving various degrees of crushing to the sciatic nerve at the neonatal stage. Motor function was estimated by the static sciatic index, and a neuronal tracer was applied to the common peroneal nerve. The total numbers of the tracer-labeled neurons of the nerve-crushed rats were 74-383 in the normal function group, 14-61 in the disordered function group, and 0-32 in the severely disordered function group. We conclude that normal motor function can be well preserved by a very small population of motor neurons (approximately 15% of the control value) in the neonatally sciatic nerve-injured rats.