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Objectives: Acute encephalopathy is an acute brain dysfunction after preceding infection, consisting of multiple syndromes. Some syndromes, such as acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), are severe with poor outcome, whereas others, such as clinically mild encephalitis/encephalopathy with reversible splenial lesion (MERS), are mild with favorable outcome. Previous study reported the association of the thermolabile polymorphism in Carnitine Palmitoyltransferase 2 (CPT2) gene and severe syndromes of acute encephalopathy. To further explore the pathogenetic role of CPT2 in acute encephalopathy, we conducted a case-control association study of a typical thermolabile CPT2 polymorphism, rs2229291, in 416 patients of acute encephalopathy, including both severe and mild syndromes., Methods: The case cohort consisted of 416 patients, including AESD, MERS, and other syndromes. The control subjects were 100 healthy Japanese. rs2229291 was genotyped by Sanger sequencing. Genetic distribution was compared between the patients and controls using Cochran-Armitage trend test., Results: Minor allele frequency of rs2229291 was significantly higher in AESD (p = 0.044), MERS (p = 0.015) and entire acute encephalopathy (p = 0.044) compared to the controls. The polymorphism showed no significant association with influenza virus, or with outcome., Conclusions: This study provided evidence that CPT2 is a susceptibility gene for overall acute encephalopathy, including both severe and mild syndromes, and suggested that impairment of mitochondrial metabolism is common to various syndromes of acute encephalopathy., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Rhinovirus is a common respiratory pathogen for children throughout the year; nevertheless, its central nervous system involvement is extremely rare, and only two cases have been reported to date: meningitis and sepsis-like illness., Patient: A previously healthy 2-year-old Japanese boy developed fever, followed by seizures and lethargy. His cerebrospinal fluid cell count and protein level were slightly increased; brain magnetic resonance imaging showed abnormal intensities in the bilateral cerebellar dentate nuclei, which were prominent in diffusion-weighted images. After his consciousness disturbance improved, cerebellar dysfunction became apparent. He was treated symptomatically, without steroids or any other immunosuppressants. He almost recovered within a few months; however, cerebellar atrophy became evident on brain magnetic resonance imaging. Using acute specimens, human rhinovirus A was detected in his throat swab and cerebrospinal fluid., Discussion: Acute cerebellitis, in which cerebellar inflammation is predominant, is occasionally accompanied by cerebral symptoms, such as consciousness disturbance and seizures. As a causative pathogen, rotavirus is the most common; however, rhinovirus-associated acute encephalitis/encephalopathy and concurrent cerebellitis have not been reported before. Further research, using recent molecular techniques to detect various central nervous system pathogens, including rhinovirus, is needed to delineate the underlying pathophysiology., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Mumps is a common childhood viral disease characterized by fever and swelling of the parotid gland. The prognosis is generally good, although some complications, such as encephalitis (0.1%), exist. Acute encephalopathy with biphasic seizures and late reduced diffusion is the most common type of acute encephalopathy. However, this type of encephalopathy has not been reported in association with mumps infection., Patient: A previously healthy 3-year-old Japanese boy had a brief convulsion after fever for 3days, and then had conscious disturbance and parotitis. After several days, he had a second brief convulsion and was admitted. Increased serum amylase levels and presence of anti-mumps immunoglobulin M antibody confirmed mumps parotitis. The patient had another brief seizure later the day of admission. He did not have status or cluster seizures, although the biphasic nature of his seizures, conscious disturbance between the seizures, no pleocytosis in cerebrospinal fluid, and brain magnetic resonance images were consistent with acute encephalopathy with biphasic seizures and late reduced diffusion., Discussion: In Japan, the mumps vaccine is not administered as a part of routine immunizations. It thus has low coverage (30-40%), and as a result, mumps infections are still common. However, this is the first case of mumps-related acute encephalopathy with biphasic seizures and late reduced diffusion. This case may be representative of only a minority of patients with mumps-associated central nervous system involvement. Nevertheless, this diagnostic possibility may be considered. In order to prevent mumps-related complications, routine mumps vaccination might be warranted., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

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.)

Background: Mucolipidosis IV (MLIV; OMIM #252650) is an autosomal recessive lysosomal storage disorder, frequently observed in the Ashkenazi Jewish population. MLIV typically results in intellectual disability, corneal opacities, and delayed motor milestones during infancy, with a relatively static course. To date, reports of MLIV in other ethnic groups have been sparse., Patient: The present study is a case report of a 9-year-old Japanese boy, diagnosed via whole-exome sequencing, with compound heterozygous mutations of MCOLN1 (OMIM(*)605248): c.410T>C (p.Leu137Pro) and c.802_803delAG (p.Ser268Trpfs*17). Although his clinical course was mild (due to a lack of corneal clouding), other relevant features were present. These included strabismus, white matter signal abnormalities, and a hypoplastic corpus callosum at 2years of age. After a molecular diagnosis, a markedly elevated serum gastrin level (which is also common in MLIV) was confirmed., Discussion: The present results suggest that MLIV could be added as a differential diagnosis for white matter disorders, regardless of ethnicity. Beyond neurological or ophthalmologic findings, serum gastrin could be a useful diagnostic marker for MLIV., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

An 11-year-old boy presented with progressive walking disturbances. He exhibited severe equinovarus feet that together presented with hyperreflexia of the patellar tendon and extensor plantar, resembling spastic paraplegia or upper neuron disease. He showed mild distal muscle atrophy, as well. We did not observe signs of cognitive impairment, cerebellar signs, or brain magnetic resonance imaging abnormalities. Nerve biopsy showed giant axon swellings filled with neurofilaments. Gene analysis revealed novel compound heterozygous missense mutations in the gigaxonin gene, c.808G>A (p.G270S) and c.1727C>A (p.A576E). He was diagnosed with mild giant axonal neuropathy (GAN) without apparent central nervous system involvement. Patients with classical GAN manifest their symptoms during early childhood. Mild GAN, particularly in early stages, can be misdiagnosed because of lack of typical hair features and incomplete or indistinct peripheral and central nervous system symptoms. This case is important since it can aid to identify atypical and milder clinical courses of GAN. This report widens the mild GAN clinical spectrum, alerting physicians for correct diagnosis., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

We describe two unrelated patients with terminal deletions in the long arm of chromosome 13 showing brain malformation consisting of holoprosencephaly and cerebellar vermis hypoplasia. Array comparative genomic hybridization analysis revealed a pure terminal deletion of 13q31.3q34 in one patient and a mosaic ring chromosome with 13q32.2q34 deletion in the other. Mutations in ZIC2, located within region 13q32, cause holoprosencephaly, whereas the 13q32.2q32.3 region is associated with cerebellar vermis hypoplasia (Dandy-Walker syndrome). The rare concurrence of these major brain malformations in our patients provides further evidence that 13q32.2q32.3 deletion, harboring ZIC2 and ZIC5, leads to cerebellar dysgenesis., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Pelizaeus-Merzbacher disease (PMD), a hypomyelinating leukodystrophy, and the related but less severe allelic spastic paraplegia 2 (SPG2) are caused by mutations in the proteolipid protein 1 (PLP1) gene. Magnetic resonance imaging (MRI) is pivotal for diagnosing these disorders. The severity of PMD/SPG2 varies, and for a milder form of PMD, there have been some reports of near-normal findings in T1-weighted images but abnormal findings in T2-weighted images., Patient: We report the case of a 5-year-old boy diagnosed with a milder form of PMD caused by a novel PLP1 mutation in exon 3: c.300delC (p.I100IfsX13). He had delayed development from several months of age and was able to walk with support at 19 months in spite of the spasticity in his lower extremities. Hypomyelination was noted at 12 months by brain MRI. Motor nerve conduction studies showed decreased velocities with reduced amplitudes. Follow-up MRI at 1-year intervals from 18 months until 55 months of age showed gradual myelination progress., Discussion: The single nucleotide deletion identified in this patient can cause a frameshift and premature termination of PLP1. Via the nonsense-mediated mRNA decay mechanism of this mutation will result in loss-of-function, leading to a milder form of PMD. The present case is compatible with previously reported cases of milder form of PMD. We incidentally identified progressive myelination in this patient by T1-weighted images obtained by serial MRI. This finding adds to our understanding of the pathological stages of a milder form of PMD., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: There have been numerous reports regarding serum or cerebrospinal fluid (CSF) biomarkers in various disorders; however, the validities of such biomarkers for more precise diagnoses and prognosis estimates remain to be determined, especially in pediatric patients with neurological disorders., Methods: Serum/CSF S100B, neuron-specific enolase, and total tau (tTau) were measured in various acute pediatric neurological disorders, and their usefulness for diagnostic and prognostic predictions was validated using receiver operating characteristic curves and area under the curve (AUC) analysis., Results: A total of 336 serum and 200 CSF specimens from 313 patients were examined, and we identified statistically significant differences that were relevant from diagnostic and prognostic viewpoints. CSF and serum tTau levels could be good predictors for diagnosis (CSF tTau; AUC=0.76) and prognosis (serum tTau; AUC=0.78)., Conclusions: Both CSF and serum tTau levels could be useful for precise diagnostic and prognostic estimations in acute pediatric neurological disorders. Further studies are needed to clarify the clinical significance of such biomarkers., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

We describe a boy with Fisher syndrome. He presented the typical symptoms of Fisher syndrome, including external ophthalmoplegia, abnormality of convergence, and areflexia, after an episode of Campylobacter enterocolitis. Atypically, however, anti-GA1 antibody was detected in his serum, though anti-GQ1b and anti-GT1a antibodies were not. In addition, the tau protein level in his cerebrospinal fluid was elevated. Generally, Fisher syndrome is a self-limiting disease and has a good prognosis. In our patient, however, mild diplopia and areflexia persisted 6 months after their onset. Here, we report on the first Fisher syndrome patient with anti-GA1 antibody in the serum and elevated tau protein in the cerebrospinal fluid., (Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Alexander disease is a major entity of leukodystrophy; magnetic resonance imaging (MRI) studies of the brain typically show extensive changes in the cerebral white matter with frontal predominance. Heterozygous missense mutations of GFAP are thought to be sufficient for the molecular diagnosis, which has widened the Alexander disease entity beyond the classical one. We report the patient, a 16-year-old Japanese boy, with infantile-onset Alexander disease, showing striking MRI findings; extreme white matter loss of cerebrum through cerebellum, severe atrophy of basal ganglia, cerebellum, brain stem, and cervical spinal cord. Molecular analysis showed a heterozygous mutation R239L (c.730G>T) in GFAP. A relative long disease course, over 15years, with the help of mechanical ventilation revealed the striking MRI progression., (Copyright © 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The high incidence of acute encephalopathy in East Asia suggests the role of genetic factors in its pathogenesis. It has recently been reported that variations of the CPT II (carnitine palmitoyl transferase II) gene may be associated with fatal or severe cases of influenza-associated encephalopathy. In the present study, we examined the genotype of CPT II in cases of acute encephalopathy associated with various preceding infections. Twenty-nine Japanese patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) or acute necrotizing encephalopathy (ANE) were studied. The frequency of F352C of CPT II exon 4 was significantly higher in patients than in controls. All patients who had allele C in F352C had allele I in V368I and allele M in M647V (CIM haplotype), which reportedly decreases CPT II activity to one third of that with FIM or FVM haplotype. The frequency of CIM haplotype was significantly different between patients and controls, but not between AESD and ANE. Our results revealed that having at least one CIM allele is a risk factor for the onset of acute encephalopathy, regardless of its antecedent infections., (Copyright © 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: We retrospectively reviewed six patients with incontinentia pigmenti (IP) who had encephalopathic manifestations during early infancy., Methods: We enrolled six patients who met the following criteria from the mailing list of the Annual Zao Conference: (1) diagnosis of IP; (2) encephalopathic manifestations with reduced consciousness and clusters of seizures by 6 months of age; and (3) no evidence of central nervous system infection or metabolic derangement., Results: The onset of the encephalopathic events was within the first 2 months of life in all but one patient. All had clusters of focal clonic seizures. The duration of seizures was typically 5 min. The seizures ceased within 5 days in all patients. Various degrees of reduced consciousness were observed in association with the frequent seizures. Diffusion-weighted imaging during the acute phase showed reduced water diffusion in the subcortical white matter, corpus callosum, basal ganglia, thalami, and internal capsule in two patients. Scattered subcortical white matter lesions were observed on fluid-attenuated inversion-recovery images in two patients., Conclusions: The encephalopathic manifestations in patients with incontinentia pigmenti were characterized by seizure clusters and reduced consciousness, albeit of relatively short duration. Magnetic resonance imaging abnormalities were predominant in the subcortical areas in most patients., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objective: To clarify the immune pathophysiology of West syndrome (WS)., Study Design: We measured peripheral blood lymphocyte subset and serum cytokine profiles in 76 WS patients and 26 age-matched controls. Adrenocorticotropic hormone (ACTH) is one of the most effective therapy for WS and presumably immune-modulating; therefore, we compared the measured parameters between before ACTH (pre-ACTH) WS patients and controls, between cryptogenic and symptomatic WS patients before ACTH (pre-ACTH), and between before (pre-ACTH) and after (post-ACTH) ACTH WS patients. The post-ACTH group included those who received the last ACTH dose within 1 month of sampling., Results: CD3+ CD25+, CD19+, and CD19+ CD95+ cells were found to be significantly lower in the pre-ACTH group than in the controls. Interleukin (IL)-1 receptor antagonist (RA), 5, 6, and 15; eotaxin; basic fibroblast growth factor (bFGF); and interferon gamma-inducible protein (IP)-10 levels were higher in pre-ACTH group than in the controls. No significant differences were found between the pre-ACTH cryptogenic and symptomatic groups. CD4+ cells, CD3+ cells, CD4+/8+ ratio, IL-1 beta, IL-12, and macrophage inflammatory protein (MIP)-1 beta were significantly higher in pre-ACTH group than in the post-ACTH group., Conclusions: Our study revealed immunological alterations in WS patients, and these responses were modified by ACTH therapy. Further study is needed to elucidate whether or how the immune system alteration is involved in the pathophysiology of WS., (Copyright © 2009 Elsevier B.V. All rights reserved.)

Baraitser-Winter syndrome (BaWS) is characterized by iris coloboma, ptosis, hypertelorism, and mental retardation; it is a rare multiple congenital anomaly or a mental-retardation syndrome of unknown etiology. Patients suffering from this syndrome have been also found to show brain anomalies such as pachygyria, subcortical-band heterotopia (SBH), and hippocampal malformations; therefore, these anomalies have been included in the phenotypic spectrum of this syndrome. We report the case of a Japanese boy suffering from BaWS; the patient's brain magnetic resonance imaging scan revealed pachygyria, SBH, and periventricular heterotopia. However, the results of the genome-wide array comparative genomic hybridization did not reveal any chromosomal rearrangements., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

We report sibling cases of aromatic L-amino acid decarboxylase (AADC) deficiency, which is a very rare congenital metabolic disorder. These patients were born to healthy and non-consanguineous parents, and presented oculogyric crises, paroxysmal dystonic attacks, and severe psychomotor retardation since early infancy. In cerebrospinal fluid the levels of homovanilic acid and 5-hydroxyindoleacetic acid were very low and the level of L-dopa was very high. The diagnosis was confirmed by the lack of AADC activity in plasma, and a point mutation in the AADC gene. MRI revealed a slightly small volume of the prefrontal areas and normal myelination in both patients. Positron emission tomography using 2-deoxy-2[(18)F] fluoro-D-glucose was performed in one patient, which revealed hypometabolism in the prefrontal cortex and bilateral basal ganglia with a little laterality. These findings suggested that the severe dystonic features were caused by abnormal function of bilateral basal ganglia and severe psychomotor retardation could be due to abnormalities in prefrontal cortical activity., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

It is known that rotavirus gastroenteritis can accompany some neurological manifestations, including encephalitis/encephalopathy or seizures. However, the detailed pathogenesis involved has not been fully understood. To date, acute cerebellitis associated rotavirus gastroenteritis has not been previously reported, except for one case. Herein, we describe two cases of acute encephalitis/encephalopathy and concurrent cerebellitis, associated rotavirus gastroenteritis. Following vomiting and diarrhea, case 1 experienced convulsions and consciousness disturbance and case 2, transient loss of consciousness with eye deviation. After these symptoms subsided, cerebellar signs became evident and a brain MRI showed cerebellar involvement in both cases. Both cases showed speech disturbances, such as mutism, slow speech and dysarthria. In this report, we will discuss the possible pathogenesis of rotavirus associated acute encephalitis/encephalopathy and concurrent cerebellitis.

Acute cerebellar ataxia is usually a self-limited benign disease, which may develop in children after certain viral infections or vaccinations. There are several reports of acute cerebellar ataxia associated with autoantibodies. Glutamate receptor delta2, a member of the glutamate receptor family, is predominantly expressed in cerebellar Purkinje cells and plays a crucial role in cerebellar functions. To date anti-GluRdelta2 autoantibody was detected in a patient with chronic cerebellitis. Herein, an 18-month-old boy presented with cerebellar ataxia 9 days following a mild respiratory tract infection. Although cerebellar ataxia gradually improved, it worsened yet again following mumps and varicella virus infection. Cerebro-spinal fluid examination and magnetic resonance imaging of the brain demonstrated pleocytosis and meningeal enhancement, respectively. Furthermore, glutamate receptor delta2 autoantibody was detected in serum and cerebro-spinal fluid. Thus, we believe that the glutamate receptor delta2 autoantibody may play a role in cerebellar ataxia and consecutive cerebellitis.