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Background Nonconvulsive status epilepticus (NCSE) comprises a range of conditions in which prolonged electrographic seizures result in nonconvulsive clinical symptoms. An understanding of NCSE is especially important in emergency care. Among the various causes of NCSE, an infectious etiology has been rarely reported to date. Case reports We report two pediatric cases of rotavirus gastroenteritis complicated by NCSE. In both cases, bilateral rhythmic delta activity (2.5–3 Hz) with occipital predominance fluctuated with the patient’s consciousness level. The paroxysmal waves disappeared completely and consciousness immediately and remarkably improved after intravenous midazolam infusion. The patients remained alive 10 and 2 years, respectively, after short-term oral anticonvulsant administration, with no epileptic seizures. Conclusion The etiology of NCSE was identical and the clinical presentations were analogous in the two patients. The seizure semiology differed from that in benign convulsion with gastroenteritis. NCSE was considered the prominent cause of neurological symptoms; however, the pathogenic mechanism remains unclear, including the coexistence of acute encephalopathy.

Heterozygous variants in TUBB encoding one of β-tubulin isotypes are known to cause two overlapping developmental brain disorders, complex cortical dysplasia with other brain malformations (CDCBM) and congenital symmetric circumferential skin creases (CSCSC). To date, six cases of CSCSC and eight cases of CDCBM caused by nine heterozygous variants have been reported. Here we report two cases with novel de novo missense TUBB variants (NM_178014.4:c.863A>G, p.(Glu288Gly) and c.869C>T, p.(Thr290Ile)). Case 1 presented brain malformations consistent with tubulinopathies including abnormalities in cortex, basal ganglia, corpus callosum, brain stem, and cerebellum along with other systemic features such as coloboma, facial dysmorphisms, vesicoureteral reflux, hypoplastic kidney, and cutis laxa-like mild skin loosening. Another case presented abnormalities of the corpus callosum, brain stem, and cerebellum along with facial dysmorphisms. We reviewed previous literature and suggest the diversity of clinical findings of TUBB-related disorders.

Clear cell meningioma (CCM) is a WHO classification Grade II meningioma. It is a very rare disease, of which only 41 cases of spinal cord CCM in children have been reported to date. CCMs sometimes do not have the “dural attachment” that is usually found in meningiomas, and our understanding of the origin of CCMs is therefore controversial. We hereby present a case of pediatric CCM of the lumbar spine, in which we examined intraoperatively, the detailed anatomical location of the tumor. The case is a 10-year-old boy, who presented to our hospital with a 2-month history of lower back and bilateral lower extremity pain upon waking, which gradually worsened. Lumbar spine CT and MRI revealed an intradural extramedullary tumor at the L3 vertebral level, and surgery was performed to remove it. The tumor was in close contact with the dura mater, and also in contact with the cauda equina via the arachnoid. The tumor was likely located primarily between the dura mater and arachnoid. The pathological diagnosis was CCM, with an MIB-1 index of less than 1%. His back pain and bilateral lower extremity pain improved after surgery, and he was discharged from our hospital. Postoperative radiation therapy was not performed. Based on this case, we suggest that intraoperative examination of the anatomical location of these tumors and accumulation of relevant experience are important to elucidate the embryological mechanisms of this rare disease.

Objectives To examine the clinical characteristics of bilirubin encephalopathy in preterm infants (pBE) in Japan. Methods We performed a two-step nationwide questionnaire survey. The initial survey determined the number of children with pBE. Using a structured questionnaire, the second survey clarified the clinical manifestations and characteristics of children with pBE, including the perinatal history, neonatal complications, neurological features, verbal communication, diet, and magnetic resonance imaging (MRI) and auditory brainstem response (ABR) findings. Results The initial survey included 190 pBE infants, indicating an incidence of approximately 10 per year. Clinical information was available for 142 of them. The median gestational age was 26 weeks and the median birthweight was 883 g. As to neonatal complications, 20% had none, 25% had one complication, 54% had two or more. Head control was observed in 45% and functional gait in 8%. Purposeful hand use was seen in 41% of patients and verbal communication in 40%. MRI showed T2 hyperintensities in the globi pallidi in 111 of 136 patients, especially between 7 and 18 months of corrected age. ABR abnormalities were present in 88 of 117 patients. Conclusions pBE was infrequent but constantly observed during the study period, especially in very preterm infants, even in those with no severe neonatal complications. Severely impaired gross motor function and relatively preserved manual function and verbal communication were characteristic. MRI and ABR abnormalities will facilitate diagnosis.

Aggressive immunosuppressive therapies have been proposed to treat primary angiitis of the central nervous system (PACNS). Here, we report the first successfully stabilized case of childhood, small-vessel PACNS with intravenous immunoglobulin (IVIG) therapy. A 12-year-old boy was admitted to our hospital complaining of recurrent headaches and upper-left homonymous quadrantanopia, since the age of 11 years. Brain computed tomography scans revealed fine calcification in the right temporal and occipital lobes. Brain magnetic resonance imaging scans revealed white matter lesions, with gadolinium enhancement, which waxed, waned, and migrated for 1 year, without immunomodulatory therapies. A cerebrospinal fluid study showed pleocytosis (12 cells per µl). No clinical or serological findings suggested systemic inflammation or vasculitis. Brain angiography was unremarkable. Brain biopsy revealed thickened and hyalinized small vessels, with intramural infiltration of inflammatory cells, which confirmed the diagnosis of small-vessel PACNS. Because the patient developed surgical site infection following biopsy, the administration of monthly IVIG (2 g/kg) was prescribed, instead of immunosuppressive agents. After IVIG therapy, the patient remained stable, except for a single episode of mild radiological exacerbation at 16 months, which occurred when the IVIG interval was expanded. Oral prednisone was added and gradually tapered. At 50 months, his intellectual abilities and motor functions were normal, although he showed residual upper-left homonymous quadrantanopia and post-exercise headache. A temporary headache, associated with the immunoglobulin infusion, was resolved by slowing the infusion rate. PACNS should be treated aggressively to improve prognosis. However, when immunosuppressants are contraindicated, IVIG may be an alternative therapeutic option.

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.

Objectives Preterm children with severe dyskinetic cerebral palsy due to bilirubin encephalopathy often suffer from marked generalised hypertonus as they age. We performed a questionnaire survey to investigate patient-reported outcomes of treatments for improving their activities of daily life. Methods A mail questionnaire was administered to the caregivers of 67 children with preterm bilirubin encephalopathy aged >4 years. We asked about the type of treatments they received and their efficacy using a five-point subjective scale for the following five domains: motor function, postural stability, sleep, pain, and care burden. The names of oral drugs and their efficacies were also explored. Results The response rate of the questionnaires was 62.7% (42/67), and we analysed the results from 41 validated cases. All children underwent rehabilitation. A total of 30 children received oral drugs, 22 botulinum toxin, 12 orthopaedic surgery, and 3 intrathecal baclofen. Each of these treatments was subjectively reported to be effective in more than half of the recipients for each of the five domains, whereas 23 (56%) required more than two types of treatments other than rehabilitation. Chlordiazepoxide was the most commonly used oral drug, by 28 children (68%), and was discontinued in 7 patients (25%) only. In the sleep domain, the rate of a positive effect was significantly higher for oral drugs (92.7%) than the other treatments (p Conclusion All treatments were partially effective, but their appropriate combination based on a multidisciplinary approach is essential for muscle tone management in children with preterm bilirubin encephalopathy.

Background: The pathogenesis of dystonia is remarkably diverse. Some types of dystonia, such as DYT5 (DYT-GCH1) and tardive dystonia, are related to dysfunction of the dopaminergic system. Furthermore, on pathological examination, cell loss in the substantia nigra (SN) of patients with dystonia has been reported, suggesting that impaired dopamine production may be involved in DYT5 and in other types of dystonia.Objectives: To investigate functional dopaminergic impairments, we compared patients with dystonia and those with Parkinson's disease (PD) with normal controls using neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and dopamine transporter single photon emission computed tomography (DAT SPECT).Methods: A total of 18, 18, and 27 patients with generalized or segmental dystonia, patients with PD, and healthy controls, respectively, were examined using NM-MRI. The mean area corresponding to NM in the SN (NM-SN) was blindly quantified. DAT SPECT was performed on 17 and eight patients with dystonia and PD, respectively. The imaging data of DAT SPECT were harmonized with the Japanese database using striatum phantom calibration. These imaging data were compared between patients with dystonia or PD and controls from the Japanese database in 256 healthy volunteers using the calibrated specific binding ratio (cSBR). The symptoms of dystonia were evaluated using the Fahn–Marsden Dystonia Rating Scale (FMDRS), and the correlation between the results of imaging data and FMDRS was examined.Results: The mean areas corresponding to NM in the SN (NM-SN) were 31 ± 4.2, 28 ± 3.8, and 43 ± 3.8 pixels in patients with dystonia, PD, and in healthy controls, respectively. The mean cSBRs were 5 ± 0.2, 2.8 ± 0.2, 9.2 (predictive) in patients with dystonia, PD, and in healthy controls, respectively. The NM-SN area (r = −0.49, p < 0.05) and the cSBR (r = −0.54, p < 0.05) were inversely correlated with the FMDRS. There was no significant difference between the dystonia and PD groups regarding NM-SN (p = 0.28). In contrast, the cSBR was lower in patients with PD than in those with dystonia (p < 0.5 × 10−6).Conclusions: Impairments of the dopaminergic system may be involved in developing generalized and segmental dystonia. SN abnormalities in patients with dystonia were supposed to be different from degeneration in PD.

Background Ataxia telangiectasia is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Quality of life is severely impaired by neurological symptoms. However, curative options for the neurological symptoms are limited. Recent studies have demonstrated short-term improvement in neurological symptoms with betamethasone therapy. However, the long-term and adverse effects of betamethasone are unclear. The aim of this study was to evaluate the long-term effects, benefits, and adverse effects of low-dose betamethasone in ataxia telangiectasia. Methods Six patients with ataxia telangiectasia received betamethasone at 0.02 mg/kg/day for two years. After cessation of betamethasone, the patients were observed for two additional years. Neurological assessments were performed, and adverse effects were monitored every three months throughout the four-year study period. Results Transient improvement of neurological symptom was observed in five of the six patients. However, after two years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, one patient showed no change, and the neurological scores of the remaining four patients deteriorated. After the cessation of betamethasone treatment, neurological symptoms worsened in all patients. As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases. Conclusions Although these findings are in agreement with previous studies suggesting that short-term betamethasone treatment transiently benefits patients with ataxia telangiectasia, the long-term benefits and risks should be carefully considered.

Background Magnetic resonance imaging (MRI) abnormalities in preterm infants with bilirubin encephalopathy (BE) become less clear as the infants age. We assessed MRI findings in children with preterm BE older than 36 months corrected age (CA). Methods In a previous questionnaire survey, hospitals were asked to provide head MRI data of patients older than 36 months CA. MRI findings were reviewed by three pediatric neurology specialists and classified as no abnormalities, partial globus pallidus (GP) lesions, or diffuse GP lesions. Results In total, 33 MRI scans were available from 28 patients. The median gestational age and birth weight were 26 weeks and 824 g, respectively. The prevalence of MRI abnormalities was 100% in patients at 37 to 48 months CA, 71% in those at 49 to 60 months CA, 50% in those at 61 to 72 months CA, 67% in those at 73 to 84 months CA, and 38% in those at 85 months CA or older. Partial GP lesions were more common than diffuse GP lesions at all ages. No significant differences in sex, gestational age, birth weight, or gross motor function impairment were observed among lesion groups. Conclusions GP lesions were detected on MRI in most children with preterm BE when studied after 36 months CA, although MRI abnormalities became less apparent along with age. Partial GP lesions may be a characteristic of older children with preterm BE.

Introduction: The aim of this study is to clarify bilirubin parameters and its treatment in preterm infants with bilirubin encephalopathy (pBE). Methods: We asked the responders to an earlier nationwide Japanese survey on pBE to provide additional information. pBE was diagnosed based on the criteria used in the nationwide survey. We collected data on serum total bilirubin (TB), direct bilirubin (DB), albumin, and unbound bilirubin (UB) levels during the first 8 weeks of life, and on phototherapy and exchange transfusion treatments. Results: We obtained clinical data from 75 patients with pBE from 58 hospitals (response rate of 59%), who were born between 2002 and 2016. The average peak TB level was 12.6 mg/dL (215 μmol/L), and the average age at peak attainment was 19.7 days after birth. Albumin level was Conclusions: Most patients with pBE lacked marked elevations in serum TB levels and the B/A ratio, the peaks of which were sometimes delayed to >4 weeks after birth.

Current assessment of patients with cerebellar disorders is based on conventional neurological examination that is dependent on subjective judgements. Quantitative measurement of cerebellar ataxias (CAs) is essential for assessment of evidence-based treatments and the monitoring of the progress or recovery of diseases. It may provide us a useful tool to navigate future treatments for ataxia. We developed a Kinect v2. sensor system with a novel algorithm to measure and evaluate movements for two tests of Scale for the Assessment and Rating of Ataxia (SARA): the nose-finger test and gait. For the nose-finger test, we evaluated and compared accuracy, regularities and smoothness in the movements of the index finger and the proximal limbs between cerebellar patients and control subjects. For the task of walking, we evaluated and compared stability between the two groups. The precision of the system for evaluation of movements was smaller than 2 mm. For the nose-finger test, the mildly affected patients tended to show more instability than the control subjects. For a severely affected patient, our system quantified the instability of movements of the index finger using kinematic parameters, such as fluctuations and average speed. The average speed appears to be the most sensitive parameter that contrasts between patients with CAs and control subjects. Furthermore, our system also detected the adventitious movements of more proximal body parts, such as the elbow, shoulder and head. Assessment of walking was possible only in patients with mild CAs. They demonstrated large sways and compensatory wide stances. These parameters appeared to show higher accuracy than SARA. This examiner-independent device measures movements of the points of interest of SARA more accurately than eye and further provides additional information about the ataxic movements (e.g., the adventitious movements of the elbow, shoulder and head in the nose-finger test and the wide-based walking with large oscillation in the gait task), which is out of the scope of SARA. Our new system enables more accurate scoring of SARA and further provides additional information that is not currently evaluated with SARA. Therefore, it provides an easier, more accurate and more systematic description of CAs.

Background Leukoencephalopathy with brain calcifications and cysts (LCC) is neuroradiologically characterized by leukoencephalopathy, intracranial calcification, and cysts. Coats plus syndrome is also characterized by the same neuroradiological findings together with defects in retinal vascular development. Indeed, LCC and Coats plus were originally considered to be the same clinical entity termed cerebroretinal microangiopathy with calcifications and cysts, but evidence suggests that they are genetically distinct. Mutations in CTS telomere maintenance complex component 1 (CTC1) and small nucleolar RNA, C/D box 118 (SNORD118) genes have been found to cause Coats plus and LCC, respectively. Materials and Methods Eight unrelated families with LCC were recruited. These patients typically showed major neuroradiological findings of LCC with no signs of extra-neurological manifestations such as retinal abnormality, gastrointestinal bleeding, or hematological abnormalities. SNORD118 was examined by Sanger sequencing in these families. Results Seven out of eight probands carry compound heterozygous mutations, suggesting that SNORD118 mutations are the major cause of LCC. We identified a total of eight mutation, including four that were novel. Some of the variants identified in this study present heterozygously in public databases with an extremely rare frequency (

Aim To clarify auditory brainstem response (ABR) in preterm infants with bilirubin encephalopathy and the relationships between ABR and clinical variables. Method We retrospectively reviewed the ABR waveforms of 56 preterm infants with BE and graded them as “no response”, “abnormal interwave separation”, or “normal”. Patient backgrounds, the peak total bilirubin level, the bilirubin/albumin ratio, verbal communication ability, and newborn hearing screening test results from an automated ABR evaluation had been collected during an earlier nationwide survey. Results The frequency of abnormal ABR findings decreased with age. Verbal communication tended to be poorer in patients with more severe ABR abnormalities. ABR findings improved in 7 of 29 infants with available serial ABR data. Both gestational age and the peak total bilirubin level were relatively lower in patients with than in those without improved ABR findings. Newborn hearing screening using automated ABR evaluation yielded data consistent with manual ABR findings in 16 of 20 patients who underwent both examinations. Conclusions ABR abnormalities in preterm infants with bilirubin encephalopathy may improve over time, especially in those with a lower gestational age and peak total bilirubin level. Newborn hearing screening using automated ABR may fail to detect abnormalities in some infants.

Highlights • Epileptic-dyskinetic encephalopathies are rare epileptic disorders characterized by EOEE with involuntary movement. • The presence of involuntary movements in patients with EOEE caused by gene variants may be a key diagnostic symptom. • Genetic diagnosis is useful and may provide a reference for treatment selection., Epileptic-dyskinetic encephalopathies are rare epilepsies characterized by early-onset epileptic encephalopathies (EOEEs) with involuntary movement. Herein, we investigated the impact of gene variants in epileptic-dyskinetic encephalopathies. Four independent patients from four families who exhibited involuntary movements were recruited from Tokyo Metropolitan Neurological Hospital. The inclusion criteria were as follows: onset within 1 year after birth, frequent seizures, severe developmental delay and accompanying involuntary movements. We detected four genetic mutations, including STXBP1, GNAO1, CYFIP2, and SCN8A variants. The involuntary movements were drug-resistant. However, pallidal electrocoagulation followed by gabapentin were partially effective in treating chorea and ballismus of the extremities in patients with GNAO1 variants, and perampanel partially suppressed seizures and involuntary movements in one patient with a SCN8A variant. Movement disorders are common to many neurodevelopmental disorders, including a variety of EOEEs. Although we could not establish a definitive correlation using genetic variants in patients with EOEE and movement disorders, involuntary movements in patients with EOEEs may be a key diagnostic finding. The usage of genetic variants could prove beneficial in the future as more patients are investigated with epileptic-dyskinetic encephalopathies.

Here, we present the case of a 15-year-old Japanese girl with Dystonia 28, childhood-onset; DYT28 (MIM#606834) showing early-onset generalized progressive dystonia and status dystonicus. The patient was genetically undiagnosed and had not responded to various medications. By trio-based whole exome sequencing and in silico analyses, we identified a de novo heterozygous variant of KMT2B: NM_014727.2: c.7828C > T, p.(Arg2610Cys). Globus pallidus internus deep brain stimulation (GPi-DBS) therapy was considered; however, the therapy could not be performed due to the patient's poor nutritional status and repeated infections. GPi-DBS is considered to be an effective treatment for patients with KMT2B mutations, and genetic diagnosis is important before progression to status dystonicus.

Objectives To investigate the clinical characteristics of children and adults with anti-N-methyl- D -aspartate receptor (anti-NMDAR) encephalitis. Methods Patients who tested positive for the anti-NMDAR antibody (by a cell-based assay) in the cerebrospinal fluid were enrolled. They were divided into two groups based on age ( Results Three children (two males and one female) and four adults (one male and three females) were examined. The age at onset was 3.0 ± 1.41 years (range: 2–5 years) for the children and 31.8 ± 6.80 years (range: 20–36 years) for the adults. The follow-up duration was 82.7 ± 23.80 months (range: 52–110 months) for the children and 61.5 ± 12.54 months (range: 43–78 months) for the adults. Prodromal symptoms such as fever and headache were observed in three adults. Two children received influenza vaccination before the onset of encephalitis. Brain magnetic resonance imaging abnormalities were observed in three children and one adult. Basal ganglia lesions were observed in two children and one adult, and the two children showed dystonia. Two children and one adult without neoplasms experienced recurrences. The modified Rankin Scale scores at the final follow-up tended to be worse in children than in adults. Conclusion Three patients had basal ganglia lesions, and two of them showed dystonia. Dystonia with basal ganglia lesions has been rarely reported in anti-NMDAR encephalitis but should be noted as a significant symptom, which severely affects the activities of daily life.

Objectives Defects in DNA damage responses or repair mechanisms cause numerous rare inherited diseases, referred to as “DNA-repair defects” or “DNA damage deficiency”, characterized by neurodegeneration, immunodeficiency, and/or cancer predisposition. Early accurate diagnosis is important for informing appropriate clinical management; however, diagnosis is frequently challenging and can be delayed, due to phenotypic heterogeneity. Comprehensive genomic analysis could overcome this disadvantage. The objectives of this study were to determine the prevalence of ataxia-telangiectasia (A-T) and A-T-like DNA-repair defects in Japan and to determine the utility of comprehensive genetic testing of presumptively diagnosed patients in facilitating early diagnosis. Methods A nationwide survey of diseases presumably caused by DNA-repair defects, including A-T, was performed. Additionally, comprehensive next-generation sequencing (NGS) analysis, targeting known disease-causing genes, was conducted. Results Sixty-three patients with A-T or other diseases with characteristics of DNA-repair defects were identified. Thirty-four patients were genetically or clinically definitively diagnosed with A-T (n = 22) or other DNA-repair defects (n = 12). Genetic analysis of 17 presumptively diagnosed patients revealed one case of ataxia with oculomotor apraxia type 1 (AOA1); one ataxia with oculomotor apraxia type 2 (AOA2); two types of autosomal dominant spinocerebellar ataxia (SCA5, SCA29); two CACNA1A-related ataxias; one microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR); and one autosomal dominant KIF1A-related disorder with intellectual deficit, cerebellar atrophy, spastic paraparesis, and optic nerve atrophy. The diagnostic yield was 58.8%. Conclusion Comprehensive genetic analysis of targeted known disease-causing genes by NGS is a powerful diagnostic tool for subjects with indistinguishable neurological phenotypes resembling DNA-repair defects.

Pallidal deep brain stimulation (DBS) improves the symptoms of dystonia. The improvement processes of phasic symptoms and tonic symptoms differ. Phasic symptoms improve rapidly after starting DBS treatment, but tonic symptoms improve gradually. This difference implies distinct neuronal mechanisms for phasic and tonic symptoms in the underlying cortico-basal ganglia (BG) neuronal network. Phasic symptoms are related to the pallido-thalamo-cortical pathway. But, the pathway related to tonic symptoms, especially truncal dystonia, has been unknown and assumed to be different from that for phasic symptoms. The purpose of this study is to investigate the different characteristics related to the two symptoms by recording local field potentials (LFPs) in the internal pallidum (GPi), external pallidum (GPe) and EEGs recorded from the motor cortex (MCx). The symptoms of dystonia are complicated and the pathophysiology of dystonia is not clear. It is possible that understanding of the neuronal circuits in the background of dystonia symptoms become a clue of pathogenesis of dystonia. LFPs and EEGs were recorded in 19 dystonic patients to analyze the differences between the two types of symptoms. Patients were divided into two groups, 10 with predominant phasic symptoms (phasic patients), and 9 with predominant tonic symptoms (tonic patients). To investigate the distinct features of oscillations and functional couplings across the GPi, GPe, and MCx by clinical phenotype, power and coherence were calculated over the delta (2-4 Hz), theta (5-7 Hz), alpha (8-13 Hz), and beta (14-35 Hz) frequencies. In phasic patients, the alpha spectral peaks emerged in the GPi oscillatory activities, and alpha GPi coherence with the GPe and MCx was higher than in tonic patients. On the other hand, delta GPi oscillatory activities were prominent, and delta GPi–GPe coherence was significantly higher in tonic than in phasic patients. However, there was no significant delta coherence between the GPi/GPe and MCx in tonic patients. These results suggest that different pathophysiological cortico-pallidal oscillations are related to tonic and phasic symptoms.

We examined oxidative stress markers, tau protein and cytokines in the cerebrospinal fluid (CSF) in six patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). In the CSF, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and hexanoyl-lysine adduct levels increased over the cutoff index in four and one out of six MERS patients, respectively. The CSF IL-6 and IL-10 levels were increased in three out of six patients, two of which had extended lesion of the cerebral white matter. The CSF value of tau protein, marker of the axonal damage, was not increased, and neuron specific enolase (NSE) in the CSF was not increased. The increased 8-OHdG levels in the CSF, DNA oxidative stress marker, in four MERS patients, suggesting involvement of oxidative stress in MERS. MERS is occasionally accompanied with hyponatremia, although our patients lacked hyponatremia. It is possible that the disequilibrium of systemic metabolism including electrolytes may lead to facilitation of oxidative stress and reversible white matter lesion in MERS. The increase of cytokine production seems to be involved in the distribution of lesions in MERS.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a recently clinicoradiologically-established encephalopathy syndrome. In the present study, we examined the levels of cerebrospinal fluid (CSF) tau protein, a marker of axonal damage, in 11 patients with AESD. CSF tau levels were normal on day 1 and increased from day 3 of the disease between the initial and the secondary seizures. Magnetic resonance imaging (MRI) reveals reduced diffusion in the subcortical white matter during days 3–7. Two patients showed elevated tau protein prior to the diffusion abnormality of subcortical white matter on MRI. Levels of CSF neuron specific enolase (NSE), a neuronal marker, were elevated in only two out of seven patients with AESD, and CSF tau levels were also increased in these patients. Our results indicated that tau protein is a more sensitive marker than NSE and axonal damage causes the conspicuous MRI findings in AESD patients. A therapeutic strategy for axonal protection should be developed to prevent severe neurological impairment of AESD patients.

We describe an autopsy female case of multiple anomalies with lobulation of caudate nucleus tail, diaphragmatic eventration, skeletal anomalies, pyramidal tract anomaly, and meningothelial meningioma. Her psychomotor development was delayed, and she developed bilateral eventration of the diaphragms on X-ray film in her third decades. Right hemi-colonectomy was performed for volvulus at the age of 44 years, and meningioma was incidentally identified. She died at the age of 47 years. Autopsy demonstrated the partial deficiency of the muscular tissue in the circular thinned membranous area predominantly on left side including the central tendon of the diaphragm. The tails of the bilateral caudate nucleus demonstrated excessive lobulations, and the brainstem pyramidal tract showed hypoplasia. Immunoreactivity for tyrosine hydroxylase was deficient in the lobulated tail of caudate. We believe that this case is characterized by a rare combination of eventration, skeletal and nervous anomalies.

In Japan, quite a few patients with spinal muscular atrophy type 1 (SMA type 1) survive with mechanical ventilation. Since a patient with SMA type 1 and continuous artificial ventilation exhibited excessive perspiration and tachycardia, we examined the autonomic functions in three cases of SMA type 1, undergoing mechanical ventilation. Two cases exhibited the common sympathetic-vagal imbalance on R-R interval analysis involving 24-h Holter ECG recordings in addition to an abnormality in finger cold-induced vasodilatation. Furthermore, one case showed blood pressure and heart rate fluctuation with the paroxysmal elevation, and a high plasma concentration of norepinephrine during tachycardia. These findings suggest that autonomic dysfunction should be examined in SMA type 1 patients with long survival, although the pathogenesis remains to be clarified.

We measured anti-N-methyl- d -aspartate receptor (NMDAR) autoantibody levels and assessed B cell subsets using multicolor flow cytometry of peripheral blood mononuclear cells (PBMCs) from a recurrent anti-NMDAR encephalitis case to evaluate the effectiveness of rituximab treatment. Rituximab depleted CD20+ fractions of naive and memory B cell subsets and reduced the number of CD20− plasmablasts. This study suggests that short-lived plasmablasts are removed by rituximab-induced depletion of the CD20+ B cell population. Increased numbers of plasmablasts in PBMCs may be a candidate predictive factor for unfavorable prognosis of anti-NMDAR encephalitis and an indication of when to commence second-line immunotherapy.

Laryngeal dystonia is characterized by stridor due to vocal cord dystonia and is observed in extrapyramidal disorders. Recently, botulinum toxin injection has been used as a primary therapy. Generally, severe motor and intellectual disabilities (SMID) are frequently complicated by various types of respiratory disorders. We report a SMID case with Japanese encephalitis sequelae showing repeated vocal cord abductor disturbance due to laryngeal dystonia, in addition to generalized dystonia, in whom MRI revealed basal ganglia lesions. Tracheostomy was effective for the case, and we believe that botulinum toxin injection may be inappropriate in SMID, both ethically and technically. Also, laryngeal dystonia should be considered as a cause of respiratory disorders in SMID.

Whether the cerebral or subcortical lesions are involved in the pathogenesis in infantile spasms (IS) remains to be determined. To investigate the functional lesions of the subcortical structures in IS, the brainstem expression of neurotransmitters, neuropeptides and calcium-binding proteins in IS autopsy cases of lissencephaly and of perinatal hypoxic ischemic encephalopathy (HIE/IS) was investigated. The IS patients consisted of four subjects each of lissencephaly and HIE. They suffered from both West and Lennox-Gastaut syndromes. The healthy and disease controls were composed of four subjects without neuromuscular disorders and six cases of HIE (HIE/C), neither of whom had the epileptic syndrome. In these subjects the expressions of tryptophan hydroxylase (TrH), tyrosine hydroxylase (TH), parvalbumin (PV), methionine-enkephalin (ME) and substance P (SP) were immunohistochemically determined in serial sections of the midbrain, pons and medulla oblongata. The immunoreactivity of neurons and neuronal processes for TH was altered in the mesencephalic periaqueductal gray matter, locus ceruleus, and dorsal vagal nucleus in the patients. The HIE/IS cases showed reduced TrH-immunoreactivity in the medullary raphe nuclei. The brainstem auditory tract was poorly discernible on anti-PV immunostaining in the IS patients. The immunoreactivity for ME in the spinal trigeminal nucleus was severely affected in the IS patients, while that for SP was comparatively well preserved. It is suggested that the presence of common brainstem lesions in IS is irrespective of etiologies. It is intriguing that some of the changes seemed to be interrelated with the neurophysiological abnormalities being reported in IS patients.

We report a male autopsy case of Fukuyama-type congenital muscular dystrophy (FCMD), with unusual neuropathological findings. The patient was a Japanese man aged 26 years at the time of death. He had shown severe psychomotor retardation and muscular dystrophy since early infancy, and was diagnosed as having FCMD at the age of 5 years. He died of respiratory failure. The main neuropathological finding was extensive cerebral and cerebellar cortical dysplasia, characteristic of this disorder. In addition, degeneration of the cerebellar efferent pathway, including the dentate nucleus, superior cerebellar peduncle, and red nucleus, and that of the lateral thalamic nucleus were observed. These findings suggest the possibility that the long survival can clarify the latent neurodegeneration in the cerebellum and thalamus in FCMD, in addition to congenital malformations. The system degeneration should be carefully evaluated in the pathological examination of this disorder.

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

We report a 7-year-old girl with acute disseminated encephalomyelitis subsequent to a mycoplasma infection. She manifested a prolonged state of akinetic mutism, during which EEG revealed well-synchronized spindles. Four months later, she regained consciousness, with no mental deficit, but complete flaccid quadriplegia persisted and magnetic resonance imaging disclosed extensive destruction of the spinal cord. Antibody against galactocerebroside was detected in her serum during the acute phase. The anti-Gal C antibody is suggested to be involved in the pathogenesis of immune-mediated demyelinating diseases in the central nervous system subsequent to mycoplasma infections.

This report concerns two autopsy cases of severe motor and intellectual disabilities (SMID) who died of bronchospasms or tracheomalasia. One case had no anatomical change in the tracheal wall except for an endotracheal granuloma, while the other showed softening of the tracheal wall. Since patients with SMID have risk factors for bronchospasms and tracheomalasia, such as gastro-esophageal reflux, aspiration, and thoracic deformities, it is important that we suspect the possibility of these conditions, when we see the respiratory distress in cases of SMID.

Although central nervous system (CNS) disorders associated with group-A beta-hemolytic streptococcal (GABHS) infection occur only rarely, Sydenham's chorea is a well-recognized disease that can arise following infection. Children may develop a tic, obsessive compulsive disorder (OCD), and extrapyramidal movement subsequent to GABHS infection. These disorders have been termed pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS). Herein we report one case each of acute disseminated encephalomyelitis (ADEM), PANDAS and subacute encephalitis associated with GABHS infection. To evaluate the pathogenesis of the CNS disorders associated with GABHS infection, we measured levels of neurotransmitters, cytokines, anti-neuronal autoantibodies, and performed immunohistochemistry using patient sera to stain human brain sections. All three cases showed psychiatric behavioral disorders. Immunotherapy was effective, and homovanillic acid levels in the cerebrospinal fluid (CSF) were elevated at the acute stage in all three cases. In each case of ADEM and PANDAS, immunohistochemistry demonstrated neuronal impairment in the basal ganglia during the acute stage. Neuronal immunoreactivity was visualized in the cerebral cortex at the acute stage in the case of subacute encephalitis. There was no direct correlation between immunoreactivity of patient sera on the brain sections and positivity of anti-neuronal autoantibodies or CSF biomarkers. The results suggest that autoimmune responses may modulate neurotransmission, and the use of patient serum for immunohistochemistry is a sensitive screening method for the detection of anti-neuronal autoantibodies in CNS disorders associated with GABHS infection.

Background: Tracheoarterial fistula (TAF) is an unusual but highly lethal complication of tracheostomy, and successful surgical intervention for TAF has been reported. Few investigations are available for TAF in severe motor and intellectual disability (SMID). The aim of the present paper was to analyzed TAF in SMID to clarify which clinical variables might predict the occurrence of TAF, and adequate management for lifesaving. Methods: Medical records at Metropolitan Fuchu Medical Center were retrospectively investigated for SMID between 1970 and 2000, and 10 TAF patients verified on operation or autopsy were identified. Details were reviewed including clinical status, emergency treatment at the occurrence of TAF, and operation and/or autopsy recordings. Results: Four of 10 patients underwent successful operation and survived, while the other six died from hemorrhagic shock. Eight patients had tracheoinnominate artery fistula, the others had tracheocarotid artery fistula. Characteristic features as SMID such as etiology of brain disease, muscle tonus and convulsion were no apparent relevance to occurrence of TAF. All patients suffered from endotracheal granuloma extending to the arterial walls. Seven of 10 patients had re-bleeding after stabilization of the first massive hemorrhage, especially fiber bronchoscopy to confirm the diagnosis of TAF precipitated to fatal re-bleeding. One patient underwent interruption of the artery at relapse of TAF, the other three underwent suturing and had good outcome. Conclusions: There were no apparent predictors of TAF in SMID. Tracheal granuloma was recognized and consequent on formation of TAF, so control of granuloma may prevent TAF. Fiber bronchoscopy for suspected TAF is not recommended because it precipitates fatal bleeding.

The authors report a patient with Lafora disease, whose myoclonus was suppressed by passive eye closure. Neurophysiologic studies disclosed that fixation was the most important enhancer of myoclonus. Magnetoencephalographic studies of visual evoked fields revealed abnormal activation of the visual corticocortical pathway via the insular cortex not seen in controls. The authors hypothesize that abnormal activation of the insular cortex may be involved in triggering the mechanism of fixation-sensitive myoclonus.

To elucidate autonomic function in spinal muscular atrophy, we evaluated finger cold-induced vasodilatation, sympathetic skin response, and R—R interval variation in 10 patients with spinal muscular atrophy: 7 of type 1, 2 of type 2, and 1 of type 3. Results of finger cold-induced vasodilatation, sympathetic skin response, and R—R interval variation were compared with those of healthy children. Finger cold-induced vasodilatation was abnormal in 6 of 10patients with spinal muscular atrophy; it was normal in the healthy children. The mean sympathetic skin response latency and amplitude did not differ significantly from those of the healthy children. Amplitudes of sympathetic skin response to sound stimulation were absent or low in all six patients with spinal muscular atrophy. No significant difference was found in the mean R—R interval variation of patients with spinal muscular atrophy and healthy children. Results show that some patients with spinal muscular atrophy have autonomic dysfunction, especially sympathetic nerve hyperactivity, that resembles dysfunction observed in amyotrophic lateral sclerosis. ( J Child Neurol 2005;20:871—875).

Brain magnetic resonance imaging was conducted in a girl with genetically confirmed spinal muscular atrophy (SMA) type I. This patient has survived 6 years, to date, under mechanical ventilation. T2-weighted and fluid-attenuated inversion recovery images revealed high signal intensity lesions in the anterolateral portions of the bilateral thalami. Electroencephalography disclosed diffuse beta activity upon awakening and during light sleep. In addition, fast and prolonged spindles were observed. Although mild neuronal changes in the lateral nucleus of the thalamus have been described in several autopsied cases, this is the first study to demonstrate neuroradiologically and neurophysiologically the thalamic lesions in genetically confirmed SMA type I.

We report an autopsy case of multiple anomalies with severe micrencephaly, bilateral microphthalmos, and hypoplastic endocrine organs. We examined expressions of calcium-binding proteins and hypothalamic and pituitary hormones. A female proband presented with microcephaly, microphthalmia, and psychomotor development delay. At the age of 23 years, she died of cardiorespiratory failure. The endocrine organs demonstrated severe underdevelopment, and the hypoplastic eyeballs had remnant lens, vitreous hemorrhage, and retinal detachment. The brain weighed 260 g; the cerebrum, cerebellum, and brain stem were extremely small; and the tertiary sulci were absent in the cerebral surface. The cross-sectional area of cerebral cortex was reduced to about one third of those in the control, although six-layered lamination, density of pyramidal neurons, and expressions of calcium-binding proteins were comparatively preserved in the cerebral cortex. The third ventricle was hypoplastic, and the bilateral thalami appeared to be fused and the hippocampus was unrolled, whereas the corpus callosum was preserved. In the hypothalamus, the paraventricular nucleus was only identified, and the adenohypophysial somatotrophs were reduced. This may be the first autopsy report of Micro syndrome, which is characterized by microcephaly, brain malformations, optic atrophy, and hypogenitalism, although the case lacked agenesis of the corpus callosum. ( J Child Neurol 2003;18:54—57).

To assess the previously proposed hypothesis that enuretic patients have a dysfunction in the pontine reticular formation.In 18 patients with intractable nocturnal enuresis, rapid eye movement (REM)-related phasic chin muscle activity loss in REM sleep was examined by means of a single-night polysomnography.In 5 of 18 patients, this physiologically seen phenomenon was found to be disturbed.Since REM-related phasic chin muscle activity loss is disturbed by the functional impairment in the pontine reticular formation, some enuretic patients could be considered as presenting a dysfunction in this structure.