Pallidal deep brain stimulation for patients with myoclonus-dystonia without SGCE mutations.

BACKGROUND: Pallidal deep brain stimulation (GPi-DBS) is effective for treating myoclonus and dystonia caused by SGCE mutations (DYT-SGCE, DYT11). However, it is unknown whether GPi-DBS is effective for the treatment of myoclonus-dystonia which is not associated with the SGCE gene mutations. In this study, we investigated the efficacy of GPi-DBS in treating myoclonus-dystonia in SGCE mutation-negative cases. METHODS: Three patients with myoclonus-dystonia without SGCE mutations who underwent GPi-DBS were evaluated preoperatively and 6 months postoperatively using the Unified Myoclonus Rating Scale (UMRS) and Fahn-Marsden Dystonia Rating Scale (FMDRS) for myoclonus and dystonia, respectively. In two of the three patients, myoclonus was more evident during action. Myoclonus was predominant at rest in the other patient, and he was unaware of his dystonia symptoms. The results were compared with those of the four DYT-SGCE cases. RESULTS: The mean UMRS score in patients with myoclonus-dystonia without SGCE mutations improved from 61.7 to 33.7 pre- and postoperatively, respectively, and the mean FMDRS score improved from 7.2 to 4.5. However, the degree of improvement in myoclonus-dystonia in patients without SGCE mutations was inferior to that in patients with DYT-SGCE (the UMRS score improved by 45% and 69%, respectively). CONCLUSIONS: GPi-DBS is effective for treating myoclonus-dystonia in patients with and without SGCE mutations. GPi-DBS should be considered as a treatment option for myoclonus-dystonia without SGCE mutations.

Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy in Children-A Literature Review.

Vagus nerve stimulation (VNS) is a palliative treatment for drug-resistant epilepsy (DRE) that has been in use for over two decades. VNS suppresses epileptic seizures, prevents emotional disorders, and improves cognitive function and sleep quality, a parallel effect associated with the control of epileptic seizures. The seizure suppression rate with VNS increases monthly to annually, and the incidence of side effects reduces over time. This method is effective in treating DRE in children as well as adults, such as epilepsy associated with tuberous sclerosis, Dravet syndrome, and Lennox-Gastaut syndrome. In children, it has been reported that seizures decreased by >70% approximately 8 years after initiating VNS, and the 50% responder rate was reported to be approximately 70%. VNS regulates stimulation and has multiple useful systems, including self-seizure suppression using magnets, additional stimulation using an automatic seizure detection system, different stimulation settings for day and night, and an automatic stimulation adjustment system that reduces hospital visits. VNS suppresses seizures and has beneficial behavioral effects in children with DRE. This review describes the VNS system, the mechanism of the therapeutic effect, the specific stimulation adjustment method, antiepileptic effects, and other clinical effects in patients with childhood DRE.

Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis.

The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by progressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to unaffected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals.

Focal tonic seizures with asymmetrical posturing could allow voluntary movements: A lesson to not be misled for a non-epileptic event.

This report documents the clinical features of supplementary motor area seizures with voluntary movements in two patients. The first case describes a 13-year-old boy with a 2-year history of nocturnal seizures, characterized by an asymmetrical brief tonic posture followed by bilateral rapid hand shaking, but without impaired awareness. Magnetic resonance imaging revealed no abnormalities. Video electroencephalogram indicated interictal focal spikes and ictal activity 2 s before clinical onset in the frontal midline area. The patient stated that he purposely shook his hands to lessen the seizure-induced upper limb stiffness. The second case describes a 43-year-old man with a 33-year history of nocturnal seizures, characterized by an asymmetric brief tonic posture, with the right hand grabbing to hold this posture, but without impaired awareness. Video electroencephalogram indicated that he voluntarily moved his right hand during the latter part of the seizures; however, no clear ictal electroencephalogram change was noted. Magnetic resonance imaging revealed a mass lesion in the right medial superior frontal gyrus. Fluorodeoxyglucose-positron emission tomography and ictal single-photon emission computed tomography indicated ictal focus in the mesial frontal area, as confirmed by invasive electroencephalogram and seizure freedom after surgery. Both patients had typical supplementary motor area seizures, except they could perform voluntary movements in the body parts. The co-occurrence of supplementary motor area seizures and voluntary movements is clinically useful, as it may help avoid the inaccurate and misleading diagnosis of non-epileptic events such as psychogenic non-epileptic seizures.

[Current practices of transition from pediatric to adult health care for patients with neurological disease: promote the cooperation between child and adult neurologists].

The Special Committee for Measures Against Transition from Pediatric to Adult Health Care of the Japanese Society of Neurology, which consists of child and adult neurologists, started to tackle the issues of pediatric to adult health care transition for patients with neurological disease in July 2020. The Committee held a workshop with a theme of "cooperation between child and adult neurologists," which is a critical issue in the pediatric to adult health care transition. To solve the many problems in the pediatric to adult health care transition, it is crucial that child and adult neurologists and primary care physicians cooperate on the following issues: preparing child neurologists for the transition, encouraging adult neurologists to study child neurology, promoting the formation of multidisciplinary teams, improving the medical system and medical fees, appealing to governmental agencies for issues of community health care and welfare services.

Safety and efficacy of avalglucosidase alfa in individuals with infantile-onset Pompe disease enrolled in the phase 2, open-label Mini-COMET study: The 6-month primary analysis report.

PURPOSE: Mini-COMET (NCT03019406; Sanofi) is a phase 2, open-label, ascending-dose, 3-cohort study, evaluating avalglucosidase alfa safety, pharmacokinetics, and efficacy in individuals with infantile-onset Pompe disease aged <18 years who previously received alglucosidase alfa and showed clinical decline (cohorts 1 and 2) or suboptimal response (cohort 3). METHODS: During a 25-week primary analysis period, cohorts 1 and 2 received avalglucosidase alfa 20 and 40 mg/kg every other week, respectively, for 6 months, whereas cohort 3 individuals were randomized (1:1) to receive avalglucosidase alfa 40 mg/kg every other week or alglucosidase alfa (current stable dose) for 6 months. RESULTS: In total, 22 individuals were enrolled (cohort 1 [n = 6], cohort 2 [n = 5], cohort 3-avalglucosidase alfa [n = 5], and cohort 3-alglucosidase alfa [n = 6]). Median treatment compliance was 100%. None of the individuals discontinued treatment or died. Percentages of individuals with treatment-emergent adverse events were similar across dose and treatment groups. No serious or severe treatment-related treatment-emergent adverse events occurred. Trends for better motor function from baseline to week 25 were observed for 40 mg/kg every other week avalglucosidase alfa compared with either 20 mg/kg every other week avalglucosidase alfa or alglucosidase alfa up to 40 mg/kg weekly. CONCLUSION: These data support the positive clinical effect of avalglucosidase alfa in patients with infantile-onset Pompe disease previously declining on alglucosidase alfa.

Loss-of-function mutations in SGCE found in Japanese patients with myoclonus-dystonia.

SGCE myoclonus-dystonia is a monogenic form of dystonia with an autosomal dominant mode of inheritance that co-occurs with a myoclonic jerk. In this study, we present 12 Japanese patients from nine families with this disease. Targeted next-generation sequencing covering major causative genes for monogenic dystonias identified nine distinct SGCE mutations from each of the families: three nonsense, two frameshift, two missense, one in-frame 15 bp deletion, and one splice donor site mutations, of which four were previously unreported. One missense mutation (c.662G>T, p.Gly221Val) was located at the 3' end of exon 5 (NM_001099400), which was predicted to cause aberrant splicing according to in silico predictions. Minigene assays performed together with the c.825+1G>C mutation demonstrated complete skipping of exon 5 and 6, respectively, in their transcripts. The other missense (c.1345A>G, p.Met449Val) and 15 bp deletion (c.168_182del, p.Phe58_Leu62del) mutations showed a significant reduction in cell membrane expression via HiBiT bioluminescence assay. Therefore, we concluded that all the detected mutations were disease-causing. Unlike the other detected mutations, p.Met449Val affects only isoform 3 (NP_001092870 encoded by NM_001099400) among the variously known isoforms of SGCE. This isoform is brain-specific and is mostly expressed in the cerebellum, which supports recent studies showing that cerebellar dysfunction is a key element in the pathophysiology of SGCE myoclonus-dystonia.

Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy.

PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

Incremental changes in interhemispheric functional connectivity after two-stage corpus callosotomy in a patient with subcortical band heterotopia.

Corpus callosotomy (CC) has been reported to be effective in reducing generalized seizures in patients with drug-resistant epilepsies. However, efficacy is measured only by seizure frequency, without any electrophysiological guidance. Herein, we conducted a quantitative analysis of interhemispheric functional connectivity using inter-electrode coherence of scalp electroencephalogram (EEG) in a clinical case of subcortical band heterotopia to evaluate its relationship with seizure frequency. In our case, seizure frequency decreased significantly after posterior CC but not after anterior CC. Inter-electrode coherence also decreased after posterior CC, suggesting it correlated with seizure frequency. This case study supports the use of inter-electrode coherence as an electrophysiological tool that is useful as predictive factor in evaluating the effectiveness of CC.

An intronic GNAO1 variant leading to in-frame insertion cause movement disorder controlled by deep brain stimulation.

GNAO1 variants are associated with a wide range of neurodevelopmental disorders including epileptic encephalopathies and movement disorders. It has been reported that some GNAO1 variants are associated with movement disorders, and the 207-246 amino acid region was proposed as a mutational hotspot. Here, we report an intronic variant (NM_020988.3:c.724-8G>A) in GNAO1 in a Japanese girl who showed mild developmental delay and movement disorders including dystonia and myoclonus. Her movement disorders were improved by deep brain stimulation treatment as previously reported. This variant has been recurrently reported in four patients and was transmitted from her mother who possessed the variant as low-prevalent mosaicism. Using RNA extracted from lymphoblastoid cells derived from the patient, we demonstrated that the variant caused abnormal splicing of in-frame 6-bp intronic retention, leading to 2 amino acid insertion (p.Thr241_Asn242insProGln). Immunoblotting and immunostaining using WT and mutant GNAO1 vectors showed no significant differences in protein expression levels, but the cellular localization pattern of this mutant was partially shifted to the cytoplasm whereas WT was exclusively localized in the cellular membrane. Our report first clarified abnormal splicing and resulting mutant protein caused by the c.724-8G>A variant.

Is Generalized and Segmental Dystonia Accompanied by Impairments in the Dopaminergic System?

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.

Identification of two novel de novo TUBB variants in cases with brain malformations: case reports and literature review.

Heterozygous variants in TUBB encoding one of ß-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.

Nonconvulsive status epilepticus following rotavirus gastroenteritis in two pediatric patients.

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.

Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy.

OBJECTIVE: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. METHODS: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. RESULTS: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. INTERPRETATION: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274-284.

Magnetic Resonance Imaging Findings in Preterm Infants With Bilirubin Encephalopathy Beyond Three Years Corrected Age.

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.

Neonatal Jaundice in Preterm Infants with Bilirubin Encephalopathy.

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 <2.5 g/dL in 44 patients, and the peak DB level was ≥2 mg/dL (34.2 µmol/L) in 20 patients. The average peak bilirubin/albumin (B/A) (mg/g) ratio was 3.8 (molar ratio of 0.475), and the average age at peak attainment was 18.6 days. The average peak UB level was 0.67 µg/dL (11.5 nmol/L). The median duration of phototherapy was 6 days, and the median day of the last session was 12. The peak TB level occurred after the last day of phototherapy in 30 of the 61 patients available for comparison. 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.

Evaluation of the Diagnostic Criteria for Anti-NMDA Receptor Encephalitis in Japanese Children.

OBJECTIVE: To evaluate the validity of the 2016 clinical diagnostic criteria proposed for probable anti-NMDA receptor (NMDAR) encephalitis in children, we tested the criteria in a Japanese pediatric cohort. METHODS: We retrospectively reviewed clinical information of patients with neurologic symptoms whose CSF was analyzed for NMDAR antibodies (NMDAR-Abs) in our laboratory from January 1, 2015, to March 31, 2019. RESULTS: Overall, 137 cases were included. Of the 41 cases diagnosed as probable anti-NMDAR encephalitis (criteria-positive) according to the 2016 criteria, 13 were positive and 28 were negative for anti-NMDAR-Abs. Of the 96 criteria-negative cases, 3 were positive and 93 were negative for anti-NMDAR-Abs. The sensitivity of the criteria was 81.2%, specificity was 76.9%, positive predictive value (PPV) was 31.7%, and negative predictive value was 96.9%. Compared with the true-positive group, the false-positive group contained more male than female patients (male:female, 4:9 in the true-positive vs 19:9 in the false-positive group, p = 0.0425). The majority of the cases with false-positive diagnoses were associated with neurologic autoimmunity. CONCLUSION: The clinical diagnostic criteria are reliable for deciding to start immunomodulatory therapy in the criteria-positive cases. Low PPV may be caused by a lower prevalence of NMDAR encephalitis or lower level of suspicion for encephalitis in the pediatric population. Physicians should therefore continue differential diagnosis, focusing especially on other forms of encephalitis. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that the proposed diagnostic criteria for anti-NMDAR encephalitis in children has a sensitivity of 81.2% and a specificity of 76.9%.

Auditory brainstem response in preterm infants with bilirubin encephalopathy.

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.

Association of early-onset epileptic encephalopathy with involuntary movements - Case series and literature review.

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.

Intraoperative Anatomical Findings in Pediatric Clear Cell Meningioma of the Lumbar Spine: Case Report and Literature Review.

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.