Introduction Pediatric brain arteriovenous malformations (AVMs) are an important cause of hemorrhagic stroke and long-term morbidity. Neurocognitive outcomes remain incompletely characterized. Objective To synthesize reported neurocognitive, educational, and occupational outcomes in individuals diagnosed with brain AVMs before 18 years of age. Methods PubMed, Scopus, Web of Science, the Cochrane Library, and ScienceDirect were searched from January 1995 through June 5, 2026, according to a prospectively registered International Prospective Register of Systematic Reviews protocol (PROSPERO; CRD420261352472). Studies reporting at least one neurocognitive, educational, or occupational outcome in individuals diagnosed with a brain AVM before 18 years of age were eligible irrespective of management strategy. Because of clinical and methodological heterogeneity, findings were synthesized narratively. Results Twelve studies involving 287 individuals diagnosed in childhood were included. Participant ages at assessment, follow-up periods, study designs, and neurocognitive instruments varied substantially. Reported intelligence quotient (IQ) scores ranged from 81 to 124, although scores from different instruments and developmental stages were not directly comparable. Across studies, reported outcomes included attention or cognitive difficulties, need for educational support, reduced academic performance, and limitations in school or work participation, while other participants maintained average or above-average functioning. Occupational outcomes were reported in only a small number of long-term follow-up studies. No comparative neurocognitive benefit of a specific management strategy could be established. Conclusion Reported neurocognitive and educational outcomes after pediatric brain AVM diagnosis were heterogeneous, and evidence concerning occupational outcomes was sparse. Prospective studies using age-appropriate, standardized longitudinal neurocognitive assessments are needed.
BACKGROUND/PURPOSE:Coronavirus disease 2019 (COVID-19) poses particular risks for patients with neuromuscular disorders, but its severity and outcomes in this population remain unclear. We investigated the clinical features, transmission routes, treatments, and prognostic factors of COVID-19 in patients with neuromuscular disorders in Japan. METHODS:A retrospective questionnaire survey was submitted to 13 neuromuscular disease centers to identify patients diagnosed with COVID-19 between December 2019 and October 2022. The collected data comprised demographics, underlying diseases, living situation, activities of daily living (ADLs), vaccination status, respiratory and cardiac management, symptoms, treatments, and outcomes. We evaluated whether pre-illness respiratory status, cardiac function, vaccination history, and age could be risk factors associated with prognosis after COVID-19 infection. RESULTS:In total, 155 patients were identified. Duchenne muscular dystrophy was the most frequent neuromuscular disease (35%), followed by myotonic dystrophy (14%). The mean patient age was 30.7 years, and 70% of patients lived at home with family. Meanwhile, 54% of patients were wheelchair users, and 8% were bedridden. The vaccination rate was 56%. Fever was the most common symptom, and 5% of patients were asymptomatic. Antipyretics were the most frequent treatments; adults mainly received antivirals. Overall, 87% recovered fully, but two patients died. Of the examined factors, only higher age at onset was predictive of worse prognosis (p = 0.0019). CONCLUSIONS:COVID-19 symptoms and transmission routes in patients with neuromuscular disease resembled those in the general population. Advanced age was associated with poorer outcomes, underscoring the need for careful monitoring in these subgroups.
BACKGROUND:Although cytokines are contributors to febrile seizures, previous studies have largely involved pathogen-heterogeneous populations. Human herpesvirus 6 (HHV-6) is a common cause of febrile seizures and is useful for studying pathogen-specific inflammatory responses. METHODS:This retrospective study included children with polymerase chain reaction-confirmed HHV-6 infection using stored plasma samples obtained within 72 h of hospital presentation, classified according to seizure status. Plasma cytokine levels were measured using a multiplex immunoassay. Multivariable linear regression was used to identify the cytokines associated with seizures, with Benjamini-Hochberg false discovery rate (FDR) correction across 15 cytokines. Correlations between cytokine levels and hematologic parameters were evaluated. Cerebrospinal fluid (CSF)-to-plasma cytokine ratios were analyzed. RESULTS:Sixty patients were included (37, without seizures; 23, seizures), with no significant differences in baseline characteristics between the groups. Plasma interleukin-8 (IL-8) showed an association with seizures (adjusted fold change 1.84, p = 0.03), but this association did not remain statistically significant after FDR correction (q = 0.45). Inverse correlations between IL-8 (and to a lesser extent macrophage inflammatory protein-1 alpha) and neutrophil and platelet counts were observed in the non-seizure group only. In the paired analyses (n = 8), the CSF-to-plasma ratios of IL-8 and monocyte chemoattractant protein-1 exceeded 1.0, with a trend toward higher IL-8 ratios in the seizure group after adjusting for age. CONCLUSIONS:Although exploratory, findings from this pathogen-homogeneous cohort suggest that IL-8 is a candidate cytokine associated with both seizure occurrence and an altered relationship with neutrophil and platelet counts, warranting further study.
OBJECTIVE:This study aimed to compare the efficacy of adrenocorticotropic hormone (ACTH) and oral prednisolone therapies in children with infantile epileptic spasms syndrome (IESS), utilizing the Burden of Amplitudes and Epileptiform Discharges (BASED) score to assess electrographic severity and the Early Childhood Epilepsy Severity Scale (E-Chess) to evaluate clinical outcomes. METHODS:This retrospective cross-sectional study included 40 children aged 1 to 16 months with IESS. Children received either ACTH (n = 23) or high-dose oral prednisolone (n = 17). Electroencephalographic severity was assessed before treatment and on day 28 post-treatment using the BASED score. Clinical epilepsy severity was evaluated at one year post-treatment using the E-Chess score. RESULTS:Both treatment groups showed significant reductions in BASED scores (overall cohort p < 0.001; ACTH group p < 0.001; prednisolone group p = 0.007). However, there was no statistically significant difference between the ACTH and prednisolone groups regarding post-treatment BASED or E-Chess scores. While clinical factors such as gender, age, and etiology were not associated with favorable outcomes, a lower post-treatment BASED score was significantly associated with a better clinical prognosis (p = 0.007). Notably, a higher number of pretreatment anti-seizure medications (ASMs) was a strong predictor of poor clinical outcome (OR: 5.474, 95% CI: 1.849-16.207; p = 0.002). CONCLUSION:High-dose oral prednisolone and ACTH therapies demonstrated comparable efficacy in reducing electrographic and clinical seizure burden in children with IESS. Improvement in epileptiform activity, as reflected by reductions in the BASED score, is strongly associated with better clinical outcomes. Additionally, a high pretreatment medication burden may serve as an early indicator of a refractory clinical course.
Background Variants in GBA1 are associated with neurodegenerative disease. This study aimed to explore pathogenic GBA1 variants. Methods Four patients with progressive myoclonic epilepsy (PME) and extremely low β-glucosidase levels were recruited. Whole-exome sequencing and long-range PCR were performed to identify GBA1 variants. Bioinformatic analyses were used to predict the impact of the identified variants. A literature review was performed to explore the genotype-phenotype correlations. GBA1 expression data across different brain regions and developmental stages were analyzed using the BrainSpan database. RT-PCR was performed to verify the splicing effects. Results Compound heterozygous GBA1 variants were identified in four patients. Five distinct variants were detected, including two novel splice site variants (c.308-2A>G and c.762-2A>C) and three previously reported variants. All identified variants were rare or absent in gnomAD. Splice site variants c.308-2A>G and c.762-2A>C were predicted to cause aberrant splicing. Minigene-based splicing assays coupled with RT-PCR and Sanger sequencing confirmed that both variants cause complete exon skipping (exon 4 and exon 7, respectively). All patients presented with PME onset in childhood/adolescence, intellectual regression, low β-glucosidase, and diffuse brain atrophy and were subsequently diagnosed with Gaucher disease type 3. GBA1 expression in the brain showed two distinct peaks: one in infancy and another after five years of age. The onset age of PME aligned with the second GBA1 expression peak (after five years of age). Conclusion This study identified compound heterozygous GBA1 variants, including two novel candidate pathogenic splice site variants, in Gaucher disease type 3 patients, expanding the known mutational spectrum.
Aim To develop an expert consensus-based clinical roadmap, informed by a structured review of current evidence, to support clinical reasoning regarding the application of non-invasive brain stimulation (NIBS) in children and adolescents with cerebral palsy (CP). Method A structured review of the literature was conducted to identify evidence regarding the use of NIBS in paediatric CP, prioritising meta-analyses, systematic reviews, and randomized controlled trials. Evidence related to stimulation targets, protocol characteristics, motor outcomes, and safety considerations was synthesised to inform the development of a preliminary clinical roadmap. The roadmap subsequently underwent refinement through a modified Delphi process involving clinicians and researchers with expertise in paediatric neurorehabilitation and neuromodulation. The Delphi process focused on evaluating the clinical applicability, feasibility, and usability of the proposed framework. Results The final roadmap integrates current evidence with multidisciplinary expert consensus to support individualized clinical decision-making across motor domains and CP clinical presentations. Current evidence most consistently supports the consideration of NIBS as an adjunct to active rehabilitation for locomotor function in spastic diplegia and upper-limb function in spastic hemiplegia. Evidence for quadriplegia, ataxia, and dystonia remains limited and should be interpreted cautiously. The roadmap also incorporates expert consensus regarding safety considerations, clinical implementation, and outcome monitoring. Interpretation This expert consensus-based roadmap provides a structured framework to support individualized and goal-oriented clinical decision-making regarding NIBS in paediatric CP. It is intended to facilitate the translation of heterogeneous evidence into clinical practice and should not be interpreted as a clinical guideline or formal recommendation document.
AIM:To elucidate the relationship between estimated cerebral perfusion pressure and cerebral blood flow velocities or resistance index in neonates and to identify optimal Doppler cut-off values for predicting estimated cerebral perfusion pressure. METHODS:This multicentre study included neonates with arterial lines admitted to neonatal intensive care units between December 2021 and August 2024. Estimated cerebral perfusion pressure, cerebral blood flow velocities, and resistance index were calculated daily from the middle cerebral artery. RESULTS:A total of 446 samples were obtained from 137 neonates with a median gestational age of 32 (interquartile range, 27-36) weeks and a median birth weight of 1551 (interquartile range, 928-2292) g. End-diastolic velocity showed the strongest correlation with estimated cerebral perfusion pressure (standardised β = 0.571, 95% confidence interval, 0.500-0.641, p < 0.001). End-diastolic velocity cut-off values increased stepwise with higher estimated cerebral perfusion pressure thresholds. CONCLUSION:End-diastolic velocity is a strong predictor of neonatal estimated cerebral perfusion pressure and may serve as a practical indicator of cerebral perfusion in neonatal intensive care units.
Purpose Tuberous sclerosis complex (TSC)-associated epilepsy often involves focal epilepsy, infantile epileptic spasms syndrome (IESS), and drug-resistant epilepsy (DRE). This article presents an executive summary of the Japanese Clinical Practice Guidelines for Tuberous Sclerosis Complex-associated Epilepsy 2025, developed to support the diagnosis, evaluation, and treatment of epilepsy in patients with TSC in Japan. Methods The guideline was developed by the Japanese Society of Child Neurology and the Japanese Society of Tuberous Sclerosis Complex in accordance with the Minds Manual for Guideline Development 2020. A clinical algorithm reflecting Japanese practices was created, and background questions (BQs) and one clinical question (CQ) were formulated. Evidence was collected through searches of PubMed and Ichushi-Web for articles published between 1983 and May 2021. For the CQ, a systematic review was conducted, and the recommendation was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) grid method. Results The guideline covers the pathway from diagnosis and evaluation to treatment, considering TSC diagnosed before and after epilepsy onset. Based on neuroimaging and EEG-based evaluations, epilepsy is broadly classified into focal epilepsy and IESS, including West syndrome. The BQs summarize treatment strategies for focal epilepsy and IESS, and address the definition, characteristics, and treatment options for DRE, including epilepsy surgery, mammalian target of rapamycin (mTOR) inhibitor therapy, vagus nerve stimulation, and dietary therapy. The only CQ addressed adjunctive mTOR inhibitor therapy for DRE. This therapy was conditionally recommended with low certainty of evidence. Conclusions This guideline provides a practical framework for TSC-associated epilepsy in Japan and shows how current evidence and expert recommendations can be applied to the Japanese healthcare system.
Early infantile developmental and epileptic encephalopathy (EIDEE) is among the most severe epilepsy syndromes, with onset before three months of age and an estimated incidence of approximately 10 per 100,000 live births. The 2022 International League Against Epilepsy classification unified the historically distinct Ohtahara syndrome and early myoclonic encephalopathy under a single diagnostic framework defined by frequent drug-resistant tonic and/or myoclonic seizures, an abnormal neurological examination, and an abnormal interictal electroencephalogram-most characteristically a burst-suppression pattern. This narrative review synthesizes the clinical, electrophysiological, neuroimaging, genetic, and therapeutic literature within the EIDEE framework. The clinical phenotype is characterized by central hypotonia, postnatal microcephaly, cortical visual impairment, and age-dependent syndromic evolution toward infantile epileptic spasms syndrome or Lennox-Gastaut syndrome in the majority of patients. Electroencephalography remains essential for syndromic classification, while systematic metabolic screening and early trio whole-exome or whole-genome sequencing are central to the etiologic workup, achieving diagnostic yields of 60-65%. The most commonly identified genetic causes include STXBP1, KCNQ2, and SCN2A variants. Outcomes are poor overall and strongly etiology-dependent: vitamin-responsive disorders carry a substantially more favorable prognosis, whereas mortality reaches 25% in genetic cohorts. Genotype-guided pharmacotherapy is now applicable to a clinically meaningful subset of patients, with sodium channel blockers, potassium channel openers, and emerging antisense oligonucleotide therapies representing important therapeutic advances. Gene therapy trials are underway but have encountered early safety signals, underscoring the vulnerability of this population. Critical unmet needs include earlier molecular diagnosis, precision therapies targeting developmental outcomes beyond seizure control, and prospective international registries to characterize the long-term natural history of EIDEE.
BACKGROUND:Structured red flag assessment guides neuroimaging decisions in pediatric emergency headache. Cumulative scoring may offer greater discriminative value than individual flag analysis; however, imaging-based cohort evidence is subject to selection and spectrum bias, limiting extrapolation to unselected populations. OBJECTIVE:To evaluate 12 predefined red flags for predicting abnormal cranial neuroimaging and explore cumulative count thresholds in a pediatric emergency department (ED) imaging-based cohort. METHODS:This single-center, retrospective, cross-sectional study enrolled consecutive pediatric patients (aged 2-18 years) who underwent cranial neuroimaging for headache at a tertiary ED (January 2022 to June 2025). Twelve red flags were coded as binary variables. Diagnostic accuracy metrics and positive likelihood ratio were calculated for individual flags and cumulative thresholds. Discriminative performance was assessed using the area under the curve (AUC) with bootstrap 95% confidence intervals (CI). RESULTS:Of 187 patients (median age 14.7 years; 60% female), 14 (7.5%; 95% CI: 4.3%-11.9%) had abnormal neuroimaging. Red flag count was significantly higher in the abnormal group (median 5 vs. 1; p < 0.001). None of 54 patients with zero red flags had abnormal neuroimaging. AUC was 0.995 (95% CI: 0.985-1.000). At ≥3 flags, sensitivity and negative predictive value (NPV) were 100%; at ≥4, sensitivity was 93%, specificity 99%, and positive predictive value (PPV) 87%. CONCLUSIONS:Cumulative red flag enumeration identified risk strata with differing rates of abnormal neuroimaging in a pediatric ED imaging-based cohort. These hypothesis-generating findings are subject to selection and spectrum bias; prospective validation in unselected populations is required before clinical application.
OBJECTIVE:Stereotypic movement disorder (SMD) is a neurodevelopmental condition frequently co-occurring with autism spectrum disorder (ASD), yet its underlying pathophysiology remains poorly understood. Emerging evidence suggests that neuroinflammatory mechanisms may contribute to the etiology of neurodevelopmental disorders. Based on this, we aimed to investigate the potential role of neuroinflammation, specifically interleukin-1β (IL-1β) and interleukin-6 (IL-6), in the etiopathophysiology of both primary SMD and ASD. METHODS:This cross-sectional study included children and adolescents aged 6-18 years, categorized into four groups: 22 with primary SMD, 20 with ASD and comorbid SMD (secondary SMD), 18 with ASD without SMD, and 18 healthy controls. Participants were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL), Childhood Autism Rating Scale (CARS), Repetitive Behavior Scale-Revised Turkish Version (RBS-R-TV), and Conners Parent Rating Scale-Revised Short Form (CPRS-RS). Plasma IL-1β and IL-6 levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS:IL-1β and IL-6 levels were significantly higher in the primary SMD and ASD groups compared to healthy controls. Both cytokines were significantly correlated with stereotyped behavior severity and emerged as significant predictors in regression analyses. CONCLUSIONS:Our findings suggest that neuroinflammatory processes may play a role in the pathophysiology of primary SMD and ASD, and that elevated cytokine levels are associated with greater stereotypy severity. To our knowledge, this is the first clinical study to explore these relationships in primary SMD. Further studies using larger samples and broader inflammatory panels are needed to validate and extend these findings.
BACKGROUND:Infantile epileptic spasm syndrome (IESS) and periventricular leukomalacia (PVL) cause developmental regression and poor neurological outcomes. The primary treatments for IESS include adrenocorticotropin and vigabatrin; however, no study has yet evaluated the efficacy of vigabatrin for patients with both IESS and PVL. Therefore, we investigated the efficacy and safety of vigabatrin in patients with both disorders. METHODS:We retrospectively enrolled patients with IESS and PVL who were treated with vigabatrin. We performed ophthalmological examinations and electroretinography (ERG) before and after vigabatrin. Treatment response was defined as complete cessation of epileptic spasms and no other seizures after 3 months of vigabatrin. We investigated the responses to vigabatrin, doses used, and adverse effects. RESULTS:Seven patients (5 males) with IESS and PVL were treated with vigabatrin. The median age at vigabatrin initiation was 10 (range, 7-25) months. Three of the seven patients (42.8%) showed complete clinical cessation of epileptic spasms after 3 months of vigabatrin. The median duration between vigabatrin initiation and epileptic spasm cessation was 5 (range: 3-61) days. The adverse effects included poor feeding (n = 1) and abnormal ERG findings during vigabatrin therapy (n = 2). These ERG findings normalized after vigabatrin was reduced or stopped. No respiratory failure, increased secretion, or somnolence was observed. CONCLUSION:Vigabatrin was effective for treating 42.8% of our patients with both IESS and PVL. Vigabatrin was well tolerated, with only a mild effect observed in patients with IESS and PVL. Some treatment-related ERG abnormalities were normalized after vigabatrin was reduced or stopped.
BACKGROUND:An understanding of the natural history and progression of spinal muscular atrophy (SMA) in untreated children, is crucial for the identification of responsive outcome measures that are used to demonstrate the effectiveness of disease-modifying therapies (DMTs). However, there have been no such studies from India. OBJECTIVES:This retrospective registry-based study was aimed at outlining the progression of type 2 SMA among children, with a median age of ten years, over a span of two years. METHODOLOGY:Data from 30 drug-naïve children diagnosed with type 2 SMA were included in the study. A semi-structured pre-tested proforma was used to collect the baseline characteristics of the participants. The outcome variables were the neuromotor function scores based on Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), and the motor milestones established by the World Health Organization (WHO) modified to include attainment of head control. RESULTS:At the one-year follow-up, clinically relevant decrements in HFMSE and RULM scores were noted in 52% and 26% of the patients, respectively. After two years, these figures rose to 67% and 37%, respectively, suggesting an earlier loss of function of the lower extremities in these children compared to the upper extremities. Motor milestone loss was not observed in any of the children. Swallowing difficulty was significantly associated with a decrease in the HFMSE score. At the end of the two-year follow-up period, the cumulative survival was found to be 0.88, and the mean survival time was estimated to be 29 months. CONCLUSION:Our results align with earlier studies indicating that disease progression in type 2 SMA varies among children, highlighting its heterogeneous nature.
BACKGROUND:Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a common pediatric acute encephalopathy characterized by biphasic seizures and development of a bright tree appearance (BTA) on diffusion-weighted MR imaging (DWI). Lesion extent and distribution have been linked to neurological prognosis, but the effects of lesion depth remained unclear. METHODS:We retrospectively analyzed 25 children with AESD onset between 1991 and 2022. Acute-phase magnetic resonance imaging (MRI) (4-14 days after onset) was evaluated using DWI. Lesions in 10 cerebral regions were classified by depth as BTA limited to the subcortical area (BTA-L) or BTA with extension into the deep white matter (BTA-E). Neurological outcomes included pediatric cerebral performance category scores and residual motor paralysis at ≥12 months. Associations between MRI findings and outcomes were analyzed using univariate logistic regression and receiver operating characteristic analyses. RESULTS:Thirteen patients had favorable outcomes, whereas 12 had unfavorable outcomes based on pediatric cerebral performance category scores. Bilateral temporal lobe involvement with BTA-L/E (odds ratio [OR], 16.8), bilateral frontal lobe involvement with BTA-E (OR, 10.0), and bilateral thalamus/basal ganglia lesions (OR, 12.0) showed significant associations with unfavorable outcomes. Residual motor paralysis was associated with lesion burden and distribution. Rolandic BTA-E showed an association with motor paralysis (OR, 90.0), even in unilateral cases. This study should be considered exploratory due to the small sample size and the lack of adjustment for multiple comparisons. CONCLUSIONS:Acute-phase MRI findings in AESD were associated with long-term neurological outcomes. Lesion distribution and deep white matter extension may serve as potential prognostic factors. Frontal BTA-E and Rolandic BTA-E were associated with cognitive impairment and motor paralysis, respectively.
INTRODUCTION/AIMS:Pneumonia onset is associated with decreased muscle mass in patients with severe cerebral palsy (CP). In this longitudinal study, we examined whether ultrasound-derived muscle thickness (MT) and echo intensity (EI) are linked to pneumonia onset in patients with severe CP. METHODS:We included 71 patients with severe CP (45 males, 26 females; mean age 43.3 years) and investigated the association between MT and EI of six muscles (quadriceps, biceps brachii, rectus abdominis, internal oblique [IO], external oblique, and transverse abdominis) and pneumonia onset over a 6-month follow-up. RESULTS:Logistic regression analysis showed that lower MT in the IO was significantly associated with pneumonia development after adjusting for prior pneumonia and other confounders. CONCLUSIONS:These findings suggest that low IO MT may help identify patients with severe CP at risk of pneumonia onset.
Background The relative age effect is associated with high rates of attention-deficit/hyperactivity disorder diagnosis in the youngest children in a classroom. However, it remains unclear whether relative age affects the earlier stage of initiating medical consultations for developmental and behavioral concerns before a diagnosis is confirmed. Methods We analyzed the Longitudinal Survey of Newborns in the 21st Century, a nationwide population-based birth cohort in Japan. We compared 23,423 January-born children (born in the relatively younger months of the academic year) with 23,592 July-born children (born in the relatively older months of the academic year). The primary outcome was caregiver-reported medical consultations for developmental and behavioral concerns between ages 7 and 12. The secondary outcome was caregiver-reported “restlessness” at age 9. Results The prevalence rates of medical consultations were 6.0% and 5.2% for January- and July-born children, respectively. The adjusted risk difference (aRD) was 0.79 percentage points, and the adjusted risk ratio (aRR) was 1.18. This association was observed in both sexes but was statistically significant mainly in boys (aRR, 1.19). Caregivers were more likely to report January-born children as “restless” at age 9 (24.4% vs. 21.4%, aRR, 1.14). Conclusions In this Japanese cohort, being born in the relatively younger months of the academic year was significantly associated with a higher frequency of medical consultations for developmental concerns. The findings suggest that relative age may serve as a contextual factor in the process of seeking medical advice, although whether this reflects true differences in clinical need or misattribution of normal immaturity remains to be elucidated. Clinicians should consider relative age when evaluating children for developmental concerns.
