Long-term efficacy of intrathecal cyclodextrin in patients with Niemann-Pick disease type C.

BACKGROUND AND OBJECTIVES: Niemann-Pick type C (NPC) is a rare lysosomal storage disease characterized by hepatosplenomegaly and progressive neurological deterioration due to abnormal intracellular cholesterol transport. Cyclic oligosaccharide 2-hydroxypropyl-ß-cyclodextrin (HPBCD) is an effective treatment for NPC; however, few reports have shown its long-term efficacy and safety. To demonstrate long-term efficacy and safety of intrathecal HPBCD (IT-HPBCD) treatment for NPC, we herein reports five patients with NPC treated using IT-HPBCD for 4-11 years. CASES AND RESULTS: Patients' ages at the onset ranged from 1.5 to 20 years. Notably, all patients showed rapid disease progression despite treatment with miglustat before IT-HPBCD treatment. Similarly, some patients showed transient improvement; however, all patients' conditions stabilized after long-term IT-HPBCD therapy. Mild-to-moderate hearing loss was observed in three patients. Furthermore, long-term treatment with IT-HPBCD may suppress neurological deterioration in patients with NPC; however, patients still experience some disease progression. CONCLUSIONS: Long-term treatment with IT-HPBCD may suppress neurological deterioration in patients with NPC; however, the treatment outcome is dependent on the neurological status at the time of diagnosis, and disease progression is not completely inhibited. Awareness of the disease and newborn screening is needed for earlier disease detection. In addition, further optimization of the treatment protocol and additional treatments are needed to improve patient outcomes.

Additional Effect of High-output Current and/or High-duty Cycle in Vagus Nerve Stimulation for Adolescent/Adult Intractable Epilepsy.

A vagus nerve stimulation (VNS) device delivers electrical pulses to the vagus nerve at a rhythm defined by the duty cycle. The standard therapeutic range is advocated for an output current of 1.5-2.25 mA and a duty cycle of 10%. As the optimal settings vary from patient to patient, some patients may benefit from additional seizure reduction when stimulated beyond the standard range. A total of 74 patients (15 children aged <12 years and 59 adolescents/adults) who underwent VNS implantation between 2011 and 2020 and who were followed up for at least 2 years were included in this retrospective study. Stimulation parameters exceeding 2.25 mA of output current, 25% of duty cycle, and 0.5625 (2.25 mA × 25%) of current × duty cycle were defined as high stimulation. The proportion achieved an additional seizure reduction of 20%, and the 50% seizure reduction rate at the last follow-up was compared between adolescents/adults and children. Approximately 40% of patients in adolescents/adults treated with high stimulation experienced an additional acute effect, resulting in a 50% or greater reduction in seizures in almost all patients. Moreover, in adolescents/adults, 22.2%-41.9% of the patients were treated with high stimulation, and the responder rate was 69.5%. Conversely, the responder rate in children was 26.7%, significantly worse than that in adolescents/adults, despite higher stimulation. VNS with high-stimulation settings is effective for adolescent and adult patients with intractable epilepsy. Even high stimulation may not be effective in extremely refractory pediatric epilepsy with a high seizure frequency.

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.

Blood coagulation dynamics during adrenocorticotropic hormone therapy in pediatric patients with infantile spasms.

INTRODUCTION: Adrenocorticotropic hormone (ACTH) therapy is a first-line treatment for infantile spasms, which may rarely cause intracranial hemorrhage. However, the changes in blood coagulation during ACTH therapy are poorly understood, with little description in the management guidelines. OBJECTIVE: To assess the changes in blood coagulation during ACTH therapy. PATIENTS/METHODS: This retrospective study reviewed the medical records of 10 patients diagnosed with infantile spasms and treated with ACTH therapy, between January 2015 and March 2021. The underlying diseases included intracranial hemorrhage, hypoxic-ischemic encephalopathy, tuberous sclerosis, and cerebral infarction. Antiepileptic drugs administered were valproic acid (VPA), vitamin B6, zonisamide, topiramate, clobazam, clonazepam, and phenobarbital. RESULTS: The 10 patients had a median age of 8 months (4-17 months) and included eight males. The median fibrinogen (Fbg) level before ACTH therapy was 202 mg/dL (125-392 mg/dL); however, this significantly decreased to 108.5 mg/dL (65-135 mg/dL) during treatment at a median of 12 days after (days 8-17) (p < 0.01). Decreased Fbg levels were observed with and without VPA. This suggests the possible influence of ACTH therapy on Fbg levels, irrespective of the VPA combination. Additionally, prothrombin time and activated partial thromboplastin time were significantly shortened when compared to those before ACTH therapy and at the lowest of Fbg levels. CONCLUSIONS: Careful coagulation monitoring, especially during the second week of treatment, is necessary for the safe completion of ACTH therapy, with or without concomitant VPA.

Monogenic causes of pigmentary mosaicism.

Pigmentary mosaicism of the Ito type, also known as hypomelanosis of Ito, is a neurocutaneous syndrome considered to be predominantly caused by somatic chromosomal mosaicism. However, a few monogenic causes of pigmentary mosaicism have been recently reported. Eleven unrelated individuals with pigmentary mosaicism (mostly hypopigmented skin) were recruited for this study. Skin punch biopsies of the probands and trio-based blood samples (from probands and both biological parents) were collected, and genomic DNA was extracted and analyzed by exome sequencing. In all patients, plausible monogenic causes were detected with somatic and germline variants identified in five and six patients, respectively. Among the somatic variants, four patients had MTOR variant (36%) and another had an RHOA variant. De novo germline variants in USP9X, TFE3, and KCNQ5 were detected in two, one, and one patients, respectively. A maternally inherited PHF6 variant was detected in one patient with hyperpigmented skin. Compound heterozygous GTF3C5 variants were highlighted as strong candidates in the remaining patient. Exome sequencing, using patients' blood and skin samples is highly recommended as the first choice for detecting causative genetic variants of pigmentary mosaicism.

Incidence and risk factors of acute encephalopathy with biphasic seizures in febrile status epilepticus.

OBJECTIVE: To clarify the incidence and risk factors of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) in pediatric patients with febrile status epilepticus (FSE). METHODS: We retrospectively surveyed patients with FSE (≥20 min and ≥40 min) who were younger than 6 years by mailing a questionnaire to 1123 hospitals in Japan. The survey period was 2 years. We then collected clinical data on patients with prolonged febrile seizures (PFS) ≥40 min and those with AESD, and compared clinical data between the PFS and AESD groups. RESULTS: The response rate for the primary survey was 42.3%, and 28.0% of hospitals which had applicable cases responded in the secondary survey. The incidence of AESD was 4.3% in patients with FSE ≥20 min and 7.1% in those with FSE ≥40 min. In the second survey, a total of 548 patients had FSE ≥40 min (AESD group, n = 93; PFS group, n = 455). Univariate analysis revealed significant between-group differences in pH, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, NH3, procalcitonin (PCT), uric acid, blood urea nitrogen, creatinine (Cr), and lactate. Multivariate analysis using stratified values showed that high PCT was an only risk factor for AESD. A prediction score of ≥3 was indicative of AESD, as determined using the following indexes: HCO3- < 20 mmol/L (1 point), Cl <100 mEq/L (1 point), Cr ≥0.35 mg/dL (1 point), glucose ≥200 mg/dL (1 point), and PCT ≥1.7 pg/mL (2 points). The scoring system had sensitivity of 84.2% and specificity of 81.0%. CONCLUSION: Incidence data and prediction scores for AESD will be useful for future intervention trials for AESD.

Ketogenic Diet Therapy for Intractable Epilepsy in Infantile Alexander Disease: A Small Case Series and Analyses of Astroglial Chemokines and Proinflammatory Cytokines.

In infantile Alexander disease (iAxD), one of the serious symptoms is intractable epilepsy, and some reports have suggested that neuroinflammation may be involved in the pathophysiology of the disease. Drug-resistant seizures adversely affect not only the quality of life of the caregivers and patients, but also patients' lifespan. Thus, controlling epilepsy is clinically important. For intractable childhood epilepsy, ketogenic diet therapy (KDT) is well-established, but its effects on iAxD have not been characterized. Here, we describe the use of KDT in three iAxD patients experiencing drug-resistant seizures. In all three cases, the formerly intractable epilepsies were well controlled by KDT. However, the brain magnetic resonance imaging findings deteriorated even after the epilepsy was controlled. In addition, the concentrations of monocyte chemotactic protein-1 and proinflammatory cytokines in the cerebrospinal fluid of the patients remained still high. KDT is effective in controlling epilepsy in iAxD. Our results clinically support previous reports arguing the involvement of neuroinflammation in the pathophysiology of iAxD.　Although KDT cannot prevent disease progression, earlier initiation might contribute to a better prognosis.

Analysis of factors related to low health-related quality of life in children with epilepsy using a self-assessed Japanese version of the KIDSCREEN-52.

BACKGROUND: There is a paucity of studies on self-assessed generic health-related quality of life (HRQOL) in children with epilepsy. The purpose of this study was to investigate generic HRQOL and associated factors among Japanese children with epilepsy. METHODS: In this clinic-based study, 277 children (aged 8-18 years) with epilepsy and 429 children without any chronic illnesses were recruited. HRQOL was evaluated using the Japanese version of the KIDSCREEN-52 self-reported questionnaire, which consisted of 52 items categorized into 10 dimensions related to the environment surrounding children. Multiple regression analysis was applied to explore related factors with low HRQOL in each dimension. RESULTS: We obtained the questionnaire from 171 (61.7%) and 306 (71.3%) children in the epilepsy and control groups, respectively. Short treatment period (<2 years), seizure lasting >30 min, and post-ictal symptoms were associated with a low HRQOL for School Environment (OR: 3.81; 95% CI: 1.34-10.86), Moods & Emotions (OR: 3.82; 95% CI: 1.67-8.78), and Parent Relations & Home Life (OR: 3.53; 95% CI: 1.29-9.72) dimensions, respectively. Complex neurodevelopmental disorders were associated with a low HRQOL for Social Support & Peers (OR: 3.59; 95% CI: 1.33-9.66), School Environment (OR: 2.49; 95% CI: 1.07-5.77), and Psychological Well-being (OR: 3.47; 95% CI: 1.20-10.00) dimensions. CONCLUSIONS: Our results suggest that early psychosocial support and better management of epilepsy may improve HRQOL. More support in school environments may be required for children with epilepsy and neurodevelopmental disorders.

PRRT2 mutations in Japanese patients with benign infantile epilepsy and paroxysmal kinesigenic dyskinesia.

PURPOSE: This study was performed to clarify the clinical features of Japanese patients with PRRT2 mutations. METHODS: The PRRT2 gene was analyzed in 135 patients with benign infantile epilepsy (BIE) or paroxysmal kinesigenic dyskinesia (PKD) using a direct sequencing method: 92 patients had BIE alone, 25 had both BIE and PKD, and 18 had PKD alone. Of the cases, 105 were familial, and 30 were sporadic. Clinical information was collected using a structured questionnaire. RESULTS: PRRT2 mutations were identified in 104 patients. Among the familial cases, PRRT2 mutations were found in at least one individual in 21 of 28 families with BIE alone, in 26 of 27 families with infantile convulsions and choreoathetosis, and in 2 of 3 families with PKD alone. Among the sporadic cases, PRRT2 mutations were observed in 7 of 25 patients with BIE alone, in 1 of 1 patient with BIE and PKD, and in 3 of 4 patients with PKD alone. The c.649dupC mutation was the most frequent, followed by the c.981C > G mutation. Among the patients with epilepsy, the median age at BIE onset was 5 months, the median age at the last seizure was 6 months, and the median number of seizures was 5. CONCLUSION: PRRT2 mutations were found in 68% of Japanese probands with BIE or PKD. The phenotypes of BIE associated with PRRT2 mutations were consistent with those of BIE diagnosed clinically.

Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing.

BACKGROUND: Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES). METHODS: We performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria. RESULTS: Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2). CONCLUSIONS: Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.

MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load.

Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10years (range: 5·4months-37years, IQR=17·9years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with LS/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094T>C.

Determination of CSF 5-methyltetrahydrofolate in children and its application for defects of folate transport and metabolism.

OBJECTIVE: To describe an assay of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid (CSF) of children, to determine reference values, and to report the clinical significance of this assay in metabolic disorders affecting folate transport and metabolism. METHODS: CSF 5MTHF was determined by high-performance liquid chromatography with fluorescent detection in pediatric patients including one with FOLR1 gene mutation and one with methylenetetrahydrofolate reductase (MTHFR) deficiency. CSF total folate was measured using an automated analyzer. RESULTS: 5MTHF and total folate were determined in 188 and 93 CSF samples, respectively. CSF 5MTHF was high throughout the first six months of life and subsequently declined with age. Reference values of CSF 5MTHF and total folate were determined from 162 and 82 samples, respectively. The patient with FOLR1 gene mutation had extremely low CSF 5MTHF and total folate, though these values normalized after folinic acid supplementation. The patient with MTHFR deficiency had extremely low 5MTHF and moderately low total folate; these values were not associated and showed no significant change after folic acid supplementation. CONCLUSIONS: This 5MTHF assay is simple, rapid, sensitive, reliable, and cost-effective. It will aid in the diagnosis and therapeutic monitoring of metabolic disorders affecting folate transport and metabolism.

Remitted epilepsy with dysembryoplastic neuroepithelial tumor involving the thalamus.

Dysembryoplastic neuroepithelial tumors (DNT) are benign hamartomatous tumors characterized by intractable epilepsy and common localization in the supratentorial cortex, but thalamic involvement in DNT is extremely rare. A 2-year 4-month-old boy presented with intractable epilepsy due to a tumorous lesion in the frontal lobe expanding to the thalamus. Under chronic intracranial electrocorticography guidance, partial lesionectomy with adjacent cortical resection was performed, and the lesion was pathologically diagnosed as DNT, complex form. Subsequently, the seizures completely disappeared without any neurological deficits despite the presence of full residual thalamic lesions. The epileptogenicity of DNT is closely associated with various clinicopathological factors, and the thalamic contribution to the seizure activity remains unclear. Due to the essential epileptogenic characteristics of DNT, the residual thalamic lesions and associated clinical features should be strictly observed in the future in the present case.

Novel pathological abnormalities of deep brain structures including dysplastic neurons in anterior striatum associated with focal cortical dysplasia in epilepsy.

OBJECT: Some patients are not seizure free even after epileptogenic cortical resection. The authors recently described a case of frontal lobe epilepsy cured after the resection of periventricular white matter and striatum, in which dysplastic neurons were revealed. The authors attempted to confirm similar cases. METHODS: They reviewed the records of 8 children with frontal lobe epilepsy who had daily (7) or monthly (1) seizures and underwent resections including deep brain structures. RESULTS: Five patients underwent multiple resections. Neuroimaging of the deep structures showed the transmantle sign in 3 patients, ictal hyperperfusion in 6, reduced iomazenil uptake in 2, and spike dipole clustering in 6. All patients became seizure free postoperatively. Focal cortical dysplasia of various types was diagnosed in all patients. Dysmorphic neurons were found in the cortex and subcortical white matter of 5 patients. The striatum was verified in 3 patients in whom dysmorphic neurons were scattered. In the periventricular white matter, prominent astrocytosis was evident in all cases. CONCLUSIONS: Pathological abnormalities such as dysmorphic neurons and astrocytosis in deep brain structures would play a key role in epileptogenesis.

Delayed maturation and differentiation of neurons in focal cortical dysplasia with the transmantle sign: analysis of layer-specific marker expression.

Transmantle dysplasia is a rare type of focal cortical dysplasia (FCD) characterized by expansion of the cortex from the deep white matter to the surface and in which there is a FCD IIA or IIB pathologic pattern. To characterize possible mechanisms underlying this regional disorder of radial migrating cells, we studied the expression patterns of neocortical layer-specific markers using immunohistochemistry in surgical specimens from 5 FCD IIA and 4 FCD IIB cases in children. All neuronal cells expressed the mature neuron marker MAP2/2B but not the microglia markers Iba-1 and CD68. Some layer-specific markers showed distinct expression patterns. TBR1-positive, SATB2-positive, and FOXP1-positive cells were diffusely distributed in the cortex and/or the white matter. TBR1-positive and FOXP1-positive cells were generally more numerous in FCD IIB than in FCD IIA and were mostly in the cortical molecular and upper layers. FOXP1-, FOXP2-, and CUTL1-positive cells also expressed the immature neuron marker, Nestin/PROX1, whereas TBR1-, CTIP2-, and SATB2-positive cells only expressed MAP2/2B. These data highlight differences between FCD IIB and FCD IIA with more cells having the immature marker in upper layer markers in the former. By analyzing layer-specific marker expression patterns, we identified apparent neuronal maturation differences between FCD IIA and FCD IIB in cases of transmantle dysplasia.

Evolution of hemiplegic attacks and epileptic seizures in alternating hemiplegia of childhood.

To delineate the evolution of non-epileptic and epileptic paroxysmal events in alternating hemiplegia of childhood (AHC), we reviewed clinical information of nine patients (4-40 years) with AHC. Paroxysmal abnormal ocular movements, head turning, and tonic, clonic, or myoclonic limb movements were the initial symptoms (birth-8m) in each patient. Ictal electroencephalography (EEG) of these episodes, as well as hemiplegic periods that accompanied these symptoms later in infancy showed unremarkable findings or generalized slow background activity. Presumptive epileptic seizures appeared at 2-16y in seven patients: generalized tonic, clonic, myoclonic, tonic-clonic, or complex partial seizures often accompanied by cyanosis or prolonged respiratory arrest. Ictal EEGs recorded in four patients revealed focal slow or fast activities during facial or limb twitching, and widespread sharp waves or polyspike-wave activities during clonic/myoclonic seizures. Four patients with neonatal disease onset showed lower psychomotor developmental achievements compared with other patients, and experienced repeated status epilepticus followed by progressive deterioration. Cerebellar atrophy and hippocampal high signal changes on magnetic resonance imaging were common to this group with severe phenotypes. Apart from the paroxysmal motor symptoms accompanying the hemiplegic episodes, many AHC patients suffer from true epilepsies during childhood. Status epilepticus in AHC is linked to severe outcome with psychomotor deterioration. The variations in clinical phenotypes may imply multiple causative genes for AHC. This variation should be considered while managing patients with this disorder.

Hemiconvulsion-hemiplegia syndrome in a patient with severe myoclonic epilepsy in infancy.

We report a 2-year-old girl who had repeated febrile or afebrile seizures since infancy. Prolonged left/right hemiconvulsions and myoclonus of the eyelids/extremities with generalization to tonic-clonic seizures, were refractory to antiepileptic agents. At age 1 year and 4 months, she contracted rotavirus infection, and developed status epilepticus with persistent right hemiclonic seizures. Left unilateral brain edema with subsequent emergence of cortical laminar necrosis and white matter lesions, and progressive atrophy of the left cerebral hemisphere were noted during this period. She showed residual right hemiparesis and mild intellectual disability, and had generalized/eyelid myoclonia and hot water epilepsy after a 5-month seizure-free period. Analysis for SCN1A, the gene encoding the neuronal voltage-gated Na+ channel alpha1 subunit revealed a nonsense mutation, R1892X. These indicate the potential risk in patients with severe myoclonic epilepsy in infancy (SMEI) to develop hemiconvulsion-hemiplegia (HH) syndrome. SCN1A mutations may need to be further explored in patients with HH syndrome without features of SMEI.

A case of infantile Alexander disease diagnosed by magnetic resonance imaging and genetic analysis.

We encountered a male infant with infantile Alexander disease presenting with megalencephaly and hydrocephalus as a neonate and subtle seizures at 3 months of age. At 6 months of age, bulbar paralysis appeared. Brain magnetic resonance imaging (MRI) showed abnormal findings with white matter involvement and a characteristic periventricular rim, satisfying the diagnostic criteria proposed by van der Knaap, except for MRI contrast. R239H mutation of glial fibrillary acidic protein gene was identified, representing a common cause of infantile-type Alexander disease.