Early-onset Epilepsy Research Articles

Sensory-Motor Polyneuropathy in an 11-year- old Girl with a Pathogenic Variant in SMC1A: A Case Report.

Pathogenic variants in the SMC1A gene are often dominant-negative and cause an X-linked form of Cornelia de Lange syndrome (CdLS) with growth retardation and typical facial features. However, rare SMC1A variants cause a developmental and epileptic encephalopathy (DEE) with intractable early-onset epilepsy that is absent in CdLS. Here we describe an 11-year-old girl with epilepsy, walking disorder, and neurodevelopmental disorder. A neurophysiological examination of nerve conduction velocity showed a mixed, sensory-motor, chronic 4-limb polyneuropathy. Whole-exome sequencing identified the variant c.3145C > T p.(Arg1049*) in SMC1A (NM_006306.3), which can be classified as pathogenic. To the best of our knowledge, among 79 individuals with SMC1A-related DEE reported in the literature, altered peripheral nerve conduction has never been described. In this article, we propose that severe sensory-motor polyneuropathy could be an expansion of the SMC1A-related phenotype.

Ligand distances as key predictors of pathogenicity and function in NMDA receptors.

Genetic variants in the genes GRIN1, GRIN2A, GRIN2B, and GRIN2D, which encode subunits of the N-methyl-D-aspartate receptor (NMDAR), have been associated with severe and heterogeneous neurologic and neurodevelopmental disorders, including early onset epilepsy, developmental and epileptic encephalopathy, intellectual disability, and autism spectrum disorders. Missense variants in these genes can result in gain or loss of the NMDAR function, requiring opposite therapeutic treatments. Computational methods that predict pathogenicity and molecular functional effects of missense variants are therefore crucial for therapeutic applications. We assembled 223 missense variants from patients, 631 control variants from the general population, and 160 missense variants characterized by electrophysiological readouts that show whether they can enhance or reduce the function of the receptor. This includes new functional data from 33 variants reported here, for the first time. By mapping these variants onto the NMDAR protein structures, we found that pathogenic/benign variants and variants that increase/decrease the channel function were distributed unevenly on the protein structure, with spatial proximity to ligands bound to the agonist and antagonist binding sites being a key predictive feature for both variant pathogenicity and molecular functional consequences. Leveraging distances from ligands, we developed two machine-learning based predictors for NMDA variants: a pathogenicity predictor which outperforms currently available predictors and the first molecular function (increase/decrease) predictor. Our findings can have direct application to patient care by improving diagnostic yield for genetic neurodevelopmental disorders and by guiding personalized treatment informed by the knowledge of the molecular disease mechanism.

New Insights Into TRMT10A Syndrome: Case Report and Literature Review.

TRMT10A is related to a syndrome characterized by early-onset diabetes mellitus, microcephaly, epilepsy, and intellectual disability. We report a case of a patient showing spastic-ataxic paraparesis and Dandy-Walker variant associated with a causative homozygous c.421-1G > A variant in the TRMT10A gene, affecting a canonical splicing site. This mutation disrupts the "SAM-dependent methyltransferase TRM10-type domain", which is implicated in methylation and S-adenosylmethionine metabolic biological processes, crucial for mitochondrial and glucose metabolism. The prominent neurological involvement of our patient enhances the implication of TRMT10A in the brain development, suggesting a potential association between TRMT10A variants and dominant neurological phenotypes. This case expands the clinical spectrum of TRMT10A syndrome highlighting the importance of considering this gene in the evaluation of patients with brain/cerebellar malformations and spastic-ataxic paraparesis. Further research is warranted to elucidate the underlying pathogenic mechanisms and potential therapeutic implications.

WONOEP appraisal: The role of glial cells in focal malformations associated with early onset epilepsies.

Epilepsy represents a common neurological disorder in patients with developmental brain lesions, particularly in association with malformations of cortical development and low-grade glioneuronal tumors. In these diseases, genetic and molecular alterations in neurons are increasingly discovered that can trigger abnormalities in the neuronal network, leading to higher neuronal excitability levels. However, the mechanisms underlying epilepsy cannot rely solely on assessing the neuronal component. Growing evidence has revealed the high degree of complexity underlying epileptogenic processes, in which glial cells emerge as potential modulators of neuronal activity. Understanding the role of glial cells in developmental brain lesions such as malformations of cortical development and low-grade glioneuronal tumors is crucial due to the high degree of pharmacoresistance characteristic of these lesions. This has prompted research to investigate the role of glial and immune cells in epileptiform activity to find new therapeutic targets that could be used as combinatorial drug therapy. In a special session of the XVI Workshop of the Neurobiology of Epilepsy (WONOEP, Talloires, France, July 2022) organized by the Neurobiology Commission of the International League Against Epilepsy, we discussed the evidence exploring the genetic and molecular mechanisms of glial cells and immune response and their implications in the pathogenesis of neurodevelopmental pathologies associated with early life epilepsies.

Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature

Background and objectivesDevelopmental and epileptic encephalopathy 56 (DEE-56) is caused by pathogenic variants in YWHAG and is characterized by early-onset epilepsy and neurodevelopmental delay. This study reports on a cohort of DEE-56 individuals, correlating antiseizure medication usage and comorbidities, to aid in understanding disease evolution. MethodsWe analyzed data from thirty-nine individuals aged 3–40 years with YWHAG variants, including 12 previously unreported individuals (2 of these with recurrent distal 7q11.23 deletions) and 27 previously published cases (21 families, including 3 adult individuals reported in a family case). Our assessments encompassed clinical, radiological, and genetic evaluations. All procedures adhered to standardized protocols for patient approvals, registrations, and data collection. ResultsIndividuals with YWHAG variants exhibited variable psychomotor delay, with the majority experiencing mild intellectual disability. Early-onset seizures, particularly febrile seizures, were common, with various seizure types reported. Valproic acid has emerged as an effective antiseizure medication. Movement disorders were present in a subset of individuals, primarily manifesting as ataxia and tremor. Comorbidities such as autism spectrum disorders and attention deficit-hyperreactivity disorder were observed in a proportion of individuals. We identified a novel YWHAG variant (c.634_645del/p.Asn212_Ser215del) and expanded the genotypic spectrum of the disease. ConclusionsWe provide insights into the clinical, radiological, and genetic features of YWHAG-related epileptic encephalopathy. Despite mild clinical symptoms, affected individuals face challenges in daily functioning, underscoring the need for comprehensive care. Valproic acid has been used for seizure control with variable results.

Effectiveness of add-on acetazolamide in children with drug-resistant CHD2-related epilepsy and in a zebrafish CHD2 model.

CHD2-related epilepsy is characterized by early-onset photosensitive myoclonic epilepsy with developmental delay and a high rate of pharmacoresistance. We sought to evaluate the efficacy of acetazolamide (ACZ) in CHD2-related epilepsy, due to ACZ's unexpected efficacy in our first patient harboring a pathogenic CHD2 variant. We collected patients from different Eastern European countries with drug-resistant CHD2-related epilepsy who were then treated with ACZ. Patients underwent video EEG before and during ACZ treatment. In a zebrafish model of CHD2-related epilepsy, ictal-like events were recorded 5 days post-fertilization after overnight ACZ exposure. Developmental delay preceded the onset of seizures in 10 of the 12 patients. Four had ataxia, and 6 exhibited autistic features. Seizures, primarily myoclonic, began at an average age of 3.4 years and were photosensitive in all 12 patients. Add-on ACZ treatment controlled photosensitive seizures in all patients: 6 became seizure-free, and in the remaining 6, seizure frequency decreased by over 75%. Four patients transitioned to ACZ monotherapy. The median follow-up was 13 months. In the zebrafish model, ACZ exposure reduced ictal-like events by 72%. ACZ, a well-tolerated and cost-effective medication, could be a good option for CHD2-related epilepsy, predominantly manifesting with myoclonic seizures and photosensitivity. PLAIN LANGUAGE SUMMARY: Epilepsy associated with CHD2 mutations is often pharmacoresistant and associated with developmental delay and eventually ataxia. There are several generalized seizure types, including generalized tonic-clonic seizures, but the most characteristic are jerks triggered by light stimulation. We collected 12 patients who received acetazolamide, a drug usually given as a diuretic and registered as a mild antiseizure medication. All jerks triggered by light disappeared while the frequency of spontaneous seizures decreased by over 75%. Further studies are needed to confirm this promising finding and identify the mechanism by which an old compound seems to have such a specific antiseizure effect.

Deciphering Developmental Epileptic Encephalopathies (DEE): Unravelling the Key Signs

<p><strong>Background:</strong> Epilepsy, a chronic neurological disorder affecting over 50 million people worldwide, is marked by recurrent seizures and loss of consciousness. It is categorized based on EEG features, etiologies, and comorbidities. Developmental Encephalopathy (DE) involves developmental delays and early-onset seizures without causing developmental regression. In contrast, Epileptic Encephalopathy (EE) features severe epilepsy syndromes where frequent seizures result in developmental delays or regression.</p><p><strong>Methods:</strong> This review explores the clinical definitions, epidemiology, and diagnostic criteria for DE, EE, and DEEs. It covers their etiologies, clinical features, diagnostic methods, and treatment strategies, including genetic, structural, metabolic, and immune-related factors.</p><p><strong>Results:</strong> DE features developmental impairment with epilepsy, while EE involves severe epilepsy causing cognitive and behavioral dysfunction. DEEs are marked by early-onset severe epilepsy and EEG abnormalities that worsen developmental impairments. Essential diagnostic tools include EEG, neuroimaging, and genetic testing. Effective management requires personalized interventions to control seizures and address cognitive deficits.</p><p><strong>Conclusion:</strong> DEEs are a complex epilepsy subset with major developmental and cognitive challenges. Early diagnosis and targeted treatments are crucial for improving outcomes. Ongoing research into DEEs' genetic and pathophysiological mechanisms is key to enhancing understanding and management.</p>

An algorithm for drug-resistant epilepsy in Danish national registers.

Patients with drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life. Identification of persons with DRE in administrative data can allow for effective large-scale research, and we therefore aimed to construct an algorithm for identification of DRE in Danish nation-wide health registers. We used a previously generated sample of 525 persons with medical record-validated incident epilepsy between 2010-2019, of which 80 (15%) fulfilled International League Against Epilepsy (ILAE) criteria of DRE at the time of the latest contact - this cohort was considered the gold standard. We linked information in the validated cohort to Danish national health registers and constructed register-based algorithms for identification of DRE-cases. The accuracy of each algorithm was validated against the medical record-validated gold standard. We applied the best performing algorithm according to test accuracy (F1 score) to a large cohort with incident epilepsy identified in the Danish National Patient Registry between 1995 and 2013 and performed descriptive and logistic regression analyses to characterize the cohort with DRE as identified by the algorithm. The best performing algorithm in terms of F1 score was defined as 'fillings of prescriptions for ≥ 3 distinct antiseizure medications (ASMs) within 3 years or acute hospital visit with epilepsy/convulsions following fillings of prescriptions for two distinct ASMs' (sensitivity 0.59, specificity 0.93, positive predictive value 0.59, negative predictive value 0.92, area under the receiver operating characteristic curve 0.77, and F1 score 0.595). Applying the algorithm to a register-based cohort of 83,682 individuals with incident epilepsy yielded 8,650 cases (10.3 %) with DRE. In multivariable logistic regression analysis, early onset of epilepsy, focal or generalized epilepsy, somatic co-morbidity, and substance abuse, were independently associated with risk of being classified with DRE. We developed an algorithm for the identification of DRE in Danish national registers, which can be applied for a variety of research questions. We identified early onset of epilepsy, focal or generalized epilepsy, somatic co-morbidity, and substance abuse as risk factors for DRE.

Epigenetic insights into GABAergic development in Dravet Syndrome iPSC and therapeutic implications

Dravet syndrome (DS) is a devastating early-onset refractory epilepsy syndrome caused by variants in the SCN1A gene. A disturbed GABAergic interneuron function is implicated in the progression to DS but the underlying developmental and pathophysiological mechanisms remain elusive, in particularly at the chromatin level. Induced pluripotent stem cells (iPSCs) derived from DS cases and healthy donors were used to model disease-associated epigenetic abnormalities of GABAergic development. Chromatin accessibility was assessed at multiple time points (Day 0, Day 19, Day 35, and Day 65) of GABAergic differentiation. Additionally, the effects of the commonly used anti-seizure drug valproic acid (VPA) on chromatin accessibility were elucidated in GABAergic cells. The distinct dynamics in the chromatin profile of DS iPSC predicted accelerated early GABAergic development, evident at D19, and diverged further from the pattern in control iPSC with continued differentiation, indicating a disrupted GABAergic maturation. Exposure to VPA at D65 reshaped the chromatin landscape at a variable extent in different iPSC-lines and rescued the observed dysfunctional development of some DS iPSC-GABA. The comprehensive investigation on the chromatin landscape of GABAergic differentiation in DS-patient iPSC offers valuable insights into the epigenetic dysregulations associated with interneuronal dysfunction in DS. Moreover, the detailed analysis of the chromatin changes induced by VPA in iPSC-GABA holds the potential to improve the development of personalized and targeted anti-epileptic therapies.

Epigenetic insights into GABAergic development in Dravet Syndrome iPSC and therapeutic implications.

Dravet syndrome (DS) is a devastating early-onset refractory epilepsy syndrome caused by variants in the SCN1A gene. A disturbed GABAergic interneuron function is implicated in the progression to DS but the underlying developmental and pathophysiological mechanisms remain elusive, in particularly at the chromatin level. Induced pluripotent stem cells (iPSCs) derived from DS cases and healthy donors were used to model disease-associated epigenetic abnormalities of GABAergic development. Chromatin accessibility was assessed at multiple time points (Day 0, Day 19, Day 35, and Day 65) of GABAergic differentiation. Additionally, the effects of the commonly used anti-seizure drug valproic acid (VPA) on chromatin accessibility were elucidated in GABAergic cells. The distinct dynamics in the chromatin profile of DS iPSC predicted accelerated early GABAergic development, evident at D19, and diverged further from the pattern in control iPSC with continued differentiation, indicating a disrupted GABAergic maturation. Exposure to VPA at D65 reshaped the chromatin landscape at a variable extent in different iPSC-lines and rescued the observed dysfunctional development of some DS iPSC-GABA. The comprehensive investigation on the chromatin landscape of GABAergic differentiation in DS-patient iPSC offers valuable insights into the epigenetic dysregulations associated with interneuronal dysfunction in DS. Moreover, the detailed analysis of the chromatin changes induced by VPA in iPSC-GABA holds the potential to improve the development of personalized and targeted anti-epileptic therapies.

Fenfluramine treatment in pediatric patients with Dravet syndrome reduces seizure burden and overall healthcare costs: A retrospective and observational real-world study.

Dravet syndrome is a developmental and epileptic encephalopathy characterized by early onset epilepsy with multiple seizure types often intractable to treatment. Randomized clinical trials have demonstrated how treatment with fenfluramine significantly reduces seizure frequency in patients with Dravet syndrome. The study aims to (1) describe the efficacy and tolerability of fenfluramine in a Danish cohort of patients with Dravet syndrome; and (2) evaluate whether treatment with fenfluramine reduces epilepsy-related hospital contacts administrated by pediatricians or epilepsy-trained nurses. A retrospective registry-based cohort study at the Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark, enrolled 30 pediatric patients with Dravet syndrome treated with fenfluramine between 2017 and 2023. Thirty patients with Dravet syndrome (aged 3-21 years, 12 females) with a verified pathogenic SCN1A variant were included. They were treated with fenfluramine at a mean duration of 29 months with a mean maintenance dose of 0.5 mg/kg/day. The number of patient-years on treatment was 75 years. At last follow-up, 6 patients had discontinued treatment due to lack of efficacy or adverse effects. In the remaining 24 patients, generalized tonic-clonic seizures were reduced by ≥30% in 83%, by ≥50% in 67%, and by 100% in 25%. Additionally, 71% of the patients were reduced in concomitant anti-seizure medication, and 75% experienced a reduction (mean reduction at 52%, range 11%-94%) in epilepsy-related hospital contacts from baseline to the end of the treatment period. Treatment with fenfluramine effectively reduced seizure frequency and concomitant antiseizure medication in patients with Dravet syndrome. Furthermore, a decrease in epilepsy-related contacts by 80% was observed over 6 years of treatment, which may indicate cost-effective benefits. Patients with Dravet syndrome suffer from severe epileptic seizures that are difficult to treat with medication. Earlier, treatment with fenfluramine (an anti-seizure medication) has been documented to decrease the total number of seizures in patients with Dravet syndrome. This publication summarizes the experiences with fenfluramine in children with Dravet syndrome at the Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark. Our publication also illustrates that treatment with fenfluramine may reduce the patients' number of yearly contacts with doctors and nurses specialized in epilepsy treatment, which may indicate cost-effectiveness.

Hsp90aa1/JUN/Ccl2 regulatory axis mediates migration and differentiation of NSPCs, promoting the onset and progression of early post-ischemic stroke epilepsy

Early-onset epilepsy following ischemic stroke is a severe neurological condition, the pathogenesis of which remains incompletely understood. Recent studies suggest that Neural stem/progenitor cells (NSPCs) play a crucial role in the disease process, yet the precise molecular mechanisms regulating NSPCs have not been thoroughly investigated. This study utilized single-cell transcriptome sequencing and bioinformatics analysis to identify disease-related genes, which were subsequently validated in both in vitro and in vivo experiments. The findings revealed that Hsp90aa1 (heat shock protein 90 kDa alpha, class A member 1), Jun proto-oncogene (JUN), and CC Motif Ligation 2 (Ccl2) constitute an important regulatory axis influencing the migration and differentiation of NSPCs, potentially impacting the onset and progression of early-onset epilepsy post-ischemic stroke. Additionally, the expression of Hsp90aa1 was found to influence the likelihood of seizure occurrence and the severity of brain ischemia.

Multiplex Consanguineous Family Highlights CLASP1 as a Candidate Gene for Lissencephaly.

Noncentrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CLASP family of molecules. To date, no human monogenic disorder has been associated with the CLASP1 gene. In this study, we aimed to delineate the clinical and neuroradiologic phenotype associated with biallelic CLASP1 variants. We analyzed clinical characteristics, MRI data, and genotypes of a cohort of 3 patients with homozygous variants in CLASP1. Homozygous CLASP1 variant is associated with primary microcephaly, severe neurodevelopmental delay, and early-onset refractory epilepsy. The neuroradiologic phenotype comprises a highly recognizable combination of classic lissencephaly, with the posterior gradient more severe than the anterior gradient, a thin/hypoplastic splenium of the corpus callosum, mild enlargement of the lateral ventricles primarily posteriorly with a squared pattern, and pontine hypoplasia. This study underscores the role of CLASP1 in brain development and suggests that the identified variant disrupts CLASP1 interaction with the microtubule cytoskeleton, contributing to lissencephaly pathogenesis.

WONOEP appraisal: Modeling early onset epilepsies.

Epilepsy has a peak incidence during the neonatal to early childhood period. These early onset epilepsies may be severe conditions frequently associated with comorbidities such as developmental deficits and intellectual disability and, in a significant percentage of patients, may be medication-resistant. The use of adult rodent models in the exploration of mechanisms and treatments for early life epilepsies is challenging, as it ignores significant age-specific developmental differences. More recently, models developed in immature animals, such as rodent pups, or in three-dimensional organoids may more closely model aspects of the immature brain and could result in more translatable findings. Although models are not perfect, they may offer a more controlled screening platform in studies of mechanisms and treatments, which cannot be done in pediatric patient cohorts. On the other hand, more simplified models with higher throughput capacities are required to deal with the large number of epilepsy candidate genes and the need for new treatment options. Therefore, a combination of different modeling approaches will be beneficial in addressing the unmet needs of pediatric epilepsy patients. In this review, we summarize the discussions on this topic that occurred during the XVI Workshop on Neurobiology of Epilepsy, organized in 2022 by the Neurobiology Commission of the International League Against Epilepsy. We provide an overview of selected models of early onset epilepsies, discussing their advantages and disadvantages. Heterologous expression models provide initial functional insights, and zebrafish, rodent models, and brain organoids present increasingly complex platforms for modeling and validating epilepsy-related phenomena. Together, these models offer valuable insights into early onset epilepsies and accelerate hypothesis generation and therapy discovery.

Preclinical studies of gene replacement therapy for CDKL5 deficiency disorder

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by a mutation in the X-linked CDKL5 gene. CDKL5 is a serine/threonine kinase that is critical for axon outgrowth and dendritic morphogenesis as well as synapse formation, maturation, and maintenance. This disorder is characterized by early-onset epilepsy, hypotonia, and failure to reach cognitive and motor developmental milestones. Because the disease is monogenic, delivery of the CDKL5 gene to the brain of patients should provide clinical benefit. To this end, we designed a gene therapy vector, adeno-associated virus (AAV)9.Syn.hCDKL5, in which human CDKL5 gene expression is driven by the synapsin promoter. In biodistribution studies conducted in mice, intracerebroventricular (i.c.v.) injection resulted in broader, more optimal biodistribution than did intra-cisterna magna (i.c.m.) delivery. AAV9.Syn.hCDKL5 treatment increased phosphorylation of EB2, a bona fide CDKL5 substrate, demonstrating biological activity invivo. Our data provide proof of concept that i.c.v. delivery of AAV9.Syn.hCDKL5 to neonatal male Cdkl5 knockout mice reduces pathology and reduces aberrant behavior. Functional improvements were seen at doses of 3e11 to 5e11 vector genomes/g brain, which resulted in transfection of ≥50% of the neurons. Functional improvements were not seen at lower doses, suggesting a requirement for broad distribution for efficacy.

Chromosomal instability in a patient with ring chromosome 14 syndrome: a case report

BackgroundRing chromosome 14 syndrome is a rare disorder primarily marked by early-onset epilepsy, microcephaly, distinctive craniofacial features, hypotonia, intellectual disability, and delay in both development and language acquisition.Case presentationA 21-year-old woman with a history of epileptic seizures since the age of 1.5 years presented with distinctive craniofacial features, including a prominent and narrow forehead, sparse and short eyebrows, palpebral ptosis, horizontal palpebral fissures, a broad nasal bridge, a prominent nasal tip, a flat philtrum, hypertelorism, midfacial hypoplasia, horizontal labial fissures, a thin upper lip, crowded teeth, an ogival palate, retrognathia, and a wide neck. Additional physical abnormalities included kyphosis, lumbar scoliosis, pectus carinatum, cubitus valgus, thenar and hypothenar hypoplasia, bilateral hallux valgus, shortening of the Achilles tendon on the left foot, and hypoplasia of the labia minora. Chromosomal analysis identified a ring 14 chromosome with breakpoints in p11 and q32.33. An aCGH study revealed a ~ 1.7 Mb deletion on chromosome 14qter, encompassing 23 genes. Genomic instability was evidenced by the presence of micronuclei and aneuploidies involving the ring and other chromosomes.ConclusionThe clinical features of our patient closely resembled those observed in other individuals with ring chromosome 14 syndrome. The most important point was that we were able to verify an instability of the r(14) chromosome, mainly involving anaphasic lags and its exclusion from the nucleus in the form of a micronucleus.

Structural and functional abnormalities and cognitive profiles in older adults with early-onset and late-onset focal epilepsy.

This study aimed to determine the patterns of changes in structure, function, and cognitive ability in early-onset and late-onset older adults with focal epilepsy (OFE). This study first utilized the deformation-based morphometry analysis to identify structural abnormalities, which were used as the seed region to investigate the functional connectivity with the whole brain. Next, a correlation analysis was performed between the altered imaging findings and neuropsychiatry assessments. Finally, the potential role of structural-functional abnormalities in the diagnosis of epilepsy was further explored by using mediation analysis. Compared with healthy controls (n = 28), the area of reduced structural volume was concentrated in the bilateral cerebellum, right thalamus, and right middle cingulate cortex, with frontal, temporal, and occipital lobes also affected in early-onset focal epilepsy (n = 26), while late-onset patients (n = 31) displayed cerebellar, thalamic, and cingulate atrophy. Furthermore, correlation analyses suggest an association between structural abnormalities and cognitive assessments. Dysfunctional connectivity in the cerebellum, cingulate cortex, and frontal gyrus partially mediates the relationship between structural abnormalities and the diagnosis of early-onset focal epilepsy. This study identified structural and functional abnormalities in early-onset and late-onset focal epilepsy and explored characters in cognitive performance. Structural-functional coupling may play a potential role in the diagnosis of epilepsy.

The course of tumor-related epilepsy in glioblastoma patients: A retrospective analysis

PurposeMany patients with glioblastoma suffer from tumor-related seizures. However, there is limited data on the characteristics of tumor-related epilepsy achieving seizure freedom. The aim of this study was to characterize the course of epilepsy in patients with glioblastoma and the factors that influence it. MethodsWe retrospectively analyzed the medical records of glioblastoma patients treated at the University Hospital Erlangen between 01/2006 and 01/2020. ResultsIn the final cohort of patients with glioblastoma (n = 520), 292 patients (56.2 %) suffered from tumor-related epilepsy (persons with epilepsy, PWE). Levetiracetam was the most commonly used first-line antiseizure medication (n = 245, 83.9 % of PWE). The onset of epilepsy was preoperative in 154/292 patients (52.7 %). 136 PWE (46.6 %) experienced only one single seizure while 27/292 PWE (9.2 %) developed drug-resistant epilepsy. Status epilepticus occurred in 48/292 patients (16.4 %). Early postoperative onset (within 30 days of surgery) of epilepsy and total gross resection (compared with debulking) were independently associated with a lower risk of further seizures. We did not detect dose-dependent pro- or antiseizure effects of radiochemotherapy. ConclusionTumor-related epilepsy occurred in more than 50% of our cohort, but drug-resistant epilepsy developed in less than 10% of cases. Epilepsy usually started before tumor surgery.

SCN8A Encephalopathy with a Significant Long-Term Response to Lacosamide

AbstractDevelopmental and epileptic encephalopathy associated with SCN8A variants (i.e., SCN8A encephalopathy) causes early-onset epilepsy, involuntary movements, hypotonia, and developmental delay. Sodium channel blockers are effective for treating SCN8A encephalopathy; however, the long-term effects are unknown. Herein, we report the long-term efficacy of lacosamide (LCM) treatment in a patient with SCN8A encephalopathy. Our patient, a 7-year-old girl, presented with a hyperekplexia-like excessive startle response, drug-resistant epilepsy with sinus arrest, and prolonged respiratory failure during the neonatal period. The patient was diagnosed with SCN8A encephalopathy caused by a de novo pathogenic variant of SCN8A: c.3979A > G; p.Ile1327Val. The patient experienced tonic clustered seizures daily, with dramatic responses to high doses of LCM, lasting approximately 3 years.

Vitamin D prophylaxis in persons with epilepsy?

Limited guidelines exist regarding osteoporosis prevention in the general population. Despite being a subject of controversy, the majority of research suggests that decreased vitamin D levels correlate with increased bone turnover, that is, an important risk factor for osteoporosis development. In most guidelines, daily vitamin D supplementation is recommended. In persons with epilepsy (PWE), the situation is more complex, as other factors can increase the chance of being vitamin D deficient. Currently, there are no internationally accepted guidelines regarding monitoring bone health in PWE. Our aim was to review the existing evidence in PWE on: (1) risk factors for vitamin D deficiency, (2) the identification of higher risk groups, and (3) the optimal ways to monitor bone health. Our narrative review shows that: (1) anti-seizure medication (ASM) use, especially enzyme-inducing ASM (EIASM) and valproic acid, is identified as an important risk factor for impaired bone health (e.g., increased risk for osteoporosis/fractures and/or vitamin D deficiency); (2) higher risk groups within the PWE population are present: intellectual or physical disability, institutionalized patients, puberty, early onset epilepsy and developmental epileptic encephalopathies, postmenopausal women, and use of multiple ASM/concomitant drugs (e.g. corticosteroids); and (3) a monitoring scheme can be suggested including laboratory tests, bone density measurements, managing of risk factors, and/or vitamin D supplementation. Overall, regular vitamin D measurement in PWE is a cost-effective and practical method for monitoring vitamin D deficiency, whereas in high-risk patients the combination of vitamin D measurement and bone densitometry is recommended. There is not enough evidence to advocate continuous vitamin D supplementation in all PWE. Children with epilepsy should receive the recommended daily intake of vitamin D for age and additional monitoring and supplementation if at higher risk of deficiency. There is a need for prospective trials exploring the potential benefit of vitamin D supplementation in PWE.