Infantile Spasms Research Articles

Metabolic etiologies in children with infantile epileptic spasm syndrome: Experience at a tertiary pediatric neurology center

ObjectiveInfantile epileptic spasm syndrome (IESS), including West syndrome (WS) and infantile spasm (IS), causes a challenging prognosis, particularly when associated with metabolic etiologies. MethodsThis study, conducted at a tertiary pediatric neurology center, explored the prevalence and clinical features of inborn errors of metabolism in 112 children with IESS over 10 years. ResultsMost patients presented with seizures, primarily flexor spasms, and the median age at onset was 5 months. Comprehensive clinical evaluation and neuroimaging revealed structural-acquired causes as the most common etiology. Notably, inborn errors of metabolism were identified in 5.4 % of cases, with six distinct diagnoses including nonketotic hyperglycinemia, pyridoxine-dependent epilepsy, primary coenzyme Q10 deficiency 7, congenital disorder of glycosylation type IIM, 6-pyruvoyl tetrahydrobiopterin synthase deficiency, and argininosuccinate lyase deficiency. The prevalence of inborn errors of metabolism in this cohort was consistent with global variations reported in the literature. Genetic testing, including karyotype analysis and whole exome sequencing, was performed in a subset of cases with no clear diagnosis, revealing abnormalities in approximately 50 % of cases. Adrenocorticotropic hormone emerged as the most frequently prescribed antiseizure medication. ConclusionThis study provides insight into the diagnostic challenges associated with IESS and highlights the importance of metabolic investigations, especially in cases without a clear etiology. The findings emphasize the need for further genetic and metabolic studies to enhance prognostic accuracy and guide potential treatment options for children with IESS, particularly in populations with high rates of consanguinity.

Analysis of clinical characteristics and histopathological transcription in 40 patients afflicted by epilepsy stemming from focal cortical dysplasia.

This study aims to comprehensively analyze the clinical characteristics and identify the differentially expressed genes associated with drug-resistant epilepsy (DRE) in patients with focal cortical dysplasia (FCD). A retrospective investigation was conducted from July 2019 to June 2022, involving 40 pediatric cases of DRE linked to FCD. Subsequent follow-ups were done to assess post-surgical outcomes. Transcriptomic sequencing and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to examine differential gene expression between the FCD and control groups. Among the 40 patients included in the study, focal to bilateral tonic-clonic seizures (13/40, 32.50%) and epileptic spasms (9/40, 22.50%) were the predominant seizure types. Magnetic resonance imaging (MRI) showed frequent involvement of the frontal (22/40, 55%) and temporal lobes (12/40, 30%). In cases with negative MRI results (13/13, 100%), positron emission tomography/computed tomography (PET-CT) scans revealed hypometabolic lesions. Fused MRI/PET-CT images demonstrated lesion reduction in 40.74% (11/27) of cases compared with PET-CT alone, while 59.26% (16/27) yielded results consistent with PET-CT findings. FCD type II was identified in 26 cases, and FCD type I in 13 cases. At the last follow-up, 38 patients were prescribed an average of 1.27 ± 1.05 anti-seizure medications (ASMs), with two patients discontinuing treatment. After a postoperative follow-up period of 23.50 months, 75% (30/40) of patients achieved Engel class I outcome. Transcriptomic sequencing and qRT-PCR analysis identified several genes primarily associated with cilia, including CFAP47, CFAP126, JHY, RSPH4A, and SPAG1. This study highlights focal to bilateral tonic-clonic seizures as the most common seizure type in patients with DRE due to FCD. Surgical intervention primarily targeted lesions in the frontal and temporal lobes. Patients with FCD-related DRE showed a promising prognosis for seizure control post-surgery. The identified genes, including CFAP47, CFAP126, JHY, RSPH4A, and SPAG1, could serve as potential biomarkers for FCD. This study aimed to comprehensively evaluate the clinical data of individuals affected by focal cortical dysplasia and analyze transcriptomic data from brain tissues. We found that focal to bilateral tonic-clonic seizures were the most prevalent seizure type in patients with drug-resistant epilepsy. In cases treated surgically, the frontal and temporal lobes were the primary sites of the lesions. Moreover, patients with focal cortical dysplasia-induced drug-resistant epilepsy exhibited a favorable prognosis for seizure control after surgery. CFAP47, CFAP126, JHY, RSPH4A, and SPAG1 have emerged as potential pathogenic genes for the development of focal cortical dysplasia.

Electroretinogram as a Screening Tool to Assess Vigabatrin-Induced Retinal Toxicity in Children With Infantile Spasms.

To assess the utility of electroretinogram (ERG) as a screening tool for vigabatrin-induced retinal toxicity in children with infantile spasms. This was an observational cohort study including children with infantile spasms receiving treatment with vigabatrin. A 30-Hz flicker potential ERG, using the RETeval system (LKC Technologies), was done at baseline before starting vigabatrin at 6 months and 1 year. The amplitudes were recorded. Eleven children were included in the study. The most common etiologic factor for infantile spasms was tuberous sclerosis (36.4%) followed by West syndrome (27.3%). The mean age of the children was 7.14 ± 2.9 months, with a range of 3 to 16 months. The mean difference in amplitude was 3.21 ± 2.45 and 5.72 ± 4.18 µV at 6 and 12 months follow-up, respectively (P < .001). Eight of the 11 children (72.7%) showed vigabatrin-induced retinal toxicity, and all 8 children were receiving vigabatrin for more than 6 months. ERG can be used for vigabatrin-induced retinal toxicity monitoring in children with infantile spasms. Vigabatrin-induced retinal toxicity is related to the duration of treatment rather than cumulative dosage. [J Pediatr Ophthalmol Strabismus. 2024;61(4):273-278.].

Negative Regulator of Reactive Oxygen Species-Related Microgliopathy: A Tale of Epileptic Spasms With Intracranial Calcifications.

Negative Regulator of Reactive Oxygen Species-Related Microgliopathy: A Tale of Epileptic Spasms With Intracranial Calcifications.

Predictors of medical intractability in children with epilepsy onset during the first two years of life, excluding infantile epileptic spasm syndrome

PurposeEarly childhood epilepsy presents a significant challenge, with approximately 30 % of individuals experiencing treatment failure. This study aimed to identify predictors of medical intractability in children with epilepsy onset during the first two years of life, excluding infantile epileptic spasm syndrome. MethodsA total of 323 children were retrospectively evaluated. The analyses included a review of medical records for demographic, laboratory, radiological, and electroencephalographic (EEG) findings. Children were diagnosed with drug-resistant epilepsy (DRE) according to the ILAE diagnostic criteria. Twenty-one potential prognostic predictors were examined in relation to medical intractability. ResultsAmong the 323 children (56.7 % male), 119 (36.8 %) had unknown epilepsy, 131 (40.6 %) had structural epilepsy, 53 (16.4 %) had genetic epilepsy, and 20 (6.2 %) had metabolic epilepsy. Over a median follow-up of 68 months, 55.4 % of the children achieved ≥6 months of seizure freedom, 33.1 % developed DRE, and the remaining 11.5 % had rare ongoing seizures but did not meet the criteria for DRE because they were only treated with one antiseizure medication at the last follow-up. Univariate logistic regression analyses identified ten risk factors significantly associated with DRE. Multivariate logistic regression analyses revealed that the presence of developmental delay at epilepsy onset (p = 0.000; OR 7.890; 95 %CI 2.713 to 22.945), history of status epilepticus (p = 0.000; OR 8.247; 95 %CI 3.619 to 18.793), number of antiseizure medications (ASMs) at the sixth month of diagnosis (p = 0.000; OR 20.585; 95 %CI 8.993 to 47.117), and initial EEG findings (p = 0.046; OR 2.366; 95 %CI 1.015 to 5.518) were predictors of medical intractability. Nineteen (5.9 %) children died during follow-up for various reasons, including progressive neurogenetic or neurodegenerative disorders. ConclusionDevelopmental delay at epilepsy onset, a history of status epilepticus, the use of two or more ASMs in the sixth month of diagnosis, and abnormal initial EEG findings were associated with medical intractability.

The Necessity of Speech and Language Assessment in “West Syndrome”: A case report

West syndrome is an epileptic encephalopathy accounting for one-fourth of epilepsies occurring in the first year of life and is highly associated with cognitive impairment. Autism spectrum disorders refer to a group of developmental disorders that are characterized by a wide range of impairments in social and communicative abilities, stereo-typed behaviors, and restricted range of interests with an onset of initial symptoms present before three years of age. In children with West syndrome, autism symptoms arise frequently. The present case study reports the speech and language characteristics of a 7-year-old boy followed with the emphasis and the association of West syndrome and autism.

Genetic variant reanalysis reveals a case of Sandhoff disease with onset of infantile epileptic spasm syndrome

BackgroundSandhoff disease (SD) i s an autosomal recessive lysosomal disease with clinical manifestations such as epilepsy, psychomotor retardation and developmental delay. However, infantile SD with onset of infantile epilepsy spasm syndrome (IESS) is extremely rare.Case presentationThe case presented here was a 22-month-old boy, who presented with IESS and psychomotor retardation/regression at 6 months of age. The patient showed progressive aggravation of seizures and excessive startle responses. The whole exome sequencing data, which initially revealed negative results, were reanalyzed and indicated a homozygous mutation at the c.1613 + 4del splice site of the HEXB gene. The activities of β-hexosaminidase A and total hexosaminidase were significantly decreased. The fundus examination showed cherry red spots at the macula.ConclusionsIESS can be an epileptic phenotype of infantile SD. Clinical phenotypes should be adequately collected in genetic testing. In the case of negative sequencing results, gene variant reanalysis can be performed when the patients show clinically suspicious indications.

Biomimetic Deep Learning Networks With Applications to Epileptic Spasms and Seizure Prediction.

In this study, we present a novel biomimetic deep learning network for epileptic spasms and seizure prediction and compare its performance with state-of-the-art conventional machine learning models. Our proposed model incorporates modular Volterra kernel convolutional networks and bidirectional recurrent networks in combination with the phase amplitude cross-frequency coupling features derived from scalp EEG. They are applied to the standard CHB-MIT dataset containing focal epilepsy episodes as well as two other datasets from the Montefiore Medical Center and the University of California Los Angeles that provide data of patients experiencing infantile spasm (IS) syndrome. Overall, in this study, the networks can produce accurate predictions (100%) and significant detection latencies (10 min). Furthermore, the biomimetic network outperforms conventional ones by producing no false positives. Biomimetic neural networks utilize extensive knowledge about processing and learning in the electrical networks of the brain. Predicting seizures in adults can improve their quality of life. Epileptic spasms in infants are part of a particular seizure type that needs identifying when suspicious behaviors are noticed in babies. Predicting epileptic spasms within a given time frame (the prediction horizon) suggests their existence and allows an epileptologist to flag an EEG trace for future review.

Efficacy and safety of corticosteroids and ACTH in epileptic syndromes beyond Infantile Epileptic Spasms Syndrome (IESS): A systematic review and meta-analysis.

We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti-seizure medication (ASM). We included retrospective and prospective studies reporting on more than five patients and with clear case definitions and descriptions of treatment and outcome measures. We searched multiple databases and registries, and we assessed the risk of bias in the selected studies using a questionnaire based on published templates. Results were summarized with meta-analyses that pooled logit-transformed proportions or rates. Subgroup analyses and univariable and multivariable meta-regressions were performed to examine the influence of covariates. We included 38 studies (2 controlled and 5 uncontrolled prospective; 31 retrospective) involving 1152 patients. Meta-analysis of aggregate data for the primary outcomes of seizure response and reduction of electroencephalography (EEG) spikes at the end of treatment yielded pooled proportions (PPs) of 0.60 (95% confidence interval [CI] 0.52-0.67) and 0.56 (95% CI 0.43-0.68). The relapse rate was high (PP 0.33, 95% CI 0.27-0.40). Group analyses and meta-regression showed a small benefit of ACTH and no difference between all other corticosteroids, a slightly better effect in electric status epilepticus in slow sleep (ESES) and a weaker effect in patients with cognitive impairment and "symptomatic" etiology. Obesity and Cushing's syndrome were the most common adverse effects, occurring more frequently in trials addressing continuous ACTH (PP 0.73, 95% CI 0.48-0.89) or corticosteroids (PP 0.72, 95% CI 0.54-0.85) than intermittent intravenous or oral corticosteroid administration (PP 0.05, 95% CI 0.02-0.10). The validity of these results is limited by the high risk of bias in most included studies and large heterogeneity among study results. This report was registered under International Prospective Register of Systematic Reviews (PROSPERO) number CRD42022313846. We received no financial support.

Genetic Advancements in Infantile Epileptic Spasms Syndrome and Opportunities for Precision Medicine.

Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of developmental regression or stagnation and hypsarrhythmia on EEG. A myriad of aetiologies are associated with the development of IESS; broadly, 60% of cases are thought to be structural, metabolic or infectious in nature, with the remainder genetic or of unknown cause. Epilepsy genetics is a growing field, and over 28 copy number variants and 70 single gene pathogenic variants related to IESS have been discovered to date. While not exhaustive, some of the most commonly reported genetic aetiologies include trisomy 21 and pathogenic variants in genes such as TSC1, TSC2, CDKL5, ARX, KCNQ2, STXBP1 and SCN2A. Understanding the genetic mechanisms of IESS may provide the opportunity to better discern IESS pathophysiology and improve treatments for this condition. This narrative review presents an overview of our current understanding of IESS genetics, with an emphasis on animal models of IESS pathogenesis, the spectrum of genetic aetiologies of IESS (i.e., chromosomal disorders, single-gene disorders, trinucleotide repeat disorders and mitochondrial disorders), as well as available genetic testing methods and their respective diagnostic yields. Future opportunities as they relate to precision medicine and epilepsy genetics in the treatment of IESS are also explored.

Identification of CYFIP2 Arg87Cys Ligands via In Silico and In Vitro Approaches.

The advancement of next-generation sequencing has enabled the identification of specific mutations associated with early infantile epileptic encephalopathies (EIEEs). In EIEE, epileptic spasms and seizures that occur since early childhood lead to impaired neurological development. The CYFIP2 p.Arg87Cys variant was recently related to EIEE. CYFIP2 participates in the Wave Regulatory Complex (WRC), which is related to the regulation of actin dynamics. The variant residue is at the interface between the CYFIP2 protein and WAVE1 protein inside the WRC. Thus, the weakening of this interaction induced by the residue modification, which also causes the flexibilization of the loop 80-110 within the CYFIP2 structure, allows the constant activation of the WCR. This study aimed to identify ligands for CYFIP2 p.Arg87Cys and potential therapy targets using in silico in vitro approaches. Models of different CYFIP2 versions were constructed, and molecular docking analyses were conducted. A total of 3946 ligands from the PDE3 and Drugbank databases were screened, leading to the identification of 11 compounds that selectively bind to the variant protein. The impact of binding in CYFIP2 was also evaluated using a thermal stability assay. These findings contribute to a better understanding of CYFIP2's functional role in pathology and can guide more in vitro experiments, facilitating the development of targeted therapies for CYFIP2-related conditions.

Role of TRAK1 variants in epilepsy: genotype-phenotype analysis in a pediatric case of epilepsy with developmental disorder.

The TRAK1 gene is mapped to chromosome 3p22.1 and encodes trafficking protein kinesin binding 1. The aim of this study was to investigate the genotype-phenotype of TRAK1-associated epilepsy. Trio-based whole-exome sequencing was performed on a cohort of 98 patients with epilepsy of unknown etiologies. Protein modeling and the VarCards database were used to predict the damaging effects of the variants. Detailed neurological phenotypes of all patients with epilepsy having TRAK1 variants were analyzed to assess the genotype-phenotype correlations. A novel TRAK1 compound heterozygous variant comprising variant c.835C > T, p.Arg279Cys and variant c.2560A > C, p.Lys854Gln was identified in one pediatric patient. Protein modeling and VarCards database analyses revealed that the variants were damaging. The patient received a diagnosis of early infantile epileptic spasms with a developmental disorder; he became seizure-free through valproate and adrenocorticotropic hormone treatment. Further results for six variants in 12 patients with epilepsy indicated that biallelic TRAK1 variants (including homozygous or compound heterozygous variants) were associated with epilepsy with developmental disorders. Among these patients, eight (67%) had epileptic spasms and seven (58%) were intractable to anti-seizure medicines. Moreover, eight patients experienced refractory status epilepticus, of which seven (88%) died in early life. To our knowledge, this is the first reported case of epilepsy caused by TRAK1 compound heterozygous variants. Biallelic TRAK1 variants can cause epilepsy and developmental disorders. In these patients, seizures progress to status epilepticus, suggesting a high risk for poor outcomes and the requirement of early treatment.

Clinical features and genetic analysis of five children with epilepsies due to variants of SCN8A gene

To explore the clinical and genetic characteristics of five children with epilepsies due to variants of SCN8A gene. Clinical data of five children (four males and one female) admitted to Linyi People's Hospital due to hereditary epilepsies between August 2015 and August 2022 were collected. Whole exome sequencing was carried out for these children, and candidate variants were verified by Sanger sequencing. All of the five children were found to harbor variants of the SCN8A gene. Case 1, who had benign familial infantile epilepsy, inherited a known pathogenic c.4840A>G variant from his father with similar symptoms. Cases 2 to 4 had presented with intermediate epilepsy. Among these, case 2 has harbored a de novo c.3967G>A variant which was rated as pathogenic (PS1+PS2+PM1+PM2_Supporting+PP3) based on the guidelines from the American College of Medical Genetics and Genomics. Cases 3 and 4 were found to respectively harbor a de novo c.415A>T and a c.4697C>T variant, which were both rated as likely pathogenic (PS2+PM1+PM2_Supporting+PP3). Case 5, who had early-onset infantile epileptic encephalopathy transformed into Lennox Gastaut-like syndrome, has harbored a de novo c.5615G>A variant, which was known to be pathogenic. The children had their age of onset ranging from 2 to 14 months, and all had focal seizures and generalized tonic clonic seizures. Four children (cases 1, 2, 3 and 5) had cluster seizures, four (cases 1 to 4) had become seizure-free after single or dual treatment and showed normal growth and development, whilst case 5 was drug-resistant and showed severe developmental retardation. The five children had new features such as cluster seizures, occasional benign seizures in adulthood, and intermediate epilepsy which are prone to relapse after discontinuation of medication, which may be attributed to the pathogenic variants of the SCN8A gene.

Place of the Ketogenic Diet in Refractory Infantile Spasms

Introduction: The ketogenic diet is an alternative nutritional regimen for refractory epilepsies, including infantile spasms. The objective of our study is the primary and secondary evaluation at 12 months of the effectiveness and tolerance of the ketogenic diet on seizure frequency, EEG (electroencephalogram) patterns, and side effects. Patients and Methods: We evaluated the ketogenic diet as a second- or third-line treatment, following corticosteroid therapy and/or Vigabatrin. We assessed the effectiveness and tolerance of the ketogenic diet based on patients being seizure-free, experiencing a reduction in seizures of more than 50%, improvement in EEG background pattern (suppression of hypsarrhythmia), psychomotor development, side effects, and reduction in antiepileptic drugs during clinical, electrical, and neurocognitive follow-ups at 1, 3, and 12 months. Results: Thirty-eight children, twentytwo boys, and sixteen girls, with a gender ratio of 1.37, presenting with infantile spasms visualized directly clinically or through videos and electric evaluation, with or without hypsarrhythmia on EEG, all symptomatic: genetic etiologies (14, 36.9%), structural in 18 patients (47.3%), and metabolic in six patients (15.8%). At 3 months, the number of patients who were seizure-free with a normal EEG was 22 patients (57.9%), and those with a reduction in seizures of more than 50%, 15 patients (39.5%). At 12 months on the ketogenic diet, the number of patients who were seizure-free was 24 (63.2%), and those with a reduction in seizures of more than 50% 14 patients(36.8%). Good tolerance and efficiency of the diet were confirmed by treatment compliance, maintained high response rate, and a reduction in the number of antiepileptic drugs to 1.97. The children became more vigilant, attentive, and responsive to their parents. Conclusion: Implementing the ketogenic diet within a short period of time, less than a year, would yield even better results in terms of seizure frequency and behavior in a developing infant brain.

Timing the clinical onset of epileptic spasms in infantile epileptic spasms syndrome: A tertiary health center's experience.

Lead time to treatment (clinical onset of epileptic spasms [ES] to initiation of appropriate treatment) is known to predict outcomes in infantile epileptic spasms syndrome (IESS). Timing the clinical onset of ES is crucial to establish lead time. We investigated how often ES onset could be established to the nearest week. We aimed to (1) ascertain the exact date or estimate the nearest week of ES onset and (2) compare clinical/demographic factors between patients where date of ES onset was determined or estimated to the nearest week and patients whose date of ES onset could not be estimated to the nearest week. Reasons for difficulties in estimating date of ES onset were explored. Retrospective chart review of new onset IESS patients (January 2019-May 2022) extracted the date or week of the clinical onset of ES. Predictors of difficulty in date of ES onset estimation to the nearest week were examined by regression analysis. Sources contributing to difficulties determining date of ES onset were assessed after grouping into categories (provider-, caregiver-, disease-related). Among 100 patients, date of ES onset was estimated to the nearest week in 47%. On univariable analysis, age at diagnosis (p = .021), development delay (p = .007), developmental regression/stagnation (p = .021), ES intermixed with other seizures (p = .011), and nonclustered ES at onset (p = .005) were associated with difficulties estimating date of ES onset. On multivariable analysis, failure to establish date of ES onset was related to ES intermixed with other seizures (p = .004) and nonclustered ES at onset (p = .003). Sources contributing to difficulties determining date of ES onset included disease-related factors (ES characteristics, challenges interpreting electroencephalograms) and provider/caregiver-related factors (delayed diagnosis). Difficulties with estimation of lead time (due to difficulties timing ES onset) can impact clinical care (prognostication), as even small increments in lead time duration can have adverse developmental consequences.

Electroclinical Landscape of Infantile Epileptic Spasms Syndrome.

To elucidate the electroclinical characteristics of infantile epileptic spasms syndrome (IESS) and to determine any potential association among these with underlying etiologies and response to therapy. Sixty-eight, treatment-naive children with IESS underwent long-term video electroencephalogram (EEG) recording, which was used to characterize the semiology, ictal, and inter-ictal EEG patterns. Children were further followed up to assess electroclinical predictors of etiologies and short-term therapeutic response. Of 68 children enrolled (69% boys), the median age at enrollment was 10.5 mo (IQR-8). Eighty-eight percent of children had flexor spasms, followed by mixed (7%) and extensor (4.4%). Asymmetrical spasms were noted in 17.6% children, and all of them had underlying structural etiology. Two children had the status of epileptic spasms. In the present cohort, authors recognized five distinct ictal EEG correlates of epileptic spasms; the frontocentral dominant slow wave was the most prevalent (32%), followed by the generalized slow-wave complex with superimposed fast rhythm in 29.4%. The occipital dominant slow wave complex was a peculiar pattern in 16%. The major underlying etiologies were hypoxic-ischemic brain injuries (36.7%) and neonatal hypoglycemic brain injuries (22%). Besides asymmetric spasms, authors could not identify any significant association among electroclinical characteristics, underlying etiologies and response to therapy in this study. The electroclinical landscape of IESS is peculiar and diverse in developing countries. The presence of asymmetrical spasms indicated underlying structural etiology.

Type 1 early infantile epileptic encephalopathy: A case report and literature review.

Variants in the Aristaless-related homeobox (ARX) gene lead to a variety of phenotypes, with intellectual disability being a steady feature. Other features can include severe epilepsy, spasticity, movement disorders, hydranencephaly, and ambiguous genitalia in males. X-linked Ohtahara syndrome or Type 1 early infantile epileptic encephalopathy (EIEE1) is a severe early-onset epileptic encephalopathy with arrested psychomotor development caused by hemizygous mutations in the ARX gene, which encodes a transcription factor in fundamental brain developmental processes. We presented a case report of a 2-year-old boy who exhibited symptoms such as microcephaly, seizures, and severe multifocal epileptic abnormalities, and genetic techniques such as autozygosity mapping, Sanger sequencing, and whole-exome sequencing. We confirmed that the patient had the NM_139058.3:c.84C>A; p.(Cys28Ter) mutation in the ARX gene. The patient with EIEE1 had physical symptoms and hypsarrhythmia on electroencephalogram. Genetic testing identified a causative mutation in the ARX gene, emphasizing the role of genetic testing in EIEE diagnosis.

Early life seizures and epileptic spasms in STXBP1-related disorders.

Individuals with disease-causing variants in STXBP1 frequently have epilepsy onset in the first year of life with a variety of seizure types, including epileptic spasms. However, the impact of early onset seizures and antiseizure medication (ASM) on the risk of developing epileptic spasms and impact on their trajectory are poorly understood, limiting informed and anticipatory treatment, as well as trial design. We retrospectively reconstructed seizure and medication histories in weekly intervals for individuals with STXBP1 developmental and epileptic encephalopathy (DEE) with epilepsy onset in the first year of life and quantitatively analyzed longitudinal seizure histories and medication response. We included 61 individuals with early onset seizures, 29 of whom had epileptic spasms. Individuals with neonatal seizures were likely to have continued seizures after the neonatal period (25/26). The risk of developing epileptic spasms was not increased in individuals with neonatal seizures or early infantile seizures (21/41 vs. 8/16, odds ratio [OR] = 1, 95% confidence interval [CI] = .3-3.9, p = 1). We did not find any ASM associated with the development of epileptic spasms following prior seizures. Individuals with prior seizures (n = 16/21, 76%) had a higher risk of developing refractory epileptic spasms (n = 5/8, 63%, OR = 1.9, 95% CI = .2-14.6, p = .6). Individuals with refractory epileptic spasms had a later onset of epileptic spasms (n = 20, median = 20 weeks) compared to individuals with nonrefractory epileptic spasms (n = 8, median = 13 weeks, p = .08). We provide a comprehensive assessment of early onset seizures in STXBP1-DEE and show that the risk of epileptic spasms is not increased following a prior history of early life seizures, nor by certain ASMs. Our study provides baseline information for targeted treatment and prognostication in early life seizures in STXBP1-DEE.

Effective treatment of NR2F1-related epilepsy with perampanel

BackgroundNR2F1 mutations are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS). Although ~ 46.7% of BBSOAS patients present with epilepsy, which is always drug-resistant and associated with higher rates of behavioral and cognitive problems, the treatment and outcomes of NR2F1-related epilepsy have rarely been described. Here, we present new cases of BBSOAS-related epilepsy and summarize all previously reported cases to explore the effective treatment for this type of epilepsy.MethodsWe identified six new Chinese cases of BBSOAS with epilepsy. Five different de novo heterozygous NR2F1 mutations were identified in these cases, including two novel mutations c.365G > T, p.Cys122Phe and c.449G > T, p.Gly150Val. By combining the six cases and 14 previously reported cases, we analyzed the characteristics and treatment outcomes of NR2F1-related epilepsy.ResultsTwelve of the 20 patients (60%) had infantile epileptic spasms, while the other patients had generalized tonic/tonic-clonic, focal, myoclonic, absence, or unclassified seizures. Several anti-seizure medications, steroids, and a ketogenic diet were administered in these cases. However, seizures were controlled in only 50% of previously reported cases, while all of the six new cases became seizure-free after perampanel as an add-on treatment. The average time from the addition of perampanel to seizure control was 7.33 ± 4.59 months (range, 1–12 months). The median time to seizure freedom was 14 months (1–32 months, > 19 months in 3 cases). The average dosage of perampanel needed for epilepsy control was 0.22 ± 0.17 mg/kg per day.ConclusionsIn this paper, we comprehensively summarized the clinical characteristics, treatments and outcomes of NR2F1-related epilepsy for the first time. Perampanel exhibits dramatic efficacy for NR2F1-related epilepsy. This will help optimize the treatment of this type of epilepsy and provide clues for its pathogenic mechanisms. The two novel mutations expand the genotype spectrum of this disease.

ATN1-related infantile developmental and epileptic encephalopathy responding to Ketogenic diet

BackgroundResearch has shown gene ATN1 to be associated with the nuclear receptor signaling. Its mutations in an evolutionarily conserved histidine-rich motif may cause CHEDDA, short for congenital hypotonia, epilepsy, developmental delay and digital anomalies, a recently identified neurodevelopmental syndrome that could evolve into developmental and epileptic encephalopathy (DEE). Up to date, there have been reported less than 20 cases, whose clinical features and treatment are worth in-depth exploring. MethodsThe clinical characteristics and genetic data of an infant with CHEDDA and further DEE were analyzed, who carried a de novo ATN1 variant identified by trio whole-exome sequencing. The alike patients with such a neurodevelopmental syndrome and epileptic seizures were reviewed on the literature. ResultsThe infant harboring a de novo missense mutation in ATN1 (c.3155A>C; p.His1052Pro) held almost all features of CHEDDA and presented with drug-resistant epileptic spasms, differing from one case previously reported with the same gene variant exhibiting milder seizures controlled easily. We further reviewed 11 CHEDDA patients with epileptic seizures in the literature and compared the correlation between abnormal cerebral structure and the incidence of intractable epilepsy among CHEDDA patients. Fortunately, this patient's seizures decreased remarkably after administering ketogenic diet (KD). ConclusionCHEDDA patients have significant phenotypic differences, especially in the epilepsy severity and their drug resistance, even if they carry the same mutation hotspot. Ketogenic diet and other treatments like Topiramate should be recommended for ATN1-related refractory epilepsy based on their regulation on expression of cation-chloride cotransporters and cellular hyperpolarization.