Infantile Spasms Research Articles

Long-Term Outcome of Neonatal Seizure with PACS2 Mutation: Case Series and Literature Review.

Phosphofurin Acidic Cluster Sorting Protein 2 (PACS2)-related early infantile developmental and epileptic encephalopathy (EIDEE) is a rare neurodevelopmental disorder. EIDEE is characterized by seizures that begin during the first three months of life and are accompanied by developmental impairment over time. In this article, we present three patients with EIDEE who experienced neonatal-onset seizures that developed into intractable seizures during infancy. Whole exome sequencing revealed a de novo heterozygous missense variant in all three patients in the p.Glu209Lys variant of the PACS2 gene. We conducted a literature review and found 29 cases to characterize the seizure patterns, neuroimaging features, the usage of anticonvulsants, and the clinical neurodevelopmental outcomes of PACS2-related EIDEE. The seizures were characterized by brief, recurring tonic seizures in the upper limbs, sometimes accompanied by autonomic features. Neuroimaging abnormalities were observed in the posterior fossa region, including mega cisterna magna, cerebellar dysplasia, and vermian hypoplasia. The long-term prognosis ranges from low-average intelligence to severe developmental retardation, emphasizing the importance of early recognition and accurate diagnosis by pediatric neurologists to provide personalized patient management.

Convulsion in Children with Down syndrome at Benghazi Children Hospital (2020-2021)

Introduction: Down syndrome (DS) (trisomy 21) is the most frequent chromosomal cause of mental retardation, with a frequency rate of about 1 in 700 births. The prevalence of epilepsy in subjects with DS is reported to range from 1% to 13%, higher than in the general population but lower than in patients with mental retardation. Aim: To find the prevalence of convulsion in Down syndrome patients attending pediatric hospital at Benghazi and to find the associated factors related to convulsion in Down syndrome patients. Methodology: cross –sectional study included all Down syndrome patients admitted to pediatric hospital during two years period ( 2020- 2021) , and Patients attending both genetic and neurological clinics during the same years. Results: Total number of cases was 150; History of convulsion was positive in (18)12% of Down syndrome patients. Majority (89%) of patients had generalized tonic clonic, 5.5% had focal convulsion, and 5.5 % had infantile spasm, all patients were in treatment and had good response. Males constitute to 61% of all patients with male to female ratio 1.6:1. Nearly half (50.4%) of male patients their age was 1- 5years, while 43.8% of females was in same age group. Majority of mothers age were > 32years, 88% of all mothers their age 30years or above. All patients with convulsion had no complication during delivery, while 9% of patients without convulsion had complications. More than half (61.5%) of the patients the convulsion started before the age of one year. Results of EEG were abnormal in 25% of patients with convulsion. Conclusion: Normal ECHO was found in 33% of all cases, Atrial septal defect was recorded in 27% of patients with convulsion and 19.5% of patients without convulsion, Ventricular septal defect and Atrial septal defect in 15.4% of patients with convulsion and 10.3% of patients without convulsion, Patent ductus arterious was in 11.5% of patients with convulsion and 3.2%of patients without convulsion. More than .........

The fascinating phenotypic spectrum of SCN1A gain-of-function epilepsies.

The fascinating phenotypic spectrum of SCN1A gain-of-function epilepsies.

The Effect of Smartphone Video on Lead Time to Diagnosis of Infantile Spasms

To assess whether access to smartphone video capture of infantile spasms at initial presentation is associated with improved time to diagnosis and treatment. We conducted a collaborative retrospective cohort study of 80 consecutive infants with confirmed infantile epileptic spasms syndrome initially presenting from 2015 to 2021 at 2 US pediatric centers. Statistical methods used included Mann-Whitney U test to assess the difference in lead times to electroencephalogram (EEG), diagnosis, and treatment between groups with and without video capture. A χ2 analysis was used to assess differences in demographics, clinical characteristics, and treatment outcomes between groups. Multivariate regression analysis was used to account for etiology types and infantile spasms capture on EEG. Patients with smartphone video infantile spasms capture initially presented a median of 9days earlier (P=.02), had their first EEG 16days earlier (P=.007), and were diagnosed and started treatment 17days earlier (P=.006 and P=.008, respectively) compared with the nonvideo group. The video group had a 25% greater response to initial standard treatment (P=.02) and a 21% greater freedom from infantile spasms at long-term follow-up (P=.03), although this long-term outcome lost statistical significance after adjustment for etiology type (P=.07) and EEG capture of infantile spasms (P=.059). Our findings suggest a benefit of smartphone video capture of infantile spasms in reduced time to diagnosis and initial standard treatment, which are associated with improved treatment response rates. Substantial differences in lead times and treatment response highlight the clinical importance of pediatricians recommending caregivers to obtain smartphone video of events concerning for infantile spasms.

Epilepsy Phenotypes of Vitamin B6-Dependent Diseases: An Updated Systematic Review

Vitamin B6-dependent epilepsies include treatable diseases responding to pyridoxine or pyridoxal-5Iphosphate (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects). We conducted a systematic review of published pediatric cases with a confirmed molecular genetic diagnosis of vitamin B6-dependent epilepsy according to PRISMA guidelines. Data on demographic features, seizure semiology, EEG patterns, neuroimaging, treatment, and developmental outcomes were collected. 497 published patients fulfilled the inclusion criteria. Seizure onset manifested at 59.8 ± 291.6 days (67.8% of cases in the first month of life). Clonic, tonic-clonic, and myoclonic seizures accounted for two-thirds of the cases, while epileptic spasms were observed in 7.6%. Burst-suppression/suppression-burst represented the most frequently reported specific EEG pattern (14.4%), mainly in PLPB, ALDH7A1, and PNPO deficiency. Pyridoxine was administered to 312 patients (18.5% intravenously, 76.9% orally, 4.6% not specified), and 180 also received antiseizure medications. Pyridoxine dosage ranged between 1 and 55 mg/kg/die. Complete seizure freedom was achieved in 160 patients, while a significant seizure reduction occurred in 38. PLP, lysine-restricted diet, and arginine supplementation were used in a small proportion of patients with variable efficacy. Global developmental delay was established in 30.5% of a few patients in whom neurocognitive tests were performed. Despite the wide variability, the most frequent hallmarks of the epilepsy phenotype in patients with vitamin B6-dependent seizures include generalized or focal motor seizure semiology and a burst suppression/suppression burst pattern in EEG.

Efficacy of vigabatrin in the treatment of infantile epileptic spasms syndrome: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to evaluate the efficacy of vigabatrin (VGB) in treating infantile epileptic spasms syndrome (IESS). Databases of PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library were systematically searched. All the relevant randomized controlled trials (RCTs) and observational studies (OSs) of VGB for IESS were included and analyzed separately. The primary outcome was the cessation of epileptic spasms (ES). Five RCTs and nine OSs compared the efficacy of VGB vs hormonal monotherapy for IESS. Meta-analysis of the five RCTs showed that hormonal monotherapy was significantly better than VGB monotherapy (OR=0.37, 95% CI=0.20-0.67) for patients with new-onset IESS. Meta-analysis of the nine OSs agrees with the result from RCTs (OR=0.61, 95% CI=0.43-0.85). VGB was more effective in patients with TSC than in those with other etiologies (five OSs, OR=5.59, 95% CI=2.17-14.41). There was no significant difference in the efficiency of VGB combined with hormonal therapy vs hormonal monotherapy for IESS (two RCTs, OR=0.75, 95% CI=0.09-6.45). Hormonal monotherapy is better than VGB monotherapy for non-TSC-associated IESS. But for patients with IESS due to TSC, VGB is the first choice. VGB combined with hormone therapy does not definitely increase ES control rates compared with that of hormonal monotherapy.

Biallelic variants of KCNQ2 in early infantile developmental and epileptic encephalopathy

Biallelic variants of KCNQ2 in early infantile developmental and epileptic encephalopathy

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk.

WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (WWOX-DEE), also known as WOREE (WWOX-related epileptic encephalopathy). We analyzed the epileptology and imaging features of WWOX-DEE, and investigated genotype-phenotype correlations, particularly with regard to survival. We studied 13 patients from 12 families with WWOX-DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense, allowing individuals to be classified into one of three genotype classes: (1) null/null, (2) null/missense, (3) missense/missense. Differences in survival outcome were estimated using the Kaplan-Meier method. All patients experienced multiple seizure types (median onset=5 weeks, range=1day-10months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic (n= 5), myoclonic (n= 2), epileptic spasms (n= 2), focal (n= 1), and migrating focal (n= 1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo-occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p-value=.0085, log-rank test). Biallelic WWOX pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.

Corticosteroids in childhood epilepsies: A systematic review.

Corticosteroids have been used for the treatment of patients with epilepsy for more than 6 decades, based on the hypothesis of inflammation in the genesis and/or promotion of epilepsy. We, therefore, aimed to provide a systematic overview of the use of corticosteroid regimes in childhood epilepsies in line with the PRISMA guidelines. We performed a structured literature search via PubMed and identified 160 papers with only three randomized controlled trials excluding the substantial trials on epileptic spasms. Corticosteroid regimes, duration of treatment (days to several months), and dosage protocols were highly variable in these studies. Evidence supports the use of steroids in epileptic spasms; however, there is only limited evidence for a positive effect for other epilepsy syndromes, e.g., epileptic encephalopathy with spike-and-wave activity in sleep [(D)EE-SWAS] or drug-resistant epilepsies (DREs). In (D)EE-SWAS (nine studies, 126 patients), 64% of patients showed an improvement either in the EEG or in their language/cognition following various steroid treatment regimes. In DRE (15 studies, 436 patients), a positive effect with a seizure reduction in 50% of pediatric and adult patients and seizure freedom in 15% was identified; however, no recommendation can be drawn due to the heterozygous cohort. This review highlights the immense need for controlled studies using steroids, especially in DRE, to offer patients new treatment options.

Re-appraisal of callosotomy: rates and predictors of short-term seizure outcome in pediatric epileptic encephalopathy

BackgroundEpilepsy is a chronic debilitating disease especially in pediatric population. Most of reported studies for corpus callosotomy as a palliative surgery in drug-resistant cases are on limited number of cases and there is scarcity in literature for outcomes reported from developing countries. Here, we present our study on a large series of cases with analysis of potential predicators outcomes in the era of more expensive devices like vagal nerve stimulation to give a litany on a universal epilepsy surgery procedure which had been missed in the literature through the last decade.ResultsAn observational retrospective study was done reviewing 129 patients with PEE underwent open microscopic corpus callosotomy. Total and drop attack seizure outcomes were studied after surgery. Potential outcomes predictors studied are: preoperative EEG and MRI. Preoperative IQ impairment epilepsy duration, age at diagnosis, MRI finding, IQ score, EEG findings, history of infantile spasm and extent of callosotomy done. All the recorded outcomes were substantially improved after callosotomy in our study population of 129 pediatric patients. The median (IQR) preoperative drop attack frequency was 70 (21–140) which decreased to 3 (0–14) postoperatively. Similarly, the number of anti-epileptics used by patients had a median of 3 (2–4) which decreased to 2 (2–3) after the surgery. All patients were experiencing status epilepticus which disappeared in 72% of the patients after callosotomy. Preoperative normal MRI was a predictor for drop attack favorable outcome and mild preoperative impairment of IQ was a predictor of favorable total seizure and drop attack outcome.ConclusionsCorpus callosotomy is a well-tolerated palliative procedure for drug-resistant generalized epilepsy notably, drop attacks which had its notorious effect on quality of life of pediatric patients and their families, no appreciable prognostic factors for favorable outcome were clearly observed except for normal preoperative MRI, mild preoperative IQ affection, and complete callosotomy.

Clinical phenotypic and genotypic characterization of NPRL3-related epilepsy

As one of the assembly factors of the GATOR1 protein complex in the mechanism of rapamycin pathway, NPRL3 plays an important role in the pathogenesis of epilepsy. However, the correlation between genotype and clinical phenotype in patients with NPRL3-related epilepsy has not been clarified. A total of 11 Chinese children with NPRL3-related epilepsy were identified through whole-exome sequencing (WES). The data from the clinical presentation, laboratory data, brain imaging findings, genetic results, and treatment methods were collected. All previously reported cases with NPRL3-related epilepsy were collected and reviewed through PubMed search. Among the 11 children, eight have not been reported, and two of them presented infantile spasms (ISs) as a new phenotype of NPRL3-related epilepsy. In addition, WES identified five frameshift mutations, three nonsense mutations, two missense mutations, and one exon deletion. Based on bioinformatics analysis, it was found that two missense mutation sites were highly conserved, and the c.400G>A mutation site of the NPRL3 gene caused the alteration of the protein structure. To date, 88 patients have been reported with NPRL3-related defects, including our 11 cases. The most common presentations were sleep-related hypermotor epilepsy (SHE), frontal lobe epilepsy (FLE), and temporal lobe epilepsy. A majority of patients (70%) presented normal neuroimaging results, and focal cortical dysplasia was the most common neuroimaging abnormality (62.5%). Among the NPRL3 gene mutations, loss of function (nonsense mutations, frameshift mutations, and exons deletion) was the most common genetic variation (75%). For 73% of patients with NPRL3-related epilepsy, monotherapy of sodium channel blockers was effective. Surgery was effective for 75% of children with neuroimaging abnormalities. Two cases unresponsive to surgery or anti-seizure medications were treated with ketogenic diets (KD), which were effective. One case was treated with rapamycin at an early stage of epilepsy, which was effective as well. NPRL3-related epilepsy has high clinical and genetic heterogeneity. SHE and FLE are the most common clinical presentations. Furthermore, ISs are the new phenotypes of NPRL3-related epilepsy, while the variants c.275G>A, c.745G>A, and c.1270C>T may be the most common NPRL3 gene mutations. Sodium channel blockers, surgery, KD, and rapamycin may be the potential treatments for these patients. Our study expanded the clinical and genetic spectrum of NPRL3-related epilepsy and provided important information for the precise treatment of patients.

Co-occurring conditions in children with Down syndrome and autism: a retrospective study

BackgroundDown syndrome (DS) is one of the most common genetic causes of intellectual disability, and it is associated with an increased incidence of numerous co-occurring conditions. Autism spectrum disorder (ASD) is common in persons with DS, with rates reported as high as 39%. However, little is known regarding co-occurring conditions in children with both DS and ASD.MethodsA single-center retrospective review of prospective longitudinally collected clinical data was performed. Any patient with a confirmed diagnosis of DS evaluated at a large, specialized Down Syndrome Program in a tertiary pediatric medical center between March 2018 and March 2022 was included. A standardized survey which included demographic and clinical questions was administered during each clinical evaluation.ResultsIn total, 562 individuals with DS were included. The median age was 10 years (IQR: 6.18–13.92). Of this group, 72 (13%) had a co-occurring diagnosis of ASD (DS+ASD). Individuals with DS+ASD were more likely to be male (OR 2.23, CI 1.29–3.84) and had higher odds of a current or prior diagnosis of constipation (OR 2.19, CI 1.31–3.65), gastroesophageal reflux (OR 1.91, CI 1.14–3.21), behavioral feeding difficulties (OR 2.71, CI 1.02–7.19), infantile spasms (OR 6.03, CI 1.79–20.34) and scoliosis (OR 2.73, CI 1.16–6.40). There were lower odds of congenital heart disease in the DS+ASD group (OR 0.56, CI 0.34–0.93). There was no observed difference in prematurity or Neonatal Intensive Care Unit complications between groups. Individuals with DS+ASD had similar odds of having a history of congenital heart defect requiring surgery to those with DS only. Furthermore, there was no difference in rates of autoimmune thyroiditis or celiac disease. There was also no difference in rates of diagnosed co-occurring neurodevelopmental or mental health conditions in this cohort, including anxiety disorders and attention-deficit/hyperactivity disorder.ConclusionsThis study identifies a variety of medical conditions which are more frequent in children with DS+ASD than DS alone, providing important information for the clinical management of these patients. Future research should investigate the role of some of these medical conditions in the development of ASD phenotypes, and whether there may be distinct genetic and metabolic contributions towards these conditions.

Clinical characteristics of children with infantile epileptic spasms syndrome from a tertiary-care hospital in Dhaka, Bangladesh

BackgroundWe describe patient characteristics and response to initial treatment in a large case series of children presenting with infantile epileptic spasms syndrome to a tertiary-care hospital with a pediatric neurology service in Bangladesh. The purpose of the study was to add to the growing body of literature on infantile epileptic spasms syndrome in low- and middle-income countries. MethodsWe enrolled 212 infants with new-onset infantile epileptic spasms syndrome (IESS) at the time of initial presentation to the National Institute of Neurosciences and Hospital (NINS) in Dhaka, Bangladesh, between January 2019 and August 2021. We collected data about seizure type and frequency, etiology, medication dosage, and available neuroimaging. ResultsMedian age at initial presentation to NINS was 9 months. Developmental delay and regression prior to presentation were found in 83% and 36%, respectively. Prior to their presentation at NINS, 197 (93%) patients had received anti-seizure medication to treat spasms, of whom only 8 (4%) had received standard therapy with ACTH, prednisolone, or vigabatrin. At NINS, 207 (98%) of patients received standard therapy, most frequently ACTH in 154 (73%). Median time between seizure onset to receipt of first-line therapy was 5 months. Of the 169 patients who were seen in follow-up at average of 5 weeks, 92 (54%) reported absence of clinical epileptic spasms. No serious adverse events requiring hospitalization were reported. ConclusionsThis study highlights the long lead times to treatment for IESS in a low- and middle-income country, and the need for early referral of children with suspected epileptic spasms to epilepsy care centers.

Response to magnesium sulfate and adrenocorticotropic hormone combination therapy for infantile spasms with failed first-line treatments.

Infantile spasm (IS) is a kind of refractory epilepsy. The first-line treatments for IS are adrenocorticotropic hormone (ACTH), oral corticosteroids, and vigabatrin. This study aimed to evaluate the efficacy of magnesium sulfate and ACTH (MgSO4+ACTH) combination therapy in patients with IS who failed first-line treatments. In this retrospective study, the clinical data of patients with IS who failed first-line treatments were collected in the Chinese PLA General Hospital. Patients received MgSO4+ACTH combination therapy after first-line treatments failed. The course of treatments was 2weeks. The therapeutic dose of ACTH and MgSO4 was 2.5 U·kg-1·d-1 and 0.25 g·kg-1·d-1, respectively. A total of 229 patients with IS who failed the first-line treatments were collected. At the end of the MgSO4+ACTH combination treatment, the seizure-free rate was 48.5% (111/229), and the resolution of hypsarrhythmia on electroencephalogram (EEG) was 72.1% (165/229). About 21.4% (49/229) of patients showed side effects, including infectious diseases, hypokalemia, and diarrhea. For patients with IS who failed first-line treatments, in terms of the seizure-free rate and resolution of hypsarrhythmia on EEG, MgSO4+ACTH combination therapy can be considered.

Cannabidiol Add-On in Glycosylphosphatidylinositol-Related Drug-Resistant Epilepsy.

Background: Glycosylphosphatidylinositol-anchored protein deficiencies (GPI-ADs) are commonly associated with drug-resistant epilepsy (DRE). Cannabidiol (CBD) is approved for the adjunctive treatment of seizures in Dravet/Lennox-Gastaut Syndromes and Tuberous Sclerosis Complex. We report on the efficacy and safety of CBD for the treatment of DRE in patients with genetically proven GPI-AD. Patients and Methods: Patients received add-on treatment with purified GW-pharma CBD (Epidyolex®). Efficacy endpoints were the percentage of patients with ≥50% (responders) or >25<50% (partial responders) reduction in monthly seizures from baseline and at 12 (M12) months of follow-up. Safety was evaluated through adverse events (AEs) monitoring. Results: Six patients (5 males) were enrolled. The median age at seizures onset was 5 months and the syndromic diagnosis was early infantile developmental and epileptic encephalopathy in 4 patients and focal non-lesional epilepsy or GEFS+ in one patient each. Five out of six (83%) patients were responders at M12, while one was a partial responder. No severe AEs were reported. Mean prescribed CBD dose was 17.85 mg/kg/day and median treatment duration is currently 27 months. Conclusions: In summary, off-label treatment with CBD was effective and safe in patients with DRE due to GPI-ADs.

A concise review on analytical profile of Vigabatrin

Vigabatrin (VGB) is a drug of Anticonvulsant class. It works by decreasing abnormal electrical activity in the brain. It inhibits the GABA-degrading enzyme i.e. GABA transaminase, it increases the GABA concentrations in the brain. Vigabatrin is used for the treatment of refractory complex partial seizures in adults and also used for children 2 years of age and older and infantile spasms in children. Vigabatrin was approved for anticonvulsant medication by USFDA on August 21, 2009. Therefore, in the present review article, we have enlisted different analytical method such as Ultraviolet (UV) visible spectroscopy, High-performance liquid chromatography (HPLC), Ultra-performance liquid chromatography (UPLC) and Gas Chromatography for both qualitative and quantitative analysis of VGB in pharmaceutical and biological. In the future, this review article will assist researchers regarding the development of a new analytical method for VGB.

Discriminating and understanding brain states in children with epileptic spasms using deep learning and graph metrics analysis of brain connectivity

Background and objectiveEpilepsy is a brain disorder consisting of abnormal electrical discharges of neurons resulting in epileptic seizures. The nature and spatial distribution of these electrical signals make epilepsy a field for the analysis of brain connectivity using artificial intelligence and network analysis techniques since their study requires large amounts of data over large spatial and temporal scales. For example, to discriminate states that would otherwise be indistinguishable from the human eye. This paper aims to identify the different brain states that appear concerning the intriguing seizure type of epileptic spasms. Once these states have been differentiated, an attempt is made to understand their corresponding brain activity. MethodsThe representation of brain connectivity can be done by graphing the topology and intensity of brain activations. Graph images from different instants within and outside the actual seizure are used as input to a deep learning model for classification purposes. This work uses convolutional neural networks to discriminate the different states of the epileptic brain based on the appearance of these graphs at different times. Next, we apply several graph metrics as an aid to interpret what happens in the brain regions during and around the seizure. ResultsResults show that the model consistently finds distinctive brain states in children with epilepsy with focal onset epileptic spasms that are indistinguishable under the expert visual inspection of EEG traces. Furthermore, differences are found in brain connectivity and network measures in each of the different states. ConclusionsComputer-assisted discrimination using this model can detect subtle differences in the various brain states of children with epileptic spasms. The research reveals previously undisclosed information regarding brain connectivity and networks, allowing for a better understanding of the pathophysiology and evolving characteristics of this particular seizure type. From our data, we speculate that the prefrontal, premotor, and motor cortices could be more involved in a hypersynchronized state occurring in the few seconds immediately preceding the visually evident EEG and clinical ictal features of the first spasm in a cluster. On the other hand, a disconnection in centro-parietal areas seems a relevant feature in the predisposition and repetitive generation of epileptic spasms within clusters.

Long-Term Outcome of Adrenocorticotropic Hormone Therapy in Children With New-Onset Infantile Spasms

BackgroundTo investigate for pretreatment clinical variables to predict the outcome of new-onset epileptic spasms after adrenocorticotropic hormone (ACTH) therapy and to identify risk factors for poor long-term outcome. MethodsWe retrospectively studied 129 consecutive patients with infantile spasms syndrome (ISS). These patients received ACTH with antiseizure medication therapy for the first time and were regularly followed up for more than six months at our hospital. The response to treatment was assessed after two weeks of ACTH injection. Kaplan-Meier survival analysis and the multivariate Cox proportional hazard regression model were used. ResultsAmong the 129 patients, 61 (47.3%) had a good response after two weeks of ACTH treatment. At the time of the latest follow-up, 71 (55%) patients were seizure-free (International League Against Epilepsy class1). The univariate analysis revealed that normal neurodevelopment (P = 0.018), time lag of less than one month (P = 0.026), no hypsarrhythmia on EEG (P = 0.004), and serum calcium level ≥2.50 mmol/L (P = 0.035) were significantly associated with a good response. Only a good response to ACTH therapy was significantly associated with a positive long-term outcome. The Kaplan-Meier survival analysis showed that serum calcium level ≧2.50 mmol/L was significantly associated with a positive long-term outcome (P = 0.030). Multivariate analysis confirmed that no response to ACTH therapy was an independent variable that predicted long-term seizure recurrence (P < 0.001, hazard ratio = 4.602, confidence interval = 2.252 to 9.406). ConclusionsA good response to ACTH therapy had a significant predictive value for long-term seizure outcomes. Calcium may play an important role in the treatment of ISS with ACTH.

Infantile Spasms without Hypsarrhythmia and Paroxysmal Eye-Head Movements in an Infant with a Pyridoxine-Dependent Epilepsy due to PLPBP/PLPHP Deficiency.

To describe a new phenotype and the diagnostic workup of a vitamin-B6-dependent epilepsy due to pyridoxal 5'-phosphate-binding protein (PLPBP) deficiency in an infant with early-onset epilepsy at the age of 5 years 6 months. Following immediate and impressive clinical response to treatment with pyridoxine, metabolic screening for vitamin-B6-dependent epilepsies and targeted next-generation sequencing (NGS)-based gene panel analysis were performed. Potentially pathogenic variants were confirmed by Sanger sequencing in the patient, and variants were analyzed in both parents to confirm biallelic inheritance. The clinical phenotype and course of disease were compared to the 44 cases reported in the literature, harboring variants in pyridoxal phosphate homeostasis protein (PLPHP) and with cases of vitamin-B6-dependent epilepsy due to other known causative genes. Levels of alpha-aminoadipic semialdehyde in urine and amino acids were normal. Two inherited pathogenic variations in PLPHP were found in compound heterozygosity, including one novel deletion. We here describe a previously unreported individual harboring biallelic pathogenic PLPHP variants presenting with paroxysmal eye-head movements followed by epileptic spasms and an almost normal interictal electroencephalogram, thus expanding the clinical spectrum of PLPBP deficiency. This warrants consideration of vitamin-B6-dependent epilepsies in patients with early-onset epilepsy, including epileptic spasms, and eye movement disorders also beyond the neonatal period even when metabolic screening for vitamin-B6-dependent epilepsies is negative. PLPHP should be included systematically in NGS epilepsy gene panels.

De novo variants in MAST4 related to neurodevelopmental disorders with developmental delay and infantile spasms: Genotype-phenotype association.

This study aims to prove that the de novo variants in MAST4 gene are associated with neurodevelopmental disorders (NDD) with developmental delay (DD) and infantile spasm (IS) and to determine the genotype-phenotype correlations. Trio-based exome sequencing (ES) was performed on the four families enrolled in this study. We collected and systematically reviewed the four probands' clinical data, magnetic resonance images (MRI), and electroencephalography (EEG). We also carried out bioinformatics analysis by integrating published exome/genome sequencing data and human brain transcriptomic data. We described four patients whose median age of seizure onset was 5 months. The primary manifestation was infantile spasms with typical hypsarrhythmia on EEG. Developmental delays or intellectual disabilities varied among the four individuals. Three de novo missense variants in MAST4 gene were identified from four families, including chr5:66438324 (c.2693T > C: p.Ile898Thr) z, chr5:66459419 (c.4412C > T: p.Thr1471Ile), and chr5:66462662 (c.7655C > G:p.Ser2552Trp). The missense variant p.Ile898Thr is mapped to the AGC-kinase C-terminal with phosphatase activity. The other variant p.Ser2552Trp is located in a phosphoserine-modified residue which may affect cell membrane stability and signal transduction. Besides, the variant p.Thr1471Ile is a recurrent site screened out in two unrelated patients. Compared to private mutations (found only in a single family or a small population) of MAST4 in the gnomAD non-neuro subset, all de novo variants were predicted to be damaging or probably damaging through different bioinformatic analyses. Significantly higher CADD scores of the variant p.Thr1471Ile indicate more deleteriousness of the recurrent site. And the affected amino acids are highly conserved across multiple species. According to the Brainspan Atlas database, MAST4 is expressed primarily in the mediodorsal nucleus of the thalamus and medial prefrontal cortex during the prenatal period, potentially contributing to embryonic brain development. Our results revealed that the variants of MAST4 gene might lead to neurodevelopmental disorders with developmental delay and infantile spasm. Thus, MAST4 variants should be considered the potential candidate gene in patients with neurodevelopmental disorders clinically marked by infantile spasms.