Generalized Epileptiform Discharges Research Articles

Clinical and Molecular Characteristics of Neuronal Ceroid Lipofuscinosis in Saudi Arabia

BackgroundNeuronal ceroid lipofuscinoses (NCLs) represent a heterogeneous group of inherited metabolic lysosomal disorders characterized by neurodegeneration. This study sought to describe the clinical and molecular characteristics of NCLs in Saudi Arabia and determine the most common types in that population. MethodsA retrospective review of electronic medical records was conducted for 63 patients with NCL (55 families) from six tertiary and referral centers in Saudi Arabia between 2008 and 2022. Clinical, radiological, and neurophysiological data as well as genetic diagnoses were reviewed. ResultsCLN6 was the predominant type, accounting for 45% of cases in 25 families. The most common initial symptoms were speech delay (53%), cognitive decline (50%) and/or gait abnormalities (48%), and seizure (40%). Behavioral symptomatology was observed in 20%, whereas visual impairment was less frequently (9.3%) encountered. Diffuse cerebral and cerebellar atrophy was the predominant finding on brain magnetic resonance imaging. Electroencephalography generally revealed background slowing in all patients with generalized epileptiform discharges in 60%. The most common genotype detected was the p.Ser265del variant found in 36% (20 of 55 families). The most rapidly progressive subtypes were CLN2 and CLN6. Two patients with each died at age five years. The earliest age at which a patient was nonambulatory was two years in a patient with CLN14. ConclusionsThis is the largest molecularly confirmed NCL cohort study from Saudi Arabia. Characterizing the natural history of specific NLC types can increase understanding of the underlying pathophysiology and distinctive genotype-phenotype characteristics, facilitating early diagnosis and treatment initiation as well as genetic counseling for families.

Etiological and risk factors in recurrent febrile seizures: Insights through EEG analysis.

Febrile seizures, convulsive episodes in young children during febrile illnesses, are a significant concern due to their potential for recurrence and associated uncertainties. This study investigated the causes and risks associated with recurrent febrile seizures and the critical role of electroencephalogram (EEG) in their accurate diagnosis. Following Institutional Review Board approval and going through the consenting process with parents, this study gathered the clinical features and EEG recordings of children admitted with febrile seizures in the Department of Pediatrics, Mahatma Gandhi Memorial Hospital, Kakatiya Medical College, Warangal, Telangana, India. Descriptive statistics, including mean, standard deviation (SD), frequencies, and percentages, were computed to understand the data comprehensively. The Chi-Square test was employed to analyze the association between variables, with a significance level of 0.05, ensuring reliable and trustworthy findings. Out of 42 children studied, 28 (66.67%) presented with simple febrile seizures, with the mean time of occurrence of seizures from the onset of fever being 7.85 hours. Abnormal EEG was seen in 50% of children with complex febrile seizures and 16% with simple febrile seizures. Generalized epileptiform discharges were the most common epileptic activity observed. Low sodium levels had a significant relationship with febrile seizures in the analysis. This study emphasizes the importance of EEG in diagnosing febrile seizures, particularly in complex cases. Our findings suggest that low sodium levels may be a significant risk factor for febrile seizures. Further research is necessary to identify other preventable risk factors to reduce the burden of the medical condition.

Association of Epileptiform Discharge and Autism Spectrum Disorder Severity in Children Attending the Outpatient Clinics, Child Welfare Teaching Hospital, Baghdad

Background: Subjects with Autism Spectrum Disorder (ASD) have a higher prevalence of seizures than the general population, according to a significant body of research. Also, seizure-free patients with ASD have been found to have a higher prevalence of epileptiform discharge abnormalities compared to healthy controls across investigations. Changes in the electroencephalogram (EEG) can manifest as sharp waves or spikes, sharp and slow waves, generally distributed or general area, or focused, and can manifest in various brain regions. There is a necessity to search for a distinctive EEG characteristic in ASD patients. Objectives: This study used electroencephalography to investigate the relationship between interictal epileptiform discharges and the severity of ASD in children. Patient and methods: The study involved a total of 65 children. The first group consisted of 30 children (seven females and 23 males, 2-12 years of age) recruited from the autism center and the pediatric neurology consultancy clinic in the Child Welfare Teaching Hospital / Medical City. The second group consisted of 35 age- and gender-matched normally-developed children (10 females 25 males, 2-12 years of age) recruited from the Pediatrics Consultation Clinics in the Child Welfare Teaching Hospital. The ASD children met the DSM-5 criteria for autism and the Childhood Autism Rating Scale was utilized to determine the severity of autism. The electroencephalography signals were recorded to detect epileptiform discharge. The data was collected during the period from 5th October 2022 to 1st April 2023. Result: A statistically significant association was found between the epileptiform discharges and the study group (ASD Vs normally developed children). The EEG records were normal in 20 (66.7%), abnormal in the form of focal epileptiform discharge in 5 (16.7%), and in the form of generalized epileptiform discharge in 5 (16.7%) of ASD children. The EEG findings and the CARS-measured autism severity showed a statistically significant association (P=0.05), as the EEG abnormalities increased with the severity of autism. Conclusion: The degree of autism was found to be associated with the abnormalities of the electroencephalogram and the degree of autism. Received: May,, 2023 Accepted: Sept, 2023 Published: Jan. 2024

Sleep quality and depression in mothers of children with epilepsy and its relation to their children’s sleep

ObjectiveThis study aimed to evaluate the relationship between sleep disturbances in children with epilepsy (CWE) and maternal sleep quality and depression severity. MethodsA Cross-sectional study was conducted in pediatric sleep disturbances using questionnaires on mother-reported sleep of CWE [Children's Sleep Habits Questionnaire (CSHQ)], maternal sleep quality [Pittsburgh Sleep Quality Index (PSQI)], and maternal depression status [Self-Rating Depression Scale (SDS)]. 114 dyads consisting of CWE and their mothers were included in this study. ResultsOver three-quarters (78.9 %) of mothers reported poor sleep quality (total PSQI score ≥ 5), and nearly a third (29.8 %) met clinical criteria for moderate or severe depression levels. The mothers' total PSQI scores were between 5.93 ± 2.44 (range: 2–16 points). The most affected PSQI subcomponents were sleep latency (AUC = 0.826p < 0.001) and daytime dysfunction (AUC = 0.800p < 0.001). The majority of children (88.6 %) were stated by their mothers to have sleep-related problems. The total CSHQ scores of the children were between 49.06 ± 9.20 (range: 33–86 points). The most affected CSHQ subcomponents were detected sleep anxiety (AUC = 0.856, p < 0.001), bedtime resistance (AUC = 0.818, p < 0.001) and daytime sleepiness (AUC = 0.807, p < 0.001). There was a statistically significant positive correlation between maternal sleep quality and depression severity (rho = 0.842; p < 0.001). A statistically significant positive moderate correlation was detected between sleep problems in CWE and maternal sleep quality and depression severity (rho = 0.406; p < 0.001, rho = 0.399; p < 0.001, respectively). As a result of multiple stepwise logistic regression analysis, the presence of seizures during sleep and generalized epileptiform discharges on electroencephalography were associated risk factors with poor maternal sleep quality (OR:6.6, p = 0.014; OR:11.5, p = 0.018, respectively). A borderline insignificant relationship was observed between a less than 50 % decrease in seizure frequency and the poor maternal sleep quality (OR:20.59p = 0.059). Seizures during sleep was associated risk factor with children's sleep disturbances (OR:7.2, p = 0.02). ConclusionsSleep problems in CWE may lead to negative consequences such as sleep quality and/or depression in mothers. Interventions planned to correct sleep disturbances in mothers suggest that children's sleep problems should be optimally managed.

Heterozygous RELN missense variants associated with genetic generalized epilepsy

PurposeThe RELN gene encodes the secreted glycoprotein Reelin and has important functions in both developing and adult brains. In this study, we aimed to explore the association between the RELN and genetic generalized epilepsy (GGE). MethodsWe performed whole-exome sequencing on a cohort of 92 patients with GGE. Based on amino acid sequence alignments, allele frequency, pedigree validation and computational modeling, the RELN variants were identified and clinical features of cases were summarized. Cell-based Reelin secretion assays were examined by Western blotting. Alterations of mutant Reelin transport through the secretion pathway were detected by immunofluorescence staining. ResultsThree novel pathogenic RELN variants (3.26%; c.2260C>T/p.R754W, c.2914C>G/p.P972A and c.3029G>A/p.R1010H) were identified. All probands showed adolescence-onset generalized seizures characterized by generalized epileptiform discharges with normal EEG backgrounds, no or mild cognitive impairment, and responded well to anti-seizure medications. All these variants were located in the central regions from 1B to 2A consecutive repeats, and protein modeling demonstrated structural alterations in Reelin. Moreover, we found that these heterozygous missense variants significantly decreased the secretion of mutant proteins in HEK-293T cells, and this impairment was due to the altered transport of mutant Reelin in the secretion pathway. ConclusionThese results suggest that RELN is potentially associated with GGE. The phenotype of GGE caused by RELN variants is relatively mild, and the pathogenic mechanism may involve a loss-of-function.

Risk of Recurrence in Patients with an Unprovoked Tonic-Clonic Seizure and Generalized Epileptiform Discharges on EEG.

The decision to initiate treatment in patients with a first unprovoked seizure remains controversial. Studies have reported a recurrence rate ranging from 21-50%, but most have included patients with different etiologies, EEG findings, and seizure types. This study aimed to determine the risk of recurrence in patients with a first unprovoked generalized tonic-clonic (GTC) seizure with evidence of generalized spike-wave discharges (GSWD) on EEG and compare the efficacy of antiseizure medications (ASM) in preventing recurrence. This prospective study included consecutive patients who presented with a single GTC seizure, evidence of GSWD on EEG, and a follow-up period of at least one year. All patients underwent extensive evaluation, including a 3-hour sleep-deprived video-EEG recording and an epilepsy protocol brain MRI. Treatment with ASM was recommended for all patients. The decision regarding the specific ASM to be used was left to the treating physician's discretion. A total of 57 patients with a median age of 19 years were included. A total of 41 patients agreed to be started on an ASM while 16 declined. Seizure recurred in 6/41 (14.6%) patients in the treated group compared to 11/16 (68.8%) in the untreated group (P = 0.00006). Valproate was significantly more efficacious than levetiracetam or lamotrigine (P = 0.04). Of the 15 patients who discontinued ASM treatment after remaining seizure free for an average of 30 months, 6 (40%) experienced a seizure recurrence. Patients with a first unprovoked GTC seizure and evidence of GSWD on EEG have a high risk of recurrence if left untreated. Valproate is the most efficacious ASD for preventing recurrence in this population. A sizeable proportion of patients can be successfully tapered off medication after a period of seizure freedom. This study provides valuable information for guiding treatment decisions in this patient population.

Seizures in Neurosarcoidosis (P9-5.011)

<h3>Objective:</h3> To determine how seizures impact the management of neurosarcoidosis and affect long-term outcomes. <h3>Background:</h3> Though neurosarcoidosis can injure the cerebral cortex via several mechanisms, seizures are uncommonly reported as a clinical manifestation of the disease (4–15%) and have been previously associated with a more severe course. <h3>Design/Methods:</h3> Patients with a diagnosis of neurosarcoidosis were included in this retrospective cohort analysis if seizures were a clinical manifestation of their disease. <h3>Results:</h3> Seizures were present in 26/216 (12.0%) patients and were an initial manifestation of neurosarcoidosis in 11/26 (42.3%). None had a pre-existing seizure disorder. Semiologies were reported in 23: generalized in 12/23 (52.2%), focal in 9/23 (39.1%), and both in 2/23 (8.7%). Status epilepticus occurred in 6/26 (23.1%); 2 (7.7%) were intubated. MRIs were obtained in 25 with cerebral parenchymal lesions (18/25, 72.0%) being the most common radiographic accompaniment, followed by leptomeningitis (13/25, 52.0%) and pachymeningitis (10/25, 40.0%). EEGs showed focal slowing in 12/19 (63.1%), focal epileptiform discharges in 5/19 (26.3%), no abnormalities in 4/19 (21.1%), generalized slowing in 2/19 (10.5%), and epileptiform discharges of unclear distribution in 1/19 (5.3%). No patients had generalized epileptiform discharges. Seizures were controlled in 22/26 (84.6%) compliant with antiseizure medicines (ASMs). Most (18/26, 69.2%) required only 1 medicine for control with levetiracetam being beneficial in 22/22 (100%) trialed. 17/25 (68.0%) had 6 or fewer lifetime seizures. 2/26 (7.7%) were ultimately weaned off ASMs. 13/26 (50.0%) required two or more lines of immunosuppression, all of whom received biologic treatments. The average last mRS was 2.0. No patients died as a result of seizures. Median follow-up of 68.4 months. <h3>Conclusions:</h3> Seizures in neurosarcoidosis occur most commonly with cerebral parenchymal lesions and are relatively easy to control with ASMs, but the accompanying neuroinflammation is often challenging to treat with a high reliance on biologic therapies for management. <b>Disclosure:</b> Dr. Ngo has nothing to disclose. Dr. Hutto has nothing to disclose.

A cross-sectional investigation of cognition and epileptiform discharges in juvenile absence epilepsy.

Despite the prevalence of cognitive symptoms in the idiopathic generalized epilepsies (IGEs), cognitive dysfunction in juvenile absence epilepsy (JAE), a common yet understudied IGE subtype, remains poorly understood. This descriptive study provides a novel, comprehensive characterization of cognitive functioning in a JAE sample and examines the relationship between cognition and 24-h epileptiform discharge load. Forty-four individuals diagnosed with JAE underwent cognitive assessment using Woodcock Johnson III Test of Cognitive Abilities with concurrent 24-h ambulatory EEG monitoring. Generalized epileptiform discharges of any length, and prolonged generalized discharges ≥3s were quantified across wakefulness and sleep. The relationship between standardized cognitive scores and epileptiform discharges was assessed through regression models. Cognitive performances in overall intellectual ability, acquired comprehension-knowledge, processing speed, long-term memory storage and retrieval, and executive processes were 0.63-1.07 standard deviation (SD) units lower in the JAE group compared to the population reference mean, adjusted for educational attainment. Prolonged discharges (≥3s) were recorded in 20 patients (47.6%) from 42 available electroencephalography (EEG) studies and were largely unreported. Duration and number of prolonged discharges were associated with reduced processing speed and long-term memory storage and retrieval. Cognitive dysfunction is seen in patients with JAE across various cognitive abilities, including those representing more stable processes like general intellect. During 24-h EEG, prolonged epileptiform discharges are common yet underreported in JAE despite treatment, and they show moderate effects on cognitive abilities. If epileptiform burden is a modifiable predictor of cognitive dysfunction, therapeutic interventions should consider quantitative 24-h EEG with routine neuropsychological screening. The growing recognition of the spectrum of neuropsychological comorbidities of IGE highlights the value of multidisciplinary approaches to explore the causes and consequences of cognitive deficits in epilepsy.

Phenotypes of a female patient with novel de novo frameshift ARX variant identified by whole-exome sequencing: a case report.

A 2-year-old girl with frequent seizures, global developmental delay, and autistic features was referred to our hospital. She was the second child of consanguineous non-affected parents. She had a high forehead, mildly prominent ears, and prominent nasal root. A generalized epileptiform discharge was noted in her electroencephalography. Brain MRI revealed corpus callosum agenesis, cerebral atrophy, and a left parafalcine cyst. The WES result showed a likely pathogenic variant identified as a novel de novo deletion in exon 4 of the ARX gene, which creates a frameshift variant. The patient is on dual therapy of antiepilepsy drugs, physiotherapy, speech therapy, occupational therapy, and oral motor exercises. Variants in the ARX gene can result in various phenotypes in males transmitted from asymptomatic carrier females. However, several reports showed that the ARX variants might cause phenotypes in females with milder symptoms than affected males. We report a novel de novo ARX variant in an affected female with a NDD. Our study confirms that the ARX variant might cause remarkable pleiotropy phenotypes in females. Moreover, WES could help to identify the pathogenic variant in NDD patients with diverse phenotypes.

The diagnostic value of electroencephalography in pediatric patients presenting with syncope Running title: The yield of electroencephalography in pediatric syncope

Aim: In the investigation of the diagnosis of pediatric syncope, it was aimed to evaluate the rate of abnormal EEG findings and the diagnostic yield of the EEG in the electroencephalography (EEG) taken following their neurological examination. Materials and Methods: EEG records of 332 patients younger than 18 years of age who presented to the pediatric neurology outpatient clinic with syncope were retrospectively analyzed. The EEG results were classified as normal and abnormal. Based on the abnormal EEG results, four subgroups were formed as focal epileptiform discharge, generalized epileptiform discharge, focal slowing and generalized slowing. Abnormal EEG results were categorized according to age and gender. Results: Of the cases included in the study, 195 (58.7%) were female and 137 (41.3%) were male. The mean age of the patients was calculated as 12.67±3.21 years. Analysis of the EEG results revealed that 92.5% were normal and 7.53% were abnormal. The most common abnormal EEG finding was focal slowing, which was detected in 12 (3.6%) patients, followed by focal epileptiform discharge which was detected in eight (2.4%) and generalized epileptiform discharge which was detected in five (1.5%) patients. Conclusion: EEG should not be routinely performed to evaluate the diagnosis of pediatric syncope. Therefore, EEG should be performed only on patients to be selected based on their medical history and the results of their neurological examination. In this way, it will be possible to derive more benefits out of EEG and to reduce the associated medical costs.

Risk of Developing Seizures in Children With Abnormal EEG Findings During Polysomnography

BackgroundPolysomnography (PSG) utilizes abbreviated electroencephalogram (EEG) to stage sleep. The aim of this study was to determine whether epileptiform abnormalities on this limited EEG coverage correlated with abnormalities on routine EEG (rEEG) and an increased risk for seizures in children without a prior diagnosis of epilepsy. MethodsA six-year retrospective chart review was performed assessing children with abnormalities on EEG during PSG. Children who underwent subsequent rEEG were included; children with a prior diagnosis of seizures were excluded. The main outcome measures were rEEG results and subsequent diagnosis of epilepsy. ResultsA total of 67 children met inclusion criteria. Average age was six years, and 43 (64%) were male. rEEG was normal in 16 (24%). Epileptiform abnormalities were focal in 36 (54%), generalized in eight (12%), and mixed in five (8%). An additional two (3%) had slow background rhythm without epileptiform discharges. Thirty-one patients had neurology clinic follow-up with an average duration of 31 months (range 4 to 65 months). Of these, nine (29%) developed seizures, including all three with generalized epileptiform discharges, four of 19 (21%) with focal epileptiform discharges, and two of five (40%) with mixed epileptiform discharges or background slowing. None of the four patients with a normal rEEG had seizures. Eight of the nine patients with seizures were treated with antiepileptic drugs. ConclusionsChildren with no history of seizures found to have abnormal EEG during PSG are likely to have an abnormal rEEG. Additionally, they have an increased risk for developing seizures.

Development of localized interictal epileptiform discharges following vagus nerve stimulation for lennox-gastaut syndrome: a case report

BackgroundLennox-gastaut syndrome (LGS) is an epileptic encephalopathy often associated with behavioral and psychiatric disorders. Vagus nerve stimulation (VNS) has been approved effective for LGS treatment. Surgical resection is also an option for LGS patients with focal pathology, offering a high probability of seizure control. However, it is challenging to accurately localize the seizure focus.Case presentationThe case presented here is a 19-year-old male with a 16-year history of epilepsy with comorbid severe cognitive and psychiatric disorders. He was diagnosed with LGS due to generalized slow spike-wave discharges and multiple seizure types. He was treated with VNS in 2017 at the age of 15. After that, the frequency of the short tonic seizures decreased from 4–5 times per day to 2–5 times per year, and the generalized tonic–clonic seizure pattern did not recur, which had a frequency of 2–4 times per month before the surgery. In 2019, the generalized abnormal interictal epileptiform discharges changed to be localized in the right frontal–temporal lobe at the age of 17 years (2019).ConclusionsThis case report suggested that the generalized epileptiform discharges evolve into localized discharges after VNS treatment, which may help reveal the primary seizure focus for resection surgery in patients with LGS.

Childhood Absence Epilepsy Associated With Concomitant Centrotemporal Spikes.

ObjectivesThe coexistence of generalized epileptiform discharges of 3Hz spike-and-wave complexes, which are the hallmark of childhood absence epilepsy (CAE), and centrotemporal spikes, which are characteristic of benign epilepsy with centrotemporal spikes (BECTs) in the same or subsequent EEGs appears to be very rare. Only a few published reports have shown a possible concomitance of CAE and BECTs electrographic changes. The study aimed to analyze electrographic and clinical features of patients with CAE who had concomitant or subsequent EEG features of BECTs.MethodDuring a five-year analysis period (2014-2018), 277 children with BECTs and 93 children with CAE were diagnosed and treated at the pediatric neurology unit of Sultan Qaboos University Hospital (SQUH) in Muscat, Oman. Nine patients were identified to have overlapping EEG findings of both epileptic syndromes. We then analyzed the nine children's clinical features, outcomes, and EEG findings in detail.ResultsThe clinical onset of all our patients aged 5-14 years (six boys, three girls) was characterized by the absence of seizures, either typical (seven children) or atypical (two children). Six out of nine patients presented with concomitant electrographic features of both syndromes, whereas three patients experienced the EEG pattern of two syndromes at different times. All nine children were treated with valproate as the first-line medication, with reasonable seizure control. However, three patients required a second add-on medication. Despite good seizure control, six of our patients had poor school performance and five children had comorbid conditions such as ADHD and learning disability.ConclusionThe coexistence of CAE and BECTS is described in the literature albeit rare. This overlap is mostly in electrographic features with or without the clinical features seen in both syndromes.

New-Onset Seizures as an Acute Presentation With Atypical EEG Findings in a Previously Healthy Child With Asymptomatic COVID-19 Infection

Coronavirus disease 2019 (COVID-19) infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This infection usually presents with upper respiratory symptoms; however, it can also present with a wide variety of other multisystem and neurological symptoms, including seizures. There are several proposed mechanisms by which COVID-19 can cause systemic signs of infections, including neurological complications and seizures.This case report describes a pediatric patient without a previously documented history of epilepsy who was admitted for new-onset focal seizures with impaired consciousness. No other cause and triggers of seizures were found, and the child was tested positive for COVID-19 infection. The patient had six electroclinical seizures during EEG. Video EEG findings showed atypical features of onset of intermittent rhythmic delta activity (IRDA) slowing over the left hemisphere with evolution/generalization of rhythmic delta/theta activity and without clear typical generalized epileptiform discharges. These EEG findings correlated with a clinical change of behavior arrest, staring, and yawning. Similar spells were reported multiple times a day prior to the admission, and past EEG was normal. A review of current literature on COVID-19 and neurological manifestations in children, including new seizures and prior diagnosis of epilepsy, is also provided in this case report.The clinical experience in children with newly diagnosed or chronic epilepsy suggests that exacerbation of seizures, especially from systemic effects such as those caused by severe COVID-19 infection, will be a major concern.

Etiology and prognostic significance of ictal EEG patterns in patients with non-convulsive seizures.

We aimed to study the ictal EEG patterns in patients with non-convulsive seizures (NCS) and their relationship with underlying etiology and patient outcome. We conducted a retrospective review of EEG studies from patients undergoing continuous EEG (cEEG) monitoring for indication of altered mental status with a suspicion of NCS. Ictal EEG findings of NCS were categorized as three patterns: focal or generalized epileptiform discharges (EDs) at frequencies >2.5Hz (Pattern 1); EDs at frequencies of ≤2.5Hz or rhythmic activity >0.5Hz with spatiotemporal evolution (Pattern 2); and EDs with ≤2.5Hz with subtle clinical correlate during the ictal EEG or clinical and EEG improvement after a trial of IV anti-seizure drugs (Pattern 3). Patients with anoxic brain injury were excluded from the study. Associations between ictal EEG patterns and underlying etiology and their impact on in-hospital mortality was measured. Of 487 patients included in the study, NCS was recorded on cEEG monitoring in 57 (12%). The ictal EEG Pattern 2 was the most commonly seen ictal EEG finding in our cohort of patients with NCS (70%, n=40/57), followed by Pattern 3 (15%, n=9/57) and Pattern 1(14%, n=8/57). In patients with acute brain injury, Pattern 2 (67%, n=27/40) was a commonly seen ictal EEG finding, whereas Pattern 1 (62% n=5/8) was seen in patients with underlying acute medical illness. No statistically significant difference was found between ictal EEG patterns and underlying neurological versus medical etiologies (p=0.27) or in-hospital mortality (p=0.5). Spatiotemporal evolution of epileptiform discharges at a lower frequency was the most commonly recorded ictal EEG pattern in our cohort. Further prospective studies with a larger sample size of patients with NCS may provide valuable clinical data that could be used to evaluate the etiologic correlate of the various ictal EEG patterns and their effect on outcome.

The Role of Focal Epilepsy Features in Defining SCN1A Mutation-positive Dravet Syndrome as Generalized and Focal Epilepsy.

Background and PurposeThis study was aimed to describe focal epilepsy features of SCN1A mutation-positive Dravet syndrome patients.MethodsA total of 82 SCN1A mutation-positive patients were reviewed retrospectively (39 boys and 43 girls). Seizure type and electroencephalography (EEG) findings were investigated according to the stage, disease onset, and steady state (after age 2 years). Long-term video EEG data were used to classify the seizure type.ResultsFocal seizures at onset and the steady state were found in 54.9% (45/82) and 90% (63/70) of patients, respectively. Afebrile focal seizures were an initial seizure in about one fourth of the patients (22/82, 26.8%). Of 48 seizures captured during long-term video EEG monitoring of 30 patients, 19 seizures were classified as focal onset (39.6%). Of the 19 focal seizures, 12 were either focal motor or focal non-motor seizures, and seven were focal onset bilateral tonic-clonic seizure. Focal epileptiform discharges were more frequent than generalized epileptiform discharges at seizure onset and during the clinical course on conventional EEG (3.7% vs. 0%, 52.9% vs. 32.9%, respectively).ConclusionsOur study provides a comprehensive description of focal epilepsy features of SCN1A mutation-positive Dravet syndrome patients. Recognizing these features as defining the clinical spectrum of Dravet syndrome may lead to earlier genetic diagnosis and tailored management.

Gain-of-function variants in GABRD reveal a novel pathway for neurodevelopmental disorders and epilepsy.

A potential link between GABRD encoding the δ subunit of extrasynaptic GABAA receptors and neurodevelopmental disorders has largely been disregarded due to conflicting conclusions from early studies. However, we identified seven heterozygous missense GABRD variants in 10 patients with neurodevelopmental disorders and generalized epilepsy. One variant occurred in two sibs of healthy parents with presumed somatic mosaicism, another segregated with the disease in three affected family members, and the remaining five occurred de novo in sporadic patients. Electrophysiological measurements were used to determine the functional consequence of the seven missense δ subunit variants in receptor combinations of α1β3δ and α4β2δ GABAA receptors. This was accompanied by analysis of electroclinical phenotypes of the affected individuals. We determined that five of the seven variants caused altered function of the resulting α1β3δ and α4β2δ GABAA receptors. Surprisingly, four of the five variants led to gain-of-function effects, whereas one led to a loss-of-function effect. The stark differences between the gain-of-function and loss-of function effects were mirrored by the clinical phenotypes. Six patients with gain-of-function variants shared common phenotypes: neurodevelopmental disorders with behavioural issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. The EEG showed qualitative analogies among the different gain-of-function variant carriers consisting of focal slowing in the occipital regions often preceding irregular generalized epileptiform discharges, with frontal predominance. In contrast, the one patient carrying a loss-of-function variant had normal intelligence and no seizure history, but has a diagnosis of autism spectrum disorder and suffers from elevated internalizing psychiatric symptoms. We hypothesize that increase in tonic GABA-evoked current levels mediated by δ-containing extrasynaptic GABAA receptors lead to abnormal neurotransmission, which represent a novel mechanism for severe neurodevelopmental disorders. In support of this, the electroclinical findings for the gain-of-function GABRD variants resemble the phenotypic spectrum reported in patients with missense SLC6A1 (GABA uptake transporter) variants. This also indicates that the phenomenon of extrasynaptic receptor overactivity is observed in a broader range of patients with neurodevelopmental disorders, because SLC6A1 loss-of-function variants also lead to overactive extrasynaptic δ-containing GABAA receptors. These findings have implications when selecting potential treatment options, as a substantial portion of available antiseizure medication act by enhancing GABAergic function either directly or indirectly, which could exacerbate symptoms in patients with gain-of-function GABRD variants.

Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications.

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

Neuroimaging of Childhood Epilepsy: Focal versus Generalized Epilepsy

AbstractNeuroimaging plays an increasingly crucial role in delineating the pathophysiology, and guiding the evaluation, management and monitoring of epilepsy. Imaging contributes to adequately categorizing seizure/epilepsy types in complex clinical situations by demonstrating anatomical and functional changes associated with seizure activity. This article reviews the current status of multimodality neuroimaging in the pediatric population, including focal lesions which may result in focal epileptic findings, focal structural abnormalities that may manifest as generalized epileptiform discharges, and generalized epilepsy without evidence of detectable focal abnormalities.

Partially empty sella with generalized epileptiform discharges presented as manic episode in an elderly female: A case with diagnostic dilemma - Causation or coincidence?

Partially empty sella with generalized epileptiform discharges presented as manic episode in an elderly female: A case with diagnostic dilemma - Causation or coincidence?