Prospective study of epilepsy with generalized tonic-clonic seizures alone: Clinical features, response to treatment, and likelihood of medication withdrawal.

OBJECTIVE: This prospective study aimed to delineate the demographics, natural progression, and treatment response of patients newly diagnosed with epilepsy with generalized tonic-clonic seizures alone (EGTCA). Furthermore, our objective includes assessing the seizure recurrence rate post antiseizure medication (ASM) discontinuation within this cohort, alongside exploring predictive factors for seizure relapse. METHODS: The study cohort, derived from an ongoing, prospective, multicenter investigation on children and adults with new-onset unprovoked seizures, included consecutive patients enrolled between March 2010 and March 2020, and meeting mandatory ILAE criteria for EGTCA diagnosis. Participants underwent a 3-h sleep-deprived video-EEG recording along with an epilepsy protocol brain magnetic resonance imaging (MRI) with repeat EEG at each follow-up. Cumulative time-dependent probabilities of seizure recurrence were calculated using Kaplan-Meier survival analysis. Logistic regression identified variables associated with seizure recurrence following ASM taper. RESULTS: Eighty-nine patients with a median age of 16 years were included, constituting 31% of those diagnosed with an idiopathic generalized epilepsy. Regarding the circadian distribution of seizures, 59.6% of patients exclusively experienced diurnal seizures, 12.4% exclusively nocturnal, and 28.1% experienced both diurnal and nocturnal seizures. Generalized spike-wave discharges (GSWD) were present in the initial EEG of 88% of patients. A GTC recurred in 14% of patients treated with ASM compared with 73% of untreated patients (p < 0.00001). ASM discontinuation was attempted in 50 patients after a median treatment duration of 3 years, with 44% experiencing a recurrence. Patient-initiated taper and a mixed circadian seizure pattern independently predicted a higher likelihood of recurrence post-ASM discontinuation. SIGNIFICANCE: Our findings underscore the importance of prompt treatment upon the diagnosis of EGTCA. Notably, lifelong treatment may not be imperative; patients seizure-free for at least 2 years, with the absence of GSWD on EEG, often maintained seizure freedom after ASM withdrawal, especially with physician-initiated tapering. PLAIN LANGUAGE SUMMARY: Seizures in individuals diagnosed with "epilepsy with generalized tonic-clonic seizures alone" (EGTCA) typically start during adolescence and often respond well to antiseizure medications. An electroencephalogram, which measure brain waves, will show abnormal discharges in most patients with EGTCA. Lifelong treatment with antiseizure medication is not necessary for everyone with EGTCA; approximately, 40% can successfully stop treatment without facing seizure recurrence. Patients who stop medication on their own have a higher risk of seizures returning compared with those who undergo cessation under a doctor's supervision.

Early predictors of remission in children and adolescents with new-onset epilepsy: A prospective study.

PURPOSE: This study aims to identify predictive factors of a two-year remission (2YR) in a cohort of children and adolescents with new-onset seizures based on baseline clinical characteristics, initial EEG and brain MRI findings. METHODS: A prospective cohort of 688 patients with new onset seizures, initiated on treatment with antiseizure medication was evaluated. 2YR was defined as achieving at least two years of seizure freedom during the follow-up period. Multivariable analysis was performed and recursive partition analysis was utilized to develop a decision tree. RESULTS: The median age at seizure onset was 6.7 years, and the median follow-up was 7.4 years. 548 (79.7%) patients achieved a 2YR during the follow up period. Multivariable analysis found that presence and degree of intellectual and developmental delay (IDD), epileptogenic lesion on brain MRI and a higher number of pretreatment seizures were significantly associated with a lower probability of achieving a 2YR. Recursive partition analysis showed that the absence of IDD was the most important predictor of remission. An epileptogenic lesion was a significant predictor of non-remission only in patients without evidence of IDD, and a high number of pretreatment seizures was a predictive factor in children without IDD and in the absence of an epileptogenic lesion. CONCLUSION: Our results indicate that it is possible to identify patients at risk of not achieving a 2YR based on variables obtained at the initial evaluation. This could allow for a timely selection of patients who require close follow-up, consideration for neurosurgical intervention, or investigational treatments trials.

Risk of recurrence in patients with an unprovoked tonic-clonic seizure and generalized epileptiform discharges on EEG.

OBJECTIVE: 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, electroencephalography (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 (GSWDs) on EEG and compare the efficacy of antiseizure medications (ASMs) in preventing recurrence. METHODS: This prospective study included consecutive patients who presented with a single GTC seizure, evidence of GSWDs on EEG, and a follow-up period of at least 1 year. All patients underwent extensive evaluation, including a 3-hour sleep-deprived video-EEG recording and an epilepsy protocol brain magnetic resonance imaging (MRI). Treatment with ASMs was recommended for all patients. The decision regarding the specific ASM to be used was left to the treating physician's discretion. RESULTS: 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 of 41 patients (14.6%) in the treated group compared to 11 of 16 (68.8%) in the untreated group (p = .00006). Valproate was significantly more efficacious than levetiracetam or lamotrigine (p = .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. SIGNIFICANCE: Patients with a first unprovoked GTC seizure and evidence of GSWDs on EEG have a high risk of recurrence if left untreated. Valproate is the most efficacious ASM 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.

Brain magnetic resonance imaging findings and brain volumetric differences in a large series of benign rolandic epilepsy.

BACKGROUND: Several studies with a small sample size have investigated the relationship between structural and functional changes on MRI and the clinical and natural history of BRE. We aim to assess the frequency of incidental epileptogenic lesions on brain MRI in a large cohort of patients diagnosed with BRE and to assess the difference in volumetric brain measurements in BRE patients compared to healthy controls. METHODS: The case-control study includes 214 typical BRE cases and 197 control children with non-epileptic spells. Brain MRIs were evaluated for abnormalities which were classified into normal and abnormal with or without epileptogenic lesions with categorization of epileptogenic lesions. Brain segmentation was also performed for a smaller group of BRE patients and another healthy control group. Pearson's chi-squared test and two-tailed independent samples t-test were used. RESULTS: In patients with BRE, 7% had an epileptogenic lesion on their MRI. The frequency of epileptogenic lesion in the control group was 10.2% and not significantly different from those with BRE (p= 0.2). Significantly higher intracranial and white matter volumes were found in BRE patients compared to the healthy group while lower gray matter volume was found in BRE patients. Cortical and subcortical regions showed either higher or lower volumes with BRE. Interestingly, altered subcallosal cortex development which has a known association with depression was also found in BRE. CONCLUSIONS: Our findings confirm the absence of any association between specific brain MRI abnormalities and BRE. However, the altered cortical and subcortical development in BRE patients suggests a microstructural-functional correlation.

COVID-19-Associated Acute Asymmetric Hemorrhagic Necrotizing Encephalopathy: A Case Report.

Background: Coronavirus disease 2019 (COVID-19) has been associated with many neurological complications affecting the central nervous system. Purpose: Our aim was to describe a case of COVID-19 associated with a probable variant of acute necrotizing encephalopathy (ANE). Results: A 60-year-old man who presented with a 3-day history of dyspnea, fever, and cough tested positive for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Five days following his admission, the patient was intubated secondary to respiratory failure. Following his extubation 16 days later, he was found to have a left-sided weakness. Magnetic resonance imaging (MRI) of the brain showed hemorrhagic rim-enhancing lesions involving the right thalamus, left hippocampus, and left parahippocampal gyrus. These lesions showed decreased relative cerebral blood flow on MR perfusion and restricted on diffusion-weighted imaging. These neuroimaging findings were consistent with ANE. The left-sided weakness gradually improved over the subsequent weeks. Conclusions: We concluded that COVID-19 can be associated with ANE, a condition believed to be the result of an immune-mediated process with activation of the innate immune system. Future studies must address whether biological drugs targeting the pro-inflammatory cytokines could prevent the development of this condition.

Predicting the occurrence of thrombocytopenia from free valproate levels: A prospective study.

PURPOSE: The likelihood of valproate (VPA) induced thrombocytopenia increases with higher VPA levels. In critically ill patients, the biological active free VPA level cannot be predicted from the total serum level. In this study, we evaluated the relationship between trough free VPA serum levels and concomitant platelet counts and assessed risk factors for the development of thrombocytopenia with the aim of generating a formula specifying the probabilities of developing thrombocytopenia based on trough free serum VPA levels. METHODS: Trough free VPA levels and concomitant platelet counts were collected from a large cohort of patients who participated in a prospective VPA monotherapy trial. Significant variables associated with thrombocytopenia in a univariate analysis were evaluated in a multivariate model. A receiver operator curve was performed to compute the trough free VPA levels with the greatest discriminating power in predicting thrombocytopenia. RESULTS: 844 trough free VPA levels and concomitant platelet counts obtained from 264 patients were analyzed. In a multivariate analysis, trough free VPA levels, gender, and baseline platelet counts were significantly associated with thrombocytopenia. Using stepwise regression and multivariate logistic regression analyses, we generated gender-specific formulas for predicting platelet counts and probabilities of developing thrombocytopenia. The trough free VPA with the greatest discriminating power to predict platelet values ≤ 100,000/µL was 16.65 µg/mL. CONCLUSIONS: The generated model was based on trough free VPA levels and achieved high sensitivity and specificity. Our results are therefore generalizable and can be applied to estimate the probability of developing thrombocytopenia in critically ill patients.

The importance of acknowledging diagnostic uncertainty in patients with new-onset paroxysmal spells.

OBJECTIVE: The aims of this study were to evaluate the frequency of paroxysmal spells of indeterminate nature (PSIN) in a large cohort of children and adults with suspected new-onset seizures, to evaluate the reasons for including patients in this category, and to calculate the rate of erroneous diagnoses if the epileptologists were compelled to label those events as epileptic seizures or nonepileptic paroxysmal spells. METHODS: Patients identified for this study participated in a prospective study evaluating patients with suspected new-onset unprovoked seizures. The workup included a detailed history and a thorough description of the spells, a 3-hour video EEG recording, and an epilepsy protocol brain MRI. Based exclusively on a detailed description of the ictal events, two epileptologists were asked to independently classify each patient into those with a definite diagnosis of unprovoked seizures or a definite diagnosis of a nonepileptic paroxysmal spells (group 1) and those with PSIN (group 2). RESULTS: A total of 1880 consecutive patients were enrolled with 255 (13.6%) included in the PSIN group. Patients with PSIN were significantly younger than those with a definite diagnosis, and PSIN were significantly more frequent in children with developmental delay. The most common reason for including patients in the PSIN group was the inability to categorically discriminate between a seizure and a nonepileptic mimicker. When the raters were compelled to classify the spells in the PSIN group, the frequencies of erroneous diagnoses ranged between 32% and 38%. The final diagnoses on those patients were made based on the results of the EEG, MRI, and follow-up visits. SIGNIFICANCE: Our data indicate that a diagnostic category of PSIN should be recognized and ought to be used in clinical practice. Acknowledging this uncertainty will result in lower frequencies of erroneous diagnoses, possible stigma, and potential exposure to unnecessary antiseizure medications.

Depression and anxiety in patients from Lebanon with new onset functional seizures.

OBJECTIVES: To prospectively compare the frequencies of depression and anxiety in patients with new onset functional seizures versus two age and gender-matched control groups consisting of patients with new onset epileptic seizures and normal individuals. METHODS: Consecutive patients, 16 years and older, enrolled in a prospective study for suspected new onset epileptic seizures and diagnosed with documented functional seizures were included. We compared the depression and state and trait anxiety scores using the Beck Depression Inventory (BDI) and the State Trait Anxiety Inventory (STAI) between patients with functional seizures and the other two control groups. RESULTS: The 33 patients with functional seizures had significantly higher depression and anxiety scores compared to those with epileptic seizures and normal controls. Twenty patients (60.6%) in the functional seizures group scored in the "depression" range compared to 5/33 (15.2%) in the epileptic seizures and 1/33 (3%) in the control groups. In the functional seizures group, 14/33 (42.4%) had scores in the "state anxiety" range compared to 6/33 (18.2%) and 2/33 (6.1%) in the epileptic seizures and normal control groups, respectively. Similarly, 15/33 (51.5%) of patients in the functional seizures group had scores in the "trait anxiety" range compared to 4/33 (12.1%) and 1/33 (3%) in the epileptic seizures and normal control groups, respectively. CONCLUSIONS: Our results indicate that patients with new onset functional seizures frequently suffer from depression and anxiety at the time of their initial evaluation. These findings underscore the importance of screening for depression and anxiety in that patient population.

A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant.

Seizure threshold-2 (SZT2) gene variants have been associated with a decrease in seizure threshold resulting in variable phenotypic expressions ranging from mild-moderate intellectual disabilities without seizures, to an early-onset epileptic encephalopathy with severe cognitive impairment. In addition, hypotonia and distinctive facial dysmorphism, including a high forehead and to a lesser extent ptosis and down-slanting palpebral fissures, were present in the majority. We herein report a novel SZT2 variant in one of two siblings both diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). This report is the fourth to document a possible familial case in EIMFS, a condition that was not previously associated with SZT2 variant. This report expands the phenotypic expression of SZT2, corroborates the importance of genetic counseling in some cases of EIMFS, and highlights the efficacy of potassium bromide in controlling the seizures associated with this condition.

FARS2 Mutations: More Than Two Phenotypes? A Case Report.

FARS2, a nuclear gene, encodes the mitochondrial phenylalanyl-tRNA synthetase (mtPheRS). Previous reports have described two distinct phenotypes linked to FARS2 gene mutation: an early onset epileptic encephalopathy and spastic paraplegia. This report describes a distinctive phenotype of FARS2-linked, juvenile onset refractory epilepsy, caused by a hemizygous mutation in a compound heterozygous state (p.V197M and exon 2 microdeletion). A 17-year- old woman with normal development presented with a super refractory focal motor status epilepticus. Only an emergency life-saving surgery aborted her status after all therapeutic interventions, including anesthesia, failed to control her seizures. Pathological and biochemical activities on muscle biopsy showed mitochondrial proliferation with enhanced isolated activities of complexes II and IV, suggestive of a compensatory mechanism for the bioenergetic deficiency. Postoperatively, the patient started experiencing focal aware motor seizures originating from the contralateral hemisphere after being seizure free for a few months. This report suggests a third phenotypic manifestation of FARS2 gene mutation.