Bilateral Tonic-clonic Seizures Research Articles

Predictors of seizures in patients with cerebral venous thrombosis in the Thai population: A retrospective study

PurposeThis study aimed to define independent factors associated with the onset of early seizure (ES) amongst patients with cerebral venous thrombosis (CVT). MethodsThis retrospective cohort study recruited patients diagnosed with CVT and hospitalised between 2002 and 2020. Demographic, clinical, and seizure characteristics; neuroimaging findings; and clinical outcomes were compared between the seizure and non-seizure groups. Factors with p-values of <0.05 in univariate analysis were included in multivariate logistic regression analysis to determine independent predictors of ES. ResultsAmongst 180 CVT patients, the incidence of ES was 38.3%. Most seizures presented as the initial symptom. Focal to bilateral tonic-clonic seizure was the most common seizure type (82.6%). Recurrent serial seizure and non-fatal status epilepticus accounted for 56.5% and 8.7% cases, respectively. Intracerebral haemorrhage (adjusted odds ratio [aOR]=6.57, 95% confidence interval [CI], 2.25‒19.21, p = 0.001) and dependency status at admission (aOR=3.32, 95% CI, 1.08‒10.18, p = 0.036) independently predicted ES, whereas isolated increased intracranial pressure (aOR=0.05, 95% CI, 0.01‒0.24, p < 0.001), isolated headache (aOR=0.10, 95% CI, 0.02‒0.45, p = 0.002), straight sinus thrombosis (aOR=0.03, 95% CI, 0.00‒0.37, p = 0.007), and cavernous sinus thrombosis (aOR=0.50, 95% CI, 0.01‒0.53, p = 0.012) showed protective effects. ConclusionIntracerebral haemorrhage and dependency status at admission independently predicted seizures, whereas isolated increased intracranial pressure, isolated headache, straight sinus thrombosis, and cavernous sinus thrombosis showed preventive effects.

A study of brain functional network and alertness changes in temporal lobe epilepsy with and without focal to bilateral tonic\u2013clonic seizures

BackgroundTemporal lobe epilepsy (TLE) is commonly refractory. Epilepsy surgery is an effective treatment strategy for refractory epilepsy, but patients with a history of focal to bilateral tonic-clonic seizures (FBTCS) have poor outcomes. Previous network studies on epilepsy have found that TLE and idiopathic generalized epilepsy with generalized tonic-clonic seizures (IGE-GTCS) showed altered global and nodal topological properties. Alertness deficits also were found in TLE. However, FBTCS is a common type of seizure in TLE, and the implications for alertness as well as the topological rearrangements associated with this seizure type are not well understood.MethodsWe obtained rs-fMRI data and collected the neuropsychological assessment data from 21 TLE patients with FBTCS (TLE- FBTCS), 18 TLE patients without FBTCS (TLE-non- FBTCS) and 22 controls, and constructed their respective functional brain networks. The topological properties were analyzed using the graph theoretical approach and correlations between altered topological properties and alertness were analyzed.ResultsWe found that TLE-FBTCS patients showed more serious impairment in alertness effect, intrinsic alertness and phasic alertness than the patients with TLE-non-FBTCS. They also showed significantly higher small-worldness, normalized clustering coefficient (γ) and a trend of higher global network efficiency (gE) compared to TLE-non-FBTCS patients. The gE showed a significant negative correlation with intrinsic alertness for TLE-non-FBTCS patients.ConclusionOur findings show different impairments in brain network information integration, segregation and alertness between the patients with TLE-FBTCS and TLE-non-FBTCS, demonstrating that impairments of the brain network may underlie the disruptions in alertness functions.

Epilepsy surgery in patient with monogenic epilepsy related to SCN8A mutation.

Epilepsy surgery is superior to prolonged medical therapy in patients with drug-resistant focal epilepsy, but reports on epilepsy surgery outcomes for patients with a genetic etiology are limited, especially in adults. This is the first documented report of a stereoelectroencephalography (SEEG) evaluation and resective surgery outcome in an adult patient with epilepsy related to SCN8A mutation. We describe a patient with epilepsy related to SCN8A mutation which was reported as a variant of uncertain significance at time of his pre-surgical evaluation and reclassified as likely pathogenic about 3years after resective epilepsy surgery. Most of his pre-surgical evaluation results suggested right temporal lobe epilepsy, but few reported semiological symptoms, ictal SPECT, and neuropsychology results were discordant, and brain MRI was non-lesional. Therefore, SEEG was recommended; ultimately, seizures were localized to the right hippocampus. He was seizure-free for 1.5years after right anterior temporal lobectomy, then reported three focal to bilateral tonic-clonic (FBTC) seizures in the subsequent 12months (preoperatively, 6 focal impaired awareness seizures and 4-6 FBTC per year). This case demonstrates that epilepsy surgery reduced seizure burden in a patient with SCN8A-related epilepsy granting him short-term seizure freedom after resection, and then decreased seizure frequency after relapse compared to the preoperative baseline.

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.

Focal cortical dysplasia links to sleep-related epilepsy in symptomatic focal epilepsy

ObjectiveIn sleep-related epilepsy (SRE), epileptic seizures predominantly occur during sleep, but the clinical characteristics of SRE remain elusive. We aimed to identify the clinical features associated with the occurrence of SRE in a large cohort of symptomatic focal epilepsy. MethodsWe retrospectively included patients with four etiologies, including focal cortical dysplasia (FCD), low-grade tumors (LGT), temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), and encephalomalacia. SRE was defined as more than 70% of seizures occurring during sleep according to the seizure diary. The correlation between SRE and other clinical variables, such as etiology of epilepsy, pharmacoresistance, seizure frequency, history of bilateral tonic-clonic seizures, and seizure localization was analyzed. ResultsA total of 376 patients were included. Among them 95 (25.3%) were classified as SRE and the other 281(74.7%) as non-SRE. The incidence of SRE was 53.5% in the FCD group, which was significantly higher than the other three groups (LGT: 19.0%; TLE-HS: 9.9%; encephalomalacia: 16.7%; P < 0.001). The etiology of FCD (p < 0.001) was significantly associated with SRE (OR: 9.71, 95% CI: 3.35–28.14) as an independent risk factor. In addition, small lesion size (p = 0.009) of FCD further increased the risk of SRE (OR: 3.18, 95% CI: 1.33–7.62) in the FCD group. SignificanceOur data highlight that FCD markedly increased the risk of sleep-related epilepsy independently of seizure localization. A small lesion of FCD further increased the risk of sleep-related epilepsy by 2.18 times in the FCD group.

A post-approval observational study to evaluate the safety and tolerability of perampanel as an add-on therapy in adolescent, adult, and elderly patients with epilepsy

ObjectivePerampanel is a once-daily oral anti-seizure medication for focal-onset seizures, with or without focal to bilateral tonic-clonic seizures (FBTCS), and generalized tonic-clonic seizures. Study 402 (NCT02033902) collected safety information on clinically important treatment-emergent adverse events (TEAEs) from real-world clinical practice in patients aged ≥12 years with refractory epilepsy who were receiving perampanel as an add-on therapy. MethodsStudy 402 was a multicenter, observational, 52-week cohort study conducted in Austria, Belgium, Czech Republic, Denmark, France, Israel, Sweden, and the United Kingdom. Safety data were gathered prospectively from patients at clinic visits. The primary endpoint was the incidence of clinically important TEAEs defined as dizziness; blurred vision; somnolence; aggression; balance disorders (including ataxia and falls); weight gain; suicidality; drug abuse, misuse, dependence, and withdrawal; skin photosensitivity; and unintended pregnancy while taking levonorgestrel-containing contraceptives. Off-label use of perampanel and outcomes associated with any suspected drug–drug interaction were also monitored and recorded. Secondary endpoints included the Hospital Anxiety and Depression Scale (HADS) and Clinical Global Impression of Change. ResultsOf 483 patients in the Safety Analysis Set, mean (standard deviation [SD]) age was 38.3 (15.1) years, 48.4% were female, mean (SD) time since diagnosis was 23 (14.8) years, 56.5% had focal impaired awareness seizures, and 48.7% had FBTCS. Overall, 243 (49.3%) patients treated with perampanel completed the study and 227 (46.0%) patients discontinued. The most common primary reason for discontinuation was adverse events (n = 130 [26.4%]).A total of 301 (62.3%) patients reported at least one TEAE, of which 45 (15.0%) patients had severe TEAEs and 256 (85.0%) patients had TEAEs judged as mild to moderate in severity. Overall, 51 (10.6%) patients had serious TEAEs, including two deaths that were judged as not related to perampanel, and 136 (28.2%) patients experienced a TEAE that led to treatment discontinuation. Clinically important TEAEs were reported by 153 (31.7%) patients, with the most common being dizziness (13.9%), balance disorders (5.6%), aggression (5.4%), and weight gain (5.4%). In general, the frequencies of clinically important TEAEs were lower in this study compared with previous interventional clinical studies, except for the incidence of suicidality (2.1% vs 1.0%) and aggression (5.4% vs 5.1%). Mean total HADS scores were similar at the end of the study compared with baseline; at the end of treatment, most (>60%) patients had no shift in HADS score category; ∼15% of patients moved to a worse category vs baseline and ∼20% of patients moved to an improved category vs baseline for both anxiety and depression. Based on investigator assessment, disease severity was improved in 185/415 (44.6%) patients. A subanalysis in elderly patients aged ≥65 years showed similar results to the overall population. ConclusionsThe data from this observational study are consistent with the known safety profile of perampanel derived from previous interventional phase II and III clinical studies. No unusual or unexpected TEAEs were observed in this real-world clinical practice setting.

Coffee consumption and seizure frequency in patients with drug-resistant focal epilepsy

ObjectiveTo assess the relation between coffee consumption and seizure frequency in patients with drug-resistant focal epilepsy. MethodsCross-sectional analysis of data collected in the SAVE study, which included patients with drug-resistant focal epilepsy during long-term EEG monitoring. Patients in whom both coffee consumption and data about seizure frequency, including focal to bilateral tonic-clonic seizures (FBTCS), were available were selected. Coffee consumption was collected using a standardized self-report questionnaire and classified into four groups: none, rare (from less than 1 cup/week to up 3 cups/week), moderate (from 4 cups/week to 3 cups/day), and high (more than 4 cups/day). ResultsSix hundred and nineteen patients were included. There was no relation between coffee consumption and total seizure frequency (p = 0.902). In contrast, the number of FBTCS reported over the past year was significantly associated with usual coffee consumption (p = 0.029). Specifically, number of FBCTS in patients who reported moderate coffee consumption was lower than in others. In comparison with patients with moderate coffee consumption, the odds ratio (95%CI) for reporting at least 1 FBTCS per year was 1.6 (1.03–2.49) in patients who never take coffee, 1.62 (1.02–2.57) in those with rare consumption and 2.05 (1.24–3.4) in those with high consumption. Multiple ordinal logistic regression showed a trend toward an association between coffee consumption and number of FBTCS (p = 0.08). Conclusions and relevanceOur data suggest that effect of coffee consumption on seizures might depend on dose with potential benefits on FBTCS frequency at moderate doses. These results will have to be confirmed by prospective studies.

Electroencephalogram (EEG) Features of Post-Stroke Seizure Patients in the Department of Neurology, Dr. Soetomo General Hospital Surabaya

Backgrounds: Seizures are one of the most common and hazardous neurological complications of stroke. Post-stroke seizures were classified as early onset seizure and late onset seizure, depending on seizure onset after stroke. Stroke is one of the most common risk factors for seizures and epilepsy, especially in older patients, accounting for 39-45% of all seizure incidents. Knowledge of various risk factors and capability to perform supporting examinations such as EEG are essential to do with the aim of early detection, improving the prevention and treatment of post-stroke seizures so that it is expected to reduce the prevalence and mortality rate of post-stroke seizures. Objectives: This study aims to determine the electroencephalogram (EEG) features found in post-stroke seizure patients in the Department of Neurology, Dr. Soetomo Surabaya Hospital Methods: This study is a descriptive observational study using secondary data obtained from the medical records of patients with post-stroke seizures at the Department of Neurology, Dr. Soetomo Surabaya Hospital within the time period of January 2017 ? December 2019. Results: In this research, we evaluated seizure characteristics in 230 patients who had ischemic and hemorrhagic stroke. 116 patients were male (50.4%) while 114 patients were female (49.6%). The highest age range found in the study sample was > 19-60 years. In addition, this study revealed that 58.7% of seizures were focal seizures and 39.1% were generalized seizures, the remaining 2.2% were unknown seizures. Focal seizures become bilateral tonic clonic seizures are the most common type of focal seizures while generalized tonic clonic seizures are the most common type of generalized seizures seen. 80% of patients with focal seizures have impaired awareness during seizures. Seizures occurred in 148 ischemic stroke patients (64.3%) and 82 hemorrhagic stroke patients (35.7%). 97 Patients with ischemic stroke had thrombus etiology (65. 5%) and 32 had an embolic etiology (21.6 %), while patients with hemorrhagic stroke had the most dominant etiology, namely ICH as many as 53 patients (64.6%). lesions were cortical (47.8%) and 91 patients had lesions located subcortical (39.6%). The majority of patients experienced early onset seizures (55.2%) and the majority of patients had EEG recordings 7 - < 14 days and 3 - < 7 days after seizure manifestations (29.1%). EEG results showed abnormal features in 78.7% patients. Slow activity EEG is the most visible EEG picture with Continuous Slow Activity (CSA) as the most dominant pattern, while in epileptiform EEG the sharp/spike wave image is the most common pattern. In the EEG special pattern, the most common picture is asymmetry decreased background rhythm accompanied by CSA. Conclusion: This hospital-based study showed that post-stroke seizures were associated with young and middle aged (>19-60 years), male gender, ischemic stroke, thrombus type, cortical location, and comorbid hypertension, with a high prevalence rate in patients with hypertension. Based on this study, our data showed that patients with post-stroke seizures after stroke were more likely to have impaired awareness during the seizure. The most EEG features found in this study are continuous slow activity waves. In this study, post stroke seizures occurred more commonly after ischemic stroke, middle aged, and when stroke occurred in the cortical region

Cluster analysis: Predicting the seizure outcome in temporal lobe epilepsy

ObjectivesWe applied the Two-Step cluster analysis on a large cohort of patients with temporal lobe epilepsy (TLE). We hypothesized that there are distinct clusters of patients with TLE based on their clinical characteristics and these clusters may predict their seizure outcome. MethodsThis was a longitudinal study of a prospectively developed database. All patients with a diagnosis of TLE were studied at the outpatient epilepsy clinic, Shiraz, Iran, from 2008 until 2021. The Two-Step cluster analysis (Schwarz’s Bayesian Criterion: BIC) was applied to the whole dataset considering the demographic data, clinical characteristics, imaging, and electroencephalography data. The seizure outcome was compared between the clusters of patients. ResultsThree hundred and seventy-four patients had the inclusion criteria and were studied. The Two-Step cluster analysis showed that there were two distinct clusters of patients with TLE. The most important clinical predictors were the presence (or absence) of focal impaired awareness seizures or focal to bilateral tonic-clonic seizures, aura with seizures, and the brain imaging findings. The seizure outcomes were significantly different between these two clusters (p = 0.008). ConclusionThe Two-Step cluster analysis could identify two distinct clusters of patients with TLE; these data are helpful in providing prognosis and counseling for patients and their care-givers. These data may also be used to develop a practical outcome prediction tool for patients with TLE.

Does the type of seizure influence heart rate variability changes?

ObjectiveHeart rate variability (HRV), an index of the autonomic cardiac activity, is decreased in patients with epilepsy, and a low HRV is associated with a higher risk of sudden death. Generalized tonic-clonic seizures are one of the most consistent risk factors for SUDEP, but the influence (and relative risk) of each type of seizure on cardiac function is still unknown. Our objective was to assess the impact of the type of seizure (focal to bilateral tonic-clonic seizure – FBTCS – versus non-FBTCS) on periictal HRV, in a group of patients with refractory epilepsy and both types of seizures. MethodsWe performed a 48-hour Holter recording on 121 patients consecutively admitted to our Epilepsy Monitoring Unit. We only included patients with both FBTCS and non-FBTCS on the Holter recording and selected the first seizure of each type to analyze. To evaluate HRV parameters (AVNN, SDNN, RMSSD, pNN20, LF, HF, and LF/HF), we chose 5-min epochs pre- and postictally. ResultsWe included 14 patients, with a median age of 36 (min–max, 16–55) years and 64% were female. Thirty-six percent had cardiovascular risk factors, but no previously known cardiac disease.In the preictal period, there were no statistically significant differences in HRV parameters, between FBTCS and non-FBTCS. In the postictal period, AVNN, RMSSD, pNN20, LF, and HF were significantly lower, and LF/HF and HR were significantly higher in FBTCS.From preictal to postictal periods, FBTCS elicited a statistically significant rise in HR and LF/HF, and a statistically significant fall in AVNN, RMSSD, pNN20, and HF. Non-FBTCS only caused statistically significant changes in HR (decrease) and AVNN (increase). Significance/conclusionThis work emphasizes the greater effect of FBTCS in autonomic cardiac function in patients with refractory epilepsy, compared to other types of seizures, with a significant reduction in vagal tonus, which may be associated with an increased risk of SUDEP.

Temporal Lobe Epilepsy and Psychiatric Comorbidity.

Most focal seizures originate in the temporal lobe and are commonly divided into mesial and lateral temporal epilepsy, depending upon the neuronal circuitry involved. The hallmark features of the mesial temporal epilepsy are aura, unconsciousness, and automatisms. Symptoms often overlap with the lateral temporal epilepsy. However, the latter present a less evident psychomotor arrest, frequent clones and dystonic postures, and common focal to bilateral tonic–clonic seizures. Sclerosis of the hippocampus is the most frequent cause of temporal lobe epilepsy (TLE). TLE is among all epilepsies the most frequently associated with psychiatric comorbidity. Anxiety, depression, and interictal dysphoria are recurrent psychiatric disorders in pediatric patients with TLE. In addition, these alterations are often combined with cognitive, learning, and behavioral impairment. These comorbidities occur more frequently in TLE with hippocampal sclerosis and with pharmacoresistance. According to the bidirectional hypothesis, the close relationship between TLE and psychiatric features should lead to considering common pathophysiology underlying these disorders. Psychiatric comorbidities considerably reduce the quality of life of these children and their families. Thus, early detection and appropriate management and therapeutic strategies could improve the prognosis of these patients. The aim of this review is to analyze TLE correlation with psychiatric disorders and its underlying conditions.

Epilepsy and EEG Abnormalities in Children with Autism Spectrum Disorders.

To evaluate the prevalence of epilepsy and electroencephalographic abnormalities in children with autism spectrum disorders (ASD) and determine their risk factors. This cross-sectional study was conducted over one year in children with ASD aged between 3 and 14 y. Classification of epilepsy and routine electroencephalography (EEG) recordings were done for all the patients. Developmental and cognitive assessments were done using Developmental Profile 3. Children were divided into three groups: ASD with epilepsy, ASD with isolated electroencephalographic abnormalities, and ASD with neither epilepsy nor electroencephalographic abnormalities. One hundred children with ASD were enrolled. Epilepsy was reported in 23% and subclinical electroencephalographic abnormalities were documented in 8%. The most common seizure types were generalized-onset tonic-clonic (48%), focal-onset with impaired awareness (17%), and focal to bilateral tonic-clonic seizures (17%). In children with subclinical epileptiform discharges, focal abnormalities were most common (75%) and were maximally seen over the temporal region (50%). Subnormal intellect (88.6%) and abnormal global developmental score (82%) were noted in the majority of children. Female gender, abnormal neurological examination, and adverse perinatal events were significantly associated with epilepsy. Of these, female gender and adverse perinatal events were independent predictors of epilepsy. Isolated EEG abnormalities were significantly associated with abnormal neurological examination in comparison with autistic children without epilepsy/EEG abnormalities. Epilepsy is seen in up to one-fourth children with ASD. Female gender and adverse perinatal events are independent risk factors for epilepsy. Subclinical or isolated EEG abnormalities are associated with abnormal neurological examination.

Simulated driving in the epilepsy monitoring unit: Effects of seizure type, consciousness, and motor impairment.

People with epilepsy face serious driving restrictions, determined using retrospective studies. To relate seizure characteristics to driving impairment, we aimed to study driving behavior during seizures with a simulator. Patients in the Yale New Haven Hospital undergoing video-electroencephalographic monitoring used a laptop-based driving simulator during ictal events. Driving function was evaluated by video review and analyzed in relation to seizure type, impairment of consciousness/responsiveness, or motor impairment during seizures. Fifty-one seizures in 30 patients were studied. In terms of seizure type, we found that focal to bilateral tonic-clonic or myoclonic seizures (5/5) and focal seizures with impaired consciousness/responsiveness (11/11) always led to driving impairment; focal seizures with spared consciousness/responsiveness (0/10) and generalized nonmotor (generalized spike-wave bursts; 1/19) usually did not lead to driving impairment. Regardless of seizure type, we found that seizures with impaired consciousness (15/15) or with motor involvement (13/13) always led to impaired driving, but those with spared consciousness (0/20) or spared motor function (5/38) usually did not. These results suggest that seizure types with impaired consciousness/responsiveness and abnormal motor function contribute to impaired driving. Expanding this work in a larger cohort could further determine how results with a driving simulator may translate into real world driving safety.

Distinct Patterns of Brain Metabolism in Patients at Risk of Sudden Unexpected Death in Epilepsy.

Objective: To characterize regional brain metabolic differences in patients at high risk of sudden unexpected death in epilepsy (SUDEP), using fluorine-18-fluorodeoxyglucose positron emission tomography (18FDG-PET).Methods: We studied patients with refractory focal epilepsy at high (n = 56) and low (n = 69) risk of SUDEP who underwent interictal 18FDG-PET as part of their pre-surgical evaluation. Binary SUDEP risk was ascertained by thresholding frequency of focal to bilateral tonic-clonic seizures (FBTCS). A whole brain analysis was employed to explore regional differences in interictal metabolic patterns. We contrasted these findings with regional brain metabolism more directly related to frequency of FBTCS.Results: Regions associated with cardiorespiratory and somatomotor regulation differed in interictal metabolism. In patients at relatively high risk of SUDEP, fluorodeoxyglucose (FDG) uptake was increased in the basal ganglia, ventral diencephalon, midbrain, pons, and deep cerebellar nuclei; uptake was decreased in the left planum temporale. These patterns were distinct from the effect of FBTCS frequency, where increasing frequency was associated with decreased uptake in bilateral medial superior frontal gyri, extending into the left dorsal anterior cingulate cortex.Significance: Regions critical to cardiorespiratory and somatomotor regulation and to recovery from vital challenges show altered interictal metabolic activity in patients with frequent FBTCS considered to be at relatively high-risk of SUDEP, and shed light on the processes that may predispose patients to SUDEP.

Impulsivity in persons with epilepsy: Association with seizure severity and suicide risk

PurposeClinical research regarding impulsivity in patients with epilepsy is limited. The present study investigated the associations between impulsivity and seizure-related factors or suicidality in patients with epilepsy, independent of depression and anxiety. MethodsThe multicenter study included 146 subjects (63% men). We utilized the Barratt Impulsiveness Scale-11 (BIS-11), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and suicidality module of the Mini International Neuropsychiatric Interview (MINI). Stepwise regression analyses and an analysis of covariance with interaction terms were performed. ResultsThe mean BIS-11 score was 59.3 (SD = 10.7). Psychiatric pathologies, including suicidality, were reported in relatively large proportions of patients, including PHQ-9 score ≥ 10 in 29 (19.9%) patients, GAD-7 score ≥ 7 in 35 (24.0%) patients, and MINI suicidality score ≥ 6 in 15 (10.3%) patients. Stepwise linear regression revealed that BIS-11 score was positively associated with the PHQ-9 scores (p < 0.001), antiseizure medication polytherapy (p < 0.001), use of lamotrigine (p = 0.009), and recurrence of generalized or focal to bilateral tonic clonic seizures (p = 0.010). The coefficient of determination for the model was 0.397. Generalized or focal to bilateral tonic clonic seizure recurrence tended to be positively associated with total BIS-11 scores in men but not in women. In subscale analyses, somewhat different variables were associated with different BIS-11subscales. A trend for a positive association between BIS-11 score and suicidality was found (p = 0.066). ConclusionsThis study identified a positive association between clinical seizure severity and impulsivity, and found that this association tended to be sex-specific, occurring only in males. Impulsivity could potentially be weakly associated with suicidality in patients with epilepsy.

High prevalence of pathological alertness and wakefulness on maintenance of wakefulness test in adults with focal-onset epilepsy

BackgroundExcessive daytime sleepiness (EDS) is a common complaint in adults with epilepsy (AWE), but objective evaluation is lacking. We used the maintenance of wakefulness test (MWT) to objectively measure the ability of adults with focal-onset epilepsy to maintain wakefulness in soporific conditions. MethodsAdults with epilepsy participating in a study investigating the effects of lacosamide on sleep and wakefulness underwent baseline ambulatory polysomnography (PSG)/EEG followed by MWT. Mean sleep latency (MSL) and mean percent sleep time (MST, mean percentage of non-wake EEG scored in 3-sec bins from lights out to sleep onset averaged over the 4 MWT trials) were quantified. Subjective sleepiness was assessed by the Epworth Sleepiness Scale (ESS). Spearman correlation and linear regression assessed relationships between MWT parameters, ESS and relevant sleep and epilepsy-related variables. ResultsMaintenance of wakefulness test MSL in 51 AWE (mean age 43.5 ± 13 years, 69% female, mean BMI 24.6 ± 11.2 kg/m2) was 21.7 ± 11.9 min; 45.1% had an abnormally short MSL <19.4 min and 15.7% <8 min. MST was 9.3% [3.3, 19.1]. Mean ESS score was 8.8 ± 5.7; 39% had elevated ESS (>10). No correlation between subjective ESS and objective MSL (p = 0.67) or MST (p = 0.61) was found. MSL was significantly shorter in subjects with focal to bilateral tonic-clonic seizures (FBTCS; 7.9 min [13.6, 22.3]) compared to those without (27.4 min [21.2, 33.6], p = 0.013). Younger subjects had shorter MSL; MSL increased 3.2 min for every 10-year increase in age. ConclusionWe found a high prevalence of objective sleepiness/difficulty maintaining wakefulness on the MWT and subjective sleepiness using the ESS in AWE without a correlation between the two. More severe objective sleepiness was found in subjects with a history of FBTCS and younger age. Further research is needed to determine mechanistic underpinnings and optimal measurements of pathological sleepiness in people with epilepsy given the burden of it on quality of life.

Perampanel as first add-on antiseizure medication: Italian consensus clinical practice statements

BackgroundWhen use of a single antiseizure medication (ASM) fails to induce seizure remission, add-on therapy is justified. Perampanel (PER) is approved in Europe as adjunctive therapy for focal, focal to bilateral tonic-clonic seizures and generalized tonic-clonic seizures. Aim of the study was to establish whether PER is suitable for first add-on use.MethodsA Delphi methodology was adopted to assess consensus on a list of 39 statements produced by an Expert Board of 5 epileptologists. Using an iterative process, statements were finalized by a Delphi Panel of 84 Italian pediatric and adult neurologists. Each statement was rated anonymously to determine level of agreement on a 9-point Likert scale. Consensus was established as agreement by at least 80% of the panelists. The relevance of each statement was also assessed on a 3-point scale.ResultsConsensus was achieved for 37 statements. Characteristics of PER considered to justify its use as first add-on include evidence of a positive impact on quality of life based on long term retention data, efficacy, tolerability, and ease of use; no worsening of cognitive functions and sleep quality; a low potential for drug interactions; a unique mechanism of action. Potential unfavorable factors are the need for a relatively slow dose titration; the potential occurrence of behavioral adverse effects; lack of information on safety when used in pregnancy; limited access to plasma PER levels.ConclusionPerampanel has many features which justify its use as a first add-on. Choice of an ASM as first add-on should be tailored to individual characteristics.

Teaching NeuroImage: Pseudo–Figure-of-4 Sign

A 37-year-old right-handed man with spastic quadriparetic cerebral palsy, congenital hydrocephalus, and anxiety was admitted for seizure characterization with video-EEG monitoring. Neurologic examination demonstrated marked upper extremity spasticity and left elbow flexion contracture. Three habitual focal to bilateral tonic-clonic seizures (Figure 1) were recorded on EEG (Figure 2).

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.

Efficacy of cenobamate for uncontrolled focal seizures: Post hoc analysis of a Phase 3, multicenter, open-label study.

ObjectiveTo report long‐term post hoc efficacy and safety data from 10 US study sites from an open‐label Phase 3 study of adjunctive cenobamate (NCT02535091).MethodsPatients with uncontrolled focal seizures taking stable doses of 1–3 antiseizure medications (ASMs) were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2‐week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50‐mg/day increments biweekly were allowed during the maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until the last clinic visit on or after September 1, 2019.ResultsOf 255 patients, 240 with focal aware motor, focal impaired awareness, or focal to bilateral tonic–clonic seizure data while on treatment were evaluated (median [maximum] exposure = 30.2 [43.0] months across the entire study). Median baseline seizure frequency/28 days was 2.8 (mean = 18.1). Of the 240 patients, 177 (73.8%) were continuing cenobamate treatment at data cutoff. The ≥50% responder rate for the total treatment duration was 71.7% (172/240). During titration, the ≥50% responder rates were 48.1% during Weeks 1–4 (12.5–25 mg/day cenobamate) and 61.7% during Weeks 5–8 (50–100 mg/day cenobamate). Among all patients who received a dose of cenobamate in the maintenance phase (n = 214), 13.1% (28/214) and 40.2% (86/214) achieved 100% and ≥90% seizure reduction during their entire maintenance treatment duration (median = 29.5 months). Among all patients, 87 (36.3%) had any consecutive ≥12‐month duration of 100% seizure reduction. Common treatment‐emergent adverse events among all 240 patients included fatigue (34.6%), dizziness (32.1%), and somnolence (29.6%).SignificanceThis post hoc analysis of a subset of patients from the long‐term open‐label study showed high rates of sustained 100% and ≥90% seizure reduction, with many achieving response early during titration. These findings suggest durable seizure frequency reduction with cenobamate in adults with uncontrolled focal seizures.