Epilepsy Currents

Epilepsy and psychiatric illness have been long studied and today are better accepted as co-occurring than as discrete illnesses that are independent even if associated. Common pathophysiology may not be easily explained, but clearly exists given the significant overrepresentation of psychiatric illness among individuals with epilepsy. Conditions like autism spectrum disorder, anxiety, depression, and attention deficit hyperactivity disorder are prevalent in pediatric epilepsy much more than expected, even in the context of chronic neurologic disease. The interplay between pediatric epilepsy and neuropsychiatric symptoms represents a complex clinical circumstance that is not well subtended by the chasm-like division of labor between psychiatrists and neurologists. The unfortunate result is that children and families often experience care that is fractured and at worst, counterproductive for their quality of life. A neuropsychiatric paradigm is essential to address epilepsy and its intrinsic psychiatric symptoms. Practical strategies will be discussed to address this challenge.

Hospital Variation of Outcomes in Status Epilepticus

Terman SW, Guterman EL, Lin CC, Thompson MP, Burke JF. Epilepsia. 2024 May;65(5):1415-1427. Epub 2024 Feb 26. PMID: 38407370; PMCID: PMC11087197. doi: 10.1111/epi.17927

Objective: Understanding factors driving variation in status epilepticus outcomes would be critical to improve care. We evaluated the degree to which patient and hospital characteristics explained hospital-to-hospital variability in intubation and postacute outcomes. Methods: This was a retrospective cohort study of Medicare beneficiaries admitted with status epilepticus between 2009 and 2019. Outcomes included intubation, discharge to a facility, and 30- and 90-day readmissions and mortality. Multilevel models calculated percent variation in each outcome due to hospital-to-hospital differences. Results: We included 29 150 beneficiaries. The median age was 68 years (interquartile range [IQR] = 57-78), and 18 084 (62%) were eligible for Medicare due to disability. The median (IQR) percentages of each outcome across hospitals were: 30-day mortality 25% (0%-38%), any 30-day readmission 14% (0%-25%), 30-day status epilepticus readmission 0% (0%-3%), 30-day facility stay 40% (25%-53%), and intubation 46% (20%-61%). However, after accounting for many hospitals with small sample size, hospital-to-hospital differences accounted for 2% to 6% of variation in all unadjusted outcomes, and approximately 1% to 5% (maximally 8% for 30-day readmission for status epilepticus) after adjusting for patient, hospitalization, and/or hospital characteristics. Although many characteristics significantly predicted outcomes, the largest effect size was cardiac arrest predicting death (odds ratio = 10.1, 95% confidence interval = 8.8-11.7), whereas hospital characteristics (eg, staffing, accreditation, volume, setting, and services) all had lesser effects. Significance: Hospital-to-hospital variation explained little variation in studied outcomes. Rather, certain patient characteristics (eg, cardiac arrest) had greater effects. Interventions to improve outcomes after status epilepticus may be better focused on individual or prehospital factors, rather than at the inpatient systems level.

Clinical Effectiveness of the Psychological Therapy Mental Health Intervention for Children with Epilepsy in Addition to Usual Care Compared with Assessment-Enhanced Usual Care Alone: A Multicentre, Randomised Controlled Clinical Trial in the UK

Bennett SD, Cross JH, Chowdhury K, Ford T, Heyman I, Coughtrey AE, Dalrymple E, Byford S, Chorpita B, Fonagy P, Moss-Morris R, Reilly C, Smith JA, Stephenson T, Varadkar S, Blackstone J, Quartly H, Hughes T, Lewins A, Moore E, Walji F, Welch A, Whelan E, Zacharia A, D'Oelsnitz A, Shah M, Xu L, Vezyroglou A, Mitchell K, Nizza IE, Ganguli P, Shafran R. Lancet. 2024;403(10433):1254–1266. doi: 10.1016/S0140-6736(23)02791-5.

Background: Mental health difficulties are common in children and young people with chronic health conditions, but many of those in need do not access evidence-based psychological treatments. The study aimed to evaluate the clinical effectiveness of integrated mental health treatment for children and young people with epilepsy, a common chronic health condition known to be associated with a particularly high rate of co-occurring mental health difficulties. Methods: We conducted a parallel-group, multicenter, open-label, randomized controlled trial of participants aged 3–18 years, attending epilepsy clinics across England and Northern Ireland who met diagnostic criteria for a common mental health disorder. Participants were randomized (1:1; using an independent web-based system) to receive the Mental Health Intervention for Children with Epilepsy (MICE) in addition to usual care, or assessment-enhanced usual care alone (control). Children and young people in both groups received a full diagnostic mental health assessment. MICE was a modular psychological intervention designed to treat common mental health conditions in children and young people using evidence-based approaches such as cognitive behavior therapy and behavioral parenting strategies. Usual care for mental health disorders varied by site but typically included referral to appropriate services. Participants, along with their caregivers, and clinicians were not masked to treatment allocation but statisticians were masked until the point of analysis. The primary outcome, analyzed by modified intention-to-treat, was the parent-report Strengths and Difficulties Questionnaire (SDQ) at 6 months post-randomization. The study is complete and registered with ISRCTN (57823197). Findings: Precisely, 1401 young people were potentially deemed eligible for study inclusion. Following the exclusion of 531 young people, 870 participants were assessed for eligibility and completed the SDQ, and 480 caregivers provided consent for study inclusion between May 20, 2019, and January 31, 2022. Between August 28, 2019, and February 21, 2022, 334 participants (mean ages 10.5 years [SD 3.6] in the MICE group vs 10.3 [4.0] in the control group at baseline) were randomly assigned to an intervention using minimization balanced by age, primary mental health disorder, diagnosis of intellectual disability, and autistic spectrum disorder at baseline. One hundred and sixty-eight (50%) of the participants were female and 166 (50%) were male. One hundred and sixty-six participants were randomly assigned to the MICE group and 168 were randomly assigned to the control group. At 6 months, the mean SDQ difficulties for the 148 participants in the MICE group was 17.6 (SD 6.3) and 19.6 (6.1) for the 148 participants in the control group. The adjusted effect of MICE was −1.7 (95% CI −2.8 to −0.5; p = .0040; Cohen's d, 0.3). Fourteen (8%) patients in the MICE group experienced at least 1 serious adverse event compared with 24 (14%) in the control group. Sixty-eight percent of serious adverse events (50 events) were admission due to seizures. Interpretation: MICE was superior to assessment-enhanced usual care in improving symptoms of emotional and behavioral difficulties in young people with epilepsy and common mental health disorders. The trial therefore shows that mental health comorbidities can be effectively and safely treated by a variety of clinicians, utilizing an integrated intervention across ages and in the context of intellectual disability and autism. The evidence from this trial suggests that such a model should be fully embedded in epilepsy services and serve as a model for other chronic health conditions in young people.

Long-Term Neuropsychological Trajectories in Children With Epilepsy: Does Surgery Halt Decline?

Eriksson MH, Prentice F, Piper RJ, Wagstyl K, Adler S, Chari A, Booth J, Moeller F, Das K, Eltze C, Cooray G, Perez Caballero A, Menzies L, McTague A, Shavel-Jessop S, Tisdall MM, Cross JH, Martin Sanfilippo P, Baldeweg T. Brain. 2024;147(8):2791–2802. doi: 10.1093/brain/awae121.

Neuropsychological impairments are common in children with drug-resistant epilepsy. It has been proposed that epilepsy surgery may alleviate these impairments by providing seizure freedom; however, findings from prior studies have been inconsistent. We mapped long-term neuropsychological trajectories in children before and after undergoing epilepsy surgery, to measure the impact of disease course and surgery on functioning. We performed a retrospective cohort study of 882 children who had undergone epilepsy surgery at Great Ormond Street Hospital (1990–2018). We extracted patient information and neuropsychological functioning—obtained from intelligence quotient (IQ) tests (domains: full-scale IQ, verbal IQ, performance IQ, working memory, and processing speed) and tests of academic attainment (reading, spelling, and numeracy)—and investigated changes in functioning using regression analyses. We identified 500 children (248 females) who had undergone epilepsy surgery (median age at surgery = 11.9 years, interquartile range = [7.8,15.0]) and neuropsychology assessment. These children showed declines in all domains of neuropsychological functioning in the time leading up to surgery (all p-values ≤ .001; eg, βFSIQ = −1.9, SEFSIQ = 0.3, pFSIQ < 0.001). Children lost on average 1 to 4 points per year, depending on the domain considered; 27% to 43% declined by 10 or more points from their first to their last preoperative assessment. At the time of presurgical evaluation, most children (46% to 60%) scored 1 or more standard deviations below the mean (<85) on the different neuropsychological domains; 37% of these met the threshold for intellectual disability (full-scale IQ < 70). On a group level, there was no change in performance from pre- to postoperative assessment on any of the domains (all p-values > .128). However, children who became seizure-free through surgery showed higher postoperative neuropsychological performance (eg, rrb-FSIQ = 0.37, p < .001). These children continued to demonstrate improvements in neuropsychological functioning over the course of their long-term follow-up (eg, βFSIQ = 0.9, SEFSIQ = 0.3, pFSIQ = 0.004). Children who had discontinued antiseizure medication (ASM) treatment at 1-year follow-up showed an 8-to-13-point advantage in postoperative working memory, processing speed, and numeracy, and greater improvements in verbal IQ, working memory, reading, and spelling (all p-values < .034) over the postoperative period compared to children who were seizure-free and still receiving ASMs. In conclusion, by providing seizure freedom and the opportunity for ASM cessation, epilepsy surgery may not only halt but reverse the downward trajectory that children with drug-resistant epilepsy display in neuropsychological functioning. To halt this decline as soon as possible, or potentially prevent it from occurring in the first place, children with focal epilepsy should be considered for epilepsy surgery as early as possible after diagnosis.

Epilepsy and the Risk of Adverse Cardiovascular Events: A Nationwide Cohort Study

Mayer J, Fawzy AM, Bisson A, Pasi M, Bodin A, Vigny P, Herbert J, Marson AG, Lip GYH, Fauchier L. Eur J Neurol. 2024;31(3):e16116. doi: 10.1111/ene.16116

Background and purpose: Epilepsy is associated with higher morbidity and mortality compared to people without epilepsy. We performed a retrospective cross-sectional and longitudinal cohort study to evaluate cardiovascular comorbidity and incident vascular events in people with epilepsy (PWE). Methods: Data were extracted from the French Hospital National Database. PWE (n = 682 349) who were hospitalized between January 2014 and December 2022 were matched on age, sex, and year of hospitalization with 682 349 patients without epilepsy. Follow-up was conducted from the date of first hospitalization with epilepsy until the date of each outcome or date of last news in the absence of the outcome. The primary outcome was the incidence of all-cause death, cardiovascular death, myocardial infarction, hospitalization for heart failure, ischaemic stroke (IS), new-onset atrial fibrillation, sustained ventricular tachycardia or fibrillation (VT/VF), and cardiac arrest. Results: A diagnosis of epilepsy was associated with higher numbers of cardiovascular risk factors and adverse cardiovascular events compared to controls. PWE had a higher incidence of all-cause death (incidence rate ratio [IRR] = 2.69, 95% confidence interval [CI] = 2.67-2.72), cardiovascular death (IRR = 2.16, 95% CI = 2.11-2.20), heart failure (IRR = 1.26, 95% CI = 1.25-1.28), IS (IRR = 2.08, 95% CI = 2.04-2.13), VT/VF (IRR = 1.10, 95% CI = 1.04-1.16), and cardiac arrest (IRR = 2.12, 95% CI = 2.04-2.20). When accounting for all-cause death as a competing risk, subdistribution hazard ratios for IS of 1.59 (95% CI = 1.55-1.63) and for cardiac arrest of 1.73 (95% CI = 1.58-1.89) demonstrated higher risk in PWE. Conclusions: The prevalence and incident rates of cardiovascular outcomes were significantly higher in PWE. Targeting cardiovascular health could help reduce excess morbidity and mortality in PWE.

Evaluation of a Seizure Action Plan in an Adult Epilepsy Center

Long L, Reynolds SS, Lewis LS, Webb MA, Epley C, Maturu S. Neurol: Clin Pract 2024;14:e200275. doi:10.1212/CPJ.0000000000200275

Background: Seizure action plans (SAPs) provide valuable information for patients to manage seizure emergencies, but are underutilized in adult epilepsy centers. The purpose of this project was to implement a structured SAP for adult patients with epilepsy. Methods: A pre-/post-implementation design was used. Provider SAP utilization rates were analyzed over a 16-week period. A pre- and post-implementation survey assessed participants' perceived impact of the SAP on knowledge and comfort associated with managing seizure emergencies. Provider barriers and facilitators were also assessed. Results: The average provider SAP utilization rate was 51.45%. A total of 204 participants completed the surveys, which showed a significant increase in knowledge and comfort for all items, P < .001. At post-survey analysis, 98% of participants felt that all patients with epilepsy should have an SAP regardless of seizure burden. Discussion: Implementing a structured SAP increased provider utilization and patient and care partner knowledge and comfort in managing seizure emergencies.

Hippocampal Sclerosis and Temporal Lobe Epilepsy Following Febrile Status Epilepticus: The FEBSTAT Study

Lewis DV, Voyvodic J, Shinnar S, Chan S, Bello JA, MoshéSL, Nordli DR Jr, Frank LM, Pellock JM, Hesdorffer DC, Xu Y, Shinnar RC, Seinfeld S, Epstein LG, Masur D, Gallentine W, Weiss E, Deng X, Sun S, FEBSTAT Study Team. Epilepsia. 2024;65(6):1568–1580. doi: 10.1111/epi.17979.

Objective: This study was undertaken to determine whether hippocampal T2 hyperintensity predicts sequelae of febrile status epilepticus, including hippocampal atrophy, sclerosis, and mesial temporal lobe epilepsy. Methods: Acute magnetic resonance imaging (MRI) was obtained within a mean of 4.4 (SD = 5.5, median = 2.0) days after febrile status on >200 infants with follow-up MRI at approximately 1, 5, and 10 years. Hippocampal size, morphology, and T2 signal intensity were scored visually by neuroradiologists blinded to clinical details. Hippocampal volumetry provided quantitative measurement. Upon the occurrence of 2 or more unprovoked seizures, subjects were reassessed for epilepsy. Hippocampal volumes were normalized using total brain volumes. Results: Fourteen of 22 subjects with acute hippocampal T2 hyperintensity returned for follow-up MRI, and 10 developed definite hippocampal sclerosis, which persisted through the 10-year follow-up. Hippocampi appearing normal initially remained normal on visual inspection. However, in subjects with normal-appearing hippocampi, volumetrics indicated that male, but not female, hippocampi were smaller than controls, but increasing hippocampal asymmetry was not seen following febrile status. Forty-four subjects developed epilepsy; 6 developed mesial temporal lobe epilepsy and, of the 6, 2 had definite, 2 had equivocal, and 2 had no hippocampal sclerosis. Only 1 subject developed mesial temporal epilepsy without initial hyperintensity, and that subject had hippocampal malrotation. Ten-year cumulative incidence of all types of epilepsy, including mesial temporal epilepsy, was highest in subjects with initial T2 hyperintensity and lowest in those with normal signal and no other brain abnormalities. Significance: Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy. Normal hippocampal appearance in the acute postictal MRI was followed by maintained normal appearance, symmetric growth, and lower risk of epilepsy. Volumetric measurement detected mildly decreased hippocampal volume in males with febrile status.

Characterizing Frontal Lobe Seizure Semiology in Children.

van Dalen T, Kirkham JF, Chari A, D’Arco F, Moeller F, Eltze C, Cross JH, Tisdall MM, Thornton RC. Ann Neurol. 2024;95(6):1138–1148. DOI: 10.1002/ana.26922

Objective: The objective was to analyze seizure semiology in pediatric frontal lobe epilepsy patients, considering age, to localize the seizure onset zone for surgical resection in focal epilepsy. Methods: Fifty patients were identified retrospectively, who achieved seizure freedom after frontal lobe resective surgery at Great Ormond Street Hospital. Video-electroencephalography recordings of preoperative ictal seizure semiology were analyzed, stratifying the data based on resection region (mesial or lateral frontal lobe) and age at surgery (≤4 vs. >4). Results: Pediatric frontal lobe epilepsy is characterized by frequent, short, complex seizures, similar to adult cohorts. Children with mesial onset had higher occurrence of head deviation (either direction: 55.6% vs. 17.4%; p = 0.02) and contralateral head deviation (22.2% vs. 0.0%; p = 0.03), ictal body-turning (55.6% vs. 13.0%; p = 0.006; ipsilateral: 55.6% vs. 4.3%; p = 0.0003), and complex motor signs (88.9% vs. 56.5%; p = 0.037). Both age groups (≤4 and >4 years) showed hyperkinetic features (21.1% vs. 32.1%), contrary to previous reports. The very young group showed more myoclonic (36.8% vs. 3.6%; p = 0.005) and hypomotor features (31.6% vs. 0.0%; p = 0.003), and fewer behavioral features (36.8% vs. 71.4%; p = 0.03) and reduced responsiveness (31.6% vs. 78.6%; p = 0.002). Interpretation: This study presents the most extensive semiological analysis of children with confirmed frontal lobe epilepsy. It identifies semiological features that aid in differentiating between mesial and lateral onset. Despite age-dependent differences, typical frontal lobe features, including hyperkinetic seizures, are observed even in very young children. A better understanding of pediatric seizure semiology may enhance the accuracy of onset identification, and enable earlier presurgical evaluation, improving postsurgical outcomes.

The Value of Additional Electrodes When Stereo-Electroencephalography is Inconclusive

Ilyas A, Vilella L, Restrepo CE, Johnson J, Pati S, Lacuey N, Lhatoo S, Thompson SA, Tandon N. Epilepsia. 2024;65(3):641–650.

Objective: Stereo-electroencephalography (SEEG) is the preferred method for intracranial localization of the seizure-onset zone (SOZ) in drug-resistant focal epilepsy. Occasionally SEEG evaluation fails to confirm the pre-implantation hypothesis. This leads to a decision tree regarding whether the addition of SEEG electrodes (two-step SEEG [2sSEEG]) or placement of subdural electrodes (SDEs) after SEEG (SEEG2SDE) would help. There is a dearth of literature encompassing this scenario, and here we aimed to characterize outcomes following unplanned two-step intracranial electroencephalogram (iEEG). Methods: All 225 adult SEEG cases over 8 years at our institution were reviewed to extract patient data and outcomes following a 2-step evaluation. Three raters independently quantified the benefits of additional intracranial electrodes. The relationship between the 2-step iEEG benefit and clinical outcome was then analyzed. Results: Fourteen patients underwent 2sSEEG and 9 underwent SEEG2SDE. In the former cohort, the second SEEG procedure was performed for these reasons-precise localization of the SOZ (36%); defining margins of eloquent cortex (21%); and broadening coverage in the setting of nonlocalizable seizure onsets (43% of cases). Sixty-four percent of 2sSEEG cases were consistently deemed beneficial (Light's κ = 0.80). 2sSEEG performed for the first 2 indications was much more beneficial than when onsets were not localizable (100% vs 17%, P = .02). In the SEEG2SDE cohort, SDEs identified the SOZ and enabled delineation of margins relative to the eloquent cortex in all cases. Significance: The 2-step iEEG is useful if the initial evaluation is broadly concordant with the original electroclinical hypothesis, where it can clarify onset zones or delineate safe surgical margins; however, it provides minimal benefit when the implantation hypothesis is erroneous, and we recommend that 2sSEEG not be generally utilized in such cases. SDE implantation after SEEG minimizes the need for SDEs and is helpful in delineating surgical boundaries relative to ictal-onset zones and eloquent cortex.

Increasing Risk of Dementia Among Patients With Subsequent Epilepsy Within 2 Years Post-Traumatic Brain Injury: A Population-Based Case-Control Study

Chu SF, Liao KH, Wei L. J Multidiscip Healthc. 2024;17:1447–1457. doi:10.2147/JMDH.S452086. PMID: 38577293; PMCID: PMC10992670.

Background: Although the association between neurodegenerative diseases, such as dementia, and traumatic brain injury (TBI) has long been known, the association between dementia and TBI with epilepsy has been controversial. Aim: This data-driven population-based study is designed to investigate the association between dementia and epilepsy after TBI within a 2-year period. Methods: This case-control cohort study was conducted using the Longitudinal Health Insurance Database 2000 (LHID2000). We included 784 individuals ambulatory or hospitalized for TBI with epilepsy from 2001 to 2011, compared with 2992 patients with TBI without epilepsy who were matched for characteristics including sex, age, and healthcare resource use index date. Every participant was followed up for 5 years to ascertain any dementia development. Data were stratified and analyzed using the Cox proportional hazards regression. Results: Through the 5-year follow-up period, 39 patients (5.21%) with TBI with epilepsy and 55 (1.53%) with TBI without epilepsy developed dementia. TBI with epilepsy was independently associated with a >3.03 times risk of dementia after correcting for age, sex, and comorbidities. Conclusion: These findings suggest an increased risk of dementia in patients with TBI with epilepsy. Our research recommends that individuals with TBI and epilepsy be monitored more intensively.

Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure

Sonia Hernández-Díaz, Loreen Straub, Brian T Bateman, Yanmin Zhu, Helen Mogun, Katherine L Wisner, Kathryn J Gray, Barry Lester, Christopher J McDougle, Elyse DiCesare, Page B Pennell, Krista F Huybrechts. N Engl J Med. 2024;390(12):1069–1079. PMID: 38507750. doi: 10.1056/NEJMoa2309359

Background: Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use. Methods: We identified a population-based cohort of pregnant women and their children within 2 healthcare utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control. Results: The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score-adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine. Conclusions: The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate.

Recognition and Perception of Emotions in Juvenile Myoclonic Epilepsy

Rainer LJ, Kuchukhidze G, Trinka E, Braun M, Kronbichler M, Langthaler P, Zimmermann G, Kronbichler L, Said-Yürekli S, Kirschner M, Zamarian L, Schmid E, Jokeit H, Höfler J. Epilepsia. 2023;64(12):3319-3330. doi:10.1111/epi.17783. Epub 2023 Oct 18. PMID: 37795683

Objective: Perception and recognition of emotions are fundamental prerequisites of human life. Patients with juvenile myoclonic epilepsy (JME) may have emotional and behavioral impairments that might influence socially desirable interactions. We aimed to investigate perception and recognition of emotions in patients with JME by means of neuropsychological tests and functional magnetic resonance imaging (fMRI). Methods: Sixty-five patients with JME (median age = 27 years, interquartile range [IQR] = 23-34) were prospectively recruited at the Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University, Salzburg, Austria. Patients were compared to 68 healthy controls (median age = 24 years, IQR = 21-31), matched for sex, age, and education. All study participants underwent the Networks of Emotion Processing test battery (NEmo), an fMRI paradigm of “dynamic fearful faces,” a structured interview for psychiatric and personality disorders, and comprehensive neuropsychological testing. Results: JME patients versus healthy controls demonstrated significant deficits in emotion recognition in facial and verbal tasks of all emotions, especially fear. fMRI revealed decreased amygdala activation in JME patients as compared to healthy controls. Patients were at a higher risk of experiencing psychiatric disorders as compared to healthy controls. Cognitive evaluation revealed impaired attentional and executive functioning, namely psychomotor speed, tonic alertness, divided attention, mental flexibility, and inhibition of automated reactions. Duration of epilepsy correlated negatively with parallel prosodic and facial emotion recognition in NEmo. Deficits in emotion recognition were not associated with psychiatric comorbidities, impaired attention and executive functions, types of seizures, and treatment. Significance: This prospective study demonstrated that as compared to healthy subjects, patients with JME had significant deficits in recognition and perception of emotions as shown by neuropsychological tests and fMRI. The results of this study may have importance for psychological/psychotherapeutic interventions in the management of patients with JME.

Fallik N, Trakhtenbroit I, Fahoum F, Goldstein L. Therapeutic drug monitoring in pregnancy: Levetiracetam. Epilepsia. 2024 May;65(5):1285-1293. Epub 2024 Feb 24. PMID: 38400747. doi:10.1111/epi.17925.

Objective: Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women. Methods: This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020–2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1–2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance. Results: A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the third trimester, the most significant C/D decrease was observed at the first trimester (slope = .85), with no significant change in the second trimester (slope = .11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (μg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the third trimester. Significance: LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period.

Perucca P, Bourikas D, Voinescu PE, Vadlamudi L, Chellun D, Kumke T, Werhahn KJ, Schmitz B. Lacosamide and pregnancy: data from spontaneous and solicited reports. Epilepsia. 2024 May;65(5):1275-1284. Epub 2024 Feb 27. PMID: 38411300. doi:10.1111/epi.17924.

Objective: In pregnancy, it is important to balance the risks of uncontrolled epileptic seizures to the mother and fetus against the potential teratogenic effects of antiseizure medications. Data are limited on pregnancy outcomes among patients taking lacosamide (LCM), particularly when taken as monotherapy. The objective of this analysis was to evaluate the pregnancy outcomes of LCM-exposed pregnancies. Methods: This analysis included all reports in the UCB Pharma pharmacovigilance database of exposure to LCM during pregnancy from spontaneous sources (routine clinical settings) or solicited reports from interventional clinical studies and noninterventional postmarketing studies. Prospective and retrospective reports were analyzed separately. Results: At the data cutoff (August 31, 2021), there were 202 prospective pregnancy cases with maternal exposure to LCM and known outcomes. Among these cases, 44 (21.8%) patients received LCM monotherapy and 158 (78.2%) received LCM polytherapy. Most patients received LCM during the first trimester (LCM monotherapy: 39 [88.6%]; LCM polytherapy: 143 [90.5%]). From the prospective pregnancy cases with maternal LCM exposure, there were 204 reported outcomes (two twin pregnancies occurred in the polytherapy group). The proportion of live births was 84.1% (37/44) in patients who received LCM as monotherapy, and 76.3% (122/160) for LCM polytherapy. The overall proportion of abortions (for any reason) was 15.9% (7/44) with LCM monotherapy, and 22.5% (36/160) with LCM polytherapy. Congenital malformations were reported in 2.3% (1/44) of known pregnancy outcomes with maternal exposure to LCM monotherapy, and 6.9% (11/160) with polytherapy. Significance: Our preliminary data do not raise major concerns on the use of LCM during pregnancy. Most pregnancies with LCM exposure resulted in healthy live births, and no new safety issues were identified. These findings should be interpreted with caution, as additional data are needed to fully evaluate the safety profile of LCM in pregnancy.

Chemogenetic Approaches Reveal Dual Functions of Microglia in Seizures

Aastha Dheer, Dale B Bosco, Jiaying Zheng, Lingxiao Wang, Shunyi Zhao, Koichiro Haruwaka, Min-Hee Yi, Abhijeet Barath, Dai-Shi Tian, Long-Jun Wu. Brain Behav Immun 2024;115:406–418. PMID: 37926132. doi:10.1016/j.bbi.2023.11.002

Microglia are key players in maintaining brain homeostasis and exhibit phenotypic alterations in response to epileptic stimuli. However, it is still relatively unknown if these alterations are pro- or anti-epileptic. To unravel this dilemma, we employed chemogenetic manipulation of microglia using the artificial Gi-Designer Receptors Exclusively Activated by Designer Drugs (Gi-DREADD) receptor within a kainic acid (KA) induced murine seizure model. Our results indicate that acute Gi-DREADD activation with clozapine N-oxide can reduce seizure severity. Additionally, we observed increased interaction between microglia and neuronal soma, which correlated with reduced neuronal hyperactivity. Interestingly, prolonged activation of microglial Gi-DREADDS by repeated doses of clozapine N-oxide (CNO) over 3 days, arrested microglia in a less active, homeostatic-like state, which is associated with increased neuronal loss after KA-induced seizures. RNAseq analysis revealed that prolonged activation of Gi-DREADD interferes with interferon β signaling and microglia proliferation. Thus, our findings highlight the importance of microglial Gi signaling not only during status epilepticus (SE) but also within later seizure-induced pathology.

Identification of Four Biotypes in Temporal Lobe Epilepsy via Machine Learning on Brain Images

Jiang Y, Li W, Li J, Li X, Zhang H, Sima X, Li L, Wang K, Li Q, Fang J, Jin L, Gong Q, Yao D, Zhou D, Luo C, An D. Nat Commun. 2024;15(1):2221. PMCID: PMC10933450

Artificial intelligence provides an opportunity to try to redefine disease subtypes based on similar pathobiology. Using a machine-learning algorithm (Subtype and Stage Inference) with cross-sectional magnetic resonance imaging from 296 individuals with focal epilepsy originating from the temporal lobe epilepsy (TLE) and 91 healthy controls, we show phenotypic heterogeneity in the pathophysiological progression of TLE. This study was registered in the Chinese Clinical Trials Registry (number: ChiCTR2200062562). We identify 2 hippocampus-predominant phenotypes, characterized by atrophy beginning in the left or right hippocampus; a third cortex-predominant phenotype, characterized by hippocampus atrophy after the neocortex; and a fourth phenotype without atrophy but amygdala enlargement. These 4 subtypes are replicated in the independent validation cohort (109 individuals). These subtypes show differences in neuroanatomical signature, disease progression, and epilepsy characteristics. Five-year follow-up observations of these individuals reveal differential seizure outcomes among subtypes, indicating that specific subtypes may benefit from temporal surgery or pharmacological treatment. These findings suggest a diverse pathobiological basis underlying focal epilepsy that potentially yields stratification and prognostication—a necessary step for precise medicine.

Testing of Putative Antiseizure Medications in a Preclinical Dravet Syndrome Zebrafish Model

Whyte-Fagundes PA, Vance A, Carroll A, Figueroa F, Manukyan C, Baraban SC. Brain Commun. 2024;6(3):fcae135.

Dravet syndrome is a severe genetic epilepsy primarily caused by de novo mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening seizures that are largely resistant to available anti-seizure medications. Preclinical Dravet syndrome animal models are a valuable tool to identify candidate anti-seizure medications for these patients. Among these, scn1lab mutant zebrafish, exhibiting spontaneous seizure-like activity, are particularly amenable to large-scale drug screening. Thus far, we have screened more than 3000 drug candidates in scn1lab zebrafish mutants, identifying valproate, stiripentol, and fenfluramine e.g. Food and Drug Administration-approved drugs, with clinical application in the Dravet syndrome population. Successful phenotypic screening in scn1lab mutant zebrafish is rigorous and consists of two stages: (i) a locomotion-based assay measuring high-velocity convulsive swim behaviour and (ii) an electrophysiology-based assay, using in vivo local field potential recordings, to quantify electrographic seizure-like events. Historically, nearly 90% of drug candidates fail during translation from preclinical models to the clinic. With such a high failure rate, it becomes necessary to address issues of replication and false positive identification. Leveraging our scn1lab zebrafish assays is one approach to address these problems. Here, we curated a list of nine anti-seizure drug candidates recently identified by other groups using preclinical Dravet syndrome models: 1-Ethyl-2-benzimidazolinone, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat. First-stage locomotion-based assays in scn1lab mutant zebrafish identified only 1-Ethyl-2-benzimidazolinone, chlorzoxazone and lisuride. However, second-stage local field potential recording assays did not show significant suppression of spontaneous electrographic seizure activity for any of the nine anti-seizure drug candidates. Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of anti-seizure medications.

Glial KCNQ K+ Channels Control Neuronal Output by Regulating GABA Release From Glia in C. elegans

Graziano B, Wang L, White OR, Kaplan DH, Fernandez-Abascal J, Bianchi L. Neuron. 2024;112(11):1832–1847.e7. doi: 10.1016/j.neuron.2024.02.013. Epub 2024 Mar 8. PMID: 38460523; PMCID: PMC11156561.

KCNQs are voltage-gated K+ channels that control neuronal excitability and are mutated in epilepsy and autism spectrum disorder. KCNQs have been extensively studied in neurons, but their function in glia is unknown. Using voltage, calcium, and GABA imaging, optogenetics, and behavioral assays, we show here for the first time in Caenorhabditis elegans (C. elegans) that glial KCNQ channels control neuronal excitability by mediating GABA release from glia via regulation of the function of L-type voltage-gated Ca²⁺ channels. Further, we show that human KCNQ channels have the same role when expressed in nematode glia, underscoring conservation of function across species. Finally, we show that pathogenic loss-of-function and gain-of-function human KCNQ2 mutations alter glia-to-neuron GABA signaling in distinct ways and that the KCNQ channel opener retigabine exerts rescuing effects. This work identifies glial KCNQ channels as key regulators of neuronal excitability via control of GABA release from glia.

Ndnf Interneuron Excitability Is Spared in a Mouse Model of Dravet Syndrome

Liebergall SR, Goldberg EM. J Neurosci. 2024;44(17):e1977232024. doi: 10.1523/JNEUROSCI.1977-23.2024. PMID: 38443186; PMCID: PMC11044195

Dravet syndrome (DS) is a neurodevelopmental disorder characterized by epilepsy, developmental delay/intellectual disability, and features of autism spectrum disorder, caused by heterozygous loss-of-function variants in SCN1A encoding the voltage-gated sodium channel α subunit Nav1.1. The dominant model of DS pathogenesis is the “interneuron hypothesis,” whereby GABAergic interneurons (INs) express and preferentially rely on Nav1.1-containing sodium channels for action potential (AP) generation. This has been shown for three of the major subclasses of cerebral cortex GABAergic INs: those expressing parvalbumin (PV), somatostatin, and vasoactive intestinal peptide. Here, we define the function of a fourth major subclass of INs expressing neuron-derived neurotrophic factor (Ndnf) in male and female DS (Scn1a+/−) mice. Patch-clamp electrophysiological recordings of Ndnf-INs in brain slices from Scn1a+/– mice and wild-type (WT) controls reveal normal intrinsic membrane properties, properties of AP generation and repetitive firing, and synaptic transmission across development. Immunohistochemistry shows that Nav1.1 is strongly expressed at the axon initial segment (AIS) of PV-expressing INs but is absent at the Ndnf-IN AIS. In vivo two-photon calcium imaging demonstrates that Ndnf-INs in Scn1a+/− mice are recruited similarly to WT controls during arousal. These results suggest that Ndnf-INs are the only major IN subclass that does not prominently rely on Nav1.1 for AP generation and thus retain their excitability in DS. The discovery of a major IN subclass with preserved function in the Scn1a+/− mouse model adds further complexity to the “interneuron hypothesis.”

Targeting Pathological Cells With Senolytic Drugs Reduces Seizures in Neurodevelopmental mTOR-Related Epilepsy

Ribierre T, Bacq A, Donneger F, Doladilhe M, Maletic M, Roussel D, Le Roux I, Chassoux F, Devaux B, Adle-Biassette H, Ferrand-Sorbets S, Dorfmuller, G, Chipaux, M, Baldassari, S, Poncer, JC, Baulac, S. Nature Neuroscience. 2024:1–12.

Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, senescence-associated secretory phenotype expression, and senescence-associated β-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an MtorS2215F FCDII preclinical mouse model, providing proof of concept that senotherapy may be a useful approach to control seizures. These findings pave the way for therapeutic strategies selectively targeting mutated senescent cells in FCDII brain tissue.

Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults

King DR, Demirtas M, Tarasov M, Struckman HL, Meng X, Nassal D, Moise N, Miller A, Min D, Soltisz AM, Anne MNK, Alves DPA, Wagnon JL, Weinberg SH, Hund TJ, Veeraraghavan R, Radwański PB. JACC Clin. Electrophysiol. 2024;10(5):829–842. doi:10.1016/j.jacep.2024.01.003.

Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy epilepsy patients. Dravet syndrome (DS) is an inherited epileptic disorder resulting from loss-of-function of the voltage-gated sodium channel, Na_V 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that Na_Vs abundant in the brain also occur in the heart, suggesting that the very molecular mechanisms underlying epilepsy could also precipitate cardiac arrhythmias and sudden death. Despite marked reduction of Na_V 1.1 functional expression in DS, pathogenic late sodium current (INa,L) is paradoxically increased in DS hearts. However, the mechanisms by which DS directly impacts the heart to promote sudden death remain unclear. In this study, the authors sought to provide evidence implicating remodeling of Na⁺- and Ca²⁺-handling machinery, including NaV 1.6 and Na⁺/Ca²⁺ exchanger (NCX) within transverse (T)-tubules in DS-associated arrhythmias. The authors undertook scanning ion conductance microscopy (SICM)-guided patch clamp, super-resolution microscopy, confocal Ca²⁺ imaging, and in vivo electrocardiography studies in Scn1a haploinsufficient murine model of DS. DS promotes INa,L in T-tubular nanodomains, but not in other subcellular regions. Consistent with increased Na_V activity in these regions, super-resolution microscopy revealed increased Na_V 1.6 density near Ca²⁺ release channels, the ryanodine receptors (RyR2), and NCX in DS relative to WT hearts. The resulting INa,L in these regions promoted aberrant Ca²⁺ release, leading to ventricular arrhythmias in vivo. Cardiac-specific deletion of Na_V 1.6 protects adult DS mice from increased T-tubular late Na_V activity and the resulting arrhythmias, as well as sudden death. These data demonstrate that Na_V 1.6 undergoes remodeling within T-tubules of adult DS hearts serving as a substrate for Ca²⁺-mediated cardiac arrhythmias and may be a druggable target for the prevention of SUDEP in adult DS subjects.

Molecular and Cellular Context Influences SCN8A Variant Function

Vanoye CG, Abramova TV, DeKeyser J-M, Ghabra NF, Oudin MJ, Burge CB, Helbig I, Thompson CH, George AL. JCI Insight 2024; 9(12). doi:10.1172/jci.insight.177530.

Pathogenic variants in SCN8A, which encodes the voltage-gated sodium (NaV) channel NaV1.6, associate with neurodevelopmental disorders, including developmental and epileptic encephalopathy. Previous approaches to determine SCN8A variant function may be confounded by use of a neonatally expressed, alternatively spliced isoform of NaV1.6 (NaV1.6N) and engineered mutations rendering the channel tetrodotoxin (TTX) resistant. We investigated the impact of SCN8A alternative splicing on variant function by comparing the functional attributes of 15 variants expressed in 2 developmentally regulated splice isoforms (NaV1.6N, NaV1.6A). We employed automated patch clamp recording to enhance throughput and developed a neuronal cell line (ND7/LoNav) with low levels of endogenous NaV current to obviate the need for TTX-resistance mutations. Expression of NaV1.6N or NaV1.6A in ND7/LoNav cells generated NaV currents with small, but significant, differences in voltage dependence of activation and inactivation. TTX-resistant versions of both isoforms exhibited significant functional differences compared with the corresponding WT channels. We demonstrated that many of the 15 disease-associated variants studied exhibited isoform-dependent functional effects and that many of the studied SCN8A variants exhibited functional properties that were not easily classified as either gain- or loss-of-function. Our work illustrates the value of considering molecular and cellular context when investigating SCN8A variants.

Heterogeneous Subpopulations of GABAAR-Responding Neurons Coexist Across Neuronal Network Scales and Developmental Stages in Health and Disease

Colombi I, Rastogi M, Parrini M, Alberti M, Potenzieri A, Chellali MM, Rosati S, Chiappalone M, Nanni M, Constabile A, Cancedda L. iScience 2024;27:109438.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in adults. Depolarizing GABA responses have been well characterized at the neuronal-population average level during typical neurodevelopment and partially in brain disorders. However, no investigation has specifically assessed whether a mosaicism of cells with either depolarizing or hyperpolarizing/inhibitory GABAergic responses exists in animals in health/disease at diverse developmental stages, including adulthood. Here, we showed that such mosaicism is present in wild-type (WT) and Down syndrome (DS) neuronal networks, as assessed at increasing scales of complexity (cultures, brain slices, behaving mice). Nevertheless, WT mice presented a much lower percentage of cells with depolarizing GABA than DS mice. Restoring the mosaicism of hyperpolarizing and depolarizing GABA-responding neurons to WT levels rescued anxiety behavior in DS mice. Moreover, we found heterogeneous GABAergic responses in developed control and trisomic human-induced pluripotent stem-cell-derived neurons. Thus, a heterogeneous subpopulation of GABA-responding cells exists in physiological/pathological conditions in mouse and human neurons, possibly contributing to disease-associated behaviors.