Margaret Gopaul

Objective: To characterize serum and cerebrospinal fluid (CSF) cytokine dynamics according to immunotherapy exposure in cryptogenic new‐onset refractory status epilepticus (cNORSE). Methods: We analyzed cytokine profiles in 94 serum and 42 CSF samples from 29 and 14 patients, respectively, with cNORSE. Nine contributed both sample types, resulting in 34 patients. Samples were categorized according to immunotherapy exposure as no immunotherapy (NT), first‐line (FL), and second‐line (SL), and stratified by innate‐ or adaptive‐directed therapies. SL represented cumulative exposure, as all SL samples followed initiation of both FL and SL therapies. Linear mixed‐effects models accounted for repeated measures and time from cNORSE onset. A systematic literature review included 27 studies and 63 patients. Results: Serum cytokine levels were generally lower during FL ( n = 24) than NT ( n = 9), whereas most cytokines were higher during SL ( n = 61) than FL. CXCL8 (C‐X‐C motif ligand 8)/IL‐8 and CCL2 (C‐C motif chemokine ligand 2) were higher during SL than FL, with CCL2 remaining significant after multiple‐testing correction. No serum differences remained significant when analyses were restricted to samples collected 7–30 days after onset. CSF levels were generally lower during FL ( n = 10) and SL ( n = 25) than NT ( n = 7). Innate‐directed therapies were associated with higher serum IL‐6, CXCL8/IL‐8, and CCL2 and CSF IL‐4, whereas adaptive‐directed therapies were associated with lower CSF MIP‐1α (Macrophage Inflammatory Protein‐1 alpha). The association with higher serum IL‐6 was no longer observed after excluding tocilizumab‐treated patients. No temporal association after SL initiation or status epilepticus resolution remained significant after multiple‐testing correction. The literature review showed more frequent reductions in pro‐inflammatory cytokines in CSF than serum following immunotherapy initiation. Significance: Cytokine profiles in cNORSE differ by treatment exposure and compartment. Persistent serum inflammation during SL may reflect disease severity, systemic inflammation, treatment effects, or their combination, whereas CSF showed more consistent reductions after immunotherapy exposure. These findings highlight the importance of treatment timing and compartment when interpreting cytokine measurements and support prospective studies integrating baseline immune phenotypes and standardized clinical outcomes.

Epilepsy prevalence sharply increases after age 65 years, but elderly adults are chronically underrepresented in key trials that form the licensing evidence base for antiseizure medications (ASMs), leaving clinicians to extrapolate from the experiences of younger cohorts. This narrative review aims to consolidate real-world evidence regarding the efficacy, safety, and tolerability of 4 commonly prescribed newer ASMs, perampanel (PER), lacosamide (LCM), eslicarbazepine acetate (ESL), and brivaracetam (BRV) among adults ≥65 years, provide pragmatic prescribing recommendations based on this evidence, and define key gaps where further study should be prioritized. Collating data from our structured search of observational cohorts, interventional trials and extensions, pooled and post hoc analyses, pharmacovigilance databases, and case series and reports, we found that reported effectiveness outcomes in older adults were generally comparable to those observed in broader adult populations, although heterogeneity across studies limits direct comparisons. ESL monotherapy produced 1-year retention rates of 72.7% and 6- and 12-month seizure freedom rates of 72.2% and 67.3% among patients ≥65 years; adjunctive LCM demonstrated superior seizure freedom rates among older versus younger patients (56.7% vs. 43.1%); and dedicated ≥65-year-old studies of ESL and BRV reaffirmed efficacy observed in overall populations, frequently at lower doses and slower titration schedules. Key safety signals were drug-specific: hyponatremia (more common and symptomatic in older adults) for ESL; dose-dependent PR interval prolongation and rare high-grade atrioventricular block/ventricular tachycardia, Brugada morphology, and sinus node dysfunction for LCM; and psychiatric or behavioral events, dose-dependent falls for PER. Evidence supported a class-wide relationship between chronic ASM exposure and falls and fractures, while a FAERS analysis found no significant drug reaction with eosinophilia and systemic symptoms (DRESS) signal for BRV and analysis-dependent findings for LCM. In conclusion, newer ASMs are efficacious and generally well tolerated among older adults. However, optimized safe prescribing in this population requires ASM selection tailored to comorbidities, lower starting doses with slower titration, and drug-specific follow-up (e.g., serum sodium monitoring for ESL, cardiac conduction assessment for LCM, and behavior and fall risk assessment for PER). Evidence remains lacking in adults ≥65 years of age, particularly for brivaracetam.

Memory impairment is a common cognitive comorbidity of epilepsy and can substantially affect quality of life. Most memory testing tasks measure learning and memory over about 20 to 30 minutes, which may not capture the complexity of long-term memory formation. Because long-term memories continue to consolidate over hours or days, weeks, or longer, more comprehensive evaluation methods may be needed to assess whether memories persist over time.This raises an important question: Do conventional memory assessments adequately assess the longevity of memory? One issue is accelerated long-term forgetting (ALF), characterized by relatively intact learning and short-delay recall, followed by disproportionately rapid forgetting over longer intervals. ALF has been studied most extensively in epilepsy and has been associated with abnormalities involving the hippocampus and related memory networks. In temporal lobe epilepsy, accelerated memory decay has been demonstrated between conventional delayed and longer-term recall. Impaired systems consolidation is a leading explanation, with possible contributions from sleep disruption, interictal epileptiform activity, and broader network dysfunction. However, substantial methodological variability across studies, including differences in learning procedures, retention intervals, outcome measures, and definitions of abnormal forgetting, limits comparison and interpretation of findings.This review integrates current knowledge from diverse areas, including epilepsy, neuroscience, sleep studies, brain imaging, and aging. It discusses the role of ALF as a measure of memory deficits, explores its biological basis, and assesses the strengths and limitations of existing research. We also consider whether ALF could serve as a candidate behavioral marker of hippocampal network vulnerability. Before this role can be established, extended-delay memory paradigms require greater methodological standardization and prospective multimodal validation. Understanding memory persistence as a key component of cognitive function may help refine memory assessment tools, improve understanding of neurological conditions, and develop new approaches to assessing cognitive health in patients with epilepsy and other neurological conditions.

Background and ObjectivesPsychiatric comorbidities are highly prevalent in people with epilepsy, which adversely affect treatment outcomes. The proper choice of antiseizure medication (ASM) is ther...

Mental health equity is a critical issue for people with epilepsy (PWE), who bear a disproportionate burden of psychiatric and cognitive comorbidities. Conditions such as depression, anxiety, attention-deficit/hyperactivity disorder, autism spectrum disorder, functional/dissociative seizures, and cognitive impairment occur more frequently in PWE, contributing to elevated morbidity, mortality, and reduced quality of life. Many of these disorders have bidirectional relationships with epilepsy, reflecting overlapping biological, psychological, and social mechanisms. Social Determinants of Health (SDoH), including educational opportunities, access to health care, neighborhood and environmental exposures, social and community context, and economic stability, further shape risk, presentation, and outcomes across the lifespan. Children with epilepsy and neurodevelopmental disorders face academic and service inequities, while adults encounter barriers in mental health access and stigma that may worsen depression and anxiety. Older adults with epilepsy and dementia experience additional disparities driven by socioeconomic status and minority status. This narrative review synthesizes current evidence on the epidemiology, risk factors, and mechanisms linking epilepsy with psychiatric, neurodevelopmental, and neurodegenerative conditions, with an emphasis on how SDoH exacerbates inequities. We identify gaps in mechanistic research and highlight the underrepresentation of vulnerable populations. To advance equity, strategies must include routine SDoH screening, integration of psychosocial and neurologic care, stigma-reduction efforts, and development of culturally competent, patient-centered interventions. Policy initiatives that address structural barriers to care are also essential. Together, these approaches can improve outcomes and promote health equity for PWE.

Status epilepticus (SE) is a life‐threatening neurological emergency with consensus‐driven definitions for onset but no standardized criteria for its end point. This gap creates uncertainty in research and clinical practice. We conducted a scoping review to evaluate how end points have been defined in SE research and to identify key areas of variability. Comprehensive searches of MEDLINE, Embase, and CENTRAL (Cochrane Central Registry of Controlled Trials; 1980–2025) yielded 3940 citations (1674 unique). After screening, 207 studies met the inclusion criteria and were charted using scoping review methodology (Preferred Reporting Items of Systematic Reviews and Meta‐Analyses, extension for scoping reviews). Data were extracted on terminology, electroencephalography (EEG) use, temporal thresholds, and definitions of therapeutic success across retrospective and prospective designs. Five domains of heterogeneity were identified: (1) semantic terminology (e.g., “resolved,” “controlled,” “terminated,” “cessation”); (2) EEG confirmation of the SE end point (reported in 54% of studies, with variable criteria); (3) whether time was included in defining the end point; (4) how quickly seizures were judged to have stopped, based on clinical signs, EEG findings, or both; and (5) how long seizure freedom had to be maintained to count as a successful end point. No consistent global or time‐based patterns were identified, and overlapping terminology further limited comparison across studies. Despite established consensus definitions for SE onset, the end point remains variably defined, undermining methodological rigor and limiting cross‐study synthesis. A unified, consensus‐driven framework is urgently needed to standardize SE end points through the use of standard terminology and methodologies, thereby strengthening clinical trial design and facilitating regulatory evaluation of novel therapies.

Objective: Cryptogenic new onset refractory status epilepticus (cNORSE) carries high risks of long‐term disability and post‐NORSE epilepsy, but mechanisms remain unclear. We aimed to assess the predictive value of inflammatory and brain injury biomarkers and determine whether immune disturbances persist in the chronic phase. Methods: We enrolled 93 cNORSE patients from the Pitié‐Salpêtrière Hospital and the Yale NORSE/FIRES biorepository (2013–2025). Serum and cerebrospinal fluid (CSF) samples were collected during status epilepticus (SE), with outcomes assessed 6–12 months after resolution. To investigate post‐cNORSE epilepsy, we compared 39 post‐cNORSE patients (25 with paired acute samples) to 40 patients with temporal lobe epilepsy due to hippocampal sclerosis (TLE‐HS) and 20 with chronic immune‐mediated encephalitis. Results: During cNORSE, elevated innate cytokines (serum CXCL8, CCL2; CSF IL‐6, CXCL8, CCL2, MIP‐1α, G‐CSF) and brain injury biomarkers (serum and CSF neurofilament light chain [NfL], CSF neuron‐specific enolase) correlated with worse functional outcomes. Multivariate models demonstrated that adding serum NfL to cytokines improved poor outcome prediction (area under the curve = .75). In contrast, no acute biomarker predicted post‐cNORSE epilepsy, which was instead associated with prolonged SE, magnetic resonance imaging abnormalities, and the need for more intensive treatment. In paired analyses, most serum cytokines normalized during the chronic phase, particularly IL‐6, IL‐10, and IL‐1β, although new adaptive immune disturbances (IL‐17A, IL‐12p70, TNFα) appeared in 20% of patients. No chronic elevations of innate cytokines were observed in post‐cNORSE patients. Conversely, elevated age‐adjusted NfL levels were more frequent in post‐cNORSE epilepsy (64%) than encephalitis (45%) and TLE‐HS (20%), ( p < .001), with elevated NfL levels correlating with poor functional outcomes ( p = .019). Significance: Innate immune activation is a hallmark of acute cNORSE but largely resolves in the chronic phase, arguing against persistent innate inflammation as the driver of post‐cNORSE epilepsy. In contrast, persistently elevated NfL levels suggest ongoing axonal injury, potentially contributing to poor outcomes. Integrating inflammatory and neuroaxonal injury biomarkers may improve risk stratification and guide long‐term management.