Feyissa, Anteneh M.

Immune-mediated epilepsies represent an etiologically unique category defined by immune activation within the central nervous system that initiates a pathophysiological cascade resulting in seizures, encephalopathy, and sometimes epileptogenesis with long-term epilepsy. Once considered rare and largely confined to paraneoplastic or postinfectious syndromes, immune-mediated and inflammatory mechanisms are now recognized across a broad spectrum ranging from acute autoimmune encephalitis with reversible seizures, new-onset refractory status epilepticus, or febrile illness-related refractory status epilepticus, to chronic autoimmune-associated epilepsy and drug-refractory structural epilepsies. This review integrates historical perspectives, mechanistic insights from animal and human studies, and contemporary clinical frameworks. It synthesizes advances in neuroimmunology, clinical phenotyping, diagnostics, immunomodulatory and antiseizure therapies, neuromodulation, and patient and family centered outcomes, and outlines future directions focused on biomarker-driven precision medicine, disease-modifying strategies, and interdisciplinary care models.

Preserving Cognition and Reducing Dementia Risk in Focal Epilepsy Tai XY, Zhao S, Liem B, Galovic M, Husain M, Sen A, Manohar S. The Relationship Between Sleep, Cognition, and Dementia Risk in People With Focal Epilepsy. Neurology. 2026 May 26;106(10):e214985. doi: 10.1212/WNL.0000000000214985. Epub 2026 Apr 22. PMID: 42018962 Background and objectives: Sleep disruption and cognitive impairment are important comorbidities of focal epilepsy. However, the nature to which sleep affects cognition and long-term dementia risk in focal epilepsy, compared with other brain conditions, remains unclear. We examined the relationship between sleep, cognition, and dementia risk in patients with focal epilepsy compared with healthy controls and stroke patients. Methods: We conducted an analysis of the prospective UK Biobank cohort study, with baseline assessments performed between 2006 and 2010 and follow-up until 2021. Study groups were mutually exclusive participants with focal epilepsy and stroke at baseline assessment and healthy controls. Sleep characteristics included reports of sleep duration, obstructive sleep apnea, insomnia, napping, and dozing. Main outcomes were risk of incident all-cause dementia and Alzheimer’s disease from Cox proportional hazard modeling and comparison of executive function measures and brain total hippocampal and gray matter volumes using generalized linear modeling. Results: We examined a sample of 482,207 participants, aged between 38 and 72 years (mean [SD] 57.6 [8.1] years; 53.8% female), without dementia at baseline and a nested imaging subsample of 42,345 participants. Optimal sleep duration (6-8 h) was associated with better executive function in control, focal epilepsy, and stroke groups. The impact of optimal sleep was significantly higher in individuals with focal epilepsy compared with controls (interaction term, p = 0 . 009), but not in the stroke group (interaction term, p = 0 . 574). Nonoptimal sleep was associated with worse executive function up to 8 years before the diagnosis of focal epilepsy. A fivefold increased risk of developing dementia was seen in individuals with focal epilepsy and nonoptimal sleep (hazard ratio [HR] 5.15, 95% CI: 3.77–7.04, p < 0 . 001) compared with healthy controls with optimal sleep. This was greater than in stroke individuals with poor sleep (HR 3.48, 95% CI: 2.82–4.26, p < 0 . 001). Optimal sleep compared with nonoptimal sleep modified the dementia risk in individuals focal epilepsy, with a significantly greater improvement compared with healthy controls (interaction term p = 0 . 017), while no significant difference was seen in the stroke group (interaction term p = 0 . 991). Discussion: Optimal sleep modified both cognitive performance and dementia risk in individuals with focal epilepsy compared with stroke patients and healthy controls. Based on self-reported sleep data, these findings suggest that improving sleep may be an impactful intervention to improve cognition and reduce dementia risk particularly in focal epilepsy.

Purpose: Subcortical functional brain mapping is a valuable technique, especially involving lesions within or near white matter tracts. Motor and language deficits caused by intraoperative damage to these subcortical fibers are associated with worse outcomes. However, there are variable approaches to performing subcortical functional brain mapping. This systematic review was performed to better understand indications and optimal stimulation parameters. Methods: A systematic review was performed by PRISMA guidelines, using PubMed, Scopus, and Medline databases. Search dates ranged from inception to November 30th, 2024. Studies included adults who underwent subcortical electrical stimulation for functional brain mapping. Results: A total of 55 articles (249 patients, mean age 44.8 years, 114 female) were included. The most common pathology was brain tumor (96.3%), primarily gliomas and metastases, and 24.4% of all cases had a history of epilepsy. The most frequently mapped white matter tracts were the arcuate fasciculus, corticospinal/pyramidal tract, and inferior fronto-occipital fasciculus, involving motor, language, and cognitive functions. Bipolar stimulation (50–60 Hz, 0.5–1 millisecond, 1–10 mA) was preferred over monopolar stimulation. Among 147 patients with outcome data, 89.1% did not suffer permanent adverse outcomes including neurologic deficits, although long-term outcomes were inconsistently reported. Conclusions: The methodologic variability of subcortical functional brain mapping and lack of long-term follow-up reported limits determination of optimal parameter selection for electrical stimulation although common trends are reported. Functional brain mapping approaches may be guided by the tract and network involved. Further studies are needed to develop a standardized approach and more definitive guideline to its performance.

Introduction: Glutamic acid decarboxylase 65 (GAD65) antibody-associated temporal lobe epilepsy (GAD65-TLE) is a rare form of autoimmune-associated epilepsy characterized by medically refractory seizures and cognitive decline. Diagnosis typically requires antibody testing and clinical correlation, and treatment options include immunotherapy and antiseizure medications (ASMs). However, many patients experience persistent or worsening symptoms despite ongoing treatment. Case Report: A 20-year-old woman presented with mild cognitive impairment and focal aware seizures that gradually progressed in frequency and severity. A diagnostic workup revealed GAD65-TLE, and the patient began treatment with intravenous methylprednisolone infusions and antiseizure medications within 6 months of her presentation. After 20 months of treatment, the patient was on stable doses of levetiracetam and lamotrigine and finished tapering immunosuppressive therapy with methylprednisolone. The frequency of her focal aware seizures significantly decreased, whereas the focal impaired aware and focal bilateral tonic-clonic seizures resolved. The patient was able to return to all of her previous daily activities. Conclusions: In patients presenting with new-onset seizures characterized by unusual semiology and frequent focal aware seizures, it is crucial to consider GAD65-TLE in the list of potential diagnoses. Delayed diagnosis may lead to resistance to both ASMs and immunotherapy. This case report emphasizes how prompt identification and early initiation of immunotherapy can significantly impact the course of the disease.

Human Epilepsy Project (1) Investigators. Treatment Response to Antiseizure Medications in People With Newly Diagnosed Focal Epilepsy Barnard SN, Chen Z, Holmes M, Kanner AM, Hegde M, Kuzniecky R, Lowenstein D, French JA. JAMA Neurol . 2025 Aug 25:e252949. doi: 10.1001/jamaneurol.2025.2949. Epub ahead of print. PMID: 40853673 Importance: Epilepsy affects approximately 65 million people worldwide, and 60% have focal seizures. Predicting seizure response and drug resistance to antiseizure medications (ASMs) in people with focal epilepsy remains difficult. Objective: To describe the expected short- and long-term response to treatment with ASMs in people with focal epilepsy using recognized definitions by the International League Against Epilepsy. Design, setting, and participants: The Human Epilepsy Project is an international, prospective, observational cohort study that followed up people with newly diagnosed focal epilepsy for up to 6 years between 2012 and 2020. Data were analyzed from 2023 to 2024. The Human Epilepsy Project was conducted at 34 tertiary epilepsy centers across the US, Australia, and Europe. Participants with confirmed diagnosis of focal epilepsy aged 12 to 60 years were enrolled within 4 months of treatment initiation with ASM(s). Data were analyzed from February 2024 to July 2024. Exposure: ASM (variable). Main outcomes and measures: The primary outcome was seizure freedom, defined as a period without seizures for 12 months or 3 times the longest pretreatment seizure-free interval, whichever was longer. Treatment response was categorized as sensitive, meaning seizure free receiving 2 or fewer adequate ASM trials; resistant, meaning having 2 or more adequate ASM trials fail; or indeterminate (neither treatment sensitive nor resistant). Results: Among 448 enrolled participants, 267 (59.6%) were female, and median (IQR) participant age was 32 (21–44) years at treatment initiation. Median (IQR) follow-up duration was 3.13 (2.33–3.55) years. Most achieved seizure freedom (267 participants of 448 [59.6%]), largely without relapse (223 [83.5%]). There were 245 treatment-sensitive participants (54.7%), 102 treatment-resistant participants (22.8%), and 101 indeterminate participants (22.5%). Among treatment-sensitive participants, most (217 [89.3%]) responded to monotherapy and half (121 [49.4%], or 27% of total cohort) became seizure free while receiving their first ASM. In the first year of treatment, 251 participants (63%) had ongoing or worsening seizures. Median time to first seizure freedom was 12.1 months (95% CI, 9.7–16.1). This occurred earlier in those who never relapsed (median, 2.2 months; 95% CI, 0.8–3.2) than those who did (median, 7.4 months; 95% CI, 4.0–10.7). Those with infrequent pretreatment seizures were 0.30-fold less likely to be treatment resistant than those with very frequent seizures (hazard ratio, 0.30; 95% CI, 0.14–0.64; P = .002; Holm–Bonferroni-corrected P = .006). Participants with self-reported comorbid psychological disorders were 1.78-fold more likely to be treatment resistant than those without (relative risk, 1.78; 95% CI, 1.26–2.52; P = .001). Conclusions and relevance: In the Human Epilepsy Project multicenter prospective cohort study, most people with newly diagnosed focal epilepsy took more than a year and more than 1 ASM to become seizure free. Drug resistance can be identified earlier in those with frequent pretreatment seizures, and a history of psychiatric comorbidities at epilepsy diagnosis is an important prognostic factor.

OBJECTIVE The aim of this study was to compare 3 electrode designs—a novel 22-contact circular grid, standard 6-contact strip, and high-density (HD) grid between 32 and 64 contacts—for the detection of epileptiform activity during awake craniotomy. METHODS This study included patients who underwent functional brain mapping with and without direct electrical stimulation during awake craniotomy. Demographic, clinical, and electrocorticography (ECoG) data were collected. RESULTS A total of 194 patients were included, with 264 instances of electrode use: 113 circular grid, 96 strip electrode, and 55 HD grid. The HD grid (15%) was used less to record ECoG during direct electrical stimulation than the circular grid (80%, p < 0.001) and strip electrodes (69%, p < 0.001). Sporadic interictal epileptiform activity was better detected with circular (45%, p < 0.001) and HD (40%, p = 0.006) grids compared with strip electrodes (16%). Spontaneous seizures were recorded more frequently with the circular grid (16%, p = 0.018) compared with the strip electrode (9.4%) and HD grid (1.8%). Afterdischarges were more frequently detected by the circular grid (69%, p = 0.031) and with circular and HD grids (combined) compared with strip electrodes (67% vs 48%, p = 0.024), at lower median intensity (3 mA vs 5 mA, p < 0.001). Multivariable analyses demonstrated circular grids (p < 0.001) to be more sensitive in detecting spontaneous epileptiform activity than strip and HD grid electrodes, and grids (circular and HD) to be better in recording stimulus-induced epileptiform activity (p = 0.01). CONCLUSIONS This study demonstrates a higher rate of detection of epileptiform activity with circular and standard grids when compared with strip electrodes. The standard HD grid was used less during electrical stimulation, demonstrating the importance of both the number of contacts and design array when considering optimal conditions for ECoG and functional brain mapping.