Feyissa, A 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.

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.

Background: Electroencephalography (EEG) is increasingly used in intensive care units (ICUs), primarily for seizure detection. However, the complex clinical context of critically ill patients and the dynamic ICU environment can complicate interpretation. Purpose: To highlight common pitfalls in ICU EEG interpretation and strategies to distinguish epileptic seizures from mimics. Research Design: Retrospective case series. Study Sample: Five ICU patients undergoing continuous video EEG (cvEEG) for altered mental status, status epilepticus, or paroxysmal events, with underlying conditions including malignancy, autoimmune encephalitis, neuromodulation therapy, and drug-resistant epilepsy. Results: Physiological artifacts, such as non-epileptic rhythmic movements, and device-related artifacts (e.g., pacemakers, ventilators) can mimic epileptic seizures. Plateau waves from elevated intracranial pressure may produce deficits resembling epileptic seizures. Accurate differentiation requires attention to clinical context, EEG features, and video correlation. Maintaining a broad differential and avoiding diagnostic anchoring are also essential to prevent misdiagnosis and unnecessary antiseizure medication therapy. Conclusions: ICU EEG interpretation is challenged by artifacts and non-epileptic movements that mimic epileptic seizures. Awareness of these issues, along with a thoughtful, multidisciplinary approach, is critical for improving diagnostic accuracy and optimizing patient outcomes during cvEEG monitoring.

Association of Seizure Control with Mortality, Cognition, and Function in People With Dementia Zawar I, Quigg M, Ghosal S, Punia V, Calle-Lopez Y, Manning C, Kapur J. Ann Neurol . 2025;97(2):358–368. doi: 10.1002/ana.27125 . Epub 2024 Oct 30. PMID: 39475168 Objectives: The effects of seizure control on outcomes in persons with dementia (PWD) remain unclear. Our study aimed to investigate the impact of seizure control on mortality, function, cognition, and mood among PWD. Methods: This longitudinal, multicenter study is based on 39 Alzheimer's disease centers (ADCs) in the United States from September 2005 to December 2021. PWD were grouped by seizure status into recurrent (seizures in the past year), remote (prior seizures but none in the past year), and no seizures (controls). The primary outcome was all-cause mortality among seizure groups. We used Weibull survival analysis to assess the mortality risks by seizure status after adjusting for age, sex, education, race, ethnicity, hypertension, diabetes, hyperlipidemia, degree of cognitive impairment, dominant Alzheimer's disease (AD) mutation, brain trauma, stroke, Parkinson's disease, alcohol abuse, and depression. Cognition (Clinical Dementia Rating), function (physical dependence and nursing home residence), day-to-day activities (Functional Assessment Scores), and mood (Geriatric Depression Scale) were compared among seizure groups after adjusting for dementia duration and age. Results: Among 26,501 participants, 374 (1.4%) had recurrent seizures and 510 (1.9%) had remote seizures. In multivariable survival analysis, recurrent seizures were associated with a higher mortality risk than remote and no seizures (adjusted hazard ratio [aHR], 95% confidence interval [95% CI]; recurrent aHR = 1.79, 95% CI = 1.51 to 2.12; remote aHR = 1.17, 95%CI = 0.98 to 1.38). Median time-to-death for recurrent, remote, and no seizures was 2.4, 4.0, and 4.7 years, respectively. People with recurrent seizures had worse cognition, day-to-day function, and physical dependence than those with remote seizures and controls. Interpretation: PWD with poorly controlled recurrent seizures have worse mortality, functional, and cognitive outcomes than PWD with remote and no seizures. These findings underscore the need for timely identification and management of ongoing seizures in PWD. Risk Factors Associated With Late-Onset Epilepsy in Dementia and Mild Cognitive Impairment Zawar I, Quigg M, Johnson EL, Ghosal S, Manning C, Kapur J. JAMA Neurol . 2025;82(6):605–613. doi: 10.1001/jamaneurol.2025.0552 . PMID: 40227723. Importance: The risk of developing epilepsy substantially increases after the age of 60 years (late-onset epilepsy [LOE]), particularly in people with cognitive decline (PWCD, ie, dementia and/or mild cognitive impairment). Epilepsy is associated with worse cognitive and mortality outcomes in PWCD. Identifying PWCD at risk for developing LOE can facilitate early screening and treatment of epilepsy. Objective: To investigate factors associated with LOE in PWCD. Design, Setting, and Participants: This longitudinal, multicenter study is based on participants from 39 US Alzheimer's Disease Research Centers from September 2005 through December 2021. Of 44 713 participants, 25 119 PWCD were identified. Of these, 14 685 were included who did not have epilepsy at enrollment, had 2 or more visits, and were 60 years or older at the most recent follow-up. Exposure: The association between various factors and LOE development in PWCD was investigated. Main Outcomes and Measures: The primary outcome was LOE, defined as seizures starting at or after 60 years of age. Those who did not develop LOE but were 60 years or older at follow-up served as controls. A multivariable Cox regression analysis assessed the association between various factors and LOE. Independent variables included age, sex, and socioeconomic factors (education, race, ethnicity), cardiovascular risks (hypertension, diabetes, hyperlipidemia), cerebrovascular disease (stroke or history of transient ischemic attack [TIA]), other neurologic comorbidities (Parkinson disease [PD], traumatic brain injury), cognition (age at dementia onset, dementia severity, type of dementia [Alzheimer disease (AD) versus non-AD]), genetics (apolipoprotein E4 [ APOE4 ] status), lifestyle (alcohol misuse, smoking), and depression. Results: Of the 14 685 participants (7355 female [50%] and 7330 male [50%]; mean [SD] age, 73.8 [8.5] years) who met the inclusion criteria, 221 participants (1.5%) developed LOE during follow-up. After adjusting for demographics, cardiovascular risks, neurologic comorbidities, genetics, cognitive factors, and depression, the following were associated with a higher risk of developing LOE: APOE4 allele (adjusted hazard ratio [aHR], 1.39; 95% CI, 1.04–1.86; P = .03), dementia onset before age 60 years (aHR, 2.46; 95% CI, 1.53–3.95; P < .001), worse cognition (aHR, 2.35; 95% CI, 1.97–2.79; P < .001), AD dementia subtype (aHR, 1.68; 95% CI, 1.13–2.49; P = .01), stroke/TIA (aHR, 2.03; 95% CI, 1.37–3.01; P < .001), and PD (aHR, 2.53; 95% CI, 1.08–5.95; P = .03). In sensitivity analysis, using an alternative LOE definition of epilepsy onset after age 65 years revealed the same factors associated with LOE. Conclusion and Relevance: This study showed that the APOE4 allele, dementia onset before age 60 years, AD dementia subtype, worse cognition, stroke/TIA, and PD are associated with LOE development in PWCD. PWCD with these risk factors may be considered for routine screening with an electroencephalogram for early identification of LOE.

Quantitative susceptibility mapping of iron deposition in sporadic cerebral cavernous malformation-related epilepsy Zhang S, Liu Y, Ma L, Yuan J, Wu C, Wang S. Epilepsia . 2025 Jan 13. doi: 10.1111/epi.18263 . Epub ahead of print. PMID: 39804066. Objective: To evaluate iron deposition patterns in patients with cerebral cavernous malformation-related epilepsy (CRE) using quantitative susceptibility mapping (QSM) for detailed analysis of iron distribution associated with a history of epilepsy and severity. Methods: This study is part of the Quantitative Susceptibility Biomarker and Brain Structural Property for Cerebral Cavernous Malformation-Related Epilepsy (CRESS) cohort, a prospective multicenter study. QSM was used to quantify iron deposition in patients with sporadic cerebral cavernous malformation (CCMs). Lesions were segmented into intralesional, perilesional, and extralesional areas, with mean susceptibility values calculated for each subregion and analyzed in relation to epilepsy severity and duration. Results: Among the 46 patients studied, those with a history of epilepsy had significantly higher iron deposition values in the perilesional ( P = .012) and extralesional areas ( P = .01), as well as a greater extent of iron deposition ( P < .001) compared to those without epilepsy. The extent of iron deposition effectively distinguished patients with and without epilepsy, with an area under the curve (AUC) of 0.901 (95% confidence interval [CI]: 0.816-0.985). Among patients with epilepsy, iron deposition in the extralesional area was positively correlated with the severity of epilepsy (r2 = 0.181, P = .043), and the extent of iron deposition was positively correlated with the duration of epilepsy (r2 = .214, P = .026). Significance: This study highlights QSM as a noninvasive tool for assessing iron deposition in CRE, identifying distinct subregional iron deposition patterns linked to epilepsy status and severity.

Antiseizure Medication Use and Outcomes After Suspected or Confirmed Acute Symptomatic Seizures Zafar SF, Sivaraju A, Rubinos C, Ayub N, Awodutire PO, McKee Z, Chandan P, Byrnes M, Bhansali SA, Rice H, Smith-Ayala A, Haider MA, Tveter E, Erlich-Malona N, Ibanhes F, DeMarco A, Lewis S, Dhakar MB, Punia V. JAMA Neurol . 2024;81(11):1159–69. doi: 10.1001/jamaneurol.2024.3189. Importance: Antiseizure medications (ASMs) are frequently prescribed for acute symptomatic seizures and epileptiform abnormalities (EAs; eg, periodic or rhythmic patterns). There are limited data on factors associated with ASM use and their association with outcomes. Objectives: To determine factors associated with ASM use in patients with confirmed or suspected acute symptomatic seizures undergoing continuous electroencephalography, and to explore the association of ASMs with outcomes. Design, Setting, and Participants: This multicenter cohort study was performed between July 1 and September 30, 2021, at 5 US centers of the Post Acute Symptomatic Seizure Investigation and Outcomes Network. After screening 1717 patients, the study included 1172 hospitalized adults without epilepsy who underwent continuous electroencephalography after witnessed or suspected acute symptomatic seizures. Data analysis was performed from November 14, 2023, to February 2, 2024. Exposure: ASM treatment (inpatient ASM continuation ≥48 h). Main Outcomes and Measures: Factors associated with (1) ASM treatment, (2) discharge ASM prescription, and (3) discharge and 3-month Glasgow Outcome Scale score of 4 or 5 were ascertained. Results: A total of 1172 patients (median [IQR] age, 64 [52-75] years; 528 [45%] female) were included. Among them, 285 (24%) had clinical acute symptomatic seizures, 107 (9%) had electrographic seizures, and 364 (31%) had EAs; 532 (45%) received ASM treatment. Among 922 patients alive at discharge, 288 (31%) were prescribed ASMs. The respective frequencies of inpatient ASM treatment and discharge prescription were 82% (233 of 285) and 69% (169 of 246) for patients with clinical acute symptomatic seizures, 96% (103 of 107) and 95% (61 of 64) for electrographic seizures, and 64% (233 of 364) and 48% (128 of 267) for EAs. On multivariable analysis, acute and progressive brain injuries were independently associated with increased odds of inpatient ASM treatment (odds ratio [OR], 3.86 [95% CI, 2.06-7.32] and 8.37 [95% CI, 3.48-20.80], respectively) and discharge prescription (OR, 2.26 [95% CI, 1.04-4.98] and 10.10 [95% CI, 3.94-27.00], respectively). Admission to the neurology or neurosurgery service (OR, 2.56 [95% CI, 1.08-6.18]) or to the neurological intensive care unit (OR, 7.98 [95% CI, 3.49-19.00]) was associated with increased odds of treatment. Acute symptomatic seizures and EAs were significantly associated with increased odds of ASM treatment (OR, 14.30 [95% CI, 8.52-24.90] and 2.30 [95% CI, 1.47-3.61], respectively) and discharge prescription (OR, 12.60 [95% CI, 7.37-22.00] and 1.72 [95% CI, 1.00-2.97], respectively). ASM treatment was not associated with outcomes at discharge (OR, 0.96 [95% CI, 0.61-1.52]) or at 3 months after initial presentation (OR, 1.26 [95% CI, 0.78-2.04]). Among 623 patients alive and with complete data at 3 months after discharge, 30 (5%) had post-discharge seizures, 187 (30%) were receiving ASMs, and 202 (32%) had all-cause readmissions. Conclusions and Relevance: This study suggests that etiology and electrographic findings are associated with ASM treatment for acute symptomatic seizures and EAs; ASM treatment was not associated with functional outcomes. Comparative effectiveness studies are indicated to identify which patients may benefit from ASMs and to determine the optimal treatment duration.