Epilepsia[JOURNAL]
Sun
200 papers
Long-term prognosis of pharmacotherapy in newly diagnosed focal epilepsy patients and the predictive value of baseline seizure timing: A prospective cohort study.
Sun L, Sun S, Zhang X … +1 more , Lin W
Epilepsia · 2026 Jun · PMID 42227311 · Publisher ↗
OBJECTIVE: Epilepsy is a highly heterogeneous neurological disorder with significant prognostic variability. Accurate long-term outcome prediction remains a clinical challenge. We investigated pharmacotherapeutic prognos...
OBJECTIVE: Epilepsy is a highly heterogeneous neurological disorder with significant prognostic variability. Accurate long-term outcome prediction remains a clinical challenge. We investigated pharmacotherapeutic prognosis and key predictors, particularly baseline seizure timing, to guide individualized treatment. METHODS: This prospective cohort study consecutively enrolled newly diagnosed focal epilepsy patients from the epilepsy specialist clinic of the Department of Neurology in our hospital between September 2015 and September 2025. We applied the Cox proportional hazards regression model to analyze the association between baseline factors and prognosis to identify independent predictors. RESULTS: A total of 563 patients with ≥36-month follow-up (median = 48.0 months, interquartile range [IQR] = 36.0-78.0) were analyzed. Among them, 64.8% (365/563) achieved seizure freedom at least once (median = 27.0 months, 95% confidence interval [CI] = 22.5-31.5), and 35.9% (131/365) relapsed after seizure freedom; 25.4% (143/563) developed drug resistance, with 6.3% (9/143) later converting to drug-responsive status. At the end of follow-up, 50.8% (286/563) were classified as drug-responsive, 23.8% (134/563) as having drug-resistant epilepsy (DRE), and 25.4% (143/563) as having an undetermined prognosis. Among patients with drug-responsive epilepsy, 63.6% (182/286) achieved seizure freedom with monotherapy. Multivariate analysis identified baseline wake-related seizures (hazard ratio [HR] = 1.743, 95% CI = 1.101-2.760, p = .018), cluster seizures (HR = 2.630, 95% CI = 1.845-3.749, p < .001), status epilepticus (HR = 2.126, 95% CI = 1.394-3.242, p < .001), and sleep problems (HR = 1.740, 95% CI = 1.178-2.572, p = .005) as independent DRE risk factors. SIGNIFICANCE: This prospective large-sample study revealed the inherent complexity and dynamic nature of prognostic assessment in patients with newly diagnosed focal epilepsy. We identified independent prognostic predictors for this condition, first confirming baseline wake-related seizures as a predictor of poor prognosis to guide early risk stratification and personalized treatment.
Interview with Lennart N. Kersting, recipient of the 2026 Epilepsia Prize for clinical research.
Cendes F, Auvin S
Epilepsia · 2026 Jun · PMID 42227032 · Publisher ↗
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Interview with Jeffrey A. Mensah, recipient of the 2026 Epilepsia Prize for basic science research.
Cendes F, Auvin S
Epilepsia · 2026 Jun · PMID 42227024 · Publisher ↗
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Influence of histopathologic type of hippocampal sclerosis on neuropsychological profile.
Le Thanh N, Houot M, Mere M … +6 more , Denos M, Samson S, Mathon B, Navarro V, Bielle F, Dupont S
Epilepsia · 2026 Jun · PMID 42222911 · Publisher ↗
OBJECTIVE: Hippocampal sclerosis (HS) is the most common histopathological abnormality in adults with drug-resistant mesial temporal lobe epilepsy (MTLE) who are candidates for surgery. In 2013, the International League...
OBJECTIVE: Hippocampal sclerosis (HS) is the most common histopathological abnormality in adults with drug-resistant mesial temporal lobe epilepsy (MTLE) who are candidates for surgery. In 2013, the International League Against Epilepsy (ILAE) Task Force subdivided HS into three types: HS-ILAE type 1 (severe neuronal loss and gliosis predominantly in CA1 and CA4), HS-ILAE type 2 (CA1-predominant), and HS-ILAE type 3 (CA4-predominant). The aim of this study was to assess the association between HS-ILAE types and cognitive profiles of MTLE-HS patients. METHODS: A total of 302 patients were retrospectively included, comprised of 253 MTLE-HS patients with a postoperative ILAE classification of HS as follows: 194 HS-ILAE type 1, 57 HS-ILAE type 2, and two HS-ILAE type 3; and 49 MTLE patients without HS. Demographic variables, clinical characteristics, postoperative outcome, and cognitive performance were compared between patients with HS-ILAE type 1, with HS-ILAE type 2, and without HS, who served as internal controls. Height cognitive domains were examined: general cognition, verbal and nonverbal episodic memory, language, executive functions, short-term and working memory, perceptual-motor speed, and visuoconstructive abilities. RESULTS: The pattern of hippocampal neuronal loss was not associated with age at epilepsy onset, the presence of specific initial precipitating events, other clinical characteristics, or postoperative outcome. Patients with HS-ILAE type 1 demonstrated significantly poorer performance in visuoconstructive and language tasks compared with those with HS-ILAE type 2 or patients without HS. No significant differences were observed between groups in verbal and nonverbal episodic memory, short-term memory, executive functions, or perceptual-motor speed. SIGNIFICANCE: HS-ILAE subtype has a modest yet differential impact on patient performance, with HS-ILAE type 1 patients demonstrating overall poorer outcomes across two cognitive domains: language and visuoconstructive function. These findings suggest that cognitive impairment in MTLE-HS likely reflects a complex interplay among multiple pathological processes, including, in part, neuronal loss within specific hippocampal subfields. More targeted neuropsychological assessments focusing on the functional integrity of distinct hippocampal subregions are warranted.
Are comorbid sleep disorders associated with higher risk for sudden unexpected death in epilepsy? Observations from a Canadian epilepsy clinic.
Lazaj M, Lee E, Derry T … +5 more , Driver H, Winston GP, Boissé Lomax L, Johnson A, Shukla G
Epilepsia · 2026 Jun · PMID 42220249 · Publisher ↗
OBJECTIVE: Pooled mortality is nearly three times higher in people with epilepsy (PWE). Approximately 80% of sudden unexpected death in epilepsy (SUDEP) events occur during sleep, and primary sleep disorders are prevalen...
OBJECTIVE: Pooled mortality is nearly three times higher in people with epilepsy (PWE). Approximately 80% of sudden unexpected death in epilepsy (SUDEP) events occur during sleep, and primary sleep disorders are prevalent in the general population and PWE. Currently, research extensively explores SUDEP risk and biomarkers, whereas limited studies investigate the connection between sleep and SUDEP/all-cause mortality risk in epilepsy. This study assessed the relationship between SUDEP risk in epilepsy and primary sleep disorder diagnoses. METHODS: This retrospective chart review included consecutive patients with active epilepsy from a Canadian epilepsy clinic over a 4-year period. The database included demographic, clinical, neurophysiological, sleep information, accident, and hospitalization records. The revised SUDEP-7 Inventory (rSUDEP-7) evaluated SUDEP risk, and sleep disorder diagnoses were accepted if evaluated by a sleep specialist based on International Classification of Sleep Disorders version 3.0 criteria. Patients were categorized into those without comorbid sleep disorders (NoSleepDis) and those with sleep disorders (SleepDis), and sociodemographic and clinical characteristics were compared. The association between sleep disorders and SUDEP risk was assessed using logistic and ordinal logistic regression models. RESULTS: The study enrolled 1506 PWE (1130 in NoSleepDis, 376 in SleepDis). The groups were similar in age, sex, living situation, epilepsy duration, epilepsy type, and percentage seizure-free for >1 year. Univariately, the SleepDis group exhibited a significantly higher SUDEP risk, as well as higher all-cause mortality and accidents, but not hospitalizations. Sleep disorder presence was associated with increased odds of high SUDEP risk (rSUDEP-7 ≥ 5, odds ratio [OR] = 1.93, 95% confidence interval [CI] = 1.02-3.64) and higher SUDEP-7 scores when analyzed ordinally (OR = 1.46, 95% CI = 1.17-1.81). SIGNIFICANCE: Comorbid primary sleep disorders among PWE are associated with higher SUDEP risk (rSUDEP-7 scores), all-cause mortality, and accident rates. This study offers insights for developing more accurate predictive tools for assessing SUDEP risk for epilepsy.
Modeling temporal lobe epilepsy with hippocampal sclerosis in rats using the selective neurotoxin stable substance P-saporin.
Gupta S, Kesler MT, Scantlebury MH … +2 more , Sloviter RS, Teskey GC
Epilepsia · 2026 Jun · PMID 42220243 · Publisher ↗
OBJECTIVE: Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS+) is a common and often refractory form of human epilepsy. In the hippocampus, the neurotoxin stable substance P-saporin (SSP-SAP) targets hilar inhibi...
OBJECTIVE: Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS+) is a common and often refractory form of human epilepsy. In the hippocampus, the neurotoxin stable substance P-saporin (SSP-SAP) targets hilar inhibitory interneurons and has been used to determine whether hilar neuron loss in an otherwise normal brain is sufficient to initiate the epileptogenic process. We determined the time course of SSP-SAP-induced epileptogenesis, as well as the loss of principal cells and astrogliosis, two defining features of TLE-HS+. METHODS: We started with 70-day-old male and female Sprague Dawley rats and injected SSP-SAP into four unilateral sites along the longitudinal axis of the rat dentate gyrus. We determined how long SSP-SAP is detectably present in inhibitory interneurons and then analyzed the electroencephalographic characteristics and behavioral expression of the "reactive" seizures that developed several days after SSP-SAP injection. We then quantified the number of self-generated 7-Hz epileptiform events over 3 months. Finally, we counted the numbers of principal cells and astrocytes up to 2 months postinjection. RESULTS: SSP-SAP was internalized within 2 h after injection and was immunocytochemically undetectable by 5 days. Rats exhibited spontaneous electrographic and behavioral reactive seizures between days 4 and 6 after SSP-SAP injection, with most seizures having a Racine score of either 1 or 2. After the early seizures had abated, the number and duration of self-generated 7-Hz epileptiform events, which were associated with behavioral arrest, progressively increased over the 3-month observation period, indicating epileptogenesis. We also observed the progressive loss of CA1 and CA3 neurons and the progressive increase in astrocytes over time, two defining features of HS, a common pathological observation in TLE patients. SIGNIFICANCE: This study confirms that the SSP-SAP model reproduces the defining features of human TLE and that a primary, selective, and longitudinally extensive γ-aminobutyric acidergic defect is sufficient to trigger epileptogenesis that results in TLE-HS+.
Gene burden meta-analysis of 748 879 individuals identifies LGI1-ADAM23 protein complex association with epilepsy.
Lal JC, Leu C, Boßelmann CM … +3 more , Ivaniuk A, Pérez-Palma E, Lal D
Epilepsia · 2026 May · PMID 42216960 · Publisher ↗
Epilepsy affects more than 50 million individuals globally and has a substantial genetic component that remains to be completely understood. Traditional studies have focused on severe, early onset cases enrolled through...
Epilepsy affects more than 50 million individuals globally and has a substantial genetic component that remains to be completely understood. Traditional studies have focused on severe, early onset cases enrolled through clinical or research settings. Recent biobank-based approaches, leveraging large-scale population datasets, offer opportunities to explore genetic associations in broader epilepsy phenotypes, including milder, later onset forms. We analyzed data from more than 750 000 individuals across the UK Biobank, All of Us, and Massachusetts General Brigham Biobank, including 20 026 individuals with epilepsy. Rare coding variant burden testing revealed a significant association with LGI1, a known epilepsy gene. Among the other top 10 associated genes, seven had prior evidence linking them to epilepsy (GABRG2, ATP1A3), neurological disorders with comorbid seizures (HTRA2, KRIT1, STAG1), possible involvement in seizure phenotypes (ADAM23), or roles in neuronal function (PDCD4). Thus, we provide the first statistical evidence for ADAM23 as a candidate gene for epilepsy, based on the suggestive association signal combined with prior biological evidence from both animal (canine and murine) and one recent human epilepsy case study, potentially contributing to human epilepsy through its direct interaction with LGI1. Phenome-wide analyses highlighted the pleiotropic effects of epilepsy genes, with LGI1 and ADAM23 predominantly associated with epilepsy, whereas other genes such as KRIT1, TSC1, and TSC2 exhibited broader systemic involvement. Our study shows the potential of population-scale genomic data and suggests that integrating these datasets with deep phenotyping will uncover more novel insights into epilepsy genetics in the future.
High incidence of Y-chromosome mosaicism in male and female individuals with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy.
Cecchini E, Hartlieb T, Gaballa A … +11 more , Kobow K, Katoch M, Chasani P, Vasileiou G, Hofer W, Reisch LM, Kudernatsch M, Bien CG, Coras R, Blümcke I, Hoffmann L
Epilepsia · 2026 May · PMID 42216953 · Publisher ↗
OBJECTIVE: Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is an underrecognized pediatric cortical lesion associated with somatic X-linked SLC35A2 variants in approximatel...
OBJECTIVE: Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is an underrecognized pediatric cortical lesion associated with somatic X-linked SLC35A2 variants in approximately 50% of individuals. The genetic etiology in individuals without detectable SLC35A2 mutations remains undefined, which limits our understanding of its pathomechanism and clinical characterization. The aim is to identify genetic correlates of MOGHE in individuals lacking pathogenic SLC35A2 variants and to investigate the clinicopathological and genomic correlations. METHODS: We investigated archival brain tissue of 29 individuals (19 males, 10 females) with histopathologically confirmed MOGHE. Twenty individuals carried SLC35A2 variants, and nine individuals lacked detectable mutations in SLC35A2 or other epilepsy-related genes. Brain tissue samples were analyzed using DNA methylation-derived copy number variation (CNV) analysis, polymerase chain reaction (PCR), and chromogenic/fluorescent in situ hybridization (ISH). RESULTS: CNV analysis identified Y-chromosomal material in five of 10 females (50%) and mosaic Y-chromosome gains in 16 of 19 males (84%), confirmed by PCR and ISH, and associated with lesional tissue. Exploratory stratification of the cohort by SLC35A2 status and Y-chromosome gain revealed a tendency toward earlier seizure onset, multilobar involvement, and cognitive impairment in patients carrying both SLC35A2 mutations and Y-chromosome gain; however, these differences did not reach statistical significance in our small cohort. SIGNIFICANCE: The combined presence of Y-chromosomal material in females, mosaic Y-chromosome gains in males, and SLC35A2 variants represents a recurrent genomic feature in patients with MOGHE. These findings suggest that sex-chromosome anomalies may contribute to the pathobiology of this epilepsy-associated cortical malformation, highlighting the need to clarify the underlying molecular mechanisms of this clinicohistopathologic entity. Although the root cause, biological consequence, and clinical significance of brain somatic Y-chromosomal gain remain to be further clarified, our findings identify a previously unrecognized genomic feature of MOGHE and provide a rationale for future research in MOGHE cohorts.
Maternal and umbilical cord plasma concentrations of antiseizure medications: Results from the observational MONEAD study.
Avachat C, Meador KJ, Pennell PB … +2 more , Birnbaum AK, MONEAD Investigator Group
Epilepsia · 2026 May · PMID 42207607 · Publisher ↗
OBJECTIVE: Unanticipated changes in antiseizure medication (ASM) exposure can lead to subtherapeutic or toxic medication concentrations in the mother and unnecessary drug exposure for the fetus. The objectives of this st...
OBJECTIVE: Unanticipated changes in antiseizure medication (ASM) exposure can lead to subtherapeutic or toxic medication concentrations in the mother and unnecessary drug exposure for the fetus. The objectives of this study were to characterize ASM concentrations in mother's and cord blood at delivery in women with epilepsy (PWWE). METHODS: The analysis included PWWE (aged 14-45 years) from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study who were on ASM monotherapy or polytherapy at delivery. Women with an intelligence quotient < 70, major medical illness, substance use, and poor treatment adherence were excluded. Blood samples were collected from the mother and umbilical cord on the day of delivery. The ratio of umbilical cord to maternal plasma concentration at birth was used as a measure of fetal in utero exposure. Pearson correlation coefficients were calculated to determine the degree of correlation between ASM maternal and cord plasma concentrations. A p-value of <.05 was deemed to be significant. RESULTS: Data from 207 infants included eight pairs of twins (104 females and 103 males) born to 199 women (140 on monotherapy and 59 on polytherapy), yielding 305 paired maternal and umbilical cord ASM concentrations. Significant correlation was observed between umbilical cord and maternal plasma concentrations for total and unbound carbamazepine, total and unbound carbamazepine-10,11-epoxide, gabapentin, lamotrigine, levetiracetam, total and unbound oxcarbazepine, and zonisamide. The mean ratios (SD) of umbilical cord plasma concentration to maternal plasma concentration were as follows: carbamazepine = .84 (.18), unbound carbamazepine = 1.15 (.47), carbamazepine-10,11-epoxide = .87 (.18), unbound carbamazepine epoxide = 1.17 (.36), gabapentin = 1.56 (.28), lacosamide = .96 (.29), levetiracetam = 1.1 (.53), lamotrigine = .92 (.26), oxcarbazepine = 1.01 (.22), unbound oxcarbazepine = 1.1 (.46), topiramate = .98 (.38), valproic acid = 1.03 (.85), unbound valproic acid = .73 (.74), and zonisamide = .93 (.12). SIGNIFICANCE: Umbilical cord to maternal ASM concentration ratios were close to 1.0, indicating placental passage of ASMs. Gabapentin had the highest ratio, suggesting possible accumulation of drug. Additional studies are needed for infrequently prescribed ASMs.
Development and preclinical evaluation of a hybrid stereoelectroencephalographic-laser depth electrode for magnetic resonance imaging-guided interstitial thermal therapy in drug-resistant epilepsy.
Mathon B, Mokhtari K, Galanaud D … +1 more , Carpentier A
Epilepsia · 2026 May · PMID 42184169 · Publisher ↗
OBJECTIVE: This study was undertaken to design and validate a hybrid depth electrode combining stereoelectroencephalographic (sEEG) recording and magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) und...
OBJECTIVE: This study was undertaken to design and validate a hybrid depth electrode combining stereoelectroencephalographic (sEEG) recording and magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) under real-time magnetic resonance thermometry, to streamline the transition from invasive localization to focal ablation in patients with drug-resistant focal epilepsy. METHODS: We engineered a magnetic resonance imaging (MRI)-compatible depth probe that integrated intracerebral EEG contacts and a central optical fiber for laser delivery. The contact materials and geometry were optimized to reduce susceptibility artifacts and preserve the proton resonance frequency (PRF) thermometry. Preclinical testing included MRI artifact screening in phantoms, thermal performance testing, PRF thermometry validation against temperature sensors in phantoms and ovine brain, artifact quantification versus clinical depth electrodes, electrophysiologic signal quality assessment before/after thermal stress, and in vivo canine feasibility with serial MRI and histology. MRI compatibility was confirmed for a next generation contact variant. RESULTS: The optimized contact design produced small MRI artifacts and preserved PRF thermometry outside an approximately 2-mm pericontact exclusion zone. Thermal testing showed localized heating with rapid postlaser decay, modulation by coolant flow, and performance comparable to that of clinical LITT applicators. In dipole-phantom testing, baseline electrophysiological recordings from the new hybrid electrode were comparable to clinical depth-electrode controls, whereas a previously heated hybrid electrode showed increased noise under low-amplitude conditions. In vivo, MRgLITT produced sharply demarcated lesions that scaled with the delivered energy without hemorrhage, edema, midline shift, or device damage. Histological examination revealed coagulative necrosis with a narrow perilesional zone and no carbonization at the contacts. SIGNIFICANCE: This patented hybrid sEEG-laser electrode supports a "diagnose-model-treat-verify" strategy along a single stereotactic trajectory, enabling sEEG confirmation followed by MRgLITT without a second stereotactic implantation in selected patients. These data support progression to first-in-human evaluation and integration into epilepsy surgery workflows, particularly for MRI-negative focal epilepsies, where minimally invasive strategies are favored.
Epileptic and developmental encephalopathy secondary to inversion-duplication of chromosome 15: Description of epilepsy characteristics and therapeutic outcomes.
Benítez-Provedo C, García-Fernández M, Gutiérrez-Delicado E … +31 more , González-Alguacil E, Ortiz-Cabrera NV, Fernández-Garoz B, García Peñas JJ, Lamagrande Casanova N, Ballarà-Petitbò M, Rodríguez AD, Román IS, Gil-Nagel Rein A, de Toledo M, González-Giráldez B, Losada-Del Pozo R, Martínez-Cayuelas E, Pérez-Poyato MS, Turon-Viñas E, Iglesias-Escalera G, Ramos-Fernández JM, Cancho-Candela R, Urbano-Martín M, Vázquez-López M, Ibáñez-Mico S, Fernández-Ramos JA, Barrios DG, Ferragut F, Blasco JAA, la Mota CC, Gonzalez-Santiago P, Camacho A, Conejo D, Navarro-Romero JP, Soto-Insuga V
Epilepsia · 2026 May · PMID 42184160 · Publisher ↗
OBJECTIVE: Inversion-duplication syndrome of chromosome 15 (invdup15) is a chromosomal disorder characterized by an inverted duplication of 15q11.2-q13.1. Epilepsy is highly prevalent (60%-80%), drug-resistant, and may p...
OBJECTIVE: Inversion-duplication syndrome of chromosome 15 (invdup15) is a chromosomal disorder characterized by an inverted duplication of 15q11.2-q13.1. Epilepsy is highly prevalent (60%-80%), drug-resistant, and may progress to developmental epileptic encephalopathies (DEEs) such as Lennox-Gastaut syndrome (LGS). Despite its impact, epilepsy and optimal treatments remain poorly described. METHODS: A retrospective multicenter study across 37 Spanish hospitals analyzed 54 patients, divided into two genetic subgroups: invdup15q and intdup15q. Clinical and genetic data were reviewed, focusing on epilepsy onset, seizure types, syndrome progression, electroencephalographic (EEG) findings, and treatment response. RESULTS: Epilepsy was present in 29 of 54 (54%) patients, with a mean age at onset of 7.4 years (range = 1 month-24 years, SD = 6.4). LGS (16/29, 55%) and focal epilepsy (15/29, 52%) were the most frequent epilepsy types, although infantile epileptic spasms predominated in younger patients (5/6, 83%). Late onset LGS (>8 years) occurred in 38%. Initial seizures were mostly focal motor (10/29, 34%) and generalized tonic-clonic seizures (8/29, 28%), later evolving to tonic, myoclonic, and atypical absence seizures. Twenty-six of 29 (90%) reported drug-resistant epilepsy. Epilepsy was more frequent (65% vs. 35%, p < .05) and had earlier onset (median = 5.7 vs. 12.3 years) in invdup15q than intdup15q. EEG demonstrated unusual activities including diffuse fast activity, along with repetitive trains of paroxysmal fast activity during sleep. The most effective antiseizure drugs were oxcarbazepine for focal (9/11, 81%) and for generalized (2/3, 67%) epilepsy and valproic acid (6/10, 60%) for generalized epilepsy, whereas vigabatrin, zonisamide, and brivaracetam showed limited efficacy. In LGS, oxcarbazepine (8/12, 66%), valproic acid (11/18, 61%), and cannabidiol (6/9, 66%) yielded the best responses. All patients had early developmental delay; autism spectrum disorder was diagnosed in 22 of 54 (41%) and behavioral disorders in 30 of 54 (56%). SIGNIFICANCE: Epilepsy in invdup15 is highly drug-resistant and exhibits features consistent with DEEs, particularly LGS. EEG findings may serve as disorder biomarkers. Oxcarbazepine and valproic acid were the treatments most often associated with seizure improvement in this sample.
Clinical validation of a patient-friendly saliva microsampling approach to monitor perampanel levels in people with epilepsy.
Franco V, Dattrino F, Palmisani M … +12 more , Tacchella F, Tartara E, De Giorgis V, Quaranta CA, Pasca L, Rota P, Russo E, Romigi A, Johannessen Landmark C, Fedele G, Tassorelli C, Nicotera P
Epilepsia · 2026 May · PMID 42171659 · Publisher ↗
Perampanel (PER) is a third-generation antiseizure medication (ASM) with a well-established concentration-effect relationship. Saliva represents a non-invasive alternative to plasma for therapeutic drug monitoring (TDM)...
Perampanel (PER) is a third-generation antiseizure medication (ASM) with a well-established concentration-effect relationship. Saliva represents a non-invasive alternative to plasma for therapeutic drug monitoring (TDM) of PER, as it reflects the free plasma fraction. Volumetric absorptive microsampling (VAMS) enables standardized, patient-friendly saliva collection. This study aimed to clinically validate saliva-VAMS by directly comparing it with conventional liquid saliva sampling for PER quantification. In a prospective study, saliva was collected from 11 people with epilepsy receiving PER therapy (dose range = 2-10 mg/day) using both VAMS and conventional saliva sampling. PER concentrations were measured by liquid chromatography coupled with tandem mass spectrometry and compared using repeated measures Bland-Altman analysis and Lin's concordance correlation coefficient to evaluate agreement between methods. PER concentrations measured in saliva-VAMS showed excellent agreement with those obtained from conventional saliva sampling, with mean bias of -0.126 ng/mL (95% confidence interval = -0.582 to 0.330). No relevant constant or proportional bias was observed, and limits of agreement were within predefined acceptance criteria. Concordance between methods was high, supporting analytical equivalence. The demonstrated interchangeability between saliva-VAMS and conventional saliva sampling supports adoption of saliva-VAMS in clinical TDM workflows, enabling standardized fixed-volume collection, simplified storage/transport, and potential home-based sampling for remote dose optimization of PER and potentially other ASMs.
Treatment adequacy outweighs treatment sequence in non-convulsive status epilepticus.
Misirocchi F, Zilioli A, Zinno L … +1 more , Florindo I
Epilepsia · 2026 May · PMID 42159101 · Publisher ↗
OBJECTIVE: Treatment strategies for non-convulsive status epilepticus (NCSE) are largely extrapolated from convulsive SE, despite biological and clinical differences. NCSE arises from heterogeneous etiological substrates...
OBJECTIVE: Treatment strategies for non-convulsive status epilepticus (NCSE) are largely extrapolated from convulsive SE, despite biological and clinical differences. NCSE arises from heterogeneous etiological substrates that may influence treatment response and prognosis. We examined the association between treatment sequence, anti-seizure medication (ASM) adequacy, etiological context, and clinical outcomes in NCSE. METHODS: We analyzed 189 adult non-anoxic NCSE patients from a 6-year ambispective registry. Treatment variables included first-line benzodiazepine (BDZ) use, ASM underdosing, and escalation to continuous intravenous anesthetic drugs (CIVADs). Etiology was classified according to International League Against Epilepsy (ILAE) categories and further stratified as potentially fatal v non-fatal and as primary vs secondary central nervous system (CNS) pathology. Outcomes were failure of NCSE cessation, in-hospital mortality, and functional worsening at discharge. Associations between treatment patterns and outcomes were evaluated using univariate and multivariable logistic regression analyses, with exploratory pre-specified subgroup analyses across etiological categories. RESULTS: ASM underdosing occurred in 73 of 189 episodes (38.6%) and was independently associated with failure of NCSE cessation (odds ratio [OR] 6.56, 95% confidence interval [CI] 1.98-21.78) and in-hospital mortality (OR 4.38, 95% CI 2.01-9.54). Lack of first-line BDZs (93/189, 49.2%) and escalation to CIVADs (41/189, 21.7%) were not independently associated with outcome. In subgroup analyses, the association between ASM underdosing and adverse outcomes was observed more consistently in acute primary CNS pathology and non-fatal etiologies. SIGNIFICANCE: In NCSE, outcome appears more closely associated with ASM dosing adequacy than strict adherence to a pre-defined treatment sequence, particularly in clinical contexts where epileptic activity is likely to contribute substantially to prognosis. Pending future prospective, ideally randomized, investigations, optimal therapeutic strategies across heterogeneous NCSE subtypes remain to be clearly established.
A translational multimodal machine-learning prototype predicting valproate response in epilepsy treatment.
Platte S, Kumar A, Guerini G … +13 more , Pandolfo M, Haslinger D, Josephson CB, Delgado-García G, Kaur N, Lux MP, Stempfle H, Depondt C, Kälviäinen R, Rosenow F, von Brauchitsch S, Klein KM, Chiocchetti AG
Epilepsia · 2026 May · PMID 42159090 · Publisher ↗
OBJECTIVE: Epilepsy affects ~1% of the global population and often requires lifelong antiseizure medication (ASM) therapy. Valproic acid (VPA) is a commonly prescribed first-line ASM, yet only approximately half of patie...
OBJECTIVE: Epilepsy affects ~1% of the global population and often requires lifelong antiseizure medication (ASM) therapy. Valproic acid (VPA) is a commonly prescribed first-line ASM, yet only approximately half of patients achieve sustained seizure freedom. Treatment selection remains largely empirical. We aimed to develop and independently validate a multimodal predictive model to estimate response to VPA and support more individualized treatment strategies. METHODS: This cross-sectional treatment response modeling study used data from a subset of the international Epi25 cohort (Belgium, Finland, Germany). Individuals with epilepsy were included if they had received VPA monotherapy and had available genetic or clinical data. Discovery data (1965-2021, 58% female) were split into a training set (n = 196) and test set (n = 133). Independent validation was performed in a Canadian cohort (2021-2022, n = 156, 40% female). The primary outcome was binary VPA response. Responders achieved ≥12 months of seizure freedom attributed to VPA; nonresponders had >50% seizure recurrence or discontinued VPA due to inefficacy, adverse effects, or unclear reasons. The predictive algorithm integrated features derived from common and rare variants in VPA pharmacokinetic and pharmacodynamic genes, in vitro neuronal VPA response measures, and clinical features. Model performance was assessed using accuracy, predictive values (negative predictive value [NPV]/positive predictive value [PPV]), and area under the curve (AUC). RESULTS: In the independent validation cohort, the multimodal classifier achieved a balanced accuracy of 63% (95% confidence interval [CI] = 52%-73%), NPV of 70% (95% CI = 51%-85%), PPV of 60% (95% CI = 46%-72%), and AUC of .73 (95% CI = .63-.83). Models restricted to single or dual data modalities showed consistently lower predictive performance. SIGNIFICANCE: This proof-of-concept study demonstrates that integrating genetic, cellular, and clinical data enables prediction of VPA treatment response with clinically meaningful accuracy. Although not yet ready for clinical application, this approach supports the feasibility of biomarker-informed ASM selection and may ultimately reduce time to effective seizure control.
Predicting seizure freedom in the postpartum period: Findings from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study.
Osterhaus EC, Kerr WT, Meador KJ … +5 more , French JA, Birnbaum AK, Voinescu PE, Gerard E, Pennell PB
Epilepsia · 2026 May · PMID 42159064 · Publisher ↗
OBJECTIVE: This study was undertaken to evaluate whether seizure freedom in pregnancy predicts seizure freedom in the postpartum period in women with epilepsy (WWE). Prior studies have shown that seizure freedom prior to...
OBJECTIVE: This study was undertaken to evaluate whether seizure freedom in pregnancy predicts seizure freedom in the postpartum period in women with epilepsy (WWE). Prior studies have shown that seizure freedom prior to conception strongly predicts seizure freedom during pregnancy. The postpartum period is considered especially vulnerable to recurrent seizures given rapid hormonal changes, shifting antiseizure medication pharmacokinetics, and disrupted sleep. There is a lack of sufficient data on whether seizure freedom during pregnancy predicts postpartum outcomes. METHODS: Pregnant WWE (aged 14-45 years) were enrolled at <20 weeks gestation in the prospective Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study. Participants completed electronic daily seizure and medication diaries with study visits each trimester, and at 6-12 weeks and 6 and 9 months postpartum. Participants also reported retrospective seizure frequency for the 9 months preconception. We used logistic regression to assess whether seizure freedom during pregnancy predicted seizure freedom postpartum, with additional analyses by seizure types. In participants with seizures during pregnancy, we evaluated median percent change in seizure frequency. RESULTS: This analysis included 331 pregnant WWE. Overall, 60.7% were seizure-free during pregnancy and 61.0% postpartum. Seizure freedom during pregnancy strongly predicted seizure freedom postpartum (odds ratio [OR] = 6.78, 95% confidence interval [CI] = 4.15-11.1, p < .0001), with a predictive value of 78% (95% CI = 72%-84%). Retrospectively reported preconception seizure freedom was also independently associated with postpartum seizure freedom (OR = 5.84, 95% CI = 3.57-9.58, p < .0001). Long-term seizure freedom during pregnancy and preconception was associated with 85% postpartum seizure freedom, whereas long-term presence of seizures was associated with only 36% postpartum seizure freedom. There were no significant differences by seizure type. Among participants with seizures during pregnancy, median postpartum seizure frequency declined by 77% (interquartile range = seizure-free to 31% reduced). SIGNIFICANCE: Our data demonstrated that seizure freedom during pregnancy was a robust predictor of seizure freedom during the postpartum period. These data can be used to counsel patients about seizure risk in the postpartum period.
Feasibility and signal quality of the Minder® implantable continuous EEG monitoring® system compared to 10-20 scalp electrodes over extended monitoring periods.
Ganguly TM, Lai A, Niemiec A … +13 more , Cameron T, Conrad EC, Raghupathi R, Ellis C, Halliday AJ, Gillinder L, Seneviratne U, Kwan P, Perucca P, McGonigal A, Vogrin S, Fontenot H, Cook MJ
Epilepsia · 2026 May · PMID 42157720 · Publisher ↗
OBJECTIVE: To evaluate the signal quality of the Minder implantable continuous EEG monitoring (iCEM) system compared to traditional scalp EEG in the context of long-term, continuous monitoring in individuals with epileps...
OBJECTIVE: To evaluate the signal quality of the Minder implantable continuous EEG monitoring (iCEM) system compared to traditional scalp EEG in the context of long-term, continuous monitoring in individuals with epilepsy. METHODS: Twenty-six patients implanted with the Minder iCEM system (November 2019 to July 2023) underwent 7-day video-EEG co-monitoring with full montage scalp EEG at 4 and 24 weeks post-implantation. Co-monitored EEG segments were rated for clarity on a 5-point ordinal scale by blinded expert reviewers for ictal and interictal periods. Minder vs scalp ratings were compared using Wilcoxon signed-rank test; 4- vs 24-week comparisons used Wilcoxon rank-sum test. Objective quantitative EEG analysis of the signal bandwidth was performed by application of spectral coherence analysis and Pearson's correlation coefficients. RESULTS: No significant difference was found between interictal signal clarity reviewer ratings for Minder vs scalp EEG (p = .97), and there was no statistically significant difference between the Minder signal clarity ratings at 4 vs 24 weeks (p = .95). Pearson's correlation between Minder vs scalp EEG also indicated a high degree of similarity (median correlation = .69) and no statistically significant difference between correlations at 4 vs 24 weeks (p = .99). All electrographic seizures identified on full 10-20 scalp EEG were also identified on Minder; however, the full 10-20 montage received statistically higher seizure clarity ratings than Minder (p < .001). SIGNIFICANCE: This study supports the feasibility of sub-scalp EEG as a reliable long-term monitoring tool. Interictal signal quality was statistically equivalent to limited-montage scalp EEG, and all seizures identified on full 10-20 scalp EEG were also visualized on Minder. The full 10-20 montage did receive statistically higher seizure clarity ratings, reflecting its greater spatial resolution. The signal quality was stable through 24 weeks, demonstrating the fidelity of the device. These findings position the Minder system as a complement to full montage scalp EEG, particularly in ambulatory settings where continuous long-term recording is required.
Low diagnostic yield of presurgical genetic testing in adult patients with epilepsy.
Jünemann C, Stuart A, Kaur N … +8 more , Wiebe S, Jette N, Singh S, Borlot F, Knake S, Calgary Comprehensive Epilepsy Program Collaborators, Billie Au PY, Klein KM
Epilepsia · 2026 May · PMID 42157695 · Publisher ↗
OBJECTIVE: To determine the diagnostic yield of genetic testing in patients undergoing presurgical evaluation for epilepsy. METHODS: We conducted a cohort study including 115 adult patients who underwent presurgical eval...
OBJECTIVE: To determine the diagnostic yield of genetic testing in patients undergoing presurgical evaluation for epilepsy. METHODS: We conducted a cohort study including 115 adult patients who underwent presurgical evaluation in the Calgary Epilepsy Program between 2019 and 2023 and who had undergone research exome sequencing. A curated epilepsy gene panel comprising 765 Online Mendelian Inheritance in Man (OMIM)-listed epilepsy-associated genes was applied. Variants were classified according to American College of Medical Genetics and Genomics guidelines and assessed for clinical relevance and association with postsurgical outcomes. RESULTS: Pathogenic or likely pathogenic variants in DEPDC5, NPRL2, KCNT2, and PRRT2 were identified, respectively, in 4 individuals (3.5%, 4/115). All variants met stringent quality criteria with high pathogenicity scores (Combined Annotation Dependent Depletion (CADD) 34-37) and absent or extremely low population frequencies in gnomAD v4.1. None of these patients had intellectual disability, and only one patient (PRRT2) had a positive family history. The patient with the KCNT2 variant underwent epilepsy surgery with good outcome (Engel class ID). SIGNIFICANCE: This presurgical cohort demonstrates a low diagnostic yield of genetic testing in adult epilepsy surgery candidates. However, three of four patients with (likely) pathogenic variants did not have features that would have prompted clinical genetic testing, indicating that their genetic diagnosis would have been missed based on typical clinical genetic testing criteria in many jurisdictions.
Corticocortical evoked potential amplitude is altered by cortical stimulation in epilepsy.
Stieve BJ, Struck AF, Scott D … +2 more , Chappell R, Knox AT
Epilepsia · 2026 May · PMID 42157615 · Publisher ↗
OBJECTIVE: Neurostimulation is an established therapy for drug-resistant epilepsy, but optimizing stimulation parameters remains a major challenge. Corticocortical evoked potential (CCEP) amplitude may serve as an immedi...
OBJECTIVE: Neurostimulation is an established therapy for drug-resistant epilepsy, but optimizing stimulation parameters remains a major challenge. Corticocortical evoked potential (CCEP) amplitude may serve as an immediate biomarker of neurostimulation effects, enabling rapid parameter optimization. This study was undertaken to determine whether changes in CCEP amplitude reflect immediate neurostimulation effects. METHODS: We conducted a prospective study in 17 patients undergoing stereoelectroencephalographic monitoring. Each cortical site received randomized 5-s stimulation trains at low (7 Hz) and high (100 Hz) frequencies, preceded and followed by 30-s 1-Hz trains to evoke CCEPs. We analyzed 1210 pre-/posttreatment CCEP pairs using nonparametric tests and linear mixed-effects modeling. RESULTS: High-frequency stimulation produced significantly greater reductions in CCEP amplitude than low-frequency stimulation (median change: -1.6% vs. -.02%, p = .002), independent of total charge and epileptiform activity. These effects persisted for minutes to more than an hour and were most pronounced within the seizure onset zone. In contrast, low-frequency stimulation caused greater reductions in the mesial temporal region. SIGNIFICANCE: Relative changes in CCEP amplitude by high- and low-frequency neurostimulation reflect region-specific effects and may have utility for rapid parameter optimization. These findings highlight a potential strategy to accelerate personalization of neurostimulation therapy for epilepsy.
Diagnostic value of stand-alone videos after inconclusive inpatient EEG-video monitoring.
Azevedo MO, Amin U, Rivera-Cruz A … +6 more , Zemina K, Armanious M, Omura A, Tenney N, Huang Y, Benbadis SR
Epilepsia · 2026 May · PMID 42141960 · Publisher ↗
Inpatient electroencephalographic (EEG)-video monitoring occasionally fails to capture the events in question, leaving patients without a definitive diagnosis. Management after an inconclusive admission is generally limi...
Inpatient electroencephalographic (EEG)-video monitoring occasionally fails to capture the events in question, leaving patients without a definitive diagnosis. Management after an inconclusive admission is generally limited to repeating monitoring or empirical adjustment of antiseizure medications. Although stand-alone videos are increasingly used in clinical practice, their diagnostic value in this setting has not been well established. We aimed to assess the diagnostic contribution, submission rate, and interrater reliability of stand-alone videos obtained after inconclusive inpatient EEG-video monitoring. Over a 26-month period, we prospectively identified patients with inconclusive epilepsy monitoring unit (EMU) admissions who were instructed to submit videos of typical events not captured during their stay. Submitted videos were independently reviewed by two epileptologists, with adjudication by a third reviewer when consensus was not achieved. Among 619 EMU admissions, 165 (27%) were inconclusive. Twenty-seven (16%) patients submitted a stand-alone video. A definitive conclusion was reached in 23 (85%) patients, and in 20 (74%) patients, videos either established, confirmed, or revealed an additional diagnosis. Substantial interrater reliability was observed (κ = .690, 95% confidence interval = .456-.893), with perfect agreement for nonepileptic and physiologic events. This study provides preliminary evidence that stand-alone videos have the potential to be a valuable adjunct in the evaluation of seizures and seizurelike events after inconclusive EMU admissions. Early and systematic reinforcement of video collection may improve diagnostic yield and reduce health care utilization when inpatient studies are unrevealing.
Pyruvate dehydrogenase autoantibodies in autoantibody-negative patients with seizures are associated with reduced pyruvate dehydrogenase activity.
Breuer A, Hummel CA, Baumgartner T … +10 more , Berns JL, Said AM, Bünger I, Schoch S, Zsurka G, Prüss H, Kunz WS, Surges R, Becker AJ, Pitsch J
Epilepsia · 2026 May · PMID 42132967 · Publisher ↗
OBJECTIVE: We investigated the presence and potential functional relevance of antimitochondrial autoantibodies in patients suspicious for autoimmune encephalitis (AIE) associated with psychiatric symptoms and/or seizures...
OBJECTIVE: We investigated the presence and potential functional relevance of antimitochondrial autoantibodies in patients suspicious for autoimmune encephalitis (AIE) associated with psychiatric symptoms and/or seizures, who were negative for known antineuronal autoantibodies. METHODS: We screened serum samples from 387 patients autoantibody-negative for known antineuronal autoantibodies with psychiatric disturbances and/or epileptic seizures, including patients with temporal lobe epilepsy of unknown etiology. Various techniques, including immunoblotting, immunoprecipitation, mass spectrometry, immunohistochemistry, and in vitro assays assessing neuronal autoantibody uptake, neuronal viability, pyruvate dehydrogenase (PDH) enzyme activity, and mitochondrial DNA levels in biofluids were applied. RESULTS: Mass spectrometry detected all three subunits of the intramitochondrial PDHc-pyruvate dehydrogenase, dihydrolipoyl acetyltransferase, and dihydrolipoyl dehydrogenase-as targets of antibodies present in serum samples from three index patients suspicious for AIE with psychiatric symptoms or seizures. The presence of the anti-PDHc autoantibodies was confirmed by immunoblotting in 12 of 387 patients. Exposure of cultured primary neurons to commercial anti-PDH antibodies resulted in neuronal uptake and loss of neuronal viability. Patient-derived autoantibodies also impaired PDH enzyme activity in vitro. Additionally, cell-free mitochondrial DNA fragment levels were elevated in the serum and cerebrospinal fluid of PDH-positive patients compared to controls. SIGNIFICANCE: Anti-PDH autoantibodies were detected in patients suspicious for AIE with seizures and/or psychiatric symptoms as core manifestation in the absence of known antineuronal autoantibodies. These autoantibodies bind neuronal structures and reduce PDH enzyme activity under experimental conditions, supporting mechanistic plausibility of a functional role in disease.
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