Epilepsia最新文献

Objective: Seizure risk is modulated by multiscale brain rhythms. Previous studies using cycles in electroencephalography, heart rate, and wearable data suggest the possibility of forecasting seizures days in advance. However, they commonly rely on methods requiring (days of) information from time points beyond the moment of forecast (noncausal processing). Although applicable to retrospective analyses, such an approach is not feasible for real-time clinical applications. Here, we systematically investigated the impact of using only past data (causal processing) to estimate long-timescale cycles of epileptic brain activity on forecasting performance.

Methods: We analyzed long-term interictal epileptiform activity (IEA) recordings from 18 patients implanted with the RNS system. Circadian/multidien IEA cycles were extracted using two approaches: (1) noncausal filters also requiring future data; and (2) causal filters utilizing only past data, simulating real-time scenarios. Forecasting was performed using Poisson regression, and the performance was benchmarked against established baseline models.

Results: Noncausal models achieved high performance, consistent with previous literature. However, when strict causal constraints were applied, performance deteriorated significantly ( , Wilcoxon signed-rank test). For hourly forecasting, the median area under the curve dropped from .76 to .63, time in warning increased from 35% to 60%, and patients with above-chance performance decreased from 89% to 72%. Crucially, for daily forecasting, the causal models failed to perform better than chance for all patients. Performance loss was attributable to the input-output time lag and cycle deformation inherent to filters when analyzing data in a real-time scenario without access to future signal trends.

Significance: Clinically beneficial seizure forecasting requires algorithms that function prospectively, using only past data. Our findings reveal a substantial performance gap between theoretical (noncausal, retrospective) performance and realistic (causal, prospective) capabilities. This suggests that prior studies may have overestimated forecasting accuracy. Future research must focus on developing novel cycle-extraction methods that remain robust under real-time prospective conditions.

Objective: Magnetic resonance imaging (MRI)-negative type II focal cortical dysplasia (FCD) is challenging to localize and treat. Emerging evidence suggests that the sulcal bottom is the critical site of epileptogenicity. This study investigated whether MRI-negative type II FCD represents a subtle form of bottom-of-sulcus dysplasia (BOSD) and evaluated the safety and efficacy of sulcus bottom-targeted minimally invasive therapy.

Methods: Fifty-eight patients (mean age = 18.0 ± 10.0 years, range = 4-41) with drug-resistant epilepsy and MRI-negative scans were clinically diagnosed with FCD type II and included in the study. Of these, 27 met inclusion criteria for stereoelectroencephalographic (SEEG) analysis to compare interictal spike counts, high-frequency oscillation (HFO) counts, and epileptogenicity index (EI) values between sulcal bottom and nonbottom contacts. Histopathological analysis (n = 15) evaluated the spatial distribution of dysmorphic neurons (DNs) and balloon cells (BCs) using nonphosphorylated neurofilament (SMI32), phospho-S6 ribosomal protein (pS6), and Nestin immunoreactivity. An additional 19 patients received magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) targeting the sulcal bottom, with seizure outcomes and ablation coverage systematically evaluated.

Results: SEEG demonstrated significantly higher spike counts, HFOs, and EI values at sulcal bottom contacts than at nonbottom regions (all p < .0001), showing strong negative correlations with distance from the sulcal bottom (R = -.85 to -.68). Histopathology revealed a consistent spatial gradient, with DN density and diaminobenzidine intensity significantly enriched at the sulcal bottom across SMI32 and pS6 labeling (all p < .05). BCs, when present, were confined to the sulcal bottom. In the MRgLITT cohort, sulcus bottom-targeted ablation achieved seizure freedom (Engel IA) in 73.7% of patients, with a mean ablation coverage of 28.3% and no permanent neurological deficits.

Significance: MRI-negative type II FCD exhibits sulcus bottom-centered epileptogenicity, consistent with a subtle form of BOSD. These findings support sulcus bottom-targeted MRgLITT as a safe and effective minimally invasive therapy and provide a rationale for sulcus bottom-centered surgical planning in MRI-negative FCD II.

Objective: Despite being safe and effective, surgery for pediatric epilepsy is underutilized. Social determinants of health (SDoH) are important to consider when examining this treatment gap. This study examined the potential systemic inequities at three different stages in the journey toward epilepsy surgery across the Pediatric Epilepsy Research Consortium (PERC).

Methods: Any youth in the PERC prospective surgery database (≤18 years) was eligible and included if sociodemographic factors were also available. We examined if there were differences in disparity factors in: (1) referral to Phase I evaluation, (2) offering of surgery, and (3) completion of surgery.

Results: Of 1309 patients, the majority were male (53%, p = .04), White (82.2%, p < .001), not Hispanic or Latino (84.3%, p < .001), and privately insured (56.3%, p < .001). Of the youth who were offered surgical treatment (n = 1103, 84.3%), there were no significant differences in race/ethnicity or sex. Those with a structural lesion were more likely to be offered surgery, and historically marginalized youth were more likely to have a lesion. Of patients who completed surgery (n = 927, 84.0%), White patients were 1.88 times (95% confidence interval [CI]: 1.14-3.04) more likely than Black patients to complete surgery (p = .01).

Significance: Youth who began surgery evaluation are not representative of the demographics of those with epilepsy in the United States, with greater representation of White, non-Hispanic male individuals. In addition, youth who began surgery evaluation disproportionally have private insurance. At the next stage of offering surgery, there were no differences based on SDoH. However, there is evidence that underrepresented youth that were magnetic resonance negative were less likely to be referred for surgical workup and that Black youth were less likely to undergo surgery. Therefore, efforts to provide equitable opportunity for all youth with refractory epilepsy should be concentrated at the referral for surgery evaluation point of care; however, additional efforts are also needed at later stages.

Objective: Posttraumatic stress disorder (PTSD) is more prevalent in epilepsy than in the general population. However, it remains unclear whether this association is specific to epilepsy or a broader consequence of experiencing unpredictable acute episodes within chronic diseases. This study aimed to (1) compare PTSD prevalence and severity in patients with drug-resistant epilepsy (DRE) and patients with other chronic episodic diseases, namely, type 1 diabetes (T1D) and drug-resistant atrial fibrillation (AF); and (2) examine psychiatric comorbidities, emotion regulation, and quality of life across groups.

Methods: A total of 122 patients (64 with DRE; 58 with chronic diseases: 30 with AF, 28 with T1D) completed questionnaires assessing PTSD symptoms, trauma exposure, anxiety, depression, dissociation, emotion regulation, and quality of life. Statistical analyses included χ² tests, t-tests, analyses of covariance controlling for age, and correlation analyses.

Results: PTSD was significantly more prevalent in the DRE group (34.94%) than in the chronic disease group (12.07%; χ² = 9.5, p = .004). DRE patients also reported significantly more repeated trauma exposures (54.69% vs. 27.59%, p = .004). Compared to other groups, DRE patients showed higher anxiety (p = .002), depression (p = .002), and dissociation (p < .001), poorer emotion regulation (p = .003), and lower quality of life (p < .001).

Significance: Our findings suggest that the psychiatric burden observed in DRE cannot be solely attributed to chronic episodic disease status. Instead, it may reflect the impact of early and repeated traumatic exposures and their interaction with the neurobiological underpinnings of epilepsy. The strong association between complex trauma, psychiatric comorbidities, and poor quality of life supports the hypothesis of psychoepileptogenesis and calls for integrated trauma-informed care in epilepsy management.

Objective: Pathogenic variants of KCNQ2 lead to a spectrum of disorders including self-limited familial neonatal-infantile epilepsy (SeL(F)NIE), developmental and epileptic encephalopathies (DEEs), and neurodevelopmental disorders (NDDs) with intellectual disability (ID). This study aimed to delineate the clinical progression and underlying pathogenesis of these disorders. Particularly, we unraveled the role of gain-of-function (GoF) variants in neurodevelopmental impairment.

Methods: We conducted a longitudinal study of a 90-patient Chinese cohort with KCNQ2-related disorders, classified into SeL(F)NIE, DEEs, and NDDs subgroups. Clinical phenotyping was integrated with functional analyses (electrophysiology, biochemistry) of five missense variants in homomeric and heteromeric (with Kv7.3/Kv7.5) channel assemblies.

Results: Despite comparable seizure control to SeL(F)NIE (96% vs 100%), the NDDs group exhibited significant cognitive impairment. All deceased patients (8/90) were in the DEEs group. Functional profiling revealed a spectrum from loss-of-function (LoF) to GoF. LoF variants (e.g., S247L in DEEs) were linked to severe epilepsy. Crucially, we identified strong GoF variants (P335A/L in NDDs) in the S6-HelixA domain that confer insensitivity to phosphatidylinositol 4,5-bisphosphate (PIP₂) regulation and are associated with a primary neurodevelopmental phenotype, distinct from the severe epileptic phenotype of established voltage-sensing domain (VSD) GoF variants.

Significance: Our integrated clinical and functional analysis showed that the clinical outcome relies on the functional consequence of a KCNQ2 variant (LoF vs GoF) and its behavior in heteromeric complexes, rather than its mere location. We defined a novel class of strong GoF KCNQ2 variants that are mechanistically and phenotypically distinct, highlighting aberrantly enhanced channel function as a key driver of cognitive dysfunction and presenting new targets for precision medicine.

Objective: Nonadherence to antiseizure medications in pediatric epilepsy affects ~60% of youth. The aim of this multisite two-stage sequential, multiple assignment, randomized trial (SMART) was to evaluate the effectiveness of mHealth intervention strategies for improving adherence in caregivers of young children with epilepsy, particularly those who are underserved. It was hypothesized that participants initially randomized to treatment would exhibit significantly greater improvements in adherence compared to an active control group at the end of stage 1. Secondary outcomes included longitudinal adherence, seizure freedom/severity, and health-related quality of life.

Methods: Participants across four epilepsy centers were recruited (n = 461, mean age = 7.6 ± 3.0 years, 51% males, 62% White non-Hispanic, 71% underserved). Baseline questionnaires were completed, and electronic adherence monitors were provided. Three intervention strategies were embedded in this SMART: (1) active control (mHealth education + automated digital reminders), (2) treatment (mHealth education + automated digital reminders + individualized adherence feedback) in stage 1 continuing in stage 2 regardless of responsiveness in stage 1, and (3) treatment in stage 1 continuing in stage 2 if patient is responsive in stage 1 or augmented by problem-solving if patient is nonresponsive in stage 1. Active intervention was 5 months, with two posttreatment follow-ups. Standard analysis of covariance was conducted for the primary aim. Secondary analyses compared mean change from baseline associated with each intervention strategy.

Results: The treatment group had significantly better mean adherence percentage change from baseline to the end of stage 1 compared to the active control group (13.2% vs. 3.1% change, t = 2.82, p = .005, d = .37). Adherence rates declined over time across all SMART strategies. An increased probability of seizure freedom at 6 and 12 months across all SMART strategies was found.

Significance: This pediatric epilepsy SMART trial demonstrated adherence improvements for the treatment group that did not persist over time. Improvements in seizure freedom that were independent of SMART strategy were also identified. mHealth education, automated digital reminders, and individualized adherence feedback appear to have been efficacious.

Objective: Benzodiazepines (BZDs) are the recommended first-line treatment in early status epilepticus (SE). At least 30% of episodes are resistant, leading to established SE. Chronic BZD use may induce pharmacological tolerance. We hypothesized that chronic exposure to BZDs may reduce their efficacy as first-line treatment in early SE.

Methods: This retrospective case-control study included SE episodes from 2010 to 2023 at a tertiary center in Brussels. Postanoxic and Alcohol- or BZD withdrawal-related SE episodes were excluded, as well as those in which BZDs were not used as first-line treatment. Chronic BZD use was defined as a daily use for at least 6 months. Chronic BZD users (cases) were matched 1:1 with nonusers (controls) for age, sex, etiology, and semiology. Univariable and multivariable comparisons were performed. The primary outcome was evolution of early SE to established SE, defined as the use of second-line treatment.

Results: Ninety-eight cases and 98 controls were included and matched. Chronic use of BZDs was associated with more frequent need for second-line treatment or evolution to established SE (85% vs. 64%, p = .022). Established SE (n = 146) was also associated with longer in-hospital stay (15 vs. 5 days, p < .001) and more complications (Complications Burden Index: 1 vs. 2.5, p < .001). After adjusting for both timing and dose of first-line treatment, multivariable analysis confirmed chronic BZD use as an independent risk factor for established SE (odds ratio = 3.34, 95% confidence interval = 1.66-7.03, p = .001). Among chronic users, no association was observed between modalities of BZD chronic use (dose, half-life time, duration) and the establishment or refractoriness of SE episodes.

Significance: Chronic BZD use is associated with a higher rate of second-line treatment administration in SE, suggesting greater resistance to acute BZD administration. This association should be considered when managing early SE. Chronic BZD use should be considered with extreme caution in patients with epilepsy at risk of SE.

Objective: We previously reported in a prior cohort that fetal exposure to antiseizure medications (ASMs), especially valproate, was associated with reduced right-handedness and poorer verbal versus nonverbal performance in children at age 6 years. Given changes in prescribing practices in epilepsy over the past 2 decades, we enrolled a new cohort of the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study to determine whether fetal exposure to newer generation ASMs is associated with altered cerebral lateralization in children at age 6 years and to assess exposure-dependent effects on handedness, manual dexterity, and verbal/nonverbal abilities.

Methods: The MONEAD multicenter prospective cohort study followed children of women with epilepsy (WWE) on ASMs and healthy women (HW) until age 6 years. We assessed handedness using the Edinburgh Handedness Inventory, manual dexterity through the Grooved Pegboard Test, and verbal/nonverbal abilities with the Differential Ability Scales-II. Outcomes were analyzed in relation to ASM exposure, controlling for confounders.

Results: Of 1123 screened pregnant women, 351 children born to WWE and 105 to HW were enrolled. The overall distribution of handedness and verbal/nonverbal scores did not differ between groups. However, subgroup analyses revealed that higher third-trimester levetiracetam concentrations were significantly associated with nondextrality (p = .03, 95% confidence interval [CI] = .03-.67). Across the WWE cohort, higher ASM concentrations correlated with poorer manual dexterity (coefficient = 6.76, 95% CI = .40-13.11, p = .037). Additionally, periconceptional folate supplementation was associated with better nonverbal outcomes (coefficient = 2.54, 95% CI = .93-4.15, p = .002) and parental stress was linked to poorer verbal scores (coefficient = -19.74, 95% CI = -28.48 to -11, p < .001).

Significance: This cohort reassuringly showed no overall difference in verbal/nonverbal abilities between WWE and HW. Fetal ASM exposure had exposure-dependent effects on manual dexterity. Modifiable factors, including folate supplementation and parental stress, significantly influenced developmental outcomes, underscoring the importance of proactive screening and providing intervention when appropriate.

Objective: Determining patient-specific thalamic connectivity alterations may be an important step toward personalized surgical and neuromodulation strategies, but no data are available to support this concept in pediatric cohorts. This study investigated thalamocortical structural connectivity profiles in children with focal-onset epilepsy of different seizure-onset zones.

Methods: This neuroimaging, case-control study compared structural connectivity of four thalamic nuclei (anteroventral [AV], centromedian [CM], mediodorsal [MDPf], and pulvinar [PUL]) between 81 children who underwent surgery for focal-onset epilepsy (median age = 12.2 years) and 63 controls (median age = 12.8 years). Using preoperative 3-Tesla diffusion magnetic resonance imaging (dMRI), brain (Lausanne) and thalamic (THOMAS) parcellations combined with tractography generated structural connectomes based on streamline counts. Connectivity strength of each thalamic nucleus was calculated by summing the weights of each connecting brain region.

Results: Patients had higher structural connectivity strengths than controls of the thalamic nuclei (effect size (η²ₚ) = .072; p = .015), differentially involving nucleus regions, but there was no overall difference in nucleus volumes (η²ₚ < .000; p = .968). When comparing patient groups defined by seizure-onset zones, it emerged that reduced AV connectivity strength was specific to the hippocampal sclerosis group, whereas CM, MDPf, and PUL connectivity was similarly high in all the patient groups, including those with frontal or temporal lobe epilepsy. Patients who were seizure-free after surgery had a lower ipsilateral and a higher contralateral connectivity strength (η²ₚ = .111; p = .005) and volumes (η²ₚ = .073; p = .025) of thalamic nuclei compared to those who were not.

Significance: This study provides unique data suggesting that different pediatric focal epilepsies have distinct structural thalamocortical connectivity and volumetric profiles. The structural connectivity and volumetric asymmetries of the thalami have an association with postoperative seizure freedom. More studies are required to further understand the thalamic connectivity signatures that may have implications for precision surgical planning and neuromodulation targeting for focal-onset epilepsy.