レノックス・ガストー症候群他

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy defined by polymorphic seizures, intellectual disability (ID), and characteristic electroencephalographic (EEG) patterns. The applicability and biological validity of current electroclinical criteria remain debated. This study evaluated the concordance between clinical and electroclinical definitions of LGS and applied unsupervised clustering to identify data-driven profiles within LGS. METHODS: We retrospectively analyzed patients clinically fulfilling LGS criteria, with longitudinal electroclinical documentation and at least one sleep EEG. Patients meeting complete electroclinical criteria were compared with those meeting clinical criteria alone. Additionally, exploratory unsupervised K-modes clustering and discriminant correspondence analysis were applied in adolescent and adult patients. RESULTS: We included 105 patients (60.9% female), with a median age of 24 years (interquartile range = 16-35). Sixty-nine patients (65.7%) met complete electroclinical criteria, yet neurodevelopmental features, seizure types, magnetic resonance imaging (MRI) findings, and treatment refractoriness were comparable to the clinically defined subgroup. K-modes clustering (n = 97 patients) identified three data-driven electroclinical profiles. Cluster 1 comprised patients with the earliest seizure onset, profound intellectual and motor impairment, EEG background slowing, lower prevalence of generalized paroxysmal fast activity (GPFA), highest prevalence of structural etiologies, and lowest likelihood of meeting complete electroclinical criteria for LGS. Among clusters more frequently fulfilling complete electroclinical criteria, Cluster 2 represented an early onset profile with higher rates of ID, EEG background slowing, and high prevalence of polymorphic seizures. Cluster 3 included comparatively preserved patients, characterized by later onset, milder neurodevelopmental impairment, and higher frequency of normal MRI. Despite similar clinical severity, Cluster 1 patients had undergone fewer antiseizure medication trials. SIGNIFICANCE: Exploratory data-driven clustering identified clinically relevant electroclinical profiles that may help refine phenotypic stratification within clinically defined LGS. These included a severe GPFA-underrepresented profile and two GPFA-positive phenotypes differing in developmental severity, seizure profile, and age at onset.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a severe treatment-resistant epilepsy. Although vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are established therapies, comparative data and the impact of dual neuromodulation remain limited. We compared seizure outcomes across VNS, DBS, and combined DBS + VNS therapy in LGS. METHODS: This retrospective cohort study at Mayo Clinic (2005-2024) included LGS patients treated with VNS and/or DBS. Seizure frequency was assessed at 6, 12, and 24 months post-stimulation. Responder was defined as 50% or more seizure reduction. RESULTS: Forty patients were included (42% female, median, 150 seizures/month). Eleven patients underwent sequential VNS followed by DBS and contributed data to 2 treatment epochs, yielding 3 treatment groups: VNS alone (n = 29), DBS alone (n = 12), and DBS + VNS (n = 10). At 24 months, median seizure reduction rate was comparable between VNS (50%; 95% confidence interval [CI], 44-75%) and the overall DBS cohort (59%, 95% CI, 33-86%) (p = 0.54). However, a significant difference emerged when comparing the 3 treatment arms (p = 0.027). Specifically, DBS + VNS therapy yielded significantly greater median reduction rate (81%, 95% CI, 60-99%) than DBS alone (43%, 95% CI, 0-58%) (padj = 0.027) or VNS alone (50%, 95% CI, 44.4-75.0%) (padj = 0.048). Four patients attained sustained seizure freedom above 1 year at last follow-up. INTERPRETATION: VNS and DBS provide comparable seizure reduction in LGS over a 2-year follow-up period. DBS + VNS was associated with further improvements in seizure reduction in this small, retrospective dataset. This possibility warrants further investigation. ANN NEUROL 2026.

OBJECTIVE: To characterize the single- and multiple-dose pharmacokinetics, safety, and tolerability of carisbamate oral suspension in adult and pediatric patients with Lennox-Gastaut syndrome (LGS). METHODS: This phase 1, open-label study (NCT03731715) enrolled patients into four age cohorts: Cohort I (C-I), ≥ 18 years; Cohort II (C-II), 12 to < 18 years; Cohort III (C-III), 6 to < 12 years; Cohort IV (C-IV), 2 to < 6 years (C-IV withdrawn due to inability to enroll patients). On Day 1, patients received a single dose of carisbamate: 200 mg (C-I), 140 mg (C-II), 60 mg (C-III), followed by twice-daily multiple-dosing Days 3-17: 100 mg (C-I), 70 mg (C-II), 30 mg (C-III). Pharmacokinetic parameters were determined using noncompartmental analysis. Safety was also assessed. RESULTS: Eighteen patients (C-I: n = 8; C-II: n = 3; C-III: n = 7) were included; 16 (89%) completed the study. Following single doses, carisbamate was rapidly absorbed (tmax, 1-2 h post-dose), with a mean t1/2 of ∼12 h in C-I and C-II and ∼8 h in C-III. After single- and multiple-doses, mean Cmax, AUC0-last, and AUC0-inf increased dose-proportionally. Total carisbamate exposures were comparable across cohorts after dose normalization. Mean (SD) accumulation ratios following multiple dosing were 1.66 (0.15; C-I) and 1.69 (0.06; C-II). Treatment-emergent adverse events (TEAEs) occurred in 66.7% of patients, most commonly nervous system TEAEs (22.2%). One severe TEAE (affective disorder) occurred, and one patient discontinued due to an AE (sedation). No serious TEAEs or deaths occurred. CONCLUSIONS: In this small phase 1 PK/safety study, carisbamate appeared to exhibit linear, dose-proportional pharmacokinetic parameters in pediatric and adult LGS patients at doses of 60-200 mg/day and was generally well tolerated during short-term treatment.

OBJECTIVES: Sleep dysfunction is a common but poorly characterized symptom in people living with Lennox-Gastaut syndrome (LGS). Sleep impairments exacerbate seizures while ictal activity causes sleep disturbance, leading to a cycle of sleep-epilepsy worsening. The HEADFIRST study was conducted to assess whether caregivers could self-operate a dry-electrode EEG headband (Waveband) to collect in-home EEG data from participants with LGS and neurotypical controls (siblings). METHODS: In this observational cohort study caregivers were instructed on how to place/operate the dry-EEG electrode device on participants with LGS and their neurotypical siblings (aged 5-18 years). Overnight recordings were collected for 2 non-consecutive 5-night blocks (including ≥ 2 consecutive nights). Data collected included EEG recordings, automated sleep staging, and caregiver-reported diaries/outcomes. Statistical differences in sleep parameters were calculated for the LGS versus control cohorts. RESULTS: Recordings from 10/12 participants with LGS and 10/10 controls were included. Caregivers successfully recorded 83 % (10/12) of the LGS cohort and 90 % (9/10) of neurotypical controls for the instructed 5 nights, including ≥ 2 consecutive nights. Distinct EEG-based sleep and epileptiform differences were observed across groups. During non-REM sleep, the LGS cohort demonstrated characteristic EEG abnormalities, including slow spike-wave discharges, sporadic interictal epileptiform discharges, generalized paroxysmal fast activity, or electrographic seizures. Total sleep time (LGS: 465.8 min; control: 440.6 min) and sleep onset latency (LGS: 17.3 min; control: 28.5 min) were similar between groups; significant increases in wake after sleep onset (LGS: 43.0 min; control: 18.0 min), decreases in REM sleep duration (LGS: 51.3 min; control: 100.6 min), and number of sleep cycles (LGS: 2.6; control: 4.6) were observed in the LGS vs control groups (all p < 0.05). SIGNIFICANCE: Multi-night, at-home, caregiver-conducted EEG recordings were feasible and provided usable data. The HEADFIRST study demonstrated statistically and clinically significant sleep disruptions in LGS versus control cohorts. Significant differences in sleep architecture were observed, including loss of sleep cycling and reduced REM sleep. Ambulatory EEG-based systems may aid in further understanding sleep pathology in people living with epilepsy.