Michela Quintiliani

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: CDKL5 deficiency disorder (CDD) is an early‐onset developmental and epileptic encephalopathy characterized by frequent drug‐resistant seizures, cerebral visual impairment, motor dysfunction, and sleep and gastrointestinal disturbances. Preliminary evidence suggests that highly purified cannabidiol (CBD) may reduce seizure frequency, but data on its effects on comorbidities are lacking. This study aimed to evaluate the efficacy and safety of CBD in individuals with CDD. Methods: We conducted a prospective, open‐label, single‐center study including patients with CDD aged >1 year. Outcomes included motor seizure frequency, caregiver‐ and clinician‐rated Clinical Global Impression (CGI), and changes in sleep, motor abilities, and EEG at 3, 6, and 12 months. CBD plasma levels were measured with High‐Performance Liquid chromatography–Mass Spectrometry (HPLC‐MS). Results: Eight of nine patients (all females; median age 10 years, range 1–24) completed the study, with a retention rate at 12 months of 8/9 (89%). One discontinued at 6 months due to a skin rash. A > 50% seizure reduction was observed in 8/9 patients at 3 months, 6/9 at 6 months, and 1/8 at 12 months. Seven patients showed some degree of vigilance improvements, three in motor performance, and two in sleep and constipation. All caregivers reported at least minimal overall improvement (CGI score 3) at 3 months, and three reported marked improvement (CGI score 2), with a peak at 3 months. Five patients showed adverse events during the trial, but none were considered serious. The median CBD dose at all time‐points was 15.6 mg/kg/day (IQR 10.0–18.9) corresponding to a plasma dose of 69.9 ng/mL (IQR 29.8–114.6) and the median concentration/dose ratio was 4.7 (IQR 2.7–6.8). Significance: The safety and efficacy of highly purified CBD in CDD were consistent with previous reports in the literature, with possible benefits beyond seizure control. Further studies are warranted to assess non‐seizure outcomes and compare long‐term efficacy across treatment options. Plain Language Summary: We studied nine girls with CDKL5 deficiency disorder who had frequent, hard‐to‐treat seizures. They received cannabidiol for up to 1 year, added to their usual medicines. Most children had fewer seizures in the first months of treatment. Some families also noticed better alertness, eye contact, movement, sleep, or constipation. Side effects were usually mild and manageable. Although seizure frequency often returned to baseline by the end of the study, most families chose to continue cannabidiol. Because this was a small study without a placebo group, these results are preliminary, and larger controlled trials are needed.

Objective: Dravet syndrome (DS) is a rare disease with a high clinical and socioeconomic impact on patients, society, and the healthcare system. The recent approval of therapies such as fenfluramine (FFA) has transformed the treatment landscape; however, data on their cost‐effectiveness are still scarce. This study evaluates the real‐world cost‐effectiveness of adding FFA to existing therapies for DS patients from the Italian National Healthcare System perspective. Methods: This retrospective multicenter observational study included 124 Italian DS patients initiating FFA as add‐on treatment between February 2017 and August 2022 and followed until December 2022 or disenrollment (post‐FFA period). Data on drug treatments, healthcare resource utilization, and main outcomes—rescue medication, hospital admission, and status epilepticus (SE) episodes—were collected both in the post‐FFA period and in a pre‐FFA period matching each patient's follow‐up duration (median 2.9 years). Annual per‐patient rates and costs, with 95% confidence intervals (CI), were determined for each outcome in both periods. Incremental cost‐effectiveness ratios (ICERs) with 95% CIs and cost‐effectiveness acceptability curves (CEACs) were also calculated. Results: The median age at FFA initiation was 8.5 years. Mean annual healthcare cost of patients with DS was €5740 (95% CI 2896–9930) in the pre‐FFA period. FFA introduction added an annual per‐patient drug acquisition cost of €16 476, but it significantly reduced frequency and costs associated with hospital admissions and acute events. ICERs were €2187 per rescue medication avoided, €12 935 per hospital admission avoided, and €17 301 per SE episode avoided. Significance: This real‐world study demonstrates that despite increased drug acquisition costs, FFA provides clinical and economic benefits by reducing acute events and related healthcare costs. The investment required to reduce acute events is justifiable given the young age of DS patients and its impact on the healthcare system, families, and caregivers. Future research should incorporate indirect costs and a broader societal perspective. Plain Language Summary: Dravet syndrome is a severe and rare type of epilepsy that can be very hard on patients and their families. It also puts a great burden on healthcare systems. A new treatment, fenfluramine (FFA), helps better control seizures. Although FFA increases drug treatment costs, this cost is actually balanced out by reduced emergency visits and hospital stays for severe seizures, leading to overall lower healthcare expenses.

Objective: Highly purified cannabidiol (CBD) is approved as adjunctive therapy for seizures associated with Dravet syndrome (DS), Lennox–Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC), although its role in other developmental and epileptic encephalopathies (DEEs) remains unexplored. The aim of this study was to assess the real‐world use, efficacy, and safety of CBD across a broad cohort of patients with DEEs, including off‐label indications. Methods: In this retrospective study, we evaluated 107 patients with DEEs treated with CBD for ≥3 months between 2020 and 2024. Data on seizure frequency, tolerability, retention, and non‐seizure outcomes were collected. Efficacy was defined as ≥50% or ≥75% seizure reduction. Statistical analyses explored predictors of response. Results: Patients had LGS (55.1%), DS (16.8%), TSC (8.4%), or other DEEs (19.6%), with a genetic etiology in 56.1%. At a median follow‐up of 20 months, 69% achieved ≥50% seizure reduction, and 21% achieved ≥75% reduction. Patients with LGS, TSC, and other DEEs showed higher efficacy and retention rates compared to DS. Genetic or unknown etiology was associated with better outcomes ( p = 0.011). Combination with valproate was associated with reduced efficacy ( p = 0.006), while combination with clobazam had no significant effect on efficacy nor safety. Non‐seizure improvements included increased alertness (56%), improved sleep quality (25%), and enhanced motor performance (14%). Adverse events occurred in 33.6%, mostly mild and transient; 9% discontinued due to side effects. Significances: This study confirms the effectiveness and good tolerability of CBD in a real‐world DEE population, including off‐label use. These findings support expanding CBD indications and underscore the need for prospective studies targeting both seizure and developmental outcomes. Plain language summary: This study looked at the use of cannabidiol (CBD), a cannabis‐based medicine, in 107 people with severe forms of epilepsy called developmental and epileptic encephalopathies (DEEs). With CBD add‐on, about two‐thirds of patients had fewer seizures, and some caregivers noticed improvements in alertness, sleep, or movement. Most patients tolerated the treatment well, but some experienced side effects, and a few had to stop taking it. While the results are promising, more research is needed to confirm how effective and safe CBD is for different types of DEEs, especially those not currently approved for treatment with CBD.

Objective: To study the current practice of epilepsy surgery in Italy and the relative impact of coronavirus disease 2019 (COVID‐19) pandemic on it. Methods: We launched a survey through the Italian National Virtual Epilepsy Institute, to identify centers with epilepsy surgery programs and collect data on the current preoperative and surgical practices. We reported changes in surgical volumes and complications and seizure outcomes between 2018 and 2022, that is, before and after the COVID‐19 pandemic in Italy. Results: A total of 21 of the 26 surveyed centers (80.7%) responded. Eleven centers (52.4%) reported having an established epilepsy surgery program, with most performing complex procedures, such as multilobar, disconnective, and hemispheric interventions. However, only a few carry out minimally invasive surgeries. Presurgical evaluation protocols vary across centers, but in keeping with international standards. Globally, 618 surgeries were performed in children and 621 in adults (total 1239) between 2018 and 2022. The most frequent type of surgery was unilobar extratemporal lobectomy for children (38.7%, p < 0.0001) and unilobar temporal lobectomy for adults (63.3%, p < 0.0001). Hemispheric surgeries were more frequent in children than in adults (11.5% vs 2.1%, p = 0.001), whereas interventions in unrevealing magnetic resonance (MRI) cases were more frequent in adults than in children ( p = 0.030). At the onset of COVID‐19outbreak in Italy (March 2020), we observed a significant decrease in the total number of operations compared to 2019, especially for hemispheric interventions ( p = 0.027). Surgical volumes resumed in 2021, particularly for temporal lobe epilepsies and in adult cohorts. Surgical complications increased significantly in 2020 (Incidence Rate Ratio [IRR] = 13.13), whereas seizure outcome did not change significantly between 2018 and 2022. Significance: Advanced pre‐ and postsurgical evaluation protocols are currently implemented across Italy, with a great variability between centers. Starting in 2021, epilepsy surgery volumes have regained their pre‐pandemic levels, albeit with a slight loss of complexity, whereas seizure outcome has remained stable.

Objective: Fenfluramine (FFA), stiripentol (STP), and cannabidiol (CBD) are approved add‐on therapies for seizures in Dravet syndrome (DS). We report on the long‐term safety and health care resource utilization (HCRU) of patients with DS treated with FFA under an expanded access program (EAP).Methods: A cohort of 124 patients received FFA for a median of 2.8 years (34.4 months). We compared data on safety and HCRU during FFA treatment with those from a same pre‐treatment period. Echocardiography was conducted every 6 months. Information collected included gender, age, and auxological parameters (height, weight, and body mass index [BMI]) at the start (T0) and follow‐up (T1); FFA treatment details (start, withdrawal, dosage); adverse events (AEs); and HCRU data including hospital admissions, status epilepticus (SE) episodes, and rescue medication use. We grouped patients by weight: ≤37.4 kg (n = 68, 54.8%) and ≥37.5 kg (n = 56; 45.1%), with FFA dosing adjusted accordingly. Statistical analyses included paired t test, Wilcoxon signed‐rank test, Kaplan–Meier analysis, and Bonferroni correction to adjust for multiple testing.Results: Mean age was 47 months at clinical diagnosis and 81 months at T0. The last follow‐up average FFA dose was .5 mg/kg/day, with a median of .4 mg/kg/day. FFA led to a 9.5% reduction in prior treatment load. At last follow‐up, 118 of 124 (91.5%) remained on FFA. Rescue medication use decreased significantly from 4.5 to 1, hospitalizations from 1 to 0, and SE episodes from 0–240 to 0–180 (p < .001 for all). Seizure freedom was achieved in 9 of 118 patients (7.6%). AEs occurred in 39 of 124 patients (31.5%), with no cardiac issues or deaths. There was an overall mean reduction in BMI, with no statistical significance, and never requiring FFA withdrawal.Significance: FFA is well tolerated, without cardiac toxicity, and reduces treatment load and HCRU, suggesting improved patient management. BMI reduction in young children highlights the need for growth and nutritional monitoring.