Marco Perulli

Objective: Lennox–Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy typically diagnosed in childhood. The 2022 International League Against Epilepsy (ILAE) criteria provide a diagnostic framework built on pediatric data, but their applicability in adulthood is challenged by disease evolution, treatment effects, and missing pediatric records. This scoping review aimed to identify adult LGS features and to evaluate the adaptability of current criteria in adults. Methods: We conducted a systematic search on MEDLINE (PubMed) following the Preferred Reporting Items for Systematic reviews and Meta‐Analyses extension for Scoping Reviews (PRISMA‐ScR) guidelines. Studies involving individuals 16 years of age and older with LGS or suspected LGS were included. Data were extracted on seizure semiology, electroencephalography (EEG) patterns, comorbidities, and etiological factors across the lifespan. Results: Forty‐five sources (78% case reports/series) encompassing 421 patients were included, with substantial heterogeneity in reporting. The analysis suggests a longitudinal attenuation or under‐documentation of several classical LGS features: studies with fulfillment of the ILAE seizure‐type criteria decreased from 73% in childhood to 41% in adulthood; tonic seizures often persisted (frequently during sleep), whereas atonic and atypical absence seizures significantly declined. The mandatory EEG hallmarks (generalized paroxysmal fast activity and slow spike‐and‐wave complexes) were documented in less than half of adult patients, possibly due to the reduced frequency of sleep EEG monitoring. Comorbidities were reported inconsistently, representing a major knowledge gap, as sleep and behavioral disorders may further mask diagnostic markers. Significance: Given the heterogeneity and predominantly low‐level evidence of the included literature, these findings warrant cautious interpretation; nonetheless, strict adherence to pediatric‐centric criteria in adults may plausibly contribute to underdiagnosis or false negatives. Transitioning from a “snapshot” to a “longitudinal” diagnostic mindset is essential. Clinicians should prioritize life‐spanning anamnesis and recognize that the clinical and EEG core criteria of LGS may evolve or diminish over time. Age‐adapted diagnostic frameworks are needed to ensure that adult patients receive appropriate diagnosis and therapeutic pathways.

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.

This multicenter retrospective study evaluated the effectiveness and safety of highly purified cannabidiol (CBD) in 22 patients with 15q11.2‐q13.1 duplication or deletion syndromes (15q‐DDS), including 12 with 15q duplication syndrome (dup15q) and 10 with Angelman syndrome (AS). Median (interquartile range [IQR]) age at CBD initiation was 14.5 (10–22.5) years, with a median (IQR) follow‐up of 21 (14–33) months. All dup15q and two AS patients presented with a Lennox–Gastaut phenotype. At last observation, mean seizure reduction was 55.7% (95% confidence interval 38.7–72.7), with 63.6% patients achieving ≥50% reduction, 40.9% achieving ≥75% reduction, and 18.2% achieving seizure freedom. Tonic seizures in dup15q and myoclonic seizures in AS showed the most notable reductions. EEG improvement was observed in 7/16 patients, with marked improvement observed in two dup15q patients. Clinical improvement on the Clinical Global Impression‐Improvement scale was reported in 72.7%, alongside nonseizure benefits such as improved sleep, behavior, and attention in a subset of patients. CBD was well tolerated; no patient discontinued CBD due to side effects alone, and retention at last visit was 81.8%. These findings suggest that CBD may provide clinically meaningful benefit in patients with 15q‐DDS, including seizure reduction and improvements in sleep, behavior, and attention in selected cases. Plain Language Summary: Epilepsy secondary to 15q11.2‐q13.1 duplication or deletion syndromes (15q‐DDS) is often severe, making daily life difficult for patients and their families. In this study, treatment with highly purified cannabidiol (CBD) reduced seizures in many patients with 15q‐DDS. CBD was generally well tolerated, and caregivers also reported improvements in sleep, behavior, and attention in a number of cases. Overall, these findings suggest that CBD may be a helpful treatment option for people with 15q‐DDS.

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: 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 characterize the clinical, electroencephalographic, and genetic features of epilepsies featuring absence seizures within monogenic etiology, highlighting the diagnostic, treatment and prognostic implications. Methods: We conducted a retrospective, multicenter study including patients with monogenic epilepsies and electroencephalography (EEG)–documented absence seizures. We analyzed clinical data, electroclinical findings, neurodevelopmental outcomes, and treatment responses through standardized questionnaires and medical records. We classified genetic variants according to American College of Medical Genetics and Genomics (ACMG) guidelines and performed univariate and multivariate analyses to identify predictors of developmental outcomes. Results: We included 160 patients (111 female; median age at last follow‐up: 13 years) with absence seizures and confirmed pathogenic or likely pathogenic monogenic variants. The most frequently implicated genes were SLC2A1, SLC6A1, SYNGAP1 , CHD2, and SCN1A . Four genes— HESX1, NCKAP1, SON, STARD9 —had not been previously associated with absence seizures. In 35% of patients, absence seizures were the only seizure type and in 67% were the initial manifestation. Atypical features included irregular EEG discharges (56%) eyelid myoclonia (42%), and automatisms (33%). Early‐onset (before age 3) seizures occurred in 58% and was significantly associated with atypical features ( p < .03). Using existing International League Against Epilepsy (ILAE) epilepsy syndrome classification, 60% of patients could not be classified. Developmental delay occurred in 54%, intellectual disability in 65%, and other neurodevelopmental comorbidities in 49%. Predictors of poor developmental outcomes included early developmental delay, drug‐resistant epilepsy, and early absence onset. We found no difference in the prevalence of drug resistance across the various genetic etiologies. The most effective medications for absence seizures included valproate, ethosuximide, benzodiazepines, and lamotrigine. Disease‐specific therapies (e.g., ketogenic diet in SLC2A1 , stiripentol/fenfluramine in SCN1A) were effective in select cases. Significance: Absence seizures are a common manifestation of different monogenic epilepsies, often associated with early onset, atypical clinical and/or EEG features, developmental delay or drug resistance. Classification models should incorporate genetic data alongside electroclinical features, especially as next‐generation sequencing is increasingly used.

Background/Objectives: Sturge–Weber syndrome (SWS) is a rare neuro-oculocutaneous disorder characterized by leptomeningeal angioma, naevus flammeus, and ocular manifestations, including diffuse choroidal hemangioma (DCH). This study compares the diagnostic performance of near-infrared reflectance (NIR) imaging and enhanced depth imaging spectral-domain optical coherence tomography (EDI-SDOCT) with fundus photography in detecting DCH. Methods: Seventeen patients with SWS underwent comprehensive ophthalmologic evaluation, including fundus photography, NIR, and EDI-SDOCT imaging. Sensitivity, specificity, and accuracy of fundus photography, NIR, and EDI-SDOCT were calculated. Results: Sixteen patients had evaluable data. DCH was identified by fundus photography in five (31%), NIR in three (18.75%), and EDI-SDOCT in fourteen patients (87.50%). EDI-SDOCT alone demonstrated 100% sensitivity and 100% accuracy, outperforming both NIR (21.4% sensitivity; 31.6% accuracy) and fundus photography (35.7% sensitivity; 43.8% accuracy). When positive findings on NIR and/or SDOCT were combined, sensitivity and accuracy reached 100%. EDI-SDOCT provided detailed morphologic visualization of the choroid, allowing for early diagnosis of DCH even in pediatric cases with limited patient cooperation. Conclusions: EDI-SDOCT significantly improves the detection of DCH in SWS compared with fundus photography and NIR. Given its superior sensitivity and accuracy, incorporating EDI-SDOCT into routine clinical assessment may enable earlier diagnosis and reduce retinal complications in SWS.