Elisabetta Cesaroni

Objective: The transition from pediatric to adult healthcare services is a particularly sensitive phase for young adults with chronic conditions, including epilepsy. In European countries, there is a lack of standardized protocols for an appropriate and detailed transition path. This study aimed to investigate the experiences of both patients and clinicians during the transition process to adulthood, with the goal of contributing to a nationwide consensus document to standardize practices across Italy. Methods: This multicentric, observational, prospective, qualitative study included interviews with young people who turned 18 between 2018 and 2022 belonging to four regional epilepsy centers. In addition, pediatric and adult neurologists completed questionnaires addressing epilepsy type, comorbidities, daily life impact, and details of the transition process. Results: Thirty‐seven patients (92.5%) participated in the study, 34 of them began the transition process, and the remaining three included two patients who continued to receive care within pediatric services and one patient who was lost to follow up. At the time of the interview, 30 (88%) patients were still under the care of the public adult service, while one returned to the pediatric service, one was followed by a private epileptologist, and two were not under any specialist care. The study revealed significant variability in the duration of the preparatory phase, the time elapsed between referral and access to adult services, and the methods of communication/reporting. The caregivers of patients with epilepsy and associated disabilities reported greater difficulty accessing referrals for multidisciplinary and specialized care for rare or complex epilepsies in adulthood. Significance: While most patients successfully transitioned, the absence of uniform, structured protocols, in particular for patients with disabilities, created a significant difference in managing transition. The study strongly underscores the urgent need for standardized, shared national guidelines to ensure a consistent, equitable, and effective transition from pediatric to adult epilepsy care across Italy.

Objective: This study aimed to identify risk factors and develop a predictive scoring system for autoimmune‐associated epilepsy in subjects with autoimmune encephalitis presenting with new onset refractory status epilepticus (NORSE). Methods: This retrospective, multicenter, cohort study included subjects who presented with NORSE at the onset of autoimmune encephalitis and had at least 24 months of follow‐up after immunotherapy. The outcome was the development of autoimmune‐associated epilepsy, defined as persistent seizures despite adequate immunotherapy and absence of active inflammation. Factors independently associated with the outcome were identified through a backward stepwise selection. Adjusted regression coefficients of each independent predictor were transformed to produce a points‐based risk‐scoring system. Results: Seventy participants were included (median age = 24.2 years, 38.6% male). During a median follow‐up of 53 months, 54.3% of subjects developed autoimmune‐associated epilepsy. Status epilepticus duration ≥ 10 days (odds ratio [OR] = 31.14, 95% confidence interval [CI] = 2.12–456.87, p = .012), positivity for antibodies against surface antigens (OR = .12, 95% CI = .02–.85, p = .034), bitemporal magnetic resonance imaging (MRI) abnormalities suggestive of autoimmune encephalitis during acute stage (OR = 49.80, 95% CI = 2.95–841.77, p = .007), and interictal epileptiform discharges during electroencephalographic (EEG) follow‐up (OR = 71.32, 95% CI = 6.48–785.32, p < .001) were independently associated with the study outcome. The duration–antibodies–MRI–EEG (DAME) score was developed as an integer‐based scoring system predictive of autoimmune‐associated epilepsy. With an optimal cutoff of ≥3 points, it yielded a sensitivity of 86.8%, a specificity of 87.5%, and an overall accuracy of 87.1%. Significance: The DAME score could serve as a user‐friendly score to predict the risk of autoimmune‐associated epilepsy in patients with NORSE due to autoimmune encephalitis.

Objective: Variants in GABRG2 , encoding the γ2 subunit of the γ‐aminobutyric acid type A receptor, are linked to epilepsy phenotypes of varying severity, with gain‐of‐function (GoF) variants associated with the more severe phenotypes than loss‐of‐function variants. Here, we provide a comprehensive analysis of the early clinical features, motor, language, and eating abilities, and structural consequences of the recurrent GABRG2 p.(Ala106Thr) GoF variant, aiming to refine genotype–phenotype correlations and deepen the understanding of GoF‐associated GABRG2 disorders. Methods: Individuals were recruited through international collaborations, literature review, and patient advocacy groups. Clinical data were collected via standardized interviews and physician reports. Functional effects were assessed using electrophysiological recordings. Structural modeling was performed using homology‐based approaches to evaluate conformational changes. Results: We collected 23 unrelated individuals harboring the GABRG2 p.(Ala106Thr) variant. Symptoms began with early dysphagia (median onset age = 1 month), hypotonia, seizures (median onset age = 2 months), and hyperkinetic movement disorders (median onset age = 3 months). Epilepsy was present in 91% of the individuals, 71% featuring a developmental and epileptic encephalopathy; 33% of the individuals with epilepsy achieved seizure freedom during the follow‐up. All individuals exhibited moderate to severe cognitive/neurodevelopmental impairment, with profound deficits in motor, language, and other domains. Functional analysis confirmed a GoF effect of the p.(Ala106Thr) variant. By contrast, another variant affecting the same residue, p.(Ala106Pro), which is observed in population databases, was functionally characterized as neutral. Structural modeling indicated that the p.(Ala106Thr) variant may enhance receptor gating by facilitating a hydrogen bond between the extracellular and transmembrane domains, a mechanism not observed with the p.(Ala106Pro) variant. Significance: Although some individuals exhibited severe developmental impairment without epilepsy, our findings demonstrate that the recurrent GABRG2 p.(Ala106Thr) GoF variant is consistently associated with a severe neurodevelopmental phenotype. Despite its profound clinical impact, in silico tools consistently predict this variant as benign, highlighting a critical gap in current predictive models.

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.

This report details a patient with a GRIA1 pathogenic variant presenting with intellectual disability (ID) and epilepsy. We describe clinical features, genetic findings, a personalized treatment approach, and a literature review of GRIA1-related disorders. We describe clinical presentation, neuropsychological assessment, and genetic analysis. We conducted a literature review of published GRIA1-related disorders using PubMed, Simons Foundation Autism Research Initiative (SFARI) Gene, and ClinVar databases. An 8-year-old girl with ID, focal-to-bilateral tonic clonic seizure since age 5, and later atypical absences was diagnosed with a novel, de novo GRIA1 c.2530T > G, p.Leu844Val pathogenic variant. After genetic diagnosis, she was titrated to 4 mg of perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, which led to seizure control and improvements in cognition and school performance. Literature review identified 31 patients carrying 15 different pathogenic variants. The c.1906G > A, p.Ala636Thr variant was recurrent in 17 individuals. Intellectual disability and autism spectrum disorder were common while epilepsy was reported in approximately a quarter of patients. Two patients with gain-of-function missense variants in GRIA1 and GRIA2, successfully treated with perampanel, have also been reported. This case emphasizes the role of targeted interventions in the management of rare genetic disorders and underscores the potential of precision medicine in addressing GRIA1-related symptoms.