Carlo Alberto Quaranta

Background: Idiopathic Generalized Epilepsies (IGEs) are electroclinical syndromes characterized by distinct seizure types, EEG patterns, and presumed polygenic inheritance. While seizure prognosis is often favorable, sleep disturbances, behavioral and emotional difficulties, and executive function impairment are common, especially during adolescence. Objective: To investigate the relationship between subjective sleep quality, emotional–behavioral functioning, and executive functions in adolescents with IGE. Methods: In this single‐center observational study, 28 adolescents (mean age 15.0 ± 2.4 years) with IGE were evaluated with the following standardized measures: PSQI (sleep), BRIEF‐2 (executive functions), CBCL and YSR (emotional–behavioral profile), SAFA‐A/‐D/‐S (internalizing and somatic symptoms). Dream‐related experiences were also collected. Pearson correlations tested behavioral and emotional associations with sleep quality. Results: Poor sleep quality (PSQI ≥5) occurred in 28.6% of patients, although only 14.8% reported sleep problems in their clinical history. Poor sleepers showed significantly higher anxiety, depression, somatic complaints, and stress‐related symptoms ( p < .05). Executive function impairment, particularly in emotional control and cognitive flexibility, was more frequent in this group. Significance: Sleep quality is an under‐recognized but clinically relevant dimension in patients with IGE, closely linked to emotional vulnerability and executive function difficulties. Routine sleep screening and targeted sleep‐focused management should be integrated into pediatric IGE care to support psychological well‐being.

Perampanel (PER) is a third‐generation antiseizure medication (ASM) with a well‐established concentration–effect relationship. Saliva represents a non‐invasive alternative to plasma for therapeutic drug monitoring (TDM) of PER, as it reflects the free plasma fraction. Volumetric absorptive microsampling (VAMS) enables standardized, patient‐friendly saliva collection. This study aimed to clinically validate saliva‐VAMS by directly comparing it with conventional liquid saliva sampling for PER quantification. In a prospective study, saliva was collected from 11 people with epilepsy receiving PER therapy (dose range = 2–10 mg/day) using both VAMS and conventional saliva sampling. PER concentrations were measured by liquid chromatography coupled with tandem mass spectrometry and compared using repeated measures Bland–Altman analysis and Lin's concordance correlation coefficient to evaluate agreement between methods. PER concentrations measured in saliva‐VAMS showed excellent agreement with those obtained from conventional saliva sampling, with mean bias of −0.126 ng/mL (95% confidence interval = −0.582 to 0.330). No relevant constant or proportional bias was observed, and limits of agreement were within predefined acceptance criteria. Concordance between methods was high, supporting analytical equivalence. The demonstrated interchangeability between saliva‐VAMS and conventional saliva sampling supports adoption of saliva‐VAMS in clinical TDM workflows, enabling standardized fixed‐volume collection, simplified storage/transport, and potential home‐based sampling for remote dose optimization of PER and potentially other ASMs.

Objective: Electroencephalography (EEG) plays a fundamental role in the diagnosis and classification of epilepsy, and inducing sleep during EEG can improve patient cooperation and enhance the detection of epileptiform activity. Despite its importance, there is currently no standardized approach for sleep induction in pediatric EEG recordings. Consequently, practices such as melatonin administration and sleep deprivation are commonly utilized. This study aimed to compare the effectiveness of 5 mg melatonin versus partial sleep deprivation in inducing sleep during nap‐time EEGs in children with epilepsy. Methods: A randomized crossover trial was conducted involving 33 participants (mean age 14.5 years), each undergoing EEG following either melatonin administration or partial sleep deprivation. In the melatonin arm, participants received an oral dose 30 min before the recording, while in the sleep deprivation arm, sleep was restricted the previous night. The primary outcome was sleep onset latency, defined as the time from relaxation to non‐REM stage 2 sleep on EEG. Additionally, melatonin and its metabolite, 6‐hydroxy‐melatonin, were measured using liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). Results: The study showed a mean sleep onset latency of 8.5 min after sleep deprivation and 10.1 min after melatonin administration, with a mean difference of 1.5 min. The analysis of covariance conducted with stratification based on sleep onset latency (five classes) and considering all patients confirmed that melatonin is non‐inferior to sleep deprivation in sleep onset latency, with 97.5% lower confidence limits of −0.37. Melatonin levels in the treated group confirmed adequate absorption, while they were undetectable in the sleep‐deprived group. Significance: Melatonin is non‐inferior to partial sleep deprivation in reducing sleep onset latency, with comparable diagnostic yield and a favorable tolerability profile. The study demonstrates that 5 mg of melatonin is a safe, effective, and well‐tolerated alternative to partial sleep deprivation for sleep induction in pediatric EEG evaluations. Given its ease of use and consistent results, melatonin may be recommended as a practical standard for facilitating EEG recordings in children, particularly those with neurodevelopmental disorders. Plain Language Summary: This randomized crossover trial evaluated the effectiveness and tolerability of melatonin administered before an EEG recording to induce sleep, compared with partial sleep deprivation. The results showed that melatonin helped children achieve sleep and was non‐inferior to sleep deprivation. Moreover, melatonin demonstrated a favorable tolerability profile, representing a safe and easier alternative to support sleep during EEG, particularly in children with neurodevelopmental disorders, and could enhance the efficiency and quality of pediatric EEG recordings.

Background/Objectives: Hereditary spastic paraplegias (HSPs) comprise a heterogenous spectrum of rare neurogenetic disorders predominantly characterized by progressive spasticity and weakness of the lower extremities. Among autosomal-dominant forms of HSP, molecular defects in the SPAST gene—particularly those associated with the SPG4 subtype—represent the most frequent genetic cause. SPAST encodes spastin, a microtubule-severing ATPase, crucial for cytoskeletal remodeling, neuronal connectivity, and intracellular trafficking. Disruption of spastin function can impair neurite outgrowth and synaptic formation, processes increasingly implicated in neurodevelopmental disorders (NDDs). Methods: We conducted a comprehensive clinical, neurological, and dysmorphological evaluation of a 4-year-old male. Standardized neuropsychological assessments were administered. Whole-exome sequencing (WES) was performed to identify underlying genetic causes. EEG and 3T-brain MRI were also acquired. Results: The proband harbored two novel de novo heterozygous missense variants in cis of the SPAST gene, displaying the typical features of early-onset and complex HSP, in addition to global developmental delay and severe autism spectrum disorder (ASD), an underexplored manifestation in this rare genetic disorder. Conclusions: These findings broaden the clinical and mutational spectrum of SPG4, underscoring the importance of considering SPAST gene analysis in patients with ASD in the early years of life and early motor delay, even in the presence of only subtle pyramidal signs. We advocate for comprehensive neuropsychiatric assessment in the diagnostic pathway of early-onset complex HSP presentations and support further investigation into the role of spastin in neuronal connectivity.

This study describes the development and validation of a fully automated workflow for serum sample preparation, enabling the quantitative determination of cannabidiol (CBD) and its active metabolite, 7-hydroxy-CBD, via liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) analysis. Implemented on an automated platform, the workflow performs key steps such as solvent dispensing, mixing, centrifugation, filtration, and supernatant transfer, producing 96-well plates ready for analysis. Human serum samples were obtained from patients with epilepsy treated with CBD. All samples were processed using both manual and automated methods to evaluate method agreement. Quantification was performed by LC–MS/MS with CBD-d₃ as the internal standard (IS). Method validation was conducted in accordance with European Medicine Agency (EMA) guidelines, confirming that the automated protocol meets the recommended acceptance criteria for both intraday and interday precision and accuracy. Calibration curves demonstrated excellent linearity across the concentration ranges. Comparative analysis using Passing–Bablok regression and Bland–Altman plots demonstrated strong agreement between the methods. These findings support the clinical applicability of the automated method for the therapeutic drug monitoring (TDM) of CBD and 7-hydroxy-CBD, and its robust performance and scalability provide a solid foundation for the development of an expanded analytical panel covering a broader range of antiseizure medications (ASMs), enabling more standardized TDM protocols in clinical practice.