A real-world comparison among third-generation antiseizure medications: Results from the COMPARE study.

OBJECTIVE: There are few comparative data on the third-generation antiseizure medications (ASMs). We aimed to assess and compare the effectiveness of brivaracetam (BRV), eslicarbazepine acetate (ESL), lacosamide (LCM), and perampanel (PER) in people with epilepsy (PWE). Efficacy and tolerability were compared as secondary objectives. METHODS: This multicenter, retrospective study collected data from 22 Italian neurology/epilepsy centers. All adult PWE who started add-on treatment with one of the studied ASMs between January 2018 and October 2021 were included. Retention rate was established as effectiveness measure and described using Kaplan-Meier curves and the best fitting survival model. The responder status and the occurrence of adverse events (AEs) were used to evaluate efficacy and safety, respectively. The odds of AEs and drug efficacy were estimated by two multilevel logistic models. RESULTS: A total of 960 patients (52.92% females, median age = 43 years) met the inclusion criteria. They mainly suffered from structural epilepsy (52.29%) with monthly (46.2%) focal seizures (69.58%). Compared with LCM, all the studied ASMs had a higher dropout risk, statistically significant in the BRV levetiracetam (LEV)-naïve (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.17-3.29) and PER groups (HR = 1.64, 95% CI = 1.06-2.55). Women were at higher risk of discontinuing ESL (HR = 5.33, 95% CI = 1.71-16.61), as well as PER-treated patients with unknown epilepsy etiology versus those with structural etiology (HR = 1.74, 95% CI = 1.05-2.88). BRV with prior LEV therapy showed lower odds of efficacy (odds ratio [OR] = .08, 95% CI = .01-.48) versus LCM, whereas a higher efficacy was observed in women treated with BRV and LEV-naïve (OR = 10.32, 95% CI = 1.55-68.78) versus men. PER (OR = 6.93, 95% CI = 3.32-14.44) and BRV in LEV-naïve patients (OR = 6.80, 95% CI = 2.64-17.52) had a higher chance of AEs than LCM. SIGNIFICANCE: Comparative evidence from real-world studies may help clinicians to tailor treatments according to patients' demographic and clinical characteristics.

Gain of function SCN1A disease-causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication.

OBJECTIVE: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype-genotype relationship and functional consequences of SCN1A variants in a cohort of patients. METHODS: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants. RESULTS: Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non-DS, non-GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature. SIGNIFICANCE: The boundaries of SCN1A disorders are wide and still expanding. In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication.

Long-term effectiveness of add-on perampanel in patients with Lennox-Gastaut syndrome: A multicenter retrospective study.

This retrospective study assessed long-term effectiveness of add-on perampanel (PER) in patients with Lennox-Gastaut syndrome (LGS). Outcomes included time to PER failure and time to seizure relapse in responders. PER failure was defined as either discontinuation of PER or initiation of another treatment. Seizure relapse in responders was defined as occurrence of a seizure in seizure-free patients and increase of at least 50% in average monthly seizure frequency for those who were responders. Eighty-seven patients were included. Treatment failure occurred in 52 (59.8%) subjects at a median time of 12 months. Treatment failure was due to lack of efficacy in 27 (52.0%) patients, lack of tolerability in 14 (27.0%), and both reasons in 11 (21.0%). A slower titration was associated with a lower risk of PER failure compared to faster titration schedules, and the occurrence of adverse events increased the risk of treatment failure. Thirty-six patients (41.4%) were responders during a median follow-up of 11 months. Seizure relapse occurred in 13 of 36 (36.1%) patients after a median time of 21 months. The overall rate of seizure responders was 23 of 87 (26.4%) at the end of follow-up. This study provides real-world evidence on the effectiveness of PER as adjunctive treatment in LGS patients.

Neurovisual Manifestations in Children with Mild COVID-19: An Association to Remember.

Neurovisual involvement has been reported in a number of patients with severe SARS-CoV-2 disease (COVID-19), mainly among adult patients. In children, such involvement has been reported in rare cases, often in those presenting with severe forms of COVID-19. The aim of this work is to explore the association between mild COVID-19 and neurovisual manifestations. We report the cases of three previously healthy children who developed neurovisual manifestations following mild acute COVID-19, analysing the clinical phenotype, the latency between the onset of acute COVID-19 and neurovisual involvement, and the kinetic of resolution. Our patients developed different clinical patterns, including visual impairment and ophthalmoplegia. In two cases, these clinical features occurred during acute COVID-19, while in the third patient their development was delayed after 10 days from disease onset. Furthermore, the dynamics of resolution were different, with one patient showing remission after 24 hours, the second after 30 days, and the third showing persistence of the strabismus after 2 months of follow-up. The spreading of COVID-19 among the paediatric population will probably lead to an increase of atypical disease forms, including those presenting with neurovisual involvement. Therefore, a better knowledge of the pathogenic and clinical features of these manifestations is warranted.

Epilepsy, electroclinical features, and long-term outcomes in Pitt-Hopkins syndrome due to pathogenic variants in the TCF4 gene.

BACKGROUND AND PURPOSE: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by deletions/variants in the TCF4 gene. Seizures may be present in up to half of the patients, leading to a more severe disease burden. This study aims to analyse the electroclinical phenotype, treatment options, and long-term outcomes of epilepsy in PTHS. METHODS: A multicentre observational cohort study was performed, and the electroclinical data of PTHS individuals affected by epileptic seizures were retrospectively reviewed and analysed. RESULTS: The series includes 21 patients (11 female) with a median age at seizure onset of 2 years (range = 0.5-8). The median time of follow-up was 7.9 years (range = 2-27). Both generalized and focal epilepsies were present at the same prevalence (42.8%), whereas a minority of patients presented developmental and epileptic encephalopathies (14.4%). At the long-term follow-up, 42.8% achieved seizure freedom, whereas 42.8% developed drug-resistant epilepsy (DRE). The age at seizure onset was found to be an independent predictor for seizure outcome; in this regard, patients having seizure onset after the age of 2 years were more prone to achieve seizure freedom (odds ratio = 0.04, 95% confidence interval = 0.003-0.53; p = 0.01). During evolution, seizures tended to settle down, and even in patients with DRE, seizures tended to persist at a lower frequency and appeared to be more easily manageable over time. CONCLUSIONS: This study provides new insight into the natural history of epilepsy in PTHS. Better characterization of epileptic phenotype and prompt tailored treatment improve overall management and quality of life.

Development and Validation of a UHPLC-MS/MS-Based Method to Quantify Cenobamate in Human Plasma Samples.

Cenobamate (CNB) is the newest antiseizure medication (ASM) approved by the FDA in 2019 to reduce uncontrolled partial-onset seizures in adult patients. Marketed as Xcopri in the USA or Ontozry in the EU (tablets), its mechanism of action has not been fully understood yet; however, it is known that it inhibits voltage-gated sodium channels and positively modulates the aminobutyric acid (GABA) ion channel. CNB shows 88% of oral bioavailability and is responsible for modifying the plasma concentrations of other co-administered ASMs, such as lamotrigine, carbamazepine, phenytoin, phenobarbital and the active metabolite of clobazam. It also interferes with CYP2B6 and CYP3A substrates. Nowadays, few methods are reported in the literature to quantify CNB in human plasma. The aim of this study was to develop and validate, according to the most recent guidelines, an analytical method using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) to evaluate CNB dosage in plasma samples. Furthermore, we provided a preliminary clinical application of our methodology by evaluating the pharmacokinetic parameters of CNB in two non-adult patients. Plasma levels were monitored for two months. Preliminary data showed a linear increase in plasma CNB concentrations, in both patients, in agreement with the increase in CNB dosage. A seizure-free state was reported for both patients at the dose of 150 mg per day.

Reading-writing disorder in children with idiopathic epilepsy.

Several studies have documented learning disabilities (LDs) in subjects with epilepsy, who have been shown to be at greater risk of mild neuropsychological damage, with the consequent risk of academic failure. This retrospective study aimed to investigate the peculiarities of reading and writing disorders in subjects with idiopathic epilepsy. The reading and writing performance of 35 children affected by reading and writing disorders and idiopathic epilepsy (R/WD + E group) has been compared with the performance of 37 children with only reading and writing disorders (R/WD group). A comparison group of 22 typical developing healthy children (TDC group) was also included in the study. As expected, the TDC group reached better performances in the reading and writing tests administered. Between R/WD + E and R/WD groups, there was a substantial analogy in reading and writing disabilities. The differences between the two clinical groups concern writing ability in sentences dictation and verbal and visuospatial short-term memory in digit span and memory-for-location (MFL) tests.

Effects on executive functions of antiepileptic monotherapy in pediatric age.

OBJECTIVES: Cognitive abilities and executive functions in children and adolescents are important indicators of quality of life as well as academic and social achievements. Cognitive and executive functioning are often impaired in patients with epilepsy and can be exacerbated by seizures and antiseizure drugs. The aim of our observational retrospective study was to assess executive functioning in patients with pediatric epilepsy, currently taking a single antiseizure medication. MATERIALS AND METHODS: Records of 172 children and adolescents aged between 6 and 18 years (mean age = 12 ±â€¯3.4 years) with newly diagnosed epilepsy who had not yet commenced an antiepileptic treatment were included in the study. Longitudinal changes in executive functioning were assessed using the EpiTrack Junior test at baseline, before the introduction of antiepileptic monotherapy, and at 3-month, 6-month, and 9-month follow-up visits. All patients commenced a single antiepileptic treatment (levetiracetam n = 54; valproic acid n = 52; ethosuximide n = 20; oxcarbazepine n = 22; carbamazepine n = 24). Age, sex, seizure types, and seizure baseline frequency were also recorded. RESULTS: Relative to baseline, Epitrack Junior mean scores deteriorated at the 9-month follow-up visit for patients taking valproic acid, ethosuximide, and carbamazepine, but this was only statistically significant for patients taking carbamazepine. In contrast, mean scores improved for subjects taking levetiracetam and oxcarbazepine at the 9-month follow-up visit relative to baseline, but this was only statistically significant for patients taking levetiracetam. CONCLUSIONS: Levetiracetam was the only antiseizure medication that led to slight improvements in executive functioning; whereas carbamazepine led to deteriorations in cognitive functioning. Further research using double-blinded, placebo-controlled trials are needed to confirm these results.

Cognitive, adaptive, and behavioral effects of adjunctive rufinamide in Lennox-Gastaut syndrome: A prospective observational clinical study.

INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by multiple drug-resistant seizure types. Children with LGS usually experience cognitive regression, and LGS is almost always associated with moderate to severe cognitive impairment. Rufinamide (RFM) was approved by the European Medicines Agency in 2007 for the adjunctive treatment of seizures associated with LGS in patients ≥4 years of age. The primary objective of our study was to assess cognitive, adaptive, and behavior functioning of patients with LGS after 12 months of RFM therapy. METHODS: This was an observational, multicenter, prospective study involving 16 patients diagnosed with LGS aged between 7 and 58 years (mean = 22 ±â€¯16.3). Fourteen of 16 patients were already on therapy with 3 antiseizure drugs and 2/16 with 4 antiseizure drugs; RFM has been added with 100 mg/week increments up to a dose of 300-2400 mg/day. The participants and their parents underwent a neuropsychological evaluation for the assessment of intellectual, adaptive, and emotional/behavioral functioning (Leiter International Performance Scale-Revised (LEITER-R), Vineland, and Child Behavior CheckList (CBCL), respectively) before the RFM introduction (baseline) and 12 months after the RFM therapy (T2). Physical and neurological examination, electroencephalography (EEG) recording, seizure type and frequency, and adverse reactions were also considered. RESULTS: After 12 months, the total intelligence quotient (IQ) assessed by LEITER-R did not show statistical significant changes, such as there were no statistically significant changes in adaptive functions, assessed by Vineland. Furthermore, there were no statistically significant changes in internalizing and externalizing problems assessed by CBCL. CONCLUSION: Adjunctive treatment with RFM did not negatively affect cognitive, adaptive function, and emotional profile in patients with LGS after 1 year of follow-up.

Perampanel tolerability in children and adolescents with focal epilepsy: Effects on behavior and executive functions.

OBJECTIVES: Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist recently approved for focal and generalized epilepsies as an add-on therapy. It is well tolerated and effective as treatment of various pediatric epilepsy syndromes; PER does not seem to negatively affect the cognitive profile of children and adolescents, but its influence on executive functions is still to be assessed. METHODS: Our sample included 37 children aged 12-18 years, with focal pharmacoresistant epilepsy already in therapy with 2 or 3 antiepileptic drug (AED); PER was added with 1 mg/week increments up to a dose of 2-4 mg/day. Changes in executive functions were assessed by the EpiTrack Junior test. Emotional and behavioral aspects were evaluated through the interview for parents Child Behavior Checklist (CBCL). Both tests were performed before taking PER and after 6 and 12 months of treatment. RESULTS: After 12 months of PER in 22/30 patients, global score of the EpiTrack Junior test remained almost unchanged; in 7/30 patients, this score improved. The CBCL did not show significant changes in emotional or behavioral problems. CONCLUSIONS: Adjunctive treatment with PER did not negatively affect executive functions that could also be improved. No emotional/behavioral negative effects have been reported, and this suggests a good tolerability in the middle/long term.

Psychogenic Non-Epileptic Status as Refractory, Generalized Hypertonic Posturing: Report of Two Adolescents.

Psychogenic non-epileptic seizures (PNES) or dissociative seizures are found under the umbrella headings of functional/dissociative neurological disorders (FND) in psychiatric classifications (DSM-5; ICD-11). PNES are not characterized by any specific ictal or postictal EEG abnormalities. Patients with PNES can present with motor or non-motor symptoms, frequently associated with a change in the level of consciousness. PNES duration is variable, often longer than that of epileptic seizures. Prolonged PNES, sometimes termed PNES status, involve continuous or repetitive events that exceed 30 min. Prolonged PNES are often misdiagnosed as an epileptic event and are often inappropriately treated with high doses of antiseizure drugs. In this report, we describe two adolescent patients who presented with prolonged PNES characterized by generalized hypertonic posturing and low levels of consciousness. Despite multiple presentation to the Emergency department, and multiple normal video-EEG, the patients were misdiagnosed with epilepsy and were inappropriately treated with antiseizure medications. Both patients presented psychiatric comorbidity, consisting of a major depressive disorder, obsessive-compulsive symptoms, social withdrawal, difficulty of social interaction, and anxious-perfectionist personality traits. The episodes of prolonged PNES gradually declined within 18 months in both patients.

Electroencephalographic Abnormalities in Autism Spectrum Disorder: Characteristics and Therapeutic Implications.

A large body of literature reports the higher prevalence of epilepsy in subjects with Autism Spectrum Disorder (ASD) compared to the general population. Similarly, several studies report an increased rate of Subclinical Electroencephalographic Abnormalities (SEAs) in seizure-free patients with ASD rather than healthy controls, although with varying percentages. SEAs include both several epileptiform discharges and different non-epileptiform electroencephalographic abnormalities. They are more frequently associated with lower intellectual functioning, more serious dysfunctional behaviors, and they are often sign of severer forms of autism. However, SEAs clinical implications remain controversial, and they could represent an epiphenomenon of the neurochemical alterations of autism etiology. This paper provides an overview of the major research findings with two main purposes: to better delineate the state-of-the-art about EEG abnormalities in ASD and to find evidence for or against appropriateness of SEAs pharmacological treatment in ASD.

Parental stress in a sample of children with epilepsy.

OBJECTIVE: To assess maternal and paternal stress in two groups of children with different types of epilepsy, at the time of diagnosis and after one year of follow-up. METHODS: We investigated parental stress in a sample of 85 children aged between 2 and 14 years, divided into two groups based on the diagnosis: Group 1 (50 patients) with childhood absence epilepsy or idiopathic focal epilepsy with rolandic discharges and Group 2 (35 patients) with different forms of drug-resistant epilepsy. Parents independently completed the Parental Stress Index-Short Form at Time 0, when they received the diagnosis and patients started therapy, and at Time 1, after 1 year of follow-up. RESULTS: We found high levels of stress in both mothers and fathers at Time 0, without statistically significant differences between the two groups. At Time 1, stress values were unchanged in Group 1 mothers; conversely, the levels of stress in Group 1 fathers reduced, with average values that all fell within the "normal range." In Group 2, stress levels were reduced both in mothers and in fathers at Time 1, compared to Time 0, but equally fell into the "pathological range," for both parents. CONCLUSION: In our study, the diagnosis of the epilepsy itself tended to increase parental stress, apparently regardless of the severity of the epilepsy; even after a period of follow-up, when the epilepsy was better controlled, overall parental stress remained high. It might have been related to feelings of parental inadequacy or concerns about issues such as safety or the outcome for the child.

Parental stress in pediatric epilepsy after therapy withdrawal.

OBJECTIVE: The objective of the study was to explore stress levels in the parents of children with idiopathic epilepsy at different time points of the disease, specifically, at the time of diagnosis, during follow-up, and 1 and 2 years after discontinuation of antiepileptic drugs. METHODS: Our study included 50 patients between 5 and 14 years of age, who were diagnosed with childhood absence epilepsy or idiopathic focal epilepsy with Rolandic paroxysms. Parents of the participants independently completed the Parenting Stress Index-Short Form at the time of initial diagnosis, and when the children started antiepileptic drugs (Time 0), and at 1 year (Time 1) and 2 years (Time 2) after discontinuation of therapy. RESULTS: At Time 0, parental stress levels were increased, both in mothers and fathers, with average scores in the "clinical range" of the parental distress (PD), dysfunctional parent-child interaction (P-CDI), and total stress (TS) scales. At Time 1, the scores on these scales remained high. At Time 2, a mild reduction in the stress scores was observed in both parents, despite values remaining in the "clinical range" for all the scales. CONCLUSIONS: Results suggested that parents of children with epilepsy were not reassured about the child's condition, even after clinical improvement. Parental stress levels remained higher than expected, even 2 years after the discontinuation of therapy and freedom from seizures. This was probably due to concerns with the reappearance of new seizures or a more severe type of epilepsy with the discontinuation of drug(s), and feelings of inadequacy with their parental role(s).

Cognitive profile in BECTS treated with levetiracetam: A 2-year follow-up.

INTRODUCTION: Benign epilepsy with centrotemporal spikes (BECTS) is a common epileptic syndrome in childhood, characterized by brief and infrequent partial motor seizures, with or without generalization and mostly recurring during sleep. Because of its favorable efficacy, tolerability, and safety profile, levetiracetam (LEV) monotherapy is often administered in these patients. Long-term effects of LEV therapy and its influence on cognitive functions remain controversial. PURPOSE: This evaluated the changes in the cognitive profile of children with BECTS treated with LEV monotherapy for 2 years, compared with a control group of children with specific learning disabilities. METHOD: Our patient cohort included 20 children aged 8-14 years diagnosed as having BECTS and administered LEV monotherapy and 10 age/sex-matched controls with specific learning disabilities. All participants underwent a standardized test for assessing cognitive profile (Wechsler Intelligence Scale for Children - Fourth Edition [WISC-IV]) before drug therapy and after 2 years of treatment. Average LEV blood level and electroencephalographic (EEG) recordings were periodically monitored. Several factors such as age, sex, response to therapy, and EEG pattern changes were considered. Statistical analysis was performed using Student's t-test for paired and independent samples. p < 0.05 was considered statistically significant. RESULTS: Children administered LEV for 24 months showed a mild but statistically significant improvement in overall cognitive abilities. Verbal skills, visual-perceptual reasoning, working memory, and processing speed showed slight but significant improvement. In the control group, cognitive profile remained substantially unchanged at 2-year follow-up. CONCLUSIONS: Not only do our data suggest a nonworsening of the cognitive profile in BECTS with LEV but, on the contrary, cognitive scores also improved over time, unlike the control group.

Emotional Awareness and Cognitive Performance in Borderline Intellectual Functioning Young Adolescents.

According to DSM-5 and ICD-10, borderline intellectual functioning (BIF) should not be classified properly as a disorder. However, BIF people may present relevant problems of adaptive functioning in several areas of daily activities, and they seem to be more vulnerable to mental diseases. Young adolescence may be considered a particular period for emotional information processing. The "own and others' emotions" awareness can play a crucial role in many daily life situations, such as decision making, interpersonal relationships, and decoding of facial expressions. On this background, a BIF young adolescents group underwent a neuropsychological assessment including emotional and cognitive domains, and was compared with a healthy young adolescents control group (HC). In the overall sample, a significant negative correlation between general intellectual abilities and emotional awareness was found. The BIF group showed a significantly greater level of alexithymia and a poorer performance in higher cognitive tasks than HC group. As hypothesized, a border cognitive functioning influences mentalization processes as ability to discriminate and monitor emotions, as well as higher domains of cognition.

Mozart's music in children with drug-refractory epileptic encephalopathies: Comparison of two protocols.

In this prospective, randomized, open label study, we compared the effect on seizure recurrence and quality-of-life parameters, of two different protocols of music therapy in children and adolescents with refractory epileptic encephalopathies. Nine out of 19 patients (13 males and 6 females, aged between 1 and 24years) were randomized to listen to Mozart's sonata in D major for two pianos K448 for 2h/day for 2weeks; other 10 children were randomized on a set of Mozart's compositions. In group 1 (K448), 2/9 children (22.2%) had a ≥75% seizure decrease; two patients had less than 50% seizure reduction, and the other five were unchanged. In group 2 (set Mozart), 7/10 patients (70%) had a significant seizure reduction (specifically, ≥50% in 1/10; ≥75% in 4/10; 100% in 2/10). An overall more significant behavioral improvement including less irritability and tearfulness, reduced self-/heteroaggression, a better daytime vigilance, and nighttime sleep quality, was also reported in children from group 2. In conclusion, the present study seems to confirm that music therapy may be an additional, nonpharmacological, effective treatment for patients with refractory epileptic seizures in childhood. The Mozart's set of different compositions can be better accepted and effective than the K448.

Mozart's music in children with drug-refractory epileptic encephalopathies.

Mozart's sonata for two pianos in D major, K448, has been shown to decrease interictal EEG discharges and recurrence of clinical seizures in both adults and young patients. In this prospective, open-label study, we evaluated the effect of listening to a set of Mozart's compositions, according to the Tomatis method, on sleep quality and behavioral disorders, including auto-/hetero-aggression, irritability, and hyperactivity, in a group of children and adolescents with drug-resistant epilepsy. The study group was composed of 11 outpatients (7 males and 4 females), between 1.5years and 21years of age (mean age: 11.9years), all suffering from drug-resistant epileptic encephalopathy (n=11). All of them had a severe/profound intellectual disability associated with cerebral palsy. During the study period, each patient had to listen to a set of Mozart's compositions 2h per day for fifteen days for a total of 30h, which could be distributed over the day depending on the habits and compliance of each patient. The music was filtered by a device preferably delivering higher sound frequencies (>3000Hz) according to the Tomatis principles. The antiepileptic drug therapy remained unchanged throughout the study period. During the 15-day music therapy, 2 out of 11 patients had a reduction of 50-75% in seizure recurrence, and 3 out of 12 patients had a reduction of 75-89%. Overall, 5 (45.4%) out of 11 patients had a ≥50% reduction in the total number of seizures, while the percentage decrease of the total seizure number (11/11) compared with baseline was -51.5% during the 15-day music therapy and -20.7% in the two weeks after the end of treatment. All responders also had an improvement in nighttime sleep and daytime behavior.

PLASTAMINATION: Outcomes on the Central Nervous System and Reproduction.

BACKGROUND: Environmental exposures to non-biodegradable and biodegradable plastics are unavoidable. Microplastics (MPs) and nanoplastics (NPs) from the manufacturing of plastics (primary sources) and the degradation of plastic waste (secondary sources) can enter the food chain directly or indirectly and, passing biological barriers, could target both the brain and the gonads. Hence, the worldwide diffusion of environmental plastic contamination (PLASTAMINATION) in daily life may represent a possible and potentially serious risk to human health. OBJECTIVE: This review provides an overview of the effects of non-biodegradable and the more recently introduced biodegradable MPs and NPs on the brain and brain-dependent reproductive functions, summarizing the molecular mechanisms and outcomes on nervous and reproductive organs. Data from in vitro, ex vivo, non-mammalian and mammalian animal models and epidemiological studies have been reviewed and discussed. RESULTS: MPs and NPs from non-biodegradable plastics affect organs, tissues and cells from sensitive systems such as the brain and reproductive organs. Both MPs and NPs induce oxidative stress, chronic inflammation, energy metabolism disorders, mitochondrial dysfunction and cytotoxicity, which in turn are responsible for neuroinflammation, dysregulation of synaptic functions, metabolic dysbiosis, poor gamete quality, and neuronal and reproductive toxicity. In spite of this mechanistic knowledge gained from studies of non-biodegradable plastics, relatively little is known about the adverse effects or molecular mechanisms of MPs and NPs from biodegradable plastics. CONCLUSION: The neurological and reproductive health risks of MPs/NPs exposure warrant serious consideration, and further studies on biodegradable plastics are recommended.

CDKL5 deficiency-related neurodevelopmental disorders: a multi-center cohort study in Italy.

CDKL5 deficiency disorder (CDD) is a complex clinical condition resulting from non-functional or absent CDKL5 protein, a serine-threonine kinase pivotal for neural maturation and synaptogenesis. The disorder manifests primarily as developmental epileptic encephalopathy, with associated neurological phenotypes, such as hypotonia, movement disorders, visual impairment, and gastrointestinal issues. Its prevalence is estimated at 1 in 40,000-60,000 live births, and it is more prevalent in females due to the lethality of germline mutations in males during fetal development. This Italian multi-center observational study focused on 34 patients with CDKL5-related epileptic encephalopathy, aiming to enhance the understanding of the clinical and molecular aspects of CDD. The study, conducted across 14 pediatric neurology tertiary care centers in Italy, covered various aspects, including phenotypic presentations, seizure types, EEG patterns, treatments, neuroimaging findings, severity of psychomotor delay, and variant-phenotype correlations. The results highlighted the heterogeneity of seizure patterns, with hypermotor-tonic-spasms sequence seizures (HTSS) noted in 17.6% of patients. The study revealed a lack of clear genotype-phenotype correlation within the cohort. The presence of HTSS or HTSS-like at onset resulted a negative prognostic factor for the presence of daily seizures at long-term follow-up in CDD patients. Despite extensive polypharmacotherapy, including medications such as valproic acid, clobazam, cannabidiol, and others, sustained seizure freedom proved elusive, affirming the inherent drug-resistant nature of CDD. The findings underscored the need for further research to explore response rates to different treatments and the potential role of non-pharmacological interventions in managing this challenging disorder.