Electroclinical Features of Epilepsy in Kleefstra Syndrome.

BACKGROUND: Kleefstra syndrome (KS) or 9q34.3 microdeletion syndrome (OMIM #610253) is a rare genetic condition featuring intellectual disability, hypotonia, and dysmorphic facial features. Autism spectrum disorder, severe language impairment, and sleep disorders have also been described. The syndrome can be either caused by a microdeletion in 9q34.3 or by pathogenic variants in the euchromatin histone methyltransferase 1 gene (EHMT1, *607001). Although epilepsy has been reported in 20 to 30% of subjects, a detailed description of epileptic features and underlying etiology is still lacking. The purpose of this study is to investigate epilepsy features in a cohort of epileptic patients with KS. METHODS: This multicenter study investigated eight patients with KS and epilepsy. Our findings were compared with literature data. RESULTS: We included five patients with 9q or 9q34.33 deletions, a subject with a complex translocation involving EHMT1, and two with pathogenic EHMT1 variants. All patients presented with moderate to severe developmental delay, language impairment, microcephaly, and infantile hypotonia. Although the epileptic manifestations were heterogeneous, most patients experienced focal seizures. The seizure frequency differs according to the age of epilepsy onset, with patients with early-onset epilepsy (before 36 months of age) presenting more frequent seizures. An overtime reduction in seizure frequency, as well as in antiseizure drug number, was observed in all patients. Developmental delay degree did not correlate with seizure onset and frequency or drug resistance. CONCLUSION: Epilepsy is a frequent finding in KS, but the underlying pathogenetic mechanism and specific features remain elusive.

Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins.

Early infantile epileptic encephalopathy 38 (EIEE38, MIM #617020) is caused by biallelic variants in ARV1, encoding a transmembrane protein of the endoplasmic reticulum with a pivotal role in glycosylphosphatidylinositol (GPI) biosynthesis. We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants. Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features. Flow cytometric analysis on patient fibroblasts showed a decrease in GPI-anchored proteins on the cell surface, supporting a lower residual activity of the mutant ARV1 as compared to the wildtype. A rescue assay through the transduction of lentivirus expressing wild type ARV1 cDNA effectively rescued these alterations. This study expands the clinical and molecular spectrum of the ARV1-related encephalopathy, confirming the essential role of ARV1 in GPI biosynthesis and brain function.

Cognitive Profile, Emotional-Behavioral Features, and Parental Stress in Boys With 47,XYY Syndrome.

OBJECTIVE: To describe (a) the observed cognitive, emotional, and behavioral phenotype in a cohort of male children with 47,XYY syndrome and (b) stress levels in their parents. METHODS: We conducted a cross-sectional observational study of 11 boys diagnosed with 47,XYY syndrome and compared them with 11 age-matched boys with normal karyotype (46,XY). The participants performed standardized assessments of cognitive function, emotional state, and behavioral features; the parents completed a questionnaire evaluating parental stress. All data were analyzed using parametric and nonparametric statistical methods. RESULTS: All of the boys exhibited a normal cognitive profile. However, emotional-behavioral profiling revealed that internalizing and externalizing problems were more prevalent in the 47,XYY group. In addition, the stress levels of the parents of the 47,XYY group were reportedly higher than those of the parents of the 46,XY group. We also found that the time of the diagnosis had an effect on the mothers' stress levels; that is, postnatal fetal 47,XYY diagnosis was associated with higher maternal stress, whereas prenatal fetal 47,XYY diagnosis was not. CONCLUSIONS: Generally, 47,XYY syndrome is associated with certain cognitive, emotional, and behavioral features. High stress levels have been reported by the mothers of 47,XYY boys who had been diagnosed postnatally because of unexpected developmental delay and/or learning difficulties. The present study highlights the need to better define the neuropsychiatric phenotype of 47,XYY children; namely, the effect of the chromosomal abnormality on their cognitive function and emotional-behavioral (internalizing and externalizing) features. This study could improve prenatal counseling and pediatric surveillance.

Prevalence of cerebral visual impairment in developmental and Epileptic Encephalopathies: a systematic review protocol.

BACKGROUND: Developmental and Epileptic Encephalopathies (DEEs) are defined by drug-resistant seizures and neurodevelopmental disorders. Over 50% of patients have a genetic cause. Studies have shown that patients with DEEs, regardless of genetic diagnosis, experience a central visual function disorder known as Cerebral (cortical) Visual Impairment (CVI). The prevalence of CVI in DEE patients is currently unknown. A quantitative synthesis of existing data on the prevalence rates of this condition would aid in understanding the magnitude of the problem, outlining future research, and suggesting the need for therapeutic strategies for early identification and prevention of the disorder. METHODS: The protocol followed the PRISMA-P statement for systematic review and meta-analysis protocols. The review will adhere to the JBI Manual for Evidence Synthesis (Systematic Reviews of Prevalence and Incidence) and use the CoCoPop framework to establish eligibility criteria. We will conduct a comprehensive search of several databases, including MEDLINE, EMBASE, Science Direct, Scopus, PsychINFO, Wiley, Highwire Press, and Cochrane Library of Systematic Reviews. Our primary focus will be determining the prevalence of cerebral visual impairments (Condition) in patients with developmental and epileptic encephalopathy (Population). To ensure clarity, we will provide a narrative summary of the risk of bias in the studies we include. The Cochrane Q statistic will be used to assess heterogeneity between studies. If the quantitative synthesis includes more than 10 studies, potential sources of heterogeneity will be investigated through subgroup and meta-regression analyses. Meta(bias)es analysis will also be performed. The quality of evidence for all outcomes will be evaluated using the Grading of Recommendations Assessment Development and Evaluation (GRADE) working group methodology. DISCUSSION: This protocol outlines a systematic review and meta-analysis to identify, collect, evaluate, and integrate epidemiological knowledge related to the prevalence of CVI in patients with DEEs. To the best of our knowledge, no other systematic review and meta-analysis has addressed this specific issue. The results will provide useful information for understanding the extent of the problem, outlining future research, and suggesting the need for early identification strategies. SYSTEMATIC REVIEW REGISTRATIONS: This Systematic Review Protocol was registered in PROSPERO (CRD42023448910).

Early Developmental Intervention and Enriched Environment in CDKL5 Developmental and Epileptic Encephalopathy: A Case Report.

Objectives: CDKL5 developmental and epileptic encephalopathy (CDKL5-DEE) is a rare X-linked dominant genetic disorder. Family-centered Early Intervention (EI) programs, which promote axonal plasticity and synaptic reorganization through exposure to an enriched environment, should be integrated into clinical practice. However, there is presently a dearth of dedicated EI protocols for patients with CDKL5-DEE and cerebral visual impairment (CVI). Methods: We present a girl with a deletion of the CDKL5 gene (MIM*300203). At the age of 2 months, the child presented with severe epilepsy. The neurologic examination was abnormal, and she had severe CVI. At the first assessment, at 5 months old, her Developmental Quotient (DQ) on the Griffiths Mental Developmental Scales III (GMDS-III) was equivalent to 3-month-old skills (95% CI). The child was enrolled in an EI program for 6 months. Results: At 12 months of age, the DQ score was 91. There has been improvement in the neurovisual functions. The findings from the scales show a gradual improvement in neuromotor and psychomotor development, which is in contrast to the expected outcome of the disease. Discussion: The case study shows that a family-centered EI and prompt assessment of CVI can promote and enhance neurodevelopment.

Learnings in developmental and epileptic encephalopathies: what do we know?

INTRODUCTION: Developmental and Epileptic Encephalopathies (DEEs) encompass a group of neurological disorders caused by either abnormal neuronal development and white matter maturation or even by weak synaptic plasticity. Hitherto, patients commonly have epileptic seizures featuring cognitive dysfunction, such as neurosensory disorders, difficulties in learning, behavioral disturbances, or speech delay. AREAS COVERED: This paper provides a comprehensive review of the current knowledge of DEEs and cognition. Medline/Pubmed database was screened for in-English articles published between 1967-2022 dealing with the topic of DEEs and cognitive development. Two authors independently screened the title and abstract of each record and reviewed the selected articles. Reviews, randomized clinical trials, and case reports were selected. EXPERT OPINION: Scientific literature has never explicitly dealt with the early neuro-psychomotor rehabilitation and neuropsychological assessment of patients with DEEs. Targeted intervention and environmental stimuli can influence the maturation of neuronal circuits and shape changes in physical and mental development based on neuronal plasticity, particularly if applied in 'critical periods' liable to heightened sensitivity. Thus, 'early neurorehabilitation interventions' are worthy of being more and more applied to clinical practice to improve the quality of life and reduce the psychosocial burden on families and caregivers.

Cannabidiol Add-On in Glycosylphosphatidylinositol-Related Drug-Resistant Epilepsy.

Background: Glycosylphosphatidylinositol-anchored protein deficiencies (GPI-ADs) are commonly associated with drug-resistant epilepsy (DRE). Cannabidiol (CBD) is approved for the adjunctive treatment of seizures in Dravet/Lennox-Gastaut Syndromes and Tuberous Sclerosis Complex. We report on the efficacy and safety of CBD for the treatment of DRE in patients with genetically proven GPI-AD. Patients and Methods: Patients received add-on treatment with purified GW-pharma CBD (Epidyolex®). Efficacy endpoints were the percentage of patients with ≥50% (responders) or >25<50% (partial responders) reduction in monthly seizures from baseline and at 12 (M12) months of follow-up. Safety was evaluated through adverse events (AEs) monitoring. Results: Six patients (5 males) were enrolled. The median age at seizures onset was 5 months and the syndromic diagnosis was early infantile developmental and epileptic encephalopathy in 4 patients and focal non-lesional epilepsy or GEFS+ in one patient each. Five out of six (83%) patients were responders at M12, while one was a partial responder. No severe AEs were reported. Mean prescribed CBD dose was 17.85 mg/kg/day and median treatment duration is currently 27 months. Conclusions: In summary, off-label treatment with CBD was effective and safe in patients with DRE due to GPI-ADs.

Case Report: Novel biallelic moderately damaging variants in RTTN in a patient with cerebellar dysplasia.

Rotatin, encoded by the RTTN gene, is a centrosomal protein with multiple, emerging functions, including left-right specification, ciliogenesis, and neuronal migration. Recessive variants in RTTN are associated with a neurodevelopmental disorder with microcephaly and malformations of cortical development known as "Microcephaly, short stature, and polymicrogyria with seizures" (MSSP, MIM #614833). Affected individuals show a wide spectrum of clinical manifestations like intellectual disability, poor/absent speech, short stature, microcephaly, and congenital malformations. Here, we report a subject showing a distinctive neuroradiological phenotype and harboring novel biallelic variants in RTTN: the c.5500A>G, p.(Asn1834Asp), (dbSNP: rs200169343, ClinVar ID:1438510) and c.19A>G, p.(Ile7Val), (dbSNP: rs201165599, ClinVar ID:1905275) variants. In particular brain magnetic resonance imaging (MRI) showed a peculiar pattern, with cerebellar hypo-dysplasia, and multiple arachnoid cysts in the lateral cerebello-medullary cisterns, in addition to left Meckel cave. Thus, we compare his phenotypic features with current literature, speculating a possible role of newly identified RTTN variants in his clinical picture, and supporting a relevant variability in this emerging condition.

A real-life pilot study of the clinical application of pharmacogenomics testing on saliva in epilepsy.

Response to antiseizure medications (ASMs) can be influenced by several gene polymorphisms, causing either lower efficacy or higher occurrence of adverse drug reactions (ADRs). We investigated the clinical utility of salivary pharmacogenomic testing on epilepsy patients. A commercialized pharmacogenomic salivary test was performed in a cohort of epileptic patients. Genetic variants on five genes (i.e., CYP1A2, CYP2C9, CYP2C19, EPHX1, and ABCB1) involved in common ASMs metabolism were selected. Twenty-one individuals (median age [Q1 -Q3 ]: 15 [6.5-28] years) were enrolled. Six patients harboring the homozygous *1F allele in CYP1A2 could have reduced chance of response to stiripentol due to fast metabolism. CYP2C9 had reduced activity in 10 patients (alleles *2 and *3), potentially affecting phenytoin (PHT), phenobarbital (PB), primidone, lacosamide (LCM), and valproic acid metabolism. Seven patients, carrying the *2 allele of CYP2C19, had an increased risk of ADRs with clobazam (CLB), PB, PHT, LCM, brivaracetam; while one individual with the *17 allele in heterozygosity reported a CLB fast metabolism. Six patients showed a CC polymorphism of EPHX1 associated with the impaired efficacy of carbamazepine. ABCB1 polymorphisms related to drug-resistance (3435 CC) or drug-sensitive phenotype (CT or TT) were found in 6 out of 7 patients. Pharmacogenomic testing on saliva proved easy and safe in clinical practice to convey information for the management of epileptic patients, especially those resistant to treatment or sensitive to severe ADRs.

Pharmacokinetic considerations surrounding the use of levetiracetam for seizure prophylaxis in neurocritical care - an overview.

INTRODUCTION: Levetiracetam (LEV) is one of the most widely used anti-seizure medications (ASMs) in clinical practice. This is due both to a different mechanism of action when compared to other ASMs and its easy handling. Indeed, because of its interesting pharmacokinetic properties, it is often used outside of the labeled indications, notably in the neurocritical setting as prophylaxis of epileptic seizures. AREAS COVERED: A literature search was conducted and the most relevant studies on the pharmacokinetic properties of LEV were selected by two independent investigators. Current evidence on the use of ASM prophylaxis in the neurocritical setting was also reviewed, highlighting and discussing the strengths and limits of LEV as drug of choice for anti-epileptic prophylaxis in this scenario. EXPERT OPINION: LEV has a 'near-ideal' pharmacokinetic profile, which makes it an attractive drug for ASM prophylaxis in neurocritical care. However, current recommendations restrict ASMs prophylaxis to very selected circumstances and the role of LEV is marginal. Moreover, studies are generally designed to compare LEV versus phenytoin, whereas studies comparing LEV versus placebo are lacking. Further, randomized trials will be needed to better elucidate LEV utility and its neuroprotective role in the neurocritical setting.

Genetic paroxysmal neurological disorders featuring episodic ataxia and epilepsy.

OBJECTIVE: This review article focuses on clinical and genetic features of paroxysmal neurological disorders featuring episodic ataxia (EA) and epilepsy and help clinicians recognize, diagnose, and treat patients with co-existing EA and epilepsy. It also provides an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders. METHODS: Based on a literature review on Pubmed database, a list of genes linked to paroxysmal neurological disorders featuring EA and epilepsy were compiled. Online Mendelian Inheritance in Man (OMIM) was used to identify further reports relevant to each gene. RESULTS: Among the various forms of EAs, only EA1 (KCNA1), EA2 (CACNA1A), EA5 (CACNB4), EA6 (SLC1A3), and EA9 (SCN2A) phenotypes with associated epilepsy have been described. Next-generation sequencing (NGS) has helped in the identification of other genes (e.g.: KCNA2, ATP1A3, SLC2A1, PRRT2) which have shown an overlapping phenotype with EA and epilepsy. CONCLUSION: Overlapping clinical features between EA and epilepsy may hinder an accurate classification, and complex genotype-phenotype correlation may often lead to misdiagnosis. NGS has increased the awareness of common genetic etiologies for these conditions. In the future, extensive genetic and phenotypic characterizations can help us to elucidate the boundaries of a wide phenotypic spectrum. These insights may help develop new precision therapies in paroxysmal neurological disorders featuring EA and epilepsy.

Impact and management of drooling in children with neurological disorders: an Italian Delphi consensus.

BACKGROUND: The rate of chronic drooling in children older than 4 years is 0.5%, but it rises to 60% in those with neurological disorders. Physical and psychosocial consequences lead to a reduction in the quality of Life (QoL) of affected patients; however, the problem remains under-recognized and under-treated. We conducted an Italian consensus through a modified Delphi survey to discuss the current treatment paradigm of drooling in pediatric patients with neurological disorders. METHODS: After reviewing the literature, a board of 10 experts defined some statements to be administered to a multidisciplinary panel through an online encrypted platform. The answers to the questions were based on a 1-5 Likert scale (1 = strongly disagree; 5 = strongly agree). The scores were grouped into 1-2 (disagreement) and 4-5 (agreement), while 3 was discarded. The consensus was reached when the sum of the disagreement or agreement was ≥75%. RESULTS: Fifteen statements covered three main topics, namely clinical manifestations and QoL, quantification of drooling, and treatment strategies. All statements reached consensus (≥75% agreement). The 55 Italian experts agreed that drooling should be assessed in all children with complex needs, having a major impact on the QoL. Attention should be paid to investigating posterior hypersalivation, which is often neglected but may lead to important clinical consequences. Given that the severity of drooling fluctuates over time, its management should be guided by the patients' current needs. Furthermore, the relative lack of validated and universal scales for drooling quantification limits the evaluation of the response to treatment. Finally, the shared therapeutic paradigm is progressive, with conservative treatments preceding the pharmacological ones and reserving surgery only for selected cases. CONCLUSION: This study demonstrates the pivotal importance of a multidisciplinary approach to the management of drooling. National experts agree that progressive treatment can reduce the incidence of complications, improve the QoL of patients and caregivers, and save healthcare resources. Finally, this study highlights how the therapeutic strategy should be reconsidered over time according to the available drugs on the market, the progression of symptoms, and the patients' needs.

Current and promising therapeutic options for Dravet syndrome.

INTRODUCTION: Dravet Syndrome (DS) is a developmental and epileptic encephalopathy carrying high-level psychobehavioral burdens. Although the disease has been known for almost 4 decades, and despite significant progress in the understanding of its physiopathology and natural course, the pharmacological treatment leaves patients and caregivers with significant unmet needs. This review provides a summary of the current and promising therapeutic options for DS. AREAS COVERED: PubMed and ClinicalTrials.gov were screened using 'Dravet Syndrome' OR 'DS,' AND 'pharmacotherapy,' AND 'treatments.' Randomized clinical trials, structured reviews, and meta-analyses were selected for in-human application of well-known anti-seizure medications; while in-vivo experiments on models of DS were selected to evaluate the potential of new therapeutic strategies. EXPERT OPINION: The search for new pharmacological treatment options is led by the need for care and defeat of the natural course of the disease, an aspect still largely neglected by the available therapeutic strategies. Yet, the last 6 years have led to a climate of increased interest and availability of clinical trials. Particularly, gene therapy could hopefully prevent DS evolution by directly relieving the specific genetic defect, although the possibility of off-target editing, and the uneasy administration route have still largely prevented its use.

Abnormal course of the corticospinal tracts in KIF5C-related encephalopathy.

KIF5C encodes a protein belonging to the kinesin family and involved in cellular transport. Variants in KIF5C were first associated a decade ago with microcephaly and malformations of cortical development, with a phenotypic spectrum ranging from polymicrogyria to pachygyria. Currently, eight patients have been reported so far. Here we describe a new paediatric patient carrying the recurrent p.(Glu237Lys) KIF5C variant associated with a distinctive neuroradiological pattern of abnormal posterior course of the corticospinal tract at the level of the pons with a thickened anterior component of the transverse pontine fibers. This finding is likely related to altered axonal guidance and requires further evidence in other patients with KIF5C-related disorder.

Acute Neurological Presentation in Children With SARS-CoV-2 Infection.

Background: In the pediatric population, the knowledge of the acute presentation of SARS-CoV-2 infection is mainly limited to small series and case reports, particularly when dealing with neurological symptoms. We describe a large cohort of children with acute SARS-CoV-2 infection, focusing on the neurological manifestations and investigating correlations between disease severity and population demographics. Methods: Patients aged 0-18 years with a positive molecular swab were recruited between April 2020 and March 2021 from a tertiary Italian pediatric centre. Clinical data, imaging, and laboratory test results were retrieved from our local dataset and statistically analyzed. Results: A total of 237 patients with a median age of 3.2 years were eligible; thirty-two (13.5%) presented with neurological symptoms, including headache (65.6%), altered awareness (18.8%), ageusia/anosmia (12.5%), seizures (6.3%), and vertigo (6.3%), combined in 7 (21.9%) cases. Respiratory (59.5%) and gastrointestinal (25.3%) symptoms were the most common among the 205 (86.5%) patients without neurological involvement. Neurological symptoms did not significantly influence the severity of the triage access codes. Moreover, pre-existing medical conditions were not higher in the group with neurological manifestations. Overall, fifty-nine patients (25%, 14/59 with neurological symptoms) required treatment, being antibiotics, systemic steroids, and heparin those most prescribed. Conclusion: Our study supports the overall benign course of the SARS-CoV-2 infection in children. Neurological manifestations, except for headache, remain a rare presenting symptom, and disease severity seems unrelated to pre-existing medical conditions.

Cannabidiol, ∆9-tetrahydrocannabinol, and metabolites in human blood by volumetric absorptive microsampling and LC-MS/MS following controlled administration in epilepsy patients.

Cannabidiol (CBD) exhibits anti-inflammatory, anxiolytic, antiseizure, and neuroprotective proprieties without addictive or psychotropic side effects, as opposed to Δ9-tetrahydrocannabinol (THC). While recreational cannabis contains higher THC and lower CBD concentrations, medical cannabis contains THC and CBD in different ratios, along with minor phytocannabinoids, terpenes, flavonoids and other chemicals. A volumetric absorptive microsampling (VAMS) method combined with ultra-high-performance liquid chromatography coupled with mass spectrometry in tandem for quantification of CBD, THC and their respective metabolites: cannabidiol-7-oic acid (7-COOH-CBD); 7-hydroxy-cannabidiol (7-OH-CBD); 6-alpha-hydroxy-cannabidiol (6-α-OH-CBD); and 6-beta-hydroxycannabidiol (6-ß-OH-CBD); 11- Hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH). After overnight enzymatic glucuronide hydrolysis at 37°C, samples underwent acidic along with basic liquid-liquid extraction with hexane: ethyl acetate (9:1, v/v). Chromatographic separation was carried out on a C18 column, with the mass spectrometer operated in multiple reaction monitoring mode and negative electrospray ionization. Seven patients with intractable epilepsy were dosed with various CBD-containing formulations and blood collected just before their daily morning administration. The method was validated following international guidelines in toxicology. Linear ranges were (ng/ml) 0.5-25 THC, 11-OH-THC, THCCOOH, 6-α-OH-CBD and 6-ß-OH-CBD; 10-500 CBD and 7-OH-CBD; and 20-5000 7-COOH-CBD. 7-COOH-CBD was present in the highest concentrations, followed by 7-OH-CBD and CBD. This analytical method is useful for investigating CBD, THC and their major metabolites in epilepsy patients treated with CBD preparations employing a minimally invasive microsampling technique requiring only 30 µL blood.

Pediatric SARS-CoV-2-Related Diplopia and Mesencephalic Abnormalities.

Objective: This case report describes a patient with mesencephalic MRI signal abnormality and diplopia, possibly associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods: We describe a boy with binocular diplopia and nystagmus. The pattern of serology positivity and negative direct research of SARS-CoV-2 RNA in our patient allowed us to consider novel coronavirus as the trigger of possible immune-mediated phenomena against the central nervous system. Results: During hospitalization, blood tests revealed a recent SARS-CoV-2 infection. MRI revealed hyperintensity of the mesencephalic tegmentum and periaqueductal region, consistent with an inflammatory lesion of the midbrain tegmentum. Viral and bacterial molecular screening on cerebrospinal fluid and isoelectrofocusing analysis, anti-myelin oligodendrocyte glycoprotein, anti-aquaporine-4, and anti-N-methyl-d-aspartate antibodies were negative. The patient was treated with steroids and immunoglobulin therapy with complete remission of neurologic symptoms. Discussion: This report expands the spectrum of pediatric COVID-19-associated neurologic symptoms and highlights a possible isolated neurologic COVID-19-related symptom.

Epilepsy Course and Developmental Trajectories in STXBP1-DEE.

Background and Objectives: Clinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy. Methods: Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE. Results: Forty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course. Discussion: The disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.

Exploring treatments for drooling in children with neurological disorders.

Introduction: Drooling represents a major problem in the every-day life of pediatric patients with neurological disorders. The significant burden, both physical and socio-psychological, of the disorder requires adequate clinical evaluation and proper management. However, treating drooling remains a challenge for clinicians. This is a review of the most up-to-date therapeutic options for the treatment of drooling in the pediatric population, hence both conservative, pharmacological, and surgical approaches are discussed. Areas covered: Randomized clinical trials (RCTs), structured reviews, and case reports are included. Special focus is paid on the methods used to evaluate the efficacy and safety outcomes in the selected RCTs, trying to promote the use of more validated scales to assess drooling in the future. Expert opinion: The lack of reliable metrics to assess efficacy and safety outcomes in drooling limits researchers from identifying the best patient-suitable treatment. The relatively small number of clinical trials carried out over the last two decades is also due to the difficulty in assessing drooling using subjective scales. A key enabler for new efficient therapies stands in the introduction of accurate and robust metrics to measure treatment effectiveness on drooling.