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INTRODUCTION: Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants' genetic profiles. METHODS AND ANALYSIS: EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will be given a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent to the study to access pre-existing clinical data. Participants will be added to the EAGER registry and data will be shared externally through established AIMS-2-TRIALS mechanisms. ETHICS AND DISSEMINATION: To date, EAGER has received full ethical approval for 11 out of the 13 sites in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023), Spain (HCB/2023/0038, PIC-164-22), Sweden (Dnr 2023-06737-01), Ireland (230907) and Italy (CET_62/2023, CEL-IRCCS OASI/24-01-2024/EM01, EM 2024-13/1032 EAGER). Findings will be disseminated via scientific publications and conferences but also beyond to participants and the wider community (eg, the AIMS-2-TRIALS website, stakeholder meetings, newsletters).
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Trastorno Autístico , Genómica , Sistema de Registros , Secuenciación Completa del Genoma , Niño , Humanos , Masculino , Trastorno Autístico/genética , Estudios de Cohortes , Europa (Continente) , Estudios Multicéntricos como Asunto , Proyectos de InvestigaciónRESUMEN
Epilepsy surgery is effective for patients with medication-resistant seizures, however 20-40% of them are not seizure free after surgery. Aim of this study is to evaluate the role of linear and non-linear EEG features to predict post-surgical outcome. We included 123 paediatric patients who underwent epilepsy surgery at Bambino Gesù Children Hospital (January 2009-April 2020). All patients had long term video-EEG monitoring. We analysed 1-min scalp interictal EEG (wakefulness and sleep) and extracted 13 linear and non-linear EEG features (power spectral density (PSD), Hjorth, approximate entropy, permutation entropy, Lyapunov and Hurst value). We used a logistic regression (LR) as feature selection process. To quantify the correlation between EEG features and surgical outcome we used an artificial neural network (ANN) model with 18 architectures. LR revealed a significant correlation between PSD of alpha band (sleep), Mobility index (sleep) and the Hurst value (sleep and awake) with outcome. The fifty-four ANN models gave a range of accuracy (46-65%) in predicting outcome. Within the fifty-four ANN models, we found a higher accuracy (64.8% ± 7.6%) in seizure outcome prediction, using features selected by LR. The combination of PSD of alpha band, mobility and the Hurst value positively correlate with good surgical outcome.
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Electroencefalografía , Aprendizaje Automático , Humanos , Electroencefalografía/métodos , Niño , Femenino , Masculino , Preescolar , Adolescente , Epilepsia/cirugía , Epilepsia/fisiopatología , Epilepsia/diagnóstico , Redes Neurales de la Computación , Resultado del Tratamiento , Lactante , Sueño/fisiologíaRESUMEN
BACKGROUND: Epilepsy, a globally prevalent neurological condition, presents distinct challenges in management, particularly for focal-onset types. This study aimed at addressing the current challenges and perspectives in focal epilepsy management, with focus on the Italian reality. METHODS: Using the Delphi methodology, this research collected and analyzed the level of consensus of a panel of Italian epilepsy experts on key aspects of focal epilepsy care. Areas of focus included patient flow, treatment pathways, controlled versus uncontrolled epilepsy, follow-up protocols, and the relevance of patient-reported outcomes (PROs). This method allowed for a comprehensive assessment of consensus and divergences in clinical opinions and practices. RESULTS: The study achieved consensus on 23 out of 26 statements, with three items failing to reach a consensus. There was strong agreement on the importance of timely intervention, individualized treatment plans, regular follow-ups at Epilepsy Centers, and the role of PROs in clinical practice. In cases of uncontrolled focal epilepsy, there was a clear inclination to pursue alternative treatment options following the failure of two previous therapies. Divergent views were evident on the inclusion of epilepsy surgery in treatment for uncontrolled epilepsy and the routine necessity of EEG evaluations in follow-ups. Other key findings included concerns about the lack of pediatric-specific research limiting current therapeutic options in this patient population, insufficient attention to the transition from pediatric to adult care, and need for improved communication. The results highlighted the complexities in managing epilepsy, with broad consensus on patient care aspects, yet notable divergences in specific treatment and management approaches. CONCLUSION: The study offered valuable insights into the current state and complexities of managing focal-onset epilepsy. It highlighted many deficiencies in the therapeutic pathway of focal-onset epilepsy in the Italian reality, while it also underscored the importance of patient-centric care, the necessity of early and appropriate intervention, and individualized treatment approaches. The findings also called for continued research, policy development, and healthcare system improvements to enhance epilepsy management, highlighting the ongoing need for tailored healthcare solutions in this evolving field.
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Consenso , Técnica Delphi , Epilepsias Parciales , Humanos , Italia , Epilepsias Parciales/terapia , Medición de Resultados Informados por el PacienteRESUMEN
Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. Infants with DS are especially vulnerable to the detrimental effects of prolonged and frequent seizures on development. Fenfluramine (FFA) is approved for the treatment of DS in patients aged 2 years and older. This study aims to evaluate the safety and efficacy of FFA in patients with DS younger than 2 years. We analyzed safety, tolerability, seizure, and neuropsychological outcome in a real-world setting. Developmental profile was investigated using Griffiths Mental Development Scales (GMDS). Five patients received FFA at a mean age of 14.9 months (9.6-18.6). Median follow-up was 13 months (interquartile range [IQR] = 12.9-24.4). All patients showed good tolerance to FFA. No significant variation of body mass index or echocardiographic issue was observed. Monthly median convulsive seizure frequency (MCSF) was 1.71 (IQR = 1.56-3.27) at the 6-month baseline period and .92 (IQR = .43-1.28) at last follow-up, with a median 54.43 (IQR = 40.91-60.83) percentage reduction in MCSF. Two of five patients had a performance improvement on GMDS subscales. Overall, the use of FFA below the age of 2 years in our small sample of patients was safe and represents a promising opportunity for seizure control and for protection of the neurodevelopmental outcome.
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Epilepsias Mioclónicas , Fenfluramina , Lactante , Humanos , Fenfluramina/efectos adversos , Anticonvulsivantes/uso terapéutico , Resultado del Tratamiento , Epilepsias Mioclónicas/tratamiento farmacológico , Convulsiones/tratamiento farmacológicoRESUMEN
Introduction: SLC6A1 pathogenic variants have been associated with epilepsy and neurodevelopmental disorders. The clinical phenotype includes different seizure types, intellectual disability, and psychiatric symptoms affecting mood and behavior. Few data regarding neuropsychological features have been described, and details on cognitive profiles are often missing due to the lack of standardized tests. Methods: We retrospectively reviewed the neuropsychological assessments of five subjects carrying heterozygous missense genetic variants in SLC6A1. We also collected data on epileptic features, EEGs, and brain MRIs. Additionally, we reviewed neuropsychological data from 204 previously reported patients with SLC6A1 pathogenic variants. Results: In our series, at the last evaluation (median 12.6 years), three patients had borderline intellectual functioning, one patient had mild cognitive impairment, and one patient presented with a moderate cognitive disability. Three out of five patients underwent at least two neuropsychological evaluations, which revealed a worsening of cognitive functions over time. We detected attention deficits in all patients. In addition, we observed anxiety, disruptive behavior disorder, emotional instability, and hetero aggressiveness. We also performed a literature review that highlighted that most of the patients with SLC6A1 pathogenic variants have mild-to-moderate intellectual disability and that one-third of cases have autistic traits. Discussion: Based on the literature review and the detailed description of our cases, we conclude that patients with SLC6A1-related epilepsy mostly present with mild-to-moderate intellectual disability, often associated with attention disorders. Such symptoms may worsen over time. Periodic standardized neuropsychological tests may be useful tools to follow development over time, and patient-specific rehabilitation programs could be tailored consistently.
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CSNK2B encodes a regulatory subunit of casein kinase II, which is highly expressed in the brain. Heterozygous pathogenic variants in CSNK2B are associated with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) (OMIM #618732), characterized by facial dysmorphisms, seizures, intellectual disability, and behavioral disturbances. We report ten new patients with CSNK2B-related Neurodevelopmental Syndrome associated with heterozygous variants of CSNK2B. In three patients, a pathogenic variant was inherited from an affected parent. We describe both molecular and clinical features, focusing on epileptic and neurodevelopmental phenotypes. The median age at follow-up was 8.5 years (range 21 months-42 years). All patients had epilepsy, with onset at a median age of 10.5 months range 6 days-10 years). Seizures were both focal and generalized and were resistant to anti-seizure medications in two out of ten patients. Six patients had mild to moderate cognitive delays, whereas four patients had no cognitive disability. Although all previously reported patients had a de novo CSNK2B pathogenic variant, here we report, for the first time, two familial cases of CSNK2B-related Neurodevelopmental Syndrome. We confirmed the highly variable expressivity of the disease among both interfamilial and intrafamilial cases. Furthermore, this study provides information about the long-term outcome in adult patients and underlines the importance of detailed family history collection before performing genetic testing in patients with epilepsy and neurodevelopmental disorders.
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Epilepsia , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Adulto , Humanos , Lactante , Recién Nacido , Epilepsia/genética , Epilepsia/patología , Trastornos del Neurodesarrollo/complicaciones , Trastornos del Neurodesarrollo/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Discapacidad Intelectual/genética , Síndrome , FenotipoRESUMEN
The clinical phenotype of Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder (CDD) has been delineated but neuroimaging features have not been systematically analyzed. We studied brain magnetic resonance imaging (MRI) scans in a cohort of CDD patients and reviewed age at seizure onset, seizure semiology, head circumference. Thirty-five brain MRI from 22 unrelated patients were included. The median age at study entry was 13.4 years. In 14/22 patients (85.7%), MRI in the first year of life was unremarkable in all but two. In 11/22, we performed MRI after 24 months of age (range 2.5-23 years). In 8 out of 11 (72.7%), MRI showed supratentorial atrophy and in six cerebellar atrophy. Quantitative analysis detected volumetric reduction of the whole brain (-17.7%, P-value = 0.014), including both white matter (-25.7%, P-value = 0.005) and cortical gray matter (-9.1%, P-value = 0.098), with a reduction of surface area (-18.0%, P-value = 0.032), mainly involving the temporal regions, correlated with the head circumference (ρ = 0.79, P-value = 0.109). Both the qualitative structural assessment and the quantitative analysis detected brain volume reduction involving the gray and white matter. These neuroimaging findings may be related to either progressive changes due to CDD pathogenesis, or to the extreme severity of epilepsy, or both. Larger prospective studies are needed to clarify the bases for the structural changes we observed.
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Espasmos Infantiles , Humanos , Espasmos Infantiles/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Convulsiones/patología , Atrofia/patología , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
Epilepsy is a neurological disorder characterized by recurrent seizures, which result from excessive, synchronous discharges of neurons in different brain areas. In about 30% of cases, epileptic discharges, which vary in their etiology and symptomatology, are difficult to treat with conventional drugs. Ferroptosis is a newly defined iron-dependent programmed cell death, characterized by excessive accumulation of lipid peroxides and reactive oxygen species. Evidence has been provided that ferroptosis is involved in epilepsy, and in particular in those forms resistant to drugs. Here, whole cell patch clamp recordings, in current and voltage clamp configurations, were performed from layer IV principal neurons in cortical slices obtained from adult mouse brain. Application of the ferroptosis inducer RAS-selective lethal 3 (RSL3) induced interictal epileptiform discharges which started at RSL3 concentrations of 2 µM and reached a plateau at 10 µM. This effect was not due to changes in active or passive membrane properties of the cells, but relied on alterations in synaptic transmission. In particular, interictal discharges were dependent on the excessive excitatory drive to layer IV principal cells, as suggested by the increase in frequency and amplitude of spontaneously occurring excitatory glutamatergic currents, possibly dependent on the reduction of inhibitory GABAergic ones. This led to an excitatory/inhibitory unbalance in cortical circuits. Interictal bursts could be prevented or reduced in frequency by the lipophilic antioxidant Vitamin E (30 µM). This study allows identifying new targets of ferroptosis-mediated epileptic discharges opening new avenues for the treatment of drug-resistant forms of epilepsy.
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OBJECTIVE: To evaluate whether ictal phase-amplitude coupling (PAC) between high-frequency activity and low-frequency activity could be used as a preoperative biomarker of Focal Cortical Dysplasia (FCD) subtypes. We hypothesize that FCD seizures present unique PAC characteristics that may be linked to their specific histopathological features. METHODS: We retrospectively examined 12 children with FCD and refractory epilepsy who underwent successful epilepsy surgery. We identified ictal onsets recorded with stereo-EEG. We estimated the strength of PAC between low-frequencies and high-frequencies for each seizure by means of modulation index. Generalized mixed effect models and receiver operating characteristic (ROC) curve analysis were used to test the association between ictal PAC and FCD subtypes. RESULTS: Ictal PAC was significantly higher in patients with FCD type II compared to type I, only on SOZ-electrodes (p < 0.005). No differences in ictal PAC were found on non-SOZ electrodes. Pre-ictal PAC registered on SOZ electrodes predicted FCD histopathology with a classification accuracy > 0.9 (p < 0.05). CONCLUSIONS: The correlations between histopathology and neurophysiology provide evidence for the contribution of ictal PAC as a preoperative biomarker of FCD subtypes. SIGNIFICANCE: Developed into a proper clinical application, such a technique may help improve clinical management and facilitate the prediction of surgical outcome in patients with FCD undergoing stereo-EEG monitoring.
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Epilepsia , Displasia Cortical Focal , Malformaciones del Desarrollo Cortical , Niño , Humanos , Estudios Retrospectivos , Epilepsia/cirugía , Convulsiones , Biomarcadores , Malformaciones del Desarrollo Cortical/diagnóstico , Malformaciones del Desarrollo Cortical/cirugía , Malformaciones del Desarrollo Cortical/patología , Electroencefalografía , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Literature data report that the first COVID-19 pandemic had an impact on the progression of migraine both in adults and children. The present study aimed to verify how the migraine course and psychological aspects varied in adolescent patients in relation to some of the different phases of the COVID-19 pandemic and compared with the months before COVID-19. In addition, the relationship between the characteristics of headache episodes and psychological and school-related aspects were analyzed. METHODS: The study included 418 adolescents. Based on the timing of the evaluation, they were categorized into patients observed before the COVID-19 pandemic (pre COVID) or during the first (COVID 1) or second (COVID 2) wave of the pandemic. Subjects were also categorized into three further groups: those who had high or low frequency of migraine attacks during the month, those who had mild or severe pain during the attack, and those who were taking prophylactic drugs. The Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7) scales were utilized to assess depression and anxiety. RESULTS: We observed a significant increase in the frequency of attacks and the use of prophylactic drugs during the COVID 2 period compared to the COVID 1 and pre-COVID periods (p < 0.05). Patients showed higher levels of anxiety and depression during each of the two COVID periods compared with the pre-COVID months (p < 0.05), especially during the COVID 2 period (p < 0.05). CONCLUSION: Our results show long-term negative impacts of the COVID-19 pandemic on clinical parameters and psychological symptoms in adolescents with migraine.
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Introduction: Concern of a correlation between disease relapse in patients with acquired demyelinating disorders of central nervous system (CNS) and SARS-CoV2 vaccines has been raised. In this single center study, we retrospectively evaluated safety of SARS-CoV2 vaccination and COVID-19 short-term outcome in pediatric acquired demyelinating disorders of CNS. Materials and methods: Patients with multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD) with disease onset before 18 years of age were included. Demographic and clinical data, and information regarding previous SARS-CoV-2 infection and vaccination were collected. Results: We included nine patients with MOGAD. Six patients received SARS-CoV2 vaccination and complained pain at injection site while only one had fever and fatigue. Median follow-up was 28 weeks (range 20-48). Seven patients had COVID-19 occurring with mild flu-like symptoms and median follow-up was 28 weeks (range 24-34). Nobody had disease relapse. Five patients with NMOSD were included. All patients received SARS-CoV2 vaccination (BNT162b2-Pfizer-BioNTech). The median follow-up was 20 weeks (range 14-24) and only two patients complained pain at injection site, fever and fatigue. Three patients had also COVID-19 with mild flu-like symptoms, despite two of them being under immunosuppressive treatment. Lastly, forty-three patients with MS were included. 35 out of 43 received SARS-CoV2 vaccination with a median follow-up of 24 weeks (range 8-36). Fourteen patients had no side effects, while 21 complained mild side effects (mainly pain at injection site) and one experienced a disease relapse with complete recovery after steroid therapy. At vaccination, all but one were under treatment. Sixteen patients had COVID-19 occurring with mild symptoms. Discussion: COVID-19 outcome was good although many patients were under immunosuppressive treatment. Vaccine-related side effects were frequent but were mild and self-limited. Only one MS patient had a post-vaccination relapse with complete recovery after steroid therapy. In conclusion, our data support the safety of SARS-CoV-2 vaccines in pediatric MS, MOGAD and NMOSD.
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Vacunas contra la COVID-19 , COVID-19 , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Esclerosis Múltiple , Neuromielitis Óptica , Humanos , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/uso terapéutico , Fatiga , Fiebre , Inmunosupresores , Dolor , Estudios Retrospectivos , ARN Viral , SARS-CoV-2 , Esteroides , Vacunación/efectos adversos , Enfermedades DesmielinizantesRESUMEN
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.
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Epilepsias Mioclónicas , Epilepsias Parciales , Canal de Sodio Activado por Voltaje NAV1.1 , Humanos , Causalidad , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/genética , Mutación con Ganancia de Función , Discapacidad Intelectual/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Fenotipo , Bloqueadores de los Canales de Sodio/uso terapéuticoRESUMEN
AIM: To illustrate the epileptological and electroencephalographic (EEG) characteristics of a cohort of patients with KBG syndrome and epilepsy. METHOD: Clinical history, age at epilepsy onset, seizure types, EEG findings, duration of epilepsy, and response to therapies were retrospectively reviewed in 11 patients (three females, eight males) with KBG syndrome. RESULTS: All detected genetic mutations were pathogenic and affected the C-terminal region at exon 9 of ANKRD11. One patient had 16q24.3 microdeletion including the ANKRD11 gene. Mean age at onset was 67 months. Epilepsy type was focal in five patients and generalized in four. Two patients had developmental and epileptic encephalopathies. Seizure freedom was obtained after a period varying between 15 days and 6 years. INTERPRETATION: In our patients, epilepsy appeared to respond well to treatment and, in some cases, to be self-limiting. The molecular characteristics of our patients' genetic abnormalities did not point towards any specific epilepsy hot spot. Epilepsy should be considered in the diagnostic work-up of patients with KBG syndrome. WHAT THIS PAPER ADDS: Some of the epilepsy types of KBG syndrome appear to be self-remitting. The epilepsy phenotypes associated with KBG syndrome are quite variable.
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Anomalías Múltiples , Enfermedades del Desarrollo Óseo , Epilepsia Generalizada , Discapacidad Intelectual , Anomalías Dentarias , Masculino , Femenino , Humanos , Anomalías Múltiples/diagnóstico , Discapacidad Intelectual/diagnóstico , Enfermedades del Desarrollo Óseo/diagnóstico , Enfermedades del Desarrollo Óseo/genética , Anomalías Dentarias/diagnóstico , Anomalías Dentarias/genética , Facies , Estudios Retrospectivos , Proteínas Represoras/genética , Deleción Cromosómica , FenotipoRESUMEN
Background: Cenobamate (CNB) is an anti-seizure medication (ASM) approved in 2021 in Europe for adjunctive treatment of focal-onset seizures in adults who were not adequately controlled with at least two previous ASMs. Methods: seizure outcome, treatment-emergent adverse events, neuropsychological profile, and blood levels of CNB and concomitant ASM were analyzed in a real world setting in two different Italian epilepsy centers in the context of CNB early access program. All patients performed a general cognitive evaluation, while 32 patients underwent the administration of a battery of neuropsychological tests at baseline and 6 months after CNB treatment. We performed CNB quantification in plasma in 31 patients at different doses in the range of 100-400 mg/day (65 measures). Results: we enrolled 54 patients with a median age of 27.9 years. The mean follow-up was 10.7 months. Most (91%) completed the efficacy analysis. At last follow-up visit, a 69.5% median seizure reduction was registered. Thirty-two patients (59.2%) had a ≥50% reduction of seizures that was ≥75% in 20 (42.0%) cases, whilst 10 (20.2%) patients were seizure-free. The most common adverse events were somnolence (53.1%), dizziness (28.1%) and diplopia (12.5%). The correlation between CNB dose and plasma concentration, revealed a significant linear correlation (r = 0.86, p < 0.0001), and there was a significant difference in mean plasma concentration/dose administered ratio (C/D ratio) between patients taking or not at least one inducer (0.10 ± 0.04 [(µg/mL)/(mg/day)]; n = 47 vs. 0.13 ± 0.05 [(µg/mL)/(mg/day)]; n = 18, p = 0.04). CNB dose was inversely correlated (r = -0.31, p = 0.02) to the C/D ratio of Carbamazepine blood levels. and positively correlated (r = 0.74, p < 0.0001) with an increased plasma concentration of the active Clobazam metabolite N-desmethylclobazam. General Anxiety Disorder-7 showed a significant improvement of score from baseline evaluation of 6.82 to follow-up 6 months evaluation of 4.53 (p = 0.03). Conclusion: In this real-world study, we registered a clinically meaningful reduction in seizure frequency after CNB administration in most patients along with a good tolerability profile. CNB treatment is correlate to a reduction in symptom severity of anxiety score. Plasma levels measurements confirm that CNB acts both as "victim" and as "perpetrator" of drug-drug interactions.
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This study aimed to evaluate the consensus level between a representative group of Italian neurologists and people with Drug-Resistant Epilepsy (DRE) regarding a series of statements about different aspects involved in the management of epilepsy to identify the unmet needs of the People with Epilepsy (PwE) and the future perspectives for the management of this disease. This observational study was conducted using a classic Delphi technique. A 19-statement questionnaire was administered anonymously through an online platform to a panel of expert clinicians and a panel of PwE, analyzing three main topics of interest: drug resistance, access to care, and PwE's experience. The consensus was achieved on 8 of the 19 statements administered to the panel of medical experts and on 4 of the 14 submitted to the panel of PwE, particularly on the definition of DRE and its consequences on treatment, Quality of Life (QoL), and autonomy of PwE. Most of the items, however, did not reach a consensus and highlighted the lack of a shared univocal view on some topics, such as accessibility to care throughout the country and the role of emerging tools such as telemedicine, narrative medicine, and digital devices. In many cases, the two panels expressed different views on the statements. The results outlined many fields of possible intervention, such as the need for educational initiatives targeted at physicians and PwE - for example, regarding telemedicine, digital devices, and narrative medicine - as well as the spread of better knowledge about epilepsy among the general population, in order to reduce epilepsy stigma. Institutions, moreover, could take a cue from this survey to develop facilities aimed at enhancing PwE's autonomy and promoting more equal access to care throughout the country.
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Epilepsia Refractaria , Epilepsias Parciales , Epilepsia , Humanos , Calidad de Vida , Epilepsia/epidemiología , Encuestas y Cuestionarios , Estigma Social , Epilepsia Refractaria/terapiaRESUMEN
PURPOSE: Mutations in the MED13 gene are reported in the literature in association with clinically variable, neurodevelopmental disorders, which are characterized by mild-to-severe intellectual disability, autism spectrum disorder, attention deficit/hyperactivity disorder, epilepsy, ocular or skeletal abnormalities, congenital cardiac defects, and facial dysmorphisms. Here, we report a patient with an epileptic phenotype carrying a novel missense mutation characterized by developmental and epileptic encephalopathy with infantile spasms. METHODS: Through trio-based WES, we identified a novel de novo heterozygous missense variant c.2501A>G in the MED13 gene. We reviewed all medical charts of the present patient and reviewed all previously reported cases with pathogenic variants of MED13. RESULTS: This study involves a 24-month-old boy with epilepsy onset at the age of 3 months with drug-resistant focal seizures followed by infantile spasms at the age of 10 months. He had a severe, developmental delay along with microcephaly and dysmorphic features. From a literature review, it emerged that epilepsy is described in only one out of nineteen of previously reported patients with a phenotype of generalized, drug-resistant epilepsy with myoclonic-atonic seizures. Microcephaly, developmental delay, hypotonia, corpus callosum abnormalities, deafness, and retinal atrophy were common features in the previously described cases. CONCLUSION: This case expands the genetic landscape of infantile spasms as well as the phenotype of MED13-related disorders adding the electroclinical features of early-onset developmental and epileptic encephalopathy with infantile spasms to the previously described, generalized epilepsy with myoclonic-atonic seizures.
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Trastorno del Espectro Autista , Epilepsia , Discapacidad Intelectual , Microcefalia , Espasmos Infantiles , Trastorno del Espectro Autista/complicaciones , Epilepsia/complicaciones , Epilepsia/genética , Humanos , Discapacidad Intelectual/complicaciones , Masculino , Complejo Mediador/genética , Microcefalia/complicaciones , Mutación/genética , Fenotipo , Convulsiones/complicaciones , Espasmos Infantiles/complicaciones , Espasmos Infantiles/genéticaRESUMEN
BACKGROUND: Goldenhar syndrome (GS) is a rare congenital disease characterized by impaired development of different facial structures and deformations of the teeth structures. Sialorrhea, which can cause difficulties in breathing and language impairment, is very common in GS and often difficult to treat. This case report highlights the short- and long-term importance of the therapeutic choice - glycopyrronium in oral solution - for the treatment of sialorrhea in children with poly-malformative syndrome, complicated by outcomes of post-hemorrhagic hydrocephalus. CASE PRESENTATION: We report the case of a 6-year-old child with GS, carrying a percutaneous endoscopic gastrostomy after tracheostomy. The child also presented developmental dysfunction of oral motor skills of feeding, complicated by severe sialorrhea, related to the maxillo-facial dysmorphism. Sialorrhea caused several respiratory tract infections and led to an increase in the care burden. Both the inoculations of botulinum toxin and the treatment with scopolamine transdermal patch have shown mild and transient efficacy. The therapeutic choice of glycopyrronium in oral solution was the most suitable for this patient, leading to long-term sialorrhea control. CONCLUSIONS: This clinical experience represents the first long-term efficacy and tolerability evaluation in using glycopyrrolate oral solution in treating drooling in children with GS. The reduction of drooling over time and the lack of clinically relevant adverse events have contributed to the decrease of respiratory tract infections, the development of oral motor skills, and determining a positive psycho-social impact on the patient's quality of life and her family.
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Síndrome de Goldenhar , Infecciones del Sistema Respiratorio , Sialorrea , Niño , Femenino , Glicopirrolato/efectos adversos , Glicopirrolato/uso terapéutico , Síndrome de Goldenhar/inducido químicamente , Síndrome de Goldenhar/complicaciones , Síndrome de Goldenhar/tratamiento farmacológico , Humanos , Calidad de Vida , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Sialorrea/tratamiento farmacológico , Sialorrea/etiologíaRESUMEN
In 2018, the Food and Drug Administration (FDA) approval of anti-calcitonin gene-related peptide (CGRP) therapies for the treatment of migraine represented a milestone for the management of the disease in adults. On the contrary, the novelties in the field of pediatric migraine are inserted in a different scenario and still concern: (1) diagnostic criteria of the international classification of headache disorders-3 (ICHD-3) that show numerous limits of applicability in the developmental age; (2) the release of the results of the Childhood and Adolescent Migraine Prevention (CHAMP) study that raised doubts about the usefulness of traditional drugs for the treatment of pediatric migraine; (3) the Coronavirus disease 2019 (COVID-19) pandemic has put the spotlight on the importance of managing the psychological factors associated with the disease. In this mini review we discuss the most relevant news in pediatric migraine over the last 5 years.