Ensayo clínico aleatorizado, enmascarado y controlado con placebo del bloqueo anestésico del nervio occipital mayor como tratamiento a corto plazo en migraña crónica: datos clínicos y algométricos

La migraña crónica (MC) es una cefalea de alta prevalencia, con un impacto elevado sobre la calidad de vida. Por el momento existen pocos tratamientos que hayan demostrado su eficacia en esta entidad con un nivel de evidencia suficiente. Por otra parte, el conocimiento de su fisiopatología es asimismo insuficiente. El bloqueo del nervio occipital mayor (NOM) es una técnica muy extendida en el tratamiento de distintos tipos de cefaleas en la práctica clínica. Sin embargo, apenas se han realizado estudios controlados para evaluar la eficacia del bloqueo del NOM en la migraña, y sus resultados han sido, en ocasiones, contradictorios.Objetivos: Evaluar la eficacia clínica del bloqueo anestésico del NOM en la MC, y analizar su efecto a corto plazo sobre los umbrales de dolor a la presión (UDP) de distintos territorios anatómicos, tanto cefálicos como extracefálicos. Materiales y métodos: Se llevó a cabo un ensayo clínico paralelo, aleatorizado, doble ciego y controlado con placebo. Se reclutaron 36 mujeres con MC mediante un muestreo de casos consecutivos en la unidad de cefaleas de un hospital terciario. El uso excesivo de analgésicos fue criterio de exclusión..

HMGB1: A Common Biomarker and Potential Target for TBI, Neuroinflammation, Epilepsy, and Cognitive Dysfunction

High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein released by glia and neurons upon inflammasome activation and activates receptor for advanced glycation end products (RAGE) and toll-like receptor (TLR) 4 on the target cells. HMGB1/TLR4 axis is a key initiator of neuroinflammation. In recent days, more attention has been paid to HMGB1 due to its contribution in traumatic brain injury (TBI), neuroinflammatory conditions, epileptogenesis, and cognitive impairments and has emerged as a novel target for those conditions. Nevertheless, HMGB1 has not been portrayed as a common prognostic biomarker for these HMGB1 mediated pathologies. The current review discusses the contribution of HMGB1/TLR4/RAGE signaling in several brain injury, neuroinflammation mediated disorders, epileptogenesis and cognitive dysfunctions and in the light of available evidence, argued the possibilities of HMGB1 as a common viable biomarker of the above mentioned neurological dysfunctions. Furthermore, the review also addresses the result of preclinical studies focused on HMGB1 targeted therapy by the HMGB1 antagonist in several ranges of HMGB1 mediated conditions and noted an encouraging result. These findings suggest HMGB1 as a potential candidate to be a common biomarker of TBI, neuroinflammation, epileptogenesis, and cognitive dysfunctions which can be used for early prediction and progression of those neurological diseases. Future study should explore toward the translational implication of HMGB1 which can open the windows of opportunities for the development of innovative therapeutics that could prevent several associated HMGB1 mediated pathologies discussed herein

D-galactose supplementation for the treatment of mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE): A pilot trial of precision medicine after epilepsy surgery

MOGHE is defined as mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Approximately half of the patients with histopathologically confirmed MOGHE carry a brain somatic variant in the SLC35A2 gene encoding a UDP-galactose transporter. Previous research showed that D-galactose supplementation results in clinical improvement in patients with a congenital disorder of glycosylation due to germline variants in SLC35A2. We aimed to evaluate the effects of D-galactose supplementation in patients with histopathologically confirmed MOGHE, with uncontrolled seizures or cognitive impairment and epileptiform activity at the EEG after epilepsy surgery (NCT04833322). Patients were orally supplemented with D-galactose for 6 months in doses up to 1.5 g/kg/day and monitored for seizure frequency including 24-h video-EEG recording, cognition and behavioral scores, i.e., WISC, BRIEF-2, SNAP-IV, and SCQ, and quality of life measures, before and 6 months after treatment. Global response was defined by > 50% improvement of seizure frequency and/or cognition and behavior (clinical global impression of “much improved” or better). Twelve patients (aged 5–28 years) were included from three different centers. Neurosurgical tissue samples were available in all patients and revealed a brain somatic variant in SLC35A2 in six patients (non-present in the blood). After 6 months of supplementation, D-galactose was well tolerated with just two patients presenting abdominal discomfort, solved after dose spacing or reduction. There was a 50% reduction or higher of seizure frequency in 3/6 patients, with an improvement at EEG in 2/5 patients. One patient became seizure-free. An improvement of cognitive/behavioral features encompassing impulsivity (mean SNAP-IV − 3.19 [− 0.84; − 5.6]), social communication (mean SCQ − 2.08 [− 0.63; − 4.90]), and executive function (BRIEF-2 inhibit − 5.2 [− 1.23; − 9.2]) was observed. Global responder rate was 9/12 (6/6 in SLC35A2-positive). Our results suggest that supplementation with D-galactose in patients with MOGHE is safe and well tolerated and, although the efficacy data warrant larger studies, it might build a rationale for precision medicine after epilepsy surgery.IB's work was partially funded by the German Research Council (DFG Bl 421/4–1, DFG Bl 421/5–1).Peer reviewe

Therapeutic Efficacy of a Potent Anti-venezuelan Equine Encephalitis Virus Antibody Is Contingent on FC Effector functionslc6a1 Variant Pathogenicity, Molecular Function and Phenotype: A Genetic and Clinical Analysis

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10−3, 95% confidence interval: 1.5–15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/)

Inteligencia artificial en epilepsia

La aplicación de la inteligencia artificial se ha expandido en los últimos años en el ámbito de la neurología. Tal como ocurre en otras enfermedades neurológicas, en epilepsia es necesaria la interconexión entre aspectos clínicos, neurofisiológicos y de neuroimagen para tomar decisiones diagnósticas y terapéuticas. Esto conlleva que, para la toma de decisiones de cada paciente, se deba valorar una gran cantidad de información, con la consiguiente demanda de recursos, formación y tiempo por parte del médico. La gran cantidad de información que se genera en la evaluación de un paciente con epilepsia es el escenario perfecto para el desarrollo y aplicación de la inteligencia artificial, alimentando con una infinidad de datos a los sistemas de redes neuronales, además de posibilitar la validación de la metodología en bases de datos multicéntricas. En esta revisión se analizan los modelos de inteligencia artificial con mayores tasas de precisión para la predicción o detección de crisis, algunos de los cuales ya se encuentran en fase de implantación. Asimismo, el auge exponencial de dispositivos portátiles o wearables permite entrever un futuro con mayor autonomía del paciente y un manejo más objetivo y humanizado

Epilepsy treatment in neuro-oncology:A rationale for drug choice in common clinical scenarios

Epilepsy represents a challenge in the management of patients with brain tumors. Epileptic seizures are one of the most frequent comorbidities in neuro-oncology and may be the debut symptom of a brain tumor or a complication during its evolution. Epileptogenic mechanisms of brain tumors are not yet fully elucidated, although new factors related to the underlying pathophysiological process with possible treatment implications have been described. In recent years, the development of new anti-seizure medications (ASM), with better pharmacokinetic profiles and fewer side effects, has become a paradigm shift in many clinical scenarios in neuro-oncology, being able, for instance, to adapt epilepsy treatment to specific features of each patient. This is crucial in several situations, such as patients with cognitive/psychiatric comorbidity, pregnancy, or advanced age, among others. In this narrative review, we provide a rationale for decision-making in ASM choice for neuro-oncologic patients, highlighting the strengths and weaknesses of each drug. In addition, according to current literature evidence, we try to answer some of the most frequent questions that arise in daily clinical practice in patients with epilepsy related to brain tumors, such as, which patients are the best candidates for ASM and when to start it, what is the best treatment option for each patient, and what are the major pitfalls to be aware of during follow-up

An examination of the efficacy and safety of fenfluramine in adults, children, and adolescents with Dravet syndrome in a real-world practice setting: a report from the fenfluramine European Early Access Program

Objective: To examine the efficacy and safety of fenfluramine in patients with Dravet syndrome (DS) in three age groups: <6, 6 to 17, and ≥18 years old, treated in a real-world setting. Methods: Patients with DS were treated with fenfluramine in the European Union Early Access Program (EAP). Following a 28-day baseline period to establish the pretreatment monthly convulsive seizure frequency (MCSF), fenfluramine was started at a dose chosen by the treating physician and gradually titrated based on efficacy and tolerability up to a maximum of 0.7 mg/kg/day. Seizure incidence was recorded in a written diary, and adverse events (AEs) were reported at each patient visit. Cardiovascular safety was assessed by transthoracic echocardiography before treatment started and at least every 6 months thereafter. Results: A total of 149 patients have enrolled in the EAP and 63 were <6 years old, 62 were 6 to 17 years old, and 24 were ≥18 years old. After 3 months of treatment 62%, 53%, and 50% of patients demonstrated ≥75% reduction in MCSF in the <6, 6-17, and ≥18-year-old groups, respectively. This pattern of response was sustained through 12 months of treatment with 55%, 46%, and 80% of the <6, 6-17, and ≥18-year-old groups, respectively, experiencing a ≥75% reduction in MCSF. Most common AEs were loss of appetite (21%) and somnolence (16%). No valvular heart disease or pulmonary artery hypertension was observed. Significance: The magnitude, consistency, and durability of the response to add-on fenfluramine is consistent across age groups in patients with Dravet Syndrome

Developmental epileptic encephalopathy in DLG4-related synaptopathy

Objective: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy. Methods: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. Results: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants. Significance: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG.Jascha FondenFundacion INCERegione ToscanaHuman Brain Optical Mapping Project by Fondazione Cassa di Risparmio di FirenzeNational Center for Advancing Translational Sciences, National Institutes of Health (NIH)KAIMRCFWO (UL1TR001873, RC23R/177/02, 1861419N)5.6 Q1 JCR 20222.227 Q1 SJR 2022No data IDR 2022UE

The Charlotte Project: Recommendations for patient-reported outcomes and clinical parameters in Dravet syndrome through a qualitative and Delphi consensus study.

The appropriate management of patients with Dravet Syndrome (DS) is challenging, given the severity of symptoms and the burden of the disease for patients and caregivers. This study aimed to identify, through a qualitative methodology and a Delphi consensus-driven process, a set of recommendations for the management of DS to guide clinicians in the assessment of the clinical condition and quality of life (QoL) of DS patients, with a special focus on patient- and caregiver-reported outcomes (PROs). This study was conducted in five phases, led by a multidisciplinary scientific committee (SC) including pediatric neurologists, epileptologists, a neuropsychologist, an epilepsy nurse, and members of DS patient advocates. In phases 1 and 2, a questionnaire related to patients' QoL was prepared and answered by caregivers and the SC. In phase 3, the SC generated, based on these answers and on a focus group discussion, a 70-item Delphi questionnaire, covering six topic categories on a nine-point Likert scale. In phase 4, 32 panelists, from different Spanish institutions and with a multidisciplinary background, answered the questionnaire. Consensus was obtained and defined as strong or moderate if ≥80% and 67-79% of panelists, respectively, rated the statement with ≥7. Phase 5 consisted of the preparation of the manuscript. The panelists agreed on a total of 69 items (98.6%), 54 (77.14%), and 15 (21.43%) with strong and moderate consensus, respectively. The experts' recommendations included the need for frequent assessment of patient and caregivers QoL parameters. The experts agreed that QoL should be assessed through specific questionnaires covering different domains. Likewise, the results showed consensus regarding the regular evaluation of several clinical parameters related to neurodevelopment, attention, behavior, other comorbidities, and sudden unexpected death in epilepsy (SUDEP). A consensus was also reached on the instruments, specific parameters, and caregivers' education in the routine clinical management of patients with DS. This consensus resulted in a set of recommendations for the assessment of clinical and QoL parameters, including PROs, related to the general evaluation of QoL, neurodevelopment, attention, behavior, other comorbidities affecting QoL, SUDEP, and QoL of caregivers/relatives and patients with DS