Search

Abstract Objectives People with neurodevelopmental disorders frequently experience sleep disturbances, negatively impairing their quality of life. We aimed to determine the prevalence and nature of sleep disturbances in patients with SCN8A‐related disorders. Methods Through a collaborative network of caregivers and clinicians, we collected data about epilepsy, cognitive/motor abilities, medications, and relevant comorbidities of patients harboring a pathogenic SCN8A variant. The Sleep Disturbance Scale for Children (SDSC), the Children's Sleep Habits Questionnaire (CSHQ‐22‐items), and the Pediatric Daytime Sleepiness Scale (PDSS) were distributed and evaluated by factor scores and Composite Sleep Index. Video‐EEG‐polysomnographic recordings were performed. Results We enrolled 47 patients (age range: 2–39 years), whose phenotypes ranged from SCN8A‐DEE to intellectual disability without epilepsy. In the majority of them (82%), sleep disturbances were reported and/or observed at the SDSC. The most frequent were difficulty in initiating and maintaining sleep (64%), followed by sleep breathing disorder (43%), sleep–wake transition disorder (34%), and daytime sleepiness (34%). Sleep disturbances were more frequent in patients with severe DEE (96%) and ongoing seizures (93%) and were more severe in patients with sleep‐related seizures. The CSHQ and PDSS confirmed difficulty in initiating and maintaining sleep. Polysomnographic recordings (9 patients/20 nights) showed an altered sleep structure in 95%, with frequent arousals, mainly not seizure related. Significance More than 80% of patients with SCN8A‐related disorders presented with sleep disturbances, primarily consisting of sleep instability with difficulty of initiating and maintaining sleep. Animal studies showed sleep disturbances in SCN8A‐ and SCN1A‐Dravet Syndrome mice models, suggesting a role for voltage‐gated sodium channels in the regulation of sleep. Understanding the effects of SCN8A dysfunction on sleep stability may guide future therapeutic efforts to alleviate this often distressing symptom also in seizure‐free SCN8A patients. Plain Language Summary In this study, we analyzed sleep disturbances in patients with disorders related to a genetic mutation in the gene SCN8A. We found that the majority of the patients experienced sleep disturbances, mainly consisting in difficulty of initiating and maintaining sleep. Sleep disturbances were more frequent in patients with severe cognitive impairment and active epilepsy and more severe in patients with seizures during sleep.

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/).

AIM: To translate and culturally adapt the FRAIL scale into Spanish and perform a preliminary test of diagnostic accuracy in patients admitted to intensive care units. DESIGN: Cross-sectional diagnostic study. METHODS: Five intensive care units (ICU) in Spain were participated. Stage 1: Three native Spanish-speaking bilingual translators familiar with the field of critical care translated the scale from English into Spanish. Stage 2: Three native English-speaking bilingual translators familiar with critical care medicine. Stage 3: Authors of the original scale compared the English original and back-translated versions of the scale. Stage 4: Five nurses with more than 5 years of ICU experience and five critical care physicians assessed the comprehension and relevance of each of the items of the Spanish version in 30 patients of 3 different age ranges (65 years). RESULTS: The FRAIL scale was translated and adapted cross-culturally for patients admitted to intensive care units in Spain. The process consisted of four stages: translation, back translation, comparison and pilot test. There was good correspondence between the original scale and the Spanish version in 100% of the items. The participating patients assessed the relevance (content validity) and comprehensibility (face validity) of each of the items of the first Spanish version. The relevance of some of the items scored low when the scale was used in patients younger than 65 years. CONCLUSIONS: We have cross-culturally adapted the FRAIL scale, originally in English, to Spanish for its use in the critical care medical setting in Spanish-speaking countries. IMPLICATIONS FOR PROFESSIONALS: Physicians and nurses can apply the new scale to all patients admitted to the intensive care units. Nursing care can be adapted according to frailty, trying to reduce the side effects of admission to these units for the most fragile patients. REPORTING METHOD: The manuscripts authors have adhered to the EQUATOR guidelines, using the COSMIN reporting guideline for studies on the measurement properties of patient-reported outcome measures. PATIENT OR PUBLIC CONTRIBUTION: In a pilot clinical study, we applied the first version of the FRAIL-Spain scale to intensive care unit (ICU) patients. Five nurses with more than 5 years of ICU experience and five critical care physicians assessed the relevance (content validity) and comprehensibility (face validity) of the five items of the first Spanish version. Relevance was assessed using a 4-point Likert scale ranging from 1 (no relevance) to 4 (high relevance), and comprehensibility was assessed as poor, acceptable or good. Each health professional applied the scale to three patients (total number of patients = 30) of three different age ranges (65 years) and recorded the time of application of the scale to each patient. Although the frailty scales were initially created by geriatricians to be applied to the elders, there is little experience with their application in critically ill patients of any age. Therefore, more information is needed to determine the relevance of using this scale in critical care patients. In this pilot study, we considered that nurses and critical care physicians should evaluate frailty using this adapted scale in adult patients admitted to the Intensive Care Units.

Abstract Objective Epilepsy requires continuous medical attention from multiple healthcare specialists, specialized facilities, and community‐based care. In Spain, there is no standardized approach to epilepsy care. The aim of this study was to identify the factors impacting on the delivery of high‐quality care by exploring key steps and barriers along the patient journey through the Spanish National Healthcare System (NHS). Methods A qualitative study was conducted using opinions and experiences of neurologists, nurses, patients, and caregivers shared in discussion meetings. Using thematic content analyses, relevant aim‐focused statements were coded according to prespecified issues in a discussion map (i.e., key steps and barriers), and sub‐coded according to emerging issues. Thematic saturation and co‐occurrence of key steps/barriers were evaluated to identify the most relevant factors impacting on the delivery of high‐quality care. Results Sixty‐five stakeholders took part in discussion meetings (36 neurologists, 10 nurses, 10 patients, and nine caregivers). Six key steps on the patient journey were identified: emergency care, diagnosis, drug therapy, follow‐up, referral, and interventional treatment. Of these, follow‐up was the most relevant step impacting on the delivery of high‐quality patient care, followed by drug therapy and diagnosis. Emergency care was considered a hot‐spot step with impact throughout the patient journey. Communication (among HCPs and between HCPs and patients) was a barrier to the delivery of high‐quality care at several stages of the patient journey, including drug therapy, follow‐up, referral, and interventional treatment. Resource availability was a barrier for diagnosis (especially for confirmation), drug therapy (drug availability), and referral (lack of professionals and specialized centers, and long waiting lists). Significance This is the first study capturing perspectives of four key stakeholders involved in epilepsy care in Spain. We provide an overview of the patient journey through the Spanish NHS and highlight opportunities to improve the delivery of patient‐centered care with a chronicity perspective. Plain Language Summary Patients with epilepsy may require prolonged medical care. In Spain, care is provided by a range of specialist and non‐specialist centers. In this study, a team of Spanish neurologists, nurses, patients and caregivers identified barriers that affect the delivery of high‐quality care for patients with epilepsy at each stage of their journey through the Spanish NHS. Specific epilepsy training for healthcare providers, appropriate resources for diagnosing and treating patients, and good communication between healthcare workers and patients were identified as important factors in providing high‐quality care for patients with epilepsy.

ABSTRACT Aims To adapt the Clinical Frailty Scale (CFS) into Spanish and assess its concordance with the Spanish version of the FRAIL scale (FRAIL‐Es) in the context of intensive care. Design Validation study of frailty assessment scales in critically ill patients. Methods The study was conducted in two phases. The first phase consisted of translating, culturally adapting, and validating the CFS into Spanish. The second phase consisted of a metric descriptive study to assess the concurrent criterion validity of the adapted CFS with FRAIL‐Es in a cohort of intensive care patients. Both scales were assessed upon admission to intensive care and at 3, 6, 9, and 12 months post‐hospital discharge. Analysis was performed using T‐Student/Mann–Whitney, chi‐squared and Cohen's Kappa tests. Results Successful adaptation of the CFS with minimal changes was achieved, demonstrating its applicability in the evaluated context. The pilot study indicated that CFS‐Es is easy to assess, but some subjectivity in interpretation was noted. CFS‐Es and FRAIL‐Es were applied to 212 patients, revealing variations in frailty prevalence. The concordance and correlation between the CFS and FRAIL scales are robust. These differences suggest that the choice of scale may impact the identification of frail patients. These results emphasise the importance of considering specific characteristics of each scale when assessing frailty in critically ill patients, providing valuable information for clinical implementation and research in this field. Patient or Public Contribution Assessing frailty upon admission can be helpful in the care of frail patients, allowing the development of specific care plans based on pre‐existing frailty.

Resumen: Introducción: El objetivo del trabajo fue conocer el comportamiento de los biomarcadores ecográficos de densidad fascicular y fuerza muscular en pacientes con esclerosis lateral amiotrófica (ELA). Métodos: Estudio piloto, observacional y transversal sobre 14 pacientes con ELA (mujeres; 28,6%) y 14 controles. Se tomaron ecografías bilaterales transversales en el abductor corto del pulgar (ACP) y tibial anterior (TA) con registro del grosor muscular (GM) en reposo, en contracción y diferencia de engrosamiento. En los nervios mediano, ciático y peroneo común se analizaron el área de sección transversal (AST), el número de fascículos (NF) y la densidad fascicular (DF). Los análisis se realizaron anidados por lateralidad. Resultados: El acuerdo intra-interobservador en los recuentos de fascículos fue muy bueno con un error mínimo detectable

Introduction: The aim of this study was to determine the behaviour of ultrasound biomarkers of fascicle density and muscle strength in patients with amyotrophic lateral sclerosis (ALS). Methods: We conducted an observational, cross-sectional pilot study of 14 patients with ALS (28.6% women) and 14 controls. Bilateral cross-sectional ultrasound scans were performed in the abductor pollicis brevis (APB) and tibialis anterior (TA) muscles, with recording of muscle thickness (MT) at rest and in contraction, and the difference in thickness. In the median, sciatic, and common peroneal nerves, we analysed the cross-sectional area (CSA), number of fascicles (NF) and fascicle density (FD). Analyses were nested by laterality. Results: Intra- and interrater agreement regarding NF was very good, with a minimum detectable error of

Abstract Cyclin‐dependent kinase‐like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy caused by variants in the CDKL5 gene. The disorder is characterized by intractable early‐onset seizures, severe neurodevelopmental delay, hypotonia, motor disabilities, cerebral (cortical) visual impairment and microcephaly. With no disease‐modifying therapies available for CDD, treatment is symptomatic with an initial focus on seizure control. Another unmet need in the management of people with CDD is the lack of evidence to aid standardized care and guideline development. To address this gap, experts in CDD and representatives from patient advocacy groups from Denmark, Finland, France, Germany, Italy, Poland, Spain, and the United Kingdom convened to form an Expert Working Group. The aim was to provide an expert opinion consensus on how to ensure quality care in routine clinical practice within the European setting, including in settings with limited experience or resources for multidisciplinary care of CDD and other developmental and epileptic encephalopathies. By means of one‐to‐one interviews around the current treatment landscape in CDD, insights from the Expert Working Group were collated and developed into a Europe‐specific patient journey for individuals with CDD, which was later validated by the group. Further discussions followed to gain consensus of opinions on challenges and potential solutions for achieving quality care in this setting. The panel recognized the benefit of early genetic testing, a holistic personalized approach to seizure control (taking into consideration various factors such as concomitant medications and comorbidities), and age‐ and comorbidity‐dependent multidisciplinary care for optimizing patient outcomes and quality of life. However, their insights and experiences also highlighted much disparity in management approaches and resources across different European countries. Development of standardized European recommendations is required to align realistic diagnostic criteria, treatment goals, and management approaches that can be adapted for different settings. Plain language summary Cyclin‐dependent kinase‐like 5 (CDKL5) deficiency disorder (CDD) is a rare condition caused by a genetic mutation with a broad range of symptoms apparent from early childhood, including epileptic seizures that do not respond to medication and severe delays in development. Due to the lack of guidance on managing CDD, international experts and patient advocates discussed best practices in the care of people with CDD in Europe. The panel agreed that early testing, a personalized approach to managing seizures, and access to care from different disciplines are beneficial. Development of guidelines to ensure that care is standardized would also be valuable.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Abstract Objective To assess efficacy and tolerability of stiripentol (STP) as adjunctive treatment in Dravet syndrome and non‐Dravet refractory developmental and epileptic encephalopathies (DREEs). Methods Retrospective observational study of all children and adults with DREE and prescribed adjunctive STP at Hospital Ruber Internacional from January 2000 to February 2023. Outcomes were retention rate, responder rate (proportion of patients with ≥50% reduction in total seizure frequency relative to baseline), seizure freedom rate, responder rate for status epilepticus, rate of adverse event and individual adverse events, reported at 3, 6, and 12 months and at final visit. Seizure outcomes are reported overall, and for Dravet and non‐Dravet subgroups. Results A total of 82 patients (55 Dravet syndrome and 27 non‐Dravet DREE) were included. Median age was 5 years (range 1–59 years), and median age of epilepsy onset was younger in the Dravet group (4.9 [3.6–6] months) than non‐Dravet (17.9 [6–42.3], P

Abstract Aim To translate and culturally adapt the FRAIL scale into Spanish and perform a preliminary test of diagnostic accuracy in patients admitted to intensive care units. Design Cross‐sectional diagnostic study. Methods Five intensive care units (ICU) in Spain were participated. Stage 1: Three native Spanish‐speaking bilingual translators familiar with the field of critical care translated the scale from English into Spanish. Stage 2: Three native English‐speaking bilingual translators familiar with critical care medicine. Stage 3: Authors of the original scale compared the English original and back‐translated versions of the scale. Stage 4: Five nurses with more than 5 years of ICU experience and five critical care physicians assessed the comprehension and relevance of each of the items of the Spanish version in 30 patients of 3 different age ranges (65 years). Results The FRAIL scale was translated and adapted cross‐culturally for patients admitted to intensive care units in Spain. The process consisted of four stages: translation, back translation, comparison and pilot test. There was good correspondence between the original scale and the Spanish version in 100% of the items. The participating patients assessed the relevance (content validity) and comprehensibility (face validity) of each of the items of the first Spanish version. The relevance of some of the items scored low when the scale was used in patients younger than 65 years. Conclusions We have cross‐culturally adapted the FRAIL scale, originally in English, to Spanish for its use in the critical care medical setting in Spanish‐speaking countries. Implications for Professionals Physicians and nurses can apply the new scale to all patients admitted to the intensive care units. Nursing care can be adapted according to frailty, trying to reduce the side effects of admission to these units for the most fragile patients. Reporting Method The manuscript's authors have adhered to the EQUATOR guidelines, using the COSMIN reporting guideline for studies on the measurement properties of patient‐reported outcome measures. Patient or Public Contribution In a pilot clinical study, we applied the first version of the FRAIL‐Spain scale to intensive care unit (ICU) patients. Five nurses with more than 5 years of ICU experience and five critical care physicians assessed the relevance (content validity) and comprehensibility (face validity) of the five items of the first Spanish version. Relevance was assessed using a 4‐point Likert scale ranging from 1 (no relevance) to 4 (high relevance), and comprehensibility was assessed as poor, acceptable or good. Each health professional applied the scale to three patients (total number of patients = 30) of three different age ranges (65 years) and recorded the time of application of the scale to each patient. Although the frailty scales were initially created by geriatricians to be applied to the elders, there is little experience with their application in critically ill patients of any age. Therefore, more information is needed to determine the relevance of using this scale in critical care patients. In this pilot study, we considered that nurses and critical care physicians should evaluate frailty using this adapted scale in adult patients admitted to the Intensive Care Units.

In 2015, Catalonia introduced sickle cell disease (SCD) screening in its newborn screening (NBS) program along with standard-of-care treatments like penicillin, hydroxyurea, and anti-pneumococcal vaccination. Few studies have assessed the clinical impact of introducing NBS programs on SCD patients. We analyzed the incidence of SCD and related hemoglobinopathies in Catalonia and the change in clinical events occurring after introducing NBS. Screening 506,996 newborns from 2015 to 2022, we conducted a retrospective multicenter study including 100 screened (SG) and 95 unscreened (UG) SCD patients and analyzed SCD-related clinical events over the first six years of life. We diagnosed 160 cases of SCD, with an incidence of 1 in 3169 newborns. The SG had a significantly lower median age at diagnosis (0.1 y vs. 1.68 y, p < 0.0001), and initiated penicillin prophylaxis (0.12 y vs. 1.86 y, p < 0.0001) and hydroxyurea treatment earlier (1.42 y vs. 4.5 y, p < 0.0001). The SG experienced fewer median SCD-related clinical events (vaso-occlusive crisis, acute chest syndrome, infections of probable bacterial origin, acute anemia requiring transfusion, acute splenic sequestration, and pathological transcranial Doppler echography) per year of follow-up (0.19 vs. 0.77, p < 0.0001), a reduced number of annual emergency department visits (0.37 vs. 0.76, p < 0.0001), and fewer hospitalizations (0.33 vs. 0.72, p < 0.0001). SCD screening in Catalonia’s NBS program has effectively reduced morbidity and improved affected children’s quality of life.