Rendimiento de la técnica de "array" de hibridación genómica comparada aplicada al estudio de las discapacidades intelectuales y del desarrollo

Las discapacidades intelectuales y del desarrollo tienen una prevalencia de entre 1 y 3% y suponen un impacto significativo en el funcionamiento del individuo que se prolonga a lo largo de toda su vida, así como elevados costes para los sistemas de salud y para la sociedad en su conjunto. En más del 50% de los casos la causa de la discapacidad intelectual y del desarrollo es desconocida, lo que impide indicar un tratamiento específico en caso de que lo hubiese, emitir un pronóstico, evitar exploraciones inútiles y llevar a cabo un consejo genético familiar y reproductivo. El desarrollo y la aplicación a la práctica clínica de técnicas moleculares de cribado genómico, en concreto del array de hibridación genómica comparada (array-CGH), que permite detectar pequeñas pérdidas y ganancias de material genético con una resolución de hasta miles de veces la correspondiente a un cariotipo convencional, han duplicado la tasa de diagnósticos de reordenamientos cromosómicos submicroscópicos como causa de discapacidad intelectual o del desarrollo, al detectarlos en alrededor del 15% de los casos. Justificación del trabajo Aunque hoy día se considera el array-CGH una prueba de primer nivel en el diagnóstico etiológico de las discapacidades intelectuales y las discapacidades del desarrollo sin causa aparente y sin una sospecha sindrómica clara, y a pesar de que su precio ha ido progresivamente disminuyendo, sigue siendo una técnica cara y de realización e interpretación costosa en términos de tiempo y personal. Por ese motivo, es importante establecer en nuestra población pediátrica el rendimiento de esta técnica en el estudio de las discapacidades intelectuales y del desarrollo. Demostrar en nuestra cohorte de pacientes un rendimiento al menos similar al reportado en otras poblaciones puede servir de argumento para salvar las limitaciones de acceso a este estudio que en la actualidad existen en nuestro país..

Cannabidiol for Treatment of Childhood Epilepsy–A Cross-Sectional Survey

Background: The interest in cannabidiol (CBD) for treatment of epilepsy has been increasing over the last years. However, practitioner's attitudes concerning the use of CBD for epilepsy treatment appears to be divided and data about its clinical use in daily practice are not available.Objective: To improve the knowledge about the current use of CBD amongst European practitioners treating children and adolescents for epilepsy.Methods: Cross-sectional survey using an open-access online questionnaire for physicians treating children or adolescents for epilepsy within eight European countries from December 2017 to March 2018.Results: One-hundred fifty-five physicians participated in the survey. CBD is increasingly used by 45% (69/155) of participants, treating a mean (range) number of 3 (1–35) with CBD. Only 48% of the participants prescribing CBD are exclusively using purified CBD to treat children and adolescents with epilepsy, the remainder also applies preparations containing delta9-tetrahydrocannabinol (THC). Reported daily CBD doses range from < 10 to 50 mg/kg body weight. Management of CBD therapy in regard of monitoring side effects and adjusting concomitant therapy differs widely amongst participants. Their primary objective for commencing CBD is improving patient's quality of life. Participants frequently receive inquiries about CBD treatment but only 40% may actively suggest CBD as a treatment option. Of the 85 participants currently not using CBD for epilepsy treatment, 70% would consider using CBD if available in their country of practice or given the opportunity to become familiar with this treatment option.Conclusions: CBD is increasingly used by participating physicians but individual experience remains limited. There are very diverse opinions about the use of CBD to treat epilepsy in children and adolescents and widely differing views on how to manage the CBD treatment

Improving the ripple classification in focal pediatric epilepsy: identifying pathological high-frequency oscillations by Gaussian mixture model clustering

Objective: High-frequency oscillations (HFOs) have emerged as a promising clinical biomarker for presurgical evaluation in childhood epilepsy. HFOs are commonly classified in stereo-encephalography as ripples (80–200 Hz) and fast ripples (200–500 Hz). Ripples are less specific and not so directly associated with epileptogenic activity because of their physiological and pathological origin. The aim of this paper is to distinguish HFOs in the ripple band and to improve the evaluation of the epileptogenic zone (EZ). Approach: This study constitutes a novel modeling approach evaluated in ten patients from Sant Joan de Deu Pediatric Hospital (Barcelona, Spain), with clearly-defined seizure onset zones (SOZ) during presurgical evaluation. A subject-by-subject basis analysis is proposed: a probabilistic Gaussian mixture model (GMM) based on the combination of specific ripple features is applied for estimating physiological and pathological ripple subpopulations. Main Results: Clear pathological and physiological ripples are identified. Features differ considerably among patients showing within-subject variability, suggesting that individual models are more appropriate than a traditional whole-population approach. The difference in rates inside and outside the SOZ for pathological ripples is significantly higher than when considering all the ripples. These significant differences also appear in signal segments without epileptiform activity. Pathological ripple rates show a sharp decline from SOZ to non-SOZ contacts and a gradual decrease with distance. Significance: This novel individual GMM approach improves ripple classification and helps to refine the delineation of the EZ, as well as being appropriate to investigate the interaction of epileptogenic and propagation networks.This work was supported by Ministry of Science and Innovation (MICIIN), Spain, under Contract PID2020-117751RB-I00.Peer ReviewedPostprint (published version

SGM: a novel time-frequency algorithm based on unsupervised learning improves high-frequency oscillation detection in epilepsy

Objective. We propose a novel automated method called the S-Transform Gaussian Mixture detection algorithm (SGM) to detect high-frequency oscillations (HFO) combining the strengths of different families of previously published detectors. Approach. This algorithm does not depend on parameter tuning on a subject (or database) basis, uses time-frequency characteristics, and relies on non-supervised classification to determine if the events standing out from the baseline activity are HFO or not. SGM consists of three steps: the first stage computes the signal baseline using the entropy of the autocorrelation; the second uses the S-Transform to obtain several time-frequency features (area, entropy, and time and frequency widths); and in the third stage Gaussian mixture models cluster time-frequency features to decide if events correspond to HFO-like activity. To validate the SGM algorithm we tested its performance in simulated and real environments. Main results. We assessed the algorithm on a publicly available simulated stereoelectroencephalographic (SEEG) database with varying signal-to-noise ratios (SNR), obtaining very good results for medium and high SNR signals. We further tested the SGM algorithm on real signals from patients with focal epilepsy, in which HFO detection was performed visually by experts, yielding a high agreement between experts and SGM. Significance. The SGM algorithm displayed proper performance in simulated and real environments and therefore can be used for non-supervised detection of HFO. This non-supervised algorithm does not require previous labelling by experts or parameter adjustment depending on the subject or database considered. SGM is not a computationally intensive algorithm, making it suitable to detect and characterize HFO in long-term SEEG recordings.Peer ReviewedPostprint (published version

Altered brain rhythms and functional network disruptions involved in patients with generalized fixation-off epilepsy

Fixation-off sensitivity (FOS) denotes the forms of epilepsy elicited by elimination of fixation. FOS-IGE patients are rare cases [1]. In a previous work [2] we showed that two FOS-IGE patients had different altered EEG rhythms when closing eyes; only beta band was altered in patient 1 while theta, alpha and beta were altered in patient 2. In the present work, we explain the relationship between the altered brain rhythms in these patients and the disruption in functional brain networks

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease. Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.info:eu-repo/semantics/publishedVersio

Clinical Perspectives on Using Remote Measurement Technology in Assessing Epilepsy, Multiple Sclerosis, and Depression: Delphi Study

Background: Multiple sclerosis (MS), epilepsy, and depression are chronic central nervous system conditions in which remote measurement technology (RMT) may offer benefits compared with usual assessment. We previously worked with clinicians, patients, and researchers to develop 13 use cases for RMT: 5 in epilepsy (seizure alert, seizure counting, risk scoring, triage support, and trend analysis), 3 in MS (detecting silent progression, detecting depression in MS, and donating data to a biobank), and 5 in depression (detecting trends, reviewing treatment, self-management, comorbid monitoring, and carer alert). Objective: In this study, we aimed to evaluate the use cases and related implementation issues with an expert panel of clinicians external to our project consortium. Methods: We used a Delphi exercise to validate the use cases and suggest a prioritization among them and to ascertain the importance of a variety of implementation issues related to RMT. The expert panel included clinicians from across Europe who were external to the project consortium. The study had 2 survey rounds (n=23 and n=17) and a follow-up interview round (n=9). Data were analyzed for consensus between participants and for stability between survey rounds. The interviews explored the reasons for answers given in the survey. Results: The findings showed high stability between rounds on questions related to specific use cases but lower stability on questions relating to wider issues around the implementation of RMT. Overall, questions on wider issues also had less consensus. All 5 use cases for epilepsy (seizure alert, seizure counting, risk scoring, triage support, and trend analysis) were considered beneficial, with consensus among participants above the a priori threshold for most questions, although use case 3 (risk scoring) was considered less likely to facilitate or catalyze care. There was very little consensus on the benefits of the use cases in MS, although this may have resulted from a higher dropout rate of MS clinicians (50%). Participants agreed that there would be benefits for all 5 of the depression use cases, although fewer questions on use case 4 (triage support) reached consensus agreement than for depression use cases 1 (detecting trends), 2 (reviewing treatment), 3 (self-management), and 5 (carer alert). The qualitative analysis revealed further insights into each use case and generated 8 themes on practical issues related to implementation. Conclusions: Overall, these findings inform the prioritization of use cases for RMT that could be developed in future work, which may include clinical trials, cost-effectiveness studies, and the commercial development of RMT products and services. Priorities for further development include the use of RMT to provide more accurate records of symptoms and treatment response than is currently possible and to provide data that could help inform patient triage and generate timely alerts for patients and carers

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Neurodevelopmental problems of unaccompanied refugee and migrant children: a new challenge for pediatric neurologists

International audienc

Kallosotomien bei Sturzanfällen und epileptischen Spasmen

<jats:title>Zusammenfassung</jats:title><jats:p>Die Kallosotomie ist eine palliative Operation, die seit fast 80 Jahren bei Patienten mit therapierefraktären, bilateralen Anfällen eingesetzt wird, wenn ein resektives Verfahren nicht möglich ist. Neuere, minimal-invasive Techniken wie die MRT-gesteuerte laserinduzierte Thermokoagulation sind vermutlich vergleichbar bezüglich Outcome und Komplikationsraten, die Datenlage ist aber insgesamt noch spärlich. In vielen Fallserien war die Kallosotomie v. a. in der Reduktion von Sturzanfällen effektiv, in geringerem Ausmaß auch für epileptische Spasmen. Eine vollständige Anfallsfreiheit wird nur sehr selten erreicht. Chirurgische Komplikationen wie Blutungen oder Infektionen treten in etwa 5 % auf. Die wichtigste, jedoch sehr seltene Nebenwirkung der Kallosotomie ist ein Diskonnektionssyndrom mit Apraxie, taktiler und visueller Anomie, Neglect oder SMA(supplementär-motorisches Areal)-Syndrom. Besonders bei Kindern ist das Diskonnektionssyndrom in aller Regel transient. Ob eine anteriore oder eine komplette Kallosotomie durchgeführt wird, variiert von Zentrum zu Zentrum. Komplette Kallosotomien sind hinsichtlich der Anfallsreduktion effizienter, gehen aber mit einem höheren Risiko für Komplikationen und Nebenwirkungen einher. Eine Option ist eine zweistufige Kallosotomie, bei der zunächst eine anteriore Diskonnektion durchgeführt wird und in den Fällen ohne hinreichenden postoperativen Nutzen in einem zweiten Schritt vervollständigt wird.</jats:p&gt