Pharmacotherapy for Dravet Syndrome: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Background: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs). Objective: The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA). Methods: Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework. Results: Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol (n = 2), pharmaceutical-grade cannabidiol (n = 3), fenfluramine hydrochloride (n = 2), and soticlestat (n = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07–0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57–76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04–5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06–0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59–1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS. Conclusions: There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles

DBMI04, il database delle osservazioni macrosismiche dei terremoti italiani utilizzate per la compilazione del catalogo parametrico CPTI04

This paper describes the main features of the Macroseismic Database of Italy 2004, which for the first time put together in a critical way the macroseismic data used for the compilation of the CPTI04 (2004) parametric earthquake catalogue. Data come from varied main datasets: i) DOM4.1 (Monachesi e Stucchi, 1997); ii) CFTI version 2 (Boschi et al., 1997) and, for the time-window 1980-2002, CFTI version 3 (Boschi et al., 2000); iii) Bollettino Macrosismico ING (BMING); iv) Catalogo Macrosismico dei Terremoti Etnei, Azzaro et al. (2000; 2002). In addition, data from recent historical and field investigation were also used. DBMI04 contains 58146 macroseismic observations related to 1041 earthquakes and 14161 localities, 12943 of which in Italy. The input data used for the compilation of DBMI04 were not homogeneous with respect to the use of the intensity scale and, mainly, to geographical reference. One of the main task was the organisation of a reliable geographical reference, based on the previous ENEL-ISTAT catalogue of the Italian localities (ENEL, 1978), which was updated by means of new data. Another task consisted in correcting some mistakes performed when associating the placenames quoted by the historical sources and the geographical reference. Some problems were solved using ad hoc conventions for dealing with observations not expressed in terms of macroseismic intensity. This paper presents the adopted solutions and the results, together with the web-interface through which the database is made available to the public (http://emidius.mi.ingv.it/DBMI04/)

Interseismic ground velocities in Central Apennines from GPS and InSAR measurements: new contributions for seismic hazard models by preliminary results of ESA CHARMING project

The contribution of space geodetic techniques to interseismic velocity estimation, and thus seismic hazard modelling, has been recognized since two decades and made possible in more recent years by the increased availability and accuracy of geodetic measurements. We present the preliminary results of a feasibility study performed within the CHARMING project (Constraining Seismic Hazard Models with InSAR and GPS), funded by the European Space Agency (ESA). For a 200 km x 200 km study area, covering the Abruzzi region (central Italy) we measure the mean surface deformation rates from Synthetic Aperture Radar and GPS, finding several local to regional deformation gradients consistent with the tectonic context. We then use a kinematic finite element model to derive the long-term strain rates, as well as earthquake recurrence relations. In turn these are input to state-of-the-art probabilistic seismic hazard models, the output of which is validated statistically using data from the Italian national accelerometric and macroseismic intensity databases.Published373-3773T. Pericolosità sismica e contributo alla definizione del rischioN/A or not JCRope

Mid-term review results of the ESA STSE Pathfinder CHARMING project (Constraining Seismic Hazard Models with InSAR and GPS)

We probe the feasibility of integrating GPS and Synthetic Aperture Radar deformation rates within the seismic hazard models of the central Apennines (Italy), exploiting data from over 100 GPS stations and the ~20- year long ERS and ENVISAT SAR image archive. We then use a kinematic finite element model to derive the long-term strain rates, as well as earthquake recurrence relations. In turn these are input to state-of-the-art probabilistic seismic hazard models, the output of which is validated statistically using data from the Italian national accelerometric and macroseismic intensity databases.Published23-273T. Pericolosità sismica e contributo alla definizione del rischioN/A or not JCRrestricte

Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies

Objective: We investigated the contribution to sporadic focal epilepsies (FE) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (mTOR)complex 1 (mTORC1). Methods: We collected genetic data of 121 Italian isolated FE cases and 512 controls by Whole Exome Sequencing (WES) and single-molecule Molecular Inversion Probes (smMIPs) targeting 10 genes of the GATOR1, GATOR2, and TSC complexes. We collapsed \u201cqualifying\u201d variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls. Results: We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients (P = 0.006; exact unconditional test, one-tailed). Pathogenic variants were identified in DEPDC5 and TSC2, both major genes for Mendelian FE syndromes. Interpretation: Our findings support the contribution of ultrarare variants in genes in the mTOR pathway complexes GATOR and TSC to the risk of sporadic FE and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause