Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies: first experiences.

OBJECTIVE: This article aims to report the first clinical experiences concerning effectiveness and tolerability of perampanel (PER) in a pediatric population with refractory epilepsies. PATIENTS AND METHODS: This nonsponsored, observational, retrospective survey was conducted through collaboration with multiple centers in Europe. The clinical course of the first pediatric patients treated in these centers with PER was documented with the help of a questionnaire completed by the treating physicians. Effectiveness and adverse effects were evaluated. The study population consisted of 58 patients (mean age, 10.5 years; range, 2-17 years), suffering from various refractory epilepsies, classified as focal epilepsy (n = 36), unclassified generalized epilepsy (n = 12), Lennox-Gastaut syndrome (n = 5), West syndrome (n = 3), and Dravet syndrome (n = 2). RESULTS: The response rate (≥ 50% seizure reduction) after the first 3 months of therapy was 31% (18/58 patients) in total. Complete seizure control was achieved in five patients (9% overall). Aggravation of seizures occurred in five cases (9%). The most frequently occurring adverse effects were reduced vigilance or fatigue (n = 16) and behavioral changes (n = 14). DISCUSSION: PER seems to be effective also in children and adolescents with pharmaco-refractory epilepsies. Tolerability was acceptable.

Aspiration in children and adolescents with neurogenic dysphagia: comparison of clinical judgment and fiberoptic endoscopic evaluation of swallowing.

A total of 30 children and adolescents with dysphagia due to various chronic neurological disorders were assessed for their risk of aspiration. This assessment was performed clinically by experienced speech and swallowing therapists, and verified thereafter by fiberoptic endoscopy. We found the clinical judgment to be correct in only 70% (for aspiration of saliva), 55% (of puree), and 67% (of thin liquids). We conclude that, because of this unacceptably high error rate of clinical assessment, a fiberoptic evaluation of swallowing is a necessary diagnostic step both for the planning of therapy and for the development of feeding strategies in children and adolescents with neurogenic dysphagia.

Hydrogenases in the "active" state: determination of g-matrix axes and electron spin distribution at the active site by 1H ENDOR spectroscopy.

Hydrons and electrons are substrates for the enzyme hydrogenase, but cannot be observed in X-ray crystal structures. High-resolution 1H electron nuclear double resonance (ENDOR) spectroscopy offers a means to detect the distribution of protons and unpaired electrons. ENDOR spectra were recorded from frozen solutions of the nickel-iron hydrogenases of Desulfovibrio gigas and Desulfomicrobium baculatum, in the "active" state ("Ni-C" EPR signal) and analyzed by orientationally selective simulation methods. The experimental spectra were fitted using a structural model of the nickel-iron centre based on crystallographic results, allowing for differences in electron spin distribution as well as the spatial orientation of the g-matrix ( g-tensor), and anisotropic and isotropic hyperfine couplings of the protons nearest to the nickel ion. ENDOR signals, detected after complete deuterium exchange, were assigned to six protons of the cysteines bound to nickel. The assignment took advantage of the substitution of a selenium for a sulfur ligand, which occurs naturally between the [NiFeSe] and [NiFe] hydrogenases from Dm. baculatum and D. gigas, respectively, and was found to affect just two signals. The four signals with the largest hyperfine couplings, including isotropic contributions from 4.5 to 13.5 MHz, were assigned to the beta-methylene protons of the two terminal cysteine ligands, one of which is substituted by seleno-cysteine in [NiFeSe] hydrogenase. The electron spin is delocalized onto the nickel (50%) and its sulfur ligands, with a higher proportion on the terminal than the bridging ligands. The g-matrix was found to align with the active site in such a way that the g1- g2 plane is nearly coplanar (18.3 degrees) with the plane defined by nickel and three sulfur atoms, and the g2 axis deviates by 22.9 degrees from the vector between nickel and iron. Significantly for the reaction of the enzyme, direct evidence for the binding of hydrons at the active site was obtained by the detection of H/D-exchangeable ENDOR signals.