De novo ARHGEF9 missense variants associated with neurodevelopmental disorder in females: expanding the genotypic and phenotypic spectrum of ARHGEF9 disease in females.

Individuals harboring pathogenic variants in ARHGEF9, encoding an essential submembrane protein for gamma-aminobutyric acid (GABA)-ergic synapses named collybistin, show intellectual disability (ID), facial dysmorphism, behavioral disorders, and epilepsy. Only few affected females carrying large chromosomal rearrangements involving ARHGEF9 have been reported so far. Through next-generation sequencing (NGS)-based panels, we identified two single nucleotide variants (SNVs) in ARHGEF9 in two females with neurodevelopmental features. Sanger sequencing revealed that these variants were de novo. The X-inactivation pattern in peripheral blood cells was random. We report the first affected females harboring de novo SNVs in ARHGEF9, expanding the genotypic and phenotypic spectrum of ARHGEF9-related neurodevelopmental disorder in females.

Eslicarbazepine Acetate Modulates EEG Activity and Connectivity in Focal Epilepsy.

Introduction: Eslicarbazepine acetate (ESL) is an antiepileptic drug approved as monotherapy or add-on for the treatment of epilepsy with seizures of focal onset. ESL owns a good profile in terms of efficacy and tolerability, but its effects on EEG activity and connectivity are unknown. The purpose of this study was to investigate EEG activity and connectivity changes after ESL treatment in persons with focal epilepsy (PFE). Material and Methods: We performed a multicentre, longitudinal, retrospective, quantitative EEG study on a population of 22 PFE, and a group of 40 controls. We investigated the ESL-related changes of EEG power spectral activity and global connectivity [phase locking value (PLV), amplitude envelope correlation (AEC) and amplitude envelope correlation of orthogonalized signals (Ortho-AEC)] for standard frequency bands (delta to gamma). Seizure frequency was evaluated to assess ESL efficacy in our cohort. Results: ESL significantly enhanced both global power spectral density and connectivity for all frequency bands, similarly for all connectivity measures. When compared to the control group, Post-ESL power was significantly higher in theta and gamma band. Pre-ESL connectivity values were significantly lower than control for all frequency bands. Post-ESL connectivity increased and the gap between the two groups was no longer significant. ESL induced a 52.7 ± 41.1% reduction of seizure frequency, with 55% of clinical responders (reduction of seizures ≥50%). Discussion: ESL therapy induces significant enhancement of brain activity and connectivity. Post-ESL connectivity profile of epilepsy patients was similar to the one of healthy controls.

Effects of eslicarbazepine acetate on lipid profile and sodium levels in patients with epilepsy.

PURPOSE: Several studies have demonstrated that treatment with enzyme-inducing antiepileptic drugs is associated with increased serum lipid levels. Eslicarbazepine acetate (ESL) is a novel antiepileptic drug specifically designed with the objective to identify carbamazepine and oxcarbazepine analogues with favorable pharmacodynamic and pharmacokinetic profiles. The present study aimed to assess the changes in lipid profile and sodium levels in patients with epilepsy taking ESL as adjunctive therapy. METHOD: This report describes a retrospective cohort study of 36 adult patients with epilepsy, taking ESL as an add-on treatment. The laboratory values assessed prior and after (range 6-18 months) ESL treatment were sodium levels, total cholesterol (TC), low (LDL) and high (HDL) density lipoproteins and triglycerides. RESULTS: TC and LDL values were significantly decreased already after at least six months of therapy with ESL (191.3±29.6 vs 179.7±29.2mg/dl, p <0.0001 and 114.58±22.7 vs 103.11±19.46mg/dl, p <0.0001 respectively). HDL values before and during ESL treatment were significantly increased (57.5± 9.1 vs 63.9±8.3mg/dl; p<0.0001). No statistically significant changes have been found in triglycerides and sodium values. CONCLUSIONS: Add-on therapy with ESL, in contrast to the negative effects observed with traditional older carboxamides, positively affects lipid metabolism profile in patients with epilepsy over an average follow-up of 11 months. Further research is needed to confirm the obtained results with a focus on a comprehensive assessment of the biochemical and molecular mechanisms involved.

Effects of a selective serotonin reuptake inhibitor escitalopram on the cutaneous silent period: a randomized controlled study in healthy volunteers.

The cutaneous silent period (CSP) involves a transient inhibition of the electromyographic (EMG) activity in the hand muscles induced by a painful electrical stimulation of the digital nerves. The neurotransmitters potentially involved in mediating the CSP have not been completely elucidated thus far. However, few studies suggest that the monoaminergic system may play a role in the CSP. We elicited CSPs in the first dorsal interosseous muscle of the right hand before and 3h after administration of a single oral dose of the selective serotonin reuptake inhibitor escitalopram (20mg) or placebo. The two experimental sessions (drug and placebo) were performed in a random order at ≥1-week intervals. All recordings were numbered anonymously and analysed offline in a blind manner by one investigator. A significant increase in the CSP duration was observed 3h after escitalopram administration (p=0.01), and no changes were observed in the reflex latency and subjective pain sensation (p>0.05). No significant changes were observed in the CSP duration in subjects who received the placebo (all, p>0.05). Our results indicate that escitalopram increases the central disposition of serotonin and increases the activity of the spinal inhibitory interneurons on the α-motoneurons of the hand muscles. Thus, our results indicate the involvement of the monoaminergic system in controlling the spinal pain mechanisms by supraspinal descending pathways originating from the brainstem neural structures.

3T diffusion tensor imaging and electroneurography of peripheral nerve: a morphofunctional analysis in carpal tunnel syndrome.

OBJECTIVE: The aim of the study was to assess the diagnostic potential of diffusion tensor imaging (DTI) for pathologies of the peripheral nervous system (PNS) through clinical, electrophysiological and morphological evaluation of the median nerve. METHODS: The present work was a multilevel prospective study involving 30 subjects, 15 of whom had carpal tunnel syndrome (CTS) and 15 healthy controls. All subjects underwent clinical evaluation through administration of the Boston Carpal Tunnel Questionnaire (BCTQ), electroneurography (ENG), 3-Tesla magnetic resonance imaging with DTI, and calculation of fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) at the flexor retinaculum. Tractography was also performed for three-dimensional reconstruction of the route of the median nerve through the carpal tunnel. The degree of functional impairment was compared with the anatomical damage to the median nerve according to ENG and DTI. RESULTS: FA and ADC were significantly correlated with ENG parameters of CTS and BCTQ data. Mean FA and ADC values in the CTS patients were 0.359±0.06 and 1.866±0.050×10(-3)mm(2)/s, respectively, vs 0.59±0.014 and 1.395±0.035×10(-3)mm(2)/s, respectively, in the controls. FA was decreased and ADC increased in patients with CTS compared with healthy controls (P<0.05). CONCLUSION: DTI parameters were clearly confirmed by both clinical and ENG data and, therefore, may be used for the diagnosis of CTS.

Cutaneous silent period in hand muscles is lengthened by tramadol: Evidence for monoaminergic modulation?

The purpose of this study was to shed light on the neurochemical modulatory mechanisms of the noxious spinal inhibitory cutaneous silent period (CSP). We study the effects of 100mg of oral tramadol in 11 healthy volunteers. Tramadol has low affinity for opioid receptors and has the ability to inhibit serotonin and noradrenaline reuptake. We elicited CSPs in the first dorsal interosseus muscle and noxious withdrawal flexor reflexes (NWR) in the right biceps femoris muscle before, 30 min and each hour up to the 6th after tramadol. Subjective pain sensation was checked on an 11-point numerical scale. Tramadol increased duration of CSP, and reduced the NWR area under the curve maximally 2h after tramadol and paralleled the reduction of subjective pain perception. We suggest that the monoaminergic action of tramadol reinforces the activity of spinal inhibitory interneurons on α-motoneurons for the hand muscles.