Modulation of human corticospinal excitability by paired associative stimulation in patients with amyotrophic lateral sclerosis and effects of Riluzole

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes an impairment in both the upper and lower motor neurons. The recent description of numerous non-motor signs points to an involvement of the neocortex networks that is more complex than was previously believed. Paired associative stimulation (PAS), a combination of transcranial magnetic stimulation (TMS) and peripheral nerve stimulation, can enhance motor output in the contralateral hand through an NMDA-mediated sensorimotor mechanism. OBJECTIVE To describe the effects of PAS on ALS patients before and after Riluzole intake compared with healthy subjects. METHODS PAS was used to detect differences between 24 newly-diagnosed ALS patients and 25 age-matched healthy controls. MEP amplitude from the abductor pollicis brevis was considered before PAS, immediately after (T0) and after 10 (T10), 20 (T20), 30 (T30) and 60 (T60) minutes. Statistical significance was calculated using RM-ANOVA. RESULTS In healthy controls, PAS significantly increased MEP amplitude at T10, T20 and T30 (p < 0.05). In ALS patients, a significant increase in MEP amplitude was also observed after 60 min (p < 0.05), thus demonstrating NMDA-mediated enhanced facilitatory plasticity. After two weeks of riluzole intake, no MEP amplitude increase was evident after PAS at any time point. In three monomelic-onset ALS patients, sensorimotor facilitation was evident only in the hemisphere corresponding to the affected side and appeared in the opposite hemisphere when the patients manifested contralateral symptoms. CONCLUSIONS PAS may be considered a useful tool when investigating NMDA-mediated neocortical networks in ALS patients and the modulation of such networks after anti-glutamatergic drug intake

The Compound Muscle Action Potential as Neurophysiological Marker for Amyotrophic Lateral Sclerosis.

Objectives: To definite the peripheral nervous involvement in ALS through the repeated use of the compound motor action potential (CMAP) to test the progression of disease, to determine different change of phrenic CMAP and forced vital capacity (FVC) in spinal and bulbar onset, and to establish clinical and neurophysiological features of patients with poor prognosis. Material &amp; Methods: CMAP from phrenic, ulnar, and medial plantar nerves, Medical Research Council (MRC) score, revised ALS functional rating scale (ALSFRS-R) and FVC were evaluated in 117 ALS patients every three months in one year-period. Results: Bulbar onset patients had lower FVC but similar amplitude of phrenic CMAP at baseline compared to spinal onset patients. The patients with poor prognosis had lower phrenic CMAP and FVC at baseline. CMAP values, when compared to the rate found in the previous visit, reduced significantly in both poor and good prognosis groups during the entire follow-up period, while the FVC reduced significantly only in the first three months. Conclusions: CMAP is a reproducible sensitive marker for motor neurons loss and collateral reinnervation in ALS also in a short period of time. The changes in CMAP, MRC, FVC and ALSFRS-R score resulted correlated, but CMAP is the only parameter with the advantage to demonstrate objectively the progression of disease in both patients with poor and good prognosis for the entire period of follow-up. It should be used as clinical outcome of ALS in clinical trials, taking advantage of its objectivity and selectivity for peripheral nervous system study

Whole exome sequencing in an Italian family with isolated maxillary canine agenesis and canine eruption anomalies

Objective: The aim of this study was the clinical and molecular characterization of a family segregating a trait consisting of a phenotype specifically involving the maxillary canines, including agenesis, impaction and ectopic eruption, characterized by incomplete penetrance and variable expressivity. Design: Clinical standardized assessment of 14 family members and a whole-exome sequencing (WES) of three affected subjects were performed. WES data analyses (sequence alignment, variant calling, annotation and prioritization) were carried out using an in-house implemented pipeline. Variant filtering retained coding and splice-site high quality private and rare variants. Variant prioritization was performed taking into account both the disruptive impact and the biological relevance of individual variants and genes. Sanger sequencing was performed to validate the variants of interest and to carry out segregation analysis. Results: Prioritization of variants “by function” allowed the identification of multiple variants contributing to the trait, including two concomitant heterozygous variants in EDARADD (c.308C&gt;T, p.Ser103Phe) and COL5A1 (c.1588G&gt;A, p.Gly530Ser), specifically associated with a more severe phenotype (i.e. canine agenesis). Differently, heterozygous variants in genes encoding proteins with a role in the WNT pathway were shared by subjects showing a phenotype of impacted/ectopic erupted canines. Conclusions: This study characterized the genetic contribution underlying a complex trait consisting of isolated canine anomalies in a medium-sized family, highlighting the role of WNT and EDA cell signaling pathways in tooth development

Partial block by riluzole of muscle sodium channels in myotubes from amyotrophic lateral sclerosis patients.

International audienceDenervated muscles undergo fibrillations due to spontaneous activation of voltage-gated sodium (Na(+)) channels generating action potentials. Fibrillations also occur in patients with amyotrophic lateral sclerosis (ALS). Riluzole, the only approved drug for ALS treatment, blocks voltage-gated Na(+) channels, but its effects on muscle Na(+) channels and fibrillations are yet poorly characterized. Using patch-clamp technique, we studied riluzole effect on Na(+) channels in cultured myotubes from ALS patients. Needle electromyography was used to study fibrillation potentials (Fibs) in ALS patients during riluzole treatment and after one week of suspension. Patients were clinically characterized in all recording sessions. In myotubes, riluzole (1 μM, a therapeutic concentration) reduced Na(+) current by 20%. The rate of rise and amplitude of spikes evoked by depolarizing stimuli were also reduced. Fibs were detected in all patients tested during riluzole treatment and riluzole washout had no univocal effect. Our study indicates that, in human myotubes, riluzole partially blocks Na(+) currents and affects action potentials but does not prevent firing. In line with this in vitro finding, muscle Fibs in ALS patients appear to be largely unaffected by riluzole

Neurophysiological and clinical biomarkers of secondary progressive multiple sclerosis: A cross-sectional study

Timely diagnosis of secondary progressive multiple sclerosis (SPMS) represents a clinical challenge. The Frailty Index, a quantitative frailty measure, and the Neurophysiological Index, a combined measure of sensorimotor cortex inhibitory mechanism parameters, have recently emerged as promising tools to support SPMS diagnosis. The aim of this study was to explore the possible relationship between these two indices in MS. MS participants underwent a clinical evaluation, Frailty Index administration, and neurophysiological assessment. Frailty and Neurophysiological Index scores were found to be higher in SPMS and correlated with each other, thus suggesting that they may capture similar SPMS-related pathophysiological mechanisms

Controversies in the surgical management of thyroid follicular neoplasms. Retrospective analysis of 721 patients

n/

Somatic mosaicism represents an underestimated event underlying collagen 6-related disorders

Background: Collagen VI-related disorders (COL6-RD) are a group of heterogenous muscular diseases due to mutations in the COL6A1, COL6A2 and COL6A3 genes, encoding for collagen VI, a critical component of the extracellular matrix. Ullrich congenital muscle disorder and Bethlem myopathy represent the ends of a clinical spectrum that includes intermediate phenotypes of variable severity. UCMD are caused by recessive loss of function mutations or de-novo dominant-negative mutations. The intermediate phenotype and BM are more commonly caused by dominantly acting mutations, and less commonly by recessive mutations. Recently parental mosaicism for dominant mutations in COL6 have been reported in four COL6-RD families and germinal mosaicism has been also identified in a family with recurrence of UCMD in two half-sibs. Methods and results: Here we report three unrelated patients affected by a COL6-RD who carried de novo mosaic mutations in COL6A genes. These mutations, missed by Sanger sequencing, were identified by next generation sequencing. Conclusions: This report highlights the importance of a complete diagnostic workup when clinical and histological finding are consistent with a COL6-RD and strengthen the impression that mosaicisms are underestimated events underlying COL6-RD. (C) 2017 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.Peer reviewe

Role of prophylactic central compartment lymph node dissection in clinically N0 differentiated thyroid cancer patients: Analysis of risk factors and review of modern trends

In the last years, especially thanks to a large diffusion of ultrasound-guided FNBs, a surprising increased incidence of differentiated thyroid cancer (DTC), "small" tumors and microcarcinomas have been reported in the international series. This led endocrinologists and surgeons to search for "tailored" and "less aggressive" therapeutic protocols avoiding risky morbidity and useless "overtreatment". Considering the most recent guidelines of referral endocrine societies, we analyzed the role of routine or so-called prophylactic central compartment lymph node dissection (RCLD), also considering its benefits and risks. Literature data showed that the debate is still open and the surgeons are divided between proponents and opponents of its use. Even if lymph node metastases are commonly observed, and in up to 90 % of DTC cases micrometastases are reported, the impact of lymphatic involvement on long-term survival is subject to intensive research and the best indications of lymph node dissection are still controversial. Identification of prognostic factors for central compartment metastases could assist surgeons in determining whether to perform RLCD. Considering available evidence, a general agreement to definitely reserve RCLD to "high-risk" cases was observed. More clinical researches, in order to identify risk factors of meaningful predictive power and prospective long-term randomized trials, should be useful to validate this selective approach