Neurology November 2012 Volume 79 Issue 22

Objective: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and serve as promising therapeutic targets in many diseases. MiRNAs are also present in biological fluids and may be of use as disease biomarkers. We evaluated whether miRNAs are differentially regulated in the CSF of patients with multiple sclerosis (MS).Methods: The CSF of 53 patients with MS and 39 patients with other neurologic diseases (OND) was analyzed. First, global miRNA profiling was assessed to screen for reported miRNAs, followed by quantitative reverse transcriptase PCR to validate candidate miRNAs.Results: After global miRNA profiling, we quantitatively confirmed miR-922 (p = 0.0001), miR-181c (p = 0.0007), and miR-633 (p = 0.0014) to be differentially regulated in patients with MS as compared with OND. Importantly, miR-181c and miR-633 differentiated relapsing-remitting from secondary progressive MS courses with specificity up to of 82% and a sensitivity of 69%.Conclusion: CSF-based miRNAs were differentially regulated in patients with MS as compared with OND and in different MS disease courses. Despite the preliminary character of our case-control study, the results provide rationale for a confirmation study in larger MS cohorts.(C)2012 American Academy of Neurology

Background: Data on the long-term effect of dexamethasone on survival in bacterial meningitis are lacking.Methods: A long-term follow-up study of the European Dexamethasone in Adulthood Bacterial Meningitis Study was performed. In this double-blind, randomized clinical trial, 301 patients were randomly assigned to receive adjunctive dexamethasone (n = 157) or placebo (n = 144) between June 1993 and December 2001. We obtained survival data of patients using the Dutch Municipal Population Register.Results: Death had occurred in 32 of 301 included patients (11%) at the primary outcome measurement 8 weeks after randomization. Follow-up was obtained for 228 of 246 evaluable patients (93%), with median follow-up of 13 years. Overall, 31 of 144 patients (22%) in the dexamethasone group died and 44 of 134 patients (33%) in the placebo group died (log-rank p = 0.029). After the primary end point of the study at 8 weeks, 20 patients in the dexamethasone group died and 23 patients in the placebo group died (log-rank p = 0.27), with age being the sole predictor of death (p < 0.001).Conclusions: In adults with community-acquired bacterial meningitis, the survival benefit from adjunctive dexamethasone therapy is obtained in the acute phase of the disease and remains for years.Classification of Evidence: This study of a population of Dutch patients shows Class III evidence that dexamethasone provides an extended survival benefit in patients treated for bacterial meningitis, and this survival benefit extends as long as 20 years.(C)2012 American Academy of Neurology

Objectives: Our first objective was to explore the value of estimating 95% confidence intervals (CIs) of epidermal nerve fibers (ENFs)/mm for number of sections to be evaluated and for confidently judging normality or abnormality. Our second objective was to introduce a new continuous measure combining nerve conduction and ENFs/mm.Methods: The 95% CI studies were performed on 1, 1-2, 1-3 - - - 1-10 serial skip sections of 3-mm punch biopsies of leg and thigh of 67 healthy subjects and 23 patients with diabetes mellitus.Results: Variability of differences of ENFs/mm counts (and 95% CIs) from evaluation of 1, 1-2, 1-3 - - - 1-9 compared with 1-10 serial skip sections decreased progressively without a break point with increasing numbers of sections evaluated. Estimating 95% CIs as sections are evaluated can be used to judge how many sections are needed for adequate evaluation, i.e., only a few when counts and 95% CIs are well within the range of normality or abnormality and more when values are borderline. Also provided is a methodology to combine results of nerve conduction and ENFs/mm as continuous measures of normality or abnormality.Conclusion: Estimating 95% CIs of ENFs/mm is useful to judge how many sections should be evaluated to confidently declare counts to be normal or abnormal. Also introduced is a continuous measure of both large-fiber (nerve conduction) and small-fiber (ENFs/mm) normal structures/functions spanning the range of normality and abnormality for use in therapeutic trials.(C)2012 American Academy of Neurology

Objective: To identify the genetic variant that causes autosomal dominantly inherited motor neuron disease in a 4-generation Israeli-Arab family using genetic linkage and whole exome sequencing.Methods: Genetic linkage analysis was performed in this family using Illumina single nucleotide polymorphism chips. Whole exome sequencing was then undertaken on DNA samples from 2 affected family members using an Illumina 2000 HiSeq platform in pursuit of potentially pathogenic genetic variants that comigrate with the disease in this pedigree. Variants meeting these criteria were then screened in all affected individuals.Results: A novel mutation (p.R191G) in the valosin-containing protein (VCP) gene was identified in the index family. Direct sequencing of the VCP gene in a panel of DNA from 274 unrelated individuals with familial amyotrophic lateral sclerosis (FALS) revealed 5 additional mutations. Among them, 2 were previously identified in pedigrees with a constellation of inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) and in FALS, and 2 other mutations (p.R159C and p.R155C) in IBMPFD alone. We did not detect VCP gene mutations in DNA from 178 cases of sporadic amyotrophic lateral sclerosis.Conclusions: We report a novel VCP mutation identified in an amyotrophic lateral sclerosis family (p.R191G) with atypical clinical features. In our experience, VCP mutations arise in approximately 1.5% of FALS cases. Our study supports the view that motor neuron disease is part of the clinical spectrum of VCP-associated disease.(C)2012 American Academy of Neurology