Nerve excitability as a biomarker for amyotrophic lateral sclerosis: a systematic review and meta-analysis

Abstract

ABSTRACTObjectiveTo determine which nerve excitability outcome measures are potential biomarkers for ALS via systematic review and meta-analysis.MethodsPotential studies were identified from the following databases: MEDLINE, PubMed Central, CINAHL Plus, EMBASE, HealthSTAR, Scopus, and Web of Science up to March 2020. Only studies performed in human participants and assessing median motor axons were included. Forest Plot analyses using a random-effects model to determine pooled effect (Z-score), heterogeneity (I2) and Cohen’s d were used to identify potential biomarkers.ResultsFrom 2866 studies, 26 (patients=942, controls=719) were used in the systematic review and 23 in the meta-analysis. Seven axonal excitability indices met the three criteria for: significant Z-score, heterogeneity I2<40% and Cohen’s d >0.2 (in descending rank order): TEd 90-100 ms, strength-duration time constant (SDTC), superexcitability, TEd 40-60 ms, resting I/V slope, 50% depolarizing, and subexcitability. A sensitivity analysis restricted to patients with ‘early’ ALS indicated that four indices are potential early biomarkers of ALS (Z ranging from 2.99 to 2.16, in descending rank order): TEd 10-20 ms, TEd 90-100 ms, superexcitability, and SDTC.ConclusionSeven excitability indices differentiate ALS patients from healthy controls, four of which may serve as early biomarkers for ALS. The candidate biomarkers may be used to monitor disease progression, predict survivability, and measure treatment response in clinical trials. High quality diagnostic test accuracy studies are warranted to firmly establish the utility of these indices in individuals suspected of an ALS diagnosis.