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

  • Author / Creator
    Lugg, Anna
  • Background: Amyotrophic lateral sclerosis (ALS), like many neurodegenerative conditions, lacks definitive biomarkers for disease diagnosis, prognosis, staging and measurement of response to therapy. The Nerve Excitability Test (NET) is a suite of electrophysiological measurements that generates >30 excitability indices that characterize the electrical health of myelinated axons. The International Federation of Clinical Neurophysiology recently published consensus guidelines for the NET and advocated the use of NET as a biomarker of lower motor neuron pathology in ALS. While many primary studies have indicated pathophysiological changes in sodium and potassium channels in ALS using the NET, only narrative reviews and qualitative synthesis are currently available. A systematic review with meta-analysis was needed to consolidate the evidence for use of the excitability indices generated by NET as potential biomarkers for ALS.

    Objective: The objective was to determine which of the excitability indices were potential biomarkers that could distinguish between people diagnosed with ALS and healthy controls. A second objective was to determine if potential excitability biomarkers changed when analyzing a subset of the data from people at an earlier stage of ALS.

    Methods: Potential studies were identified by systematically searching the following databases: MEDLINE, PubMed Central, CINAHL Plus, EMBASE, HealthSTAR, Scopus, and Web of Science. Screening, full-text review, quality assessment, and data extraction were performed by two independent review authors, with conflicts resolved by a third independent author, using Covidence. Data were exported from Covidence to RevMan 5.4 for Forest Plot analysis. Only studies performed in human participants and assessing median motor axons were included.

    Results: After removal of duplicates, 2866 articles were screened, and full-text eligibility was assessed for 43 articles. 26 articles fitting the criteria for the systematic review were included, 23 of which were included in the meta-analysis. Ten axonal excitability indices had significant pooled effect (Z ranging from 9.88 to 2.81, in descending rank order): TEd 90-100 ms, strength-duration time constant (SDTC), superexcitability, maximum CMAP, TEd 40-60 ms, TEd 10-20 ms, resting I/V slope, 50% depolarizing, subexcitability, and rheobase. Six indices did not discriminate between ALS patients and healthy controls: TEh 90-100 ms, 100% hyperpolarizing, hyperpolarizing I/V slope, relative refractory period, refractoriness, and TEh 10-20 ms. A sensitivity analysis comparing patients with ‘early’ ALS and healthy controls indicated that four measures 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.

    Conclusion: Ten excitability indices clearly differentiate ALS patients from healthy controls, four of which may serve as early biomarkers for ALS. The candidate biomarker indices 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 for routine clinical evaluation in individuals suspected of an ALS diagnosis.

  • Subjects / Keywords
  • Graduation date
    Fall 2021
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.