Promising Disease Markers in Amyotrophic Lateral Sclerosis

Marisa DeNoble Loeffler, MS, for Medscape

February 23, 2022

The study covered in this summary was published on as a preprint and has not yet been peer reviewed.

Key Takeaways

  • Seven nerve excitability indices distinguish patients with amyotrophic lateral sclerosis (ALS) from healthy controls.

  • Four indices may be biomarkers of early stage ALS.

Why This Matters

  • There is no diagnostic test for ALS, and the clinical presentation of ALS differs greatly among patients.

  • Biomarkers for ALS would enhance the diagnosis and monitoring of disease and aid in the development of new therapies.

Study Design

  • Following a study search that concluded on March 12, 2020, researchers conducted a systematic review and meta-analysis of nerve excitability studies that compared ALS patients with healthy controls.

  • From among 2866 screened articles, 26 studies (representing 942 patients and 719 controls) were systematically reviewed, and 23 of these studies were used in the meta-analysis.

  • The review and meta-analysis were performed according to the Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies Guidelines and the Cochrane Handbook for Diagnostic Test Accuracy.

  • The purpose of the meta-analysis was to identify excitability indices capable of differentiating between ALS patients and healthy controls, to quantify the reliability of these indices and the magnitude of their between-group differences, and to determine whether these indices could be applied to studies of early        stage ALS.

Key Results

  • The following seven indices were identified as possible biomarkers of ALS, having each demonstrated a significant pooled effect (determined by z-test, P < .05), low-to-moderate heterogeneity among studies (I2 < 40%), and a predefined between-group effect size difference (Cohen's d > 0.2): depolarizing threshold electrotonus (TEd) 90 ms to 100 ms, TEd 40 ms to 60 ms, strength-duration time constant, superexcitability, subexcitability, resting I/V slope, and 50% depolarizing.

  • Sensitivity analysis showed that the TEd 10 ms to 20 ms, TEd 90 ms to 100 ms, strength-duration time constant, and superexcitability indices were able to differentiate patients with ALS from healthy controls before the patients' compound muscle action potential had begun to decline.


  • A dearth of disease controls makes it difficult to determine whether the excitability indices identified by this meta-analysis are biomarkers of ALS or are simply indicators of axonal disease. Future studies should include disease controls.

  • Current literature exhibits a preferential reporting of measures that successfully distinguish between patients with ALS and healthy controls. Future analyses would benefit from less biased data sharing.

  • In the current meta-analysis, it was not possible to correct for the redundant reporting of some patients' data among multiple studies by the same authors. Such redundant reporting was rare and likely of minimal effect on the results.

  • Future, longitudinal studies would complement the current analysis, which was restricted to cross-sectional studies of axon excitability.


  • This work was funded by the Natural Sciences and Engineering Research Council of Canada, which had no other role in the conduct or reporting of the study.

  • No competing interests were reported by any of the authors.

This is a summary of a preprint research study, "Nerve Excitability as a Biomarker for Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-analysis," written by Anna Lugg from the University of Alberta, Edmonton, Alberta, Canada, and colleagues on provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.