Progressive arm muscle weakness in ALS follows the same sequence regardless of onset site: use of TOMS, a novel analytic method to track limb strength

Abstract

Objective: Examine sequence of weakness in arm muscles from longitudinal hand-held dynamometry (HHD) data in ALS for congruence with contiguous spread of neurodegeneration along spinal cord segments. Methods: Longitudinal HHD data from the Ceftriaxone clinical trial were examined using nonlinear mixed models, assuming a logistic trajectory from normal to zero strength. Unobserved baseline normal strength of weak muscles was assumed using strength of the best-preserved muscle. A novel metric called “time from onset to midway strength” (TOMS) was estimated for each muscle group, and TOMS ratios were examined to identify sequence of weakness, overall and by onset site. Results: Shoulder flexion (SF), elbow flexion (EF), elbow extension (EE), wrist extension (WE), and first dorsal interosseous (FDI) were measured on each side. Over a median of 36 weeks, 513 subjects provided 2589 sets of HHD measures. TOMS increased sequentially in the following order: FDI, WE, SF, EF, and EE. TOMS ratios estimates with 95% CIs (adjusted for multiple comparisons) were: WE/FDI 1.32 (1.24–1.41), SF/WE 1.06 (1.01–1.10), EF/SF 1.06 (1.02–1.10), and EE/EF 1.18 (1.12–1.23). Elbow and shoulder flexors weakened sooner than did elbow extensors. The sequence of arm muscle weakness progression was similar regardless of onset site. Conclusion: Nonsegmental progression of arm muscle weakness that is similar for different onset sites favors cortical influence/network spread over contiguous spread of neurodegeneration in the spinal cord. Furthermore, this study confirms the “split elbow” pattern. TOMS and other proposed methods may have value as outcome measures in clinical research.

Keywords:

• Muscle strength
• hand-held dynamometry
• dissociated muscle atrophy
• non-linear mixed models

Acknowledgements

The authors thank Northeast ALS Consortium (NEALS), NCRI at Massachusetts General Hospital, Professor David Schoenfeld and Dr. Hong Yu for providing clinical trial data that we have used in this study. We are indebted to Professor Richard Bohannon for insights into HHD and muscle strength correlations. We would also like to thank the Neurological Institute Center for Outcomes, Research and Evaluation (NI-CORE) and Quantitative Health Sciences (QHS) at Cleveland Clinic for supporting this effort.

Ethics approval and patient consent

None sought for analysis of a de-identified dataset.

Declaration of interest

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was not supported by any external or internal grant. NJT has received research support from Novartis Pharmaceuticals Corp. for unrelated work. BJD was supported by NIH Award No. R01-EB014877. BRL has received research support from Novartis Pharmaceuticals Corp., Teva Pharmaceuticals USA, Inc., and PhRMA Foundation for unrelated work. EPP is holder of the Barry Winovich (Bright Side of the Road Foundation) Chair in ALS Research, receives support from the Samuel J. and Connie M. Frankino Charitable Foundation, and clinical trial and research funding from NIH/CDC and the ALS Association.