Examine sequence of weakness in arm muscles from longitudinal hand-held dynamometry (HHD) data in amyotrophic lateral sclerosis (ALS) for congruence with contiguous spread of neurodegeneration along spinal cord segments.

Factors determining timing of weakness of different muscle groups in an extremity in ALS including contiguous and network spread of neurodegeneration, cortical influences, and compensatory collateral reinnervation. Dissociated muscle atrophy is recognized, notably the 'split hand', and the recently proposed 'split elbow'.

Longitudinal HHD data from the Ceftriaxone clinical trial was examined using non-linear mixed models, assuming a logistic trajectory from normal strength to zero strength, and patient-level variability in location and scale parameters. Unmeasured patient-specific baseline strength prior to disease onset was empirically assumed from published normative values, adjusted by observed strength in the best-preserved arm or leg muscle. The estimand of interest was time to 50% strength, or "time from onset to mid-way strength" (TOMS), parameterized using the logarithm, to allow for proportional differences between muscles.

HHD assessed 5 muscle groups in each arm, namely: shoulder flexion (SF), elbow flexion (EF), elbow extension (EE), wrist extension (WE) and first dorsal interosseous (FDI). Over a median of 48 weeks, 513 subjects (110 bulbar-, 203 arm-, and 200 leg-onset) provided 2,769 sets of HHD measures. TOMS increased sequentially in the following order: FDI, WE, SF, EF, and EE. Estimated TOMS ratios with 95% CIs (adjusted for multiple comparisons) were: WE/FDI 1.30 (1.22-1.39), SF/WE 1.05 (1.01-1.10), EF/SF 1.05 (1.01-1.09), EE/EF 1.15 (1.10-1.19). Elbow flexors weakened sooner than elbow extensors. The sequence of arm muscle weakness progression was strikingly similar regardless of onset site.