Is multiple sclerosis a length-dependent central axonopathy? Some empirical data from the TONiC study

There is a long-held hypothesis that multiple sclerosis (MS) affects the central nervous system in a length dependent way reflecting the propensity of longer central axonal projections to accumulate damage, but evidence for this is lacking. To determine the prevalence of body part involvement in MS and relate this to the putative axonal length innervating each body part, we asked people with MS to indicate affected body parts on a somatic diagram. Axonal length for each body part was calculated from neuroanatomical literature. The survey was part of the TONiC-MS study. Records from 5925 respondents were analysed for involvement of eleven distinct body parts (either hand/ upper limb /lower limb, urinary bladder, neck, speech, vision, swallowing), and also balance. Participants had a wide range of age, disease duration, disease subtypes and disability levels. Body part involvement in the whole sample was highly correlated with axonal length (rho 0.933). At an individual level, a logistic regression including covariates of age, disease type and disability level demonstrated that the probability of body part involvement was substantially dependent on axonal length across all disease types. Our study supports the hypothesis that MS disability reflects a length-dependent central axonopathy.