Critical demyelinating lesions in progressive multiple sclerosis: a prospective observational study

Critical demyelinating lesions are individual lesions anatomically associated with progressive motor impairment initially described in highly selected cohorts with demyelinating disease. We aim to determine how frequently individual critical demyelinating lesions were found in an unselected consecutive cohort of people with progressive multiple sclerosis (MS) at a tertiary MS clinic over a one-year duration.

Prospective consecutively enrolled observational cohort study of newly evaluated and established people with progressive MS at Mayo Clinic from July 1, 2021 to June 30, 2022. Demographics and clinical information were extracted by chart review following evaluation by an MS subspecialty expert. Participants were evaluated as having predominantly progressive motor or non-motor (ataxic, cognitive, sensory) impairment. All brain and spinal cord MRIs were examined for demyelinating lesions involving the corticospinal motor tracts. Critical lesions were defined as T2 lesions anatomically associated with a progressive upper motor neuron impairment within the lateral columns, brainstem corticospinal tracts, or supra-tentorial corticospinal tracts. Participants were classified as having: A) one critical lesion; B) two "tandem" critical lesions or C) lesion burden too high (i.e., ≥ 3 critical tandem lesions where individual lesions could not reliably associated with motor progression).

255 participants were evaluated: 67 (26.3%) with critical lesions, (54 [21.2%] with one critical, and 13 [5.1%] with two tandem critical lesions) and 188 (73.7%) with lesion burden too high. Non-motor progression was found in 15 (5.9%). Critical lesions were identified in most within the spinal cord (cervical in 49 [90.7%] and thoracic in 3 [5.5%]). Those with critical lesions were older at evaluation than those with lesion burden too high (median 62 years IQR 55-68 vs. 58.0 IQR 49-64, p = 0.004), more likely to present with progressive hemiparesis (55.2% vs 14.4%, p < 0.001), and less likely to present with progressive para-paresis (4.5% vs 31.9% p < 0.001) or quadriparesis (1.5% vs 10.1%, p = 0.031). These groups had similar numbers of brain demyelinating lesions.

Critical demyelinating lesions, often within the spinal cord and anatomically associated with progressive motor impairment, are commonly found in people with progressive MS.