Inclusion criteria were: Mayo Clinic patients with progressive motor impairment ≥1 year, attributable to a critically located lesion/s with: a total of 1 CNS demyelinating lesion (PSS), 2-5 lesions (PPS), or >5 lesions with unilateral hemiparesis or monoparesis fulfilling 2017 McDonald criteria (PUHMS). Multiple brain and spinal cord MRI were reviewed, with lesions considered as unequivocally demyelinating. 

135 patients were included (PSS n=33, PPS n= 56 and PUHMS n= 46). Primary progressive disease course was seen in 82% PSS, 61% PPS and 52% PUHMS with the remainder having relapse associated onset. Median age at onset of progressive motor impairment was younger in PSS (49 years; range 24-73) and PPS (50 years; range 30-64) than in PUHMS (54 years; range 39-77) (p=0.02, p=0.003 respectively). Median age at onset of motor progression did not differ between primary progressive and secondary progressive clinical course nor comparing patient groups with 1-10, 11-20, and >20 brain demyelinating lesions (55, 54 and 53 years respectively; p=0.44).  

Onset of motor progression is paradoxically earlier in patients with critical demyelinating lesions and lower total CNS lesion burden (progressive solitary sclerosis and progressive paucisclerotic MS) than in progressive unilateral hemiparetic MS. The “critical” demyelinating lesion rather than brain MRI lesion burden is the major contributor to onset of motor progression in these cohorts.