Neuroimaging phenotype characterization of early aggressive and late severe multiple sclerosis: a case-control study

A subgroup of multiple sclerosis patients experiences a severe form of the disease. Although there is a lack of consensus regarding the definition of severe multiple sclerosis, it can follow two distinct temporal disability trajectories. Early aggressive multiple sclerosis is characterized by reaching an Expanded Disability Status Scale score of ≥6.0 in less than 10 years from disease onset or before reaching 40 years of age, while the same disability is reached in late severe multiple sclerosis patients over more than 10 years from onset or after the age of 40. We investigated neuroimaging phenotypes in aggressive/severe multiple sclerosis. From a retrospective, 16-year longitudinal Biomarker Understanding for Future Findings and Advancements for Long-term Outcomes in Multiple Sclerosis database, out of 3863 multiple sclerosis patients, 86 early aggressive and 368 late severe multiple sclerosis patients were included. Propensity matching for age, sex, race, disease duration, MRI scanner type and imaging protocol was used to identify early non-aggressive matched (<i>n</i> = 86) or late non-severe matched (<i>n</i> = 368) multiple sclerosis controls. Additionally, out of 675 neurologically healthy individuals from the same database, using similar matching criteria, neurologically healthy individuals were matched to early (<i>n</i> = 163) and late (<i>n</i> = 89) multiple sclerosis. MRI lesion (white matter, cortical, cervical spinal cord, thalamic dysconnectivity) and brain (whole brain, grey matter, cortex, thalamus) volumes and spinal cord area (C1-C3) measures were obtained. Statistical analyses explored group comparisons and associations with the severity of disability (Expanded Disability Status Scale defined) in aggressive/severe groups. Multiple sclerosis patients showed significantly worse MRI outcomes in all explored measures, compared to neurologically healthy individuals. Higher T2 hyperintense lesion burden (<i>P</i> = 0.008) and thalamic atrophy (<i>P</i> = 0.011) were the only significant differentiators between early aggressive and non-aggressive multiple sclerosis, while higher cortical lesion burden was the only significant correlate of disability (<i>P</i> = 0.004) in early aggressive multiple sclerosis. The late severe multiple sclerosis patients were differentiated from their matched multiple sclerosis controls by spinal cord atrophy (<i>P</i> < 0.001) and cortical atrophy (<i>P</i> < 0.001), while disability was significantly associated with spinal cord atrophy (<i>P</i> < 0.001), higher cortical lesion burden (<i>P</i> = 0.006) and thalamic atrophy (<i>P</i> = 0.024) in late severe multiple sclerosis. Early and late forms of severe multiple sclerosis share common grey matter-based pathology, with lesion burden, cortical and thalamic changes central to early aggressive multiple sclerosis and spinal cord, cortical and thalamic changes linked to late severe multiple sclerosis.