Specific Structural Damage Linked to Worsened Disability Milestones in MS

Massimo Filippi, MD

Using multi-center 3T brain and cervical cord T2- and 3-dimensional (3D) T1-weighted images, researchers concluded that brain lesion burden, cortical atrophy, and thalamic atrophy were main determinants of low multiple sclerosis (MS) clinical disability while cervical cord was the major contributor to Expanded Disability Status Scale (EDSS) score.

Senior author Massimo Filippi, MD, professor of neurology, IRCCS San Raffaele Scientific Institute, and colleagues aimed to determine the relative contributions of cortical, deep grey matter (DGM), cerebellar, and cervical cord damage to MS disability milestones. The study included 198 patients with MS and 67 healthy controls who had brain/cord lesion burden, cortical thickness (CTh), DGM and cerebellar volumetry, and cord cross-sectional area (CSA) measurements quantified.

Random forest (RF) regression/classification models were performed in all patients with MS to identify sets of MRI variables associated with the EDSS score, with the following milestones used: EDSS equal to 3.0 (mild disability); EDSS equal to 4.0 (severe disability and impairment); EDSS equal to 6.0 (requirement of an aid for walking).

The best predictors of an EDSS score of 3.0 were a reduced cord CSA; a higher T2-hyperintense lesion volume (LV); thalamic, lower DGM, and cerebellar volumes; reduced CTh in the frontal lobe; and a higher number of cervical cord lesions. Lower cord CSA, whole-cerebellar, lower posterior cerebellar and thalamic/DGM volumes, a higher number of cord lesions, and reduced sensorimotor and frontal CTh were all identified as the best predictors of EDSS score of 4.0.

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Reduced cord CSA and a higher number of cervical cord lesions were the only significant predictors of EDSS score of 6.0, which was reached by 45 patients with MS. Fillipi and colleagues concluded that, "inflammatory and neurodegenerative processes seem to have a differential weight for disability accumulation across various MS disease phases.” The most relevant predictors of EDSS score in patients with MS were normalized cervical cord CSA, number of cervical cord lesions, as well as lower normalized thalamic and cerebellar volumes.

Volumetric and CTh analysis showed that patients with MS had widespread atrophy involving the frontal, parietal, occipital, temporal, insular and sensorimotor cortices (P-range: <.001-.05), along with atrophy in the thalamus (P <.001) and other DGM nuclei (P <.001) in both anterior and posterior cerebellar lobules (P-range: <.001-.03) and in the cervical spinal cord (P = .04) compared to controls.

Of the 198 patients with MS, 139 had relapsing-remitting MS (RRMS) and 59 had progressive MS (PMS). Compared to RRMS, patients with PMS showed additional atrophy in the thalami and the cervical spinal cord, while CTh of cortical lobes, cerebellar volumes, and volume of DGM nuclei other than thalamus were similar between PMS and RRMS.

There were a few limitations to the study, including a significant age difference between controls and patients with MS. Additionally, no clinical measures of upper body impairment and no neuropsychological evaluation were obtained, leading to a bias in results towards locomotor disability, specifically linked to the EDSS score. Investigators noted that evaluating correlations with cognitive deficits, depression or fatigue symptoms would have given a more complete picture of overall patients’ impairment.

REFERENCE

Hidalgo de la Cruz M, Valsasina P, Meani A, et al. Differential association of cortical, subcortical and spinal cord damage with multiple sclerosis disability milestones: a multiparametric MRI study. Multiple Sclerosis Journal. Published online June 14, 2021. doi: 10.1177/13524585211020296