By Ulrike W. Kaunzner, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Kaunzner reports no financial relationships relevant to this field of study.

SYNOPSIS: This postmortem study of multiple sclerosis (MS) patients evaluated the presence and pathological significance of extracranial systemic and cerebral small vessel disease in patients with MS compared to healthy controls. MS patients had less systemic vascular disease and more small vessel disease in the brain compared to controls.

SOURCE: Geraldes R, Esiri MM, Perera R, et al. Vascular disease and multiple sclerosis: A post-mortem study exploring their relationships. Brain 2020;143:2998-3012.

Multiple sclerosis (MS) is an immune-mediated disease leading to demyelination, axonal loss, and progressive clinical disability. The etiology of MS remains elusive; however, different environmental and genetic factors are considered to contribute to onset of the disease. The disease course of each individual MS patient also varies significantly, and influences of vascular risk factors and vascular disease on the overall outcome have been discussed.

Geraldes et al examined a unique postmortem cohort with access to brain and whole-body pathology data of MS patients and healthy controls. They enrolled 85 MS cases (median age at death 62.0 years) and 68 age-matched controls (median age at death 58.0 years) and assessed the systemic vascular disease score based on autopsy records. Then they evaluated a subset of this original cohort and examined the postmortem brain tissue of 42 MS cases and 39 healthy controls for cerebral small vessel disease and cerebral inflammation. They took the effect of age on vascular disease into consideration and dichotomized their cohorts into younger and older age groups, below and above the median age of 60 years, respectively. The authors created a reliable method to assess the systemic vascular disease score based on autopsy reports, using the extent of atheroma and end organ damage, and found that MS patients, particularly in the younger age group, had a lower systemic cardiovascular disease burden as compared to controls, but this increased with age. On the other hand, cerebral small vessel disease was more severe in younger MS patients compared to controls. In addition, the investigators commented on pathophysiological findings that were specific for the MS cohort, noting that periarteriolar space dilatation, hemosiderin deposits, and inflammation were found, and were distinctly different from the classic demyelinating MS plaque.

COMMENTARY

The authors of this important study had access to data from body and brain autopsies of untreated MS patients, evaluating the presence of systemic vascular disease and cerebral small vessel disease. These data from an MS cohort in the pre-treatment era improve our understanding of the natural course of the disease and the potential existence of vascular comorbidities. The presence of increased cerebral small vessel disease in the younger age group, with concomitantly less peripheral vascular disease, is intriguing. The authors asked, “Is an overall proinflammatory state contributing to a decrease in systemic vascular disease in these younger MS patients?” The evaluated cohorts have a high mean and median age (MS patients: median age at death 62.0 years, range 39-84 years; healthy control: median age at death 58.0 years, range 40-85 years), which is a result of the nature of a postmortem study. Since cerebral microvascular changes already are evident in the younger group of MS patients, it would be interesting to know the extent of cerebral small vessel disease in an even younger cohort of MS patients.

The authors described perivascular space dilatation, hemosiderin deposits, and microbleeds, independent from classic MS lesions. Are these vascular changes part of the inflammatory process or do they represent an independent pathophysiology? And are these observed vascular changes the contributing factors and potential missing link to an increased disability score and more progressive outcome in a subset of MS patients? The potential presence of hypoxia in MS has been considered as an inducer of proinflammatory pathways and a potential contributor to MS pathogenesis. The direct or indirect effect of hypoxic changes on continued inflammation and progression of the disease will be crucial for the evaluation of MS patients, particularly those susceptible to vascular changes.

More studies, and ideally in vivo studies, are warranted to assess the effect of systemic and cerebral vascular disease on the disease course and disability levels of MS patients of all age groups. Thorough evaluation of vascular risk factors and vascular disease will be warranted, and imaging techniques differentiating the burden of central nervous system inflammation and vascular disease might be important in the future. A better understanding of the extent and contribution of vascular disease might offer a different target to modify the disease course of MS patients.