Journal of Multiple Sclerosis

Are Dilated Virchow Robin Spaces a Generalized Marker of Disease in Multiple Sclerosis?

Jacob Miles, Ariana Simps^* and Simon Keller ^*Correspondence: Ariana Simps, Department of Neuroscience, Central Clinical School, Monash University, Australia, Email:

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Introduction

Virchow Robin Spaces (VRS), also referred to as perivascular spaces, encompass cerebral blood vessels and facilitate fluid exchange among blood, cerebrospinal fluid, and the interstitial. Enlarged VRS are frequently observed in brain tissue, irrespective of health or disease status. While evidence indicates a correlation between increased VRS burden and cardiovascular risk factors like hypertension and higher BMI, their precise contribution to disease pathogenesis remains uncertain. Moreover, scant evidence exists linking enlarged VRS with clinical measures of disease severity across various neurological and neurodegenerative conditions where VRS are present. In Multiple Sclerosis (MS), numerous studies have suggested associations between enlarged VRS, lesion volume, and disease severity. However, a meta-analysis involving over 450 patients across nine studies failed to reproduce these associations. It revealed elevated VRS count and volume in MS patients compared to controls, yet no significant links with disease severity or progression were observed, thus questioning the utility of VRS as diagnostic or prognostic indicators in MS [ 1- 4]. The reliability of these findings is subject to scrutiny due to methodological limitations in identifying and quantifying VRS, with many previous studies employing crude assessments of VRS burden instead of precise quantification of their number or volume. Recent studies utilizing higher-resolution imaging techniques and larger patient cohorts have begun to address these limitations, revealing associations between VRS and various aspects of disease severity, lesion volume, cortical atrophy, and diffusion metrics [5].

Improvements in MRI resolution and detection methods are enhancing the identification of Virchow Robin Spaces (VRS) on clinical scans, yet their clinical significance remains uncertain. There's a hypothesis suggesting that it's not merely the presence of VRS but the dilation of these spaces that may indicate disease, although evidence supporting this notion is limited [6].

In a comprehensive study by Ineichen et al., VRS in MS patients were extensively investigated, with a particular focus on distinguishing dilated VRS (measuring >2 mm) from undilated ones. The spatial distribution of these VRS in relation to MS lesions, brain atrophy, and clinical severity was assessed. While increased numbers of both dilated and undilated VRS were noted, they did not correlate with disease stage or cognitive function. Moreover, in a subgroup with repeated MRIs, changes in clinical stage or lesion load did not correspond with alterations in the number of dilated VRS. Post-mortem histology revealed that dilated VRS did not co-localize with demyelination, axonal damage, or microglial/macrophage activation, but rather with arteries and signs of arterial disease. These findings suggest that dilated VRS may be associated more with cardiovascular disease than with MS pathology.

Overall, the study highlights the considerable variability in the number of dilated VRS among both patients and healthy controls, even after accounting for cardiovascular risk factors.

Despite a broad definition, the occurrence of dilated VRS across all participants studied remained relatively low [7-9].

The current study lacks control for variables such as time of day and sleep, both of which are believed to influence the presence of dilated Virchow Robin Spaces (VRS) [1-3]. Diurnal variation of VRS is well recognized, with dilation often occurring during sleep. The timing of MRI scans relative to wakefulness and sleep deprivation can affect the size and visibility of VRS. Additionally, a major limitation of the study is the absence of data on the use of Disease-Modifying Treatments (DMTs) by patients and the timing of DMT intervention in relation to MRI scans. Given the widespread use of DMTs in MS cohorts, the lack of association with lesion load or other markers of active neuro-inflammation is not unexpected. While the study reveals heightened levels of dilated VRS in MS patients, the limited correlation with other indicators of disease severity suggests that dilated VRS may serve as a nonspecific marker of disease, whether neurological, cardiovascular, or a combination of both. Comprehensive studies that account for these various factors are necessary, not only in MS but also across neurological and neurodegenerative diseases, to gain a better understanding of the role of VRS in disease pathogenesis and presentation.

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