Clinical Phenotypes Associated with Cerebral Small Vessel Disease – An Overview of Systematic Reviews

Introduction

Cerebral small vessel disease (cSVD) is a major contributor to stroke and vascular cognitive impairment. However, other potential physical and psychological consequences have been described. Our aim was to provide an overview of systematic reviews describing clinical phenotypes associated with cSVD.

Methods

We searched four multidisciplinary databases from inception to December 2022. We included reviews describing concurrent clinical phenotypes in individuals with neuroimaging evidence of cSVD, defined using the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE-1) criteria. We broadly classified phenotypes into cognitive, mood and neuropsychiatric, respiratory, cardiovascular, renal-urinary, peripheral nervous system, locomotor, and gastrointestinal. We included studies assessing multiple cSVD features or using a summary cSVD score, and studies examining individual cSVD markers. We extracted risk-factor adjusted effect estimates, where possible, and assessed methodological quality using the Assessment of Multiple Systematic Reviews-2 (AMSTAR-2) tool.

Results

We included 24 systematic reviews reporting on 685 original studies and >1,135,940 participants. Cognitive and neuropsychiatric phenotypes were examined most often, particularly in relation to white matter hyperintensities (range of risk ratios for neurocognitive phenotypes, 1.21-1.49; and for neuropsychiatric, 1.02-5.71). Two reviews focused solely on perivascular spaces. No reviews assessed lacunes or small subcortical infarcts separately from other cSVD features. Reviews on peripheral nervous system, urinary or gastrointestinal phenotypes were lacking. Fourteen reviews had high methodological quality. Heterogeneity in cSVD definitions and phenotypic assessments was substantial.

Discussion

Neuroimaging markers of cSVD are associated with various concurrent clinical conditions. Cognitive and neuropsychiatric phenotypes have been reviewed most extensively, while few reviews assessed gait and mobility. Reviews for many body systems were lacking. Similarly, while white matter hyperintensities were relatively well studied, there were limited data on phenotypes associated with perivascular spaces and lacunes. Future studies should characterize the full clinical spectrum of cSVD, and explore clinical associations beyond neurocognitive and neuropsychiatric presentations.