Longitudinal Changes of White Matter Hyperintensities in Sporadic Small Vessel Disease: A Systematic Review and Meta-analysis

BACKGROUND AND OBJECTIVES: White matter hyperintensities (WMHs) are frequent imaging features of small vessel disease (SVD) and related to poor clinical outcomes. WMH progression over time is well described, but regression was also noted recently, although the frequency and associated factors are unknown. This systematic review and meta-analysis aims to assess longitudinal intraindividual WMH volume changes in sporadic SVD. METHODS: We searched EMBASE and MEDLINE for articles up to 28 January 2022 on WMH volume changes using MRI on ≥2 time points in adults with sporadic SVD. We classified populations (healthy/community-dwelling, stroke, cognitive, other vascular risk factors, and depression) based on study characteristics. We performed random-effects meta-analyses with Knapp-Hartung adjustment to determine mean WMH volume change (change in milliliters, percentage of intracranial volume [%ICV], or milliliters per year), 95% CI, and prediction intervals (PIs, limits of increase and decrease) using unadjusted data. Risk of bias assessment tool for nonrandomized studies was used to assess risk of bias. We followed Preferred Reporting in Systematic Review and Meta-Analysis guidelines. RESULTS: Forty-one articles, 12,284 participants, met the inclusion criteria. Thirteen articles had low risk of bias across all domains. Mean WMH volume increased over time by 1.74 mL (95% CI 1.23–2.26; PI −1.24 to 4.73 mL; 27 articles, N = 7,411, mean time interval 2.7 years, SD = 1.65); 0.25 %ICV (95% CI 0.14–0.36; PI −0.06 to 0.56; 6 articles, N = 1,071, mean time interval 3.5 years, SD = 1.54); or 0.58 mL/y (95% CI 0.35–0.81; PI −0.26 to 1.41; 8 articles, N = 3,802). In addition, 13 articles specifically mentioned and/or provided data on WMH regression, which occurred in asymptomatic, stroke, and cognitive disorders related to SVD. DISCUSSION: Net mean WMH volume increases over time mask wide-ranging change (e.g., mean increase of 1.75 mL ranging from 1.25 mL decrease to 4.75 mL increase), with regression documented explicitly in up to one-third of participants. More knowledge on underlying mechanisms, associated factors, and clinical correlates is needed, as WMH regression could be an important intervention target.