Objective: To characterize lesion evolution and neurodegeneration in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) using multimodal MRI. 

Methods: We prospectively performed MRI and cognitive testing in RVCL-S and healthy control cohorts. Gray and white matter volume and disruption of white matter microstructure were quantified. Asymmetric spin echo acquisition permitted voxel-wise oxygen extraction fraction (OEF) calculation as an in vivo marker of microvascular ischemia. The RVCL-S cohort was included in a longitudinal analysis of lesion subtypes in which hyperintense lesions on FLAIR, T1-post-gadolinium, and diffusion-weighted imaging were delineated and quantified volumetrically.

Results: Twenty individuals with RVCL-S and 26 controls were enrolled. White matter volume and microstructure declined faster in RVCL–S compared to controls. White matter atrophy in RVCL-S was highly linear (ρ=-0.908, p<0.0001). Normalized OEF was elevated in RVCL-S, and increased with disease duration. Multiple cognitive domains, specifically those measuring working memory and processing speed, were impaired in RVCL-S. Lesion volumes, regardless of subtype, progressed/regressed with high variability as a function of age, while FLAIR lesion burden increased near time-to-death (p<0.001).

Conclusion: RVCL-S is a monogenic microvasculopathy predominantly affecting the white matter with regard to atrophy and cognitive impairment. White matter volumes in RVCL-S declined linearly, providing a potential metric against which to test efficacy of future therapies. Progressive elevation of white matter OEF suggests microvascular ischemia may underlie neurodegeneration in RVCL-S.  

Lesion Subtype Segmentation.  Five lesion subtypes were evaluated for hyperintensity including: (1) FLAIR lesions, (2) FLAIR lesions excluding pseudotumors, (3) FLAIR lesions including only pseudotumors, (4) T1 post-gadolinium lesions, and (5) diffusion weighted imaging (DWI) lesions.  Hyperintense lesions were manually outlined by a vascular neurology fellow and board-certified neurologist (V.B.) and medical student (V.C.), then reviewed and edited by a board-certified vascular neurologist (A.F.) using Medical Image Processing, Analysis, and Visualization software (https://mipav.cit.nih.gov/). Pseudotumors, including both the central lesion and surrounding vasogenic edema, were outlined on FLAIR and defined as a FLAIR hyperintense lesion aligning with a central T1 ring-enhancing lesion located near the lateral ventricles.  For “T1 post-gadolinium lesions” also referred to as “nodular contrast-enhancing lesions”, all lesions with contrast-enhancement, whether or not, they were associated with a pseudotumor (as judged by periventricular and surrounding FLAIR signal), were included. 

Only the RVCL-S participants with at least three scan time-points over at least 30 months were included for the lesion subtype analysis. Of these seven patients, five had known age of death and two were still alive with age of death imputed as the median value from all RVCL-S patients who had died.  Repeated patient data was included as a random effect in all models.  For models not meeting normality assumptions, data underwent transformation prior to regression, using the natural logarithmic function or non-linear fits, as needed.  Across all study analyses, results were presented only if valid without collinearity and with normal residuals.

This is supplemental data that did not fit into the manuscript.

Clayco Foundation, Energy 4 A Cure Foundation, Cure CRV Research, National Institutes of Health: National Heart, Lung, and Blood Institute (R01HL129241, A.L.F); Washington University St. Louis CTSA (UL1 TR000448, A.L.F.).