Lesion evolution and neurodegeneration in RVCL-S: A monogenic microvasculopathy

Abstract

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 fluid-attenuated inversion recovery (FLAIR), T1-postgadolinium, 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 those with 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 affecting predominantly 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 the efficacy of future therapies. Progressive elevation of white matter OEF suggests that microvascular ischemia may underlie neurodegeneration in RVCL-S.

Figure 1. Participant enrollment scheme

Participants with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) and healthy controls were prospectively enrolled with a standard imaging protocol. These participants had advanced MRI analyses to evaluate atrophy, white matter microstructure, and metrics of tissue ischemia (CBF, OEF). This RVCL-S cohort was enlarged to include patients with scans dating farther back (without standard imaging), who had been followed over many years. Given that these scans did not have a standard imaging protocol, only the lesion segmentation analysis was performed in the larger cohort. FA = fractional anisotropy; MD = mean diffusivity.

Figure 2. White matter, but not gray matter, atrophy is accelerated in RVCL-S

(A) Normalized gray matter (GM) volumes did not differ between healthy controls (CTLs) and individuals with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S). (B) Normalized white matter (WM) volumes were significantly lower in those with RVCL-S compared to CTLs (p < 0.0001). (C) Rate of GM atrophy did not differ between CTLs and individuals with RVCL-S. (D) Rate of WM atrophy was faster in individuals with RVCL-S compared to CTLs (p = 0.0002 for interaction of age and RVCL-S status).

Figure 3. Progression in cerebral atrophy and evolution of lesion subtypes in RVCL-S

Top row shows fluid-attenuated inversion recovery (FLAIR) images; middle row shows diffusion-weighted imaging (DWI) images; bottom row shows T1 postgadolinium images. (A) A 45-year-old woman with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) demonstrated a pseudotumor adjacent to the right frontal horn. The pseudotumor demonstrates an underlying ring-enhancing lesion on T1 postgadolinium with central hyperintensity on DWI and surrounding vasogenic edema on FLAIR. MRI scan a decade later demonstrates that the previous pseudotumor is inactive without central diffusion restriction, contrast enhancement, or significant vasogenic edema on FLAIR. Diffuse central > peripheral atrophy is prominent, and additional white matter lesions have developed a decade after the baseline MRI. (B) MRI scan of a 54-year-old woman with RVCL-S shows multiple subcortical and periventricular white matter lesions, several which are hyperintense on DWI and a few of which show nodular enhancement on T1 postgadolinium. Five years later, her MRI scan just before death demonstrates a relative decrease/regression in number and overall burden of white matter lesions on FLAIR, DWI, and T1 postgadolinium, with greater lesion burden near the ventricles and less within the subcortical white matter; however, substantial atrophy (central and peripheral) has progressed over the 5 years before death. Sequential neuroimaging on this patient never revealed any pseudotumors. (C) A 43-year-old woman with RVCL-S demonstrates periventricular and subcortical white matter lesions on FLAIR imaging, several, but not all, of which are bright on DWI and show nodular enhancement on T1 postgadolinium. Follow-up MRI scan 7 years later near the time of death shows substantial progression in FLAIR lesion burden with overall decrease in DWI hyperintense lesions. Furthermore, nodular enhancement of white matter lesions has diminished, but a ring-enhancing pseudotumor lesion has appeared adjacent to the right frontal horn. Notably, there is substantial progression of atrophy (central > peripheral) over the 7-year interval.

Figure 4. White matter OEF increases with disease duration and may indicate progressive microvascular ischemia

(A) Representative cerebral blood flow (CBF), oxygen extraction fraction (OEF), and fluid-attenuated inversion recovery (FLAIR) maps in an individual with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S). (B) Normalized white matter OEF (nOEF_NAWM), but not normalized white matter CBF (nCBF_NAWM), was significantly elevated in patients with RVCL-S compared to healthy controls (CTLs). (C) nOEF_NAWM progressively increased in participants with RVCL-S compared to CTLs (p = 0.0103); however, rate of change in nCBF_NAWM was not different in those with RVCL-S compared to CTLs.

Figure 5. Lesions in RVCL-S, regardless of subtype, progress/regress with high interparticipant variability

Each line represents an individual patient. As time to death decreases, fluid-attenuated inversion recovery (FLAIR) lesion burden accelerates. To evaluate the temporal evolution of lesion subtypes in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), MRI scans from 7 patients with RVCL-S who contributed ≥3 time points over at least 30 months were evaluated across 5 lesion subtypes. Time to death was evaluated as a predictor of lesion volume in linear regression analysis with repeated patient data included as a random effect. As time to death decreased, FLAIR lesion volumes increased, including (A) a 22% increase in lesion volume per year closer to death for all FLAIR lesions (p < 0.0001) and (B) a 15% increase in lesion volume per year closer to death for FLAIR lesions excluding pseudotumors. Time to death as a predictor of (C) pseudotumor lesion volume on FLAIR, (D) contrast-enhancing lesion volume, and (E) diffusion-weighted imaging (DWI) hyperintense lesion volume produced invalid models. Significant fluctuation in lesion burden for these last 3 lesion subtypes is evident, suggesting high interparticipant variability and limited sample size.