Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Last revised by Rohit Sharma on 15 Jan 2023

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an autosomal dominant microvasculopathy of the brain, retina, and other organ systems.

RVCL-S encompasses several previously described conditions 1,2, including cerebroretinal vasculopathy (CRV), hereditary vascular retinopathy (HVR), hereditary systemic angiopathy (HAS), hereditary endotheliopathy, retinopathy, nephropathy and stroke (HERNS), and retinal vasculopathy with cerebral leukodystrophy (RVCL) 3-6.

Symptoms generally manifest between ages 30 and 50 1,2, and the most commonly reported clinical features helpfully appear in the condition's name:

  • retinal features: retinal hemorrhages and cotton wool spots may be seen on fundoscopy in the early stages before neovascularization and visual impairment 1-6

  • CNS features: most commonly focal neurological deficits, but cognitive impairment and psychiatric disease are also common, and seizures and migraine with or without aura may also uncommonly occur 1,2,4-6

  • systemic features:

    • liver disease: due to microvascular liver disease 1,2,5

    • kidney disease: due to arterio- or arteriolonephrosclerosis 1,2,4,5

    • hypertension 1,2

    • gastrointestinal bleeding: often microscopic 1,2

    • anemia: due to blood loss or secondary to inflammation 1,2

    • Raynaud phenomenon 1,2

RVCL-S is an autosomal dominant disorder caused by C-terminal frameshift mutations in the three prime repair exonuclease 1 (TREX1) gene, located on the short arm of chromosome 3 1,2,6,7. The TREX1 gene normally encodes for a DNA exonuclease that is involved in removing unnecessary nucleotides from DNA 1,2,6,7. Furthermore, the TREX1 gene also plays a role in protein glycosylation 9. It is unclear which of these functions (perhaps both) is important to lose in the development of RVCL-S.

Importantly, these mutations in TREX1 are distinct from those that cause Aicardi-Goutiéres syndrome and some cases of hereditary systemic lupus erythematosus 8.

Affected tissue, such as cerebral white matter, demonstrate ischemia, necrosis, and dystrophic calcifications, with accompanying vasculopathy 1,7. This vasculopathy, affecting primarily small to medium sized vessels, manifests as fibrinoid vascular necrosis or thickened hyalinised vessels, notably without evidence of vasculitis 1,7. In the brain, the leptomeninges, extraparenchymal vasculature, and the cortical grey matter vessels are typically spared 1,7.

Neuroimaging features have been most commonly described 1,2,6.

CT is non-specific, but approximately half of all patients demonstrate multiple intracerebral calcifications in the cerebral white matter 1,2,5,6.

Characteristic lesions have been described:

  • punctate T2-weighted hyperintense supratentorial white matter lesions that spare the grey matter and subcortical U-fibers, are incompatible for age, and may or may not demonstrate enhancement or high diffusion signal on DWI 1,2,6

  • larger T2-weighted hyperintense white matter lesions that have perilesional edema and exhibit mass effect, also demonstrate ring enhancement, and may or may not demonstrate high diffusion signal on DWI 1,2,6,10

These lesions progressively increase in size and number over time 1. Non-enhancing lesions can progress to enhancing or rim-enhancing lesions.

There is no disease-modifying therapy available. Typically, the disease has a progressive course leading to death between ages 50 and 60, which corresponds to approximately a decade after symptom onset 1,2,6.

RVCL-S was coined by Anine H Stam and colleagues in their 2016 seminal paper 1, thereby uniting multiple previously separate pathologies.

General imaging differential considerations include:

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