Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an autosomal dominant microvasculopathy of the brain, retina, and other organ systems.
Terminology
RVCL-S encompasses several previously described conditions , 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) .
Clinical presentation
Symptoms generally manifest between ages 30 and 50 , 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
- 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
- systemic features:
- liver disease: due to microvascular liver disease
- kidney disease: due to arterio- or arteriolonephrosclerosis
- hypertension
- gastrointestinal bleeding: often microscopic
- anemia: due to blood loss or secondary to inflammation
- Raynaud phenomenon
Pathology
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 . The TREX1 gene normally encodes for a DNA exonuclease that is involved in removing unnecessary nucleotides from DNA . Furthermore, the TREX1 gene also plays a role in protein glycosylation . 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 .
Microscopic appearance
Affected tissue, such as cerebral white matter, demonstrate ischemia, necrosis, and dystrophic calcifications, with accompanying vasculopathy . This vasculopathy, affecting primarily small to medium sized vessels, manifests as fibrinoid vascular necrosis or thickened hyalinised vessels, notably without evidence of vasculitis . In the brain, the leptomeninges, extraparenchymal vasculature, and the cortical grey matter vessels are typically spared .
Radiographic features
Neuroimaging features have been most commonly described .
CT
CT is non-specific, but approximately half of all patients demonstrate multiple intracerebral calcifications in the cerebral white matter .
MRI
Characteristic lesions that have been described include:
- punctate T2-weighted hyperintense 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
- some of these lesions are small ischemic strokes
- 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
Treatment and prognosis
There is currently (as of September 2019) 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 .
History and etymology
RVCL-S was coined by Anine H Stam and colleagues in their 2016 seminal paper , thereby uniting multiple previously separate pathologies.
Differential diagnosis
General imaging differential considerations include:
