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 ^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.

Epidemiology

RVCL-S is very are, and less than 50 families have been reported as being affected in the literature ¹¹. However, the condition may be under-diagnosed ¹¹.

Clinical presentation

Symptoms generally manifest between ages 30 and 50 years ^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 (including eventual blindness) ^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

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

  • hypertension ^1,2

  • gastrointestinal bleeding: often microscopic due to angiodysplasia ^1,2

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

  • Raynaud phenomenon ^1,2

  • subclinical hypothyroidism ¹¹

Pathology

Genetics

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 (or perhaps both) is important to lose in the development of RVCL-S.

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

Microscopic appearance

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.

Radiographic features

Neuroimaging features have been most commonly described ^1,2,6,11.

CT

CT is non-specific, but approximately half of all patients demonstrate multiple intracerebral calcifications in the cerebral white matter ^1,2,5,6,11.

MRI

Characteristic white matter lesions have been described:

• punctate supratentorial white matter lesions that spare the grey matter and subcortical U-fibers, and are incompatible for age ^1,2,6

  • T2/FLAIR: hyperintense

  • DWI: may or may not have high diffusion signal

    • some of these lesions are small ischemic strokes

  • T1 C+ (Gd): may or may not have nodular or rim enhancement

• larger white matter mass-like ('pseudotumor') lesions that have perilesional edema and exhibit mass effect, which may progressively increase in size and number over time, some of these may develop from the aforementioned punctate white matter lesions ^1,2,6,10-12

  • T2/FLAIR: hyperintense

  • DWI: may not demonstrate high diffusion signal

  • GRE/SWI: may have associated punctate regions of susceptibility artefact, which may represent cerebral microhemorrhages or calcifications

  • T1 C+ (Gd): typically demonstrate ring enhancement

    • initially non-enhancing lesions can progress to enhancing or rim-enhancing lesions

As the disease progresses, similar punctate lesions may be seen within the cerebellum, although mass-like lesions are very rare ¹¹.

Treatment and prognosis

There is no disease-modifying therapy available ¹¹. Immunosuppressive strategies have been trialed without definite benefit ¹¹. 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.

History and etymology

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

Differential diagnosis

General imaging differential considerations include:

• multiple sclerosis

• CADASIL

• subcortical arteriosclerotic encephalopathy

• CNS vasculitis

• brain tumor