ETIOLOGY OF ISCHEMIC STROKE
Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations
Updated on 19/06/2024, published on 13/06/2024
- Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S) is a very rare, autosomal dominant (AD) vasculopathy caused by mutations in TREX1
- in earlier reports, the following terms were used to describe RVCL-S
- cerebroretinal vasculopathy (CRV)
- hereditary vascular retinopathy (HVR)
- hereditary systemic angiopathy (HSA)
- hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS)
- RVCL-S is a multisystemic disease presenting with:
- leukoencephalopathy (stroke)
- progressive visual loss
- systemic manifestations, including Raynaud’s phenomenon, anemia, and liver and kidney disease
- RVCL-S leads to premature death, typically due to terminal pneumonia
- the TREX1 gene (also known as Three Prime Repair Exonuclease 1) encodes a DNA exonuclease that plays a critical role in DNA repair
- it helps maintain genomic stability and prevents the accumulation of single-stranded DNA (ssDNA) in the cytoplasm, which could potentially trigger autoimmunity
- mutations in this gene result in:
- RVCL-S
- Aicardi-Goutieres syndrome (early-onset neonatal form)
- Familial Chilblain Lupus (FCL) – TREX1 mutations can cause a form of monogenic lupus characterized by skin lesions, arthritis, and other systemic manifestations
- cryofibrinogenemia – an association with heterozygous mutations in TREX1 has been reported (Paradis, 2019)
Pathology and pathophysiology
- RVCL-S is caused by mutations in the TREX1 gene, which encodes a DNA exonuclease; this mutation leads to widespread endothelial dysfunction due to the accumulation of intracellular DNA debris
- the basement membrane abnormalities can be seen on electron microscopy (ELM)
- there is no evidence of either abnormal mitochondria or accumulation of mitochondria in any tissue examined
- the brain lesions are caused by cerebral infarction due to the altered capillaries and arterioles (arteriolopathy)
- fresh lesions may show contrast enhancement on MRI, indicating a breakdown of the blood-brain barrier (BBB)
Clinical presentation
- progressive visual loss
- RVCL-S typically begins in the 3rd or 4th decade of life, followed by focal neurological deficits within 4–10 years
- visual loss affects the central vision with reduced visual acuity; blind spots in the visual field are also common
- long-term psychiatric symptoms, such as depression, anxiety, and paranoia, begin as early as the second decade of life
- stroke-like episodes
- strokes or TIAs that typically occur in young adults without traditional cardiovascular risk factors
- stroke typically progresses over several days before reaching a plateau
- signs of multifocal cortico-subcortical involvement, such as dysarthria, hemiparesis, apraxia, ataxia, and dementia, are typical in advanced stages
- migraine headaches
- nephropathy (50% of cases) – may manifest as proteinuria and hematuria; HERNS can also lead to progressive renal failure
- other (liver disease, anemia, hypothyroidism, Raynaud’s phenomenon
Diagnostic evaluation
Ophthalmologic evaluation
- retinal vasculopathy is most prominent in the macular area
- fluorescein angiogram (FAG) shows juxtafoveal capillary obliteration with tortuous telangiectatic microaneurysms
- peripheral retinopathy, including telangiectasias, may occur later
Neuroimaging
- CT – nonspecific arteriolopathic changes, possible calcifications
- MR:
- multifocal T2 hyperintense lesions in the deep white matter and basal ganglia (lacunes) (Stam, 2016)
- lesions are non-specific but remarkable for relatively young patients
- tumefactive lesions surrounded by edema (in 75% of RVCL-S patients, most often in later stages) (Raynowska, 2018)
- T2 hyperintense
- T1 hypointense
- lesions spare the cortex
- lesions show long-lasting nodular or rim enhancement after gadolinium contrast
- multifocal T2 hyperintense lesions in the deep white matter and basal ganglia (lacunes) (Stam, 2016)
- some of the above-stated neuroimaging characteristics may be observed in other small-vessel diseases; the pattern and evolution of the findings are typical for RVCL-S (the long-term contrast enhancement with long-term diffusion restriction) (Hedderich, 2020)
- neuroimaging findings in RVCL-S have been mistaken for vasculitis, multiple sclerosis, or neoplasms in the past
Genetic testing
- confirmatory testing for mutations in the TREX1 gene
Main features |
|
Supportive features |
|
Treatment
- currently, there is no known causal treatment
- a clinical trial with crizanlizumab is ongoing; crizanlizumab targets a protein called P-selectin, which captures blood cells and can contribute to blockages in small blood vessels
- CRISPR-based editing technologies are developed
- antiplatelet therapy
- corticosteroid therapy can be considered for tumefactive lesions with surrounding edema
- treatment of retinopathy (laser/anti-VEGF therapy) and glaucoma