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.
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:
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.
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
- 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 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.
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 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.
General imaging differential considerations include:
- 1. Stam AH, Kothari PH, Shaikh A, Gschwendter A, Jen JC, Hodgkinson S, Hardy TA, Hayes M, Kempster PA, Kotschet KE, Bajema IM, van Duinen SG, Maat-Schieman ML, de Jong PT, de Smet MD, de Wolff-Rouendaal D, Dijkman G, Pelzer N, Kolar GR, Schmidt RE, Lacey J, Joseph D, Fintak DR, Grand MG, Brunt EM, Liapis H, Hajj-Ali RA, Kruit MC, van Buchem MA, Dichgans M, Frants RR, van den Maagdenberg AM, Haan J, Baloh RW, Atkinson JP, Terwindt GM, Ferrari MD. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain : a journal of neurology. doi:10.1093/brain/aww217 - Pubmed
- 2. Charidimou A. Defining retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain. 139 (11): 2819. doi:10.1093/brain/aww253
- 3. Grand MG, Kaine J, Fulling K, Atkinson J, Dowton SB, Farber M, Craver J, Rice K. Cerebroretinal vasculopathy. A new hereditary syndrome. Ophthalmology. 95 (5): 649-59. Pubmed
- 4. Storimans CW, Van Schooneveld MJ, Oosterhuis JA, Bos PJ. A new autosomal dominant vascular retinopathy syndrome. European journal of ophthalmology. 1 (2): 73-8. Pubmed
- 5. Winkler DT, Lyrer P, Probst A, Devys D, Haufschild T, Haller S, Willi N, Mihatsch MJ, Steck AJ, Tolnay M. Hereditary systemic angiopathy (HSA) with cerebral calcifications, retinopathy, progressive nephropathy, and hepatopathy. Journal of neurology. 255 (1): 77-88. doi:10.1007/s00415-008-0675-3 - Pubmed
- 6. Jen J, Cohen AH, Yue Q, Stout JT, Vinters HV, Nelson S, Baloh RW. Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Neurology. 49 (5): 1322-30. Pubmed
- 7. Kolar GR, Kothari PH, Khanlou N, Jen JC, Schmidt RE, Vinters HV. Neuropathology and genetics of cerebroretinal vasculopathies. Brain pathology. 24 (5): 510-8. doi:10.1111/bpa.12178 - Pubmed
- 8. Rice GI, Rodero MP, Crow YJ. Human disease phenotypes associated with mutations in TREX1. Journal of clinical immunology. 35 (3): 235-43. doi:10.1007/s10875-015-0147-3 - Pubmed
- 9. Hasan M, Fermaintt CS, Gao N, Sakai T, Miyazaki T, Jiang S, Li QZ, Atkinson JP, Morse HC, Lehrman MA, Yan N. Cytosolic Nuclease TREX1 Regulates Oligosaccharyltransferase Activity Independent of Nuclease Activity to Suppress Immune Activation. Immunity. 43 (3): 463-74. doi:10.1016/j.immuni.2015.07.022 - Pubmed
- 10. Weil S, Reifenberger G, Dudel C, Yousry TA, Schriever S, Noachtar S. Cerebroretinal vasculopathy mimicking a brain tumor: a case of a rare hereditary syndrome. Neurology. 53 (3): 629-31. Pubmed