Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Abstract

See Charidimou (doi:10.1093/aww253) for a scientific commentary on this article.

Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1, which was termed ‘retinal vasculopathy with cerebral leukodystrophy’. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different TREX1 mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhancement in 97% of them; (ii) rim-enhancing mass lesions in 84%; and (iii) calcifications in the white matter in 52%. Ninety per cent had clinical manifestations of brain disease, including focal neurological deficits (68%), migraine (59%), cognitive impairment (56%), psychiatric disturbances (42%), and seizures (17%). One mutation carrier had enhancing brain lesions and neurological features but unknown retinopathy status. Additional systemic features included liver disease (78%), anaemia (74%), nephropathy (61%), hypertension (60%), mild Raynaud’s phenomenon (40%), and gastro-intestinal bleeding (27%). Mean (± standard deviation) age at diagnosis was 42.9 ± 8.3 years and at death 53.1 ± 9.6 years. Pathological examination revealed systemic vasculopathy with luminal narrowing and multi-laminated basement membranes. The 13 mutation carriers without retinopathy or brain lesions were on average 8 years younger (mean age: 35.1 ± 10.6 years). Of them, 54% had mild Raynaud’s phenomenon, 42% had migraine, and 23% had psychiatric disturbances. Retinal vasculopathy with cerebral leukodystrophy is an autosomal dominant systemic small-vessel disease due to specific TREX1 mutations and clinically primarily characterized by (i) visual impairment from vascular retinopathy; and (ii) neurological decline and premature death due to progressive enhancing cerebral white matter lesions. Impaired liver and kidney function, anaemia sometimes associated with gastrointestinal bleeding, hypertension, migraine, and Raynaud’s phenomenon appear to be part of the clinical spectrum as well. Penetrance seems high. Because of the pathogenetic basis and the emerging clinical picture with systemic manifestations and conspicuous absence of leukodystrophy, we renamed the disease ‘retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations’. We propose diagnostic criteria to facilitate clinical recognition and future studies.

Keywords: migraine; molecular genetics; neuro-ophthalmology; neuropathology; small vessel disease.

See Charidimou (doi:10.1093/aww253) for a scientific commentary on this article. Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations is a newly recognised and often misdiagnosed neurovascular syndrome caused by mutations in TREX1. Stam et al. provide the first comprehensive clinical, pathological and radiological characterization of RVCL-S, and highlight cerebral mass lesions, impaired liver and kidney function, and premature death.

Figure 1

Typical case and clinical course of RVCL-S. At age 52, this male (Family 2, V235fs mutation) noted progressive bilateral loss of vision. Ophthalmologic examination revealed vascular retinopathy. At age 58 he developed slowly progressive right-sided hemiparesis. He became intermittently irritable and passive, and complained of headaches. His medical history revealed Raynaud’s phenomenon and paroxysmal atrial fibrillation. MRI revealed a rim-enhancing lesion with mass-effect and surrounding oedema in the left frontal white matter (A1: gadolinium-enhanced T₁-weighted; A2: non-enhanced T₁-weighted) with focal calcifications on CT (not shown). Two smaller rim-enhancing lesions were noted periventricularly in the right frontal (arrows, A3: gadolinium-enhanced T₁-weighted; A4: non-enhanced T₁-weighted) and parietal lobes (arrows, A5: gadolinium enhanced T₁-weighted; A6: non-enhanced T₁-weighted). Biopsy of the left fronto-parietal lesion revealed tissue necrosis. Dexamethasone (60 mg for 10 days) slightly improved the hemiparesis. Four months later, his headaches became worse and he developed word-finding difficulties and wide-based gait. Routine laboratory investigation revealed mild anaemia and mildly impaired renal and liver function. CSF protein was mildly increased but cell count was normal; there were no oligoclonal bands. Antinuclear antibodies, extractable nuclear antigens, anticardiolipin IgG and IgM, and anti-neutrophilic cytoplasmic antibodies were all negative. The left frontal lesion had diminished in size on MRI and enhancement was only minimal; the surrounding oedema and gliosis, however, had remained as a large zone of confluent T₂ hyperintensities with small nodular foci of faint enhancement (B1: gadolinium enhanced T₁-weighted; B2: FLAIR). Half a year later his condition worsened and he became easily agitated with emotional lability, disorientation, apathy, and urinary incontinence. Additionally, he developed left-sided hemiparesis with facial weakness and could walk only with assistance. MRI (C1: gadolinium enhanced T₁-weighted; C2: FLAIR) revealed, exactly where previous MRI’s had shown a pre-existing punctate enhancing white matter lesion, a large irregularly rim-enhancing lesion with central necrosis and a large zone of surrounding oedema, which extended into the corpus callosum, basal ganglia, and parietal and temporal lobes, and which exerted some mass-effect on the right lateral ventricle. The pre-existing lesion adjacent to the parietal horn of the right lateral ventricle had not changed significantly. A second biopsy showed mainly necrotic tissue. Corticosteroids temporarily improved his gait. Repeat MRI (D1 and D2: gadolinium enhanced T₁-weighted) 2 months later showed a persistent right frontal lesion. Open biopsy and partial debulking of the right frontal lesion were performed. Pathology showed largely necrotic tissue with scattered inflammatory cells, mainly around the vessel walls, which were thickened with adventitial fibrosis. In the following year, his condition deteriorated and he died of aspiration pneumonia at age 60. Autopsy was performed and the data are included in Fig. 3.

Figure 2

Fundoscopic (A and C) and fluorescein angiogram (B and D) images of vascular retinopathy. (A and B) Right eye of a 33-year-old male with cotton-wool spots (arrows, A), extensive areas of capillary obliteration with non-perfusion (arrows, B), and intraretinal microvascular abnormalities (arrow heads, B). (C and D) Right eye of a 48-year-old female with a neovascular membrane (arrowheads, C) and preretinal haemorrhage (arrow, C). Temporal to the macula, vascular sheathing and occlusion is present (asterisk, C). The same eye shows profuse leakage from the membrane on the disc (arrow, D) and a large avascular region involving the fovea (arrow heads, D).

Figure 3

Representative histopathologic findings in the retina, brain and kidney. Microscopic examination of various organs shows a characteristic vasculopathy. The vessels of the inner layers of the retina often demonstrate damage to the walls with occasional deposition of amorphous material [arrow (A)] or thickened collagenous walls. H&E = haematoxylin and eosin stain; Vit = vitreous; NL = nerve fibre layer; GCL = ganglion cell layer; IPL = inner plexiform layer; INL = inner nuclear layer; OPL = outer plexiform layer. The brain also shows a prominent vasculopathy in the white matter, most often adjacent to and in sites of coagulation necrosis. Small to medium sized vessels demonstrate vascular wall thickening with varying degrees of luminal narrowing [arrows; (B) haematoxylin and eosin; brain). In some cases, this progresses to a frank fibrinoid necrosis. In areas with extensive white matter ischaemic damage, granular calcifications are particularly evident (dark blue staining in lower left of B). The vasculopathy may result in luminal obliteration leading to parenchymal necrosis (C; haematoxylin and eosin; brain). There is concentric collagenous thickening of the vessel walls, mostly involving the medial layer of the vessels (D; Trichrome stain; brain). Ultrastructural examination of affected vessel walls in the brain demonstrates multilaminated basement membranes with duplication of the lamina densa [arrowheads; (E) electron microscopy] in contrast to that found in unaffected regions [arrowhead; (F) electron microscopy]. lum = lumen; EN = endothelial cell. In the kidney, the vasculopathy is manifested by arteriosclerosis [arrow; (G) haematoxylin and eosin] and glomerulosclerosis.

Figure 4

Neuroimaging in RVCL-S. (A) Characteristic changes over time of contrast-enhancing cerebral mass lesions and white matter hyperintensities indicative of small vessel disease in a patient with RVCL-S. Small to middle-large deep and periventricular non-specific T₂ hyperintense white matter lesions, as shown in the first MRI (0 months, axial FLAIR), are seen in the early phases of RVCL-S. There seem to be a predilection for the periventricular white matter next to anterior horn and, to a lesser extent, the posterior horn. The asymmetric pattern of affected white matter might be a hallmark of RVCL-S. Some small lesions showed diffusion restriction and minimal contrast-enhancement (e.g. the periventricular lesion next to the left anterior horn at 19 months). Nineteen months later, a right frontal rim-enhancing lesion with associated calcification (unenhanced CT) and perifocal oedema (gadolinium enhanced T₁-weighted MRI) has developed on the location of a pre-existing punctate white matter hyperintensity. MRIs at 2, 3 and 11 months after corticosteroid treatment for several weeks with clinical improvement show progressive reduction of the cerebral oedema and contrast enhancement (gadolinium enhanced T₁-weighted MRIs). (B) Cerebral MRI scans of five different patients, each with a different TREX1 frameshift mutation, showing that all known RVCL-S TREX1 mutations are associated with the same type of white matter lesions. V235fs: Axial T₁-weighted (left) and axial gadolinium enhanced T₁-weighted (right) MRI images of a 59-year-old male (Family 2) with a right frontal rim-enhancing lesion with mass-effect and surrounding oedema. T236fs: Axial T₁-weighted (left) and axial gadolinium enhanced T₁-weighted (right) images of a 40-year-old male (Family 7) showing a left frontal rim-enhancing lesion, a smaller rim-enhancing lesion left parietal, and an enhancing punctate right frontal periventricular white matter hyperintensity. T249fs: Axial (left) and coronal (right) gadolinium enhanced T₁-weighted images (Family 8) show a left frontal rim-enhancing lesion with mass-effect and some enhancing punctate T₂ hyperintensities in the right frontal lobes. R284fs: Axial T₁-weighted (left) and FLAIR (right) images of a 32-year-old female (Family 10) showing a large right frontal rim-enhancing lesion and non-enhancing periventricular white matter hyperintensities frontal left. L287fs: Sagittal T₁-weighted images of a 58-year-old male (Family 11) reveal small and medium-sized non-enhancing periventricular and subcortical white matter hyperintensities.