A case of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Abstract

Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) is an autosomal dominant disorder caused by mutations in the TREX1 gene, which affects medium and small arteries and veins. Reported in fewer than 50 families worldwide, RVCL typically affects individuals between 35 and 40 years of age. It commonly presents with vision disturbances due to retinal vasculopathy and neurological deficits from cerebral leukoencephalopathy. Tumefactive brain lesions are sometimes seen, which can resemble gliomas or tumefactive multiple sclerosis. RVCL is also associated with systemic manifestations, including Raynaud's phenomenon, anemia, migraines, psychological issues, and dysfunction of organs such as the kidneys, liver, gastrointestinal system, and thyroid. A positive family history is frequently noted. Early recognition of RVCL is crucial for preventing unnecessary invasive procedures, facilitating early diagnosis, and enabling family counseling. This report presents a case of RVCL-S that was initially misdiagnosed as a glioma.

Background

Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) is a rare autosomal dominant systemic small-vessel disease caused by specific mutations in the TREX1 gene [1]. It is primarily characterized by visual impairment due to vascular retinopathy and progressive neurological decline leading to premature death from enhancing cerebral white matter lesions. Additional clinical manifestations, including impaired liver and kidney function, anemia, hypertension, migraine, and Raynaud’s phenomenon, may also occur. When these systemic symptoms are present, the condition is referred to as retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) [[2], [3], [4], [5]].

RVCL-S has been identified in fewer than 50 families, which may be partly due to underdiagnosis, as awareness of the condition is limited. Its heterogeneous phenotype, with varied presentations and systemic manifestations, often leads to misdiagnosis, as RVCL mimics other disorders. A family history of autosomal dominant inheritance and middle-age onset of symptoms can help support the diagnosis of RVCL-S [[6], [7], [8], [9], [10]].

Stam et al. [7] reported neuroimaging findings in a large cohort of patients with TREX1 mutation carriers, noting T2 hyperintense white matter lesions sparing the grey matter in all but one patient. These lesions were categorized as non-enhancing punctate lesions, punctate lesions with nodular enhancement, and larger mass lesions with rim enhancement, edema, and mass effect. Non-enhancing punctate lesions were present in 97% of patients, typically in the supratentorial periventricular and subcortical white matter, with some showing diffusion restriction or calcifications. About 25% of patients had enhancing lesions, often with diffusion restriction. Rim-enhancing mass lesions, seen in 84% of patients, were more common in advanced disease and varied in size, with some reaching up to 6 cm. Focal calcifications were found in 52% of patients. The rim-enhancing lesions with surrounding edema and mass effect, called pseudotumor, are often misdiagnosed as gliomas or tumefactive multiple sclerosis.

Here, we present a case of RVCL-S that was initially misdiagnosed as a high-grade glioma.

Case report

A 43-year-old male presented to the emergency department with a 3-day history of nausea and vomiting following mild head trauma.

Initial computed tomography (CT) revealed a mass in the left basal ganglia with surrounding white matter edema in the left frontal lobe, causing mass effect on the left lateral ventricle (Fig. 1). Subsequent contrast-enhanced MRI of the brain showed a large, peripherally enhancing lesion in the left basal ganglia, with associated restricted diffusion, internal hemorrhage, surrounding edema, and mass effect on the lateral ventricle, resulting in a midline shift. Additionally, multiple small lesions were noted in the supratentorial periventricular white matter (Fig. 1). These findings raised concern for a high-grade glioma with satellite lesions.

Fig. 1.

Axial (A) images from the computed tomography (CT) scan of the brain reveal extensive white matter edema involving the left frontal lobe and left basal ganglia, with a mass effect on the left lateral ventricle causing a mild rightward midline shift. Axial T1-weighted pre-contrast image (B), axial T1 weighted post-contrast image (C, G and H), axial T2/FLAIR images (D and F), axial susceptibility-weighted images (E), axial diffusion-weighted images (I), and the apparent diffusion coefficient (ADC) map (J) from magnetic resonance imaging (MRI) of the brain show a peripherally enhancing lesion centered in the left basal ganglia, associated with diffusion restriction on DWI and ADC map (I and J) and internal hemorrhage on the susceptibility-weighted image (E). Surrounding edema extends into the left frontal lobe, as seen on FLAIR images, causing mass effect on the left lateral ventricle and resulting in a rightward midline shift. Additionally, 2 small enhancing foci in the left periventricular white matter on the T1-weighted post-contrast images (G and H) with associated edema on FLAIR (F).

An initial brain biopsy of the dominant left basal ganglia lesion revealed a macrophage-dominant inflammatory process with necrosis (Fig. 2). The differential diagnosis included atypical infection, tumefactive multiple sclerosis, or central nervous system vasculitis. Further inquiry revealed a history of Raynaud's disease in the patient and a family history of vision changes, blindness, and brain tumors in the patient’s father and other first-degree relatives.

Fig. 2.

Histological sections show brain parenchyma with mild hypercellularity. The H&E stain (A) shows inflammatory cells with tissue necrosis (marked by arrow). There is abundant macrophage infiltration stained with CD163 (B) with T-cell lymphocytic perivascular cuffing stained with CD3 (C). However, no definitive granuloma is identified. Multiple giant cells are identified. Luxol fast blue stain (D) shows myelin loss with myelin phagocytized by macrophages. Neurofilament stain (E) shows partial axon loss with a few “spheroid” structures indicating axon damage. A few polymorphonuclear cells are seen in the necrotic area. The Glial fibrillary acidic protein (F) shows reactive glial cells (marked by arrow). Overall, this represents an acute and chronic inflammatory cell infiltrate, with perivascular cuffing, reactive glial cells, myelin loss and tissue necrosis.

Ophthalmology was consulted, and fundoscopic examination revealed retinal vasculopathy with an avascular area in the peripheral retina and retinal neovascularization. Given the family history of vision changes and a presumed diagnosis of brain tumors in family members, the patient was clinically diagnosed with retinal vasculopathy and cerebral leukoencephalopathy and systemic manifestations (RVCL-S). This diagnosis was subsequently confirmed through molecular genetic testing, which identified a TREX1 gene mutation, consistent with RVCL-S.

Discussion

We present a case of RVCL-S that was initially misdiagnosed as a high-grade glioma, leading to a biopsy. RVCL-S typically presents with vascular retinopathy, which in its early stages is characterized by retinal hemorrhages, intraretinal microvascular abnormalities, and/or cotton wool spots. The other most common manifestation includes focal and/or global brain dysfunction, detectable on MRI as punctate T2 hyperintense white matter lesions with nodular enhancement, or larger mass lesions with rim enhancement, mass effect, and surrounding edema. A family history of autosomal dominant inheritance with middle-age onset of symptoms is often present. The diagnosis is often confirmed by a C-terminal frame-shift mutation in the TREX1 gene. Other features which may suggest the diagnosis include focal white matter calcifications on CT or non-enhancing punctate T2 hyperintense white matter lesions on MRI, which are unusual for age-related changes, microvascular liver disease, such as nodular regenerative hyperplasia, and microvascular kidney disease, such as arterionephrosclerosis or glomerulosclerosis. Anemia (often due to blood loss or chronic disease), microscopic gastrointestinal bleeding, hypertension, migraines (with or without aura), and mild Raynaud’s phenomenon have also been reported [7].

Stam et al. [7] reported on a large cohort of TREX1 mutation carriers, where patients were screened for RVCL-S due to visual disturbances in 61%, neurological issues in 21%, and a positive family history in 8% of cases. At the time of diagnosis, 92% of patients had vascular retinopathy, 77% experienced visual disturbances, and 26% had neurological symptoms. Over time, all patients developed vascular retinopathy, and many experienced neurological decline, with 68% developing focal deficits, 56% showing cognitive impairment, 42% exhibiting psychiatric symptoms such as depression and anxiety, and 17% having seizures. Brain lesions progressively increased in both number and size on imaging, with the exception of one patient. In the early stages of retinopathy, the condition was characterized by telangiectasias, micro-aneurysms, and cotton wool spots, which later progressed to perifoveal capillary obliteration and neovascularization. Autopsy findings in 8 cases revealed retinal micro-infarcts, thickened hyalinized walls in the retinal arteries, and localized damage to the ganglion cells and inner nuclear layer, often accompanied by vascular changes. In some cases, the disease advanced to retinal hemorrhage and neovascularization [7].

In conclusion, RVCL-S can present as large white matter mass-like lesions, also known as “pseudotumor,” which are accompanied by perilesional edema and mass effect, with the potential to progressively increase in size and number over time. However, the presence of systemic manifestations, particularly vision disturbances related to retinal vasculopathy, along with a strong family history, should raise suspicion for RVCL-S rather than glioma or tumefactive demyelination.

Patient consent

Informed consent was obtained from the patient by MK.