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Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)
Literature review current through: Jan 2024.
This topic last updated: Sep 02, 2022.

INTRODUCTION — Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an autosomal dominant inherited angiopathy caused by mutations in the three-prime repair exonuclease 1 (TREX1) gene [1,2]. RVCL-S is an underrecognized disorder. The main causes of morbidity and mortality are vascular retinopathy, focal neurologic complaints including ischemic events and cognitive decline, and kidney failure [1].

TERMINOLOGY — Other terms used for RVCL-S in early reports include the following [1,2]:

Cerebroretinal vasculopathy

Hereditary vascular retinopathy

Hereditary endotheliopathy, retinopathy, nephropathy, and stroke

Hereditary systemic angiopathy

Retinal vasculopathy with cerebral leukodystrophy

Retinal vasculopathy with cerebral leukoencephalopathy

PATHOPHYSIOLOGY — RVCL-S is caused by carboxyl terminal (C-terminal) truncating mutations in the three-prime repair exonuclease 1 (TREX1) gene [1,2].

Genetics — RVCL-S is an autosomal dominant condition caused by heterozygous frameshift or nonsense pathogenic variants in the carboxyl terminal (C-terminal) of the TREX1 gene [1,2]. Fewer than 15 pathogenic variants of TREX1 are known to cause RVCL-S [1,3-7]. The most frequently diagnosed pathogenic variant is a frameshift mutation (V235Gfs*6).

Although penetrance seems to be 100 percent, the clinical course of RVCL-S is highly variable between and within families [1]. While it seems probable that index patients are more severely affected than other relatives, this is not always the case, and the issue is complicated by misdiagnosis of family members [1,8]. More research is needed to further assess family members with a relatively late disease onset and a relatively slow progression.

TREX1 has two major domains. The N-terminus, containing three exonuclease sequence motifs, is responsible for exonuclease activity and maintains innate immune tolerance to self-DNA [9-11]. The C-terminal domain is required for its localization to and its interaction with the endoplasmic reticulum [2,9,12-14].

Pathogenic variants leading to RVCL-S result in a truncated TREX1 protein. The exonuclease function of TREX1 is not affected while the subcellular localization is shifted [2,13,14], which alters its interaction with the endoplasmic reticulum.

RVCL-S is not the only disease associated with pathogenic variants in TREX1. Variants affecting the exonuclease function of TREX1 are associated with three autoimmune diseases:

Aicardi-Goutières syndrome, an early-onset encephalopathy caused by pathogenic variants in several genes, including TREX1 [15,16].

Familial chilblain lupus, a rare form of chilblain lupus erythematosus that is caused by heterozygous pathogenic variants in the TREX1 or SAMHD1 genes. (See "Pernio (chilblains)", section on 'Chilblain lupus erythematosus'.)

Genetic predisposition to systemic lupus erythematosus. (See "Epidemiology and pathogenesis of systemic lupus erythematosus", section on 'Genetic factors'.)

Moreover, a synonymous variant in TREX1 (ie, no change in amino acid) was associated with an increased risk of systemic sclerosis in one report [17].

Vascular changes — The underlying lesion of RVCL-S is a nonatherosclerotic, amyloid-negative angiopathy involving small arteries and capillaries, primarily in the retina and brain, but also in other organs [1,18].

Morphologic studies have demonstrated thicker multilaminated basement membranes and fibrous thickening of small vessel walls in patients with RVCL-S [1]. While TREX1 transcripts have been identified at the RNA level in all tissues examined, more research is needed into the endogenous expression of the protein and the mutated protein [19]. TREX1 was found to be expressed in a subset of microglia in the normal human brain, often in close proximity to the microvasculature. Interestingly, in ischemic lesions, the amount of TREX1-positive microglia was increased [20,21]. This indicates a possible role for TREX1 and microglia in vessel homeostasis and response to ischemic injury. There is also an increased expression of TREX1 in the undamaged white matter of patients with RVCL-S, suggestive of a widespread ongoing injury that cannot be detected histologically [20,21]. Moreover, TREX1 was found to be expressed in endothelial cells in the brain of a RVCL-S patient indicating a possible direct effect on endothelium function [21].

Besides the morphologic alterations, other indications of vessel pathology in RVCL-S are also present. These include impairment of endothelial function [22] and elevated markers of chronic endothelial activation (von Willebrand factor and angiopoietin-2) [23]. Furthermore, impaired cerebrovascular reactivity, a marker for cerebrovascular health, is found in patients with RVCL-S [24].

Animal studies have found that, compared with wild-type littermates, RVCL-S transgenic knock-in mice have increased mortality, evidence of abnormal vascular function, and increased infarct volume with experimental stroke [25].

Autoinflammation could also contribute towards the observed phenotype. One study found that both erythrocyte-sedimentation rate (ESR) and fibrinogen levels were elevated in patients with RVCL-S [18]. It has been hypothesized that immune activation in RVCL-S is due to immunogenic free glycans release demonstrated in lymphoblasts of patients with RVCL-S [13]. Furthermore, in a conditional knock-in mice model of RVCL-S (carrying the V235Gfs*6 pathogenic variant), a distinct autoantibody profile was found compared with wild-type mice [26].

Pathology — Most autopsy studies have been carried out in patients with advanced disease, and several (nonspecific) findings have been reported. Histopathologic examination of the retina has demonstrated scattered microinfarctions, hemorrhages, and neovascularization [1]. Additionally, retinal artery walls show thickening and the ganglion cell and inner nuclear layer of the retina can be focally disrupted [1].

Macroscopic evaluation of the brain demonstrates involvement of the periventricular white matter, particularly in the frontoparietal regions. In few cases, the brainstem and cerebellum were also involved. Microscopic examination of the brain can also show ischemic areas, thickening of vessel walls, and substantial myelin loss [1,21]. In some patients there is a modest chronic inflammatory cell infiltrate near ischemic lesions [1]. Frequently, focal calcifications and reactive astrocytosis are demonstrated [1,21]. Less often, vascular telangiectasia are found [1].

Examination of the liver demonstrates nodular regenerative hyperplasia and steatosis, periportal inflammation, and bridging. In the kidney, arterio- or arteriolonephrosclerosis and focal or diffuse glomerulosclerosis have been found [1].

Genotype-phenotype correlations — No clear genotype-phenotype associations have been identified. Patients with RVCL-S demonstrate a surprisingly similar phenotype. An association between a higher age of onset and the V235fs mutation has been described [1,27]; however, as few patients have been described, this observation requires further confirmation.

EPIDEMIOLOGY — RVCL-S is rare. Worldwide, fewer than 35 families with confirmed RVCL-S had been identified as of 2022 [1,3-8,14,21,28-33]. However, this number is likely to be an underestimate, given the finding of three unrelated families with RVCL-S in one small country (the Netherlands) alone [1]. Moreover, RVCL-S is often confused with other disorders (see 'Differential diagnosis' below). With more awareness and new genetic screening techniques, such as whole exome sequencing, new cases and more families will be identified.

CLINICAL FEATURES

Major features — The clinical presentation of RVCL-S differs between and within families. The primary manifestations are:

Vascular retinopathy

Features of focal and/or global brain dysfunction with the following:

Ischemic stroke and transient ischemic attack (TIA)

Non-ischemic events leading to acute or subacute focal and global deficits

Cognitive decline

Migraine

Seizures

Psychiatric disturbances

Additional features often include renal dysfunction, liver dysfunction, anemia, hypertension, Raynaud phenomenon, and subclinical hypothyroidism [1,18]. Less common manifestations include avascular necrosis of the femoral head, (hypertensive) cardiomyopathy, and cutaneous abnormalities (macular rash and punctate skin lesions) [3,6,8,14,34,35].

Age of onset — The onset of symptoms with RVCL-S occurs in adulthood, typically between 30 and 50 years of age [1]. Medical assistance is also frequently sought earlier because of a positive family history [1]. Presenting symptoms are most often visual complaints or neurologic dysfunction. It is observed that the age at onset of migraine in patients with RVCL-S may be high (40 years), whereas onset of disease normally is in adolescence (<25 years), which suggests that migraine may occur secondary to the vasculopathy [18].

Vascular retinopathy — Symptomatic retinopathy appears to develop in all patients with RVCL-S [1,3-5,14,30,36-39]. Decreased visual acuity and/or visual field defects due to vascular retinopathy are the most common presenting symptoms of RVCL-S [1]. Vascular retinopathy is characterized in the early stages by telangiectasia, micro-aneurysms, and cotton wool spots. Later, perifoveal capillary obliterations and neovascularizations occur [1,38]. Secondary glaucoma and macula edema can develop as complications of the retinopathy. (See 'Ophthalmologic examination' below.)

Neurologic manifestations

Ischemic episodes – Ischemic stroke and TIAs are manifestations of RVCL-S. Ischemic episodes present as a classic lacunar syndromes (eg, pure motor stroke, ataxic-hemiparesis, dysarthria-clumsy hand syndrome, pure sensory stroke, sensorimotor stroke), but other lacunar syndromes (brainstem or hemispheric) are also observed [1,40]. (See "Lacunar infarcts".)

Note that it may be difficult to distinguish ischemic events from nonischemic causes of acute focal dysfunction in RVCL-S.

Subacute or acute focal and global brain dysfunction – Neurologic symptoms are frequent in RVCL-S. Focal neurologic symptoms and cognitive impairment are described in 68 and 56 percent of symptomatic patients, respectively [1]. At time of death, 97 percent of mutation carriers had focal brain features and 75 percent had cognitive impairment [1]. A wide range of focal neurologic symptoms are found [1,3-5,7,14,30,36,37].

Focal neurologic symptoms (eg, hemiparesis, aphasia, facial weakness, hemianopsia) can be associated with intracerebral mass lesions (image 1), called pseudotumors [1,3,5-7,14,35-37]. (See 'Neuroimaging' below.)

The global brain dysfunction seen in RVCL-S can manifest as many different complaints, most frequently bradyphrenia, apathy, irritability, and complaints of memory and judgement [1,30,39].

Cognitive decline – Cognitive deficits are one of the most frequent features of RVCL-S, observed in about 56 percent of symptomatic patients [1]. Cognitive decline seems to be slowly progressive, with additional stepwise deterioration superimposed, as may be seen in other hereditary small vessel disorders. Neuropsychologic testing usually shows deficits in multiple cognitive domains including working memory, executive function, and cognitive processing speed [1,41].

Migraine – Migraine (with and without aura) occurs in up to 42 percent of RVCL-S cases [1]. Migraine onset in patients with RVCL-S often occurs in adulthood (eg, age 40 years), whereas migraine onset in the general population typically occurs in childhood or adolescence, which suggests that migraine may occur secondary to the vasculopathy [18]. Unlike other small-vessel conditions associated with migraine (ie, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]), RVCL-S has not been associated with atypical aura symptoms such as prolonged auras (>60 minutes), motor auras, or auras with acute onset [1,18].

Epilepsy – In a large cross-sectional study 17 percent of patients with RVCL-S suffered from seizures [1,14,37].

Psychiatric disturbances — Mood disorders occur in 42 percent of patients. Many patients develop adjustment disorder or moderate depression, but major depression, psychosis, anxiety, and other psychiatric complaints have all been reported [1,14,37]. Apathy, defined as a primary loss of motivation, has been reported in clinical practice. Although apathy frequently occurs with depression, apathy may develop in the absence of depression [1,14,37].

Systemic manifestations

Renal disease – Renal involvement occurs in approximately 30 to 50 percent of the patients [1,18]. Most frequently kidney involvement has a mild phenotype, however, occasionally fatal stage 4 kidney disease occurs [1,3,4,14,30,36].

Liver disease – Mildly elevated levels of alkaline phosphatase and gamma-glutamyltransferase are the most frequent manifestations of liver disease in RVCL-S [1,30,35,37].

Additional symptoms – RVCL-S patients appear to suffer from hypertension [1,3,4,18,39]. Additionally, mild to moderate anemia occurs, which may be explained, at least partially, by the microscopic gastrointestinal bleeding that occurs in RVCL-S [1,4,18]. Raynaud phenomenon, usually mild, is present without causing ischemic injury [1,18,39]. One study demonstrated subclinical hypothyroidism as part of the phenotype [18]. Some evidence suggests that the phenotype should be extended to include avascular necrosis of the femoral head, hypertension, cardiomyopathy, and skin lesions [3,6,8,14,34,35].

There are no reports that RVCL-S is associated with complications during pregnancy.

EVALUATION AND DIAGNOSIS

When to suspect the diagnosis — The diagnosis of RVCL-S should be suspected when adult patients of middle age (eg, 30 to 50 years) present with vascular retinopathy (eg, with retinal cotton-wool spots, perifoveal telangiectasias and capillary obliteration, peripheral focal capillary occlusion, and microvascular abnormalities), and/or focal or global neurologic deficits, with characteristic "pseudotumors" and/or small T2 hyperintense lesions on brain magnetic resonance imaging (MRI) with or without gadolinium enhancement (see 'Neuroimaging' below), particularly in the setting of a positive family history of retinopathy or neurologic disease. (See 'Ophthalmologic examination' below.)

Note that a negative family history does not exclude RVCL-S, since de novo pathogenic variants of three-prime repair exonuclease 1 (TREX1) are reported [14,32]. Furthermore, family members with RVCL-S may be misdiagnosed with other conditions (eg, neurodegenerative disorder, brain tumor, multiple sclerosis, hypertensive, diabetic retinopathy). (See 'Potential misdiagnosis' below.)

Confirming the diagnosis — The diagnosis of RVCL-S is confirmed with the identification of a heterozygous pathogenic variant in TREX1 by molecular genetic testing. (See 'Molecular genetic testing' below.)

Pathologic confirmation (eg, by brain biopsy) is not required.

Investigations — Patients suspected of having RVCL-S should be evaluated with the following investigations:

Molecular genetic testing, if the clinical features, neuroimaging, and/or laboratory studies are consistent with a possible or probable diagnosis of RVCL-S

Brain MRI with and without gadolinium contrast, if not already performed

Ophthalmologic examination (including determining intraocular pressure, fluorescein angiography, and optical coherence tomography), if not already done

Serum creatinine

Measurement of urinary protein excretion (ie, urine protein and urine creatinine via a 24-hour urine collection or spot sample)

Liver enzymes, including serum aminotransferases, alkaline phosphatase, and gamma-glutamyltransferase

Complete blood count including hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, white blood cell (WBC) count, platelets, WBC differential, and reticulocytes

Examination of the peripheral blood smear

Thyroid function studies, beginning with serum thyroid stimulating hormone (TSH), followed by serum free thyroxine (T4) if the TSH level is elevated

Ophthalmologic examination — On ophthalmologic examination, patients with RVCL-S may have retinal cotton-wool spots, perifoveal telangiectasias and capillary obliteration, peripheral focal capillary occlusion, and microvascular abnormalities, predominantly affecting the posterior pole (image 2) [42,43]. Optical coherence tomography imaging often demonstrates peripapillary retinal nerve fiber layer thinning and a reduced total macular volume. Notably, in patients with a normal funduscopic examination, retinal thinning can sometimes already be detected [44].

Neuroimaging — Several different types of lesions have been described on MRI, which are all located in the white matter, sparing the cortex [1,24,45].

The most striking lesions are pseudotumors (also termed tumefactive brain lesions) that occur in up to 75 percent of symptomatic patients with RVCL-S [1,27]. Pseudotumors are mass lesions that are surrounded by extensive edema, which may lead to displacement of adjacent structures and sulci effacement (image 1). Pseudotumors are hyperintense on T2-weighted images, hypointense on T1-weighted images, and show ring enhancement with gadolinium contrast [1,3,5-8,14,35-37]. These lesions may grow in size, remain stable, or shrink over time [24].

Besides these tumefactive brain lesions, hyperintense T2-weighted punctate lesions with nodular or rim enhancement on T1-weighted sequences after gadolinium contrast frequently occur in periventricular and deep white matter, and in the basal ganglia (image 3) [1,4,24,45]. They are sometimes associated with diffusion restriction. Rim-enhancing lesions with prolonged diffusion restriction and long-lasting contrast enhancement are characteristic imaging findings in RVCL-S (image 4) [24,45].

Patients with RVCL-S can also have one or more punctate, contrast-enhancing lesions in the cerebellum, often bilateral. Cerebellar lesions appear to develop with more advanced disease and often increase in number over the years. Progression in size with rim enhancement is rare [24].

Susceptibility artefact is frequently seen in brain lesions on MRI [4,24]. As calcifications often occur in RVCL-S (best seen on computed tomography [CT] images) [1,27], not all susceptibility artefacts should be interpreted as microbleeds.

Small T2 hyperintense lesions, with minimal or no enhancement on T1 after gadolinium contrast, may be associated with diffusion restriction on MRI or calcifications on CT [1]. These lesions are present in the periventricular and deep white matter and, although nonspecific as solitary finding, occur more frequently than expected after accounting for the age of the patient [1,4,7,35].

Laboratory findings — Routine laboratory examinations demonstrate the systemic nature of the disease. The abnormalities include manifestations of [1,3,4,14,18,30,35-37]:

Kidney disease, demonstrated by increased serum creatinine and/or proteinuria

Liver disease, demonstrated by elevated liver enzymes, most frequently alkaline phosphatase and gamma-glutamyltransferase; in case of severe liver enzyme abnormalities, an ultrasound of the liver can be obtained and repeated to monitor for liver cirrhosis

Chronic anemia, most frequently normocytic and normochromic; a gastroscopy and/or colonoscopy can be performed to screen for gastrointestinal bleeding

Subclinical hypothyroidism as shown by elevated TSH and normal free T4

All abnormalities can range from mild to severe and might require treatment or further monitoring.

Molecular genetic testing — The approach to molecular genetic testing can involve single gene testing with sequence analysis of TREX1, or a multigene panel that evaluates TREX1 and other genes of interest, such as those causing adult-onset leukoencephalopathies and cerebral angiopathies [46]. Multigene panels may vary by laboratory in the included genes and the method of testing.

Diagnostic criteria — While there are no universally accepted diagnostic criteria for RVCL-S, the following criteria have been proposed [18,33]:

Diagnostic confirmation:

Demonstration of a C-terminal truncating pathogenic variant in TREX1 confirms the diagnosis

Major features:

Vascular retinopathy

Features of focal and/or global brain dysfunction associated on MRI with one or both of the following:

-Punctate T2 hyperintense white matter lesions with nodular enhancement

-Larger T2 hyperintense white matter mass lesions with rim-enhancement, mass effect, and surrounding edema

Family history of autosomal dominant inheritance with middle-age onset of disease manifestations (de novo mutations are possible)

Supportive features:

On CT, focal white matter calcifications and/or on MRI, non-enhancing punctate T2 hyperintense white matter lesions at an age that nonspecific, age-related white matter hyperintensities are infrequent

Microvascular liver disease (nodular regenerative hyperplasia)

Microvascular kidney disease (arterio- or arteriolonephrosclerosis, glomerulosclerosis)

Anemia consistent with blood loss and/or chronic disease

Microscopic gastrointestinal bleeding

Subclinical hypothyroidism

Possibly associated features:

Raynaud phenomenon (typically mild)

Migraine with or without aura

Hypertension

In order to firmly establish the diagnosis, documentation of a typical TREX1 pathogenic variant by genetic analysis is required.

Potential misdiagnosis — RVCL-S is frequently misdiagnosed as brain tumor, multiple sclerosis, vasculitis, neurodegenerative disorder, diabetic retinopathy, or other conditions [1]. Furthermore, unnecessary biopsies (eg, brain, kidney, and liver) have been performed as part of the evaluation.

DIFFERENTIAL DIAGNOSIS — Due to the systemic nature of RVCL-S, the differential diagnosis is very broad. As such, the combination of symptoms and a family history consistent with an autosomal dominant inheritance pattern are important for the diagnosis. MRI of the brain can be helpful in the differential diagnosis as rim-enhancing lesions with prolonged diffusion restriction and long-lasting contrast enhancement are characteristic imaging findings in RVCL-S [45].

A comprehensive differential diagnosis, attained by using the primary characteristics of RVCL-S, consists of a number of acquired and hereditary conditions discussed in the sections that follow.

Acquired disorders — The differential diagnosis of RVCL-S includes the following acquired disorders:

Sporadic small vessel disease (SVD) with or without hypertension as the main risk factor (see "Lacunar infarcts")

Multiple sclerosis (see "Clinical presentation, course, and prognosis of multiple sclerosis in adults" and "Evaluation and diagnosis of multiple sclerosis in adults")

Central nervous system vasculitis (see "Primary angiitis of the central nervous system in adults")

Intracranial neoplasm (see "Overview of the clinical features and diagnosis of brain tumors in adults")

Multi-infarct dementia (see "Etiology, clinical manifestations, and diagnosis of vascular dementia")

Diabetes mellitus (see "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults")

Sarcoidosis (see "Overview of extrapulmonary manifestations of sarcoidosis")

Susac syndrome, a rare disorder associated with the clinical triad of visual loss caused by branch retinal artery occlusions, sensorineural hearing loss, and subacute encephalopathy

Systemic lupus erythematosus (SLE; most frequently in SLE no autosomal inheritance pattern or genetic cause is found; however, in rare cases, monogenic SLE has been described (both autosomal dominant and recessive [47,48]) (see "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults")

Unlike RVCL-S, acquired disorders do not have a family history of autosomal dominant inheritance. However, RVCL-S could have been misdiagnosed or a de novo mutation could have occurred, so the absence of a family history alone does not exclude RVCL-S. (See 'Potential misdiagnosis' above.)

The major difference between multiple sclerosis, intracranial neoplasms, and multi-infarct dementia is that RVCL-S involves multiple organs besides the brain. Central nervous system vasculitis usually only involves the brain and is often associated with hemorrhages, which are rare in RVCL-S. Likewise, the stenosis and dilations of the vasculature seen in a vasculitis are absent in RVCL-S.

While diabetes mellitus, sarcoidosis, and SLE are all systemic diseases cerebral and liver involvement are usually absent. Characteristic granulomas are seen in sarcoidosis that are absent in RVCL-S, and SLE differs from RVCL-S in the prominent cutaneous involvement, the elevated antibody profiles, and the presence of oral and/or nasal ulcers, alopecia, and arthritis. In Susac syndrome, hearing loss is much more frequently reported and the pattern of white matter lesions is different from RVCL-S.

Inherited disorders — The differential diagnosis of RVCL-S includes the following inherited disorders:

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), due to pathogenic variants in the NOTCH3 gene (see "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)")

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is caused by pathogenic variants in the HTRA1 gene [49,50]

Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), which is due to pathogenic variants in the CTSA gene [51,52]

COL4A1- and COL4A2-related disorders [53]

Fabry disease, which is caused by pathogenic variants in the GLA gene (see "Fabry disease: Clinical features and diagnosis" and "Fabry disease: Neurologic manifestations")

Neurofibromatosis type 1, which is due to pathogenic variants in the NF1 gene (see "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis")

Tuberous sclerosis complex, which is caused by pathogenic variants in the TSC1 and TSC2 genes (see "Tuberous sclerosis complex: Clinical features")

The mode of inheritance differs between RVCL-S (autosomal dominant) and CARASIL or CARASAL (both autosomal recessive) and Fabry disease (X-linked recessive) [49,51,54]. Additionally, spasticity of lower extremities, spondylosis deformans, and alopecia are important features in CARASIL [49]. In CARASAL, cerebral hemorrhages occur; however, the entire phenotypic spectrum of CARASAL may not be fully described given the small number of reported cases [51]. The earlier onset of symptoms and the presence of angiokeratomas, hyperhidrosis, and corneal opacity that characterize Fabry disease can help to distinguish it from RVCL-S [54].

Like RVCL-S, CADASIL, neurofibromatosis type 1, COL4A1- and COL4A2-related disorders, and tuberous sclerosis complex have an autosomal dominant inheritance pattern [55-58]. However, CADASIL does not involve other organs and there is a distinct white matter lesion pattern consisting of white matter T2 hyperintensities on MRI in the anterior temporal lobe and external capsule [55]. Neurofibromatosis type 1 differs due to its distinct skin lesions, the presence of distinct osseous lesions, and a pattern of bright spots on T2-weighted MRI of the brain, which are seen commonly in children with neurofibromatosis type 1 but may disappear in adulthood; they occur most often in the basal ganglia, cerebellum, brainstem, and subcortical white matter [56]. Age of onset in COL4A1- and COL4A2-related disorders is highly variable but frequently occurs earlier than in RVCL-S. Moreover, infantile hemiparesis, hemorrhagic strokes, porencephaly (fluid-filled cavities in the brain detected by neuroimaging), intellectual disability, hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome and cerebral large vessel involvement (ie, aneurysms) occur. Moreover, isolated retinal artery tortuosity and congenital cataract can occur due to COL4A1 mutations [57]. Tuberous sclerosis complex is often diagnosed in children and causes distinct skin and lung lesions as well as hamartomas, which are all absent in RVCL-S [58].

MELAS is a mitochondrial disease primarily affecting the central nervous system and muscles. The disease has a broad phenotype including lactic acidemia, myopathy, hearing impairment, diabetes, and short stature. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS'.)

In addition to differences in clinical features, molecular genetic testing with a gene panel to detect pathogenic variants causing cerebral angiopathies and adult-onset leukoencephalopathies can often be useful for distinguishing these inherited disorders.

MANAGEMENT — There is no specific disease-modifying treatment for RVCL-S. One clinical trial investigated aclarubicin, hypothesized to correct glycan release demonstrated in lymphoblasts of patients with RVCL-S, but the trial was discontinued after only four participants were included [59]. A pilot trial studying the effectiveness of crizanlizumab is in progress [60].

Given the rarity of RVCL-S, only limited data are available regarding the management of the major manifestations of the disease.

Genetic counseling — Consultation with a clinical geneticist who is knowledgeable about RVCL-S is recommended when a patient is first diagnosed.

In addition, asymptomatic at-risk family members should be offered genetic counseling. Predictive testing is possible once a three-prime repair exonuclease 1 (TREX1) pathogenic variant has been identified in an affected family member. Potential consequences of such a test should be discussed (eg, socioeconomic effects, potential health benefits). RVCL-S differs from many hereditary neurologic diseases because early diagnosis with genetic screening can identify individuals who may benefit from prompt initiation of treatment of complications and preventive measures. Evaluation of signs of retinopathy is especially important as treatment before the onset of visual complaints may prevent early blindness.

Monitoring — To establish the extent of the disease, the following evaluations are recommended at time of diagnosis to determine the individual needs of the patient if they have not already been completed. (See 'Investigations' above.)

Eyes – Ophthalmologic evaluation, fluorescein angiography, and optical coherence tomography for signs of retinopathy, macular edema, and glaucoma.

Cerebrum – Brain MRI (if not already done) and assessment for signs of focal brain dysfunction, cognitive impairment, symptoms of migraine, seizures, and/or psychiatric symptoms.

Kidney – Assessment of renal function (serum creatinine, urinalysis, and protein excretion).

Liver – Assessment of liver enzymes (serum aminotransferases, alkaline phosphatase, and gamma glutamyl transpeptidase) and albumin. If severe liver enzyme changes are detected, lactate dehydrogenase and bilirubin can be determined and coagulations test can be performed. Liver ultrasound can be used to monitor for cirrhosis.

Cardiovascular – Assessment of blood pressure for hypertension.

Hematologic – Complete blood count and hemoglobin to look for anemia.

Thyroid – Thyroid stimulating hormone [TSH] and free thyroxine [T4]) to look for subclinical hypothyroidism.

Other – Assessment for symptoms of Raynaud phenomenon.

These evaluations should be repeated at least annually in patients diagnosed with RVCL-S to detect treatable complications and symptoms. More frequent monitoring might be necessary if symptoms are severe. If the lesions seen on brain MRI are medium to large in size, a brain MRI should be repeated at shorter intervals. In addition, a brain MRI should be obtained if neurologic signs or symptoms occur.

Referral for specialist care is indicated for patients with evidence of significant neurologic or systemic involvement due to RVCL-S. However, these specialists should be informed about RVCL-S and its diverse manifestations in order to avoid needless diagnostics procedures (like biopsies) and to prevent undertreatment or overtreatment.

Symptomatic therapy — Most symptoms of RVCL-S should be treated with standard care, including glaucoma, hypertension, migraine, seizures, hypothyroidism, anemia, Raynaud phenomenon, and psychiatric complaints.

For renal disease, control of hypertension is especially important.

Retinopathy and macular edema can be treated with retinal laser photocoagulation and intravitreal antivascular endothelial growth factor (anti-VEGF) therapy. Elevated eye pressure should be treated with standard care.

If patients suffer from anemia, coagulation of possible gastrointestinal malformations can be tried. However, in some patients, numerous small malformations occur, making coagulation of all these lesions impossible. If so, or if no malformations are found, standard care should be administrated. For severe anemia, intravenous iron therapy or blood transfusions may be necessary. (See "Indications and hemoglobin thresholds for RBC transfusion in adults".)

For symptomatic patients with imaging evidence of vasogenic cerebral edema, which is commonly associated with tumefactive white matter lesions, treatment with a course of intravenous methylprednisolone followed by oral glucocorticoids is a reasonable but unproven intervention [1]. Although evidence of efficacy is lacking, we treat tumefactive brain lesions with intravenous methylprednisolone 1000 mg daily for three days, followed by an oral prednisone taper starting at 60 mg and tapering by 5 mg every five days. Depending upon the response (assessed by evaluating neurologic deficits and neuroimaging), the taper can be reinstituted at a slower rate or at smaller decrements.

Migraine and seizures should be treated with standard care; however, CGRP antagonists are contraindicated [61].

Ischemic stroke and TIA — Transient ischemic attack and acute ischemic stroke in patients with RVCL-S are managed following the general principles of stroke medicine. (See "Initial assessment and management of acute stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

However, intravenous thrombolytic therapy is not recommended for patients with RVCL=S who have acute ischemic stroke. There is no proof that intravenous thrombolytic therapy is effective in this setting, and, as RVCL-S is an angiopathy, the bleeding risk with thrombolytic therapy may be increased. In patients with multiple microbleeds, a sign of small vessel disease, intravenous thrombolytic therapy is associated with higher risks [62,63].

For secondary stroke prevention in patients with RVCL-S who have a symptomatic ischemic event confirmed by MRI, available risk reduction strategies should be employed, including antiplatelet therapy, statin treatment, and treatment for hypertension and diabetes mellitus. In addition, smoking cessation may be particularly important. Other suggested lifestyle modifications include limited alcohol consumption, weight control, regular physical activity, and a Mediterranean diet that is rich in fruits, vegetables, and low-fat dairy products. However, specific evidence that these measures are effective for reducing stroke risk in RVCL-S is lacking. (See "Overview of secondary prevention of ischemic stroke" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

CLINICAL COURSE AND PROGNOSIS — RVCL-S is a progressive disorder, but the rate of progression is variable. Visual impairment is most frequently the presenting symptom, while cognitive impairment appears to have a later onset. (See 'Clinical features' above.)

While symptoms can remain stable for long periods of time, progression can also occur precipitously. Neurologic symptoms may be mild until the age of 50 to 55 years, after which symptoms progress rapidly during the last stage of the disease. To further elucidate the clinical course further studies are required.

Life expectancy in RVCL-S is decreased, with an average age of death 53 years (standard deviation +/- 9.6, range 32 to 72) in one study [1]. The most common cause of death is infection (pneumonia or sepsis) in the setting of general debilitation.

SUMMARY AND RECOMMENDATIONS

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare autosomal dominantly inherited angiopathy caused by mutations in the three-prime repair exonuclease 1 (TREX1) gene. (See 'Pathophysiology' above and 'Epidemiology' above.)

The onset of symptoms related to RVCL-S occurs most often between 30 and 50 years of age. The major clinical manifestations are retinopathy, focal neurologic symptoms including ischemic events, and cognitive impairment. Other symptoms include liver disease, kidney disease, anemia, gastrointestinal bleeding, subclinical hypothyroidism, Raynaud phenomenon, migraine with and without aura, and hypertension. (See 'Clinical features' above.)

The diagnosis of RVCL-S is suspected when middle-aged adults present with vascular retinopathy associated with focal or global neurologic deficits, particularly in the setting of a positive family history of retinopathy or neurologic disease. The diagnosis can be confirmed by documentation of a frameshift or nonsense pathogenic variant in the C-terminus of TREX1. (See 'Evaluation and diagnosis' above.)

Due to the systemic nature of RVCL-S, the differential diagnosis is very broad and includes many acquired and inherited disorders. (See 'Differential diagnosis' above.)

Brain MRI typically reveals several different types of lesions in the white matter in patients with RVCL-S, including pseudotumors (tumefactive lesions), punctate hyperintense T2-weighted lesions with nodular or rim-enhancement, and nonenhancing T2 hyperintense lesions more numerous than expected based upon the patient's age. Rim-enhancing lesions with prolonged diffusion restriction and long-lasting contrast enhancement are characteristic imaging findings. (See 'Neuroimaging' above.)

There is no specific disease-modifying treatment for RVCL-S. Treatment is mainly symptomatic. Annual monitoring is recommended to detect treatable complications. (See 'Management' above.)

RVCL-S is progressive, ending in premature death. However, the clinical course is highly variable between and within families. (See 'Clinical course and prognosis' above.)

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Topic 126686 Version 4.0

References

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