Rare case of Retinopathy With Multiple Cerebral Ring-Enhancing Lesions in a Young Man: JAMA

He had experienced painless decrease of vision in both eyes for 6 years but did not seek medical care. He had had hypertension for 3 years, with amlodipine taken regularly. A sibling developed uremia in their 30s. A parent died of kidney failure in their 40s.

On results of an ophthalmic examination, his best-corrected visual acuity was 20/50 OD and 20/40 OS, without visual field defects, dyschromatopsia, or relative afferent pupillary defect. Extraocular movements were intact.

Neurologic examination findings were unremarkable except for mild cognitive impairment.

Fundus fluorescein angiography showed retinal vasculitis.

Enhanced magnetic resonance imaging (MRI) of the brain showed diffuse white matter hyperintensities—leukoencephalopathy—with multiple ringenhancing lesions.

Results of routine blood tests were significant for kidney insufficiency (proteinuria, 3.47 g of protein in 24 hours; estimated glomerular filtration rate, 38.5 mL/min). Angiotensin-converting enzyme level and serum tumor marker findings were normal.

Infection panel screenings for hepatitis, HIV, syphilis, tuberculosis, and parasites were negative. Antinuclear antibodies and antineutrophil cytoplasmic antibodies were negative.

Whole-body positron emission tomographic/computed tomographic (PET/ CT) imaging detected no hypermetabolic changes.

The cerebrospinal fluid (CSF) profiling, including cytologic analysis, was normal. Culture of the CSF and blood was negative for bacteria and fungus.

Diagnosis was made of Retinal vasculopathy with cerebral leukoencephalopathy. The next step included Genetic sequencing.

This was a young man with multisystemic manifestations involving eye, brain, and kidney. Major differential diagnosis is wide, including autoimmune diseases, infection, tumor, and hereditary disorders. Systemic lupus erythematosus, Behçet disease, Sjögren syndrome, and antineutrophil cytoplasmic antibody– related vasculitis are considered but excluded by history and negative autoantibodies. Sarcoidosis can present as retinal vasculitis. Definitive diagnosis requires biopsy. However, the normal angiotensin-converting enzyme level and absence of hypermetabolism in liver, spleen, lung, and lymph nodes argue against it.

Infection and tumor are common causes for cerebral ring– enhancing lesions and multisystemic manifestations. Nevertheless, normal CSF parameters and the negative infection panel render infection unlikely. A second CSF culture helps to exclude infection, but this is not pathognomonic. Metastatic tumor is also not very likely given the normal serum tumor markers and negative PET/CT scan.

The family history and leukoencephalopathy raise suspicion of hereditary diseases. A myriad of inherited disorders can cause oculocerebral syndrome. But when kidney insufficiency is present, differential diagnosis is narrower. Collagen type IV alpha 1 chain– related disorders, Lowe syndrome, cerebral autosomal dominant angiopathy with subcortical infarcts, and leukoencephalopathy and retinal vasculopathy with cerebral leukoencephalopathy (RVCL) should be considered. However, collagen type IV alpha 1 chain sequence variations typically cause intracranial hemorrhage and bilateral retinal artery tortuosity, which is lacking in this patient. Lowe syndrome is characterized by infantile glaucoma, mental retardation, and kidney Fanconi syndrome, apparently not in line with this case. Retinopathy or nephropathy caused by cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy has been reported, but multiple cerebral ring enhancement is not its feature.

RVCL is an autosomal dominant, hereditary small vessel disease caused by the heterozygous C-terminal frameshift sequence variation in TREX. Its core symptoms are retinopathy and cerebral dysfunction, which usually develop in the third or fourth decade of life. The ophthalmic examination results and neuro images of this patient are its typical manifestations. Therefore, RVCL was the most likely diagnosis. Sequencing for TREX1 demonstrated a heterozygous C-terminal frame shift mutation V235 fs in the patient and his brother. TREX1 is a DNA-specific 3′ to 5′ exonuclease, which is widely expressed in mammalian cells.

Mutant TREX1 has intact exonuclease activity but disrupted subcellular localization, glycosylation defects, and dysregulated innate immune response, leading to vasculopathy of multiple organs. Pathologically, the thickened vessel wall with no or mild inflammatory infiltration is a nonspecific finding shown in various diseases.

RVCL is a diagnostic challenge being under recognized by clinicians globally. Clinical phenotypes of RVCL are highly heterogeneous, including retinopathy, migraine, seizures, cognitive decline, stroke like episodes, nephropathy, hepatic abnormalities, hypertension, anemia, gastrointestinal bleeding, Raynaud phenomenon, and subclinical hypothyroidism. These manifestations have no fixed constellation and can develop asynchronously. At its early stage, retinopathy may be the sole presentation, and RVCL is easily misdiagnosed as diabetic retinopathy, hypertensive retinopathy, or retinal vasculitis. Annual follow-up is necessary, and a clinical course without neurologic manifestations does not exclude the necessity of brain MRI for these patients.

The prognosis for patients with RVCL is poor. The average age at diagnosis of retinopathy is 42.5 years and patients die on average 9.0 years after symptom onset. No disease-modifying treatment is available. Early diagnosis is crucial to avoid iatrogenic complications caused by excessive treatment and unnecessary invasive procedures. RVCL should be considered when patients present with retinal vasculopathy and multisystemic manifestations.

Patient Outcome: The patient was treated with cilostazol. During an 8-month follow up, he developed left limb weakness due to expanded brain lesions. Eyesight and kidney functions were relatively stable.

Source: Nina Xie, MD; Jinxia Yang, BS; Qiying Sun, MD, PhD; JAMA Ophthalmology February 2021 Volume 139, Number 2

doi:10.1001/jamaophthalmol.2020.4620