Neurofibromatosis Type 1 Vasculopathy Presenting as Impending Central Retinal Artery Occlusion

A 36-year-old man with neurofibromatosis type 1 (NF1) experienced 2 brief (<30 minute) episodes of painless, peripheral vision loss in his left eye followed by complete visual recovery. Initial examination revealed visual acuity of 20/20 bilaterally, no relative afferent pupillary defect (RAPD), full confrontational visual fields, bilateral iris Lisch nodules, and unremarkable posterior segments. Seven days later, he developed a 90-minute episode of peripheral vision loss in his left eye, with subjective gray “splotches” persisting when examined 2 days later. Visual acuity was 20/25, left eye, with mild macular whitening and perivascular cotton wool spots in the left eye (Fig. 1A). Fundus examination of the right eye was unremarkable. Optical coherence tomography (OCT) of the left macula demonstrated inner nuclear layer hyperreflectivity consistent with paracentral acute middle maculopathy (Fig. 1B) and focal retinal nerve fiber layer thickening corresponding to the cotton-wool spots. Intravenous fluorescein angiography (IVFA) was unremarkable in the right eye and exhibited a mild global delay of arterial filling in the left eye, suspicious for incomplete central retinal artery occlusion (Fig. 1C). Embolic workup including brain and orbital magnetic resonance imaging, computed tomography angiography of the head and neck, and transthoracic echocardiogram was unrevealing. Low-density lipoprotein concentration was borderline-elevated at 145 mg/dL. Extensive hypercoagulability and systemic inflammatory laboratory studies were negative. Treatment with aspirin, clopidogrel, and atorvastatin was initiated.FIG. 1.: Retinal ischemia, left eye. A. Nine days after initial presentation, the posterior pole of the right eye appears normal, whereas in the left eye there is mild whitening of the nasal macula with perivascular cotton wool spots. B. Spectral domain optical coherence tomography of the left eye reveals mild perifoveal inner retinal thickening with patchy hyperreflectivity (arrows) in the inner nuclear layer. C. Intravenous fluorescein angiography of the left eye at approximately 30 seconds (left) and 50 seconds (right) after injection displays mildly delayed transit time, patchy blockage along the arcades, and complete filling of the retinal vasculature.Five days later, the patient experienced painless left vision loss to counting fingers, and a RAPD was noted in his left eye. Empiric therapeutic measures included ocular hypotensive medications, high-flow oxygen, and hyperbaric oxygen. Visual acuity in the left eye improved to 20/50 after 2 hours and was 20/25 the following day with resolution of the RAPD. Verapamil was added as presumptive diagnosis for retinal vasospasm. Three days later, he again developed sudden vision loss to hand motion in the left eye but poorly responsive to the above interventions plus nitroglycerin and systemic anticoagulation. A cherry-red spot was now evident. Repeat IVFA demonstrated severely delayed retinal arterial filling in the left eye without vascular narrowing or staining (Fig. 2A). OCT angiography obtained 1 week later revealed significant pruning of the superficial and deep capillary plexuses in the left eye compared with the right eye (Fig. 2B).FIG. 2.: Central retinal artery occlusion, left eye. A. Intravenous fluorescein angiography obtained 17 days after initial presentation at approximately 30 seconds (left) and 60 seconds (right) after injection displays dramatically slowed arterial filling. B. Optical coherence tomography angiography of the right and left eyes 24 days after initial presentation demonstrates significant pruning of the superficial capillary plexus in the left eye compared with the right eye. Similar findings were observed in the deep capillary plexus (not shown).One month later, visual acuity was 20/400 in the left eye and inner retinal atrophy was present on OCT. Seven months after initial presentation, visual function in the left eye was unchanged. In light of the negative systemic workup, the patient was believed to have suffered a central retinal artery occlusion secondary to NF1 vasculopathy. NF1 is associated with systemic arteriopathy, and sequelae include cerebral or visceral infarction due to vascular occlusions, aneurysms, and arteriovenous fistulae (1). The pathogenesis likely involves abnormal vascular smooth muscle cell proliferation due to aberrant signaling between smooth muscle and endothelial cells, which both express the NF1 protein product neurofibromin, a negative regulator of mitogenic signaling (1). No disease-specific treatments for NF1 vasculopathy exist. NF1 retinal vascular manifestations are rare. To the best of our knowledge, there are only 2 prior reports of acute vision loss in young NF1 patients with negative workups for alternative etiologies. One patient had macular ischemia from retinal arteriolar occlusion (2) and the other sustained an ophthalmic artery occlusion (3). Additional reported findings include isolated peripheral retinal nonperfusion and diffuse retinal arteriolar fibrosis with preretinal fibroglial proliferation in NF1 patients with chronically poor vision (4,5). Our patient's initial transient vision loss and normal initial fundus examination with subsequent stepwise progression to central retinal artery occlusion is unique. Interestingly, all reported cases of NF1 retinal vasculopathy have been unilateral, which may portend a favorable prognosis for our patient's fellow eye. Although any patient with acute central retinal artery occlusion or transient monocular vision loss merits a thorough evaluation for underlying thromboembolic disease, NF1 vasculopathy should be recognized as an etiology of retinal arterial occlusive disease in young people.