Sea Fan Frond Neovascularization: A Unique Finding in a Patient With Susac Syndrome

A 53-year-old African American man presented with cognitive impairment, social withdrawal, lethargy, and unsteadiness. Over the course of 13 years before presentation to our facility, he developed episodic clusters of neurological symptoms including headaches, acute sensorineural hearing loss, and multiple transient acute episodes of unilateral sensory loss and weakness. Ten years before, he awoke with severe right-sided sensory loss that lasted several hours. He was admitted to his local hospital for suspicion of stroke, but brain MRI findings were ultimately interpreted as consistent with multiple sclerosis (MS), and he was started on glatiramer acetate. Notably, his cerebrospinal fluid (CSF) had no elevation of oligoclonal bands or immunoglobulin G (IgG) index, and on retrospective review, there were never any typical demyelinating lesions. Monitoring over years showed relative clinical and radiographic stability; however, within 3 years of his diagnosis of MS he quit his private business because of worsening fatigue and suspected cognitive decline. Six months before presentation at our facility, he developed waxing and waning cognitive decline. He also developed worsening fatigue, weight loss, recurrent severe headaches, worsening hearing loss, auditory and visual hallucinations, and mood changes leading to hospital admission and evaluation. Neurological examination showed minimal ability to perform any component of the mental status examination. He was noted to have spasticity and brisk reflexes in the bilateral lower extremities. On ophthalmological examination, the visual acuity was 20/20 in each eye with normal pupillary response and anterior segment. There was bilateral, peripheral, vascular nonperfused retina, and elevated fronds of neovascularization (sea fans) at the junction of perfused and avascular retina and old, dehemoglobinized, vitreous hemorrhage was seen in the right eye. The sea fan fronds of neovascularization were also demonstrated using fluorescein angiography (Fig. 1). The early transit phase images from the temporal horizontal raphe in the left eye showed signs of capillary dropout with vascular remodeling and collateralized blood flow (Fig. 1).FIG. 1.: A and B. Colored widefield fundus photograph depicting sea fan frond neovascularization (arrow) temporally extending from the junction of perfused and nonperfused retina toward the ora serrata in the right (A) and left (B) eye. C and D. Fundus fluorescein angiogram showing a sea fan frond pattern of hyperfluorescence with leakage (arrowheads) representing neovascularization with areas of retinal nonperfusion (asterisk) in the right (C) and left (D) eye. Inset: Capillary dropout with vascular remodeling and collateralized blood flow, indicating chronic vascular insufficiency of the retinal microvasculature (arrow).MRI of brain showed multiple T2 hyperintense “spoke” lesions (Fig. 2) and “snowballs” in the corpus callosum and periventricular white matter (Fig. 2), along with several chronic deep white and gray matter infarcts in the left caudate head, anterior limb of the left internal capsule, and the right putamen. Of particular note, a chronic infarction was seen in the posterior body of the corpus callosum (Fig. 2). Mild leptomeningeal enhancement of the cerebellum was also apparent on T1 imaging with gadolinium. MRA of the brain with a black-blood protocol showed no evidence of vasculitis/vasculopathy. An audiogram had demonstrated moderate and severe sensorineural hearing loss on the right and the left, respectively. Lumbar puncture showed an opening pressure of 25 cm H2O and an inflammatory CSF with 45 white blood cells/µL (3% neutrophils, 81% lymphocytes, and 15% monocytes), elevated protein of 144 mg/dL, normal glucose of 42 mg/dL, and one CSF oligoclonal band with negative autoimmune encephalopathy autoantibody evaluation and infectious etiologies. Serum testing for demyelinating disease (myelin oligodendrocyte glycoprotein-IgG and aquaporin-4-IgG), infectious disease (syphilis, toxoplasma, Bartonella, Lyme, hepatitis, HIV, and tuberculosis), antibodies to lupus anticoagulant, antineutrophil cytoplasmic, antinuclear, double-stranded DNA, Ro, La, Sm, RNP, Scl 70, and Jo1 testing, hemoglobin S solubility test, serum protein electrophoresis, and serum glucose were all normal or negative.FIG. 2.: A. T2 sagittal FLAIR MRI displaying a T2 hyperintense “spoke” lesion (arrow) in the anterior body of the central corpus callosum early in the disease course. B. T2 axial FLAIR MRI demonstrating extension of a T2 hyperintense “spoke” lesion from the corpus callosum into the centrum semiovale (arrow). C. T2 sagittal FLAIR MRI with multiple T2 hyperintense “spoke” lesions and “snowballs” (posteriorly) involving the corpus callosum (arrow and arrowheads). D. T2 sagittal FLAIR MRI displaying a chronic T2 hyperintense “spoke” lesion (short arrow) and chronic deep gray matter infarction (arrow). E. Mild leptomeningeal enhancement of the cerebellum is demonstrated on T1 imaging with gadolinium (arrow). F. T1 sagittal MRI demonstrating a hypointense chronic infarction in the posterior body of the corpus callosum (arrow). FLAIR, fluid-attenuated inversion recovery image.The clinical features and audiology findings were consistent with a prolonged polyphasic presentation of Susac syndrome (1). MRI findings demonstrating multifocal T2 hyperintense “spokes,” “snowballs” and at least one lesion located centrally in the corpus callosum fulfilled neuroimaging criteria (2). Additional supportive neuroimaging findings including deep gray matter lesions and leptomeningeal enhancement of the cerebellum were also seen. Although branch retinal artery occlusion is typical for Susac syndrome, and neovascularization can be rarely seen, sea fan fronds of neovascularization have not been previously described. Sea fan fronds are classically seen in sickle cell retinopathy, which was ruled out in our patient with serum testing for hemoglobin S solubility test. Although our patient never presented with a clinical branch retinal artery occlusion, there were definite signs of capillary dropout with vascular remodeling and collateralized blood flow indicating chronic vascular insufficiency of the retinal microvasculature. Although not specific to Susac syndrome, the changes were supportive of a chronic, focal retinal microvascular disorder. Because an alternative etiology was not found, the retinal vascular changes were attributed to Susac syndrome. Glatiramer acetate was discontinued and the patient was treated with plasma exchange therapy and intravenous methylprednisolone and subsequently transitioned to rituximab for maintenance immunotherapy, which led to a remarkable improvement in symptoms sustained throughout the course of ongoing follow-up. The retinal neovascularization was monitored and was stable over the course of time, with the plan to intervene using retinal laser photocoagulation directed at the ischemic retina with signs of progression. Susac syndrome is a rare autoimmune endotheliopathy predominantly affecting microvasculature of the brain, ears, and eyes, manifesting as the pathognomonic triad of encephalopathy, deafness, and branch retinal artery occlusion (1). The branch retinal artery occlusions can cause altitudinal, paracentral, or central scotoma with corresponding whitening of the involved region of the retina. Gass plaques may be present, which are yellow, refractile lesions occurring anywhere along the vessel (not only at bifurcations). These lesions are believed to represent vessel wall inflammation. Fluorescein angiography may show areas of nonperfusion combined with other areas of nonexpansile hyperfluorescence of arteriolar vessel walls, consistent with staining. A recent series has reported that arterioarterial and arteriovenous anastomoses can also occur (3). Neovascularization has been reported in a single patient with Susac syndrome, occurring 10 years after a branch retinal artery occlusion (4). To the best of our knowledge, sea fan–shaped fronds have not been previously reported. Such vascular fronds are classic lesions associated with proliferative sickle cell retinopathy and develop at the border of the perfused and nonperfused retina. Chronic ischemia leading to increased angiogenic factors results in the development of these characteristic forms of anomalous neovascularization (5). Arteriolar obstruction with increased hydrostatic back pressure, vessel extrusion, and stimulation of endothelial cells has also been proposed to contribute to the formation of sea fan fronds. Both mechanisms are plausible in patients with Susac syndrome. Given the longstanding history of previous symptoms attributable to Susac syndrome in our patient, we hypothesize that branch retinal artery occlusions likely occurred months to years before presentation and remained asymptomatic, perhaps from the peripheral location or concurrent cognitive issues. Sea fan fronds typically form about 18 months following Goldberg stage III proliferative sickle retinopathy or the arteriovenous anastomoses stage. In our patient, chronic untreated disease contributed to this more advanced, neovascular finding. Susac syndrome is frequently misdiagnosed, especially when the clinical features do not involve the complete triad. It is important to note that only 13% of patients have the full triad (encephalopathy, retinal artery occlusion, and hearing loss) at the time of presentation (1). Our patient had retinal findings that were strongly suggestive of previous branch retinal artery occlusions, and thus we believe our patient would appropriately be categorized as “definite Susac syndrome” based on the proposed diagnostic criteria by Kleffner et al. (1) Sea fan–shaped frond neovascularization should be added to the constellation of retinal findings that may be seen in Susac syndrome, suggest chronicity, and can assist the clinician to suspect the diagnosis of this rare disease. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. A. Mansukhani, N. L. Zalewski, and J. J. Chen. Category 1: b. Acquisition of data: S. A. Mansukhani, N. L. Zalewski, M. Hur, F. Ali, M. T. Bhatti, T. W. Olsen, and J. J. Chen; c. Analysis and interpretation of data: S. A. Mansukhani, N. L. Zalewski, M. T. Bhatti, T. W. Olsen, and J. J. Chen. Category 2: a. Drafting the manuscript: S. A. Mansukhani, N. L. Zalewski, and J. J. Chen; b. Revising it for intellectual content: S. A. Mansukhani, N. L. Zalewski, T. W. Olsen, M. Hur, F. Ali, M. T. Bhatti, and J. J. Chen. Category 3: a. Final approval of the completed manuscript: S. A. Mansukhani, N. L. Zalewski, M. Hur, F. Ali, M. T. Bhatti, T. W. Olsen, and J. J. Chen.