Association of Acute Zonal Occult Outer Retinopathy With Multiple Sclerosis: A Report of 2 Cases

Acute zonal occult outer retinopathy (AZOOR) is a syndrome characterized by rapid onset of photopsia and scotomata correlated with sectoral outer retinal atrophy with subsequent choroidal atrophy.

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Association of Acute Zonal Occult Outer Retinopathy With Multiple Sclerosis: A Report of 2 Cases Muhammad Z. Chauhan, MS, MA, Joseph G. Chacko, MD, Paul H. Phillips, MD, Mohammad Z. Siddiqui, MD, Sami H. Uwaydat, MD A cute zonal occult outer retinopathy (AZOOR) is a syndrome characterized by rapid onset of photopsia and scotomata correlated with sectoral outer retinal atrophy with subsequent choroidal atrophy. Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that presents with a wide spectrum of findings. AZOOR is frequently associated with autoimmune diseases. However, there are only a few described cases of patients with AZOOR and CNS demyelinating disease, with only 3 cases in the literature of patients with clinically confirmed MS, one with clinically isolated syndrome and one with a CNS inflammatory disorder not typical of MS (Table 1) (1– 5). We add to these reports by detailing the unique history of 2 patients with AZOOR and concomitant MS with different disease progressions. We demonstrate in this report that AZOOR may present years before or after the development of MS. The first case is a 47-year-old Caucasian woman who was evaluated in the neuro-ophthalmology clinic for photopsia in her right eye that had been present for 8 months. She had an ocular history of pars planitis and mild cystoid macular edema (CME) with a resultant epiretinal membrane in her right eye. In addition, she had a 10-year history of MS. Her MS was well controlled for 9 years on glatiramer acetate, with primary symptoms on presentation of fatigue, leg pain, and occasional falls. Fluid-attenuated inversion recovery-weighted cerebral MRI revealed multiple stable hyperintense MS lesions in the periventricular and subcortical white matter and the corpus callosum. Visual acuity (VA) was 20/25 in both eyes with normal intraocular pressure (IOP) and no relative afferent pupillary defect in either eye. Anterior segment examination was normal. Dilated funduscopic examination of both eyes showed an epiretinal membrane on the macula and retinal pigment epithelium (RPE) changes with segmental choriorDepartment of Ophthalmology (MZC), College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Department of Ophthalmology (JGC, PHP, MZS, SHU), Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas. The authors report no conflicts of interest. Address correspondence to Paul H. Phillips, MD, Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences, 4301 W Markham Street # 523, Little Rock, AR 72205; E-mail: [e-mail] Chauhan et al: J Neuro-Ophthalmol 2022; 42: e377-e380 etinal scarring (Fig. 1A). There was no evidence of optic neuritis. Fluorescein angiography (FA) showed a sectoral area of staining in the superonasal periphery and along the inferior arcade and a sectoral trizonal pattern of fluorescence in the inferonasal periphery (Fig. 1B). Fluorescein angiography of the left eye showed minimal staining along the vessels. Fundus autofluorescence of the right eye revealed patchy areas of hyperautofluorescence in the posterior pole, with a sectoral trizonal pattern of fundus autofluorescence in the inferonasal periphery (Fig. 1C). Automated visual field (AVF) revealed a superotemporal arcuate scotoma in the right eye that corresponded with areas of photopsia (Fig. 1D). Optical coherence tomography (OCT) of the right eye revealed intraretinal fluid between the optic nerve and macula accompanied by notable disruption of the ellipsoid zone in the periphery with outer retinal atrophy and a relatively preserved retinal ganglion cell (RGC) layer (Fig. 1E). Laboratory evaluation, which included serum West Nile virus and toxoplasma antibodies, serum lysozyme, and angiotensin-converting enzyme, was unremarkable. A diagnosis of AZOOR and chorioretinitis was made based on the symptomatology, the trizonal pattern of retinochoroidal degeneration, and RPE/choroidal changes with disruption of the ellipsoid zone in the right eye. The patient was given 40 mg sub-Tenon triamcinolone acetonide injection with improvement in her CME. Serial examination over 2 years revealed stable chorioretinal scarring in both eyes and minimal recurrence of CME in the right eye. In addition, she was not diagnosed with optic neuritis in either eye throughout her follow-up. The second case is an 18-year-old Caucasian woman with a history of uveitis and bilateral disc edema. Previous evaluation of her uveitis included MRI of the brain and orbits, which was normal. The patient presented to our clinic with decreased vision and photopsia in both eyes for 2 years. She had a VA of 20/25 in the right eye, 20/40 in the left eye, normal IOP, 1+ cell in the right eye, no cell in the left eye, and a left relative afferent pupillary defect. Funduscopic examination revealed Grade 4 disc edema in her right eye with a pale fundus and prominent choroidal vasculature (Fig. 2A). Her left eye showed Grade 2 disc edema, scattered peripheral pigment clumping, and a pale fundus with prominent choroidal vasculature. AVFs were normal in the right eye and constricted in the left eye. Antibody and PCR testing of anterior chamber fluid was e377 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence TABLE 1. Review of case reports examining the association between AZOOR and MS. Author Year Ref. # Sample Country Jacobson (1) 1996 1 N = 1; age = 28; woman USA Hintzen et al (2) 2006 2 N = 1; age Seidova et al (3) 2007 3 N = 1; age Abo-Shasha et al (4) 2015 4 N = 1; age Wang et al (5) 5 N = 1; age 2017 Patient had acute zonal occult outer retinopathy (AZOOR) with macular involvement concomitant with the central nervous system inflammation consistent with atypical multiple sclerosis (MS). = 30; woman Netherlands Patient with clinically fulfilled criteria for AZOOR and MS. = 50; woman Germany Patient with clinically fulfilled criteria for AZOOR and MS. = 50; woman Canada Patient with clinically fulfilled criteria for AZOOR and MS. = 17; woman USA Patient presented with retrobulbar optic neuritis and AZOOR. Subsequent MRI showed demyelinating lesions associated with clinically isolated syndrome. negative for Cytomegalovirus, varicella-zoster virus, Epstein–Barr virus, toxoplasmosis, and herpes simplex virus. Two months after presentation, AVF 24-2 revealed a superior arcuate defect and enlarged blind spot in her right eye and a severely constricted field in her left eye (Fig. 2E). OCT imaging revealed bilateral loss of outer retina layers with preservation of RGCs and nerve fiber layer (Fig. 2F). Based on symptomatology, funduscopic findings with bilateral sequential trizonal progressive retinal degeneration, and negative workup, a diagnosis of AZOOR was made. She was given 40 mg sub-Tenon triamcinolone acetonide injection for uveitis control. Elevated IOP on return visits was attributed to sub-Tenon triamcinolone acetonide injections and treated with brimonidine/timolol eye drops. The peripheral retinal atrophy progressed over the course of 19 months of follow-up (Fig. 2A–D). Several years later, on follow-up visits, the patient began having lower-extremity weakness and was referred to neurology. MRI of the brain revealed demyelinating plaques in the left frontal periventricular–pericallosal region and cerebrospinal fluid analysis showed oligoclonal bands, consistent with a diagnosis of MS. She was started on intravenous Solu-Medrol with improvement in lower-extremity symptoms. IOP normalized off of sub-Tenon injections in subsequent appointments and pressure lowering drops were discontinued. Over the next 4 years, AVFs showed slow constrictive progression in both eyes. A 10-year follow-up appointment revealed a stable retina and an overall improvement in her VA. These cases reveal 2 patients who had concomitant MS, AZOOR, and chorioretinitis. These cases represent the diverse way that AZOOR may present in association with MS. Both patients were Caucasian women with presentations of photopsia and decreased VA. The first patient presented with a decade long history of MS, whereas the second patient developed MS symptoms years after the presentation of AZOOR. The e378 Summary of Findings FIG. 1. Funduscopy, fluorescein angiography, fundus autofluorescence, automated visual field (AVF), and optical coherence tomography (OCT) Case 1. Initial examination of a 47-yearold patient with multiple sclerosis revealed an epiretinal membrane on the macula in the right eye (OD) (A) and sectoral leakage in the left eye (OS) as assessed by fluorescein angiography (B). Fundus autofluorescence of the right eye showed areas of hyperautofluorescence and a sectoral trizonal pattern in the inferonasal periphery (C). Automated visual field assessments revealed a superotemporal arcuate scotoma in the right eye and a normal VF in the left eye (D). Optical coherence tomography images of the right eye showed disruption of the ellipsoid zone in the periphery (arrow) and intraretinal fluid between the optic nerve and macula (arrowhead) (E). Chauhan et al: J Neuro-Ophthalmol 2022; 42: e377-e380 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Funduscopy, FA, AVF, and OCT Case 2. Fundus findings of an 18-year-old patient over a 19-month period demonstrated bilateral optic disc edema and prominent choroidal vasculature (A–D). Automated visual field assessments revealed a superior arcuate defect in the right eye (OD) and a severely constricted visual field in the left eye (OS) (E). Optical coherence tomography imaging of the right eye showed focal loss of retinal pigment epithelium, whereas the left eye showed advance structural loss (F). AVF, automated visual field; FA, fluorescein angiography. pathophysiological mechanism linking AZOOR and MS is currently unknown. The optic nerve in MS is commonly damaged by optic neuritis, likely because of autoantibodies to myelin antigens. Retinal periphlebitis, atrophy, and pars planitis are known complications of MS (6). Notable retinal findings in MS include thinning of the outer and inner nuclear layers, retinal nerve fiber layer loss, venous sheathing, and loss of RGCs (7). Studies examining retinal changes in MS have suggested the possibility of damage occurring in the photoreceptor layer, independent of pathophysiologic changes in the optic nerve or RGCs supporting the presence of a primary retinal pathology Chauhan et al: J Neuro-Ophthalmol 2022; 42: e377-e380 in MS (8). In both patients described in this report, we observe atrophy of the photoreceptor layer with conservation of RGCs. A recent study analyzing the relationship between healthy and diseased retinal zones in patients with AZOOR found that photoreceptor outer segments are first damaged followed by RPE and choroidal atrophy, and inner retinal attenuation (9). In addition to similar structural damage, AZOOR and MS share clinical characteristics, including a female predominance, a relapsing–remitting course, inflammatory lesions, and neuronal degeneration. These findings provide additional support for the association between AZOOR and MS. In light of the e379 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence diverse presentation in these 2 patients, we recommend that patients diagnosed with AZOOR receive MRI of the brain to rule out MS and that patients with MS should have annual OCT scans to monitor the retina. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. Z. Chauhan, J. G. Chacko, P. H. Phillips, M. Z. Siddiqui, and S. H. Uwaydat; b. Acquisition of data: M. Z. Chauhan, J. G. Chacko, P. H. Phillips, M. Z. Siddiqui, and S. H. Uwaydat; c. Analysis and interpretation of data: M. Z. Chauhan, J. G. Chacko, P. H. Phillips, M. Z. Siddiqui, and S. H. Uwaydat. Category 2: a. Drafting the manuscript: M. Z. Chauhan, J. G. Chacko, P. H. Phillips, M. Z. Siddiqui, and S. H. Uwaydat; b. Revising it for intellectual content: M. Z. Chauhan, J. G. Chacko, P. H. Phillips, M. Z. Siddiqui, and S. Uwaydat. Category 3: a. Final approval of the completed manuscript: M. Z. Chauhan, J. G. Chacko, P. H. Phillips, M. Z. Siddiqui, and S. H. Uwaydat. REFERENCES 1. Jacobson DM. Acute zonal occult outer retinopathy and central nervous system inflammation. J Neuroophthalmol. 1996;16:172–177. 2. Hintzen RQ, van den Born LI. Acute zonal occult outer retinopathy and multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006;77:1373–1375. e380 3. Seidova SF, Wiescher A, Fiore B, Lanzl IM, Maier M, Zimmermann P. 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