Acute zonal occult outer retinopathy (AZOOR) is an uncommon retinal disorder associated with focal photoreceptor degeneration.1,2 Common features include visual symptoms (photopsias or scotoma) with associated visual field defects and outer retinal abnormalities on imaging (spectral-domain optical coherence tomography [SD-OCT]), fundus autofluorescence (FAF), fluorescein angiography (FA), and indocyanine green angiography (ICG).3 Funduscopic examination may initially appear normal, with retinal pigment epithelial (RPE) changes noted later in the disease course. The etiology of this disease remains poorly understood, though autoimmune4 and infectious processes5 have been proposed. Treatment of patients with AZOOR remains controversial, as neither systemic immunosuppressive nor antimicrobial therapies have shown to be consistently effective.1 We report a series of patients treated with intravitreal corticosteroid agents, the role of which has not been well-described in the management of AZOOR, and document the response to treatment with multimodal imaging.
Patients and Methods
This is a retrospective case series of adult patients diagnosed with AZOOR by the uveitis service at the Cleveland Clinic Cole Eye Institute. The diagnosis of AZOOR was based on the accepted clinical characteristics of photopsias and/or scotoma with corresponding multimodal imaging changes at the photoreceptor level and sequential involvement of the RPE and choroid.3 All patients were initially started on prednisone and transitioned to intravitreal steroids after developing worsening symptoms and/or progression of lesions on imaging with tapering of prednisone. Intravitreal steroid treatments included triamcinolone acetonide (IVTA) (Triesence 2 mg/0.05 mL; Alcon, Fort Worth, TX), dexamethasone intravitreal implant (Ozurdex; Allergan, Irvine, CA), and/or fluocinolone acetonide implant (Retisert; Bausch + Lomb, Rochester, NY). Patients who demonstrated a positive steroid response and required prolonged treatment courses or were otherwise intolerant to further management with steroids were placed on systemic immunosuppressive agents.
Response to treatment was determined through review of case history (ie, reported symptoms) and multimodal imaging findings. Specifically, available SD-OCT and fundus FAF images were analyzed for ellipsoid zone repopulation and reduced hyperautofluorescence, respectively. All patients were observed for at least 1 year after the first intervention with intravitreal steroids (range: 14 months to 63 months). This study was approved by the Cleveland Clinic Institutional Review Board, complied with the Health Insurance Portability and Accountability Act of 1996, and followed the tenets of the Declaration of Helsinki.
A total of nine eyes from five patients were identified (Table). There were four women and one man, with an average age of 53 years (range: 35 years to 73 years). All patients were white and presented with complaints of photopsia and/or scotoma. Visual acuity (VA) at presentation ranged from 20/20 to count fingers.
Baseline Characteristics and Outcomes of Patients With AZOOR Treated With Intravitreal Steroids
Seven eyes received IVTA, six eyes received dexamethasone intravitreal implant, and one eye received the fluocinolone acetonide implant. Most frequently, intravitreal treatments began with IVTA followed by intravitreal steroid delivery implants (dexamethasone or fluocinolone acetonide implants) once a positive response to intravitreal steroids was established. The mean time to first intravitreal injection from initial visit was approximately 4 months. There was an average total of two intravitreal treatments per eye per year. During their treatment course, all patients were observed to have steroid-responsive lesions on either OCT or FAF, which stabilized or improved with intravitreal therapy (Figures 1 and 2). There were no noted differences in response between different intravitreal formulations (ie, IVTA vs. dexamethasone implant vs. fluocinolone acetonide implant).
Changes in fundus autofluorescence following intravitreal steroid treatment of acute zonal occult outer retinopathy. (A) Peripapillary hyperautofluorescence in a symptomatic patient (A1) was notably reduced (A2) 6 weeks after receiving dexamethasone intravitreal implant. (B) Hyperautofluorescent border of peripapillary/perifoveal lesion (B1) was decreased (B2) following intravitreal triamcinolone acetonide 6 weeks earlier. (C) Marked progression during 4-month interval of peripapillary/perifoveal hyperautofluorescent lesion (C1 and C2) was evident in a patient treated with mycophenolate mofetil after prior response to prednisone. Intravitreal triamcinolone acetonide was given, and lesion stability was noted 3 months later (C3).
Optical coherence tomography (OCT) changes following intravitreal triamcinolone acetonide and dexamethasone intravitreal implant in a patient with acute zonal occult outer retinopathy. OCT images showing ellipsoid zone improvement before (top left) and 2 weeks after (top right) intravitreal triamcinolone acetonide. Similarly, improvement in ellipsoid zone definition is noted before (bottom left) and 5 weeks after (bottom right) administering dexamethasone implant.
Five of nine eyes developed ocular hypertension, which were all successfully managed with topical drops. All phakic eyes developed cataracts, but only one had cataract extraction during the observed period. VA 1 year after first intravitreal steroid treatment was stable or improved in four eyes. VA declines attributed to cataract formation occurred in three eyes. A choroidal neovascular membrane developed in one eye, which was effectively treated with intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA). One eye developed central serous retinopathy (CSR) that improved with eplerenone. Because this patient was found to be responsive to immunosuppression and further treatment with steroids was limited due to CSR, she was transitioned to mycophenolate mofetil. At final follow-up, two additional patients remained on systemic immunosuppression. The first patient was started on methotrexate to limit long-term glucocorticoid exposure. Due to side effects associated with methotrexate, she was later transitioned to azathioprine. The second patient responded well to intravitreal treatment, though she experienced repeated flares. She was started on mycophenolate mofetil to decrease her steroid burden.
Representative Case Descriptions: Dexamethasone Implant (Table, Case 1)
A 35-year-old female with a three-year history of nyctalopia in the right eye presented with a new onset “shadow” in the left eye. Best-corrected VA (BCVA) was 20/20 in both eyes on initial exam. Fundus photos showed diffuse chorioretinal atrophy with macular sparing in the right eye and a normal left eye. OCT demonstrated generalized retinal atrophy in the peripapillary region of the right eye and an unremarkable left eye. FAF exhibited peripapillary hypoautofluorescence in the right eye and hyperautofluorescence in the left eye.
The patient was started on 60 mg of prednisone with improvement in hyperautofluorescence at 1 month. Upon tapering the steroid dose, her symptoms worsened and increased hyperautofluorescence was noted in her left eye. Dexamethasone intravitreal implant was delivered into the left eye with subsequent symptomatic and FAF improvement (Figure 1A). Similarly, dexamethasone injection was performed in the right eye with positive symptomatic and FAF response.
The patient was asymptomatic with 20/20 vision in both eyes and a stable FAF at the most recent follow-up, 18 months since the first dexamethasone implant. A total of three intravitreal treatments were delivered to the left eye and one to the right eye during the follow-up period. The patient's course was complicated by the development of posterior subcapsular cataracts and ocular hypertension in both eyes, which was controlled with timolol.
Intravitreal Triamcinolone Acetonide (Table, Case 2)
A 57-year-old white female presented with decreased VA in her right eye along with photopsias, floaters, photophobia, and temporal field loss in both eyes. Her BCVA was 20/20-in both eyes. Fundus examination was notable for subtle peripapillary pigmentary changes extending to the nasal macula in both eyes, corresponding to areas of hyperautofluorescence on FAF. OCT exhibited epiretinal membrane and nasal ellipsoid zone disruption in both eyes. The patient was started on prednisone 60 mg daily for a diagnosis of AZOOR.
Subjective improvement was noted, and the prednisone was tapered. With decreasing oral steroid dosing, the patient's symptoms worsened and IVTA was administered in the right eye. The patient reported improved photopsias in her right eye but worsened symptoms in her left eye, at which point she received IVTA in her left eye. One month later, the patient's photopsias improved and decreased hyperautofluorescence was observed in the left eye (Figure 1B). A total of two IVTA injections were delivered in each eye during the course of 1 year.
The patient's BCVA was 20/30 in the right eye and 20/25-2 in the left eye 1 year following her first injection in each eye. The patient's course was later complicated by development of central serous retinopathy (CSR) in the left eye, which resolved with eplerenone. She experienced an additional recurrence and the patient was started on steroid-sparing immune suppression (mycophenolate mofetil).
At final follow-up, approximately 15 months from initial IVTA in the right eye and 14 months from IVTA in the left eye, her BCVA was 20/50-2 in the right eye and 20/40-2 in the left eye. Limiting her BCVA was the development of posterior subcapsular cataracts in both eyes.
Fluocinolone Acetonide Implant (Table, Case 5)
A 50-year-old white male presented for evaluation of scotoma in the left eye, which progressed during the preceding 4 months. BCVA was 20/20 in the right eye and count fingers in the left eye. Fundoscopic exam of the left eye showed RPE granularity in the nasal macula. FAF revealed peripapillary hyperautofluorescence extending into the nasal fovea and OCT demonstrated total loss of the ellipsoid zone of the left eye. The patient was started on 80 mg of prednisone and 1g daily of valacyclovir was later added. Follow-up testing 6 weeks later exhibited no disease progression. Given disease stability on systemic prednisone, the patient was transitioned to mycophenolate mofetil and oral steroids were tapered off. While on mycophenolate mofetil 1g twice daily, clear progression was seen on FAF. The patient was given IVTA and was subsequently stable for the next 3 months (Figure 1C). In light of his apparently steroid-responsive disease, a fluocinolone acetonide implant was pursued. Following implantation, the patient was successfully transitioned off all systemic immunosuppressive drugs.
There was no evident disease progression observed at last follow-up, 63 months after IVTA and 58 months after fluocinolone acetonide implantation. BCVA at final follow-up was 20/20 in the right eye and count fingers in the left eye. During the course of his treatment, the patient developed cataracts and underwent surgery with successful posterior chamber lens implants. He also developed ocular hypertension, which has been adequately managed with timolol twice daily.
With no proven pathogenic mechanism and considerable variability in clinical presentation, the management of patients with AZOOR remains uncertain. A review of 205 eyes with AZOOR found that 74% of tested eyes had a VA of 20/40 or better on presentation and many patients even retained a VA of 20/201. In one of the larger known series, 68% of patients had a final VA of 20/40 or better with 10% of eyes having worse than 4/200 vision. Further confounding the decision to treat these patients is the idea that the natural course of the disease is to burn out, as visual field loss typically stabilizes within 6 months of onset.6 Although cases of untreated AZOOR may have suitable visual outcomes, perifoveal lesions, such as those seen in several of the cases presented in this series could have potentially devastating outcomes should the disease progress.
Conclusions regarding treatment efficacy are complicated by the heterogeneity of cases in the literature described as AZOOR or AZOOR complex diseases. For example, one review of more than 400 cases diagnosed or referred as AZOOR and AZOOR complex found only 30 that fit their diagnostic definition based on multimodal imaging findings.3 Increased diagnostic consistency through wider availability of different imaging modalities will be necessary before any definitive conclusions can be made regarding treatment efficacy.
The treatment of AZOOR with systemic corticosteroids has been previously described with mixed results. Gass reported 39 of 113 episodes of acute visual loss that were treated with oral or intravenous corticosteroids and concluded that interpretation of treatment outcomes was “difficult” due to frequent early stabilization of the disease, but ultimately commented that treatment is of no proven benefit.6 However, more recently authors have suggested a positive effect with systemic corticosteroid treatment.7,8 One report described nine patients followed during a mean duration of 47 months who were treated with systemic steroids, and all experienced visual field gains along with improved or stable VA. The authors proposed that perhaps the more favorable results observed in their series were attributable to earlier initiation of steroid therapy due to improved detection of the acute/subacute stages of disease with subtle findings on previously unavailable imaging modalities (eg, spectral-domain OCT).7
Such local therapies as IVTA, dexamethasone intravitreal implant, and the fluocinolone acetonide implant effectively and safely treat inflammatory eye diseases,9–11 though little is known about their use in the management of AZOOR. Intravitreal steroids offer the advantage of local drug delivery and the possibility of diminishing systemic immunosuppression requirements. In our series of patients, intravitreal steroids appeared to be particularly effective, as one patient experienced disease progression even while on mycophenolate mofetil that only stabilized after IVTA. These cases not only highlight the potential benefit of intravitreal steroids in treating AZOOR patients, but also support the role for multimodal imaging along with patient symptomatology in guiding treatment decisions, monitoring disease activity, and establishing treatment responses. Though other imaging modalities, such as indocyanine green angiography3 and automated visual fields,7 have been used to analyze AZOOR cases, we found that SD-OCT and FAF provided quick, noninvasive, and reliable means for assessing these patients.
It should be noted that many of these patients did receive systemic antivirals and antibiotics at the onset of their evaluation prior to the establishment of a working diagnosis. However, in all cases these medications were discontinued, and fluctuations in disease activity based on imaging findings consistent with the timing of intravitreal steroid administration were observed. Such findings seem to support the role for inflammation in the pathogenesis of AZOOR.
The side effects of these agents commonly include elevated intraocular pressure and cataract development, particularly with steroid implants.10,11 In our case series, a majority of eyes experienced ocular hypertension, all of which were well-controlled with topical agents. Additionally, cataracts developed in all phakic eyes. Other steroid-related complications included the development CSR in one eye, which improved with eplerenone. Such costs and potential side effects of intravitreal agents certainly need to be considered in treatment decisions for this patient population. The rationale for intravitreal therapy in this case series was based on disease location (in most cases activity was perifoveal) and the desire to preserve central vision while limiting long-term systemic therapy. Although mild VA decline was noted at 1 year in many eyes, this was likely due cataract development, a reversible cause of vision loss, whereas no patients exhibited causes of permanent vision loss secondary to sub-foveal progression of AZOOR lesions following intravitreal steroid treatment.
This analysis is limited by its size (nine eyes) and retrospective, observational nature. There was no standardization to the follow-up schedule or imaging protocol, which consequently did not allow for regular comparison between imaging modalities (ie, correlation of hyperautofluorescence with ellipsoid zone loss on OCT). Given that these patients were evaluated at a tertiary referral center, it is possible that they were more likely to have recurrent or progressive disease that would potentially benefit from treatment than those in the community.
In conclusion, we present a series of nine eyes with a clinical diagnosis of AZOOR supported by multimodal imaging findings that were managed with intravitreal steroids. Changes in imaging characteristics and symptomatic improvement during the course of treatment suggests a positive response to intravitreal steroids, supporting the hypothesis that AZOOR is an immune-mediated entity.
- Monson DM, Smith JR. Acute zonal occult outer retinopathy. Surv Ophthalmol. 2011;56(1):23–35. doi:10.1016/j.survophthal.2010.07.004 [CrossRef]
- Li D, Kishi S. Loss of photoreceptor outer segment in acute zonal occult outer retinopathy. Arch Ophthalmol. 2007;125(9):1194–1200. doi:10.1001/archopht.125.9.1194 [CrossRef]
- Mrejen S, Khan S, Gallego-pinazo R, Jampol LM, Yannuzzi LA. Acute zonal occult outer retinopathy: A classification based on multimodal imaging. JAMA Ophthalmol. 2014;132(9):1089–1098. doi:10.1001/jamaophthalmol.2014.1683 [CrossRef]
- Jampol LM, Becker KG. White spot syndromes of the retina: A hypothesis based on the common genetic hypothesis of autoimmune/inflammatory disease. Am J Ophthalmol. 2003;135(3):376–379. doi:10.1016/S0002-9394(02)02088-3 [CrossRef]
- Gass JD. Are acute zonal occult outer retinopathy and the white spot syndromes (AZOOR complex) specific autoimmune diseases?Am J Ophthalmol. 2003;135(3):380–381. doi:10.1016/S0002-9394(03)00030-8 [CrossRef]
- Gass JD, Agarwal A, Scott IU. Acute zonal occult outer retinopathy: A long-term follow-up study. Am J Ophthalmol. 2002;134(3):329–339. doi:10.1016/S0002-9394(02)01640-9 [CrossRef]
- Chen SN, Yang CH, Yang CM. Systemic corticosteroids therapy in the management of acute zonal occult outer retinopathy. J Ophthalmol. 2015;2015:793026. doi:10.1155/2015/793026 [CrossRef]
- Kitakawa T, Hayashi T, Takashina H, Mitooka K, Gekka T, Tsuneoka H. Improvement of central visual function following steroid pulse therapy in acute zonal occult outer retinopathy. Doc Ophthalmol. 2012;124(3):249–254. doi:10.1007/s10633-012-9318-1 [CrossRef]
- Tempest-roe S, Joshi L, Dick AD, Taylor SR. Local therapies for inflammatory eye disease in translation: Past, present and future. BMC Ophthalmol. 2013;13(1):39. doi:10.1186/1471-2415-13-39 [CrossRef]
- Malclès A, Dot C, Voirin N, et al. Safety of intravitreal dexamethasone implant (Ozurdex): The SAFODEX study. Incidence and Risk Factors of Ocular Hypertension. Retina. 2017;37(7):1352–1359 doi:10.1097/IAE.0000000000001369 [CrossRef]
- Sangwan VS, Pearson PA, Paul H, Comstock TL. Use of the fluocinolone acetonide intravitreal implant for the treatment of noninfectious posterior uveitis: 3-year results of a randomized clinical trial in a predominantly Asian population. Ophthalmol Ther. 2015;4(1):1–19. doi:10.1007/s40123-014-0027-6 [CrossRef]
Baseline Characteristics and Outcomes of Patients With AZOOR Treated With Intravitreal Steroids
|Case||Demographics (Years /Sex)||Eye||Initial VA||VA 1 Year||Follow-Up (Months)||Systemic Tx||Local Tx||Systemic Tx Final||Imaging|
|1||35/F||OD||20/20||20/20-1||17||Pred||Dex x 1||None||Reduced FAF|
|OS||20/20||20/20||17||Pred||Dex x 3 None||Reduced FAF|
|2||57/F||OD||20/20-3||20/30*||15||Pred, Myc||IVTA x2||Myc||Reduced FAF|
|OS||20/20||20/25-2a*||14||Pred, Myc||IVTA x 2||Reduced FAF|
|3||73/F||OD||20/30||20/40b||31||Pred, Val, MTX, AZA||IVTA, Dex x3||AZA||Improved OCT|
|OS||HM||20/300||31||Pred, Val, MTX, AZA||AZA||Improved OCT|
|4||50/F||OD||20/20||20/30*||22||Pred, Bac, Val||IVTA x 2, Dex x 2||Myc||Reduced FAF|
|OS||20/30||20/50-2*||22||Pred, Bac, Val||IVTA x 1, Dex x 3||Myc||Reduced FAF|
|5||50/M||OS||CF||CFc||63||Pred, Val, Doxy, Myc||IVTA x 1, Flu||None||Stable FAF|