- Original article
- Open Access
Clinical course of acute zonal occult outer retinopathy complicated by choroidal neovascularization
© The Author(s) 2018
- Received: 7 May 2018
- Accepted: 23 July 2018
- Published: 29 August 2018
To report the clinical course and multimodal imaging features of acute zonal occult outer retinopathy (AZOOR) complicated by choroidal neovascularization (CNV) treated with anti-vascular endothelial growth factor (VEGF) treatment or photodynamic therapy (PDT).
Observational case series. Retrospective analysis of patients presenting to different institutions with evidence of AZOOR and neovascular lesions. Diagnosis of AZOOR was made on the basis of clinical presentation and multimodal imaging. All patients underwent a comprehensive ophthalmic evaluation and multimodal retinal imaging, including color fundus photos, fundus autofluorescence, fundus fluorescein angiography and spectral-domain optical coherence tomography.
Four patients (three males, mean age 53.5 years) were included in the study. Mean follow-up was 5.1 years. Presentation of AZOOR was unilateral in two patients and bilateral in the remainder two patients. One of the patients presenting with unilateral AZOOR developed zonal lesions in the fellow eye during follow-up. All patients presented with unilateral type 2 (subretinal) CNV. Three patients underwent intravitreal anti-VEGF injections and one patient underwent a single PDT. Multimodal retinal imaging showed zonal or multizonal progression during treatment. After treatment, visual acuity and CNV stabilization was observed in all patients.
The presence of CNV expands the clinical spectrum of AZOOR. CNV complicating AZOOR may be effectively treated with intravitreal injections of anti-VEGF, despite progression of the zonal lesions. Further studies are required to define the role of treatment in the progression of the zonal lesions.
- Acute zonal occult outer retinopathy
- Choroidal neovascularization
- Anti-vascular endothelial growth factor treatment
- Multimodal retinal imaging
As originally defined in 1992 by Gass in his Donder’s Lecture , acute zonal occult outer retinopathy (AZOOR) is a rare, condition of unknown etiology, characterized by an acute loss of one or more zones of outer retinal function. Since the original report by Gass , the term AZOOR became a general diagnostic term for chorioretinal diseases with visual loss of uncertain origin. Indeed, the definition and classification of AZOOR resulted in a heterogenic spectrum of disorders, the so-called “AZOOR complex”.
A common feature of the disease is the acute zonal lesion, or lesions, delineated by a grayish ring on funduscopy or a demarcation line of hyperautofluorescence seen on fundus autofluorescence imaging, which has been referred to as acute annular outer retinopathy (AAOR) . A more strict definition of AZOOR based on multimodal retinal imaging findings, including a demarcating line of progression between the involved and uninvolved retina and a trizonal pattern of chorioretinal degeneration, has been recently proposed [3, 4].
The development of subretinal choroidal neovascularization (CNV) in AZOOR is an extremely rare event [4–6]. Levison et al.  recently reported a case of CNV in AZOOR but long-term follow-up was not included. The purpose of this study is to report in details the clinical course and the multimodal retinal imaging of patients presenting with CNV and AZOOR.
This is an observational case series of patients included from the practices of different retina specialists. Clinical records and multimodal retinal imaging of patients presenting with AZOOR and neovascular lesions from three tertiary referring centers located in Italy (San Raffaele Scientific Institute, Vita-Salute University, Milan), France (Ophthalmic Center for Imaging and Laser, Paris, France) and United States of America (Vitreous Retina Macula Consultants of New York, New York) were collected and analysed. All patients underwent a comprehensive ophthalmic evaluation, including best-corrected visual acuity (BCVA), and multimodal retinal imaging, including color fundus photography, fundus autofluorescence (FAF), fundus fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT). Indocyanine green angiography (ICGA) was available for 3 patients (cases 2, 3 and 4).
Wide-field imaging using a system imaging 200° of the retina (200Tx; Optos plc) was available for one patient (case 3). For the other patients FAF, FA and ICGA were obtained using a fundus camera (TRC 501; Topcon Medical Systems) or scanning laser ophthalmoscopy on the Heidelberg system (Heidelberg Engineering, Heidelberg).
Diagnosis of AZOOR was made on the basis of clinical presentation and multimodal retinal imaging features including: (1) a demarcating line of progression at the level of the outer retina; (2) a trizonal pattern of sequential involvement of the outer retina, retinal pigment epithelium (RPE) and choroid; (3) zonal progression .
Extensive laboratory testing was performed in all patients to rule out chorioretinal conditions mimicking AZOOR. Humphrey visual field test was performed in two patients (cases 1 and 2) and Goldmann dynamic perimetry in one patient (case 4).
Demographic and relevant clinical findings available at baseline and at all follow-up examination visits were reviewed by the authors and retrospectively analyzed. Early data from one of the included cases (case 4) have been reported by Cohen and Jampol .
The study was conducted in agreement with the Declaration of Helsinki for research involving human subjects. Informed consent for publication of their clinical details and/or clinical images was obtained from the patients.
Four patients (3 males) were included in this study. Two patients attended the Vitreous Retina Macula Consultants of New York (cases 1 and 3); one patient attended the San Raffaele Scientific Institute in Milan (case 2); one patient attended the Ophthalmic Center for Imaging and Laser in Paris (case 4).
Demographic characteristics, main presenting symptoms and medical history of acute zonal occult outer retinopathy complicated by chorodal neovascularization in our series and in the Levison et al.a report
Systemic hypertension; aortic valve replacement
Blurred vision, scotoma, photopsia
Central scotoma and distortion
Hashimoto’s thyroiditis; ashtma
Blurred vision and photopsia
Levison et al.a
Blurred vision, scotoma, photopsia
Clinical characteristics of acute zonal occult outer retinopathy complicated by chorodal neovascularization (CNV) in our series and in the Levison et al.a report
Eye with CNV
RE 20/20 LE 20/60
RE 20/25 LE 20/50
Rani + Afli
12 + 5
RE 20/40 LE 20/20
RE 20/40b LE 20/20
Levison et al.a
RE 20/20 LE HM
In our series, mean age of the patients at the time of presentation was 53.5 year-old, ranging from 33 to 69 year-old. Central scotoma and photopsia were the most common presenting symptoms. AZOOR was unilateral in two patients (cases 1 and 4) and bilateral in the remainder two patients (cases 1 and 4). Mean follow-up was 5.1 years. One of the patients presenting with unilateral AZOOR developed zonal lesions in the fellow eye 5 years after presentation (case 4).
All patients presented with unilateral type 2 (subretinal) CNV which was treated with intravitreal anti-VEGF injections in 3 patients (bevacizumab in two patients; ranibizumab and aflibercept in one patient) and Verteporfin photodynamic therapy (PDT) in one patient (case 4). After treatment, visual acuity and CNV stabilization was observed in all patients. Multimodal retinal imaging showed progression of the zonal lesions during treatment.
AZOOR is a rare condition that occurs most frequently in young females. Presentation may be unilateral or bilateral, with simultaneous or sequential involvement. Prognosis is generally favorable as the central vision is often spared. However, photoreceptor and RPE atrophy make visual field loss recovery quite infrequent [8, 9].
Although the primary lesion seems to be related to photoreceptor outer segment dysfunction [10, 11], its underlying etiology is unknown, and its pathogenic mechanisms remain uncertain. Inflammatory disease has been hypothesized , and a history of autoimmune inflammatory systemic disease has been noted in at least 18% of patients . However the benefit of oral steroid treatment for this condition has not been well established. Moreover, some authors have found evidence of disseminated fungal infection , and a possible viral etiology has been supported by functional improvement in patients with AZOOR-like illness that were treated with oral valacyclovir .
The clinical onset of AZOOR is usually marked by photopsias and acute scotomas, with minimal or no fundus and angiographic changes. The average age at initial presentation is 36.7 years (with a range age of 13 to 79 years), with a predominance in women (76% of cases), and normal fundus appearance in 76% of cases . Our AZOOR cases are therefore atypical with regards to their age at onset, as well as their compounded clinical presentation and course. However, our cases meet the multimodal imaging diagnostic criteria of AZOOR  and present with typical autofluorescence and clinical features that are indisputably part of the AZOOR spectrum. The cases presented in this study may be classified as AAOR, described by Gass and Stern as a variant of AZOOR and characterized by a progressively irregular annular band of grey-white deep retinal opacification in a peripapillary location [2, 16]. The most noteworthy aspect of our cases is the concomitance of type 2 choroidal neovascularizations. In our series the mean age of patients was younger than the mean age reported in the literature on AZOOR . It is possible that the mean age deviation of our cases from the mean age reported in the current literature may have contributed to the development of the CNV. Of note our youngest patient (case 3) received more anti-VEGF injections than the other cases. Indeed she was highly discerning for minimal changes of her vision which usually correlated with minimal structural changes on OCT.
CNV is an extremely rare complication of AZOOR [4–6]. To the best of our knowledge only 2 cases of AZOOR complicated by CNV have been described in the current literature [5, 6]. The first case was reported by Cohen and Jampol in 2007 and PDT was used for treating the CNV . Six months after treatment, CNV enlargement and scarring with no progression of the zonal lesion was reported . In the present study we report the long-term follow-up of the case originally described by Cohen and Jampol (case 4). In this case we report a progressive enlargement of the central scar in the treated eye and subsequent mild involvement of the fellow eye with no CNV complication.
Levison et al.  recently reported another case of CNV in AZOOR in a 74 year-old female. This patient underwent treatment for bilateral AZOOR with systemic steroids, methotrexate and intravitreal dexamethasone implants. She subsequently developed a CNV in the right eye which was successfully treated with three intravitreal bevacizumab injections. However long-term follow-up was not reported .
In the present study we report the multimodal retinal imaging and the long-term clinical course of four patients presenting with AZOOR complicated by choroidal neovascularization, treated with intravitreal anti-VEGF agents (in 3 cases) and with PDT (in one case).
Although VEGF plays an important role in the maintenance of both retinal and choroidal circulations and is one of the key neurotrophic factors, intravitreal anti-VEGF injections presently represent the established treatment for active CNV. In our patients a remission of the choroidal neovascular activity was achieved following administration of anti-VEGF agents. However, zonal or multizonal progression was observed during treatment. Given the short period between the anti-angiogenic treatment and AZOOR progression, a causal relationship between the treatment and the zonal progression could be considered. Indeed, some authors have questioned the safety of VEGF neutralization, and advised cautious administration of intravitreal anti-VEGF. In preclinical studies, after systemic neutralization of VEGF, a significant increase in retinal cell apoptosis in the inner and outer nuclear layers occurred in mice . Moreover, bevacizumab has been reported to neutralize the protective effect of VEGF on retinal ganglion cells from induced oxidative stress . Other authors have raised the issue of ultrastructural toxicity, consisting of mitochondrial disruption in the inner segments of photoreceptors, after intravitreal bevacizumab injections in rabbit eyes . By contrast, multifocal electroretinography has shown no short-term cone photoreceptor toxicity after intravitreal bevacizumab administration .
In our cases, it is unclear whether the observed zonal progression was accelerated from anti-VEGF treatment, or is attributable to the natural course of the disease. In case 2, striking progression of the zonal lesions was observed in both eyes during anti-VEGF treatment administration in one eye. This finding might be related to the minimal systemic diffusion of the intravitreal drug and to its possible effect on the fellow eye, as previously hypothesized [21, 22].
The presence of CNV expands the clinical spectrum of AZOOR. While the progressive nature of AZOOR has been well documented [23–26], little is known about the clinical course of AZOOR complicated by CNV.
It is possible that in our series the zonal progression was merely related to the progressive nature of AZOOR in which the CNV was the expression of the underlying active disease.
In our experience, intravitreal anti-VEGF treatment was effective for the stabilization of the CNV complicating AZOOR. However, a concomitant progression of the zonal lesions was observed during treatment. Further studies are required to define the pathogenetic mechanisms underlying this rare association and the role of treatment in the progression of the zonal lesions.
Contributions of Authors in each of these areas: Conception and design of the study (UI, GC, SKM, LY). Analysis and interpretation (UI, GC, SKM, LY). Writing the article (UI, SKM, GC, ED-G). Critical revision of the article (LY). Data collection (UI, SKM, ED-G, GC). Provision of materials, patients, or resources (UI, SKM, ED-G, HS, CA, SC, SM, LJ). Literature search (GC, ED-G). All authors read and approved the final manuscript.
We thank the Macula Foundation, Inc., New York, NY, USA. This organization had no role in the design or conduct of this research.
The authors declare that they have no competing interests.
Availability of data and materials
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from the patients.
Ethics approval and consent to participate
The institutional review board of San Raffaele Scientific Institute determined that approval was not required for this study because it contains a retrospective review of functional and imaging data and no patient identifiers are included.
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