MULTIZONAL OUTER RETINOPATHY AND RETINAL PIGMENT EPITHELIOPATHY (MORR)

This longitudinal description of acute zonal occult outer retinopathy patients over a long-term period using multimodal imaging uncovered an unusual entity characterized by multizonal involvement and a prolonged progressive clinical course.

Abstract

Purpose:

To describe specific clinical, multimodal imaging, and natural history features of an unusual variant of acute zonal occult outer retinopathy.

Methods:

Retrospective, observational, longitudinal, multicenter case series. Patients exhibiting this unusual clinical condition among cases previously diagnosed with acute zonal occult outer retinopathy were included. Multimodal imaging, laboratory evaluations, and genetic testing for inherited retinal diseases were reviewed.

Results:

Twenty eyes from 10 patients (8 females and 2 males) with a mean age of 54.1 ± 13.3 years (range, 38–71 years) were included. The mean follow-up duration was 13.1 ± 5.3 years (range, 8–23 years). Presenting symptoms were bilateral in 7 patients (85% of eyes) and included scotomata and photopsia. All patients had bilateral lesions at presentation involving the peripapillary and far peripheral retina. Baseline optical coherence tomography showed alteration of the retinal pigment epithelium and photoreceptor layers corresponding to zonal areas of fundus autofluorescence abnormalities. Centrifugal and centripetal progression of the peripapillary and far-peripheral lesions, respectively, occurred over the follow-up, resulting in areas of complete outer retinal and retinal pigment epithelium atrophy.

Conclusion:

Initial alteration of photoreceptors and retinal pigment epithelium and a stereotypical natural course that includes involvement of the far retinal periphery, characterize this unusual condition. It may represent a variant of acute zonal occult outer retinopathy or may be a new entity. We suggest to call it multizonal outer retinopathy and retinal pigment epitheliopathy.

In 1992, Gass¹ described acute zonal occult outer retinopathy (AZOOR) in 13 patients with rapid loss of one or more zones of outer retinal function, photopsia, minimal fundoscopic changes, and electroretinographic anomalies affecting one or both eyes. Most of these patients were young women, some of whom had evidence of autoimmune diseases and developed persistent visual field defects and eventually zones of retinal pigment epithelium (RPE) clumping and atrophy.¹ Extensive medical and neurologic evaluations did not reveal any associated findings and no effective treatment was found.¹ Years later, long-term follow-up of “AZOOR” patients revealed that more than half of the eyes had a normal fundus on final examination and only a minority showed progression of visual field loss.²

Over time, the term “AZOOR” has been applied to heterogenous causes of unexplained vision loss related to varying patterns of outer retinal disruption, which resulted from a lack of specific diagnostic criteria. Distinguishing “AZOOR” from other diseases sharing similar symptoms and clinical presentation was challenging, especially before the advent of multimodal imaging modalities. To refine the diagnosis of “AZOOR”, a classification based on multimodal imaging was proposed, which primarily relied on identifying a trizonal pattern of outer retinal, RPE, and choroidal degeneration.³ This classification helped refine the diagnosis of “AZOOR” to a specific group of cases. However, significant heterogeneity still existed within this classification, because the clinical appearance, natural course, and response to treatment varied among the cases included.³

To clarify our understanding of “AZOOR” and explain the high variability among patients, we reviewed the clinical presentation and long-term follow-up of our “AZOOR” cases diagnosed through previous imaging classification.³ During this process, we identified a distinct entity with unique clinical manifestations, multimodal imaging characteristics, and long-term course.

The purpose of this study is to describe the clinical features, multimodal imaging findings, treatment responses, and long-term course of this distinctive entity.

Methods

This was an observational, longitudinal, retrospective, multicenter case series. Institutional review boards at the Vitreous Retina Macula Consultants of New York (New York City), San Raffaele Scientific Institute (Milan), and Northwestern University Feinberg School of Medicine (Chicago) approved this study. This report adhered to the tenets of the Declaration of Helsinki and complied with the Health Insurance Portability and Accountability Act.

Patients diagnosed with AZOOR according to the multimodal imaging classification were retrospectively reviewed and included in the analysis.³ Exclusion criteria were age <18 years, lack of multimodal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), or patients receiving a definite diagnosis during follow-up. Detailed chart reviews were performed and ophthalmoscopic and multimodal imaging findings, long-term follow-up, laboratory evaluations, genetic testing, and treatment outcomes were analyzed.

All patients had a complete ophthalmologic examination at baseline and follow-up visits, including measurement of the best-corrected visual acuity using Snellen charts and converted into logarithm of the minimum angle of resolution, slit-lamp biomicroscopy, and indirect fundus ophthalmoscopy. Color fundus photographs (Topcon TRC-50IX retinal camera, Topcon Medical Systems, Oakland, NJ or Optos, plc, Dunfermline, Scotland), spectral-domain OCT (SD-OCT; Spectralis, Heidelberg Engineering, Heidelberg, Germany), swept-source OCT and OCT-angiography (OCTA, PLEX Elite 9000, Carl Zeiss Meditec, Inc, Dublin, CA), FAF imaging, and fluorescein and indocyanine green angiography (Spectralis HRA, Heidelberg Engineering, or Topcon TRC-50IX retinal camera, Topcon Medical Systems, or Optos, plc) were reviewed when available.

Each case was retrospectively reviewed by two independent graders at each center (P.R. and A.M.) and presented to a panel of experts (K.B.F., D.A.G., L.M.J., and L.A.Y.) for open discussion during a face-to-face meeting. Cases deemed to represent a specific entity showing a characteristic phenotype, based on multimodal imaging and clinical course, were identified.

Quantitative and qualitative data are presented as mean ± SD and median, and absolute and relative proportions, respectively.

Results

From our previously published dataset comprising 30 patients who were diagnosed with AZOOR,² we included 7 cases that displayed distinct and similar multimodal imaging characteristics and exhibited a prolonged clinical course. Throughout the follow-up period, 8 other patients received specific diagnoses, which encompassed pachychoroid diseases (3 patients), idiopathic multifocal choroiditis with zonal retinochoroidal atrophy (3 patients), inherited retinal disease (TOPORS autosomal dominant retinitis pigmentosa in 1 patient), and acute annular outer retinopathy (1 patient). The remaining 15 cases (50% of the entire cohort) demonstrated long-term clinical manifestations that aligned with Gass' definition of AZOOR.

Demographic Data

A total of 20 eyes from 10 patients (8 women and 2 men) were included. Seven cases have been published in prior studies and 3 cases have not been published.^3–8 The mean follow-up duration was 13.1 ± 5.3 years (range, 8–23 years; median, 10 years). At presentation, the mean age was 54.1 ± 13.3 years (range, 38–71 years; median, 53.0 years) and the mean best-corrected visual acuity was 0.18 logarithm of the minimum angle of resolution (Snellen equivalent, 20/30; range, 20/20–20/200).

Presenting symptoms were bilateral in 7 patients (85% of eyes) and included scotomata and photopsia, whereas 3 patients (15% of eyes) had unilateral symptoms. None of the patients exhibited systemic symptoms at any time. Past ocular history was unremarkable in all cases. One or more medical conditions were present in 7/10 patients (70%). An autoimmune disease had been diagnosed in 5/10 patients (50%). The family medical history was recorded in all cases and was positive for Type 1 diabetes (2/7 patients) and thyroid diseases (2/7 patients). None of the patients had a familial history of retinal dystrophy.

Extensive laboratory investigations, often repeated by multiple physicians at multiple eye centers, were performed in all cases during follow-up and were uniformly unremarkable. Panel-based genetic testing for inherited retinal diseases and whole genome sequencing were performed in 6/10 (60%) and 2/10 patients (20%), respectively, and no pathogenic mutations were found.

Treatments were administered in 7/10 patients (70%) and included oral corticosteroid, immunosuppressive therapies, and oral acyclovir for 8 weeks. One patient with secondary choroidal neovascularization was treated with repeated intravitreal bevacizumab injections. Two patients were treated with repeated intravitreal injections of a dexamethasone implant 0.7 mg and then fluocinolone acetonide intravitreal implant. Tables 1 and 2 summarizes the demographic and clinical findings.

Table 1.

Demographic and Clinical Data of Patients With Multizonal Outer Retinopathy and Retinal Pigment Epitheliopathy (MORR)

Characteristics	Number
No. of patients	10
No. of eyes	20
Age at presentation (mean years ± SD, range)	54.1 ± 13.3 (38–71)
Follow-up duration (mean years ± SD, range)	13.1 ± 5.3 (8–23)
Gender n (%)
Male	2/10 (20.0%)
Female	8/10 (80.0%)
Ocular involvement at presentation
Bilateral	10/10 (100%)
Peripapillary lesion	20/20 (100%)
Additional midperipheral lesion	3/20 (15%)
Far-peripheral lesion	20/20 (100%)
BCVA in LogMAR (mean Snellen equivalent, range)
Initial	0.18 (20/30, range 20/20–20/200)
Final	1.04 (20/214, range 20/20 to hand motion)
Presenting symptoms n (%)
Scotoma	17/20 (85.0%)
Photopsia	17/20 (85.0%)
Asymptomatic	3/20 (15.0%)
Treatments n (%)
None	7/10 (70.0%)
Oral corticosteroid	2/10 (20.0%)
Immunosuppressive therapy	2/10 (20.0%)
Intravitreal corticosteroid	2/10 (20.0%)
Intravitreal bevacizumab	1/10 (10.0%)

BCVA, best-corrected visual acuity; LogMAR, logarithm of the minimum angle of resolution.

Table 2.

Clinical Features of 10 Patients With Multizonal Outer Retinopathy and Retinal Pigment Epitheliopathy (MORR)

Patient No./Sex/Age, y	Laterality	Follow-Up Duration, y	Initial Visual Acuity	Final Visual Acuity	Medical History	Systemic Work-Up and Genetic Testing	Treatment	Natural Course and Complications
1/F/43	Bilateral	23	20/20 OD 20/20 OS	20/30 OD 20/20 OS	Graves' disease	Negative laboratory and genetic panel testing	Mycophenolate mofetil	Centripetal and centrifugal progression with foveal sparing OU
2/F/71	Bilateral	17	20/25 OD 20/25 OS	20/40 OD 20/60 OS	Rheumatoid arthritis, hypertension, asthma	Negative laboratory and whole genome sequencing	None	Centripetal and centrifugal progression with foveal sparing OU
3/M/69	Bilateral with marked asymmetry	10	20/40 OD 20/30 OS	20/200 OD 20/50 OS	Hypercholesterolemia	Negative laboratory and genetic panel testing	None	Centripetal and centrifugal progression with foveal involvement OD Discrete progression of peripapillary lesion with foveal sparing OS
4/F/53	Bilateral with marked asymmetry	21	20/60 OD 20/20 OS	HM OD HM OS	Hashimoto thyroiditis, hypercholesterolemia	Negative laboratory and genetic panel testing	Acyclovir	Complete retinal degeneration OU
5/F/64	Bilateral	10	20/30 OD 20/40 OS	20/150 OD 20/200 OS	Hashimoto's thyroiditis, Type 1 diabetes, hypertension, liver hemangiomas, ovarian cancer	Negative laboratory and whole genome sequencing	None	Centripetal and centrifugal progression with foveal involvement OU
6/M/41	Bilateral	10	20/20 OD 20/20 OS	20/100 OD 20/100 OS	Ulcerative colitis, primary sclerosing cholangitis	Negative laboratory testing	Repeated IVI of dexamethasone implant 0.7 mg, then of fluocinolone acetonide intravitreal implant (0.19 mg)	Centripetal and centrifugal progression with foveal involvement OU. Temporary cessation of the peripapillary lesion progression and partial regression of the fringe-like hyperautofluorescent border after intravitreal corticosteroids Subretinal fibrosis OD
7/F/53	Bilateral	10	20/40 OD 20/20 OS	20/300 OD 20/40 OS	Congenital pulmonary valve disease, hypercholesterolemia, Type 2 diabetes	Negative laboratory and genetic panel testing	Repeated IVI of dexamethasone implant 0.7 mg, then of fluocinolone acetonide intravitreal implant (0.18 mg)	Centripetal and centrifugal progression with foveal involvement OD Temporary cessation of the peripapillary lesion progression and partial regression after repeated IVI of dexamethasone 0.7 mg then centripetal and centrifugal progression with foveal involvement OS
8/F/38	Bilateral	13	20/20 OD 20/200 OS	20/40 OD 20/400 OS	Unremarkable	Negative laboratory and genetic panel testing	Corticosteroid, mycophenolate mofetil, methotrexate, adalimumab, infliximab	Centripetal and centrifugal progression with foveal sparing OD and foveal involvement OS
9/F/40	Bilateral	8	20/20 OD 20/20 OS	20/20 OD 20/20 OS	Unremarkable	Negative laboratory testing	Corticosteroid, adalimumab	Centripetal and centrifugal progression with foveal sparing OU
10/F/69	Bilateral	9	20/20 OD 20/40 OS	20/200 OD 20/200 OS	Unremarkable	Negative laboratory and genetic panel testing	Intravitreal injections of bevacizumab	Centripetal and centrifugal progression with foveal involvement OU Choroidal neovascularization OS and subretinal fibrosis OU

IVI, intravitreal injection; OD, right eye: OS, left eye.

Ophthalmoscopic Features

At presentation, ophthalmoscopic examination showed bilateral involvement including peripapillary and far-peripheral lesions in all study eyes. Additional midperipheral or macular lesions not connected with the peripapillary lesion were observed in 3/20 eyes (15%).

The peripapillary lesion was characterized by a well-demarcated yellow–gray zone of RPE alterations (core) bordered by a thin demarcation line of pigmentary changes (orange, yellowish drusen-like, or hyperpigmented line) in 5/20 eyes (25%) (Figures 1–4). The other 15 eyes (75%) presented with more widespread RPE atrophy surrounding the optic disk, sometimes with hyperpigmentary changes (from subtle RPE stippling to granular RPE clumping), and increased visibility of the choroidal vasculature (Figures 5 and 6). None of the cases showed optic disk edema, perivascular exudation, vascular sheathing, vitritis, or anterior uveitis.

Fig. 1.

Multimodal imaging correlation of initial stage and long-term course of MORR (Case 8). A. At baseline, color fundus photography of the right eye shows a peripapillary lesion characterized by a well-demarcated yellow–gray core of RPE alterations (yellow arrowhead) and bordered by a thin hyperpigmented demarcation line (white arrowhead). B. At baseline, FAF image of the right eye shows the peripapillary lesion characterized by a speckled hyperautofluorescent core (yellow arrowhead) surrounded by a thin, continuous, hyperautofluorescent demarcation line (white arrowhead). C. At baseline, intermediate phase of fluorescein angiography of the right eye shows a hyperfluorescent peripapillary core (window defect, yellow arrowhead) and blockage of the pigmented demarcation line (white arrowhead). Note the absence of optic disk or retinal vascular staining or leakage. D. At baseline, late phase of indocyanine green angiography of the right eye shows hypofluorescence of the peripapillary core (reduced RPE uptake, yellow arrowhead). The demarcation line shows no distinctive features on indocyanine green angiography (white arrowhead). E and F. At baseline, near infrared reflectance image (E) of the right eye shows the peripapillary lesion with hyperreflective changes within the demarcation line (white arrowhead). The green line indicates the location of the OCT B-scan displayed in (F). Corresponding OCT B-scan (F) shows RPE disruption at the core, including RPE thickening interspersed with focal RPE atrophy (between white arrowheads). The hyperautofluorescent demarcation line colocalizes with focal RPE mottling (white arrowheads). The ellipsoid zone is attenuated, but still visible above areas of RPE alterations. G–J. Fundus autofluorescence images of the right eye acquired at 4 years (G), 4.5 years (H), 8 years (I), and 10 years (J). The peripapillary lesion shows centrifugal extension of the hypoautofluorescent core and shifting of the demarcation line toward the periphery. Note the episodic pattern of progression. The timepoint is displayed.

Fig. 4.

Complete RPE degeneration resulting from merging of peripapillary and far-peripheral lesions in MORR (Case 4). A. At baseline, color fundus photography of the right eye shows peripapillary RPE alterations involving the fovea (white arrowhead). The timepoint is displayed. B. At baseline, color fundus photography of the left eye shows a well-demarcated, peripapillary yellowish–gray lesion surrounded by an orange demarcation line (white arrowhead). The timepoint is displayed. C. At 3 years, montage of FAF images of the right eye shows a peripapillary lesion with a hypoautofluorescent core and surrounded by large interrupted demarcation line with fringe-like hyperautofluorescent features radiating outward (white arrowhead). The timepoint is displayed. D. At 3 years, montage of FAF images of the left eye shows progression of the peripapillary lesion with a hypoautofluorescent core and surrounded by large interrupted demarcation line with fringe-like hyperautofluorescent features radiating outward (white arrowhead). Note the far-peripheral lesions inferiorly bordered by a large interrupted demarcation line with fringe-like hyperautofluorescent features radiating inward (blue arrowheads). The timepoint is displayed. E–J. Ultra-widefield FAF images of the right and left eye, respectively, acquired at 10 years (E and F), 13 years (G and H), and 21 years (I and J). The peripapillary lesion (white arrowheads) shows centrifugal extension of the hypoautofluorescent core and shifting of the demarcation line toward the periphery. Centripetal progression of the far-peripheral lesions is associated with merging of peripapillary and far-peripheral lesions, resulting in complete outer retinal and RPE degeneration at the final visit. The timepoint is displayed.

Fig. 5.

Episodic pattern of progression of MORR (Case 2). A. At baseline, ultra-widefield FAF image of the left eye acquired few days after symptoms' onset shows a subtle hyperautofluorescent peripapillary lesion (white arrowhead) and a macular lesion (green arrowhead). The timepoint is displayed. B. At 6 weeks, merging of the peripapillary and macular lesion is noted. The core of the peripapillary lesion shows a speckled hyperautofluorescence surrounded by a thin, continuous, hyperautofluorescent demarcation line (white arrowhead). Note the midperipheral lesions in the supero-temporal and infero-nasal areas (green arrowheads). The timepoint is displayed. C. At 6 years, ultra-widefield FAF image shows extension of the hypoautofluorescent core and minimal shifting of the demarcation line toward the periphery (white arrowhead). The pattern of the demarcation line progresses into a larger interrupted border with fringe-like hyperautofluorescent features radiating outward (white arrowhead). Note the centripetal progression of the hypoautofluorescent far-peripheral lesions (blue arrowheads). The timepoint is displayed. D. At 13 years, ultra-widefield FAF image shows further extension of the hypoautofluorescent core and minimal shifting of the demarcation line toward the periphery (white arrowhead). Attenuation and thinning of the demarcation line with loss of the hyperautofluorescent features are observed (white arrowhead). Note the relative stability of the hypoautofluorescent far-peripheral lesions (blue arrowheads). The timepoint is displayed. E. At 6 years, ultra-widefield FAF image of the right eye shows a peripapillary lesion with a hypoautofluorescent core surrounded by a large interrupted demarcation line with fringe-like hyperautofluorescent features radiating outward (white arrowhead). Note the annular hypoautofluorescent far-peripheral lesions (blue arrowhead). The timepoint is displayed. F. At 13 years, ultra-widefield FAF image of the right eye shows extension of the hypoautofluorescent core, thinning of the demarcation line with attenuation of the hyperautofluorescent features (white arrowhead). Note the centripetal progression of the hypoautofluorescent far-peripheral lesions (blue arrowhead). The timepoint is displayed. G and H. At 13 years, ultra-widefield pseudocolor fundus photographs of the right (G) and left eye (H) show peripapillary atrophy of the RPE and increased visibility of the choroidal vasculature (white arrowheads). Note the far-peripheral pigmented lesions (blue arrowheads). The timepoint is displayed. I. At 6 years, near infrared reflectance image of the right eye shows hyperreflective changes within the demarcation line radiating outward. The green line indicates the location of the OCT B-scan displayed in (J).J.At 6 years, OCT B-scan of the right eye shows peripapillary RPE disruption and loss of the ellipsoid zone and interdigitation zone. The hyperautofluorescent features of the demarcation line colocalizes with the focal RPE thickening (white arrowhead). The timepoint is displayed.K. At 13 years, near infrared reflectance image of the right eye shows centrifugal extension of the peripapillary lesion. The green line indicates the location of the OCT B-scan displayed in (L).L. At 13 years, OCT B-scan of the right eye shows extension of the peripapillary RPE disruption toward the fovea (white arrowhead). Note the further loss of the outer nuclear layer indicating photoreceptor cell loss and development of outer retinal tubulation (orange arrowhead). The timepoint is displayed.

Fig. 6.

Centrifugal and centripetal progression in MORR (Case 5). A–D. Ultra-widefield pseudocolor fundus photographs of the right eye acquired at baseline (A), 4 years (B), 6 years (C), and 10 years (D). At baseline (A), peripapillary (white arrowhead) and far-peripheral annular lesions of the RPE (blue arrowheads) are observed. Note the macular lesion (green arrowhead). During the follow-up, the peripapillary lesion (white arrowheads) shows centrifugal progression and merges with the macular lesion and the far-peripheral lesion at 6 and 10 years, respectively. Far-peripheral lesions are characterized by well-demarcated, 360-degree, annular zones of RPE atrophy accompanied by large spots of RPE hyperpigmentation (blue arrowheads). Centripetal progression of the far-peripheral lesions is noted. The timepoint is displayed. E–H. Ultra-widefield FAF images of the right eye acquired at baseline (E), 4 years (F), 6 years (G), and 10 years (H). At baseline (E), the peripapillary lesion shows a hypoautofluorescent core bordered by a large interrupted demarcation line with fringe-like hyperautofluorescent features radiating outward (white arrowhead). Note the macular lesion showing similar autofluorescent characteristics (green arrowhead). Far-peripheral annular lesions are hypoautofluorescent and bordered by a large interrupted demarcation line with fringe-like hyperautofluorescent features radiating inward (blue arrowheads). During the follow-up, the peripapillary lesion (white arrowheads) shows centrifugal extension of the hypoautofluorescent core and shifting of the demarcation line toward the periphery. Centripetal progression of the far-peripheral lesions associated with thinning and loss of the hyperautofluorescent features inside the demarcation line is noted at the final visit (blue arrowheads). The timepoint is displayed. I–L. Ultra-widefield pseudocolor fundus photographs of the left eye acquired at baseline (I), 4 years (J), 6 years (K), and 10 years (L). Centrifugal and centripetal progression of the peripapillary (white arrowhead) and far-peripheral (blue arrowheads) lesions, respectively, is noted during the follow-up. The timepoint is displayed. M–P. Ultra-widefield FAF images of the left eye acquired at baseline (M), 4 years (N), 6 years (O), and 10 years (P). The peripapillary lesion (white arrowheads) shows centrifugal extension of the hypoautofluorescent core and shifting of the demarcation line toward the periphery. Centripetal progression of the far-peripheral lesions associated with thinning and loss of the hyperautofluorescent features inside the demarcation line is noted at the final visit (blue arrowheads). The timepoint is displayed.

Far-peripheral lesions were characterized by well-demarcated, 360-degree, annular zones of RPE atrophy accompanied by large spots of RPE hyperpigmentation in all cases (Figures 2, 5, and 6). None of the cases showed bone spicule pigmentation. Additional lesions located in the midperiphery or macula were characterized by well-demarcated zones of RPE atrophy surrounded by hyperpigmentary changes. These additional lesions were singular in 2 eyes (66.6%) and multiple in 1 eye (33.3%; four lesions) (Figures 5 and 6).

Fig. 2.

Peripapillary and far-peripheral lesions of initial stage of MORR (Case 9). A. At baseline, color fundus photography of the right eye shows a subtle peripapillary gray lesion of the RPE (white arrowhead). The timepoint is displayed. B. At baseline, color fundus photography of the left eye shows a more apparent peripapillary gray lesion of the RPE surrounded by an orange demarcation line (white arrowheads). The timepoint is displayed. C. At baseline, FAF image of the right eye shows a subtle peripapillary lesion with hyperautofluorescent features (white arrowhead). The timepoint is displayed. D. At baseline, FAF image of the left eye shows a peripapillary lesion with a speckled hyperautofluorescent core surrounded by a thin continuous hyperautofluorescent demarcation line (white arrowhead). The timepoint is displayed. E and F. At 2 years, FAF images of the right (E) and left (F) eye show centrifugal progression of the peripapillary lesion characterized by a hypoautofluorescent core surrounded by a large interrupted demarcation line with fringe-like hyperautofluorescent features radiating outward (white arrowheads). The timepoint is displayed. G and H. At 2 years, ultra-widefield pseudocolor fundus photographs of the right (G) and left (H) eye show far-peripheral lesions characterized by well-demarcated, 360-degree, annular zones of RPE atrophy accompanied by large spots of RPE hyperpigmentation (blue arrowheads). The timepoint is displayed. I and J. At 2 years, ultra-widefield FAF images of the right (I) and left (J) eye show peripapillary lesions (white arrowheads) and the far-peripheral annular lesions (blue arrowheads). The timepoint is displayed. K and L. At 2 years, horizontal OCT B-scans through the fovea of the right (K) and left eye (L) show peripapillary RPE disruption and attenuation of the ellipsoid zone (white arrowheads). The timepoint is displayed.

Multimodal Imaging Features

On FAF imaging, the peripapillary lesions were characterized by a speckled hyperautofluorescent core surrounded by a thin, continuous, hyperautofluorescent demarcation line in 5/20 eyes (25%) (Figures 1–3, and 7). The other 15 eyes (75%) showed a hypoautofluorescent core surrounded by a larger interrupted demarcation line with fringe-like hyperautofluorescent features radiating outward (Figures 4–6). Far-peripheral lesions were hypoautofluorescent and bordered by a similar demarcation line with fringe-like hyperautofluorescent features radiating inward in all cases. Midperipheral or macular lesions showed a hypoautofluorescent core surrounded by a hyperautofluorescent border in all cases (Figures 5–7). Areas of unaffected retina showed a normal autofluorescent signal.

Fig. 3.

Initial stage and 15-year follow-up multimodal imaging of MORR (Case 1). A. At presentation, color fundus photography of the right eye acquired few days after symptoms' onset shows a well-demarcated yellow–gray core of RPE alterations (yellow arrowhead) bordered by a thin, yellowish, drusen-like demarcation line (white arrowhead). Note the absence of optic disk edema, perivascular exudation or sheathing, or vitritis. The timepoint is displayed. B. At 6 years, the size of the peripapillary lesion (yellow arrowhead) is relatively stable and attenuation of the demarcation line is noted (white arrowhead). The timepoint is displayed. C. At 15 years, centrifugal progression of the peripapillary lesion is noted. The core (yellow arrowhead) shows extension of the RPE atrophy and increased visibility of the choroidal vasculature. The demarcation line is shifted toward the periphery (white arrowhead). The timepoint is displayed. D. At presentation, FAF image shows a speckled hyperautofluorescent core (yellow arrowhead) surrounded by a thin, continuous, hyperautofluorescent demarcation line (white arrowhead). The timepoint is displayed. E. At 6 years, FAF image shows extension of the hypoautofluorescent core (yellow arrowhead), which is more apparent than seen on color fundus photography. The pattern of the demarcation line progresses into a larger interrupted border with fringe-like hyperautofluorescent features radiating outward (white arrowhead). The timepoint is displayed. F. At 15 years, centrifugal extension of the hypoautofluorescent core (yellow arrowhead) is noted. The demarcation line is shifted toward the periphery (white arrowhead). Note the thinning of the demarcation line and the reduced amount of the hyperautofluorescent features radiating outward. The timepoint is displayed. G. At 6 years, OCT B-scan through the fovea shows subtle RPE alterations in the peripapillary area (white arrowhead). The overlying ellipsoid zone is attenuated. The inset is the near infrared reflectance image with the green line indicating the location of the OCT B-scan. The timepoint is displayed. H. At 15 years, tracked OCT B-scan shows progression of the RPE atrophy toward the fovea (white arrowhead). Note the loss of the overlying ellipsoid zone and outer nuclear layer, and the secondary thinning of the underlying choroid. The inset is the near infrared reflectance image with the green line indicating the location of the OCT B-scan. The timepoint is displayed. I and J. At 15 years, ultra-widefield fundus autofluorescence images of the right (I) and left eye (J) show bilateral intermediate-stage peripapillary lesions (white arrowheads). Note the far-peripheral, annular, hypoautofluorescent lesions bordered by an interrupted demarcation line with fringe-like hyperautofluorescent features radiating inward (blue arrowheads). The timepoint is displayed.

Fig. 7.

Fundus autofluorescence imaging and OCT of initial stage of MORR (Case 3). A. At baseline, montage of FAF images of the right eye shows a peripapillary lesion with a speckled hyperautofluorescent core superiorly and bordered by a thin continuous hyperautofluorescent demarcation line (white arrowhead). Note the midperipheral lesion inferiorly (green arrowhead). The timepoint is displayed. B. At 4 years, the peripapillary lesion shows centrifugal progression of the hypoautofluorescent core and shifting of the demarcation line toward the periphery (white arrowhead). Note the merging of the midperipheral lesion with far-peripheral lesions (blue arrowhead). The timepoint is displayed. C. At 10 years, the peripapillary lesion shows further centrifugal progression of the hypoautofluorescent core and shifting of the demarcation line toward the periphery (white arrowhead). Note the persistence of fringe-like hyperautofluorescent features inside the demarcation line and radiating outward. Centripetal progression of far-peripheral lesions is seen (blue arrowhead). The timepoint is displayed. D. At baseline, near infrared reflectance image of the right eye shows speckled hyperreflectivity of the early-stage peripapillary lesion. The green line indicates the location of the OCT B-scan shown in (E). E. At baseline, OCT B-scan of the core shows focal mottling of the RPE interspersed with RPE atrophy (between white arrowheads). Note the disruption of the overlying ellipsoid zone. The hyperautofluorescent demarcation line colocalizes with focal RPE mottling (white arrowheads). The timepoint is displayed. F–M. Near infrared reflectance images and corresponding tracked OCT B-scans acquired at 4 years (F and G), 5 years (H and I), 6 years (J and K), and 10 years (L and M). On OCT, the demarcation line (white arrowheads) shows progressive shifting toward the periphery and attenuation of the RPE thickening. Extension of the RPE atrophy at the core of the peripapillary lesion is associated with secondary loss of the overlying ellipsoid zone and outer nuclear layer and thinning of the underlying choroid. The timepoint is displayed.

On cross-sectional OCT, the core of the peripapillary lesion was primarily characterized by RPE disruption, including RPE thickening interspersed with focal RPE atrophy in 5/20 eyes (25%) (Figures 1 and 2). In these eyes, the ellipsoid zone was preserved in one eye, attenuated in 3 eyes, and absent in 1 eye. The other 15 eyes (75%) showed a combination of complete RPE atrophy, ellipsoid zone and interdigitation zone loss, and outer nuclear layer thinning (Figure 5). Outer retinal tubulations were observed in 2 eyes (10%). The underlying choroidal thickness and architecture were preserved compared with adjacent zones of unaffected retina. The demarcation line of the peripapillary lesion was characterized by focal RPE thickening and overlying alteration of the ellipsoid zone/interdigitation zone.

On swept-source OCTA (n = 3 patients), flow signal deficits at the level of the choriocapillaris colocalized with the peripapillary alteration of the outer retina and RPE.

On fluorescein angiography (n = 7 patients), early and late phases showed a window defect at the core of the peripapillary lesion and blockage from the demarcation line. None of the cases showed optic disk or retinal vascular staining or leakage (Figure 1).

On indocyanine green angiography (n = 4 patients), early phases showed minimal hypofluorescence of the peripapillary lesion in two eyes (25%) with normal fluorescence of the underlying larger choroidal vessels (100%), and late phases showed increased hypofluorescence of the peripapillary lesion suggesting choriocapillaris loss and reduced RPE uptake (Figure 1).

Natural Course, Treatment Outcomes, and Complications

The mean final best-corrected visual acuity was 1.04 logarithm of the minimum angle of resolution (Snellen equivalent, 20/214; range, 20/20 to hand motion) and foveal involvement was noted in 12 eyes (60%) at the most recent follow-up.

In all cases (treated and untreated), centrifugal progression of the peripapillary lesions and centripetal extension of the far-peripheral lesions were observed, and ultimately merged with the midperipheral or macular lesions. The progression of the lesions exhibited an episodic pattern, displaying sporadic episodes of rapid extension, interspersed with periods of relative stability (Figure 5).

Ophthalmoscopic examination showed extension of RPE atrophy and hyperpigmentary changes in the peripapillary and far-peripheral zones of involvement. None of the cases developed typical bone spicule pigmentation or retinal vascular narrowing as observed in retinitis pigmentosa.

On FAF images, the progression of the peripapillary lesions followed a stereotypical course characterized by: 1) extension of the hypoautofluorescent core, 2) transformation of the thin, continuous, hyperautofluorescent demarcation line into a larger interrupted border with fringe-like hyperautofluorescent features radiating outward, and 3) thinning of the demarcation line and loss of the hyperautofluorescent features. The progression of the far-peripheral annular lesions followed the same sequential course with centripetal extension of the hypoautofluorescent zones. The persistence of fringe-like hyperautofluorescent features inside the demarcation line was associated with the continuous progression of the lesions (Figures 2 and 7). In contrast, one case (Case 2) showing loss of the hyperautofluorescent features inside the demarcation line demonstrated minimal progression of the lesions over 4 years (Figure 5).

On OCT, progression of the peripapillary lesions corresponded to extension of the RPE atrophy, loss of the overlying outer retina, and secondary choroidal thinning. Conversely, the inner retinal layers remained unaffected in all cases (Figure 7).

Two cases (Case 6 and 7) managed with multiple intravitreal injections of long-acting corticosteroid implants showed temporary stabilization and partial regression of the peripapillary lesion, which was eventually followed by further progression. In one case (Case 4) followed for 21 years, the lesions progressed to complete outer retinal and RPE atrophy.

Complications included macular subretinal fibrosis in 3 eyes (15%), and macular choroidal neovascularization requiring intravitreal injections of bevacizumab in 1 eye (5%). Table 2 summarizes the natural course, treatment outcomes, and complications.

Discussion

From a cohort of patients previously diagnosed with AZOOR, we identified a distinct phenotype in 20 eyes from 10 patients showing characteristic features including early peripapillary changes that affected photoreceptors and the RPE and a stereotypical natural course that included far-peripheral lesions exhibiting centripetal progression in a concentric pattern. A sequential progression of the disease was identified based on ophthalmoscopy, FAF, and OCT imaging. Extensive systemic evaluations and genetic testing were unremarkable. Although a subset of patients included in this cohort (7/10 patients) had been diagnosed with “AZOOR” in earlier publications,^3–8 reevaluation of multimodal imaging showed minimal resemblance to Gass¹' original description of AZOOR. In fact, in his seminal study, Gass¹ reported a series of patients presenting with acute scotomata and photopsia associated with loss of large zones of outer retinal function on electroretinogram in the absence of fundus changes. Early signs of intraocular inflammation, including vitritis, optic disk edema, and perivascular sheathing and exudation were also frequently noted within several weeks after the symptoms' onset.² Subsequently, long-term follow-up examination by Gass et al² showed normal fundi in 52% of eyes with AZOOR, whereas 43% of eyes demonstrated retinitis pigmentosa-like features, including pigment bone spicules and narrowing of retinal arteries. None of these initial or late findings were observed in our cohort. Moreover, upon analyzing the multimodal images of the cases included in Mrejen et al.‘s study, distinct differences emerged in comparison to our description, including the lack of relentless progression or peripheral concentric involvement in 50% of cases.² Therefore, we believe the phenotype we describe may represent a new entity or an unusual variant of “AZOOR” and we propose the term multizonal outer retinopathy and retinal pigment epitheliopathy (MORR): 1) MORR is characterized by an acute onset, but is a chronic disease exhibiting inexorable long-term progression of the lesions; 2) MORR is not confined to a single retinal zone, but involves several areas of retina (i.e., peripapillary lesion, far-peripheral annular lesion, and midperipheral or macular lesions); 3) MORR is not occult, but displays early fundus changes corresponding to RPE and photoreceptor disruption on multimodal imaging; 4) MORR affects the outer retina, but predominantly the RPE. Possibly, 2 cases (Case 3 and 10) in Gass¹' seminal study may be consistent with our definition of MORR. Seven cases of MORR were embedded in the Mrejen et al.‘s study, although they were not recognized as a separate entity at that time.² Furthermore, a PubMed-based search using the terms “AZOOR” and “acute zonal occult outer retinopathy” revealed seven additional cases published by other groups and showing multimodal images compatible with MORR.^9–15

We propose a disease characterization based on multimodal imaging correlation of noninvasive modalities. Fundus autofluorescence and OCT imaging are crucial diagnostic tools. Initial imaging findings showed predominant RPE disruption, which can mimic the presentation of placoid chorioretinitis.^16,17 The extent of choroidal layer involvement remains unclear because of the limited availability of indocyanine green angiography and OCTA imaging. Progression of the outer retinal and RPE lesions exhibited an episodic pattern characterized by intermittent periods of rapid progression interspersed with intervals of relative stability. Hence, time course from the early to late findings showed considerable variability, with some patients progressing rapidly over several weeks (Case 2), whereas others remaining relatively stable for several years before showing lesion progression (Case 1). Our multimodal imaging description may aid in earlier identification of this condition because the previously proposed trizonal degeneration was absent in some cases at presentation.³ Secondary complications, including choroidal neovascularization and subretinal fibrosis may occur during the course of the disease. Importantly, the presence of fringe-like hyperautofluorescent features within the demarcation line may be a reliable indicator of persistent disease activity and further lesion progression, whereas loss of this feature suggested minimal progression. Therefore, the presence of diffuse hyperautofluorescent features at the core and border of the lesion may represent a promising target for therapeutic intervention. In fact, 1 patient (Case 7) treated promptly with multiple sequential intravitreal injections of dexamethasone implant 0.7 mg showed temporary stabilization and partial regression of the peripapillary lesion.⁵ Nonetheless, assessing the treatment efficacy was challenging because treatment protocols were not standardized. Further research is necessary to evaluate treatment strategies of MORR.

The etiology of MORR is unknown and previous speculations included infectious, genetic, and autoimmune causes. Gass described that some patients presented with visual field loss limited to the extreme periphery, suggesting damage of the retinal receptor fields adjacent to the ora serrata.² He postulated that the edge of the optic disk and the ora serrata could be possible sites of viral invasion because of the proximity of the outer retina with the systemic circulation.¹⁸ Anecdotal reports have suggested the efficacy of valacyclovir in treating “AZOOR” based on electroretinogram and visual field testing.¹⁹ However, this result was not replicated in our series (Case 4). No convincing evidence of an infectious etiology exists at the present time. The disease pattern is distinct from other retinal infections. Panel-based genetic testing for inherited retinal diseases and whole genome sequencing were performed in most cases (80%) and revealed no suggestive mutations. In particular, the peripheral concentric RPE changes observed in all cases can masquerade as autosomal dominant vitreoretinochoroidopathy.²⁰ None of our cases had bestrophin 1 mutations, and family medical histories were negative for inherited retinal diseases.²¹ Half of our cohort had autoimmune diseases. Jampol and Becker proposed a common genetic hypothesis, stating that “AZOOR” may result from combinatorial interactions of common non–disease-specific loci, disease-specific loci, and specific environmental triggers.^22,23 The infrequency of discernible improvement after immunosuppressive therapies may suggest additional unknown pathogenic mechanisms of MORR. Vitreous inflammation was notably absent in our patients.

Limitations of this study include the partial overlapping of MORR with previous description of AZOOR, especially when using the imaging classification suggested by Mrejen et al.³ Peripheral involvement and continuous progression were not obvious at the time of this publication. Notably, 7 cases from the Mrejen et al.‘s study corresponded to MORR. We believe that recognizing this unique group of patients with common features as a variant of AZOOR or a newly recognized entity will help future efforts to explore potential causes and appropriate management. We advocate for distinguishing the MORR entity from “AZOOR,” given that MORR exhibits distinct and clearly defined clinical and multimodal imaging characteristics.

In conclusion, long-term follow-up of a group of patients previously diagnosed with AZOOR by our group revealed an unusual entity with unique multimodal imaging features and prolonged progressive clinical course. We propose the term MORR to describe this condition. Multizonal outer retinopathy and retinal pigment epitheliopathy may be a new entity or represent an atypical variant of AZOOR.