IDIOPATHIC MULTIFOCAL CHOROIDITIS WITH OUTER RETINAL OR CHORIORETINAL ATROPHY JESSE J. JUNG, MD,*†‡ SAMIRA KHAN, MD,§ SARAH MREJEN, MD,†¶ ROBERTO GALLEGO-PINAZO, MD, PHD,*†** EMMETT T. CUNNINGHAM, JR, MD, PHD, MPH,††‡‡§§ K. BAILEY FREUND, MD,*†¶‡ LEE M. JAMPOL, MD,§ LAWRENCE A. YANNUZZI, MD*†¶‡ Purpose: To report thirteen cases of idiopathic multifocal choroiditis with discrete chorioretinal lesions who were found to have zonal, multizonal, or diffuse outer retinal or chorioretinal atrophy. Methods: A retrospective observational case series using multimodal imaging including high-definition optical coherence tomography, fundus autofluorescence imaging, and fluorescein and indocyanine green angiography. Results: Twenty-one eyes in 13 patients with idiopathic multifocal choroiditis were found to have zonal, multizonal, or diffuse outer retinal or chorioretinal atrophy visualized using multimodal imaging. Thirteen eyes presented with diffuse disease, six eyes with multizonal, and two with zonal atrophy. Patterns of atrophy included zones surrounding the optic nerve, multiple geographic zones in the mid and far periphery, and a diffuse peripheral pattern with relative sparing of the central macula until later in the course of disease. Eleven of the 13 patients were treated with topical, periocular, or systemic corticosteroids, and 1 patient was also treated with systemic immunomodulatory treatment. The atrophic changes progressed over an average of 8 years of follow-up in 10 eyes despite therapy. Conclusion: Idiopathic multifocal choroiditis can present with an uncommon pattern of zonal, multizonal, or diffuse outer retinal or chorioretinal atrophy as part of its clinical spectrum. The severity, extent, and progression of these atrophic changes are best appreciated using multimodal diagnostic imaging. RETINA 34:1439–1450, 2014
I
cell identified as MFC with panuveitis.3,7,8 Patients will have negative histoplasmin skin reaction and serologic testing,7 and MFC can usually be distinguished from presumed ocular histoplasmosis syndrome (POHS) based on clinical history,7,9,10 fundus photography,11,12 and clinical course.7–12 Recently, there is growing support that MFC and punctate inner choroidopathy are the same entity.13–15 The purpose of this report is to describe 21 eyes of 13 patients with idiopathic MFC that developed a unique presentation of zonal, multizonal, or diffuse outer retinal, retinal pigment epithelium (RPE), and/or chorioretinal atrophy. Using multimodal imaging including spectral domain and enhanced depth imaging optical coherence tomography (SD- and EDI-OCT), fundus autofluorescence imaging (FAF), fluorescein angiography (FA), and indocyanine green angiography (ICG), we are able to further expand the clinical
diopathic multifocal choroiditis (MFC) is an inflammatory disorder classically associated with punchedout chorioretinal lesions, little or no anterior and/or posterior segment inflammation, and a high risk of both secondary choroidal neovascularization and subretinal fibrosis.1–3 This inflammatory condition presents predominantly in young healthy, myopic women with no known associated systemic disease.1 Although idiopathic MFC may represent an ocular manifestation of autoimmune disease in genetically susceptible patients, the precise etiopathogenesis remains unclear.1,4 Clinically, patients may complain of decreased vision, photopsias, floaters, and a temporal blind spot.1,5,6 Affected eyes typically show multiple punched-out chorioretinal lesions ranging from 50 to 350 mm in both the posterior pole and periphery, often with clustering of lesions nasal to the disk, and a range of inflammation with those having both anterior chamber and vitreous 1439
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spectrum of idiopathic MFC and describe a distinct form of outer retinal or chorioretinal zonal atrophy. Methods This was a retrospective observational case series conducted at three referral institutions: Vitreous Retina Macula Consultants of New York; Department of Ophthalmology, Feinberg School of Medicine of Northwestern University in Chicago, IL; and West Coast Retina in San Francisco, CA. At presentation and each subsequent follow-up visit, each patient underwent a complete examination including slit-lamp biomicroscopy; indirect ophthalmoscopy; FA; ICG; conventional photographs (Topcon America, Paramus, NJ) and widefield photographs (Optos, Marlborough, MA); FAF using scanning laser ophthalmoscope’s short-wave blue autofluorescence (Heidelberg Engineering, Heidelberg, Germany), and/or green autofluorescence with Spaide filters (Topcon America, Paramus, NJ), and/or green wide-field autofluorescence (Optos, Marlborough, MA); and/or high-resolution SD-OCT (Topcon 3D OCT; Topcon America, Paramus, NJ, or Heidelberg Spectralis; Heidelberg Engineering, Heidelberg, Germany), and EDI-OCT (Heidelberg Spectralis; Heidelberg Engineering, Heidelberg, Germany). Outer retinal structural damage was assessed by SD-OCT as a disruption and/or thinning of the outer retinal layers. Retinal pigment epithelium cell loss was further assessed by FAF imaging as confluent areas of absent autofluorescence. Choroidal degeneration was assessed by EDI-OCT as choroidal thinning and/or loss of choroidal vascular layers. A medical evaluation was performed in each patient to rule out possible associated diseases, including sarcoidosis, tuberculosis, syphilis, histoplasmosis, and other infectious diseases using directed laboratory From the *Department of Ophthalmology, New York University School of Medicine, New York, New York; †Vitreous Retina Macula Consultants of New York, New York, New York; ‡Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, New York; §Department of Ophthalmology, Feinberg School of Medicine of Northwestern University, Chicago, Illinois; ¶LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Hospital, New York, New York; **Department of Ophthalmology, University and Polytechnic Hospital La Fe, Valencia, Spain; ††Department of Ophthalmology California Pacific Medical Center, San Francisco, California; ‡‡Department of Ophthalmology, Stanford University School of Medicine, Stanford, California; and §§West Coast Retina Medical Group, San Francisco, California. Supported by the Macula Foundation, Inc; an unrestricted grant from Research to Prevent Blindness, Inc, NYC (Northwestern University); and a grant from Mary Dempsey and Kevin Hitzeman. None of the authors have any conflicting interests to disclose. Lee M. Jampol and Lawrence A. Yannuzzi are co-senior authors. Reprint requests: Lawrence A. Yannuzzi, MD, Vitreous Retina Macula Consultants of New York, 460 Park Avenue, Fifth Floor, New York, NY 10022; e-mail: [email protected]
2014 VOLUME 34 NUMBER 7
testing. Several patients were tested, and none showed evidence of either neoplastic or nonneoplastic antiretinal antibodies. All eyes included in this series were diagnosed with noninfectious, idiopathic MFC13 and demonstrated zonal, multizonal, or diffuse outer retinal and/or choroidal atrophy. Regarding the referral patterns to these centers, we reviewed a study involving six institutions across the United States including our two tertiary referral centers in New York and Chicago; and the total number of newly diagnosed patients with MFC/punctate inner choroidopathy was 54.4 Further analysis of this population included six new cases of idiopathic MFC per year from Northwestern University in Chicago and nine new cases of idiopathic MFC per year from Vitreous Retina Macula Consultants in New York. Extrapolating numbers from the longest followup, which was 16 years, approximately 240 patients would have been diagnosed with idiopathic MFC from these 2 institutions. Of these patients over 16 years of follow-up, the reported idiopathic MFC cases with zonal atrophy from the New York and Chicago referral center in this series represent only 8 patients (3.3%) and 4 patients (1.7%), respectively. Using the same approximation, the San Francisco referral center would have evaluated 1 patient (0.4%) with this form of MFC during this time period (Table 1).
Results Twenty-one eyes of 13 patients (11 women and 2 men) who had a mean age of 31.8 years (median age 32 years; range, 21–46) at the time of initial symptoms and mean age of 38.9 years (median age 42 years; range, 22–76) during evaluation were diagnosed with idiopathic MFC with retinal or chorioretinal atrophy (Table 2). Each eye was graded independently of its fellow eye, and as such, one patient had diffuse chorioretinal atrophy in one eye and multizonal chorioretinal atrophy in the fellow eye. None of the patients were found to have an underlying systemic disorder. All the patients underwent multimodal imaging to document the location and extent of both the focal chorioretinal lesions and the areas of outer retinal or chorioretinal zonal atrophy. The patients in this series have been followed longitudinally by 4 of the authors (L.A.Y., E.T.C., K.B.F., and L.M.J.) for an average of 8.4 years (median age 7 years; range, 0.083–16 years) (Table 2). The median visual acuity at the first visit to our referral practice was 20/40 (range, 20/16–20/2,000). The median visual acuity at the most recent visit was 20/50 (range, 20/16–20/20,000). Most of the cases maintained good visual acuity, but 6 eyes developed decreased central vision to 20/400 or less. Three of
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Table 1. Characteristics of Outer Retinal and/or Chorioretinal Atrophy
Pattern of atrophy (n = 21 eyes)
Layer of atrophy (n = 21 eyes) Laterality (n = 13 patients) Referral centers
Type of Zonal Atrophy
Number of Cases
Diffuse Multizonal to diffuse Multizonal Zonal Outer retinal Chorioretinal Unilateral Bilateral Vitreous Retina Macula Consultants of New York, New York, NY Department of Ophthalmology, Feinberg School of Medicine of Northwestern University, Chicago, IL West Coast Retina Medical Group, San Francisco, CA
13 1 5 2 15 6 5 8 8 (3.3%*) 4 (1.7%*) 1 (0.4%*)
*Approximate percentage based on two referral centers’ (Vitreous Retina Macular Consultants in New York and Northwestern University) number of new idiopathic MFC cases per year. Approximately 15 cases of newly diagnosed idiopathic MFC is seen per year at both institutions, and extrapolating over a follow-up of 16 years, approximately 240 patients would have been diagnosed with idiopathic MFC, which is the denominator in the percentages.
these six eyes also developed a relative afferent pupillary defect. Only 1 of the 21 reported eyes, which had unilateral, multizonal chorioretinal atrophy (Case 9), developed choroidal neovascularization. The fellow eye also developed choroidal neovascularization, but did not show evidence of zonal or diffuse atrophic changes. The choroidal neovascularization in both eyes was successfully treated with verteporfin photodynamic therapy. All 21 affected eyes had focal chorioretinal lesions characteristic of idiopathic MFC. No eyes had anterior chamber inflammation, and nine eyes showed mild vitreous inflammation. Thirteen eyes of 7 patients (Cases 1–7) showed diffuse disease, defined by multiple, atrophic, pigmented chorioretinal lesions, with confluent areas of atrophy and subretinal fibrous proliferation in the peripheral retina, along the major vascular arcades, and peripapillary region (Figures 1–3). Diffuse disease was bilateral in six patients and unilateral in one patient. Progression was noted with increased number of widespread chorioretinal atrophic spots in the periphery that spread centripetally, but still spared the macula until late in the disease course (Figures 2 and 3). Humphrey visual field or Goldmann visual fields showed two patterns: either severe concentric peripheral field loss or a large scotoma progressing from the blind spot. Full-field electroretinogram demonstrated an extinguished signal from both rod and cone photoreceptors. Multifocal electroretinogram showed significant peripheral depression with preservation of the central macula signal. These functional tests were asymmetric, and one eye was typically worse than the fellow eye in bilateral diffuse cases. Six eyes demonstrated multizonal disease (Cases 8–11). Multizonal disease was defined as multiple,
atrophic, pigmented chorioretinal lesions, and geographical areas of multizonal atrophy (Figures 5 and 6). This form of atrophy was unilateral in 2 patients and bilateral in 2 patients, one (Case 8, Figure 4) progressed from multizonal to diffuse chorioretinal atrophy over the 14-year follow-up. These geographic zones were typically hypopigmented and were found throughout the fundus including the peripapillary region, mid periphery, or far periphery. Multifocal electroretinogram highlighted mainly a central scotoma with abnormal amplitudes and implicit times. Two eyes demonstrated zonal disease (Case 12–13), which presented with the typical focal chorioretinal scarring and either an inferotemporal visual field scotoma (Case 12) or a focal peripapillary zone of outer retinal atrophy (Case 13). In Case 12, functional testing with Goldmann visual fields highlighted the visual field scotoma. Indocyanine green angiography angiography and FAF did not show any defects that corresponded to this inferotemporal scotoma, but SD-OCT through the superonasal retina did show attenuation of the photoreceptors (Figure 7). These focal zonal defects either in the mid periphery or peripapillary area only affected the outer photoreceptors and did not involve the RPE or choroid; therefore it was only seen with SD-OCT. Fifteen eyes had only outer retinal disease, and six eyes had chorioretinal atrophy. Three forms of imaging (ICG, FAF, and SD-OCT) were essential in determining the extent of involvement of the retina or choroid. Indocyanine green angiography was performed in 4 of the 13 cases and demonstrated multiple hypofluorescent spots corresponding to the atrophic scars, zonal areas of atrophy, and pigmentary changes. This form of imaging was especially helpful in identifying subtle inflammatory changes affecting the choroid in the multizonal and
Age at Case Affected Initial Age at Initial Visual No./Race/Sex Eye Symptoms Examination Acuity 22
22
Case 2/W/M
OU
32
32
Case 3/W/F
OU
46
76
Case 4/W/F
OU
39
39
Case 5/W/F
OS
28
28
Case 6/W/F
OU
44
51
Case 7/W/M
OU
41
43
Case 8/W/F
OD
23
OS Case 9/W/F
20/20 OD; 20/20 OS 20/40 OD; 20/50 OS 20/40 OD; 20/2,000 OS 20/25 OD; 20/2,000 OS 20/50 OS
20/30 OD; 20/20 OS 20/60 OD; 20/100 OS 20/40 OD; 20/2,000 OS 20/25 OD; 20/2,000 OS 20/400 OS
15
No
Posterior
Diffuse; retinal
No
16
No
Posterior
Diffuse; retinal
No
15
No
None
Diffuse; chorioretinal
No
Yes: OS
None
Diffuse; retinal
No
Systemic and topical steroids
16
Yes
Posterior
Diffuse; chorioretinal
No
7
No
None
Diffuse; retinal
No
Systemic, periocular and topical steroids None
0.083
No
None
Diffuse; retinal
No
None
Multizonal progressing to diffuse; chorioretinal Multizonal; chorioretinal
No
Systemic, periocular and topical steroids
No Yes
Systemic, periocular and topical steroids Systemic steroids
1.08
55
20/200 OD; 20/20,000 OD; 20/200 20/20,000 OS OS 20/20 OD; 20/20 OD; 20/20 OS 20/20 OS 20/2,000 OD 20/2,000 OD
14
Yes
Posterior
23
55
20/40 OS
20/80 OS
14
No
Posterior
OD
42
42
20/25 OD
20/40 OD
No
None
Case 10/W/F
OU
28
42
20/70 OD; 20/20 OS
20/70 OD; 20/20 OS
14
No
None
Multizonal; chorioretinal Multizonal; retinal
Case 11/W/F
OS
21
27
20/16 OS
20/16 OS
1
No
Posterior
Multizonal; retinal
No
Case 12/W/F Case 13/W/F
OS OD
30 17
30 19
20/20 OS 20/30 OD
20/20 OS 20/50 OD
1 7
No Yes
None Posterior
Zonal; retinal Zonal; retinal
No No
F, female; M, male; OD, right eye; OS, left eye; OU, both eyes; W, white.
Treatment Type (Systemic, Periocular, Topical)
1.5
No
Systemic topical Systemic topical Systemic topical
and steroids and steroids and steroids
Systemic, Periocular and topical steroids Systemic and topical steroids None Systemic and topical steroids; systemic CellCept
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OU
Inflammation Pattern of Atrophy; (Anterior or Involved Area Choroidal Posterior) of Retina or Choroid Neovascularization
Case 1/W/F
Final Visual Acuity
Follow- Afferent up Time Pupillary (years) Defect
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Table 2. Clinical Case Information
MFC AND RETINAL OR CHORIORETINAL ATROPHY JUNG ET AL
Fig. 1. Case 1. Bilateral diffuse outer retinal atrophy. Color fundus photos of the right (OD, A) and left eye (OS, B) at presentation shows subtle peripapillary atrophy and a few faint white chorioretinal lesions OD greater than OS in the temporal area of the macula. Peripheral color photographs OD (C) and OS (D) demonstrate small chorioretinal white lesions circumferentially. Upon 1-year follow-up: color montage photos of right (OD, E) and left eye (OS, F) highlight multiple small pigmented chorioretinitic lesions with some degree of confluence and occasional fibrous proliferation in the peripheral retina and generalized retinal vascular narrowing and attenuation of the RPE. After 15 years of follow-up: color montage photos OD (G) and OS (H) reveal increased number of widespread chorioretinal atrophic spots in the periphery that had spread centripetally, but sparing the central macula. Fundus
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diffuse idiopathic MFC cases. Of note, ICG angiography did not highlight any lesions in the unilateral zonal outer retinal atrophy case (Case 12) likely due to minimal involvement of the choroid, and inflammatory damage mainly occurring at the level of the photoreceptors. By FAF imaging, the chorioretinitic scars were hypoautofluorescent along with the zonal areas of atrophy where there was corresponding loss of RPE. In the diffuse cases, the hypoautofluorescent signal radiated centripetally from the peripapillary region and spared the fovea. In all of the cases, fundus autofluorescence imaging did not show in any case a demarcating line between the progressive lesions and normal uninvolved retina; nor a hypoautofluorescent area of zonal atrophy if it did not involve the RPE or choroid. Fundus autofluorescence imaging in the multizonal cases showed a heterogeneous amount of autofluorescence. In cases with advanced geographic zones of chorioretinal atrophy, these corresponding areas were hypoautofluorescent; whereas if only the outer retina was involved, there were discrete hyperautofluorescent bands surrounding each zone, which could be due to a bleaching effect from the loss of the outer photoreceptors16 or increased fluorophores within the RPE.17 SD- and EDI-OCT was instrumental in defining the depth of inflammatory involvement. In cases of chorioretinal atrophy, there was complete absence of the outer nuclear layer, external limiting membrane, ellipsoid, and interdigitation zones, as well as choroidal thinning corresponding to the zones of atrophy seen on examination and FAF. In chronic, severe cases of chorioretinal atrophy, outer retinal tubulations were also observed. SD-OCT in cases of only outer retinal atrophy typically showed widespread disruption of the ellipsoid and loss of the outer photoreceptor layer. Most of the patients (11 of 13) were treated with systemic corticosteroids, 4 received periocular corticosteroids, and 10 received topical treatment. One received corticosteroid sparing immunosuppressive treatment with systemic mycophenolate mofetil but no other biologic agents such as cyclosporine, methotrexate, azathioprine, infliximab, or tacrolimus were used. Multimodal imaging after treatment showed no change in the number of chorioretinal lesions or improvement in the extent of zonal atrophy; in fact,
autofluorescence imaging montage OD (I) and OS (J) demonstrate hypoautofluorescent zonal peripapillary RPE atrophy, speckled RPE loss extending from the arcades peripherally but sparing the macula, and hypoautofluorescence areas correlating with the chorioretinitic scars. Spectral domain optical coherence tomography OD (K) and OS (L) demonstrate asymmetric (OD greater than OS) mottled disruption of the inner and outer photoreceptor segment junction and loss of the outer retinal and RPE layers, but sparing the fovea in both eyes.
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six patients slowly progressed over the lengthy periods of follow-up despite multiple treatment attempts with corticosteroids.
Discussion
Fig. 2. Case 2. Bilateral diffuse outer retinal atrophy. Color fundus photographs of the right (OD, A) and left eye (OS, B) at presentation revealing peripapillary atrophy and a normal appearing posterior pole. Peripheral photographs (C, D) show small punched-out chorioretinal atrophic lesions in both eyes. Seventeen year later, ultra wide-field color photographs OD (E) and OS (F) highlight the extensive peripapillary atrophy extending along both major arcades, peripheral chorioretinitic scars greater inferotemporally, and peripheral pigment migration along the peripheral venules. Ultra wide-field fundus autofluorescence imaging OD (G) and OS (H) accentuates the retinal pigment epithelial loss with hypoautofluorescence in the areas of the chorioretinitic scars, zonal peripapillary region, and diffuse centripetal extension peripherally from the major arcades. Spectral domain optical coherence tomography OD (I) and OS (J) with higher magnification highlighted by the white boxes OD (K) and OS (L) demonstrates mottled disruption of the inner and outer photoreceptor segment junction and outer retinal thinning extending to the subfoveal region.
The nomenclature and clinical description of idiopathic MFC has changed considerably over the years.13 Multifocal choroiditis was first used by Krill et al in 1969 to describe POHS.5,13 Nozik and Dorsch in 19736 then expanded idiopathic MFC to include active vitreous and anterior chamber inflammation associated with characteristic fundus lesions and negative histoplasmin skin test and chest X-ray. This entity was further delineated and distinguished from POHS by Dreyer and Gass7 in a larger case series where they described multifocal chorioretinal lesions associated with anterior segment inflammatory cells, significant vitreous infiltration, and subretinal fibrosis. Many of the patients described in these earlier series would now be characterized as MFC with panuveitis based on the presence of clinically significant anterior and posterior vitreous inflammation; whereas eyes with minimal inflammation as those in this case series have been identified as idiopathic MFC.13 Further findings associated with idiopathic MFC also include peripapillary atrophy, scarring, and curvilinear chorioretinal streaks in the far periphery.1,10–12,18,19 Our 13 patients (21 eyes) presented with idiopathic MFC involving the posterior pole and peripheral fundus. Systemic diseases including ocular sarcoidosis were not present after thorough evaluation and longterm follow-up. Symptoms included photopsias and field loss. The degree of retinal and vitreous inflammation varied. All the patients demonstrated chorioretinal lesions and a spectrum of zonal outer retinal, RPE, and/or chorioretinal atrophy in the involved eyes. These zonal changes were distinct from the focal lesions seen typically in eyes with MFC. Foveal sparing was common until late into the disease course. Within the chorioretinal atrophic zones, SD-OCT and FAF imaging demonstrated geographic areas of both photoreceptor and RPE disruption. More advanced zones showed corresponding atrophy of the inner choroid. Interestingly, one case (Case 8, Figure 4) of bilateral multizonal disease initially, progressed to diffuse disease in one eye (right eye); whereas the fellow eye maintained multizonal disease. Based on these findings, it is possible that this zonal atrophy represents a spectrum of inflammatory disease associated with idiopathic MFC. As seen in the unilateral zonal atrophy case (Case 12, Figure 7), inflammation may initially only affect the outer photoreceptors and cause
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Fig. 3. Case 3. Bilateral diffuse chorioretinal atrophy. Fundus autofluorescence imaging montage of the right (OD, A) and left eye (OS, B) at presentation, accentuating retinal pigment epithelial damage with extensive zones of hypoautofluorescence worse OS versus OD, and multiple spots of hypoautofluorescence extending from the zones of atrophy into the peripheral retina. Spectral domain optical coherence tomography OD (C) and OS (D) and higher magnification OD (E) and OS (F) highlighted by the white boxes demonstrating sparing of the subfoveal inner and outer photoreceptor segment junction, but loss of this junction, outer retinal thinning, and choroidal attenuation in the areas of peripapillary atrophy. Similar findings were also noted in the left eye.
an associated visual field scotoma. As bouts of inflammation recur, continued progression to multizonal or diffuse disease may occur. Eventually, involvement of the RPE and choroid leads to end-stage disease, which includes severe chorioretinal atrophy as seen on EDIOCT, SD-OCT, and FAF (Case 3, Figure 3; Case 8, Figure 4). In most of the cases, central acuity was still maintained although the field of vision had diminished significantly. However, visual rehabilitation including a Seeing Eye dog was necessary in two patients with bilateral involvement and completely extinguished ERGs. To the best of our knowledge, there has been no report of patients with similar findings. Cases similar to ours, namely a MFC picture with a diffuse photoreceptor and RPE degeneration, have been previously described and were often categorized as AZOOR or AZOOR complex.20–22 AZOOR as described by Gass is associated with a zonal loss of outer retinal function, irreversible electroretinographic abnormalities, and permanent field loss.23 At the onset of AZOOR, Gass noted a normal appearing fundus in 76% of the cases;24 and if a zonal defect was present, it was commonly seen as an increased blind spot on visual fields. Loss of retinal function was usually noted around the disk in the area of peripapillary atrophy and
sometimes peripherally.23–25 We acknowledge that Gass’ original description of AZOOR has several similar findings to those described in our patients based on clinical examination alone. For example, central visual acuity in most patients with AZOOR is typically good with relative sparing of the subfoveal photoreceptors till late in the disease course;22,24 and vitreous inflammation can also be seen in AZOOR, with those patients lacking cellular infiltration of the vitreous most likely to recover vision and less likely to develop clinically apparent retinal pathology.22 These clinical findings suggest that both have an inflammatory etiology, but do not establish that they are a single disease complex. Although several clinical characteristics are similar, the majority of Gass’ patients bear only a slight resemblance on imaging to the patients we describe in this report.22–25 In his original case series of AZOOR, he described 2 patients who had unique findings of multifocal lesions (one diagnosis as MEWDS-Case 14 and one described as Pseudo-POHS-Case 15).23 Using only clinical observation and FA, the pseudo-POHS/ AZOOR case had bilateral scattered focal atrophic chorioretinal scars and narrowing of retinal arteries, but no discernible zonal atrophic areas on fundus examination,
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Fig. 4. Case 8. Bilateral; diffuse chorioretinal atrophy, right eye (OD); multizonal chorioretinal atrophy, left eye (OS). Fundus photograph OD (A) demonstrating peripapillary scarring, attenuated vessels, and diffuse atrophy within the macula. There is peripheral scarring and remarkable pigment clumping. Fundus photograph OS (B) shows peripapillary and central macular scarring. There are round discrete chorioretinal scars in the inferior and nasal periphery. Fundus autofluorescence imaging shows diffuse hypoautofluorescence in the peripapillary zone, macula, and in the periphery of OD (C). Fundus autofluorescence imaging OS shows hypoautofluorescence of the central and peripheral scars with a ring of mild hyperautofluorescence (D). Spectral domain optical coherence tomography (SDOCT) through the fovea OD (E) demonstrates diffuse loss of ellipsoid layer, RPE, and anterior choroid including under the fovea. OS (F), there are normal retinal layers nasally and loss of the ellipsoid layer, outer retina, and anterior choroid temporally.
and on visual field testing demonstrated marked enlargement of the blind spot and loss of a large segment of the inferior nasal field in the left eye.23 This case probably represented the entity we describe in this report, and diagnosis was limited by the fact that only FA and clinical observation were available at that time. Based on these initial observations, Gass initially proposed that AZOOR and MFC could be part of the same spectrum of inflammatory disease.22,23 Presently, we do not accept this hypothesis and argue that each white spot syndrome has a characteristic appearance and prognosis and that the syndromes do not represent manifestations of a single disease complex.1,26 In classic cases of AZOOR, a delineating line (“demarcation”) can often be seen with a boundary of autofluorescence abnormality, which can be either hyper- or hypoautofluorescent.27,28 In attempt to clarify the definition of AZOOR, we believe that in AZOOR, the inflammatory process primarily targets the outer retina in a zonal topography demarcated by a pathognomonic orangeto-gray line on ophthalmoscopic examination that appears hyperautofluorescent on FAF imaging27–30 and is a harbinger of further progression in classic AZOOR. These zonal areas never resolve and usually progress outward from the peripapillary area or centrifugally,
leading to a typical trizonal degeneration visualized in the FAF, ICG, and OCT images as follows: first, a normal area; second, an area of degeneration of the photoreceptors and/or RPE; and third, a degeneration of the choroid (Yannuzzi LA, Gallego-Pinazzo R, Mrejen S, et al. Charles M. Schepens Lecture: AZOOR. JAMA Ophthalmology, in press). Interestingly, genetic factors including inflammatory complement factor H have a strong association with both MFC and age-related macular degeneration,31 and having an underlying genetic susceptibility may predispose a single patient to more than one inflammatory disease. The nature of any retinal atrophy seen in Gass’ AZOOR patients was not studied with modern multimodal imaging including high-definition SD-OCT, EDI-OCT, and FAF imaging; and with these advancements in imaging, this case series demonstrates a distinct, rare variant of idiopathic MFC with retinal or chorioretinal atrophy. Spaide et al14 recently demonstrated with SD- and EDI-OCT the imaging stages by which MFC lesions occur. In MFC, the conical RPE elevations would occasionally rupture through the RPE and pour inflammatory infiltrate into the outer retina.14 These inflammatory active lesions appeared to have increased choroidal thickness compared with the surrounding
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Fig. 5. Case 10. Bilateral multizonal outer retinal atrophy. Color fundus photo of the right eye (OD, A) and left eye (OS, B) demonstrated chorioretinal lesions and asymmetric multizonal atrophic areas involving the mid periphery and macula with pigment migration into these zones. Fundus autofluorescence imaging OD showed multiple geographic zones of hypoautofluorescence in areas of the atrophy with a discrete hyperautofluorescent band surrounding the zone of macular and peripapillary atrophy OD (C). Fundus autofluorescence imaging OS (D) demonstrated multiple small zones of atrophy with confluence of these zones inferiorly but sparing of the central macula. Spectral domain optical coherence tomography (SD-OCT) through the fovea OD demonstrated loss of the ellipsoid layer, outer photoreceptors, and RPE disruption (E). SD-OCT through the fovea OS demonstrated a mild epiretinal membrane but normal ellipsoid layer (F).
choroid regardless of classification as punctate inner choroidopathy or MFC with panuveitis.14,32 On FAF imaging, the RPE elevations were minimally hyperautofluorescent, but if there was dehiscence of the RPE, the corresponding spot demonstrated absence of autofluorescence.14 After treatment and resolution of the acute inflammatory episode, the RPE elevations and choroidal inflammation resolved and left small white scars that showed the FA appearance of early slight hyperfluorescence with late staining, a punchedout lesion of absent RPE and disruption of the outer retina; or complete restoration of the outer retinal architecture with no visible alteration either by ophthalmoscopy or FA.14,32 Several of our authors (J.J.J., S.M., K.B.F., and L.A.Y. Idiopathic multifocal choroiditis with peripapillary zonal inflammation: a multimodal imaging analysis. Retinal Cases and Brief Reports, in press) recently reported a case of idiopathic MFC that demonstrated a zone of transient structural damage at the level of the outer retina and ellipsoid layer over areas of choroidal thickening. As the inflammation subsided, the zone of peripapillary outer retinal and choroidal inflammation resolved along with restoration of the outer retinal architecture, but a more
prominent area of subretinal inflammation developed into a chorioretinal atrophic scar. Given these observations, we hypothesize that recurrent episodes of inflammation in MFC involving the outer retina and/ or choroid could eventually produce permanent damage. Initially, acute inflammation may cause transient disruption of the outer retina as observed in our Case 12 (Figure 7) of unilateral, zonal atrophy, which demonstrated attenuation of the photoreceptors on SD-OCT but no change on FAF or ICG. As the inflammatory episodes continue to recur, they may be associated with additional heterogeneous zonal atrophy similar to development of chorioretinal scars either as multizonal or diffuse outer retinal atrophy, and some may even progress to the end-stage patterns of chorioretinal atrophy. Autofluorescence imaging in our cases of idiopathic MFC with zonal outer retinal or chorioretinal atrophy showed the typical multifocal hypoautofluorescent chorioretinal lesions,14,33 and also highlighted the unique patterns of zonal, multizonal, and diffuse areas of hypoautofluorescence as seen in the advanced cases of chorioretinal atrophy due to the complete lack of fluorophores. Interestingly, in some cases as in Case 11 (Figure 6), the borders of the zones may also show
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Fig. 6. Case 11. Unilateral multizonal chorioretinal atrophy. Wide-field color imaging of the left eye (OS) demonstrated scattered MFC lesions in the nasal peripapillary region and a curvilinear array of MFC lesions in the temporal retina. There were also two large zones of peripapillary and inferotemporal chorioretinal atrophy that spared the fovea and pigment migration within the inferotemporal region (A). Fundus autofluorescence imaging accentuated the two geographic zones of atrophy; whereas the peripapillary zone was hyperautofluorescent and the inferotemporal zone was faintly hyperautofluorescent with areas of granular hypoautofluorescence and surrounded by a ring of more intense hyperautofluorescence (B). Over one year of follow-up, multimodal imaging demonstrated stable chorioretinal atrophy on wide-field color and FAF (C and D). Spectral domain optical coherence tomography through the fovea OS (E) demonstrated loss of the ellipsoid zone and photoreceptor interdigitation disruption in the peripapillary region coinciding with the large zone of peripapillary atrophy seen on FAF but normal retinal architecture subfoveally.
mild hyperautofluorescence relative to their background autofluorescence at the boundary of the zonal abnormality depending on the involvement of the outer retina, RPE, or choroid. The zones that were hyperautofluorescent typically demonstrated outer photoreceptor and ellipsoid layer disruption, whereas those that had long-standing damage involving the outer retina, RPE, and inner choroid were typically hypoautofluorescent. The etiology to the heterogeneity in these autofluorescent patterns is unclear but the hyperautofluorescence could be due to a bleaching effect from loss of the outer photoreceptors16 or increased fluorophores within the RPE.17
In terms of treatment, corticosteroid treatment (systemic, periocular, or topical) was transiently used in 11 of 13 patients, and 1 patient received systemic mycophenolate mofetil. Currently, there is no recommended standard treatment available for idiopathic MFC. Corticosteroid therapy is typically the first-line treatment,34 and in conjunction with immunomodulatory therapy, has shown to reduce the amount of inflammatory infiltration of the subretinal space and outer retina and reduce the damage seen on multimodal imaging.3,14,35 Two retrospective series evaluating 14 and 15 patients, respectively, evaluated the use of systemic corticosteroids along with immunosuppressive
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Fig. 7. Case 12. Unilateral zonal outer retinal atrophy. Fundus photograph of the left eye shows a normal posterior pole with discrete chorioretinal scars in the periphery (A). Spectral domain optical coherence tomography (SD-OCT) through the fovea (B) shows peripapillary RPE disruption, but otherwise is normal. Goldmann visual field maps an inferotemporal scotoma (C). Infrared photograph (D) and corresponding reproducible SDOCT of the superonasal retina (E) shows a normal ellipsoid layer in the temporal region, which becomes attenuated in the nasal zone corresponding to the area of the scotoma.
agents such as methotrexate, cyclosporine A, azathioprine, cyclophosphamide, chlorambucil, or a combination of these medicines and found that immunomodulatory therapy can be effective and safe in controlling inflammation and preserving long-term good vision.3,35 Although these series did find positive outcomes with systemic immunomodulatory therapy, relapse can occur despite aggressive treatment in these inflammatory conditions.36 One report by Benitez-del-Castillo et al36 used the anti-TNFa, infliximab, and showed that although it was able to control noninfectious posterior uveitis due to Behçet’s disease, it was unable control the inflammation related to chronic idiopathic MFC. In our case series, a few cases seemed to partially improve in subjective vision with corticosteroid treatment, but corticosteroids and even the mycophenolate mofetil had no effect on the relentless progression of multimodal imaging findings in six patients. Systemic steroid-sparing immunomodulatory treatments were not used in most of the patients because they did not have frequent, acute episodes of worsening disease, but rather showed a slow, relentless progressive loss of vision due to atrophy. We understand that there are several limitations of our study. First, the sample size of this study and all reported series remain small; and given the rarity of these diseases, it is difficult to make definitive diagnostic assumptions especially given the retrospective approach. For example, based on a retrospective review of a previous publication, we estimated the total number per year of newly diagnosed cases within two of our referral centers and extrapolated the approximate incidence of this form of idiopathic MFC. Second, the underlying pathophysiology of these entities including AZOOR and MFC remains a mystery. It is believed that idiopathic MFC may be an
autoimmune mediated disease occurring in genetically susceptible patients.1,4 Medical evaluation including examination, serologic testing, and imaging when indicated was negative for all known infectious and noninfectious etiologies. Although the individual etiologies remain unclear, we believe that combining these inflammatory diseases into one encompassing definition of AZOOR complex is too generalizing and prevents further elucidation of the disease processes. In summary, using clinical evaluation and multimodal imaging; retinal or chorioretinal zonal atrophy represents a distinct variant within the spectrum of idiopathic MFC and presents with: 1) presence of chorioretinal scars, 2) heterogeneous inflammatory involvement of the retina, RPE and/or choroid with subsequent damage at these levels, 3) variation of zonal, multizonal, or progressive diffuse zonal atrophy that may progress centripetally with relative sparing of the fovea until later in the disease course, 4) absence of a demarcating hyperautofluorescent line between involved and uninvolved retina, as often seen in AZOOR. We believe these cases should be differentiated from the AZOOR complex. Key words: AZOOR, chorioretinal atrophy, idiopathic multifocal choroiditis, multimodal imaging, outer retinal atrophy. Acknowledgments The authors thank Chandrakumar Balaratnasingam, MD, David Maberley, MD, Jerome Sherman, OD, and Quan V. Hoang, MD, PhD, for their assistance in the collection of data.
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References 1. 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; 135:376–379. 2. Fine HF, Zhitomirsky I, Freund KB, et al. Bevacizumab (avastin) and ranibizumab (lucentis) for choroidal neovascularization in multifocal choroiditis. Retina 2009;29:8–12. 3. Thorne JE, Wittenberg S, Jabs DA, et al. Multifocal choroiditis with panuveitis: incidence of ocular complications and of loss of visual acuity. Ophthalmology 2006;113:2310–2316. 4. Pearlman RB, Golchet PR, Feldmann MG, et al. Increased prevalence of autoimmunity in patients with white spot syndromes and their family members. Arch Ophthalmol 2009;127: 869–874. 5. Krill AE, Chishti MI, Klien BA, et al. Multifocal inner choroiditis. Trans Am Acad Ophthalmol Otolaryngol 1969;73: 222–245. 6. Nozik RZ, Dorsch W. A new chorioretinopathy associated with anterior uveitis. Am J Ophthalmol 1973;76:758–762. 7. Dreyer RF, Gass JDM. Multifocal choroiditis and panuveitis. A syndrome that mimics ocular histoplasmosis. Arch Ophthalmol 1984;102:1776–1784. 8. Kedhar SR, Thorne JE, Wittenberg S, et al. Multifocal choroiditis with panuveitis and punctate inner choroidopathy: comparison of clinical characteristics at presentation. Retina 2007; 27:1174–1179. 9. Burgess DB. Ocular histoplasmosis syndrome. Ophthalmology 1986;93:967–968. 10. Callanan D, Gass JDM. Multifocal choroiditis and choroidal neovascularization associated with the multiple evanescent white dot and acute idiopathic blind spot enlargement syndrome. Ophthalmology 1992;99:1678–1685. 11. Parnell JR, Jampol LM, Yannuzzi LA, et al. Differentiation between presumed ocular histoplasmosis syndrome and multifocal choroiditis with panuveitis based on morphology of photographed fundus lesions and fluorescein angiography. Arch Ophthalmol 2011;119:208–212. 12. Spaide RF, Yannuzzi LA, Freund KB. Linear streaks in multifocal choroiditis and panuveitis. Retina 1991;11:229–231. 13. Essex RW, Wong J, Jampol L, et al. Idiopathic multifocal choroiditis: a comment on present and past nomenclature. Retina 2013;33:1–4. 14. Spaide RF, Goldberg N, Freund KB. Redefining multifocal choroiditis and panuveitis and punctate inner choroidopathy through multimodal imaging. Retina 2013;33:1315–1324. 15. Shimada H, Yuzawa M, Hirose T, et al. Pathological findings of multifocal choroiditis with panuveitis and punctate inner choroidopathy. Jpn J Ophthalmol 2008;52:282–288. 16. Burns SA, Elsner AE, Lobes LA Jr. Foveal cone photopigment bleaching in central serous retinopathy. Appl Opt 1988;27: 1045–1049. 17. Schmitz-Valckenberg S, Holz FG, Bird AC, Spaide RF. Fundus autofluorescence imaging review and perspectives. Retina 2008;28:385–409.
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18. Borodoker N, Cunningham ET Jr, Yannuzzi LA, et al. Peripheral curvilinear pigmentary streak in multifocal choroiditis. Arch Ophthalmol 2002;120:520–521. 19. Morgan CM, Schatz H. Recurrent multifocal choroiditis. Ophthalmology 1986;93:1138–1147. 20. Holz FG, Kim RY, Schwartz SD, et al. Acute zonal occult outer retinopathy (AZOOR) associated with multifocal choroidopathy. Eye (Lond) 1994;8:77–83. 21. Jacobson SG, Morales DS, Sun XK, et al. Pattern of retinal dysfunction in acute zonal occult outer retinopathy. Ophthalmology 1995;102:1187–1198. 22. Gass JD, Agarwal A, Scott IU. Acute zonal occult outer retinopathy: a long-term follow-up study. Am J Ophthalmol 2002; 134:329–339. 23. Gass JD. Acute zonal occult outer retinopathy. Donders Lecture: The Netherlands Ophthalmological Society, Maastricht, Holland, June 19, 1992. J Clin Neuroophthalmol 1993;13: 79–97. 24. Monson DM, Smith JR. Acute zonal occult outer retinopathy. Surv Ophthalmol 2011;56:23–35. 25. Quillen DA, Davis JB, Gottlieb JL, et al. The white dot syndromes. Am J Ophthalmol 2004;137:538–550. 26. Jampol LM, Wiredu A. MEWDS, MFC, PIC, AMN, AIBSE, and AZOOR: one disease or many? Retina 1995;15:373–378. 27. Fujiwara T, Imamura Y, Giovinazzo VJ, Spaide RF. Fundus autofluorescence and optical coherence tomographic findings in acute zonal occult outer retinopathy. Retina 2010;30: 1206–1216. 28. Spaide RF. Collateral damage in acute zonal occult outer retinopathy. Am J Ophthalmol 2004;138:887–889. 29. Spaide RF, Koizumi H, Freund KB. Photoreceptor outer segment abnormalities as a cause of blind spot enlargement in acute zonal occult outer retinopathy-complex diseases. Am J Ophthalmol 2008;146:111–120. 30. Li D, Kishi S. Loss of photoreceptor outer segment in acute zonal occult outer retinopathy. Arch Ophthalmol 2007;125: 1194–1200. 31. Ferrara DC, Merriam JE, Freund KB, et al. Analysis of major alleles associated with age-related macular degeneration in patients with multifocal choroiditis: strong association with complement factor H. Arch Ophthalmol 2008;126: 1562–1566. 32. Vance SK, Khan S, Klancnik JM, Freund KB. Characteristic spectral-domain optical coherence tomography findings of multifocal choroiditis. Retina 2011;31:717–723. 33. Haen SP, Spaide RF. Fundus autofluorescence in multifocal choroiditis and panuveitis. Am J Ophthalmol 2008;145:847–853. 34. Brueggeman RM, Noffke AS, Jampol LM. Resolution of punctate inner choroidopathy lesions with oral prednisone therapy. Arch Ophthalmol 2002;120:996. 35. Michel SS, Ekong A, Baltatzis S, Foster CS. Multifocal choroiditis and panuveitis: immunomodulatory therapy. Ophthalmology 2002;109:378–383. 36. Benitez-del-Castillo JM, Martinez-de-la-Casa JM, Pato-Cour E, et al. Long-term treatment of refractory posterior uveitis with anti-TNFa (infliximab). Eye (Lond) 2005;19:841–845.
I
cell identified as MFC with panuveitis.3,7,8 Patients will have negative histoplasmin skin reaction and serologic testing,7 and MFC can usually be distinguished from presumed ocular histoplasmosis syndrome (POHS) based on clinical history,7,9,10 fundus photography,11,12 and clinical course.7–12 Recently, there is growing support that MFC and punctate inner choroidopathy are the same entity.13–15 The purpose of this report is to describe 21 eyes of 13 patients with idiopathic MFC that developed a unique presentation of zonal, multizonal, or diffuse outer retinal, retinal pigment epithelium (RPE), and/or chorioretinal atrophy. Using multimodal imaging including spectral domain and enhanced depth imaging optical coherence tomography (SD- and EDI-OCT), fundus autofluorescence imaging (FAF), fluorescein angiography (FA), and indocyanine green angiography (ICG), we are able to further expand the clinical
diopathic multifocal choroiditis (MFC) is an inflammatory disorder classically associated with punchedout chorioretinal lesions, little or no anterior and/or posterior segment inflammation, and a high risk of both secondary choroidal neovascularization and subretinal fibrosis.1–3 This inflammatory condition presents predominantly in young healthy, myopic women with no known associated systemic disease.1 Although idiopathic MFC may represent an ocular manifestation of autoimmune disease in genetically susceptible patients, the precise etiopathogenesis remains unclear.1,4 Clinically, patients may complain of decreased vision, photopsias, floaters, and a temporal blind spot.1,5,6 Affected eyes typically show multiple punched-out chorioretinal lesions ranging from 50 to 350 mm in both the posterior pole and periphery, often with clustering of lesions nasal to the disk, and a range of inflammation with those having both anterior chamber and vitreous 1439
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spectrum of idiopathic MFC and describe a distinct form of outer retinal or chorioretinal zonal atrophy. Methods This was a retrospective observational case series conducted at three referral institutions: Vitreous Retina Macula Consultants of New York; Department of Ophthalmology, Feinberg School of Medicine of Northwestern University in Chicago, IL; and West Coast Retina in San Francisco, CA. At presentation and each subsequent follow-up visit, each patient underwent a complete examination including slit-lamp biomicroscopy; indirect ophthalmoscopy; FA; ICG; conventional photographs (Topcon America, Paramus, NJ) and widefield photographs (Optos, Marlborough, MA); FAF using scanning laser ophthalmoscope’s short-wave blue autofluorescence (Heidelberg Engineering, Heidelberg, Germany), and/or green autofluorescence with Spaide filters (Topcon America, Paramus, NJ), and/or green wide-field autofluorescence (Optos, Marlborough, MA); and/or high-resolution SD-OCT (Topcon 3D OCT; Topcon America, Paramus, NJ, or Heidelberg Spectralis; Heidelberg Engineering, Heidelberg, Germany), and EDI-OCT (Heidelberg Spectralis; Heidelberg Engineering, Heidelberg, Germany). Outer retinal structural damage was assessed by SD-OCT as a disruption and/or thinning of the outer retinal layers. Retinal pigment epithelium cell loss was further assessed by FAF imaging as confluent areas of absent autofluorescence. Choroidal degeneration was assessed by EDI-OCT as choroidal thinning and/or loss of choroidal vascular layers. A medical evaluation was performed in each patient to rule out possible associated diseases, including sarcoidosis, tuberculosis, syphilis, histoplasmosis, and other infectious diseases using directed laboratory From the *Department of Ophthalmology, New York University School of Medicine, New York, New York; †Vitreous Retina Macula Consultants of New York, New York, New York; ‡Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, New York; §Department of Ophthalmology, Feinberg School of Medicine of Northwestern University, Chicago, Illinois; ¶LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Hospital, New York, New York; **Department of Ophthalmology, University and Polytechnic Hospital La Fe, Valencia, Spain; ††Department of Ophthalmology California Pacific Medical Center, San Francisco, California; ‡‡Department of Ophthalmology, Stanford University School of Medicine, Stanford, California; and §§West Coast Retina Medical Group, San Francisco, California. Supported by the Macula Foundation, Inc; an unrestricted grant from Research to Prevent Blindness, Inc, NYC (Northwestern University); and a grant from Mary Dempsey and Kevin Hitzeman. None of the authors have any conflicting interests to disclose. Lee M. Jampol and Lawrence A. Yannuzzi are co-senior authors. Reprint requests: Lawrence A. Yannuzzi, MD, Vitreous Retina Macula Consultants of New York, 460 Park Avenue, Fifth Floor, New York, NY 10022; e-mail: [email protected]
2014 VOLUME 34 NUMBER 7
testing. Several patients were tested, and none showed evidence of either neoplastic or nonneoplastic antiretinal antibodies. All eyes included in this series were diagnosed with noninfectious, idiopathic MFC13 and demonstrated zonal, multizonal, or diffuse outer retinal and/or choroidal atrophy. Regarding the referral patterns to these centers, we reviewed a study involving six institutions across the United States including our two tertiary referral centers in New York and Chicago; and the total number of newly diagnosed patients with MFC/punctate inner choroidopathy was 54.4 Further analysis of this population included six new cases of idiopathic MFC per year from Northwestern University in Chicago and nine new cases of idiopathic MFC per year from Vitreous Retina Macula Consultants in New York. Extrapolating numbers from the longest followup, which was 16 years, approximately 240 patients would have been diagnosed with idiopathic MFC from these 2 institutions. Of these patients over 16 years of follow-up, the reported idiopathic MFC cases with zonal atrophy from the New York and Chicago referral center in this series represent only 8 patients (3.3%) and 4 patients (1.7%), respectively. Using the same approximation, the San Francisco referral center would have evaluated 1 patient (0.4%) with this form of MFC during this time period (Table 1).
Results Twenty-one eyes of 13 patients (11 women and 2 men) who had a mean age of 31.8 years (median age 32 years; range, 21–46) at the time of initial symptoms and mean age of 38.9 years (median age 42 years; range, 22–76) during evaluation were diagnosed with idiopathic MFC with retinal or chorioretinal atrophy (Table 2). Each eye was graded independently of its fellow eye, and as such, one patient had diffuse chorioretinal atrophy in one eye and multizonal chorioretinal atrophy in the fellow eye. None of the patients were found to have an underlying systemic disorder. All the patients underwent multimodal imaging to document the location and extent of both the focal chorioretinal lesions and the areas of outer retinal or chorioretinal zonal atrophy. The patients in this series have been followed longitudinally by 4 of the authors (L.A.Y., E.T.C., K.B.F., and L.M.J.) for an average of 8.4 years (median age 7 years; range, 0.083–16 years) (Table 2). The median visual acuity at the first visit to our referral practice was 20/40 (range, 20/16–20/2,000). The median visual acuity at the most recent visit was 20/50 (range, 20/16–20/20,000). Most of the cases maintained good visual acuity, but 6 eyes developed decreased central vision to 20/400 or less. Three of
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Table 1. Characteristics of Outer Retinal and/or Chorioretinal Atrophy
Pattern of atrophy (n = 21 eyes)
Layer of atrophy (n = 21 eyes) Laterality (n = 13 patients) Referral centers
Type of Zonal Atrophy
Number of Cases
Diffuse Multizonal to diffuse Multizonal Zonal Outer retinal Chorioretinal Unilateral Bilateral Vitreous Retina Macula Consultants of New York, New York, NY Department of Ophthalmology, Feinberg School of Medicine of Northwestern University, Chicago, IL West Coast Retina Medical Group, San Francisco, CA
13 1 5 2 15 6 5 8 8 (3.3%*) 4 (1.7%*) 1 (0.4%*)
*Approximate percentage based on two referral centers’ (Vitreous Retina Macular Consultants in New York and Northwestern University) number of new idiopathic MFC cases per year. Approximately 15 cases of newly diagnosed idiopathic MFC is seen per year at both institutions, and extrapolating over a follow-up of 16 years, approximately 240 patients would have been diagnosed with idiopathic MFC, which is the denominator in the percentages.
these six eyes also developed a relative afferent pupillary defect. Only 1 of the 21 reported eyes, which had unilateral, multizonal chorioretinal atrophy (Case 9), developed choroidal neovascularization. The fellow eye also developed choroidal neovascularization, but did not show evidence of zonal or diffuse atrophic changes. The choroidal neovascularization in both eyes was successfully treated with verteporfin photodynamic therapy. All 21 affected eyes had focal chorioretinal lesions characteristic of idiopathic MFC. No eyes had anterior chamber inflammation, and nine eyes showed mild vitreous inflammation. Thirteen eyes of 7 patients (Cases 1–7) showed diffuse disease, defined by multiple, atrophic, pigmented chorioretinal lesions, with confluent areas of atrophy and subretinal fibrous proliferation in the peripheral retina, along the major vascular arcades, and peripapillary region (Figures 1–3). Diffuse disease was bilateral in six patients and unilateral in one patient. Progression was noted with increased number of widespread chorioretinal atrophic spots in the periphery that spread centripetally, but still spared the macula until late in the disease course (Figures 2 and 3). Humphrey visual field or Goldmann visual fields showed two patterns: either severe concentric peripheral field loss or a large scotoma progressing from the blind spot. Full-field electroretinogram demonstrated an extinguished signal from both rod and cone photoreceptors. Multifocal electroretinogram showed significant peripheral depression with preservation of the central macula signal. These functional tests were asymmetric, and one eye was typically worse than the fellow eye in bilateral diffuse cases. Six eyes demonstrated multizonal disease (Cases 8–11). Multizonal disease was defined as multiple,
atrophic, pigmented chorioretinal lesions, and geographical areas of multizonal atrophy (Figures 5 and 6). This form of atrophy was unilateral in 2 patients and bilateral in 2 patients, one (Case 8, Figure 4) progressed from multizonal to diffuse chorioretinal atrophy over the 14-year follow-up. These geographic zones were typically hypopigmented and were found throughout the fundus including the peripapillary region, mid periphery, or far periphery. Multifocal electroretinogram highlighted mainly a central scotoma with abnormal amplitudes and implicit times. Two eyes demonstrated zonal disease (Case 12–13), which presented with the typical focal chorioretinal scarring and either an inferotemporal visual field scotoma (Case 12) or a focal peripapillary zone of outer retinal atrophy (Case 13). In Case 12, functional testing with Goldmann visual fields highlighted the visual field scotoma. Indocyanine green angiography angiography and FAF did not show any defects that corresponded to this inferotemporal scotoma, but SD-OCT through the superonasal retina did show attenuation of the photoreceptors (Figure 7). These focal zonal defects either in the mid periphery or peripapillary area only affected the outer photoreceptors and did not involve the RPE or choroid; therefore it was only seen with SD-OCT. Fifteen eyes had only outer retinal disease, and six eyes had chorioretinal atrophy. Three forms of imaging (ICG, FAF, and SD-OCT) were essential in determining the extent of involvement of the retina or choroid. Indocyanine green angiography was performed in 4 of the 13 cases and demonstrated multiple hypofluorescent spots corresponding to the atrophic scars, zonal areas of atrophy, and pigmentary changes. This form of imaging was especially helpful in identifying subtle inflammatory changes affecting the choroid in the multizonal and
Age at Case Affected Initial Age at Initial Visual No./Race/Sex Eye Symptoms Examination Acuity 22
22
Case 2/W/M
OU
32
32
Case 3/W/F
OU
46
76
Case 4/W/F
OU
39
39
Case 5/W/F
OS
28
28
Case 6/W/F
OU
44
51
Case 7/W/M
OU
41
43
Case 8/W/F
OD
23
OS Case 9/W/F
20/20 OD; 20/20 OS 20/40 OD; 20/50 OS 20/40 OD; 20/2,000 OS 20/25 OD; 20/2,000 OS 20/50 OS
20/30 OD; 20/20 OS 20/60 OD; 20/100 OS 20/40 OD; 20/2,000 OS 20/25 OD; 20/2,000 OS 20/400 OS
15
No
Posterior
Diffuse; retinal
No
16
No
Posterior
Diffuse; retinal
No
15
No
None
Diffuse; chorioretinal
No
Yes: OS
None
Diffuse; retinal
No
Systemic and topical steroids
16
Yes
Posterior
Diffuse; chorioretinal
No
7
No
None
Diffuse; retinal
No
Systemic, periocular and topical steroids None
0.083
No
None
Diffuse; retinal
No
None
Multizonal progressing to diffuse; chorioretinal Multizonal; chorioretinal
No
Systemic, periocular and topical steroids
No Yes
Systemic, periocular and topical steroids Systemic steroids
1.08
55
20/200 OD; 20/20,000 OD; 20/200 20/20,000 OS OS 20/20 OD; 20/20 OD; 20/20 OS 20/20 OS 20/2,000 OD 20/2,000 OD
14
Yes
Posterior
23
55
20/40 OS
20/80 OS
14
No
Posterior
OD
42
42
20/25 OD
20/40 OD
No
None
Case 10/W/F
OU
28
42
20/70 OD; 20/20 OS
20/70 OD; 20/20 OS
14
No
None
Multizonal; chorioretinal Multizonal; retinal
Case 11/W/F
OS
21
27
20/16 OS
20/16 OS
1
No
Posterior
Multizonal; retinal
No
Case 12/W/F Case 13/W/F
OS OD
30 17
30 19
20/20 OS 20/30 OD
20/20 OS 20/50 OD
1 7
No Yes
None Posterior
Zonal; retinal Zonal; retinal
No No
F, female; M, male; OD, right eye; OS, left eye; OU, both eyes; W, white.
Treatment Type (Systemic, Periocular, Topical)
1.5
No
Systemic topical Systemic topical Systemic topical
and steroids and steroids and steroids
Systemic, Periocular and topical steroids Systemic and topical steroids None Systemic and topical steroids; systemic CellCept
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OU
Inflammation Pattern of Atrophy; (Anterior or Involved Area Choroidal Posterior) of Retina or Choroid Neovascularization
Case 1/W/F
Final Visual Acuity
Follow- Afferent up Time Pupillary (years) Defect
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Table 2. Clinical Case Information
MFC AND RETINAL OR CHORIORETINAL ATROPHY JUNG ET AL
Fig. 1. Case 1. Bilateral diffuse outer retinal atrophy. Color fundus photos of the right (OD, A) and left eye (OS, B) at presentation shows subtle peripapillary atrophy and a few faint white chorioretinal lesions OD greater than OS in the temporal area of the macula. Peripheral color photographs OD (C) and OS (D) demonstrate small chorioretinal white lesions circumferentially. Upon 1-year follow-up: color montage photos of right (OD, E) and left eye (OS, F) highlight multiple small pigmented chorioretinitic lesions with some degree of confluence and occasional fibrous proliferation in the peripheral retina and generalized retinal vascular narrowing and attenuation of the RPE. After 15 years of follow-up: color montage photos OD (G) and OS (H) reveal increased number of widespread chorioretinal atrophic spots in the periphery that had spread centripetally, but sparing the central macula. Fundus
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diffuse idiopathic MFC cases. Of note, ICG angiography did not highlight any lesions in the unilateral zonal outer retinal atrophy case (Case 12) likely due to minimal involvement of the choroid, and inflammatory damage mainly occurring at the level of the photoreceptors. By FAF imaging, the chorioretinitic scars were hypoautofluorescent along with the zonal areas of atrophy where there was corresponding loss of RPE. In the diffuse cases, the hypoautofluorescent signal radiated centripetally from the peripapillary region and spared the fovea. In all of the cases, fundus autofluorescence imaging did not show in any case a demarcating line between the progressive lesions and normal uninvolved retina; nor a hypoautofluorescent area of zonal atrophy if it did not involve the RPE or choroid. Fundus autofluorescence imaging in the multizonal cases showed a heterogeneous amount of autofluorescence. In cases with advanced geographic zones of chorioretinal atrophy, these corresponding areas were hypoautofluorescent; whereas if only the outer retina was involved, there were discrete hyperautofluorescent bands surrounding each zone, which could be due to a bleaching effect from the loss of the outer photoreceptors16 or increased fluorophores within the RPE.17 SD- and EDI-OCT was instrumental in defining the depth of inflammatory involvement. In cases of chorioretinal atrophy, there was complete absence of the outer nuclear layer, external limiting membrane, ellipsoid, and interdigitation zones, as well as choroidal thinning corresponding to the zones of atrophy seen on examination and FAF. In chronic, severe cases of chorioretinal atrophy, outer retinal tubulations were also observed. SD-OCT in cases of only outer retinal atrophy typically showed widespread disruption of the ellipsoid and loss of the outer photoreceptor layer. Most of the patients (11 of 13) were treated with systemic corticosteroids, 4 received periocular corticosteroids, and 10 received topical treatment. One received corticosteroid sparing immunosuppressive treatment with systemic mycophenolate mofetil but no other biologic agents such as cyclosporine, methotrexate, azathioprine, infliximab, or tacrolimus were used. Multimodal imaging after treatment showed no change in the number of chorioretinal lesions or improvement in the extent of zonal atrophy; in fact,
autofluorescence imaging montage OD (I) and OS (J) demonstrate hypoautofluorescent zonal peripapillary RPE atrophy, speckled RPE loss extending from the arcades peripherally but sparing the macula, and hypoautofluorescence areas correlating with the chorioretinitic scars. Spectral domain optical coherence tomography OD (K) and OS (L) demonstrate asymmetric (OD greater than OS) mottled disruption of the inner and outer photoreceptor segment junction and loss of the outer retinal and RPE layers, but sparing the fovea in both eyes.
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six patients slowly progressed over the lengthy periods of follow-up despite multiple treatment attempts with corticosteroids.
Discussion
Fig. 2. Case 2. Bilateral diffuse outer retinal atrophy. Color fundus photographs of the right (OD, A) and left eye (OS, B) at presentation revealing peripapillary atrophy and a normal appearing posterior pole. Peripheral photographs (C, D) show small punched-out chorioretinal atrophic lesions in both eyes. Seventeen year later, ultra wide-field color photographs OD (E) and OS (F) highlight the extensive peripapillary atrophy extending along both major arcades, peripheral chorioretinitic scars greater inferotemporally, and peripheral pigment migration along the peripheral venules. Ultra wide-field fundus autofluorescence imaging OD (G) and OS (H) accentuates the retinal pigment epithelial loss with hypoautofluorescence in the areas of the chorioretinitic scars, zonal peripapillary region, and diffuse centripetal extension peripherally from the major arcades. Spectral domain optical coherence tomography OD (I) and OS (J) with higher magnification highlighted by the white boxes OD (K) and OS (L) demonstrates mottled disruption of the inner and outer photoreceptor segment junction and outer retinal thinning extending to the subfoveal region.
The nomenclature and clinical description of idiopathic MFC has changed considerably over the years.13 Multifocal choroiditis was first used by Krill et al in 1969 to describe POHS.5,13 Nozik and Dorsch in 19736 then expanded idiopathic MFC to include active vitreous and anterior chamber inflammation associated with characteristic fundus lesions and negative histoplasmin skin test and chest X-ray. This entity was further delineated and distinguished from POHS by Dreyer and Gass7 in a larger case series where they described multifocal chorioretinal lesions associated with anterior segment inflammatory cells, significant vitreous infiltration, and subretinal fibrosis. Many of the patients described in these earlier series would now be characterized as MFC with panuveitis based on the presence of clinically significant anterior and posterior vitreous inflammation; whereas eyes with minimal inflammation as those in this case series have been identified as idiopathic MFC.13 Further findings associated with idiopathic MFC also include peripapillary atrophy, scarring, and curvilinear chorioretinal streaks in the far periphery.1,10–12,18,19 Our 13 patients (21 eyes) presented with idiopathic MFC involving the posterior pole and peripheral fundus. Systemic diseases including ocular sarcoidosis were not present after thorough evaluation and longterm follow-up. Symptoms included photopsias and field loss. The degree of retinal and vitreous inflammation varied. All the patients demonstrated chorioretinal lesions and a spectrum of zonal outer retinal, RPE, and/or chorioretinal atrophy in the involved eyes. These zonal changes were distinct from the focal lesions seen typically in eyes with MFC. Foveal sparing was common until late into the disease course. Within the chorioretinal atrophic zones, SD-OCT and FAF imaging demonstrated geographic areas of both photoreceptor and RPE disruption. More advanced zones showed corresponding atrophy of the inner choroid. Interestingly, one case (Case 8, Figure 4) of bilateral multizonal disease initially, progressed to diffuse disease in one eye (right eye); whereas the fellow eye maintained multizonal disease. Based on these findings, it is possible that this zonal atrophy represents a spectrum of inflammatory disease associated with idiopathic MFC. As seen in the unilateral zonal atrophy case (Case 12, Figure 7), inflammation may initially only affect the outer photoreceptors and cause
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Fig. 3. Case 3. Bilateral diffuse chorioretinal atrophy. Fundus autofluorescence imaging montage of the right (OD, A) and left eye (OS, B) at presentation, accentuating retinal pigment epithelial damage with extensive zones of hypoautofluorescence worse OS versus OD, and multiple spots of hypoautofluorescence extending from the zones of atrophy into the peripheral retina. Spectral domain optical coherence tomography OD (C) and OS (D) and higher magnification OD (E) and OS (F) highlighted by the white boxes demonstrating sparing of the subfoveal inner and outer photoreceptor segment junction, but loss of this junction, outer retinal thinning, and choroidal attenuation in the areas of peripapillary atrophy. Similar findings were also noted in the left eye.
an associated visual field scotoma. As bouts of inflammation recur, continued progression to multizonal or diffuse disease may occur. Eventually, involvement of the RPE and choroid leads to end-stage disease, which includes severe chorioretinal atrophy as seen on EDIOCT, SD-OCT, and FAF (Case 3, Figure 3; Case 8, Figure 4). In most of the cases, central acuity was still maintained although the field of vision had diminished significantly. However, visual rehabilitation including a Seeing Eye dog was necessary in two patients with bilateral involvement and completely extinguished ERGs. To the best of our knowledge, there has been no report of patients with similar findings. Cases similar to ours, namely a MFC picture with a diffuse photoreceptor and RPE degeneration, have been previously described and were often categorized as AZOOR or AZOOR complex.20–22 AZOOR as described by Gass is associated with a zonal loss of outer retinal function, irreversible electroretinographic abnormalities, and permanent field loss.23 At the onset of AZOOR, Gass noted a normal appearing fundus in 76% of the cases;24 and if a zonal defect was present, it was commonly seen as an increased blind spot on visual fields. Loss of retinal function was usually noted around the disk in the area of peripapillary atrophy and
sometimes peripherally.23–25 We acknowledge that Gass’ original description of AZOOR has several similar findings to those described in our patients based on clinical examination alone. For example, central visual acuity in most patients with AZOOR is typically good with relative sparing of the subfoveal photoreceptors till late in the disease course;22,24 and vitreous inflammation can also be seen in AZOOR, with those patients lacking cellular infiltration of the vitreous most likely to recover vision and less likely to develop clinically apparent retinal pathology.22 These clinical findings suggest that both have an inflammatory etiology, but do not establish that they are a single disease complex. Although several clinical characteristics are similar, the majority of Gass’ patients bear only a slight resemblance on imaging to the patients we describe in this report.22–25 In his original case series of AZOOR, he described 2 patients who had unique findings of multifocal lesions (one diagnosis as MEWDS-Case 14 and one described as Pseudo-POHS-Case 15).23 Using only clinical observation and FA, the pseudo-POHS/ AZOOR case had bilateral scattered focal atrophic chorioretinal scars and narrowing of retinal arteries, but no discernible zonal atrophic areas on fundus examination,
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Fig. 4. Case 8. Bilateral; diffuse chorioretinal atrophy, right eye (OD); multizonal chorioretinal atrophy, left eye (OS). Fundus photograph OD (A) demonstrating peripapillary scarring, attenuated vessels, and diffuse atrophy within the macula. There is peripheral scarring and remarkable pigment clumping. Fundus photograph OS (B) shows peripapillary and central macular scarring. There are round discrete chorioretinal scars in the inferior and nasal periphery. Fundus autofluorescence imaging shows diffuse hypoautofluorescence in the peripapillary zone, macula, and in the periphery of OD (C). Fundus autofluorescence imaging OS shows hypoautofluorescence of the central and peripheral scars with a ring of mild hyperautofluorescence (D). Spectral domain optical coherence tomography (SDOCT) through the fovea OD (E) demonstrates diffuse loss of ellipsoid layer, RPE, and anterior choroid including under the fovea. OS (F), there are normal retinal layers nasally and loss of the ellipsoid layer, outer retina, and anterior choroid temporally.
and on visual field testing demonstrated marked enlargement of the blind spot and loss of a large segment of the inferior nasal field in the left eye.23 This case probably represented the entity we describe in this report, and diagnosis was limited by the fact that only FA and clinical observation were available at that time. Based on these initial observations, Gass initially proposed that AZOOR and MFC could be part of the same spectrum of inflammatory disease.22,23 Presently, we do not accept this hypothesis and argue that each white spot syndrome has a characteristic appearance and prognosis and that the syndromes do not represent manifestations of a single disease complex.1,26 In classic cases of AZOOR, a delineating line (“demarcation”) can often be seen with a boundary of autofluorescence abnormality, which can be either hyper- or hypoautofluorescent.27,28 In attempt to clarify the definition of AZOOR, we believe that in AZOOR, the inflammatory process primarily targets the outer retina in a zonal topography demarcated by a pathognomonic orangeto-gray line on ophthalmoscopic examination that appears hyperautofluorescent on FAF imaging27–30 and is a harbinger of further progression in classic AZOOR. These zonal areas never resolve and usually progress outward from the peripapillary area or centrifugally,
leading to a typical trizonal degeneration visualized in the FAF, ICG, and OCT images as follows: first, a normal area; second, an area of degeneration of the photoreceptors and/or RPE; and third, a degeneration of the choroid (Yannuzzi LA, Gallego-Pinazzo R, Mrejen S, et al. Charles M. Schepens Lecture: AZOOR. JAMA Ophthalmology, in press). Interestingly, genetic factors including inflammatory complement factor H have a strong association with both MFC and age-related macular degeneration,31 and having an underlying genetic susceptibility may predispose a single patient to more than one inflammatory disease. The nature of any retinal atrophy seen in Gass’ AZOOR patients was not studied with modern multimodal imaging including high-definition SD-OCT, EDI-OCT, and FAF imaging; and with these advancements in imaging, this case series demonstrates a distinct, rare variant of idiopathic MFC with retinal or chorioretinal atrophy. Spaide et al14 recently demonstrated with SD- and EDI-OCT the imaging stages by which MFC lesions occur. In MFC, the conical RPE elevations would occasionally rupture through the RPE and pour inflammatory infiltrate into the outer retina.14 These inflammatory active lesions appeared to have increased choroidal thickness compared with the surrounding
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Fig. 5. Case 10. Bilateral multizonal outer retinal atrophy. Color fundus photo of the right eye (OD, A) and left eye (OS, B) demonstrated chorioretinal lesions and asymmetric multizonal atrophic areas involving the mid periphery and macula with pigment migration into these zones. Fundus autofluorescence imaging OD showed multiple geographic zones of hypoautofluorescence in areas of the atrophy with a discrete hyperautofluorescent band surrounding the zone of macular and peripapillary atrophy OD (C). Fundus autofluorescence imaging OS (D) demonstrated multiple small zones of atrophy with confluence of these zones inferiorly but sparing of the central macula. Spectral domain optical coherence tomography (SD-OCT) through the fovea OD demonstrated loss of the ellipsoid layer, outer photoreceptors, and RPE disruption (E). SD-OCT through the fovea OS demonstrated a mild epiretinal membrane but normal ellipsoid layer (F).
choroid regardless of classification as punctate inner choroidopathy or MFC with panuveitis.14,32 On FAF imaging, the RPE elevations were minimally hyperautofluorescent, but if there was dehiscence of the RPE, the corresponding spot demonstrated absence of autofluorescence.14 After treatment and resolution of the acute inflammatory episode, the RPE elevations and choroidal inflammation resolved and left small white scars that showed the FA appearance of early slight hyperfluorescence with late staining, a punchedout lesion of absent RPE and disruption of the outer retina; or complete restoration of the outer retinal architecture with no visible alteration either by ophthalmoscopy or FA.14,32 Several of our authors (J.J.J., S.M., K.B.F., and L.A.Y. Idiopathic multifocal choroiditis with peripapillary zonal inflammation: a multimodal imaging analysis. Retinal Cases and Brief Reports, in press) recently reported a case of idiopathic MFC that demonstrated a zone of transient structural damage at the level of the outer retina and ellipsoid layer over areas of choroidal thickening. As the inflammation subsided, the zone of peripapillary outer retinal and choroidal inflammation resolved along with restoration of the outer retinal architecture, but a more
prominent area of subretinal inflammation developed into a chorioretinal atrophic scar. Given these observations, we hypothesize that recurrent episodes of inflammation in MFC involving the outer retina and/ or choroid could eventually produce permanent damage. Initially, acute inflammation may cause transient disruption of the outer retina as observed in our Case 12 (Figure 7) of unilateral, zonal atrophy, which demonstrated attenuation of the photoreceptors on SD-OCT but no change on FAF or ICG. As the inflammatory episodes continue to recur, they may be associated with additional heterogeneous zonal atrophy similar to development of chorioretinal scars either as multizonal or diffuse outer retinal atrophy, and some may even progress to the end-stage patterns of chorioretinal atrophy. Autofluorescence imaging in our cases of idiopathic MFC with zonal outer retinal or chorioretinal atrophy showed the typical multifocal hypoautofluorescent chorioretinal lesions,14,33 and also highlighted the unique patterns of zonal, multizonal, and diffuse areas of hypoautofluorescence as seen in the advanced cases of chorioretinal atrophy due to the complete lack of fluorophores. Interestingly, in some cases as in Case 11 (Figure 6), the borders of the zones may also show
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Fig. 6. Case 11. Unilateral multizonal chorioretinal atrophy. Wide-field color imaging of the left eye (OS) demonstrated scattered MFC lesions in the nasal peripapillary region and a curvilinear array of MFC lesions in the temporal retina. There were also two large zones of peripapillary and inferotemporal chorioretinal atrophy that spared the fovea and pigment migration within the inferotemporal region (A). Fundus autofluorescence imaging accentuated the two geographic zones of atrophy; whereas the peripapillary zone was hyperautofluorescent and the inferotemporal zone was faintly hyperautofluorescent with areas of granular hypoautofluorescence and surrounded by a ring of more intense hyperautofluorescence (B). Over one year of follow-up, multimodal imaging demonstrated stable chorioretinal atrophy on wide-field color and FAF (C and D). Spectral domain optical coherence tomography through the fovea OS (E) demonstrated loss of the ellipsoid zone and photoreceptor interdigitation disruption in the peripapillary region coinciding with the large zone of peripapillary atrophy seen on FAF but normal retinal architecture subfoveally.
mild hyperautofluorescence relative to their background autofluorescence at the boundary of the zonal abnormality depending on the involvement of the outer retina, RPE, or choroid. The zones that were hyperautofluorescent typically demonstrated outer photoreceptor and ellipsoid layer disruption, whereas those that had long-standing damage involving the outer retina, RPE, and inner choroid were typically hypoautofluorescent. The etiology to the heterogeneity in these autofluorescent patterns is unclear but the hyperautofluorescence could be due to a bleaching effect from loss of the outer photoreceptors16 or increased fluorophores within the RPE.17
In terms of treatment, corticosteroid treatment (systemic, periocular, or topical) was transiently used in 11 of 13 patients, and 1 patient received systemic mycophenolate mofetil. Currently, there is no recommended standard treatment available for idiopathic MFC. Corticosteroid therapy is typically the first-line treatment,34 and in conjunction with immunomodulatory therapy, has shown to reduce the amount of inflammatory infiltration of the subretinal space and outer retina and reduce the damage seen on multimodal imaging.3,14,35 Two retrospective series evaluating 14 and 15 patients, respectively, evaluated the use of systemic corticosteroids along with immunosuppressive
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Fig. 7. Case 12. Unilateral zonal outer retinal atrophy. Fundus photograph of the left eye shows a normal posterior pole with discrete chorioretinal scars in the periphery (A). Spectral domain optical coherence tomography (SD-OCT) through the fovea (B) shows peripapillary RPE disruption, but otherwise is normal. Goldmann visual field maps an inferotemporal scotoma (C). Infrared photograph (D) and corresponding reproducible SDOCT of the superonasal retina (E) shows a normal ellipsoid layer in the temporal region, which becomes attenuated in the nasal zone corresponding to the area of the scotoma.
agents such as methotrexate, cyclosporine A, azathioprine, cyclophosphamide, chlorambucil, or a combination of these medicines and found that immunomodulatory therapy can be effective and safe in controlling inflammation and preserving long-term good vision.3,35 Although these series did find positive outcomes with systemic immunomodulatory therapy, relapse can occur despite aggressive treatment in these inflammatory conditions.36 One report by Benitez-del-Castillo et al36 used the anti-TNFa, infliximab, and showed that although it was able to control noninfectious posterior uveitis due to Behçet’s disease, it was unable control the inflammation related to chronic idiopathic MFC. In our case series, a few cases seemed to partially improve in subjective vision with corticosteroid treatment, but corticosteroids and even the mycophenolate mofetil had no effect on the relentless progression of multimodal imaging findings in six patients. Systemic steroid-sparing immunomodulatory treatments were not used in most of the patients because they did not have frequent, acute episodes of worsening disease, but rather showed a slow, relentless progressive loss of vision due to atrophy. We understand that there are several limitations of our study. First, the sample size of this study and all reported series remain small; and given the rarity of these diseases, it is difficult to make definitive diagnostic assumptions especially given the retrospective approach. For example, based on a retrospective review of a previous publication, we estimated the total number per year of newly diagnosed cases within two of our referral centers and extrapolated the approximate incidence of this form of idiopathic MFC. Second, the underlying pathophysiology of these entities including AZOOR and MFC remains a mystery. It is believed that idiopathic MFC may be an
autoimmune mediated disease occurring in genetically susceptible patients.1,4 Medical evaluation including examination, serologic testing, and imaging when indicated was negative for all known infectious and noninfectious etiologies. Although the individual etiologies remain unclear, we believe that combining these inflammatory diseases into one encompassing definition of AZOOR complex is too generalizing and prevents further elucidation of the disease processes. In summary, using clinical evaluation and multimodal imaging; retinal or chorioretinal zonal atrophy represents a distinct variant within the spectrum of idiopathic MFC and presents with: 1) presence of chorioretinal scars, 2) heterogeneous inflammatory involvement of the retina, RPE and/or choroid with subsequent damage at these levels, 3) variation of zonal, multizonal, or progressive diffuse zonal atrophy that may progress centripetally with relative sparing of the fovea until later in the disease course, 4) absence of a demarcating hyperautofluorescent line between involved and uninvolved retina, as often seen in AZOOR. We believe these cases should be differentiated from the AZOOR complex. Key words: AZOOR, chorioretinal atrophy, idiopathic multifocal choroiditis, multimodal imaging, outer retinal atrophy. Acknowledgments The authors thank Chandrakumar Balaratnasingam, MD, David Maberley, MD, Jerome Sherman, OD, and Quan V. Hoang, MD, PhD, for their assistance in the collection of data.
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