The pattern dystrophies (PD) represent a clinically heterogeneous family of inherited macular diseases frequently caused by mutations in the peripherin/RDS (PRPH2) gene.1 The condition is characterized by the accumulation of lipofuscin at the level of the retinal pigment epithelium (RPE).2 Considerable phenotypic variability has been reported, as well as names attributed to this condition.3 On fundus examination, PD is characterized by accumulation of a yellowish, orange, or brown material at the level of the RPE and by RPE alterations in the macular area. The material deposits are hyperautofluorescent on blue light fundus autofluorescence (FAF). The PD lesions appear hypofluorescent on fluorescein angiography (FA) surrounded by hyperfluorescent lesion borders in early and late frames.4 Patients with PD can develop decreased vision due to choroidal neovascularization or pigment epithelial atrophy.2,5,6 In the study of Francis et al.1 including 38 patients with PD, geographic atrophy was present in 26%, and choroidal neovascularization in 18% of patients, with the likelihood of significant visual impairment increasing in later years. Marmor et al.,5 by reexamining a family with PD after 20 years, observed that symptoms remained minimal up to the age of 60 or 70.
To the best of our knowledge, there are no clear, published data regarding the progression of macular atrophy in pattern dystrophies. Most studies describing on macular atrophy are focusing on atrophy resulting from age-related macular degeneration (AMD).7,8,9
RegionFinder software is a blue light FAF semiautomated software embedded in the Spectralis device (Heidelberg Engineering, Heidelberg, Germany) that allows an accurate, reproducible, and time-efficient identification and quantification of retinal atrophy and its progression over time.10 This software was used in several studies to measure the size and progression of atrophic areas, mostly in AMD,11,12 but also in other retinal conditions such as Stargardt disease13 or punctuate inner choroidopathy.14
The aim of this retrospective, observational case series is to quantify the progression of macular atrophy associated with pattern dystrophies using RegionFinder software and to analyze demographical and clinical data.
Patients and Methods
This retrospective study included patients clinically diagnosed with reticular PD complicated by RPE atrophy followed at the University Eye Clinic of Creteil during at least two years.
Exclusion criteria were age younger than 18 years; active intraocular inflammation or any other retinopathy (such as any other hereditary retinal dystrophy, retinal venous occlusion, diabetic retinopathy or epiretinal membrane); myopia of less than −6 diopters (spherical equivalent); and FAF images of poor quality with no grading possibilities.
French Society of Ophthalmology Ethics Committee approval was obtained for the retrospective review of the data.
All patients underwent a detailed medical and ocular history; a complete ophthalmologic examination, which included measurement of best-corrected visual acuity (BCVA) using standard Early Treatment Diabetic Retinopathy Study (ETDRS) charts expressed as logarithm of the minimum of angle of resolution (log-MAR); slit lamp biomicroscopy; intraocular pressure (IOP) assessment; and fundus biomicroscopy. Retinal imaging was performed with a confocal scanning laser ophthalmoscopy system (Spectralis HRA + OCT, Heidelberg Engineering, Germany) and included the acquisition of infrared reflectance (IR 820 nm), blue light FAF (excitation 488 nm, emission 500 nm to 700 nm), and spectral-domain optical coherence tomography (SD-OCT). FA and indocyanine green angiography were performed when necessary (ie, if presence of choroidal neovascularization was suspected).
All images were reviewed by three retinal specialists (CM, AS, OS). Criteria for diagnosis of atrophy were hypoautofluorescent lesions on the FAF, correlating thinning or loss of the RPE hyperreflective line or retinal layers on SD-OCT, and choroidal signal enhancement on SD-OCT. Multimodal imaging allowed distinguishing whether hypoautofluorescent lesions were due to blocking effect by xanthophylls pigments, exudates, hemorrhages, or due to atrophy.
Localization of atrophy (foveal, juxtafoveal, extrafoveal) was classified using a “modified EDTRS grid” with circles diameters of 1,200 µm (and not 1,000 µm), 3,600 µm, and 7,200 µm centered on the fovea. Atrophic areas were quantified using Region-Finder software at baseline and during the follow-up (every 4 months for all patients, and every month if patients receive intravitreal injection for neovascularization), with evaluation of the atrophy progression rate for each patient. Given the digital image resolution of 768 × 768 pixels for a 30° × 30° picture, one pixel roughly corresponded to 12 µm, and the minimum size of atrophic areas detection by RegionFinder software was 0.012 mm2. In addition, all images of follow-up visits were aligned to their corresponding baseline images using retinal vessels as landmarks to compensate for any differences in scaling, shifting, and rotation.
Statistical analyses were performed using STATA 13 statistical software (Stata Corporation, College Station, TX). Qualitative variables were described in percentages and quantitative variables were described by their median with interquartile ranges (Q1 to Q3). Spearman correlation was used to assess the relationship between atrophy progression rates and initial atrophy area.
Demographics and Clinical Data of the Studied Population
We included 19 eyes of 12 patients with reticular PD complicated with macular atrophy. The median follow-up was 4.5 years (interquartile range [IQR]: 2.7–5.5]. The median age of this group was 76 years (IQR: 69 years to 78 years), and 36.8% of the patients were female.
The median initial BCVA was 0.2 logMAR (IQR: 0.05–0.4; 20/32 [IQR: 20/25–20/50]). The medial final BCVA was 0.2 logMAR (IQR 0.1–0.4; 20/32 [IQR: 20/25–20/50]). The median variation of visual acuity (logMAR) was 0 [IQR: −0.1–0.1].
Decreased vision (defined as loss of 5 or more letters) occurred in 16% of cases (three of 19).
Choroidal neovascularization was observed in 16% of affected eyes (three of 19) during the follow-up (Figure 1). Intravitreal injections of anti-vascular endothelial growth factor (VEGF) ranibizumab (Lucentis; Genentech, South San Francisco, CA) 0.5 mg were used to treat choroidal neovascularization, with a mean of 5.7 injections per patient (standard deviation: 4.0). Mean BCVA demonstrated an average gain of 0.1 logMAR (standard deviation: 0.08) among these patients.
Choroidal neovascularization secondary to pattern dystrophy. Left: Right eye fundus autofluorescence image with increased autofluorescence areas corresponding to subretinal deposits. Middle: Late leakage on fundus fluorescein angiogram due to juxta foveolar classic choroidal neovascular membrane associated with reticular hypofluorescence corresponding to macular pattern dystrophy. Right: Corresponding spectral-domain optical coherence tomography scans reveal the presence of a subretinal hyperreflective neovascular lesion (thin arrow) with adjacent areas of disruption of the outer retinal layers and focal hyperreflective subretinal deposits (thick arrows) consistent with acquired vitelliform deposits.
Analysis of Qualitative and Quantitative Parameters of Atrophy
Using multimodal analysis, we found that the localization of atrophy was retrofoveal in 21% (four of 19) of cases (Figure 2).
Retrofoveal atrophy in the left eye of a 76-year-old woman with pattern dystrophy. Left: Left eye fundus autofluorescence image with a foveal hypofluorescent lesion corresponding to retinal atrophy, surrounded by hyperautofluorescent lesions corresponding to materiel deposits. Right: Corresponding spectral-domain optical coherence tomography scan reveals thinning of retinal layers and choroidal signal enhancement.
The median initial atrophy area evaluated by Region-Finder software was 0.294 mm2 (IQR: 0.18–0.398), and the median final atrophy area was 0.844 (IQR: 0.06–1.4) (Figure 3).
Progression of retinal pigment epithelium (RPE) atrophy in a 76-year-old woman with pattern dystrophy, using RegionFinder software. Top left: initial blue laser autofluorescence image. Top right: final autofluorescence image. Bottom left: RegionFinder software analysis corresponding to the image at the top and left. Bottom right: RegionFinder software analysis corresponding to the image at the top and right.
Median atrophy progression rate evaluated by Region-Finder software was 0.101 mm2/year (IQR: 0.054–0.257).
One patient with an important initial atrophy area on both eyes had a high atrophy progression rate (1.743 mm2/year for the right eye and 2.144 mm2/year for the left eye) and a poor visual outcome, with a final BCVA of 20/400 for both eyes (Figure 4).
Fundus autofluorescence images of a 75-year-old patient with large retinal pigment epithelium (RPE) atrophy. Top: RPE atrophic area at baseline = 6.484 mm2 for the right eye and 7.439 mm2 for the left eye. Bottom: RPE atrophic area at 6-year follow-up = 18.3 mm2 for the right eye and 20.8 mm2 for the left eye, with a high atrophy progression rate (1.85 mm2/year for the right eye and 2.08 mm2/year for the left eye).
There was no statistically significant difference in atrophy progression rate between patients with choroidal neovascularization and those without (P = .613).
There was no significant correlation between the atrophy progression rate and initial atrophy area [spearman rho = 0.2206; P = .39].
Patients with foveal atrophy had a higher atrophy progression rate (mean = 1.052 mm2/year) compared with patients with foveal-sparing (mean = 0.119 mm2/year), but the difference was not statistically significant. (P = .17).
This study, conducted in a tertiary referral center, found that the atrophy progression rate was 0.101 mm2/year (IQR: 0.054–0.257) in patients affected with reticular PD. This rate is less than the progression rate of geographic atrophy related with age-related macular degeneration (AMD). Indeed, atrophy progression rates ranged from 1.3 mm2/year to 2.8 mm2/year in atrophic AMD.8,9 Schmitz-Valckenberg et al.15 measured a mean progression in atrophic AMD of 1.85 mm2 at 12 months. In AMD, atrophic areas usually derived from degeneration of drusen.16 Accumulation of lipofuscin interferes with the metabolism of RPE cells conducting to death of RPE cells, and this contributes to dysfunction and death of photoreceptors. It is hypothesized that material deposits at the level of RPE in PD may induce RPE dysfunction and then atrophy. Marmor et al.5 showed that pigmentary changes become coarser and more fragmented over the years in PD, and varying degrees of depigmentation and atrophy maculopathy develop.
Fujinami et al.17 assessed the median rate of atrophy enlargement in 67 patients with Stargardt disease, which was 0.45 mm2/year. To quantify areas of hypoautofluorescence, the authors used a different custom software (retinal analysis tool): the areas outlined manually were expressed in square degrees and converted to square millimeters. The patients were classified into three FAF subtypes: Type 1 had a localized low signal at the fovea surrounded by a homogeneous background, Type 2 had a localized low signal at the macula level surrounded by a heterogeneous background with numerous foci of abnormal signal, and Type 3 had multiple low signal areas at the posterior pole with a heterogeneous background. The rate of atrophy enlargement based upon subtypes was significantly different; 0.06 mm2/year in type 1, 0.67 mm2/year in Type 2, and 4.37 mm2/year in Type 3. With fewer patients with Stargardt disease (12 patients), McBain et al.18 evaluated that the rate of atrophy enlargement was 1.58 mm2/year in their sample. In this inherited disease, the accumulation of lipofuscin is due to the dysfunction of ABCA4 gene, which encodes a transmembrane rim protein in the outer segment discs of photoreceptors that is involved in active transport of retinoids from photoreceptor to RPE.17 The progression of atrophy of RPE in patients with pattern dystrophies seems to be slower compared with patients with Stargardt disease.
In geographic atrophy related with AMD, central macular areas appeared most susceptible for the occurrence and expansion of geographic atrophy.19 In our sample of PD, there is a trend toward a higher atrophy progression rate in patients with foveal atrophy (mean = 1.052 mm2/year) compared with those with foveal sparing (mean = 0.119 mm2/year), although it was not statistically significant (P = .17), given the small number of patients included.
Francis et al. showed that the risk of complications such as macular atrophy increases with age in patient with pattern dystrophy1 and is higher after 70 years old. In our study, patients are quite old (median age: 76 years [IQR 69 years - 78 years]); this could be a bias since patients with PD are often asymptomatic until the fifth decade and may be undiagnosed.
In the present report, vision is globally preserved: the medial final BCVA was 0.2 logMAR (IQR: 0.1–0.4; 20/32 [IQR: 20/25–20/50]). PD is classically described as having a slowly progressive course.20 However, several studies have shown that the disease can progress with age, and older individuals may exhibit atrophic depigmented lesions and/or choroidal neovascularization that can result in severe vision loss.21–24 Indeed, a 75-year-old patient with PD in our study had a large atrophy area with a high rate of atrophy progression and a poor visual outcome (Figure 3). Those cases could also be misdiagnosed with atrophic AMD.
Moreover, we found that 16% of affected eyes (three of 19) developed choroidal neovascularization. A similar proportion of choroidal neovascularization (18%) was identified by Francis et al.1 In our study, there was no statistically significant difference in atrophy progression rate between patients with choroidal neovascularization and those without (P = .613).
It is known that PDs represent a clinically heterogeneous family of inherited macular diseases frequently caused by mutations in the PRPH2 gene.1 Different forms have been described in the literature: reticular dystrophy, butterfly-shaped dystrophy, multifocal pattern dystrophy simulating Stargardt disease, fundus pulverulentus, and adult vitelliform dystrophy.4 In our study, all patients presented with reticular PD.
The progression of macular atrophy in these different forms could be evaluated; however, different types of PD are known to occur in different members of the same family carrying an identical mutation. PD can sometimes mutate from one to another clinical form within a single patient; therefore, PD should be considered as a single disease expressed in various manners.4,15 Finally, the progression of macular atrophy in PD could rather be correlated with genetic data than with the form of PD.
Our retrospective study has several limitations. First is the time of follow-up (median follow-up: 4.5 years [IQR: 2.7–5.5]). Then, the occurrence of choroidal neovascularization (three of 19 eyes) could interfere with the detection of macular atrophy, due to subretinal fibrosis for example. Nevertheless, the atrophy progression rate does not seem to differ in those patients with choroidal neovascularization (P = .613). Moreover, we had a relatively small number of patients and included eyes. However, one must consider that pattern dystrophy is a rare macular disorder.
To our knowledge, this is the first study to assess the progression of atrophy in pattern dystrophy using RegionFinder software.
We showed that multimodal imaging including FAF and RegionFinder software are useful for the evaluation of atrophy in pattern dystrophy and should be used in the future therapeutic trials.
Larger, multicentric studies are necessary to confirm these results.
This study shows that the progression of atrophy in pattern dystrophy is relatively slow, and the vision is globally preserved. Nevertheless, some older patients may have large atrophic area or choroidal neovascularization that can compromise the visual outcome. Multimodal imaging, including RegionFinder software is an effective tool to follow these patients. Further studies are necessary to confirm this trend and to correlate the progression of atrophy with genetic data.
- Francis PJ, Schultz DW, Gregory AM, et al. Genetic and phenotypic heterogeneity in pattern dystrophy. Br J Ophthalmol. 2005;89(9):1115–1119. doi:10.1136/bjo.2004.062695 [CrossRef]
- Zhang K, Garibaldi DC, Li Y, Green WR, Zack DJ. Butterfly-shaped pattern dystrophy: a genetic, clinical, and histopathological report. Arch Ophthalmol. 2002;120(4):485–490. doi:10.1001/archopht.120.4.485 [CrossRef]
- Aaberg TM, Han DP. Evaluation of phenotypic similarities between Stargardt flavimaculatus and retinal pigment epithelial pattern dystrophies. Trans Am Ophthalmol Soc. 1987;85:101–119.
- Marmor MF, Byers B. Pattern dystrophy of the pigment epithelium. Am J Ophthalmol. 1977;84(1):32–44. doi:10.1016/0002-9394(77)90320-8 [CrossRef]
- Marmor MF, McNamara JA. Pattern dystrophy of the retinal pigment epithelium and geographic atrophy of the macula. Am J Ophthalmol. 1996;122(3):382–392. doi:10.1016/S0002-9394(14)72065-3 [CrossRef]
- Yang Z, Lin W, Moshfeghi D, et al. A novel mutation in the RDS/peripherin gene causes adult-onset foveomacular dystrophy. Am J Ophthalmol. 2003;135(2):213–218. doi:10.1016/S0002-9394(02)01815-9 [CrossRef]
- Sunness JS, Gonzalez-Baron J, Applegate CA, et al. Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration. Ophthalmology. 1999;106(9):1768–1779. doi:10.1016/S0161-6420(99)90340-8 [CrossRef]
- Klein R, Davis MD, Magli YL, Segal P, Klein BE, Hubbard L. The Wisconsin age-related maculopathy grading system. Ophthalmology. 1991;98(7):1128–1134. doi:10.1016/S0161-6420(91)32186-9 [CrossRef]
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- Schmitz-Valckenberg S, Brinkmann CK, Alten F, et al. Semiautomated image processing method for identification and quantification of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011;52(10):7640–7646. doi:10.1167/iovs.11-7457 [CrossRef]
- Lindner M, Böker A, Mauschitz MM, et al. Fundus autofluorescence in age-related macular degeneration study group. Directional kinetics of geographic atrophy progression in age-related macular degeneration with foveal sparing. Ophthalmology. 2015;122(7):1356–1365. doi:10.1016/j.ophtha.2015.03.027 [CrossRef]
- Lee JY, Lee DH, Lee JY, Yoon YH. Correlation between subfoveal choroidal thickness and the severity or progression of nonexudative age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013;54(12):7812–7818. doi:10.1167/iovs.13-12284 [CrossRef]
- Kuehlewein L, Hariri AH, Ho A, et al. Comparison of manual and semiautomated fundus autofluorescence analysis of macular atrophy in Stargardt disease phenotype. Retina. 2016;36(6):1216–1221. doi:10.1097/IAE.0000000000000870 [CrossRef]
- Hua R, Liu L, Chen L. Evaluation of the progression rate of atrophy lesions in punctate inner choroidopathy (PIC) based on autofluorescence analysis. Photodiagnosis Photodyn Ther. 2014;11(4):565–569. doi:10.1016/j.pdpdt.2014.07.002 [CrossRef]
- Schmitz-Valckenberg S, Sahel JA, Danis R, et al. Natural history of geographic atrophy progression secondary to age-related macular degeneration (Geographic Atrophy Progression Study). Ophthalmology. 2016;123(2):361–368. doi:10.1016/j.ophtha.2015.09.036 [CrossRef]
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- McBain VA, Townend J, Lois N. Progression of retinal pigment epithelial atrophy in Stargardt disease. Am J Ophthalmol. 2012;154(1):146–154. doi:10.1016/j.ajo.2012.01.019 [CrossRef]
- Mauschitz MM, Fonseca S, Chang P, et al. Topography of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2012;53(8):4932–4939. doi:10.1167/iovs.12-9711 [CrossRef]
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- Zhang K, Garibaldi DC, Li Y, Green WR, Zack DJ. Butterfly-shaped pattern dystrophy: a genetic, clinical, and histopathological report. Ophthlmic Mol Genet. 2002;120(4):485–490.
- Parodi MB. Choroidal neovascularizaiton in fundus pulverulentus. Acta Ophthlmol Scan. 2002;80(5):559–560.
- Feist RM, White MF Jr., Skalka H, Stone EM. Choroidal neovascularazation in a patient with adult foveomacular dystrophy and a mutation in the retinal degeneration slow gene (Pro210Arg). Am J Ophthalmol. 1994;118(2):259–260. doi:10.1016/S0002-9394(14)72913-7 [CrossRef]