Geographic Chorioretinal Atrophy in Pseudoxanthoma Elasticum




Purpose


To describe a series of patients with geographic atrophy independent of choroidal neovascularization (CNV) in pseudoxanthoma elasticum and to report progression over time.


Design


Retrospective observational case series.


Methods


Records of all Vanderbilt Eye Institute patients with pseudoxanthoma elasticum and at least 1 set of color fundus photographs were reviewed (41 eyes of 21 patients). Fluorescein angiography, fundus autofluorescence, and optical coherence tomography images were reviewed, when available. In patients with geographic atrophy and at least 1 year of follow-up, atrophy was measured using fundus photographs. Main outcome measures included incidence of geographic atrophy, progression over time, and macular features associated with development or progression of geographic atrophy.


Results


Eight eyes (20%) of 5 patients had geographic atrophy independent of CNV. Progression was documented in 6 eyes of 4 patients followed for at least 1 year (mean 3.5 years). Mean initial and final area was 2.9 and 9.5 mm 2 , respectively, and growth rate was 1.7 mm 2 per year. Of the 6 eyes, 3 had a final visual acuity of 20/20 and the other 3 ranged from 20/150 to 20/400. All 8 eyes had pattern dystrophy, and 5 had linear pigment deposits that appeared to predict development or growth of atrophy.


Conclusions


Isolated geographic atrophy independent of CNV can develop in pseudoxanthoma elasticum, causing significant vision loss. Linear pigmented pattern dystrophy appears to predate geographic atrophy. Progression is similar to age-related macular degeneration. Recognition of this feature is important, especially if therapies to slow or reverse geographic atrophy become available.


Pseudoxanthoma elasticum is a systemic disease that primarily affects the elastic tissue of the skin, cardiovascular system, and eyes. Inheritance is usually autosomal recessive and the causative mutation is in subclass C of the ATP-binding cassette transporter gene, where numerous mutations are reported. Pathologic changes are most pronounced in the dermis, Bruch membrane, and blood vessels. Characteristic fundus lesions include angioid streaks, peau d’orange, optic disc drusen, pattern dystrophy, crystalline bodies, midperipheral “comet-tail” atrophic spots, and choroidal neovascularization (CNV). Numerous retinal pigment epithelium (RPE) alterations have been described, including atrophy along angioid streaks, atrophy associated with CNV, and pattern dystrophy. With CNV, RPE alterations include rips, multilobular areas of atrophy, and broad areas of poorly demarcated thinning/atrophy.


The most common cause of vision loss is CNV and disciform scarring, which occurs in 68%-86% of cases. Little has been reported regarding primary geographic atrophy in the absence of CNV. Identified cases only exist in case reports or hidden in larger studies. Longitudinal follow-up information and proposed mechanisms of pathogenesis of the atrophy are lacking.


The purpose of the current study is to describe a series of patients with geographic chorioretinal atrophy independent of CNV in pseudoxanthoma elasticum. Serial photography allowed for measuring progression rates of geographic atrophy. We also attempt to identify other clinical features of pseudoxanthoma elasticum that may predict the development or progression of geographic atrophy.


Methods


Patient Selection


A retrospective observational study was performed on all patients seen at the Vanderbilt Eye Institute between 2002 and 2012 with a diagnosis of “angioid streaks” or “pseudoxanthoma elasticum” based on ICD-9 coding. Vanderbilt University Institutional Review Board approval was obtained for this retrospective review. Data were collected in accordance with compliance set forth by the Health Insurance Portability and Accountability Act of 1996. The study adhered to the tenets of the Declaration of Helsinki.


All patients with a diagnosis of “angioid streaks” or “pseudoxanthoma elasticum” were identified. Only those with at least 1 set of digital color fundus photographs and medical records were reviewed. Each patient’s diagnosis of pseudoxanthoma elasticum was made based on fundus findings with or without a skin examination or biopsy. Clinical findings, fundus photographs, fluorescein angiography (FA), optical coherence tomography (OCT), and fundus autofluorescence (FAF) were reviewed.


Identification and Measurement of Geographic Atrophy


Geographic atrophy was determined based on fundus photography. Patients who had geographic atrophy distinct from peripapillary atrophy or chorioretinal atrophy that followed angioid streaks were identified. Patients were excluded if geographic atrophy was associated with CNV. This was defined by the presence of subretinal hemorrhage, lipid, fluid, subretinal fibrosis, or pigment epithelial hyperplasia contiguous with geographic atrophy.


Geographic atrophy was measured on color fundus photographs using OIS WinStation XP 5000 software (Ophthalmic Imaging Systems, Inc, Sacramento, California, USA). Fifty-degree images centered at the posterior pole were used in all cases, allowing for standardization of measurements. If present, FA and FAF were used to help identify areas of atrophy, but they were not used for measurements. The magnification obtained on FAF images does not conform to the standard magnification obtained on fundus photographs; hence these images were not used. The lesions were measured separately by each author (S.D.S., A.A.) and the mean value for each eye was used for reporting. Growth per year was determined using the first and last digital fundus photograph showing geographic atrophy.


Other Features of Pseudoxanthoma Elasticum


In addition to geographic atrophy, photographs were also reviewed for angioid streaks, atrophy attributable to CNV, atrophy along angioid streaks, disc drusen, peau d’orange, comet-tail lesions, pattern dystrophy, crystalline bodies, and signs of CNV (subretinal hemorrhage, lipid, fluid, subretinal fibrosis, or pigment epithelial hyperplasia). Patient demographics and other examination findings were reviewed. Main outcome measures included the incidence of geographic atrophy without CNV, progression over time, and other macular features associated with development or progression of geographic atrophy.




Results


Patients


A total of 41 eyes (21 patients) were identified with a clinical diagnosis of pseudoxanthoma elasticum and at least 1 set of digital fundus photographs. One patient had photographs performed only in 1 eye but had bilateral disease. Mean age of the 21 patients at initial photography was 50 years (range 19-71 years). Signs of active or inactive CNV were present in 24 eyes (59%). Other findings included angioid streaks (41 eyes, 100%), pattern dystrophy (19 eyes, 46%), chorioretinal atrophy along angioid streaks (17 eyes, 41%), peau d’orange (16 eyes, 39%), atrophy with CNV (15 eyes, 37%), disc drusen (10 eyes, 24%), crystalline bodies (9 eyes, 22%), and comet-tail lesions (7 eyes, 17%). All eyes with pattern dystrophy had isolated pigment clumps consistent with fundus pulverulentus. In addition, linear pigment deposits similar to the butterfly-type pattern dystrophy were present in 7 eyes of 4 patients.


Geographic Atrophy


Geographic atrophy separate from angioid streaks or CNV was identified in 8 eyes (20%) of 5 patients. Mean age of eyes when geographic atrophy was first identified was 50 years (range 37-53 years). Pattern dystrophy was present in all 8 eyes (100%), compared to 33% without this finding. The type of pattern dystrophy present was clumps of RPE distributed in a random fashion in the macula, typical of fundus pulverulentus, and sometimes arranged in a linear pattern resembling the butterfly type. Those with multiple sets of photographs separated by at least 1 year (6 eyes of 4 patients) were measured for area of geographic atrophy. Two eyes of 1 patient with geographic atrophy had only 3-month follow-up and were excluded from measurement analysis. The mean initial and final area of the 6 eyes was 2.9 mm 2 (range 0.3-8.1 mm 2 ) and 9.5 mm 2 (range 0.8-21.2 mm 2 ), respectively, and mean growth rate was 1.7 mm 2 per year (range 0.4-2.5 mm 2 per year). Of the 6 eyes measured, 3 had visual acuity (VA) of 20/20 at both initial and final visits. Three other eyes worsened over time, with initial VA ranging from 20/25 to 20/200 and final VA ranging from 20/150 to 20/400. Further characteristics of the 6 eyes measured are described below and in the Table .



Table

Demographic Information and Ocular Features Over Time in 6 Eyes With Progressive Geographic Chorioretinal Atrophy Attributable to Pseudoxanthoma Elasticum










































































Patient (Eye) Age, Sex Initial Visual Acuity Initial Area of Geographic Atrophy Length of Follow-up Final Visual Acuity Final Area of Geographic Atrophy Growth of Geographic Atrophy Linear Pigment Deposits
1 (OD) 52, M a 20/20 1.50 mm 2 2 years 20/20 6.51 mm 2 2.51 mm 2 /y Yes
1 (OS) 50, M 20/20 2.50 mm 2 4 years, 5 months 20/20 7.13 mm 2 1.05 mm 2 /y Yes
2 (OD) 53, F 20/200 8.07 mm 2 6 years 20/400 21.20 mm 2 2.19 mm 2 /y Yes
2 (OS) 53, F 20/60 3.14 mm 2 6 years 20/150 17.47 mm 2 2.39 mm 2 /y Yes
3 (OS) 41, M 20/25 1.92 mm 2 15 months 20/200 3.71 mm 2 1.43 mm 2 /y Yes
4 (OS) 37, M 20/20 0.34 mm 2 15 months 20/20 0.80 mm 2 0.37 mm 2 /y No

a The right eye of Patient 1 developed geographic atrophy 2 years and 5 months after his initial evaluation, whereas atrophy was present in his left eye at initial evaluation.



Patient 1


Patient 1 was a 50-year-old man with VA of 20/20 associated with paracentral scotomas in both eyes. Fundus photography at presentation showed angioid streaks, pattern dystrophy, comet-tail lesions, and disc drusen in both eyes ( Figure 1 , Top row). His left eye had a small patch of geographic atrophy in the macula, measuring 2.50 mm 2 . He also had a “plucked chicken skin” appearance on his neck. Two years and five months later, the atrophy had enlarged in his left eye and he developed geographic atrophy in the macula of his right eye (1.50 mm 2 ), but he retained 20/20 vision OU (not shown). At his final visit, four years and five months after initial presentation, VA remained 20/20 OU. The atrophy continued to enlarge in both eyes, with an area of 6.51 mm 2 OD and 7.13 mm 2 OS ( Figure 1 , Bottom row). The atrophy had enlarged by 2.51 mm 2 per year OD and 1.05 mm 2 per year OS. Isolated pigment clumps (white arrows) and linear pigment deposits (black arrowheads) were present. FAF revealed numerous intensely hyperautofluorescent areas scattered in the macula corresponding to isolated pigment clumps ( Figure 2 , Top row; white arrows). Temporal to geographic atrophy in both eyes were linear areas of mild hyperautofluorescence corresponding to linear pigment deposits (black arrowheads). Infrared and spectral-domain OCT imaging was performed on the right ( Figure 2 , Middle row) and left ( Figure 2 , Bottom row) eyes, which showed hyperreflectivity at the level of the outer nuclear layer corresponding to the linear pigment deposits ( Figure 2 , Middle row and Bottom row, white arrowhead; magnified on left insets). Subretinal hyperreflectivity corresponding to RPE was present in areas of isolated pigment clumps ( Figure 2 , Middle row and Bottom row, white asterisk; magnified on right insets).




Figure 1


Fundus photographs of a 50-year-old man (Patient 1) with pseudoxanthoma elasticum showing the evolution of pattern dystrophy with progressive non-neovascular geographic atrophy. (Top left and Top right) Images at presentation display angioid streaks, disc drusen, and pattern dystrophy that appeared in some areas as isolated pigment clumps (white arrows) and in other areas as linear pigment deposits (black arrowhead). Geographic atrophy is present in the left eye measuring 2.50 mm 2 . (Bottom left and Bottom right) Four years and 5 months later, the right eye has geographic atrophy (6.51 mm 2 ), while the atrophy in the left eye is larger (7.13 mm 2 ). Disappearance of the linear pigment deposits is observed with progression of the geographic atrophy.



Figure 2


Fundus autofluorescence (FAF), infrared, and spectral-domain optical coherence tomography (SDOCT) imaging of a 54-year-old man (Patient 1) with pseudoxanthoma elasticum showing multiple types of pattern dystrophy with non-neovascular geographic atrophy. (Top left and Top right) FAF shows geographic atrophy (hypoautofluorescence) and pattern dystrophy (hyperautofluorescence). The highly hyperautofluorescent areas correspond to pigment clumps (fundus pulverulentus, white arrows), while the linear pigment deposits are mildly hyperautofluorescent (butterfly-pattern dystrophy, black arrowheads). (Middle row and Bottom row) Infrared and SDOCT imaging show hyperreflectivity at the level of the outer nuclear layer corresponding to the linear pigment deposits (white arrowheads; magnified in left insets). Subretinal hyperreflectivity is present in areas of isolated pigment clumps (white asterisks; magnified in right insets).


Patient 2


Patient 2 was a 49-year-old woman with angioid streaks, peau d’orange, pigment clumps, and linear pigment deposits in the macula consistent with pattern dystrophy in both eyes, without signs of CNV or geographic atrophy ( Figure 3 , Top row; linear pigment deposits, black arrowheads). Visual acuity at that time was 20/30 OD and 20/40 OS. At age 53, her vision worsened to 20/200 OD and 20/60 OS. Central geographic atrophy was present in both eyes, measuring 8.07 mm 2 OD and 3.14 mm 2 OS ( Figure 3 , Second row). Over the next 6 years, VA declined to 20/400 OD and 20/150 OS with enlargement of geographic atrophy in both eyes, measuring 21.20 mm 2 OD and 17.47 mm 2 OS ( Figure 3 , Third row). The progression rate was 2.19 mm 2 per year OD and 2.39 mm 2 per year OS. FAF showed geographic atrophy to be distinct from peripapillary atrophy and angioid streaks ( Figure 3 , Bottom row). FAF also showed extensive areas of hyper- and hypoautofluorescence, indicative of widespread RPE disease. Pigment clumps of pattern dystrophy were more easily seen on FAF than on the photographs (white arrows).




Figure 3


Fundus photographs of a 49-year-old woman (Patient 2) with pseudoxanthoma elasticum showing the evolution of pattern dystrophy with progressive non-neovascular geographic atrophy. (Top left and Top right) Fundus photographs at presentation show pigment clumps (white arrows) and linear pigment deposits (black arrowheads) in both eyes without geographic atrophy. (Second row left and Second row right) Four years later there are large areas of geographic atrophy in both eyes, measuring 8.07 mm 2 OD and 3.14 mm 2 OS. (Third row left and Third row right) Photographs 6 additional years later demonstrate enlargement of atrophy in both eyes, measuring 21.20 mm 2 OD and 17.47 mm 2 OS. (Bottom left and Bottom right) Fundus autofluorescence shows hypoautofluorescence of the geographic atrophy. Pigment clumps are subtle on photography but more evident on autofluorescence (white arrows). The linear pigment deposits gradually disappear with enlargement of the geographic atrophy.


Patient 3


Patient 3 was a 41-year-old man with VA of 20/20 OD and 20/25 OS. Angioid streaks, pattern dystrophy, and midperipheral comet-tail lesions were seen in both eyes on fundus photography. He had subfoveal fibrosis OD and several distinct areas of atrophy OS measuring a total of 1.92 mm 2 ( Figure 4 , Top left) that were also seen on FAF ( Figure 4 , Top right). Intensely hyperautofluorescent pigment clumps (white arrows) and mildly hyperautofluorescent linear pigment deposits were seen (black arrowhead). Fifteen months later, VA declined to 20/50 OD and 20/200 OS. Fundus photographs ( Figure 4 , Bottom left) and FAF ( Figure 4 , Bottom right) showed enlargement of geographic atrophy in the left eye, now measuring a total of 3.71 mm 2 . The rate of enlargement was 1.43 mm 2 per year. Some pigment clumps remained (white arrows), while the linear pigment deposits evolved into a ring.


Jan 9, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Geographic Chorioretinal Atrophy in Pseudoxanthoma Elasticum

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