Purpose
To investigate the prevalence of a peripapillary dark choroid ring on fluorescein angiography (FA) and the associated clinical features in patients with Stargardt disease.
Design
Retrospective review of 135 patients with Stargardt disease.
Methods
The presence or absence of a peripapillary dark choroid ring on FA was noted and was compared with patient demographics and clinical features.
Results
Thirty-seven percent (50/135) had a peripapillary dark choroid ring on FA. When evaluated in subgroups, this sign was present in 41% (9/22) of patients with 2 causative ABCA4 mutations, in 28% (5/18) of patients with 1 causative ABCA4 mutation and a clinical diagnosis of Stargardt disease, and in 38% (36/95) of patients with a clinical diagnosis of Stargardt disease pending mutational analysis. Ninety-four percent (44/47) of patients for whom mutational testing confirmed the presence of ABCA4 mutations demonstrated a dark choroid sign. The peripapillary dark choroid ring sign was associated with diffuse flecks ( P < .001), worse logarithm of the minimal angle of resolution visual acuity ( P = .03), larger central scotoma size ( P = .0146), and the presence of complete macular atrophy ( P = .0017) compared with patients without this sign.
Conclusions
The presence of a peripapillary dark choroid ring on FA should prompt further evaluation for Stargardt disease by examination of peripheral retinal FA images for a dark choroid sign, followed by subsequent ABCA4 mutation screening.
Stargardt disease is the most common juvenile-onset macular dystrophy. It is inherited in an autosomal recessive fashion and is caused by mutations in the ABCA4 gene. The ABCA4 protein is a cell membrane transport ATPase (a class of enzymes that catalyze the decomposition of adenosine triphosphate) found in rod and cone disc membranes that transports a complex of N-retinylidine-phosphatidyl-ethanolamine, from the disc lumen into the cytoplasm. A defective ABCA4 protein leads to less efficient handling of the N-retinylidine-phosphatidyl-ethanolamine and an alternate pathway leads to the formation of the waste product N-retinylidene-N-retinylethanolamine in the retinal pigment epithelium (RPE). N-Retinylidene-N-retinylethanolamine subsequently accumulates as lipofuscin and is 1 of at least 17 constituents of lipofuscin that have been identified. These initial pathophysiologic events at the cellular level lead to the development of the characteristic clinical signs associated with Stargardt disease.
The RPE lipofuscin absorbs visible light at short wavelengths, preventing transmission of the choroidal fluorescence during fluorescein angiography (FA). This causes the dark or silent choroid first described by Bonnin and associates and further characterized by others. The most often quoted prevalence of this sign in Stargardt disease is 86%. Although a dark choroid is not 100% specific for Stargardt disease, even in an era of increasing availability of genetic testing, it remains a useful auxiliary test for diagnostic purposes.
The characteristic pisciform flecks typically seen in Stargardt disease were shown by Eagle in an autopsy case report to be aggregates of swollen RPE cells. These flecks frequently are hyperfluorescent on FA because of fluorescein binding, and in more advanced cases they become confluent, which obscures the dark choroid sign. Clinicians misled by the relative absence of a dark choroid may not consider Stargardt disease in the differential diagnosis when this phenomenon occurs in these patients. It has been noted in the literature that the dark choroid sign can be robust regardless of disease state in the periphery and around the optic nerve head. The presence of fundus flecks also has been correlated to the presence of a dark choroid sign.
The purpose of the current study was to investigate the frequency of a peripapillary dark choroid ring on FA in patients with a diagnosis of Stargardt disease. We have substantiated the presence of the dark choroid sign in Stargardt disease and have corroborated the evidence of peripapillary involvement using diagnostic methods. A peripapillary dark choroid ring sign can be a useful tool leading to diagnostic confirmation in patients presenting with severe, longstanding, and undiagnosed Stargardt disease.
Methods
A retrospective review was conducted of patients with a diagnosis of Stargardt disease who were evaluated at the Kellogg Eye Center, University of Michigan, and at Jules Stein Eye Institute, University of California, Los Angeles, by the senior author (J.R.H.). All patients with a clinical diagnosis of Stargardt disease were selected for review from a clinical database containing patient visits dating from 1979 to 2009. Institutional review board approval was obtained for this study. Stringent inclusion criteria were used to verify the diagnosis of Stargardt disease. Patients qualified for the study if they carried a clinical diagnosis of Stargardt disease, had a pedigree consistent with autosomal recessive inheritance, underwent FA testing, and met one of the following inclusion criteria: (1) 2 causative mutations in ABCA4 ; (2) 1 documented causative mutation in ABCA4 and documented pisciform flecks, macular atrophy with reduced central acuity, or the presence of central scotoma on Goldmann visual field testing; or (3) clinical diagnosis made by combined presence of classic fundus flecks and a dark choroid on FA, with mutational analysis pending.
All patients underwent ophthalmologic examinations, Goldmann perimetry testing, electroretinography, fundus photography, and FA. Standardized FA was performed using 2.5 ml 25% or 5 ml 10% fluorescein sodium solution injected intravenously in an antecubital vein. Photographs were obtained using either a Zeiss (Dublin, California, USA), Topcon (Paramus, New Jersey, USA), or Canon (Lake Success, New York, USA) fundus camera with film or an OIS digital capture system. ABCA4 mutation screening was performed at the University of Michigan, the University of Iowa, Columbia University, and the University Medical Centre Nijmegen.
Clinical data collected included age, family history, best-corrected visual acuity, the area of central scotomata for standardized isopters (I 4e , III 4e , IV 4e ) on Goldmann visual field testing measured by digital planimetry (Placom 45C digital planimeter; EngineerSupply, Lynchburg, Virginia, USA), retinal distribution of flecks and atrophy on fundus photographs, the presence or absence of a dark choroid sign, a peripapillary dark choroid ring sign, and peripapillary flecks or atrophy. The location of retinal flecks and atrophy were recorded and categorized into 3 groups: macular, extending to the vascular arcades, and diffuse posterior pole. All of the color and FA fundus photographs were graded by 2 retinal specialists (T.J., J.R.H.). A peripapillary dark choroid ring sign was identified on FA when peripapillary choroidal fluorescence was absent throughout the FA study and the peripapillary region was surrounded by hyperfluorescence in the posterior pole.
Statistical analysis was performed using SAS statistical software version 9.1 (SAS Inc, Cary, North Carolina, USA). Because the patients had bilateral and symmetric disease, only the data for the right eye of each patient were used in statistical analyses. For patients with multiple data entries, the initial recorded value was used to illustrate the frequency of the measured outcomes during the period of clinical diagnosis. The frequencies for each sign and prevalence of clinical findings for the 2 groups (patients with and without a dark choroid ring sign) were tested using the chi-square test and the Student t test.
Results
Fluorescein angiograms were available for 135 patients with Stargardt disease for analysis of the peripapillary dark choroid ring sign. Representative FA images exhibiting the dark choroid ring sign are shown in Figure 1 . The age of the patients ranged from 7 years to 80 years, with a median age of 32 years. A peripapillary dark choroid ring was found in 50 (37%) of 135 patients, and when divided into the 3 inclusion groups, the sign was found in 41% (9/22) of the patients with 2 causative mutations, in 28% (5/18) of the patients with 1 causative mutation, and in 38% (36/95) of patients with a clinical diagnosis of Stargardt disease pending mutational analysis. Ninety-four percent (44/47) of patients for whom mutational testing confirmed the presence of ABCA4 disease-causing mutations (either 1 or 2 proven mutations) demonstrated the dark choroid sign on FA.
The clinical characteristics of patients with and without a peripapillary dark choroid ring sign are given in Table 1 . The presence of a peripapillary dark choroid ring sign was associated with the presence of diffuse posterior pole retinal flecks (flecks beyond the vascular arcades), but not diffuse posterior pole retinal atrophy (atrophy beyond the vascular arcades).
| Characteristic | Present | Absent | P Value |
|---|---|---|---|
| Diffuse posterior pole flecks | 82.6% (38/49) | 28.6% (22/86) | < .0001 a |
| Flecks to temporal arcades | 80.4% (37/49) | 32.5% (25/86) | < .0001 a |
| Diffuse posterior pole retinal atrophy | 8.7% (4/49) | 5.2% (4/86) | .4462 a |
| Central circumscribed macular atrophy | 39.1% (18/49) | 14.3% (11/86) | .0017 a |
| Mean logMAR right eye | 0.78 (n = 49; Snellen 20/120) | 0.57 (n = 86; Snellen 20/74) | .0322 b |
| Central scotoma size for I-4-e target (cm 2 ) | 4.53 (n = 49) | 9.64 (n = 86) | .0146 b |
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