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The Effect of Light Deprivation in Patients with Stargardt Disease

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The Effect of Light Deprivation in Patients with Stargardt Disease The Effect of Light Deprivation in Patients With Stargardt Disease MICHEL M. TEUSSINK, MICHELE D. LEE, R. THEODORE SMITH, RAMON A.C. VAN HUET, CAROLINE C. KLAVER, B. JEROEN KLEVERING, THOMAS THEELEN, AND CAREL B. HOYNG PURPOSE: To investigate whether long-term protection in the ABCA4 gene, which encodes a retina-specific from light exposure affects the rate of disease progression transporter protein (ABCR) in the rims of rod and cone in patients with autosomal recessive Stargardt disease photoreceptor outer segment discs.2–4 Retinal (STGD1), measured using fundus autofluorescence degeneration in ABCA4-linked Stargardt disease is imaging. believed to result from the toxic effects of lipofuscin that DESIGN: Longitudinal, retrospective, interventional accumulates in the retinal pigment epithelium (RPE) and case series. the subsequent degeneration of photoreceptors.5 METHODS: Five patients with Stargardt disease Light can induce photochemical injury at the ocular protected 1 eye from light exposure by applying a black fundus. Depending on the level and duration of the irradi- contact lens during waking hours for ‡12 months. Dis- ance, the primary site of damage can be either the photore- ease progression was followed by performing autofluores- ceptors or the RPE.6 In ABCA4-linked retinopathies, cence imaging at semi-regular intervals. Longitudinal products generated by the visual cycle accumulate and changes in autofluorescence were studied by evaluating contribute to retinal damage via both direct toxic effects areas of decreased autofluorescence and areas of increased and increased photosensitivity. A major fluorophore of lipo- autofluorescence as a measure of retinal pigment epithe- fuscin, bis-retinoid N-retinylidene-N-retinyl-ethanolamine lium damage and lipofuscin accumulation, respectively. (A2E), accumulates with other, currently unidentified lipo- 7–9 RESULTS: We observed less progression of decreased fuscin constituents within the RPE. Thus, an excessive autofluorescence in 4 out of 5 light-protected eyes relative accumulation of A2E has been observed in both Abca4-/- to their respective nonprotected eyes. The progression of mice and patients with Stargardt disease.5,10 Lipofuscins increased autofluorescence, on the other hand, was highly (and A2E in particular) are potent photosensitizers11–14 variable and did not respond consistently to treatment. that can induce oxidative damage, thereby accelerating 14–16 CONCLUSIONS: Areas of decreased autofluorescence light-induced retinal damage and RPE atrophy. This may serve as a useful biomarker for measuring the pro- oxidative damage may affect the rate of disease progression gression of Stargardt disease. The reduced progression in patients with Stargardt disease. of decreased autofluorescence in the light-protected eyes The total quantity of A2E oxiranes in Abca4-/- mice in- suggests that light deprivation might be beneficial in creases in response to light exposure.17 In addition, a recent patients with Stargardt disease. (Am J Ophthalmol review of light-induced and inherited retinal degenerations 2015;159(5):964–972. Ó 2015 by Elsevier Inc. All suggested that light exposure might modify the disease rights reserved.) course of genetically well-defined retinal dystrophies, including Stargardt disease.18 An early study used func- tional and ophthalmoscopic examinations to test the effect UTOSOMAL RECESSIVE STARGARDT DISEASE of 5 years of unilateral light deprivation in a patient with (STGD1) is the most common inherited juvenile autosomal recessive retinitis pigmentosa and in a patient 1 A macular degeneration. Most patients develop with autosomal dominant retinitis pigmentosa; the author bilateral loss of vision in childhood or early adulthood. observed symmetrical disease progression.19 However, in This subtype of Stargardt disease is caused by mutations the absence of a genetic diagnosis, and without clear insight into the pathogenesis of these 2 RP patients, no conclusions can be drawn with respect to patients with Supplemental Material available at AJO.com. Stargardt disease. Accepted for publication Feb 3, 2015. From the Department of Ophthalmology, Radboud University Medical Because the aforementioned results suggest that patients Center (Radboudumc), Nijmegen, Netherlands (M.M.T., R.A.C.H., with Stargardt disease might be more sensitive to light, we B.J.K., T.T., C.B.H.); Department of Ophthalmology, Columbia considered using light protection as a means to slow disease University, New York, New York (M.D.L.); Department of Ophthalmology, New York University School of Medicine, New York, progression in patients with Stargardt disease. Therefore, New York (R.T.S.); and Erasmus University Medical Center, we retrospectively examined the effects of using a single Rotterdam, Netherlands (C.C.K.). black contact lens in an attempt to spare disease progres- Inquiries to Thomas Theelen, Department of Ophthalmology, Radboudumc, PO Box 9101, 6500 HB Nijmegen, Netherlands; e-mail: sion in 1 eye in patients with Stargardt disease. We [email protected] followed disease progression in 5 patients using the fundus 964 Ó 2015 BY ELSEVIER INC.ALL RIGHTS RESERVED. 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2015.02.004 autofluorescence imaging data, as this test provides a sensi- was defined as the age at which visual loss was first recorded. tive, noninvasive measure of RPE abnormalities and lipo- Best-corrected visual acuity (BCVA) was measured using a fuscin accumulation in patients with Stargardt disease.20–22 Snellen chart or the finger-counting method. To provide the most complete light protection, a customized, black, soft contact lens designed to cover the entire cornea (Ercon, Assen, the Netherlands) was applied; this lens METHODS blocked >90% of light in the visible spectrum. Patients underwent a routine ophthalmologic examina- THIS STUDY WAS A LONGITUDINAL, RETROSPECTIVE, INTER- tion, including BCVA, slit-lamp examination, binocular ventional case series of patients diagnosed with Stargardt funduscopy, and confocal fundus autofluorescence imaging disease. The intervention was applied in the context of of both eyes with a Spectralis device (Heidelberg Engineer- clinical care at the request of the patients (or legal guard- ing, Heidelberg, Germany). After pharmacologic pupil ian) and not in the context of a prospective clinical trial. dilation to >_6 mm with phenylephrine 2.5% and tropica- Therefore, nonstandard analyses (eg, routine imaging) mide 0.5% eye drops, we recorded fundus autofluorescence were performed to ensure internal quality control and to images centered on the fovea and including part of the detect any adverse events in a timely manner. All patients optic disc; images were obtained using an excitation wave- had been diagnosed previously as having Stargardt disease length of 488 nm and a barrier filter (>_500 nm) in high- with at least 1 ABCA4 mutation, and all patients presented resolution mode (30-degree field of view, 1536 pixels 3 with the typical clinical symptoms associated with this 1536 pixels). Baseline and follow-up images of both eyes retinal dystrophy. were captured with equal system sensitivity settings. Clin- All genetic analyses were performed by the Department ical phenotyping was performed in accordance with Fish- of Human Genetics at Radboudumc (Nijmegen, the man and associates (1999)24 by an experienced clinician Netherlands). Patients were screened for known ABCA4 (author R.H.) who was masked with respect to the study re- mutations using the arrayed primer extension microarray sults. Fundus autofluorescence was used to phenotype the (Asper Biotech, Tartu, Estonia), and exon duplications disease stages as described by Cideciyan and associates.25 and/or deletions were detected using multiplex ligation- Fundus autofluorescence images were acquired using a dependent probe amplification (P151 and P152; standard procedure as follows. First, focusing was performed MRC-Holland, Amsterdam, the Netherlands). If no using the near-infrared reflection mode of the Spectralis. mutations—or only a single heterozygous mutation— To account for chromatic aberrations, slight refocusing in were identified, the exons and intron-exon boundaries the autofluorescence mode was performed, and 9 separate were sequenced using the Sanger method to screen for mu- images were acquired after sensitivity adjustment, thereby tations in the other allele. All identified mutations were covering the entire macular area and including part of confirmed using Sanger sequencing. the optic disc. To increase the signal-to-noise ratio, all im- The study was performed in accordance with the tenets ages were aligned and a mean image was calculated using established by the Declaration of Helsinki, and informed the internal software (without normalization by histogram consent was obtained from all patients (or from the legal stretch). All other image processing and analysis was guardians of underage patients) for a retrospective analysis performed using scripts written in MatLab (R2006; Math- of therapy-related data. Patients were previously advised Works, Natick, Massachusetts, USA). Initial and final regarding the potential benefits of wearing sunglasses, fundus autofluorescence images were automatically regis- avoiding direct light exposure, and limiting their dietary tered as reported previously.20 The alignment of each im- intake of vitamin A.23 Complete protection from light age pair was manually confirmed; if necessary, registration exposure was suggested as a treatment option to patients
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