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Figure 1. These colour fundus photographs show atrophy at the posterior pole, moreso in the left (1b) than the right eye (1a).
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Figure 2. This SD-OCT reveals patchy atrophy of outer retinal layers at the macula of the right eye (2a) and, epiretinal membrane and a full thickness macular hole with outer retinal atrophy involving the center in the left eye (2b).
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Figure 3. Optical coherence tomography angiography at level of choriocapillaris, showing significant flow voids and vascular dropouts at the macula in both the right eye (3a. and left (3b).
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Figure 4: The right eye fundus autofluorescence images (4a) shows large patches of hypoautofluorescence at the macula, within a stippled background of hypoautofluorescent and hyperautofluorescent spots. The left eye (4b) showing diffuse hypoautofluorescence at the posterior pole.
A 77-year-old woman presented for evaluation of a macular pathology. She presented with photophobia, but no flashes, floaters, diplopia, distortion, pain, or dryness. She was not using any ocular medications. Her Snellen best corrected visual acuity (BCVA) was 20/40 in the right eye and 20/600 in the left eye. She had no visual field deficits in either eye by counting fingers. Pupils were bilaterally equal and responded briskly to light. Intraocular pressure (IOP) was 21 mm Hg in the right eye and 19 mm Hg in the left eye. Anterior segment exam revealed pseudophakia of both eyes and no abnormalities. Dilated fundus exam of the right eye showed patchy geographic-like atrophy at the macula in both eyes.
We performed multimodal imaging. Colour fundus photographs (CFP) of both eyes showed retinal atrophy, more in the left eye than the right. Optical coherence tomography (OCT) of the right eye showed patchy atrophy of the outer retinal layers. OCT of the left eye revealed an epiretinal membrane and a full thickness macular hole (FTMH), along with outer retinal atrophy involving the centre, which explained the poor visual acuity. OCT angiography (OCT-A) of both eyes at the level of the choriocapillaris revealed significant flow deficits and regions of vascular dropout, principally at the macula. Fundus autofluorescence (FAF) of the right eye demonstrated large patches of hypoautofluorescence at the macula, within a stippled background of hypoautofluorescent and hyperautofluorescent spots. FAF of the left eye revealed diffuse hypoautofluorescence at the posterior pole.
Her medical history was significant for hypertension, hyperlipidema and interstitial cystitis, for which she had been prescribed pentosan polysulfate sodium (PPS). She had noticed a drop in vision and reported receiving a single intravitreal anti-vascular endothelial growth factor (VEGF) injection several years prior.
Pentosan polysulfate sodium (PPS) is the only FDA-approved oral drug for the treatment of interstitial cystitis (IC). The drug was approved in 1996, and reports of retinal toxicity first emerged in 2018.1 The mechanism suggested was either a direct toxic...
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Pentosan polysulfate sodium (PPS) is the only FDA-approved oral drug for the treatment of interstitial cystitis (IC). The drug was approved in 1996, and reports of retinal toxicity first emerged in 2018.1 The mechanism suggested was either a direct toxic effect of a PPS metabolite on the retinal pigment epithelium (RPE), or the disruption of the interphotoreceptor matrix, which comprises glycosaminoglycans, similar to PPS. This would ultimately interfere with and impair photoreceptor outer segment processing by the RPE.2
Patients typically report a long duration of PPS intake, as in this patient who took it for 24 years, with a cumulative exposure of 2628 g, well above the reported risk of toxicity at higher than 1500 g.3 A cumulative drug exposure of more than 500 g warrants screening. After taking it for 24 years, she discontinued this drug when its potential for toxicity was brought to her attention. Progression of the condition even after cessation of the drug has been well-documented.4,5
Symptoms typically comprise dimming of vision, difficulty reading, and prolonged dark adaptation. The condition invariably presents as bilateral and symmetric. Colour Fundus photograph (CFP) in early stages shows parafoveal clumps of hyperpigmentation and scattered yellow subretinal vitelliform deposits. In later stages, RPE and retinal atrophy sets in, beginning paracentrally and spreading to involve the entire posterior pole.1,2 FAF reveals an irregular, stippled pattern of hypoautofluorescence and hyperautofluorescence in milder disease (which is seen to correspond to the yellow vitelliform lesions on CFP), and well-demarcated areas of hypoautofluorescence in severe disease (reflecting regions of RPE atrophy). OCT demonstrates focal thickening of RPE, which correlate with hyperpigmented clumps on CFP. These are believed to be debris accumulated by improper processing of photoreceptor outer segments. With progression, these nodular excrescences collapse and there is ensuing outer retinal and RPE atrophy. More recently, OCT-A has shown flow voids in the choriocapillaris, suggesting that the choroidal vasculature may be the initial site of toxicity, heralding its use as a tool for early diagnosis.6
Complications of this condition include choroidal neovascular membrane and cystoid macular edema. This patient had a FTMH, with superimposed outer retinal atrophy, indicating that a degenerative FTMH may also be a complication of PPS-related maculopathy.
Management includes counselling of the patient, and the discontinuation of the drug in consult with the prescribing physician.
A diagnosis of geographic atrophy (GA) from age related macular degeneration (AMD) is unlikely, considering the absence of drusen and the young age at diagnosis. Lack of a family history of retinal disease makes the diagnosis of an inherited pattern dystrophy of the retina less likely. The presence of a peripapillary hypoautofluorescent halo is also considered a clinching diagnostic feature for PPS-related maculopathy.
Dr. Arora is an M.S in Ophthalmology from Sri Ramachandra Institute of Higher Education and Research, Chennai, India, and currently a research trainee at Massachusetts Eye and Ear Infirmary, Boston.
Dr. Hoyek is a postdoctoral research fellow in Ophthalmology at Massachusetts Eye and Ear and Harvard Medical School, Boston
Dr. Patel is an Assistant Professor of Ophthalmology at Massachusetts Eye and Ear and Harvard Medical School and Director of Pediatric Retina at Boston Children’s Hospital, Boston
References
1. Pearce WA, Chen R, Jain N. Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium. Ophthalmol. 2018;125(11):1793-1802. doi:10.1016/j.ophtha.2018.04.026
2. Hanif AM, Armenti ST, Taylor SC, et al. Phenotypic spectrum of pentosan polysulfate sodium-associated maculopathy: a multicenter study. JAMA Ophthalmol. 2019;137(11):1275-1282. doi:10.1001/jamaophthalmol.2019.3392
3. Wang D, Au A, Gunnemann F, et al. Pentosan-associated maculopathy: prevalence, screening guidelines, and spectrum of findings based on prospective multimodal analysis. Can J Ophthalmol J Can Ophtalmol. 2020;55(2):116-125. doi:10.1016/j.jcjo.2019.12.001
4. Shah R, Simonett JM, Lyons RJ, Rao RC, Pennesi ME, Jain N. Disease course in patients with pentosan polysulfate sodium–associated maculopathy after drug cessation. JAMA Ophthalmol. 2020;138(8):894-900. doi:10.1001/jamaophthalmol.2020.2349
5. Barnett JM, Jain N. Potential new-onset clinically detectable pentosan polysulfate maculopathy years after drug cessation. Retin Cases Brief Rep. 2022;16(6):724. doi:10.1097/ICB.0000000000001090
6. Levin MF, Santina A, Corradetti G, et al. Pentosan polysulfate sodium-associated maculopathy: early detection using OCT angiography and choriocapillaris flow deficit analysis. Am J Ophthalmol. 2022;244:38-47. doi:10.1016/j.ajo.2022.07.015
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