Progressive Maculopathy After Discontinuation of Pentosan Polysulfate Sodium

Introduction

Chronic use of pentosan polysulfate sodium (PPS) (Elmiron; Janssen, Titusville, NJ), a drug used for the treatment of interstitial cystitis (IC), was recently reported in association with a pigmentary retinopathy. Pearce et al.¹ described six women with pigmentary maculopathies who exhibited overlapping clinical features and who were further unified by long-term use of PPS with a median duration of 15.5 years. Genetic testing did not reveal pathogenic mutations in genes associated with inherited retinal degenerations (IRDs) in the four individuals for whom it was performed. This key report identified a potentially preventable cause of vision loss and also identified questions that need further investigation including the prognosis after discontinuing PPS.² Here, we describe an individual with PPS-associated maculopathy that continued to progress after stopping this drug and resulted in severe vision loss.

Case Report

A 62-year-old woman complained of blurry vision in her left eye and difficulty seeing at night for 1 year. Her ophthalmic history was otherwise unremarkable. Her medical history included breast cancer managed with lumpectomy, radiation, and ongoing aromatase inhibition as well as fibromyalgia, chronic fatigue syndrome, ulcerative colitis, and IC treated with PPS. There was no family history of retinal disease beyond age-related macular degeneration diagnosed late in her mother's life.

The patient's corrected visual acuity (VA) was 20/20 in the right eye (OD) and 20/50 in the left eye (OS). Humphrey 24-2 visual field testing performed by the referring ophthalmologist was full OD but showed central depression OS. Anterior segment exam was notable for mild bilateral nuclear sclerosis. Fundus exam of both eyes (OU) revealed coarse foveal and parafoveal pigmented deposits with patchy surrounding atrophy of the retinal pigment epithelium (RPE) as well as poorly defined vitelliform deposits (Figure 1A). The retinal periphery OU was normal aside from a minimally elevated choroidal nevus OS with surrounding drusen. Fluorescein angiography demonstrated bilateral RPE disturbances without leakage (Figure 1A). Optical coherence tomography (OCT) showed hyperreflective RPE deposits OU as well as patchy RPE disruption OD with frank RPE and photoreceptor loss OS (Figure 2A). The findings raised suspicion for a toxic etiology, but there was no history of exposure to known retinotoxic agents. The exam and retinal imaging remained stable 3 months later.

Figure 1. Serial en face macular imaging shows progressive atrophy. Fundus photography taken at the initial visit (A, age 62) demonstrated hyperpigmented macular deposits with surrounding atrophy and poorly defined vitelliform subretinal deposits. Fluorescein angiography at the same visit (A) demonstrated disturbance of the retinal pigment epithelium (RPE), particularly in the left eye. The patient stopped taking pentosan polysulfate sodium (PPS) approximately 1 year after this visit. Fundus photos and fundus autofluorescence from the subsequent visits approximately 4 years (B, age 67) and 6 years (C, age 69) after stopping PPS show progressive RPE atrophy. Stable-appearing radially arrayed hyperfluorescent deposits can be seen at the edges of the hypofluorescent regions in both eyes at the later visits with well-defined corresponding drusen-like deposits on fundus photography. The edge of a choroidal nevus is visible superotemporally in fundus photos of the left eye

Figure 2. Serial optical coherence tomography (OCT) imaging. OCT at the initial visit (A, age 62) demonstrated bilateral hyperreflective nodular deposits at the level of the retinal pigment epithelium (RPE) in addition to disruption and loss of RPE and photoreceptors that was most pronounced in the left eye. Subsequent visits approximately 4 and 6 years after stopping PPS (B, age 67; C, age 69) showed bilateral progressive fovea-involving atrophy of the RPE and photoreceptors. Outer retinal tubulations were present in the right eye at the second two visits.

The patient returned 6 years later at age 67 and described worsening vision in both eyes. Her interval history included resection of a non-metastatic cutaneous melanoma. Her VA was 20/30 OD and 20/60 OS. Goldmann perimetry demonstrated bilateral central depression that was more extensive OS (Figure 3A). Fundus exam showed extensive bilateral macular RPE atrophy with limited foveal sparing and with loss of the previous pigmented deposits (Figure 1B). The choroidal nevus in the left eye was stable. Fundus autofluorescence (FAF) demonstrated extensive macular hypofluorescence (Figure 1B), and OCT revealed progressive photoreceptor and RPE atrophy with loss of the prior hyperreflective deposits (Figure 2B). Full-field electroretinography (ERG) was normal aside from borderline-reduced mixed rod-cone and cone responses OS with a mildly delayed cone implicit time. Multifocal ERG showed bilateral generalized depression most pronounced in the central macula but with normal timing. Diagnostic genetic testing using a Clinical Laboratory Improvement Amendments-certified panel of IRD genes was initiated.³

Figure 3. Progression of central scotomas on serial Goldmann perimetry after discontinuation of pentosan polysulfate sodium (PPS). Goldmann perimetry performed at the second clinic visit approximately 4 years after stopping PPS (A, age 67) demonstrated bilateral central scotomas that were enlarged and deepened at follow-up 2 years later (B, age 69). Sensitivity to the I2e stimulus, which was evaluated at the final visit only (B), was absent in the left eye and present to a limited extent in the right eye.

The patient next returned at age 69 with worsening central vision particularly in her left eye. Since her last visit, an intracranial metastatic melanoma in the temporal lobe had been excised with radiation of the resection cavity. Her VA was 20/80 OD and 20/400 OS. Enlargement and deepening of the central scotomas were present bilaterally on Goldmann perimetry (Figure 3B). Exam and retinal imaging (Figures 1C and 2C) demonstrated progressive atrophy OU. Full-field ERG showed an improved cone implicit time OS and was otherwise stable OU. Multifocal ERG OD showed similarly depressed responses that now exhibited prolonged timing; interpretation OS was limited by artifact. Diagnostic genetic testing was negative for disease-causing mutations in IRD genes, and no ophthalmic correlates of her systemic conditions were present. The cause of her disease thus remained undefined.

This patient's case was revisited following the report by Pearce et al.¹ and found to be consistent with PPS-associated maculopathy. Electronic medical records suggested that she stopped taking PPS shortly after her initial ophthalmology visit at age 62. When contacted for verification, the patient confirmed discontinuing PPS around age 63 before receiving a bladder stimulator at age 65. She reported starting PPS at age 45, thus resulting in approximately 18 years of use. This timeline indicated that the progression noted at her second and third visits had occurred after PPS discontinuation.

The patient reported a total daily PPS dose of 200 mg throughout her course of treatment, although available records indicated a prescribed dose of 300 mg daily. Her self-reported dose corresponded to 3.5 mg/kg for her weight of 125 pounds and a cumulative dose of approximately 1,300 grams versus 5.3 mg/kg and 2,000 grams if taking 300 mg daily. No liver, renal, or splenic abnormalities were known to be present.

Discussion

IC is a poorly understood chronic condition characterized by bladder-related discomfort and lower urinary tract symptoms. PPS, which is a semisynthetic polysaccharide analog of the glycosaminoglycans present within the protective mucin of the bladder epithelium, is a second-line therapy for IC first used in the early 1980s with compassionate care use granted in 1986.^4–7 Several randomized, controlled trials showed favorable results,⁵ and full U.S. Food and Drug Administration approval was granted in 1996. A post-approval study had more equivocal results but with multiple factors complicating interpretation.⁸ The most common adverse events in pivotal trials were gastrointestinal-related symptoms and alopecia.⁷ Given the generally favorable safety profile and the difficulty of treating IC, use of PPS is now widespread.²

The important findings of Pearce et al.¹ are thus concerning given the number of individuals potentially at risk. Although direct causation has not been demonstrated, the shared history of chronic PPS use in a group of patients with similar clinical features including negative genetic testing is compelling. Lab-based research has the potential to provide insights into mechanism, and as has been the case for hydroxychloroquine retinopathy, insights into risk factors will develop as more patients with suspected PPS toxicity are evaluated. The present case suggests the potential for significant toxicity at the lower end of the dose and exposure ranges reported by Pearce et al.¹

Most importantly, the present case adds a new layer of concern by demonstrating progressive maculopathy continuing for up to 6 years after cessation of PPS. Analysis of a larger group of patients is needed to evaluate the frequency of this occurrence, but this patient's course is reminiscent of recent findings regarding hydroxychloroquine retinopathy in which progression continues even after drug cessation if RPE damage is present.^9,10 This case emphasizes the need for a screening regimen that balances the demands on patients and physicians with the importance of prompt identification of early toxicity. Finally, this patient's retinal exam and imaging at the later visits shared features with hereditary maculopathies and thus highlights the importance of maintaining suspicion for PPS exposure once atrophy is present.