Pigmentary Maculopathy Associated with Chronic Exposure to Pentosan Polysulfate Sodium

doi:10.1016/j.ophtha.2018.04.026

Ophthalmology

Volume 125, Issue 11, November 2018, Pages 1793-1802

https://doi.org/10.1016/j.ophtha.2018.04.026 Get rights and content

Purpose

To describe the clinical features of a unique pigmentary maculopathy noted in the setting of chronic exposure to pentosan polysulfate sodium (PPS), a therapy for interstitial cystitis (IC).

Design

Retrospective case series.

Participants

Six adult patients evaluated by a single clinician between May 1, 2015, and October 1, 2017.

Methods

Patients were identified by query of the electronic medical record system. Local records were reviewed, including results of the clinical examination, retinal imaging, and visual function assessment with static perimetry and electroretinography. Molecular testing assessed for known macular dystrophy and mitochondrial cytopathy genotypes.

Main Outcome Measures

Mean best-corrected visual acuity (BCVA; in logarithm of the minimum angle of resolution units), median cumulative PPS exposure, subjective nature of the associated visual disturbance, qualitative examination and imaging features, and molecular testing results.

Results

The median age at presentation was 60 years (range, 37–62 years). All patients received PPS for a diagnosis of IC, with a median cumulative exposure of 2263 g (range, 1314–2774 g), over a median duration of exposure of 186 months (range, 144–240 months). Most patients (4 of 6) reported difficulty reading as the most bothersome symptom. Mean BCVA was 0.1±0.18 logarithm of the minimum angle of resolution. On fundus examination, nearly all eyes showed subtle paracentral hyperpigmentation at the level of the retinal pigment epithelium (RPE) with a surrounding array of vitelliform-like deposits. Four eyes of 2 patients showed paracentral RPE atrophy, and no eyes demonstrated choroidal neovascularization. Multimodal retinal imaging demonstrated abnormality of the RPE generally contained in a well-delineated area in the posterior pole. None of the 4 patients who underwent molecular testing of nuclear DNA returned a pathogenic mutation. Additionally, all 6 patients showed negative results for pathogenic variants in the mitochondrial gene MTTL1.

Conclusions

We describe a novel and possibly avoidable maculopathy associated with chronic exposure to PPS. Patients reported symptoms of difficulty reading and prolonged dark adaptation despite generally intact visual acuity and subtle funduscopic findings. Multimodal imaging and functional studies are suggestive of a primary RPE injury. Additional investigation is warranted to explore causality further.

Section snippets

Methods

This is a case series of patients examined by a single investigator (N.J.) in the Ophthalmic Genetics Service at the Emory Eye Center between May 1, 2015, and October 1, 2017, with a pigmentary maculopathy of unclear cause in the setting of chronic exposure to PPS. Approval for this study was obtained from the Emory University Institutional Review Board, and the study followed the tenets set forth by the Declaration of Helsinki. Information was gathered and secured in a manner compliant with

Results

A total of 38 patients evaluated at the Emory Eye Center during the study period reported active use of PPS. Of these, 6 patients (16%) had been evaluated by the study authors for an unidentified pigmentary maculopathy and were included in this series. All of these patients were women and identified themselves as non-Hispanic white. The median age at presentation was 60 years (range, 37–62 years), and the median estimated age at symptom onset was 55.5 years (Table 1). Three of the 6 patients

Discussion

This report describes a unique pigmentary maculopathy in the setting of chronic PPS exposure, as seen in 6 patients over a 2-year period at a single clinical center. Patients typically reported difficulty reading and prolonged dark adaptation and demonstrated characteristic fundus and retinal imaging findings. Clinical findings in this series suggest a pattern of RPE disease manifesting initially with parafoveal pigmentary changes that ultimately leads to atrophy in some eyes. Patients reported

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Cited by (122)

Characterization of pentosan polysulfate patients for development of an alert and screening system for ophthalmic monitoring
2024, Canadian Journal of Ophthalmology
Pentosan polysulfate (PPS; ELMIRON, Janssen Pharmaceuticals, Titusville, NJ) is a U.S. Food and Drug Administration–approved oral medication for interstitial cystitis. Numerous reports have been published detailing retinal toxicity with the use of PPS. Studies characterizing this condition are primarily retrospective, and consequently, alert and screening systems need to be developed to actively screen for this disease. The goal of this study was to characterize ophthalmic monitoring trends of a PPS-using patient sample to construct an alert and screening system for monitoring this condition.
A single-institution retrospective chart review was conducted between January 2005 and November 2020 to characterize PPS use. An electronic medical record (EMR) alert was constructed to trigger based on new PPS prescriptions and renewals offering ophthalmology referral.
A total of 1407 PPS users over 15 years was available for characterization, with 1220 (86.7%) being female, the average duration of exposure being 71.2 ± 62.6 months, and the average medication cumulative exposure being 669.7 ± 569.2 g. A total of 151 patients (10.7%) had a recorded visit with an ophthalmologist, with 71 patients (5.0%) having optical coherence tomography imaging. The EMR alert fired for 88 patients over 1 year, with 34 patients (38.6%) either already being screened by an ophthalmologist or having been referred for screening.
An EMR support tool can improve referral rates of PPS maculopathy screening with an ophthalmologist and may serve as an efficient method for longitudinal screening of this condition with the added benefit of informing pentosan polysulfate prescribers about this condition. Effective screening and detection may help determine which patients are at high risk for this condition.
Le polysulfate de pentosan sodique (PPS; ELMIRON, Janssen Pharmaceuticals, Titusville, New Jersey) est un médicament oral approuvé par la Food and Drug Administration américaine dans le traitement de la cystite interstitielle. Or, de nombreux rapports publiés font état de la toxicité rétinienne du PPS. Les études à ce sujet étant surtout de nature rétrospective, des systèmes d'alerte et de dépistage doivent être mis en place pour surveiller activement l'apparition de cet effet secondaire. Notre étude avait pour objectif de dépeindre les tendances en matière de surveillance ophtalmologique au sein d'un échantillonnage de patients qui reçoivent le PPS afin de mettre sur pied un système d'alerte et de dépistage de cette affection.
Un examen rétrospectif des dossiers médicaux des patients d'un seul établissement a été réalisé entre janvier 2005 et novembre 2020 afin de recenser l'utilisation du PPS. On a ensuite mis au point un système commandant le déclenchement d'une alerte lors de l'ajout de nouvelles ordonnances et de renouvellements d'ordonnances de PPS dans les dossiers médicaux électroniques (DME), de façon à offrir au patient la possibilité de consulter un ophtalmologiste.
Au total, 1407 patients qui ont pris le PPS pendant la période de 15 ans ont servi à décrire le patient type : 1220 sujets (86,7 %) étaient de sexe féminin; la durée moyenne de l'exposition au PPS était de 71,2 ± 62,6 mois; et l'exposition cumulée moyenne a atteint 669,7 ± 569,2 g. Une consultation en ophtalmologie figurait au dossier de 151 patients (10,7 %), et 71 patients (5,0 %) ont subi une tomographie par cohérence optique (OCT). L'alerte DME s'est déclenchée pour 88 patients sur une période de 1 an, dont 34 patients (38,6 %) qui avaient déjà été examinés par un ophtalmologiste ou avaient été dirigés vers un spécialiste en vue d'un dépistage.
Un outil annexé aux DME peut accroître le nombre de patients prenant le PPS qui sont orientés vers un ophtalmologiste en vue du dépistage d'une maculopathie. Cet outil pourrait également être efficace pour réaliser un dépistage longitudinal de cet effet toxique, sans compter qu'il permet d'aviser les prescripteurs de PPS d'un tel risque. Un dépistage efficace pourrait contribuer à identifier les patients qui courent un risque élevé de présenter cette affection.
Nationwide Usage of Pentosan Polysulfate and Practice Patterns of Pentosan Polysulfate Maculopathy Screening in South Korea
2024, Ophthalmology Retina
To investigate the nationwide use of pentosan polysulfate (PPS) and screening practices for PPS maculopathy (PPM), with a focus on the timing and modalities used.
Population-based cohort study.
For evaluation of nationwide usage, 133 762 individuals who received PPS prescriptions between 2012 and 2021 were included. To investigate practice patterns, 55 487 individuals (referred to as overall users) who initiated PPS therapy between 2018 and 2020 were identified using the Health Insurance Review and Assessment database. After excluding patients with ophthalmic diseases before PPS administration, 34 857 PPS users without prior ophthalmic diseases were identified.
Ophthalmic examinations performed after initiating PPS therapy were categorized as baseline and subsequent monitoring examinations. The timing and modalities employed for these examinations were analyzed. The annual trends in PPS utilization and maculopathy screening were evaluated by assessing the number of PPS users and determining the proportion of patients receiving retinal/macular examinations among these users.
Performance of baseline and subsequent monitoring examinations and timing and modalities used for screening.
The number of PPS users dramatically increased annually over the study period from 5494 in 2012 to 40 451 in 2021. However, the majority of PPS users did not undergo baseline or subsequent monitoring examinations for PPM. Only 27.2% and 12.4% of PPS users without prior ophthalmic disease underwent baseline and monitoring examinations, respectively. Funduscopy/fundus photography was the most commonly utilized, whereas OCT and fundus autofluorescence (FAF) were performed in only 45.2% and 5.3% of the PPS users without prior ophthalmic diseases for monitoring, respectively. The performance of the screening examinations differed significantly across the 3 different daily dose and duration groups (all P < 0.05).
This study highlights the lack of performance of baseline and monitoring examinations for maculopathy in most patients taking PPS in South Korea. The limited use of OCT and FAF suggests potential insensitivity in detecting PPM. These findings emphasize the need for improvements in screening practices, including increased awareness and referrals to ophthalmologists, utilization of more sensitive modalities, and regular monitoring to enable early detection of PPM.
The authors have no proprietary or commercial interest in any materials discussed in this article.
An unusual case of rapid resolution of bilateral vitelliform deposits after discontinuation of pentosan polysulfate sodium
2023, American Journal of Ophthalmology Case Reports
To report the structural and functional changes in a 67-year-old male with pentosan polysulfate sodium (PPS) maculopathy with a progressive resolution of bilateral vitelliform lesions after PPS cessation.
The patient was initially seen after taking daily PPS for over 26 years. Three months after discontinuing PPS, the bilateral vitelliform lesions identified on spectral-domain optical coherence tomography (SD-OCT) at initial consultation had completely resolved. Bilateral resolution of vitelliform lesions was associated with a decline in best-corrected visual acuity, and ellipsoid zone disruption on SD-OCT.
Several PPS maculopathy phenotypes have been previously described including vitelliform lesions. Our case highlights that discontinuing PPS may lead to rapid resolution of vitelliform lesions in PPS maculopathy and may be associated with a rapid reduction in vision.
Microperimetry Findings in Pentosan Polysulfate Maculopathy
2023, Ophthalmology Retina
Subretinal autofluorescent deposits: A review and proposal for clinical classification
2023, Survey of Ophthalmology
Subretinal autofluorescent deposits (SADs) may be found in the posterior pole, associated with very various conditions. These disorders usually present a typical pattern of autofluorescent lesions seen on short-wavelength fundus autofluorescence. We describe SADs according to their putative pathophysiological origin and also according to their clinical pattern, i.e., number, shape, and usual location. Five main putative pathophysiological origins of SADs were identified in disorders associated with an intrinsic impairment of phagocytosis and protein transportation, with excess of retinal pigment epithelium phagocytic capacity, with direct or indirect retinal pigment epithelium injury, and/or disorders associated with long-standing serous retinal detachment with mechanical separation between the retinal pigment epithelium and the photoreceptor outer segments. Clinically, however, they could be classified into eight subclasses of SADs, as observed on fundus autofluorescence as follows: single vitelliform macular lesion, multiple roundish or vitelliform lesions, multiple peripapillary lesions, flecked lesions, leopard-spot lesions, macular patterned lesions, patterned lesions located in the same area as the causal disorder, or nonpatterned lesions. Thus, if multimodal imaging may be required to diagnose the cause of SADs, the proposed classification based on noninvasive, widely available short-wavelength fundus autofluorescence could guide clinicians in making their diagnosis decision tree before considering the use of more invasive tools.
Progression of Pentosan Polysulfate Sodium Maculopathy in a Prospective Cohort
2023, American Journal of Ophthalmology
To describe the progression of pentosan polysulfate sodium (PPS) maculopathy after drug discontinuation qualitatively and quantitatively using multimodal imaging assessmen.
Prospective case series.
Patients with PPS maculopathy were evaluated after discontinuation of PPS. Near-infrared reflectance (NIR), fundus autofluorescence (FAF), and optical coherence tomography (OCT) were evaluated in all patients at baseline and at the final follow-up visit at least 12 months later. A qualitative and quantitative analysis of the retinal imaging findings was performed. Patterns of disease progression were evaluated. Area of disease involvement on FAF, retinal pigment epithelium (RPE) atrophy on FAF and NIR, and retinal layer thicknesses on OCT were measured at baseline and at the follow-up visit.
A total of 26 eyes were included, with a follow-up period ranging from 13 to 30 months. The diseased area measured on FAF showed significant expansion in all eyes from baseline to follow-up despite drug cessation (P = .03) with a median linearized rate of change of 0.42 mm/y. There was significant reduction in the central macular thickness (P = .04), inner nuclear layer thickness (P = .003), outer nuclear layer thickness (P = .02), and subfoveal choroidal thickness (P = .003) at follow-up vs baseline. New areas of RPE atrophy on FAF in the macula developed in 4 eyes while preexisting atrophic lesions increased in size in 5 eyes.
Eyes with baseline PPS maculopathy all exhibited remarkable progression with qualitative and quantitative multimodal imaging analysis despite drug discontinuation. Disease progression may be attributed to underlying inner choroidal ischemia or RPE impairment.

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: Financial Disclosure(s): The author(s) have made the following disclosure(s): W.A.P.: Consultant − Advanced Clinical.

: HUMAN SUBJECTS: This study included human subjects or tissues. No animals were used in this study. Study protocol was approved by the institutional review board of Emory University. Informed consent was obtained from all human subjects. This research complied with the Health Insurance Portability and Accountability (HIPAA) Act of 1996 and adhered to the tenets of the Declaration of Helsinki.

: No animals were used in this study.

: Author Contributions:

: Conception and design: Pearce, Jain

: Analysis and interpretation: Pearce, Chen, Jain

: Data collection: Pearce, Chen, Jain

: Obtained funding: None

: Overall responsibility: Pearce, Chen, Jain

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Original articlePigmentary Maculopathy Associated with Chronic Exposure to Pentosan Polysulfate Sodium

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Methods

Results

Discussion

Urology

J Urol

J Urol

Genet Med

Ophthalmology

Urology

Urology

Urology

Mitochondrion

Mol Cell Probes

Original article
Pigmentary Maculopathy Associated with Chronic Exposure to Pentosan Polysulfate Sodium