OSLI Retina

December 2020

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674 Ophthalmic Surgery, Lasers & Imaging Retina | Healio.com/OSLIRetina Practical Retina Incorporating current trials and technology into clinical practice From Bladder Pain to Blurry Vision: Pentosan Polysulfate Sodium and the Development of a Novel Maculopathy by Meera S. Ramakrishnan, MD; and Robin Vora, MD A wide number of medications have doc- umented retinal and/or choroidal toxicity, and this list continues to grow. Many phy- sicians appropriately ask why retinal tox- icity is not detected earlier, during clini- cal trials? Clinical trials are designed to test both the efficacy and safety of new po- tential therapeutics, but these trials have limitations. Two key limitations in evalu- ating safety are sam- ple size and duration of follow-up. Since the number of study subjects is typically powered to test efficacy but not safety, rare side effects can be missed. Addition- ally, side effects that take years to develop are often not detected in the relatively short time window of most clinical trials. Therefore, patients rely on astute clini- cians to expose retinal toxicity of novel medications. Pentosan polysulfate (Elmiron; Jans- sen Pharmaceuticals, Beerse, Belgium) is a prime example. Although this medication has been U.S. Food and Drug Administra- tion (FDA) approved since 1996, only in June 2020 did the FDA update the label to warn of the risks of pigmentary maculopa- thy. A number of insightful retina special- ists contributed to the early identification and characterization of the retinal toxic- ity of pentosan polysulfate. The majority of patients prior to this breakthrough ob- servation were generally (mis)diagnosed with atypical age-related macular degen- eration or pattern dystrophy. In this issue, Meera S. Ramakrishnan, MD, and Robin Vora, MD, describe how to identify, image, and diagnose pentosan polysulfate toxicity. They share insights from their population-based research of more than 4 million patients in which they detected a retinal dose-response with use of the drug. Lastly, they share their monitoring algorithm, which is a useful framework until formal screening guide- lines are established. During the last 2 years, a novel macu- lopathy has emerged that has been linked to chronic exposure to pentosane polysulfate sodium (PPS) (Elmiron; Janssen Pharmaceu- ticals, Beerse, Belgium). PPS is a semisyn- thetic heparin-like macromolecule used to treat interstitial cystitis (IC), a chronic, in- curable bladder pain syndrome manifesting as relentless bladder or pelvic pain, inconti- nence, and dyspareunia. PPS is the only oral option of the two U.S. Food and Drug Ad- ministration (FDA)-approved therapies for IC. It is estimated that IC affects more than 1 million individuals in the United States, predominantly women. 1,2 Since compassion- ate use in 1986 and regulatory approval in 1996, PPS has been prescribed by urologists and gynecologists to hundreds of thousands of patients with IC. 3,4 First reported in 2018 by Pearce et al. after remarkable diagnostic sleuthing, PPS exposure for treatment of IC was identified as the common thread linking six patients (six white women; median age: 60 years; age range: 37 to 62 years) re- porting difficulty reading, paracentral scotomas, and prolonged dark adaptation despite relatively preserved visual acuity (VA). 5 These patients were found to have retinal pigment epithelium (RPE) hyperpigmentation surrounded by subtle vitelliform-like deposits with highly irregular appearances on fundus autofluo- rescence (FAF) and near-infrared reflectance (NIR) imaging. Ge- netic screening and evaluation for hereditary retinal dystrophies and mitochondrial cytopathies were negative. Subsequent case series and cohort studies demonstrated a pattern of PPS exposure characteristics and clinical features. 6-8 In these studies, affected patients tended to be white women Meera S. Ramakrishnan Robin Vora doi: 10.3928/23258160-20201202-01 Howard F. Fine Practical Retina Co-Editor

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