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Pigmentary Maculopathy Associated with Chronic Exposure to Pentosan Polysulfate Sodium William A. Pearce, MD,1 Rui Chen, PhD,2 Nieraj Jain, MD1 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, 37e62 years). All patients received PPS for a diagnosis of IC, with a median cumulative exposure of 2263 g (range, 1314e2774 g), over a median duration of exposure of 186 months (range, 144e240 months). Most patients (4 of 6) reported difﬁculty reading as the most bothersome symptom. Mean BCVA was 0.10.18 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. Ophthalmology 2018;125:17931802 ª 2018 by the American Academy of Ophthalmology Pentosan polysulfate sodium (PPS; Elmiron [Janssen Pharmaceuticals, Titusville, NJ]) is a United States Food and Drug Administration (FDA)-approved drug for the management of bladder pain or discomfort associated with interstitial cystitis (IC).1,2 This semisynthetic compound has a molecular structure similar to that of biologic glycosaminoglycans and initially was used in the 1950s for its heparin-like thrombolytic and ﬁbrinolytic properties.3 Its putative mechanism of action in IC is through an adherence to bladder mucosal cells, where it purportedly buffers cellular permeability and protects the bladder epithelium from irritants.4 Interstitial cystitis, also known as bladder pain syndrome, is a chronic regional pain syndrome predominantly affecting women. Symptoms include bladder or pelvic pain, urinary urgency and frequency, nocturia, dyspareunia, and sleep ª 2018 by the American Academy of Ophthalmology Published by Elsevier Inc. disorders.5,6 The pathophysiologic factors remain unclear, but studies variably have implicated abnormalities in uroepithelial glycosaminoglycans, uromodulin (Tamm-Horsfall protein), and local inﬂammatory cascades.6e8 Herein we report a series of patients with a unique pigmentary maculopathy in the setting of chronic exposure to PPS for the management of IC. We characterized this new entity with multimodal imaging and functional and molecular testing and investigated possible pathogenic mechanisms. 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 https://doi.org/10.1016/j.ophtha.2018.04.026 ISSN 0161-6420/18 1793 1794 Table 1. Demographic Characteristics and Pentosan Polysulfate Exposure 5 F 62 W 20 60 2 F 60 W 20 56 3 F 46 W 14 42 1 F 60 W 39 6 F 60 W 4 F 37 W Mean 54.2 Standard deviation 10.2 Median 60.0 400 Smoking History Nuclear DNA Testing Results* 6.1 27.2 204 2482 No 8.1 18.7 240 2774 400 4.4 35.4 168 2044 56 300 5.8 19.7 144 1314 18 55 400 (200 daily 1 yr) 6.4 26.1 216 2555 13 30 400 4.1 36.3 168 2044 Yes (<1 pack-year) No No pathogenic variant No Heterozygous MPZ VOUS Yes (5 NP pack-years) No No pathogenic variant 20.7 9.5 19.0 49.8 11.5 55.5 383.3 40.8 400.0 5.8 1.4 5.9 27.2 7.5 26.7 190.0 35.9 186.0 2202.2 523.2 2263.0 400 (200 daily 2 yrs) F¼ female; MPZ ¼ myelin protein zero; NP ¼ not performed; TIMP3 ¼ tissue inhibitor of metalloproteinase 3; VOUS ¼ variant of unknown signiﬁcance; W ¼ white. Rows are sorted by disease severity as based on fundus imaging ﬁndings from least (top) to most (bottom) severe. *Sequencing of the mitochondrial gene MTTL1 in each patient revealed no pathogenic mutation suggestive of a mitochondrial cytopathy. Heterozygous TIMP3 VOUS NP Ophthalmology Volume 125, Number 11, November 2018 Patient No. Duration of Pentosan Cumulative Pentosan Time since Age at Onset Pentosan Polysulfate Interstitial of Visual Pentosan Polysulfate Sodium Daily Body Mass Polysulfate Sodium Polysulfate Sodium Age Exposure at Cystitis Exposure at Symptoms Sodium Daily Dose by Body Index Gender (yrs) Race Diagnosis (yrs) Presentation (mos) Presentation (g) (yrs) Dose (mg) Weight (mg/kg) (kg/m2) Table 2. Subjective and Objective Visual Function Findings Prolonged dark adaptation Paracentral scotoma Paracentral scotoma Right Eye Left Eye Full-Field Yes 0 0 NP Yes 0 0 Normal 3 1 Near vision difﬁculty Difﬁculty reading Generalized dimming Difﬁculty reading of vision Yes Yes 0 0.55 0 0.4 6 Generalized dimming Difﬁculty reading of vision Yes 0.1 0.1 4 Near vision difﬁculty Difﬁculty reading Yes 0 0 0.11 0.22 0.08 0.16 Mean Standard deviation Electroretinography Findings Multifocal NP Humphrey Visual Field Findings NP Mild central delay Shallow paracentral (rings 1e2), scotoma in both eyes mild pericentral attenuation Normal NP NP Low-to-normal cone-derived response Mild-to-moderate attenuation NP amplitudes with borderline timing, with variable delay normal rod-derived responses Normal Mild central Deep paracentral attenuation and scotoma in the right delay (rings 1e2) eye, shallow paracentral scotoma in the left eye Low-to-normal cone-derived response Variable Deep pericentral amplitudes with borderline timing, mild-moderate scotoma in both eyes mildly attenuated rod-derived attenuation and responses delay NP ¼ not performed. Rows are sorted by disease severity as based on fundus imaging ﬁndings from least (top) to most severe (bottom). Pigmentary Maculopathy Associated with PPS 2 Metamorphopsia Subjectively Prolonged Dark Adaptation 5 First Symptom Most Prominent Symptom Pearce et al Patient No. Best-Corrected Visual Acuity (Logarithm of the Minimum Angle of Resolution) 1795 Ophthalmology Volume 125, Number 11, November 2018 Figure 1. Fundus imaging. Columns are sorted by disease severity as based on fundus imaging ﬁndings from least (left) to most (right) severe (patients 5, 2, 3, 1, 6, and 4 from left to right, respectively). Imaging of the right eye is shown, because ﬁndings are fairly symmetric for all patients. Top row, Color fundus photographs demonstrating that nearly all eyes show subtle parafoveal pigmented deposits as well as subtle vitelliform deposits. Patchy paracentral retinal pigment epithelium atrophy is noted in some cases (patients 6 and 4). Middle row, Near-infrared reﬂectance imaging revealing an irregular reﬂectance pattern with prominent hyperreﬂectance colocalizing with hyperpigmented spots noted on fundus examination. Bottom row, Fundus autoﬂuorescence imaging demonstrating a fairly well-delineated region in the posterior pole with highly irregular autoﬂuorescence pattern, surrounded by a fairly normal autoﬂuorescence signal. The autoﬂuorescence pattern within this diseased region was characterized by a network of hyperautoﬂuorescent spots that corresponded to vitelliform-like deposits noted on funduscopic examination. 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 the Health Insurance Portability and Accountability Act. Each participant provided informed consent for inclusion in a genotypeephenotype correlation study that included consent for genetic testing on a research basis. The Emory Eye Center electronic medical record was queried for patients self-reporting use of PPS between May 2015 and October 2017. This search returned 38 patients, 6 of whom previously had been evaluated by the authors for an unidentiﬁed pigmentary maculopathy. The remaining 32 patients were followed by other providers for other ocular conditions and were not included in this analysis. Local records were reviewed for the 6 known patients. Each patient included in the study had undergone a complete ophthalmic evaluation, including measurement of bestcorrected Snellen visual acuity, slit-lamp biomicroscopy, and dilated fundus examination. All 6 patients underwent a standard panel of clinical retinal imaging, including fundus photography (Topcon 50DX; Topcon, 1796 Oakland, NJ), spectral-domain OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany), and wide-ﬁeld fundus autoﬂuorescence imaging (Optos California rg/af; Nikon Corp., Tokyo, Japan). Visual function was assessed in select patients with standard automated perimetry (Humphrey Field Analyzer II; Carl Zeiss Meditec, Inc., Dublin, CA) as well as full-ﬁeld and multifocal electroretinography (Diagnosys Espion; Diagnosys LLC, Lowell, MA) following the International Society for Clinical Electrophysiology of Vision standard.9 Each of the 6 patients were contacted by telephone to obtain additional health information. Patients were asked about the nature, timing, and progression of visual symptoms, as well as the extent of exposure to PPS. Additionally, patients were queried regarding systemic symptoms potentially related to mitochondrial disease. Self-reported estimates of height and weight were obtained, and a body mass index was calculated for each patient. Two expert graders (W.A.P., N.J.) independently evaluated each patient’s case to establish a ranking among the 6 patients of disease severity based on the extent of pigmentary changes noted on fundus imaging. An extensive literature search using Pubmed with Boolean operators for combinations of the search terms pentosan polysulfate, pps, Elmiron, interstitial cystitis, retina, Pearce et al Pigmentary Maculopathy Associated with PPS Figure 1. Continued macula, retinal pigment epithelium, ocular, toxicity, and pattern dystrophy revealed that this entity has not been reported previously. All data were de-identiﬁed and entered into a passwordprotected database. Descriptive statistics were used to summarize demographic and clinical characteristics with Microsoft Excel 2013 (Microsoft Corp., Redmond, WA). Genetic Testing Four patients underwent molecular testing with next-generation sequencing techniques, including assessment for pathogenic variants in PRPH2, ABCA4, and BEST1, among others. In 2 patients, testing was performed on a research basis: next-generation sequencing-based capture panel sequencing that included 256 genes associated with retinal disease was performed as described previously.10,11 Capture sequencing data were processed using a bioinformatics pipeline developed by our group to identify potential retinal disease-causing variants. Variants with a minor allele frequency of more than 0.5% in public databases, such as the Genome Aggregation Database, were excluded. One patient had undergone Clinical Laboratory Improvement Amendments-certiﬁed commercial genetic testing with the nextgeneration sequencing macular dystrophy panel through EGL Genetics (Tucker, GA). Another patient had undergone Clinical Laboratory Improvement Amendments-certiﬁed whole exome sequencing obtained by a referring provider using the XomeDx test (GeneDx, Gaithersburg, MD). All 6 patients underwent Clinical Laboratory Improvement Amendments-certiﬁed sequencing of the MTTL1 gene through EGL Genetics to evaluate for variants associated with mitochondrial cytopathies. Two patients (patients 2 and 3) submitted saliva samples because of geographic and travel limitations, whereas the remaining 4 patients submitted whole blood for analysis. 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 nonHispanic white. The median age at presentation was 60 years (range, 37e62 years), and the median estimated age at symptom onset was 55.5 years (Table 1). Three of the 6 patients (50%) were referred with a clinical diagnosis of pattern dystrophy, but none of the 4 patients who underwent molecular testing of nuclear DNA showed a pathogenic variant in the PRPH2 gene or any other gene associated with a hereditary retinal degeneration. All 6 patients underwent sequencing of the MTTL1 gene, and none showed a pathogenic variant. No patient had a family history of retinal disease consistent with a hereditary retinal dystrophy. Most of the eyes showed preserved central vision, with a mean best-corrected visual acuity (BCVA) of 0.10.18 logarithm of the minimum angle of resolution (Snellen equivalent, 20/25) at presentation. Only 2 eyes of 1 patient showed Snellen BCVA worse than 20/25 (patient 1 showed BCVA of 20/70 in the right eye and 20/50 in the left eye). Two patients described the initial visual symptom as a generalized dimming of vision; 2 others described 1797 Ophthalmology Volume 125, Number 11, November 2018 Figure 2. Images obtained from patient 4 over a 2-year period: (Top row) serial near-infrared reﬂectance and (Bottom row) OCT B scan demonstrating the progressive nature of the patchy retinal pigment epithelium atrophy in more severe cases. difﬁculty with near vision; one noted prominent paracentral scotomas; and the last noted metamorphopsia. Most patients identiﬁed difﬁculty reading as the most bothersome symptom, and all of the patients described difﬁculty with dark adaptation (Table 2). All patients had in common a longstanding diagnosis of IC managed with PPS. At presentation, patients had been treated with PPS for a median of 186 months (range, 144e240 months). Five patients had been treated at a dose of 400 mg daily (2 of whom had decreased to 200 mg daily after a duration of 17 years for unknown reasons), and 1 patient was treated with a 300-mg daily dose. The median cumulative exposure at presentation was 2263 g (range, 1314e2774 g). At symptom onset, median estimated exposure per patient was 1752 g (range, 876e2336 g; Table 1). Median daily dosing by recent self-reported actual body weight was 5.9 mg/kg (range, 4.1e8.1 mg/kg). Median body mass index was 26.7 kg/m2 (range, 18.7e36.3 kg/m2), with patients ranging from normal to obese according to the Centers for Disease Control and Prevention body mass index stratiﬁcation.12 Based on the authors’ ranking of disease severity within this small sample, there was no apparent correlation between daily dosing or cumulative exposure and disease severity (Table 1). Other medical comorbidities included ﬁbromyalgia (n ¼ 3), arthritis (n ¼ 2), and a verbal history of ulcerative colitis (n ¼ 2). No patient reported a constellation of symptoms consistent with a mitochondrial cytopathy or a family history of such symptoms. No patient had a known abnormality in hepatic, renal, or splenic function that would impact metabolism or excretion of PPS (Table 1). One patient had brief prior exposure to hydroxychloroquine (400 mg daily) for 6 months for a presumed diagnosis of systemic lupus erythematosus. There were no other medications reported that were used by more than 2 patients in the cohort. Examination Findings Anterior segment examination results were unremarkable in all patients, with 2 patients (4 eyes) having posterior chamber intraocular lenses. Nearly all eyes (10 eyes of 5 patients) showed subtle 1798 parafoveal pigmented deposits at the level of the retinal pigment epithelium (RPE). These were more evident in eyes judged to have a milder presentation (Fig 1). All eyes showed subtle vitelliform deposits that increased in number and extended beyond the major arcade vessels in cases judged to be more severe. Four eyes of 2 patients showed patchy paracentral RPE atrophy that was noted to increase in area and encroach on the central fovea over time (Fig 2). No patient demonstrated evidence of intraocular inﬂammation. Examination ﬁndings were fairly symmetric between eyes of each patient. Retinal Imaging Findings In nearly all eyes (except for 2 eyes of patient 4), ultrawide-ﬁeld fundus autoﬂuorescence imaging demonstrated a well-delineated region in the posterior pole with highly irregular autoﬂuorescence pattern, surrounded by a fairly normal autoﬂuorescence signal (Fig 1). The size of this diseased region varied widely among patients. The autoﬂuorescence pattern within this diseased region was characterized by a network of hyperautoﬂuorescent spots that corresponded to vitelliform-like deposits noted on funduscopic examination. Six eyes of 3 patients showed additional peripheral regions with a similarly irregular autoﬂuorescence pattern. Four eyes of 2 patients showed patchy paracentral hypoautoﬂuorescence consistent with RPE atrophy. Near-infrared reﬂectance imaging revealed a similarly irregular reﬂectance pattern with prominent hyperreﬂectance colocalizing with hyperpigmented spots noted on fundus examination. OCT images obtained in the early stages demonstrated nodular excrescences at the level of the RPE (Fig 3). These excrescences corresponded to hyperreﬂectant lesions noted on near-infrared reﬂectance imaging. The ellipsoid band and outer nuclear layer of the retina did not seem to be affected, except in association with RPE atrophy. Both patients with patchy RPE atrophy demonstrated outer retinal tubulations. No patients demonstrated choroidal neovascularization. One patient with cystoid macular edema responded to topical carbonic anhydrase inhibitors. Pearce et al Pigmentary Maculopathy Associated with PPS Figure 3. Images obtained from (Top row) patient 5 and (Bottom row) patient 6: (Left column) coregistered autoﬂuorescence, (Middle column) nearinfrared reﬂectance (NIR), and (Right column) OCT. All eyes showed highly irregular autoﬂuorescence and NIR patterns in the posterior pole, with some hyperautoﬂuorescent and hyperreﬂectant lesions colocalizing with nodular excrescences at the level of the retinal pigment epithelium (RPE) on OCT imaging (arrowheads; white line in en face images demonstrates orientation of OCT B scan). Patchy RPE atrophy was noted in some cases with associated outer retinal tubulations noted on OCT imaging (Bottom row). Functional Studies Standard automated perimetry in 3 patients demonstrated normal to mildly subnormal foveal thresholds (mean, 36.32.3 dB), deep scotomata associated with paracentral atrophy in 3 eyes of 2 patients, and otherwise fairly intact responses (Fig 4). Full-ﬁeld electroretinography testing in 5 patients yielded normal results in 4 patients and mild attenuation with delay of cone- and rod-derived responses in the other patient (patient 4). Multifocal Figure 4. Humphrey visual ﬁeld (HVF) results in (Left) patient 2 and (Right) patient 4. Humphrey visual ﬁeld 24-2 testing in patient 2 demonstrates mild paracentral scotomata in both eyes. Humphrey visual ﬁeld 10-2 testing in patient 4 demonstrates deeper paracentral scotomata in both eyes that can be seen in some cases with patchy retinal pigment epithelium atrophy. 1799 Ophthalmology Volume 125, Number 11, November 2018 electroretinography testing in 4 patients demonstrated variable mild to moderate attenuation and delay of responses that was most prominent in rings 1 through 3. Electrophysiologic abnormalities were more prominent in eyes judged to have more severe retinopathy by fundus imaging (Table 2). 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 a median of 186 months of exposure to a standard dosing regimen of PPS. Interestingly, despite relatively prominent symptoms, most patients demonstrated BCVA of 0.1 logarithm of the minimum angle of resolution (Snellen equivalent, 20/25) or better, consistent with preserved BCVA. There were no deep scotomata with the exception of the 3 eyes with parafoveal atrophy. Further investigation with dark adaptometry and contrast sensitivity will characterize better the functional impact of this condition. The extent and unique pattern of RPE changes as depicted with ultrawide-ﬁeld autoﬂuorescence imaging is particularly striking. Each patient showed a well-circumscribed region of abnormal autoﬂuorescence in the macula surrounded by normal autoﬂuorescence signal. This area of diseased RPE varied widely, and we suspect that the region of affected tissue may expand centrifugally over time as in some hereditary maculopathies. Cross-sectional evaluation with OCT imaging demonstrated paracentral nodular RPE excrescences that appear to be intraepithelial. Eyes with paracentral atrophic lesions showed outer retinal tubulations, which may be consistent with a primary RPE degeneration.13 Initial studies with radiolabeled PPS showed that the drug was found to distribute mainly to uroepithelium, and other visceral organs to a lesser degree.4 It is possible that the characteristic nodular excrescences are diseased RPE cells accumulating byproducts of the visual cycle in a pathway toward cellular death. Alternatively, these epithelial cells may be accumulating PPS or one of its many metabolites, as can be seen in the uroepithelium, the drug’s intended target.14 Our limited experience indicates that chronicity of PPS exposure plays a role, possibly supporting a hypothesis regarding long-term accumulation of a toxic metabolite. Pentosan polysulfate sodium is a semisynthetically produced heparin-like macromolecular carbohydrate derivative.4 First described in 1951 under the trade name Thrombocid (Bene GmbH; Frankfurt, Germany) it was used initially for its anticoagulant properties in the treatment of varicose veins.3 Subsequently, it was found to provide clinical beneﬁt for IC through its presumed mechanism of reducing inﬂammation by buffering the bladder mucosal wall from irritants.14 It received FDA approval in 1996 for bladder pain or discomfort associated 1800 with IC, and currently is considered a second-line pharmacotherapeutic agent in the most recent American Urological Association guideline amendment for diagnosis and treatment of IC.5 Presently, it is available in the United States under the trade name Elmiron and is dispensed in a gelatin capsule in a formulation designed for oral use. Typical dosing is 300 mg daily, but previous studies have purported efﬁcacy with up to 900 mg daily dosing.4,15 Several authors have proposed therapeutic efﬁcacy for a period of years, demonstrating that chronic administration of the drug is not without precedent.1,16 In a 3-month placebo-controlled study of 258 patients before FDA approval, there were no vision-related safety signals. In a subsequent unmasked clinical trial of 2499 patients receiving the drug for up to 4 years, vision-related adverse events included reports of optic neuritis, amblyopia, and retinal hemorrhage.4 It is unclear if these cases were attributed to the drug itself. Notably, the longest trial to our knowledge evaluated PPS for a mean duration of 90 months.1,16 It is premature to conclude that a deﬁnite causal relationship exists between PPS exposure and this maculopathy. However, this unique condition to our knowledge does not resemble any previously described hereditary or acquired maculopathy. Furthermore, it manifested in at least 6 of the 38 patients (16%) known to be taking PPS who were seen at our institution over the period of this study. Of note, only the 6 patients seen by the authors were evaluated formally as part of this study, and it is unknown at this time whether any of the other 32 patients may be manifesting a similar maculopathy. An alternative explanation for this maculopathy is that it is somehow related to the underlying diagnosis of IC. Interstitial cystitis, also known as bladder pain syndrome, is deﬁned as “an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than 6 weeks duration, in the absence of infection or other identiﬁable causes.”5 Other associated conditions include irritable bowel syndrome, ﬁbromyalgia, chronic fatigue syndrome, migraines, sleep disorders, anxiety, depression, rheumatoid arthritis, and systemic lupus erythematosus.6 However, despite an estimated prevalence of millions of affected adults in the United States,17 there is no known association between IC and retinal disease. Furthermore, the pathophysiologic features of IC are unclear, and it remains to some extent a diagnosis of exclusion without deﬁnite abnormalities noted on tissue biopsy.6e8 We are unable to hypothesize a pathophysiologic link between IC and the retinal ﬁndings we have reported herein. Some of the fundus ﬁndings resemble those seen in pattern dystrophies. Pattern dystrophy represents a genetically mediated group of retinal dystrophies known for abnormalities of pigmentation at the level of the RPE. Many cases have been attributed to mutations in the PRPH2 gene and are inherited in an autosomal dominant fashion. Mutations in the PRPH2 gene manifest in a spectrum of clinical phenotypes, including both macular dystrophies and panretinal disorders such as retinitis pigmentosa and coneerod dystrophy. As a result of this phenotypic Pearce et al Pigmentary Maculopathy Associated with PPS heterogeneity, the diagnosis of pattern dystrophy is applied widely to atypical pigmentary maculopathies in the clinical setting. However, none of the patients in this study had a family history suggestive of an autosomal dominant inheritance, and molecular testing in 4 patients did not disclose a pathogenic mutation in the PRPH2 gene or any other common gene associated with hereditary maculopathies. A similar spectrum of clinical ﬁndings can be seen in patients with mitochondrial diseases, such as mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes; maternally inherited diabetes and deafness; neuropathy, ataxia, and retinitis pigmentosa; and Kearne-Sayre syndrome. Several mitochondrial cytopathies have been shown to produce hyperpigmented and hypopigmented fundus changes, leading to a so-called salt-and-pepper fundus, as well as more subtle changes that can be mistaken for pattern dystrophy.18,19 However, it is atypical to have isolated retinal ﬁndings in these diseases, which also are associated commonly with extraocular motility deﬁcits, ptosis, and optic atrophy. More frequently, systemic signs such as encephalopathy, stroke-like episodes, neuropathy, and hearing loss are associated with mitochondrial diseases.20,21 No patient in this series had a medical or family history suggestive of a mitochondrial cytopathy, despite detailed questioning. Despite our relatively low suspicion for mitochondrial disease, all 6 patients underwent sequencing of the MTTL1 gene, which is associated with most cases of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes and maternally inherited diabetes and deafness. None of the patients demonstrated a pathogenic variant in this gene. It seems unusual to speculate on a new drug toxicity 21 years after FDA approval, particularly given the dramatic and characteristic imaging ﬁndings in this maculopathy. We attribute this delay in recognition to several factors. First, each of these individuals showed a complex phenotype, including a number of clinically diagnosed pain syndromes such as ﬁbromyalgia and IC, as well as incompletely evaluated or diagnosed systemic inﬂammatory diseases such as systemic lupus erythematosus and inﬂammatory bowel disease. These patients were taking a number of medications aimed at ameliorating the symptoms of their systemic conditions. Additionally, fundus ﬁndings are not prominent in milder forms of the maculopathy and visual acuity is relatively preserved. These early fundus ﬁndings resemble those seen in macular degeneration, pattern dystrophy, and other common forms of macular disease. It is possible that the discrepancy in subjective visual symptoms and objective ﬁndings in this medically complex population has not stimulated extensive investigations into this maculopathy. Finally, perhaps chronic exposure is a requirement for development of maculopathy, and we are only now beginning to see patients who have met the exposure threshold to manifest a toxic maculopathy. In conclusion, we report a previously undescribed and possibly preventable maculopathy related to chronic exposure to the FDA-approved medication PPS. The maculopathy seems to impact primarily the RPE, and the extent of disease is more apparent on ancillary imaging than on funduscopic examination. Although visual acuity is not impaired in most patients, affected patients have prominent symptoms of difﬁculty reading and prolonged dark adaptation. Clinicians should be aware of this condition because it can be mistaken for other well-known macular disorders such as pattern dystrophy and age-related macular degeneration. Further investigation is warranted to conﬁrm a causal relationship, to explore pathophysiologic features, and to direct dosing and surveillance guidelines. References 1. Hanno PM. Analysis of long-term Elmiron therapy for interstitial cystitis. Urology. 1997;49:93e99. 2. Nickel JC, Herschorn S, Whitmore KE, et al. Pentosan polysulfate sodium for treatment of interstitial cystitis/bladder pain syndrome: insights from a randomized, double-blind, placebo controlled study. J Urol. 2015;193:857e862. 3. Frileux C. Thrombocid: a new synthetic anticoagulant. Presse Med. 1951;59:159. 4. Janssen Pharmaceuticals. Elmiron (R) [package insert]. Titusville, NJ: Janssen Pharmaceuticals; August 2012. 5. Hanno PM, Erickson D, Moldwin R, Faraday MM. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA Guideline amendment. J Urol. 2015;193:1545e1553. 6. Patnaik SS, Laganà AS, Vitale SG, et al. Etiology, pathophysiology and biomarkers of interstitial cystitis/painful bladder syndrome. Arch Gynecol Obstet. 2017;295:1341e1359. 7. Saban R. Angiogenic factors, bladder neuroplasticity and interstitial cystitisdnew pathobiological insights. Transl Androl Urol. 2015;4:555e562. 8. Keay SK, Birder LA, Chai TC. Evidence for bladder urothelial pathophysiology in functional bladder disorders. BioMed Res Int. 2014;2014:1e15. 9. McCulloch DL, Marmor MF, Brigell MG, et al. ISCEV Standard for full-ﬁeld clinical electroretinography (2015 update). Doc Ophthalmol. 2015;130:1e12. 10. Zaneveld J, Siddiqui S, Li H, et al. Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotypeephenotype correlations and unexpected diagnostic revisions. Genet Med. 2015;17:262e270. 11. Zhao L, Wang F, Wang H, et al. Next-generation sequencingbased molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland. Hum Genet. 2015;134: 217e230. 12. Centers for Disease Control and Prevention. Deﬁning Adult Overweight and Obesity. Available at: https://www.cdc.gov/ obesity/adult/deﬁning.html. Accessed March 15, 2018. 13. Dolz-Marco R, Litts KM, Tan ACS, et al. The evolution of outer retinal tubulation, a neurodegeneration and gliosis prominent in macular diseases. Ophthalmology. 2017;124: 1353e1367. 14. Pantazopoulos D, Karagiannakos P, Sofras F, et al. Effect of drugs on crystal adhesion to injured urothelium. Urology. 1990;36:255e259. 15. Nickel JC, Forrest JB, Barkin J, et al. Safety and efﬁcacy of up to 900 mg/day polysulfate sodium (Elmiron) in patients with interstitial cystitis. Urology. 2001;57:122e123. 16. Jepsen JV, Sall M, Rhodes PR, et al. Long-term experience with pentosan polysulfate in interstitial cystitis. Urology. 1998;51:381e387. 17. Berry SH, Elliott MN, Suttorp M, et al. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. J Urol. 2001;186:540e544. 1801 Ophthalmology Volume 125, Number 11, November 2018 18. Schrier SA, Falk MJ. Mitochondrial disorders and the eye. Curr Opin Ophthalmol. 2001;22:325e331. 19. Lefevere E, Toft-Kehler AK, Vohra R, et al. Mitochondrial dysfunction underlying outer retinal diseases. Mitochondrion. 2017;36:66e76. 20. Ernst BP, Wilichowski E, Wagner M, Hanefeld F. Deletion screening of mitochondrial DNA via multiplier DNA ampliﬁcation. Mol Cell Probes. 1994;8:45e49. 21. Chae JH, Hwang H, Lim BC, et al. Clinical features of A3243G mitochondrial tRNA mutation. Brain Dev. 2004;26:459e462. Footnotes and Financial Disclosures Originally received: December 20, 2017. Final revision: April 3, 2018. Accepted: April 18, 2018. Available online: May 22, 2018. 1 Author Contributions: Manuscript no. 2017-2791. Emory Eye Center, Emory University Hospital, Atlanta, Georgia. 2 Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. 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. 1802 Conception and design: Pearce, Jain Analysis and interpretation: Pearce, Chen, Jain Data collection: Pearce, Chen, Jain Obtained funding: None Overall responsibility: Pearce, Chen, Jain Abbreviations and Acronyms: BCVA ¼ best-corrected visual acuity; FDA ¼ Food and Drug Administration; IC ¼ interstitial cystitis; MTTL1 ¼ mitochondrially encoded tRNA leucine 1; PPS ¼ pentosan polysulfate sodium; PRPH2 ¼ peripherin 2; RPE ¼ retinal pigment epithelium. Correspondence: Nieraj Jain, MD, Emory Eye Center, Emory University Hospital, 1365B Clifton Road NE, Suite 2400, Atlanta, GA 30322. E-mail: nieraj.jain@ emory.edu.