ORIGINAL ARTICLE| Volume 55, ISSUE 2, P116-125, April 2020

Pentosan-associated maculopathy: prevalence, screening guidelines, and spectrum of findings based on prospective multimodal analysis

Published:January 20, 2020DOI:



      To describe the prevalence and spectrum of multimodal imaging findings of pentosan polysulfate sodium (PPS)–associated maculopathy and to recommend dosage-related screening guidelines.


      Cross-sectional study.


      Patients previously or currently treated with PPS at University of California, Los Angeles, were randomly ascertained and prospectively screened for PPS-associated maculopathy with multimodal retinal imaging. Daily and cumulative dosages of PPS exposure were calculated for each patient. Images were studied to identify the characteristic findings of toxicity. The prevalence of PPS-associated maculopathy and screening guidelines were determined.


      The prevalence of PPS-associated maculopathy in this cohort was 20% (10/50 patients). Both average duration of PPS therapy and average cumulative dosage were significantly lower in the unaffected (6.3 ± 6.6 years, 691.7 ± 706.6 g) versus the affected groups (20.3 ± 6.6 years, 3375.4 ± 1650.0 g, p < 0.001). Near-infrared reflectance (NIR) illustrated characteristic punctate retinal pigment epithelium (RPE) macular lesions early. Fundus autofluorescence (FAF) showed speckled autofluorescence in the posterior pole with peripapillary extension. Co-localization with optical coherence tomography (OCT) displayed focal RPE thickening and, in more severe cases, RPE atrophy in the macula and even the periphery.


      A prevalence of 20% in this study cohort suggests a significant risk of macular toxicity for PPS-treated patients. Characteristic alterations are best detected with FAF and NIR. More significant PPS exposure was associated with more severe atrophy. We recommend an initial baseline eye examination to include OCT and, most importantly, NIR and FAF with annual retinal imaging thereafter especially with cumulative dosages approaching 500 g. Patients exposed to greater than 1500 g of PPS are at significant risk of retinal toxicity.
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        • Giusto L.L.
        • Zahner P.M.
        • Shoskes D.A.
        An evaluation of the pharmacotherapy for interstitial cystitis.
        Expert Opin Pharmacother. 2018; 19: 1097-1108
        • Hanno P.M.
        • Erickson D.
        • Moldwin R.
        • Faraday M.M.
        • Association A.U.
        Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment.
        J Urol. 2015; 193: 1545-1553
        • Pearce W.A.
        • Chen R.
        • Jain N.
        Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium.
        Ophthalmology. 2018; 125: 1793-1802
      1. Hanif AM, Armenti ST, Taylor SC, et al. Phenotypic spectrum of pentosan polysulfate sodium-associated maculopathy: a multicenter study [E-pub ahead of print]. JAMA Ophthalmol. doi: 10.1001/jamaophthalmol.2019.3392, Accessed 9/21/19.

        • Sadda S.R.
        • Guymer R.
        • Holz F.G.
        • et al.
        Consensus definition for atrophy associated with age-related macular degeneration on OCT: classification of Atrophy Report 3.
        Ophthalmology. 2018; 125: 537-548
      2. Guymer RH, Rosenfeld PJ, Curcio CA, et al. Incomplete retinal pigment epithelial and outer retinal atrophy in age-related macular degeneration: classification of Atrophy Meeting Report 4 [E-pub ahead of print]. Ophthalmology. doi: 10.1016/j.ophtha.2019.09.035, Accessed 11/3/19.

        • Fleckenstein M.
        • Mitchell P.
        • Freund K.B.
        • et al.
        The progression of geographic atrophy secondary to age-related macular degeneration.
        Ophthalmology. 2018; 125: 369-390
        • Holz F.G.
        • Bellman C.
        • Staudt S.
        • Schütt F.
        • Völcker H.E.
        Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration.
        Invest Ophthalmol Vis Sci. 2001; 42: 1051-1056
        • Nickel J.C.
        • Herschorn S.
        • Whitmore K.E.
        • 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: 857-862
      3. Mishra K, Patel TP, Singh MS Choroidal neovascularization associated with pentosan polysulfate toxicity [Epub ahead of print]. Ophthalmol Retina. doi: 10.1016/j.oret.2019.08.006, Accessed 10/30/19.

        • Dansingani K.K.
        • Balaratnasingam C.
        • Klufas M.A.
        • Sarraf D.
        • Freund K.B.
        Optical coherence tomography angiography of shallow irregular pigment epithelial detachments in pachychoroid spectrum disease.
        Am J Ophthalmol. 2015; 160 (e1242): 1243-1254
        • Rabiolo A.
        • Sacconi R.
        • Cicinelli M.V.
        • Querques L.
        • Bandello F.
        • Querques G.
        Spotlight on reticular pseudodrusen.
        Clin Ophthalmol. 2017; 11: 1707-1718
        • Freund K.B.
        • Laud K.
        • Lima L.H.
        • Spaide R.F.
        • Zweifel S.
        • Yannuzzi L.A.
        Acquired vitelliform lesions: correlation of clinical findings and multiple imaging analyses.
        Retina. 2011; 31: 13-25
        • Spaide R.F.
        Deposition of yellow submacular material in central serous chorioretinopathy resembling adult-onset foveomacular vitelliform dystrophy.
        Retina. 2004; 24: 301-304
        • Spaide R.
        Autofluorescence from the outer retina and subretinal space: hypothesis and review.
        Retina. 2008; 28: 5-35
        • Mollet G.
        • Silbermann F.
        • Delous M.
        • Salomon R.
        • Antignac C.
        • Saunier S.
        Characterization of the nephrocystin/nephrocystin-4 complex and subcellular localization of nephrocystin-4 to primary cilia and centrosomes.
        Hum Mol Genet. 2005; 14: 645-656
        • Jiang S.T.
        • Chiou Y.Y.
        • Wang E.
        • et al.
        Essential role of nephrocystin in photoreceptor intraflagellar transport in mouse.
        Hum Mol Genet. 2009; 18: 1566-1577
        • Hoff S.
        • Halbritter J.
        • Epting D.
        • et al.
        ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3.
        Nat Genet. 2013; 45: 951-956
        • Katsman D.
        • Sanfilippo C.
        • Sarraf D.
        Panretinal degeneration associated with long-term hydroxychloroquine use and heterozygous Ush2a mutation.
        Retin Cases Brief Rep. 2017; 11: S77-S80
        • Leschey K.H.
        • Hines J.
        • Singer J.H.
        • Hackett S.F.
        • Campochiaro P.A.
        Inhibition of growth factor effects in retinal pigment epithelial cells.
        Invest Ophthalmol Vis Sci. 1991; 32: 1770-1778
        • Greenlee T.
        • Hom G.
        • Conti T.
        • Babiuch A.S.
        • Singh R.
        Re: Pearce et al. pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium.
        Ophthalmology. 2019; 126 (Ophthalmology. 2018;125:1793–802): e51
        • Curcio C.A.
        Soft drusen in age-related macular degeneration: biology and targeting via the oil spill strategies.
        Invest Ophthalmol Vis Sci. 2018; 59: AMD160-AMD181
        • Balaratnasingam C.
        • Messinger J.D.
        • Sloan K.R.
        • Yannuzzi L.A.
        • Freund K.B.
        • Curcio C.A.
        Histologic and optical coherence tomographic correlates in drusenoid pigment epithelium detachment in age-related macular degeneration.
        Ophthalmology. 2017; 124: 644-656
        • Balaratnasingam C.
        • Yannuzzi L.A.
        • Curcio C.A.
        • et al.
        Associations between retinal pigment epithelium and drusen volume changes during the lifecycle of large drusenoid pigment epithelial detachments.
        Invest Ophthalmol Vis Sci. 2016; 57: 5479-5489