ArticlePDF Available

Maculopathy Secondary to Pentosan Polysulfate Use: A Single-Center Experience


Abstract and Figures

Aim: To investigate the prevalence of retinal pathology in patients with a history of exposure to pentosan polysulfate sodium (PPS). Methods: Patients exposed to PPS and seen in the ophthalmology clinic at Northwestern University during 1/1/2002 to 1/1/2019 were identified from electronic health records (EHR) by an electronic data warehouse (EDW) search. Visual acuity (VA), reasons for clinic visit, ocular conditions, and duration of exposure to PPS were noted. Chart review was performed for fundus exam findings and ophthalmologic imaging, specifically fundus photography, fundus autofluorescence, and ocular coherence tomography (OCT) images. When OCT or fundus photography was available, studies were evaluated by two independent graders. Results: A total of 131 patients who were exposed to PPS and seen at the Northwestern Ophthalmology clinic were identified in the EHR. Forty patients of 131 had imaging. Patients with imaging or fundus examination suspicious for PPS maculopathy were placed into the suspect group. Of the 40 patients that had imaging, 5 (12.5%) had features suspicious for PPS maculopathy. Of the remaining 91, 5 (5.4%) had macular pigmentary changes described on fundus exam. Among the 10 patients in the suspect group, the average duration of PPS use was 4.2 years (range 0.3-11.6 years, interquartile range 5.5 years) and the average cumulative dose was 380g (range 29-1092g, interquartile range 132g). Conclusion: A novel drug-induced maculopathy has been associated with PPS use with a distinct clinical constellation that can be accurately identified with multimodal imaging.
Content may be subject to copyright.
Maculopathy Secondary to Pentosan Polysulfate
Use: A Single-Center Experience
This article was published in the following Dove Press journal:
Clinical Ophthalmology
Neil S Kalbag
Nenita Maganti
Alice T Lyon
Rukhsana G Mirza
Department of Ophthalmology,
Northwestern University, Chicago,
Aim: To investigate the prevalence of retinal pathology in patients with a history of exposure
to pentosan polysulfate sodium (PPS).
Methods: Patients exposed to PPS and seen in the ophthalmology clinic at Northwestern
University during 1/1/2002 to 1/1/2019 were identied from electronic health records (EHR)
by an electronic data warehouse (EDW) search. Visual acuity (VA), reasons for clinic visit,
ocular conditions, and duration of exposure to PPS were noted. Chart review was performed
for fundus exam ndings and ophthalmologic imaging, specically fundus photography,
fundus autouorescence, and ocular coherence tomography (OCT) images. When OCT or
fundus photography was available, studies were evaluated by two independent graders.
Results: A total of 131 patients who were exposed to PPS and seen at the Northwestern
Ophthalmology clinic were identied in the EHR. Forty patients of 131 had imaging.
Patients with imaging or fundus examination suspicious for PPS maculopathy were placed
into the suspect group. Of the 40 patients that had imaging, 5 (12.5%) had features suspicious
for PPS maculopathy. Of the remaining 91, 5 (5.4%) had macular pigmentary changes
described on fundus exam. Among the 10 patients in the suspect group, the average duration
of PPS use was 4.2 years (range 0.3–11.6 years, interquartile range 5.5 years) and the average
cumulative dose was 380g (range 29–1092g, interquartile range 132g).
Conclusion: A novel drug-induced maculopathy has been associated with PPS use with
a distinct clinical constellation that can be accurately identied with multimodal imaging.
Keywords: interstitial cystitis, IC, maculopathy, pentosan polysulfate sodium, PPS
Interstitial cystitis (IC) or bladder pain syndrome is a chronic condition that causes
pain or pressure in the bladder, predominantly in women.
The pathophysiology of
this disease is still unknown. In the US, 2.7–6.5% of the population is affected by
Antihistamines, tricyclic antidepressants, cyclosporine, bacille Calmette-
Guérin, nitric oxide, and pentosane polysulfate (PPS) have all been used to treat
PPS is a sulfated polysaccharide, with a structure similar to heparin and
glycosaminoglycan and is the only United States Food and Drug Administration
(FDA)-approved drug for IC, typically dosed at 100mg three times per day.
works as a mucosal protecting agent in the bladder to provide symptomatic relief by
binding to the uroepithelium and reducing permeability to decrease irritation from
Long-term studies on PPS report nausea, diarrhea, and headache as the common
adverse effects.
Pearce et al recently described a unique pigmentary maculopathy
associated with chronic exposure to PPS in which toxic changes to the retina in 6
Correspondence: Rukhsana G Mirza
Department of Ophthalmology,
Northwestern University, Chicago, IL,
submit your manuscript | Clinical Ophthalmology 2021:15 513–519 513
DovePress © 2021 Kalbag et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at
php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the
work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For
permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (
Clinical Ophthalmology Dovepress
open access to scientific and medical research
Open Access Full Text Article
out of 38 patients studied at a single center were
They noted changes in the retinal pigment
epithelium including parafoveal pigmented deposits, para-
central atrophy, and hyperreective lesions.
Further stu-
dies have shown that key features of PPS-associated
maculopathy include a hypoautouorescent peripapillary
halo on imaging and early involvement of the central
Prior to understanding the new maculopathy,
several patients were diagnosed as having macular dystro-
phies and hereditary maculopathies.
Prospective studies
by Wang et al and Vora et al have reported the prevalence
of PPS-associated maculopathy to be 20% and 23.1%
Theorized mechanisms include the antag-
onism of the broblastic growth factor pathway in the
retina by PPS, specically in the retinal pigmental epithe-
lium layer (RPE), PPS being directly toxic to the retina, or
interaction between PPS and the glycosaminoglycans in
the photoreceptor layer of the retina.
Although PPS was
approved by the FDA in 1996, it was only recently in June
of 2020 that the FDA released an updated label to include
retinal pigmentary changes as a warning and adverse effect
of the drug.
This study reports retinal changes noted in patients on
PPS, for any duration of the drug, at a tertiary-care center
to add to the previously reported single-center case series.
The current state of identication of this disease, steps to
understand the association versus causation between PPS
and pigmentary maculopathy, and changes to improve
identication of this condition are also discussed.
A retrospective study was performed on patients from the
Northwestern Medicine EPIC electronic health records
(EHR) by using an Electronic Data Warehouse (EDW)
search. The study cohort included patients aged 18–95
years who had been exposed to PPS and seen in the
Northwestern ophthalmology clinic from January 1, 2002
to January 1, 2019. An EDW query was performed to
obtain visual acuities, duration of drug, dose of drug,
other health conditions, and demographics for patients in
the study group. Patient charts were reviewed by study
team members for fundus ndings documented in the
examination and ophthalmologic imaging, specically
multimodal imaging including fundus photography, fundus
autouorescence, and ocular coherence tomography
(OCT) images. When imaging was available, the images
were evaluated by at least two independent ophthalmolo-
gists. In cases where imaging was not available, patient
charts were reviewed for fundus examinations with clin-
ical documentation of macular pigmentary changes such as
pigmentary clumping or mottling. Subjective complaints
were not utilized to identify suspicious ndings. Patients
with fundus exam or imaging ndings suspicious for PPS-
associated maculopathy as described by Pearce et al were
separated into the suspect group for further evaluation.
This study was approved by the Institutional Review
Board of Northwestern University. All data accessed com-
plied with relevant data protection and privacy regulations.
Descriptive statistics were used to summarize patient
demographics. Continuous measures were summarized
with means and standard deviations (SD), and categorical
measures were summarized with frequencies and percen-
tages. SAS version 9.4 (SAS Institute, Cary, NC) was used
for all statistical analyses.
The study cohort comprised a total of 262 eyes of 131
patients. One hundred and eleven (84.7%) patients were
female, and the cohort’s average age was 59.5 (±16.1)
years old (range: 21–90). Demographic data are shown in
Table 1. Of the 131 patients, 40 patients (30.5%) had
imaging while 91 (69.5%) did not. Of the 40 patients
with imaging on le, 5 (12.5%) had ndings suspicious
for PPS-associated maculopathy and of the 91 patients
without imaging, 82 patients had documented fundus
examinations and 5 (6.1%) of such patients were noted
to have macular pigmentary changes. The 5 patients with
imaging ndings suspicious for PPS maculopathy and the
other 5 patients with macular pigmentary changes were
separated into a suspect group.
Individual examination and imaging ndings for the
suspect group and their classication based on degree of
suspicion as described in a recent paper by Hanif et al are
shown in Table 2.
Patients 8 and 9 had the most striking
ndings including pigmentary changes around the fovea
(Figures 1 and 2) with both hyper- and hypoautouores-
cent pigmentary changes associated with vitelliform/
hyperreective lesions on OCT. Patient 8 had multiple
studies over a 5 year period documenting progression of
RPE atrophy in the late stage of the disease. (Figure 3).
The average logMAR visual acuity (VA) for all 131
patients was 0.19. The mean duration of PPS use and mean
cumulative dose in the suspect group were 4.2 years and
380g respectively and in the non-suspect group were 3.6
years and 442g (Table 1). Common other diagnoses for
which patients were seen in the ophthalmology clinic
submit your manuscript |
Clinical Ophthalmology 2021:15
Kalbag et al Dovepress
included ocular surface issues (blepharitis, dry eye syn-
drome, meibomian gland dysfunction) (n=37), cataract:
pre- or post-op (n=30), glaucoma/ocular hypertension
(n=7), diabetic retinopathy surveillance (n=6), uveitis
(n=8), and other issues including posterior vitreous detach-
ment, retinal tear, esotropia, and migraine (n=23).
Our study evaluated the prevalence of retinal pathology in
a cohort of patients who had been exposed to PPS and
examined in a tertiary care setting. Pearce et al described
a potential association between chronic use of PPS and the
development of a vision-threatening maculopathy,
Hanif et al recently reported a strong causal relationship
between the two.
An associated study with 35 patients
noted that this maculopathy is associated with long-term
exposure to PPS with a median of 15 years and a range of
3–22 years.
Common symptoms of the maculopathy
included difculty reading, metamorphopsia, impaired
dark adaptation, and nyctalopia.
While several studies
have shown the association of PPS to a maculopathy, some
studies have discussed the possibility of IC causing the
maculopathy itself.
Given these ndings, we conducted a retrospective
chart review at our institution to look for evidence of
retinal pathology in patients with PPS. Our suspect group
was found to have been taking PPS for an average of 4.2
years and an average dosage 380g respectively while the
non-suspect group took it for an average of 3.6 years at
442g. However, the median cumulative dosage for the
non-suspect group was lower than that of the suspect
group at 188.1g as opposed to 317g. This suggests that
a majority of patients without pigmentary changes had
lower exposure to the drug, with either a shorter duration
and/or lower doses when compared to those in the suspect
Two patients from our cohort had fundus ndings that
were consistent with the maculopathy described by Pearce
et al. However, it is of note that even patients with as little
as 0.3 years on the drug had evidence of pigmentary
changes documented in their chart. In our study cohort,
age, gender, visual acuity, and duration of drug therapy
were not found to be signicant factors in the development
of PPS-related maculopathy.
Although this is a retrospective analysis, this empha-
sizes the need to start monitoring patients on PPS early on
as well as documenting a baseline comprehensive eye
exam to identify any changes that occur during the use
of the drug. When pathology was noted, it was commonly
diagnosed as age-related macular degeneration or pattern
dystrophy. Such diagnoses were also noted in the prior
study by Hanif et al.
Imaging analyses reported by Hadad
et al showed that all patients (n=17) using 100mg of PPS
daily for at least 3 years had mottling changes of the retina
on near-infrared imaging, 75% of patients showed
a hypoautouorescence defect in the macula similar to
Table 1 Characteristics of Patients Taking Pentosan Polysulfate Sodium
All Patients Patients in Suspect Group Patients without Suspicious
N Mean SD N Mean SD N Mean SD
Age (years) 131 59.5 16.1 10 (7.6%) 67.3 12.0 121 (92.4%) 58.5 16.3
Male 20 (15.3%) 2 (20%) 20 18 (14.9%) 17.5
Female 111 (84.7%) 8 (80%) 80 103 (85.1%) 82.5
Range (Interquartile
Mean Median Range (Interquartile
Mean Median Range (Interquartile
Mean Median
Visual acuity
0–1.6 0.19 0.1 0–1.6 0.19 0.1 0–1.6 0.19 0.1
PPS duration
0.1–19.1 (5.3) 3.7 2.0 0.3–11.6 (5.5) 4.2 3.0 0.1–19.1 (5.3) 3.6 1.7
dose (g)
0.3–2086 (468.1) 430.2 272.7 29–1092 (132) 380 319 0.3–2086 (645.7) 442 188.1
Clinical Ophthalmology 2021:15 submit your manuscript |
Dovepress Kalbag et al
those reported by Pearce et al,
and hyperreectivity,
thickening of the foci of the RPE, and a ying saucer
macular sign were also noted on OCT imaging.
A recent prospective study by Wang et al found that
patients with a cumulative dosage over 1500g had
a signicant risk of developing a PPS-associated
They recommend baseline ophthalmolo-
gical examinations with multimodal imaging of patients
who are to receive PPS in a cumulative dose of about
500g. In our study cohort, Patient 9 was found to have
prominent macular pigmentary ndings that were con-
sistent with the previously described PPS-associated
maculopathy. However, this patient only had
a cumulative dosage of 304.4g. Further study is needed
to determine at what cumulative dosage patients become
at risk for the development of PPS-associated macular
Additionally, some patients in our suspect group were
examined in the clinic post-drug cessation, so it is unclear at
which point in their course of treatment pigmentary changes
developed. A recent case study discussed the possibility of
progressing maculopathy after discontinuation of the drug,
where a 67-year-old woman with a history of PPS use for 18
years presented with worsening vision despite stopping the
drug at the age of 62.
Additionally, a retrospective study by
Shah et al proposed that pigmentary changes can continue to
develop for at least ten years after the cessation of PPS.
Longitudinal study is required to understand the course of the
PPS-associated maculopathy development.
Strengths of our work include the fact that our study
cohort includes all patients taking PPS seen at the
Northwestern Ophthalmology clinic during our study per-
iod, not just those seen in by a retina specialist. This
prevented potential bias towards the existence of retinal
Table 2 Clinical Findings in Patients Suspicious for PPS-Associated Maculopathy
Clinical Exam
Image Type and Findings Category
per Hanif
et al
Reason for
Patient 1 RPE mottling Fundus photo; paracentral macular pigmented spots 2 Glaucoma
Patient 2 Mild RPE mottling OCT; retinal pigment epithelial mottling 3 Diabetic
screening exam
Patient 3 Retinal pigment epithelial
OCT; retinal pigment epithelial mottling 2 Open angle
Patient 4 Early age-related macular
No imaging available 2 Nuclear cataract
Patient 5 Normal macula OCT; retinal pigment epithelial mottling and mild pigment clumping 2 Nuclear cataract
Patient 6 Parafoveal pale yellow
No imaging available 2 Dry age-related
Patient 7 Very ne central drusen No imaging available 3 Posterior
Patient 8 Multiple drusen,
pigmentary atrophy,
pigment mottling
FAF, OCT; Reticular hypo- and hyperautouorescent spots, pigment
mottling, large areas of conuent RPE atrophy, Focal RPE
1 Dry age-related
Patient 9 Multiple drusen, pigment
FAF, OCT: Reticular hypo- and hyperautouorescent spots, pigment
mottling, subretinal hyperreective deposits
1 Pigmentary
retinal dystrophy
Drusen, hard drusen,
ERM, mild pigmentary
No imaging available 3 Drusen
Abbreviations: N/A, not available; OCT, ocular coherence tomography; FAF, fundus autouorescence.
submit your manuscript |
Clinical Ophthalmology 2021:15
Kalbag et al Dovepress
ndings. We were able to establish a relationship between
the drug and macular pathology, and conrm recent nd-
ings by other authors. Lastly, since it was a retrospective
study, there was minimal selection or recall bias. There are
limitations to our study. Given that it was a single center
study, the number of patients included in the analysis were
limited. Consequently, our non-suspect group does not
serve strictly as a control group because patients in both
the suspect and non-suspect group experienced ocular
comorbidities. This is one likely explanation for the lack
Figure 1 (Patient 9) Fundus photography: Fundus autouorescence at early stage of disease showing pigment mottling, reticular hypoautouorescent and hyperautouor-
escent spots, and focal areas of RPE enlargement.
Figure 2 (Patient 8) OCT: Later stage of the disease shows large areas of conuent RPE atrophy.
Clinical Ophthalmology 2021:15 submit your manuscript |
Dovepress Kalbag et al
of difference in average visual acuity between the two
groups. Additionally, dates of medication discontinuation
may not always be entered into the appropriate sections of
the EHR and patients occasionally discontinue their med-
ications on their own. The last date of PPS use was miss-
ing in the EHR for 48% of our patients, who may or may
not have discontinued the drug. This affected our analysis
for the true duration and cumulative dosage of the drug.
Because of the retrospective nature of this study, data was
derived from the existing EHR. Consequently, not all
patients in the cohort had imaging on le, likely because
conditions for which they were seen in the ophthalmology
clinic frequently did not warrant any multimodal or poster-
ior segment imaging. Even when posterior segment exam-
ination was performed, mild ndings of early stages of the
retinopathy could be easily missed. Educating eye provi-
ders is critical in early identication of patients who are on
the drug, improving detection of new changes that develop
during therapy, and ensuring regular follow up. Further,
patients should be counseled on the potential side effects
of the drug along with a careful consideration of the risks
and benets prior to starting PPS therapy. Lyons et al also
recommend prescribing the lowest dose and duration of
the medication if the decision to start PPS is made.
Our study adds to the growing body of work that
supports the presence of a distinct pigmentary maculopa-
thy associated with chronic usage of PPS. Future study is
warranted, and guidelines are in the process of being
established for the screening for PPS-associated maculo-
pathy. A prospective analysis employing baseline ophthal-
mologic exams, regular follow-up, along with multimodal
imaging is important in understanding the course of the
disease while patients are on the medication as well as
after discontinuation.
Saena A. Sadiq, BS for her work which was critical in the
revision of the manuscript, including additional literature
review and incorporation of new ndings into the manu-
script, updating the tables, and reformatting the images.
No nancial support was received for this study.
The authors have no proprietary or commercial interest in
any of the materials discussed in this article and report no
conicts of interest in this work.
1. 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. 2011;186(2):540–544. doi:10.1016/j.
2. Chancellor MB, Yoshimura N. Treatment of interstitial cystitis.
Urology. 2004;63(3):85–92. doi:10.1016/j.urology.2003.10.034
3. Anderson VR, Perry CM. Pentosan polysulfate. Drugs. 2006;66
(6):821–835. doi:10.2165/00003495-200666060-00006
4. Pearce WA, Chen R, Jain N. Pigmentary maculopathy associated with
chronic exposure to pentosan polysulfate sodium. Ophthalmology.
2018;125(11):1793–1802. doi:10.1016/j.ophtha.2018.04.026
5. Barnes AC, Hanif AM, Jain N. Pentosan polysulfate maculopathy
versus inherited macular dystrophies: comparative assessment with
multimodal imaging. Ophthalmol Retina. 2020;4(12):1196–1201.
6. Wang D, Au A, Gunnemann F, et al. Pentosan-associated maculopa-
thy: prevalence, screening guidelines, and spectrum of ndings based
on prospective multimodal analysis. Can J Ophthalmol. 2020;55
(2):116–125. doi:10.1016/j.jcjo.2019.12.001
Figure 3 (Patient 8) Fundus autouorescence at presentation and 4 years later, depicting the increase in areas of RPE atrophy.
submit your manuscript |
Clinical Ophthalmology 2021:15
Kalbag et al Dovepress
7. Vora RA, Patel AP, Melles R. Prevalence of maculopathy associated
with long-term pentosan polysulfate therapy. Ophthalmology.
2020;27(6):835–836. doi:10.1016/j.ophtha.2020.01.017
8. Greenlee T, Hom G, Conti T, Babiuch AS, Singh R. Re: pearce et al.:
pigmentary maculopathy associated with chronic exposure to pento-
san polysulfate sodium (Ophthalmology. 2018; 125 (11):1793-1802).
Ophthalmology. 2019;126(7):e51. doi:10.1016/j.ophtha.2018.12.037
9. Hanif AM, Armenti ST, Taylor SC, et al. Phenotypic spectrum of
pentosan polysulfate sodium–associated maculopathy: a multicenter
study. JAMA Ophthalmol. 2019;137(11):1275. doi:10.1001/
10. Hanif AM, Shah R, Yan J, et al. Strength of association between
pentosan polysulfate and a novel maculopathy. Ophthalmology.
2019;126(10):1464–1466. doi:10.1016/j.ophtha.2019.04.024
11. Mogica JAP, De EJB. Pentosan polysulfate maculopathy: what urol-
ogists should know in 2020. Urology. 2020;S0090-4295(20)31240-1.
12. Ludwig CA, Vail D, Callaway NF, Pasricha MV, Moshfeghi DM.
Pentosan polysulfate sodium exposure and drug-induced maculopathy
in commercially insured patients in the United States. Ophthalmology.
2020;127(4):535–543. doi:10.1016/j.ophtha.2019.10.036
13. Jain N, Li AL, Yu Y, VanderBeek BL. Association of macular disease
with long-term use of pentosan polysulfate sodium: ndings from
a US cohort. B J Ophthalmol. 2020;104(8):1093–1097. doi:10.1136/
14. Hadad A, Helmy O, Leeman S, Schaal S, Novel Multimethod A.
A novel multimethod image analysis to quantify pentosan polysulfate
sodium retinal toxicity. Ophthalmology. 2020;127(3):429–431.
15. Huckfeldt RM, Vavvas DG. Progressive maculopathy after disconti-
nuation of pentosan polysulfate sodium. Ophthalmic Surg Lasers
Imaging Retina. 2019;50(10):656–659. doi:10.3928/23258160-
16. Shah R, Simonett JM, Lyons RJ, Rao RC, Pennesi ME, Jain N. Disease
course in patients with pentosan polysulfate sodium-associated maculo-
pathy after drug cessation. JAMA Ophthalmol. 2020;138(8):894–900.
17. Lyons RJ, Ahmad S, Ansari S, Foote JE, Jain N. Pentosan
polysulfate-associated macular disease in patients with interstitial
cystitis. Obstet Gynecol. 2020;135(5):1091–1094. doi:10.1097/
Clinical Ophthalmology Dovepress
Publish your work in this journal
Clinical Ophthalmology is an international, peer-reviewed journal cover-
ing all subspecialties within ophthalmology. Key topics include:
Optometry; Visual science; Pharmacology and drug therapy in eye dis-
eases; Basic Sciences; Primary and Secondary eye care; Patient Safety
and Quality of Care Improvements. This journal is indexed on PubMed
Central and CAS, and is the ofcial journal of The Society of
Clinical Ophthalmology (SCO). The manuscript management system
is completely online and includes a very quick and fair peer-review
system, which is all easy to use. Visit
testimonials.php to read real quotes from published authors.
Submit your manuscript here:
Clinical Ophthalmology 2021:15 submit your manuscript |
Dovepress Kalbag et al
... 7 Subsequent studies independently conducted at numerous centers have reported a significant dose-response relationship between PPS exposure and presence of maculopathy. [8][9][10][11][12][13] A study from 2020 demonstrated prevalence rates of 13%, 30%, and 42% among patients with 500-999 grams (g), 1000-1499 g, and >1500 g of cumulative PPS exposure, respectively. 8 In another study from earlier this year, researchers found prevalence rates of 46% and 83% among patients with cumulative PPS exposures of 1500-2000 g and ≥2000 g. 11 Studies of large administrative claims databases have yielded mixed findings. ...
Full-text available
Pentosan polysulfate sodium (PPS) (Elmiron; Janssen Pharmaceuticals), a drug used to treat bladder pain and discomfort associated with interstitial cystitis (IC), has been linked to a distinctive vision-threatening maculopathy. As with the case of hydroxychloroquine maculopathy, it is worthwhile for the general ophthalmologist to be familiar with this potentially preventable condition. In this article, we briefly summarize the evidence supporting this association, review the clinical manifestations of PPS maculopathy, and provide some guidance regarding screening protocols.
... A similar prevalence of 2.0% (4 out of 216) was reported by Higgins et al., 49 who conducted a chart review of a quaternary academic medical centre electronic medical record database. Kalbag et al. 50 described a prevalence of 1.5% (10 out of 131) based on electronic health record data. ...
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a rare and chronic bladder condition. Pentosan polysulfate sodium (PPS) is the only oral medication approved specifically for the management of IC/BPS. In 2018, Pearce et al. reported for the first time a unique pattern of ocular pigmentary maculopathy exclusively in IC/BPS patients following PPS exposure. This publication triggered several published studies, case reports, case series, and media reports claiming a link between PPS and pigmentary maculopathy; however, a clear interpretation of these data is still awaited and there are currently no prospective, well researched, confirmatory data available. The clinical presentation of pigmentary maculopathy is characterised by moderate visual impairments and macular hyperpigmented spots, yellow-orange deposits, and/or patchy retinal pigment epithelium (RPE) atrophy. Most patients experiencing this ocular effect used high doses of PPS over an extended period, with risk of pigmentary maculopathy associated with PPS increasing with exposure. Studies that rule out prevalent retinal abnormalities are lacking. The cause of this particular maculopathy remains unclear and further research is required. The current data suggest that a median duration of 15 years of PPS exposure must elapse before pigmentary maculopathy is detected. Furthermore, no increased incidence of any type of maculopathy is found up to a median duration of 5 years of PPS use. Thus, in line with the current European Medicines Agency (EMA) recommendation, if patients respond to therapy and a decision is made to continue PPS for longer than 6 months, a fundoscopy with optical coherence tomography (OCT) and fundus autofluorescence should be performed. In cases of no findings, the next eye examination should be after a further 5 years of PPS use; in cases of findings, continuation of the treatment should be re-evaluated by the urologist and monitored by yearly ocular fundus examinations. This review provides a framework for evidence-based treatment with PPS in patients with IC/BPS using appropriate monitoring and gives an overview of the current understanding and evidence of the association of PPS and a specific pigmentary maculopathy.
Objective: Pentosan polysulphate (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. Methods: 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. Results: 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. Conclusions: 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 polysulphate prescribers about this condition. Effective screening and detection may help determine which patients are at high risk for this condition.
Purpose To compare choriocapillaris flow deficit (CC FD) analysis using optical coherence angiography (OCT) angiography in eyes of patients treated with high cumulative dosages of pentosan polysulfate sodium (PPS) but no signs of retinal toxicity versus healthy age matched controls. Design Retrospective clinical cohort study. Methods Patients treated with PPS for interstitial cystitis with cumulative dose of more than 1000 grams underwent multimodal imaging screening to exclude evidence of PPS maculopathy or other retinal findings. All study patients and age-matched healthy controls completed a 3 × 3 mm macular volume scan OCT angiography (OCTA) using the SOLIX full range OCT. En face OCTA images at the level of the CC were exported and CC FDs were computed and compared between groups. Results Fifteen patients treated with PPS and fifteen age-matched controls were included. The mean PPS cumulative dose was 1974±666 grams over a mean of 17.6 ±6.8 treatment years. All patients registered a visual acuity of 20/25 or better and normal fundus autofluorescence (FAF), OCT, multicolor, near-infrared reflectance (NIR) and ultra-widefield fundus color and AF images. The CC FD was 32.7±3.6% in the PPS group compared to 28.6±4.3% in the control group (p=0.023). Conclusions Patients treated with PPS long enough to accumulate dosages greater than 1000 grams showed significant CC flow impairment before the development of macular toxicity signs with OCT, NIR, and FAF, compared to age-matched normal controls. Thus, the choroid may be the earliest manifestation of ocular toxicity, predating the development of clinically evident retinal pigment epithelium (RPE) injury. The subsequent RPE disruption may be the result of choriocapillaris impairment or primary PPS toxicity. Assessment of the CC on OCTA may be a useful tool for early detection of toxicity, although further longitudinal studies are required.
Full-text available
Importance Recent studies have linked a vision-threatening maculopathy with long-term use of pentosan polysulfate sodium (PPS). Objective To evaluate the disease course in PPS-associated maculopathy after drug cessation. Design, Setting, and Participants In this retrospective case series, patients diagnosed with PPS-associated maculopathy with at least 6 months of follow-up after drug cessation who were treated at the Emory Eye Center, Atlanta, Georgia, or the Casey Eye Institute, Portland, Oregon, were included. Data were collected from April 2014 through November 2019. Main Outcomes and Measures Change in visual acuity and retinal imaging characteristics over time. Results Of the 11 included patients, all were female, and the median (interquartile range [IQR]) age was 53 (44-63) years. Participants had a baseline visit at a median (IQR) of 2 (0-4) months after drug cessation and were subsequently observed for a median (IQR) of 12 (8-26) months. The median (IQR) cumulative PPS exposure was 1.97 (1.55-2.18) kg. No eyes exhibited a demonstrable improvement in disease after discontinuing PPS. A total of 9 of 11 patients (82%) reported worsening visual symptoms at the final visit. The mean (SD) logMAR visual acuity was 0.14 (0.23) and 0.14 (0.34) at the baseline and final visit, respectively. Visual acuity improved by 2 or more Snellen lines in 1 eye (5%) and declined by 2 or more Snellen lines in 2 eyes of 1 patient (9%). There was evolution in the pattern of fundus autofluorescence changes and/or optical coherence tomography findings in all eyes. A total of 17 eyes (77%) exhibited expansion of the area of involved tissue. A total of 7 eyes (32%) had macular retinal pigment epithelium atrophy at the baseline visit, and atrophy enlarged after discontinuation of PPS in all 7 eyes, with a median (IQR) growth rate of 0.32 (0.13-0.38) mm per year. Conclusions and Relevance These retrospective data among 11 patients suggest PPS-associated maculopathy continues to evolve after drug cessation for at least 10 years. In some cases, progressive retinal pigment epithelium atrophy encroaches on the foveal center and thus may pose a long-term threat to central vision.
Objective To conduct a review of current literature to assess whether an association exists between Pentosan Polysulfate Sodium and the development of macular disease, as it is the only oral medication approved by the Food and Drug Administration for the management of interstitial cystitis. Materials and Methods A systematic review was conducted by the authors separately, with review methods established prior to the conduct of the review. Databases searched included PubMed, Ovid, Medline, EBSCO, and Google Scholar. A search was conducted for the terms “Pentosan Polysulfate Maculopathy,” “Pentosan Polysulfate Retinopathy,” and “Interstitial Cystitis Maculopathy.” All papers reporting on primary data were included. There were no study sponsors. Results A total of 14 papers reporting on primary data were identified. Most papers reported on the development of macular disease in the setting of chronic pentosan polysulfate sodium exposure. No randomized controlled trials have been performed to date and data was insufficient to perform a meta-analysis. Nevertheless, patients with interstitial cystitis were more likely to receive a diagnosis of maculopathy after several years of the medication use. Conclusion Although the nature of the published studies renders them prone to confounders, currently available data suggest an increased risk for developing maculopathy after years of pentosan polysulfate sodium use. In light of this, and the marginal effectiveness of the medication for the average individual, we suggest that education be provided as to the possible association and that regular ophthalmic evaluation be recommended for patients who are continued on chronic Pentosan Polysulfate Sodium.
Purpose To evaluate whether pentosan polysulfate maculopathy manifests distinctive characteristics that permit differentiation from hereditary maculopathies with multimodal fundus imaging. Design Retrospective Review Subjects Emory Eye Center databases were queried for the following International Classification of Diseases (ICD) codes between May 20, 2014 through October 22, 2019: 362.70 (unspecified hereditary retinal dystrophy), 362.74 + H35.52 (pigmentary retinal dystrophy), 362.76 +H35.54 (dystrophies primarily involving the retinal pigment epithelium), and H35.50 (unspecified macular degeneration). Methods Fundus images for each patient were evaluated, including color fundus photographs, fundus autofluorescence images, and spectral domain optical coherence tomography images. Cases with imaging sufficient for diagnostic classification were analyzed. Masked graders classified patient images accordingly: A – Highly suggestive of PPS maculopathy, B—Some features resembling PPS maculopathy but not classic, C—Clearly distinct from PPS maculopathy. Main Outcome Measures Sensitivity and specificity for identification of PPS maculopathy by masked reviewers. Results A total of 1394 subjects were evaluated, and 1131 had sufficient imaging for classification. Fifteen patients were categorized as having findings highly suggestive of PPS maculopathy (Category A), 25 patients had some features resembling PPS maculopathy but not classic (Category B), and 1091 were clearly distinct from PPS maculopathy (Category C). All 10 patients with PPS maculopathy in this dataset were correctly placed in Category A. There were 5 patients without PPS maculopathy that were incorrectly placed in Category A. This represented a 100% sensitivity and 99.6% specificity for identification of PPS maculopathy by masked review of fundus imaging in this dataset. Conclusions The imaging characteristics of PPS maculopathy allow for differentiation from hereditary maculopathies even in the absence of known exposure to the drug.
Recent studies have implicated long-term pentosan polysulfate use with vision loss from a newly described macular condition. Affected patients report difficulty with reading and adjusting to dim lighting, and they occasionally develop severe visual disability. Macular changes resemble those seen in age-related macular degeneration, potentially leading to misdiagnosis. The objectives of this Current Commentary are to summarize studies evaluating the association between pentosan polysulfate use and macular disease, to educate pentosan polysulfate prescribers about the clinical manifestations of this condition, and to provide recommendations for screening at-risk patients.
Objective: To describe the prevalence and spectrum of multimodal imaging findings of pentosan polysulfate sodium (PPS)-associated maculopathy and to recommend dosage-related screening guidelines. Design: Cross-sectional study. Methods: 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. Results: 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. Conclusions: 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.
Background/Aims A series at a single clinical centre recently demonstrated an association between the interstitial cystitis drug pentosan polysulfate sodium (PPS) and a vision-threatening pigmentary maculopathy. The aim of this study was to determine if an association exists between PPS use and macular disease in a large national cohort. Methods A retrospective, matched cohort study using data from a large US medical claims database from 2002 to 2016 was performed. A total of 3012 and 1604 PPS users were compared with 15 060 and 8017 matched controls at 5 and 7 years, respectively. The primary outcome measures included (1) any new diagnosis of a hereditary or secondary pigmentary maculopathy (atypical maculopathy outcome), and (2) any new diagnosis of dry age-related macular degeneration (AMD) or drusen in addition to the aforementioned diagnoses (atypical maculopathy+AMD outcome). Results At the 5-year and 7-year follow-up, 9 (0.3%) and 10 (0.6%) PPS patients progressed to the atypical maculopathy outcome compared with 32 (0.2%) and 25 (0.3%) control patients, respectively. 103 (3.4%) and 87 (5.4%) PPS patients developed the atypical maculopathy+AMD outcome compared with 440 (2.9%) and 328 (4.1%) control patients at 5 and 7 years, respectively. At 5 years, multivariate analysis showed no significant association (p>0.13). At 7 years, PPS users had significantly increased odds of having the atypical maculopathy+AMD outcome (OR=1.41, 95% CI 1.09 to 1.83, p=0.009). Conclusions PPS exposure was associated with a new diagnosis of macular disease at the 7-year follow-up in a large national cohort.
Purpose: To determine the association and cumulative dose-response pattern between pentosan polysulfate sodium (PPS) use for interstitial cystitis (IC) and maculopathy. Design: Large, multicenter, retrospective cohort study of commercially insured patients in the MarketScan database (Truven Health Analytics, San Jose, CA). Participants: Two hundred twenty-seven thousand three hundred twenty-five patients with IC who were enrolled continuously in the MarketScan database. Methods: Cox proportional hazards models (controlling for patient gender, age at index diagnosis of IC, and diagnosis with diabetes mellitus) followed up patients from index diagnosis of IC for 5 years, or until patients discontinued insurance coverage, or until patients' first diagnosis with a maculopathy. As a sensitivity analysis, we re-estimate all models after excluding all patients with diabetes. To assess for dose response, we calculated the total days of PPS prescriptions filled and created a categorical variable indicating total exposure. Main outcome measures: The primary outcome measure was association between binary PPS exposure and any maculopathy. Secondary outcome measures included exposure between binary and categorical, time-dependent, exposure to PPS and to drusen, nonexudative age-related macular degeneration (AMD), exudative AMD, hereditary maculopathy, and toxic maculopathy. Results: The most common diagnoses of maculopathy in patients with IC were exudative AMD (1.5%), drusen (0.8%), nonexudative AMD (0.3%), toxic maculopathy (0.1%), and hereditary dystrophy (0.04%). In unadjusted analyses, the percentage of patients who filled a PPS prescription and were diagnosed later with a maculopathy (2.37%) was very similar to the percentage of patients who did not fill a prescription (2.77%). Survival models using a binary variable indicating PPS exposure showed no significant associations between PPS exposure and diagnosis of drusen, nonexudative AMD, exudative AMD, toxic maculopathy, hereditary dystrophy, or an aggregate variable of any maculopathy. Similarly, there was no dose-dependent relationship between PPS exposure and diagnosis of any maculopathy. These findings remained stable in sensitivity analysis models that excluded patients with diabetes mellitus. Conclusions: In this large, commercial claims database analysis, no association was found between PPS exposure and subsequent diagnosis of maculopathy.
A pigmentary maculopathy associated with chronic use of the drug pentosan polysulfate sodium (PPS) was recently described. The authors present a case of PPS-associated maculopathy that continued to progress for 6 years after discontinuation of this medication. [ Ophthalmic Surg Lasers Imaging Retina . 2019;50:656–659.]