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

Abstract

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.

Full text

ORIGINAL RESEARCH
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,
IL, USA
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
Introduction
Interstitial cystitis (IC) or bladder pain syndrome is a chronic condition that causes
pain or pressure in the bladder, predominantly in women.
1
The pathophysiology of
this disease is still unknown. In the US, 2.7–6.5% of the population is affected by
IC.
1
Antihistamines, tricyclic antidepressants, cyclosporine, bacille Calmette-
Guérin, nitric oxide, and pentosane polysulfate (PPS) have all been used to treat
IC.
2
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.
3
It
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
toxins.
3
Long-term studies on PPS report nausea, diarrhea, and headache as the common
adverse effects.
3
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,
USA
Email r-mirza@northwestern.edu
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out of 38 patients studied at a single center were
described.
4
They noted changes in the retinal pigment
epithelium including parafoveal pigmented deposits, para-
central atrophy, and hyperreective lesions.
4
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
macula.
5
Prior to understanding the new maculopathy,
several patients were diagnosed as having macular dystro-
phies and hereditary maculopathies.
5
Prospective studies
by Wang et al and Vora et al have reported the prevalence
of PPS-associated maculopathy to be 20% and 23.1%
respectively.
6,7
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.
8,9
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.
Methods
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.
Results
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.
10
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
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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).
Discussion
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,
4
and
Hanif et al recently reported a strong causal relationship
between the two.
4,9,10
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.
10
Common symptoms of the maculopathy
included difculty reading, metamorphopsia, impaired
dark adaptation, and nyctalopia.
11
While several studies
have shown the association of PPS to a maculopathy, some
studies have discussed the possibility of IC causing the
maculopathy itself.
12,13
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
group.
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.
8
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
Features
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
Gender
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
Range)
Mean Median Range (Interquartile
Range)
Mean Median Range (Interquartile
Range)
Mean Median
Visual acuity
logMAR
0–1.6 0.19 0.1 0–1.6 0.19 0.1 0–1.6 0.19 0.1
PPS duration
(years)
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
Cumulative
dose (g)
0.3–2086 (468.1) 430.2 272.7 29–1092 (132) 380 319 0.3–2086 (645.7) 442 188.1
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those reported by Pearce et al,
4
and hyperreectivity,
thickening of the foci of the RPE, and a ying saucer
macular sign were also noted on OCT imaging.
14
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
maculopathy.
6
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
changes.
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.
15
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.
16
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
Patient
#
Clinical Exam
Findings
Image Type and Findings Category
per Hanif
et al
Reason for
Examination
Patient 1 RPE mottling Fundus photo; paracentral macular pigmented spots 2 Glaucoma
suspect
Patient 2 Mild RPE mottling OCT; retinal pigment epithelial mottling 3 Diabetic
screening exam
Patient 3 Retinal pigment epithelial
mottling
OCT; retinal pigment epithelial mottling 2 Open angle
glaucoma
Patient 4 Early age-related macular
degeneration
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
spots
No imaging available 2 Dry age-related
macular
degeneration
Patient 7 Very ne central drusen No imaging available 3 Posterior
vitreous
detachment
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
enlargement
1 Dry age-related
macular
degeneration
Patient 9 Multiple drusen, pigment
mottling
FAF, OCT: Reticular hypo- and hyperautouorescent spots, pigment
mottling, subretinal hyperreective deposits
1 Pigmentary
retinal dystrophy
Patient
10
Drusen, hard drusen,
ERM, mild pigmentary
change
No imaging available 3 Drusen
Abbreviations: N/A, not available; OCT, ocular coherence tomography; FAF, fundus autouorescence.
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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.
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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.
17
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.
Acknowledgments
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.
Funding
No nancial support was received for this study.
Disclosure
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.
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