Download 1. Pearce et al. Pigmentary Maculopathy Associated with Chronic Exposure

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
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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)
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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,
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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
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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
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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.
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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
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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.
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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.