Abstract
Purpose: To describe the prevalence and spectrum of disease of pentosan polysulfate (PPS) maculopathy in a large multimodal retinal imaging study and to report the results of choroidal vascularity index (CVI) analysis.
Design: Prospective cohort study
Methods: Of 741 patients prescribed PPS within a large university database, 100 (13.4%) with any consumption agreed to participate in a prospective screening investigation. Multimodal retinal imaging including near-infrared reflectance (NIR), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT) was performed in all patients. Characteristic findings of affected patients were identified, and affected and unaffected cohorts were compared. CVI, defined as stromal choroidal area (SCA) divided by the total choroidal area, was analyzed.
Results: The prevalence of PPS maculopathy was 16%. NIR illustrated punctate hyperreflective lesions with early presentation. FAF illustrated a speckled macular network of hypo- and hyperautofluorescence colocalized with multifocal hyperreflective retinal pigment epithelial lesions on SD-OCT. Advanced cases demonstrated varying degrees of atrophy. The affected cohort exhibited significantly greater mean PPS therapy duration, mean daily dosage, and mean cumulative dosage (19.5±5.5 years, 433.9±137.6 mg, 3,103.1±1,402.2 g) compared with the unaffected cohort (7.1±6.6 years, 291.6±177.6 mg, 768.4±754.8 g). SCA was significantly lower and CVI was significantly greater in the affected vs the unaffected group.
Conclusions: This prospective cohort study identified a prevalence of PPS maculopathy of 15%-20% among PPS users who agreed to participate. A spectrum of findings may be observed with multimodal retinal imaging. Significant choroidal abnormalities associated with this characteristic maculopathy may provide surrogate markers of macular toxicity.
P P entosan polysulfate sodium (PPS) is the sole oral medication approved by the United States Food and Drug Administration for the treatment of interstitial cystitis. PPS was FDA-approved in 1996 1 ; however, recent studies have shown that long-term exposure can be associated with a pigmentary maculopathy.
Although investigations continue to provide insight into this remarkable condition, much is still to be learned regarding PPS-associated retinal toxicity. Most of the current literature regarding the imaging features is based on retrospective studies instead of prospective analyses, and there is scarce information regarding the prevalence of this condition in the population of PPS users. Our group initially prospectively screened 50 patients ascertained from the UCLA database of PPS users and noted a prevalence of approximately 20%. Vora and colleagues screened PPS patients with a cumulative dosage of at least 500 g and found a prevalence of toxicity of 23%. Our initial study demonstrated that the risk of toxicity was greatest in PPS users with a cumulative dosage of greater than 1,000 g and especially greater than 1,500 g. Our group has since doubled the number of screened PPS patients at UCLA and additionally performed formal choroidal imaging analysis in the total cohort of screened subjects.
This study aimed to describe the prevalence and spectrum of disease of PPS maculopathy from our total cohort of PPS-treated patients at UCLA that were prospectively screened with multimodal retinal imaging analysis and to report the results of choroidal vascularity index (CVI) analysis.
Methods
The University of California Los Angeles (UCLA) Institutional Review Board approved this cross-sectional study, which was conducted in accordance with the tenets set forth by the Declaration of Helsinki. Information was collected and secured in compliance with the Health Insurance Portability and Accountability Act. All data were deidentified and stored securely within the Stein Eye Institute.
A list of all patients prescribed PPS between the months of March 2013 and October 2019 from the UCLA electronic medical record was procured. The following key terms were used for the database search: Elmiron 100mg PO caps, Elmiron PO, pentosan polysulfate sodium 100mg PO caps, pentosan polysulfate sodium PO , and pentosan polysulfate sodium POWD . The search yielded 741 total UCLA patients treated with PPS arranged by date of first prescription. All 741 patients were contacted by telephone to request their participation in this study. After verbally confirming any history of PPS use, 100 patients (13%) consented to be participants. The other 641 patients who declined cited various reasons for not participating, including lack of interest, logistic limitations such as distance, out-of-state travel, or lack of transportation, and time constraints including inability to arrange visits into their schedule.
Patients were all (except for 2) prospectively screened with multimodal retinal imaging in the retina clinic. The participants first completed a questionnaire that included demographic information—date of birth, gender, identified race, height, and weight. Every participant’s body mass index (BMI) was calculated via the National Heart, Lung, and Blood Institute online calculator on the basis of weight (pounds) and height (feet and inches). The questionnaire also asked about previous medical and ocular history, smoking history, PPS history (duration, daily dosage, any regimen changes during use), and development of visual symptoms while being treated with PPS.
All 100 patients underwent Snellen visual acuity testing and were screened with a series of multimodal retinal imaging studies that included 30- and 50-degree fundus autofluorescence (FAF) of the macula (Spectralis; Heidelberg Engineering Inc, Heidelberg, Germany), multicolor and near-infrared reflectance (NIR) of the macula (Spectralis; Heidelberg Engineering Inc), ultra-widefield autofluorescence of the posterior pole and periphery (Optos California icg ; Optos Inc, Dunfermline, Scotland, UK), and color fundus photography of the posterior pole and periphery (Optos California icg ; Optos Inc). Spectral domain optical coherence tomography (SD-OCT) (Spectralis; Heidelberg Engineering Inc) of the macula was also performed in all 100 patients and included a volume analysis of 25 B-scans (30 degrees by 20 degrees, B-scans spaced 240 µm apart).
OCT angiography (OCTA) and en face OCT (Solix; Optovue Inc, Fremont, California, USA) imaging were performed only in affected patients and used the automated default segmentation at the levels of the superficial and deep retinal capillary plexuses and choriocapillaris.
Fundus photography, SD-OCT, and FAF imaging was already performed on patients 21 and 22 under the guidance of their retinal specialist at UCLA at the time of initial communication during the screening process; thus, imaging was not repeated.
To identify structural associations of the autofluorescence, FAF images were colocalized with en face OCT images. The segmentation for analysis of en face OCT was set to the retinal pigment epithelium. The upper limit of the segmentation band was set at the retinal pigment epithelial and ellipsoid zone junction; the lower limit was set at the retinal pigment epithelial and Bruch membrane junction. En face OCT slab thickness was 20 µm.
Atrophy noted with FAF and OCT were defined by criteria previously published in the literature. The criteria for complete retinal pigment epithelial and outer retinal atrophy (cRORA) includes a continuous band of hypertransmission at least 250 µm in diameter, a continuous zone of retinal pigment epithelial attenuation or disruption at least 250 µm in diameter, and superimposed photoreceptor degeneration. , Atrophy noted on FAF was defined as a well-demarcated round zone of hypoautofluorescence of nonspecific diameter. ,
The presence or absence of cRORA with OCT and atrophy with FAF were the basis for grading PPS-associated maculopathy severity in affected patients. This grading system was modified according to the original system previously published and was defined as follows 3 :
Mild PPS-associated maculopathy: Presence of a speckled pattern of hypo- and hyperautofluorescence on FAF (or only hyperautofluorescent lesions) and no evidence of well-demarcated atrophic lesions on FAF and no evidence of cRORA with SD-OCT.
Moderate PPS-associated maculopathy: Presence of well-demarcated, nummular, hypoautofluorescent atrophic lesions on FAF that colocalized with cRORA on SD-OCT within the macula but without central foveal involvement.
Severe PPS-associated maculopathy: Presence of hypoautofluorescent atrophy within the macula with colocalization with cRORA with SD-OCT and involving the central fovea.
An expert evaluator (D.S.) examined the multimodal imaging of all 100 patients to confirm the presence or absence of findings consistent with PPS-associated maculopathy based on those described in the literature. , ,
Statistical analyses were performed using Prism 8 for macOS. Patient demographics, BMI, therapy duration, and daily and cumulative doses were reported as medians, means, and standard deviations (interval variables). Retinal findings on multimodal imaging were reported as numerical counts and percentages (ordinal variables). Prevalence was calculated as number of affected individuals divided by total number of screened individuals. Snellen visual acuity was converted to logarithm of the minimum angle of resolution (logMAR) for statistical analysis, and mean logMAR was converted back to mean Snellen visual acuity as reported in the Results. The right eye was chosen arbitrarily for the comparison of visual acuity. χ 2 tests were used for sex and tobacco use (nominal variables). Wilcoxon signed-rank test was performed to compare the means of age, height, weight, BMI, visual acuity, duration of PPS intake, daily PPS dose, and cumulative PPS dose (nonparametric interval variables). P <.05 was considered statistically significant.
It is important to note that 10 of the 16 affected cases and the first 50 of the 100 total screened patients in this study were originally described in a prior published paper.
Choroidal Vascularity Index Analysis
For choroidal imaging analysis, raw OCT B-scans were analyzed using a MATLAB-based CVI quantification tool developed based on previously described image-processing methods. In brief, luminal choroidal area (LCA) and stromal choroidal area (SCA) were obtained by binarizing the choroid layer in the OCT B-scan, where dark pixels correspond to the luminal region and bright pixels correspond to the stromal region. To this end, a 2-pronged approach was adopted: (i) automated detection of the choroid layer using structural similarity index and tensor voting and (ii) automated binarization of the choroid layer based on exponential and nonlinear enhancement and median thresholding using the Otsu Technique. Shadow compensation, the process of making up for shadows that may influence visualization of posterior structures on OCT, was performed using the previously reported method. Finally, CVI (%) was calculated as the ratio of LCA to the total choroidal area (TCA) in both study cohorts. Subfoveal choroidal thickness (SFCT) was measured from the inner choroid boundary to the outer choroid boundary using the instrument calipers tool at the foveal center.
Results
Demographics and Description of the Total Cohort
A total of 100 patients (200 eyes) that reported any previous history and/or current use of PPS irrespective of duration were screened for signs of retinal toxicity ( Table 1 ). Of the 100, 97 were included in the final analysis cohort, because 3 cases based on image findings were deemed indeterminate (refer below to “Demographics and Description of the Indeterminate Cohort”). Median age of the entire cohort was 60 years (range: 23-93 years) and 89 of 97 (92%) were female. A total of 78 (80%) patients were non-Hispanic white whereas 2 (2%) patients were biracial. Mean weight and height were 144.4±33.8 pounds and 64.7±3.1 inches respectively. Mean BMI was 24.2±5.0. The mean visual acuity of the entire cohort was 20/25.
| Total (n=97) | Unaffected (n=81) | Affected (N=16) | P value | |
|---|---|---|---|---|
| Age, mean ± SD (median) | 57.4±15.5 (60) | 56.5±16 (59) | 62±11.9 (64.5) | .19 |
| Sex, n (%) | 1.0 | |||
| Male | 8 (8.2) | 7 (8.6) | 1 (6.3) | |
| Female | 89 (91.8) | 74 (91.4) | 15 (93.7) | |
| Tobacco users, n (%) | 23 (23.7) | 20 (24.7) | 3 (18.8) | 1.0 |
| Height, in., mean ± SD (median) | 64.7±3.1 (64) | 65.8±8.7 (65) | 63.6±3.4 (63.3) | .32 |
| Weight, lb, mean ± SD (median) | 144.4±33.8 (140) | 145.9±33.5 (141) | 136.6±35.8 (131.5) | .31 |
| BMI, mean ± SD (median) | 24.2±5.0 (23.1) | 24.3±4.9 (23.6) | 23.6±5.4 (22.4) | .61 |
| Visual acuity, logMAR, mean ± SD (median Snellen equivalent) | 0.1±0.3 (20/20) | 0.05±0.2 (20/20) | 0.3±0.6 (20/27.4) | .0003 |
| Duration of PPS intake, y, mean ± SD (median) | 9.2±7.9 (7) | 7.1±6.6 (5) | 19.5±5.5 (18) | <.0001 |
| Daily PPS dose, mg, mean ± SD (median) | 315.0±179.0 (300) | 291.6±177.6 (300) | 433.9±137.6 (400) | .0032 |
| Cumulative PPS dose, g, mean ± SD (median, range) | 1,153.5±1,241.2 (703, 12.2-6,023) | 768.4±754.8 (493, 12.2-3,103) | 3,103.1±1,402.2 (2,737.5, 1,533-6,023) | <.0001 |
The overwhelming majority of patients (92/97, 95%) indicated that interstitial cystitis was the reason for using PPS. The other indications included irritable bowel syndrome, pelvic pain syndrome, inner bladder wall cracks, medical accident, and bladder pain, all of which were reported by nonaffected patients. No kidney or liver abnormalities were reported in any patients.
Mean total duration of PPS use was 9.2±7.9 years, mean daily dose of PPS was 315.0±179.0 mg, and mean cumulative dose of PPS was 1,153.5±1,241.2 g ( Table 1 ). The recommended dosage of PPS is 300 mg/d.
Demographics and Description of the Affected Cohort (Compared With the Nonaffected Cohort)
Of the 97 patients, PPS-associated maculopathy was definitively identified in 16 (32 eyes), yielding a prevalence of approximately 16% (16/97), whereas 81 patients (162 eyes) failed to display any evidence of PPS maculopathy. Median age of the affected cohort was 64.5 years (range: 41-76 years). Of the 16 affected, 15 (94%) were female and 15 (94%) identified as non-Hispanic white.
The most common visual complaint in the affected cohort was nyctalopia (n = 10, 63%) followed by blurry vision (n = 6, 38%). Other symptoms included complaints of distortion by 2 patients and dulling of colors by 1 patient. Two affected patients were asymptomatic. Median Snellen visual acuity was 20/27.5 OD (range: 20/20–hand motion) and 20/27.5 OS (range: 20/20–20/400) in the affected cohort. Median IOPs were 15 mm Hg OD (range: 11-19) and 14.5 mm Hg OS (range: 9-22).
With slit lamp examination, 6 patients presented with varying forms of bilateral cataracts whereas 1 patient was pseudophakic OD with a cataract OS. One patient was noted to have asteroid hyalosis. The remaining 8 patients exhibited normal bilateral anterior segment examinations. Within the cataract group, a nasal conjunctival hemorrhage OD was noted in one patient and Krukenberg spindles OU were noted in another. On fundus examination, 8 patients and 16 eyes (16/32, 50%) displayed only bilateral pigmentary maculopathy of varying degrees. One patient and 2 eyes (2/32, 6%) displayed only bilateral retinal pigment epithelial atrophy. Five patients (10/32 eyes, 31%) displayed a combination of bilateral retinal pigment epithelial atrophy and pigmentary maculopathy to varying degrees. Normal macular examination was noted in 2 affected patients (4/32 eyes, 13%). Heme or fluid was not identified in any affected eyes.
Affected and unaffected groups were compared ( Table 1 ). No statistically significant difference was found between the 2 groups in terms of age, sex, smoking history, height, weight, or BMI. However, the affected group exhibited a significantly longer duration of PPS use, higher daily dosage, and greater cumulative dose compared with the unaffected group. The mean duration of PPS intake was 19.5±5.5 years (median: 18 years, P < .0001) in the affected group vs 7.1±6.6 years (median: 5 years) in the unaffected group. The affected cohort reported a higher mean daily dose of 433.9±137.6 mg (median: 400 mg, P = .0032) vs 291.6±177.6 mg (median: 300 mg) in the normal group. The affected group also reported a greater mean cumulative dose of 3,103.1±1,402.2 g (median: 2,737.5 g, P < .0001) vs 768.4±754.8 g (median: 493 g) in the nonaffected group. Additionally, the affected cohort exhibited significantly worse visual acuity (mean Snellen visual acuity 20/43 vs 20/22, P value = .0003).
There was overlap in the ranges of cumulative dose between the affected and unaffected groups. The minimum cumulative dose at which PPS retinal toxicity was definitively found was 1,533 g. Of note, 12 patients (12/81, 15%) of the unaffected cohort reported higher cumulative doses: patient 3 (2,336 g), patient 6 (3,103 g), patient 15 (1,643 g), patient 46 (1,889 g), patient 50 (1,898 g), patient 52 (2,701 g), patient 65 (2,737.5 g), patient 71 (2,299.5 g), patient 76 (2,920 g), patient 85 (1,861.5 g), patient 86 (1,971 g), and patient 98 (1,837 g). The prevalence of toxicity in those with cumulative dosages greater than 1,000 and 1,500 g was 40% and 55%, respectively.
Multimodal Retinal Imaging Findings of the Affected Cohort
Since the initial studies that first described PPS maculopathy, wide-field FAF and SD-OCT have been proposed to be the optimal combination to detect the characteristic macular alterations stemming from long-term PPS exposure ( Figure 1 ). , , NIR and multicolor imaging can also effectively identify PPS maculopathy alterations especially in the mildest affected cases.
