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Pentosan-associated maculopathy: prevalence, screening guidelines, and spectrum of findings based on prospective multimodal analysis
ARTICLE IN PRESS
Pentosan-associated maculopathy: prevalence, screening guidelines, and spectrum of findings based on prospective multimodal analysis Derrick Wang, BA,* Adrian Au, MD,* Frederic Gunnemann, MD,* Assaf Hilely, MD,*,y Jackson Scharf, BS,* Khoi Tran, MD,* Michel Sun, MD, PhD,* Ja-Hong Kim, MD,z David Sarraf, MD*,x ABSTRACT 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.
Pentosan polysulfate sodium (PPS) is the only U.S. Food and Drug Administrationapproved oral medication for the management of the chronic bladder pain syndrome interstitial cystitis (IC).1,2 Recently, Pearce et al3 described a pigmentary maculopathy in patients who endorsed a prolonged history of PPS therapy. Features of this maculopathy included multifocal hypertrophic, vitelliform-like deposits at the level of the retinal pigment epithelium (RPE) with or without RPE atrophy in a parafoveal distribution.3,4 Given the recency of these findings, there is still much to be learned about this novel disorder. The true prevalence of PPS-associated maculopathy in the general population of patients taking pentosan is still unclear. There is also a lack of prospective analysis of patients using PPS with uniform multimodal retinal imaging including cross-sectional and en face spectral domain optical coherence tomography (SD-OCT), near-infrared reflectance (NIR), and fundus autofluorescence (FAF), which may be the most important modality for identification of this toxic condition. In this study, we describe the findings of a prospective analysis of PPS patients ascertained from a single large university database. The prevalence within
the study cohort, spectrum of phenotypic presentations, and the dose-related screening guidelines are presented.
TAGEDH1METHODSTAGEDEN This cross-sectional study received approval from the University of California, Los Angeles (UCLA), Institutional Review Board. It was conducted according to the tenets set forth by the Declaration of Helsinki. Information was gathered and secured in accordance with the Health Insurance Portability and Accountability Act. All data were de-identified and shared securely within the Stein Eye Institute. After Institutional Review Board approval was obtained, the UCLA electronic medical record was searched for all patients ever prescribed PPS between the months of March 2013 and October 2019. Key terms used in this large database search included “Elmiron 100 mg PO caps,” “Elmiron PO,” “pentosan polysulfate sodium 100 mg PO caps,” “pentosan polysulfate sodium PO,” and “pentosan polysulfate sodium POWD.” A total of 735 patients treated with PPS at UCLA were initially identified. The 735 patients were
Published by Elsevier Inc. on behalf of Canadian Ophthalmological Society. https://doi.org/10.1016/j.jcjo.2019.12.001 ISSN 0008-4182 CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
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ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. organized by date of first prescription. Of these 735, the first 440 patients were consecutively called by telephone to request participation in this study after verbal confirmation of current or previous use of PPS for any length of time. A total of 50 patients agreed to participate in the study. All patients were screened in the retina clinic of the senior author (D.S.). Upon arrival, patients were directed to fill out a questionnaire inquiring about ocular and medical history, smoking history, and medication history, including duration and daily dosage of PPS therapy and any changes in the regimen during the period of treatment. Visual symptoms, including details regarding the nature and timing of problems since starting PPS, were also queried. Patient demographic information, including date of birth, sex, identified race, height, and weight, was recorded. Body mass index (BMI) was calculated as weight in pounds divided by height in feet and inches for each patient screened. All 50 patients underwent complete eye examination and a standard multimodal retinal imaging protocol. Ocular examination included Snellen visual acuity testing, intraocular pressure measurement, and anterior segment and retinal evaluation including ophthalmoscopy of the posterior pole and periphery. Multimodal retinal imaging included color fundus photography of the posterior pole and periphery (Topcon 50DX; Topcon, Inc, Oakland, N,J & Optos California icg; Optos, Inc, Dunfermline, Scotland, UK), 30- and 50-degree FAF of the macula (Spectralis; Heidelberg Engineering, Inc, Heidelberg, Germany), ultra-widefield autofluorescence of the periphery (Optos California icg; Optos, Inc, Dunfermline, Scotland, UK), and multicolor and NIR (Spectralis; Heidelberg Engineering, Inc, Heidelberg, Germany). The wavelengths of autofluorescence were 488 nm (excitation filter) and 500 nm (barrier filter) for Spectralis and 532 nm (excitation filter) and 633 nm (barrier filter) for Optos. SD-OCT (Spectralis; Heidelberg Engineering, Inc, Heidelberg, Germany) of the macula was performed using a volume scan analysis of 25 scans (30° by 20° with B scans spaced 240 mm apart). OCT angiography (OCTA) and en face optical coherence tomography (OCT) (Solix & Avanti XR; Optovue, Inc, Fremont, CA) were also performed using the automated default segmentation protocol that included segmentation at the levels of the superficial and deep retinal capillary plexus and choriocapillaris. Co-localization of the FAF images with en face OCT scans was performed to determine structural associations of the autofluorescent patterns. Segmentation was aligned to the RPE for en face OCT co-localization analysis. The upper limit was set between the RPE and ellipsoid zone. The lower limit was set between the RPE and Bruch’s membrane. The thickness of the en face OCT slab was 20 mm. Areas of atrophy on OCT & FAF were defined according to previous publications.58 Defining criteria of complete RPE and outer retinal atrophy (CRORA) included a continuous band of hypertransmission of at least 250 mm in diameter in any lateral dimension, a continuous zone of attenuation or disruption of the RPE of at least 250 mm in diameter, and
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overlying photoreceptor degeneration.5,6 Atrophy on FAF was defined as a well-circumscribed round area of marked hypoautofluorescence of no specific minimal diameter.7,8 The severity of PPS-associated maculopathy was graded according to the presence or absence of atrophy with FAF and CRORA with OCT. Mild forms of PPS-associated maculopathy failed to show any evidence of frank atrophy with FAF, and hypoautofluorescent lesions on FAF failed to correspond to CRORA on OCT. Moderate forms of PPS-associated maculopathy illustrated well-demarcated areas of hypoautofluorescent RPE atrophy with FAF that co-localized with CRORA in the macula on OCT. Severe forms of PPSassociated maculopathy displayed more diffuse patterns of atrophy including CRORA in the posterior pole and hypoautofluorescent atrophy with FAF in the periphery. One patient underwent a Clinical Laboratory Improvement Amendmentscertified Invitae-Spark panel for commercial genetic testing. This panel evaluated 248 genes for variants associated with genetic disorders of inherited retinal dystrophies. A saliva sample was submitted for analysis. An expert grader (D.S.) evaluated every patient’s set of multimodal images to confirm presence or absence of retinal findings consistent with PPS-associated maculopathy based on prior publications.3,4 Statistical analyses were performed using R version 3.5.0 (www.r-project.org). Patient demographics, daily and cumulative dosages, BMI, and retinal findings on multimodal imaging were reported as medians, means, and standard deviations with interval variables or numerical counts and percentages with ordinal variables. Prevalence was calculated by the number of affected individuals over unaffected individuals. Snellen visual acuity was converted to logMAR for statistical analysis. Comparison of visual acuity was performed only on the right eye, which was chosen arbitrarily. The x2 test was performed for nominal variables (sex and tobacco use). The Wilcoxon signed-rank test was performed to compare the means of nonparametric interval variables (age, duration of PPS intake, daily PPS dose, cumulative PPS dose, BMI, weight, height, and visual acuity). p < 0.05 was considered statistically significant.
TAGEDH1RESULTSTAGEDEN Demographics and Description of the Total Cohort
A total of 50 patients (100 eyes) who reported previous or current use of PPS regardless of duration were consecutively screened for evidence of maculopathy (Table 1). Two affected patients (patients 21 and 22) were contacted and had already completed fundus photography, SD-OCT, and FAF with their retinal specialist, and therefore repeat imaging was not performed. Of the 50 patients, 46 (92%) were female and 43 (86%) self-reported as non-Hispanic Caucasian. Median age of this total cohort was 60 years (range 2393 years). Across the entire cohort, mean duration of PPS intake was 9.1 § 8.6 years, mean daily PPS dose was 330.4 § 214.3 mg, and cumulative PPS dose was 1228.4 § 1439.9 g
ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. Table 1—Demographics, dosage parameters, and visual acuity of total cohort, and unaffected and affected groups Age (average § STD, median) Sex
Male, n (%) Female, n (%)
Number of tobacco users (%) Average duration of PPS intake § STD in years (median) Mean daily PPS dose § STD in milligrams (median) Average cumulative PPS dose § STD in grams, (median) Average BMI § STD (median) Average weight § STD in pounds (median) Average height § STD in inches (median) Average visual acuity § STD in logMAR (median Snellen equivalent)
Total (N = 50)
Unaffected (N = 40)
Affected (N = 10)
57 § 17.3 (60) 4 (8.0) 46 (92.0) 13 (26.0) 9.1 § 8.6 (6.5) 330.4 § 214.3 (300) 1228.4 § 1439.9 (730.0) 23.6 § 5.2 (22.6) 140.0 § 34.1 (131.5) 64.4 § 3.0 (64) 0.2 § 0.4 (20/20)
55.5 § 17.8 (59) 3 (7.5) 37 (92.5) 11 (27.5) 6.3 § 6.6 (4.8) 301.8 § 222.9 (300) 691.7 § 706.6 (456.3) 24 § 5.5 (22.7) 143.0 § 35.1 (132.5) 64.7 § 2.6 (65) 0.1 § 0.3 (20/20)
63.2 § 14.7 (69.5) 1 (10.0) 9 (90.0) 2 (20.0) 20.3 § 6.6 (19.2) 444.8 § 128.5 (443.8) 3375.4 § 1650.0 (3066) 22.2 § 3.5 (22.4) 128.2 § 28.3 (124.5) 63.6 § 4.3 (62.5) 0.3 § 0.6 (20/20)
p 0.15 1.0 0.94 <0.001 <0.001 <0.001 0.57 0.24 0.19 0.29
STD, standard deviation; PPS, pentosan polysulfate sodium.
(Table 1). For reference, the recommended daily dosage of PPS is 300 mg.9 Mean BMI was 23.6 § 5.2, weight was 140.0 § 34.1 lbs, and height was 64.4 § 3.0 inches (Table 1). Average visual acuity at the time of screening was 0.2 § 0.3 (Snellen 20/31, Snellen median 20/20) across the entire cohort in both eyes. The majority of patients (48/50, 96%) reported IC as the indication for PPS therapy. The other 2 indications were irritable bowel syndrome (1/50, 2%) and pelvic pain syndrome (1/50, 2%) both in nonaffected patients. None of the patients reported any kidney or liver abnormalities. For detailed medical history for each of the 50 patients, please see Supplementary Table 1 (available online).
Demographics and Description of the Affected Cohort and Comparison with the Nonaffected Cohort
PPS-associated maculopathy was identified in 10 patients (20 eyes), whereas 40 patients (80 eyes) were noted to be normal with no evidence of pentosan maculopathy, resulting in a prevalence of 20% (i.e., 10/50) (Table 2). Of the 10 affected patients, 9 (90%) were female and 9 (90%) identified as
non-Hispanic Caucasian. Median age of the positive patients was 69.5 years (range 4176 years). Within the 10 affected patients with the characteristic maculopathy, a variety of associated visual complaints were reported. The most common symptom was nyctalopia or night blindness (n = 5, 50%) although mild cataract may be the etiology in 2 of these cases. One patient complained of distortion, 2 complained of blurry vision, and 2 were asymptomatic. In the affected patients, median Snellen visual acuity was 20/20 OD (range: 20/20hand motion) and 20/31 OS (range: 20/2020/60). The median intraocular pressures were 15 mm Hg OD (range 1116) and 15 mm Hg OS (range 918). On slit lamp examination, 6 patients were normal bilaterally, 3 had mild nuclear sclerotic cataracts, 1 showed asteroid hyalosis in the left eye, and 1 presented with bilateral Krukenberg’s spindles. On retinal examination, 6 patients demonstrated bilateral pigmentary maculopathy. Half of the eyes (10/20, 50%) showed evidence of bilateral RPE atrophy. No patients presented with heme or fluid in either eye. Comparison of the unaffected and affected patients was performed (Table 1). There was no statistically significant
Table 2—Body mass index (BMI), cumulative exposure, symptoms, Snellen visual acuity, anterior and posterior segment examination findings, and grading of disease severity of affected cases Patient No.
BMI
Cumulative Exposure (g)
Visual Symptoms
Visual Acuity
Intraocular Pressure (mm Hg)
Slit Lamp Exam
Fundus Exam
Severity Grading
47 18 10 43
25.4 23.1 24.3 22.1
1752 4745 2847 5402
None Distortion None Nyctalopia
20/20 OD 20/20 OS 20/40 OD 20/40 OS 20/20 OD 20/50 OS 20/25 OD 20/40 OS
16 OD 15 OS 12 OD 10 OS 11 OD 9 OS 13 OD 12 OS
Normal Normal Normal Normal
Mild Mild Mild Mild
34
19.2
1825
Nyctalopia
20/40 OD 20/30 OS
16 OD 18 OS
39
15.9
3285
Nyctalopia
20/20 OD 20/20 OS
15 OD 18 OS
Focal atrophy
Moderate
29
19.8
4334
Nyctalopia
20/20 OD 20/25 OS
15 OD 16 OS
20.9
1533
Blurry vision
20/20 OD 20/20 OS
15 OD 14 OS
44
28.5
2007.5
Blurry vision
20/30 OD 20/50 OS
16 OD 15 OS
21
22.65
6023
Nyctalopia
HM OD 20/60 OS
15 OD 16 OS
Normal
Parafoveal pigmentation, drusen Peripapillary atrophy, focal atrophy patches, macular granularity Parafoveal and peripapillary pigmentation, peripheral atrophy around arcades Extensive diffuse atrophy & reticular degeneration of the pigment epithelium
Moderate
22
Nuclear sclerotic 2 (OD) & nuclear sclerotic 1 (OS) cataracts Nuclear sclerotic 1 cataracts Dense asteroid hyalosis OS Nuclear sclerotic 1 cataracts, Krukenberg's spindles OU Normal
Normal Normal Parafoveal pigmentation Parafoveal and peripapillary pigmentation Parafoveal pigmentation, focal atrophy
Mild
Moderate
Severe
Severe
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ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. difference between groups in regard to age, sex, tobacco use, BMI, weight, height, or visual acuity (Table 1). However, when comparing duration of exposure, mean daily dose, and cumulative dose, the affected group was notable for significantly longer exposures and higher dosing. Specifically, the mean duration of PPS intake was 6.3 § 6.6 years (median: 4.8 years) in the unaffected group versus 20.3 § 6.6 years (median: 19.2 years, p < 0.001) in the affected group. The PPS-maculopathy group also exhibited a greater mean daily dose of 444.8 § 128.5 mg (median: 443.8 mg) versus 301.8 § 222.9 mg (median: 300 mg, p < 0.001) in the nonaffected group. The mean cumulative dose in the affected patient group was significantly greater at 3375.4 § 1650.0 g (median: 3066.0 g) versus 691.7 § 706.6 g (median: 456.3 g, p < 0.001) in the nonaffected group. Comparing ranges of cumulative dose between the affected and unaffected groups revealed overlap. The minimum cumulative dose at which PPS-associated maculopathy was identified was 1533 g. In the unaffected cohort, 5 patients (5/40, 12.5%) presented with greater cumulative doses: patient 3 (2336 g), patient 6 (3103 g), patient 15 (1643 g), patient 46 (1889 g), and patient 50 (1898 g).
Multimodal Retinal Imaging Findings of the Affected Cohort
In the eyes of the affected patients, wide-field FAF combined with SD-OCT best illustrated the PPS-induced macular findings (Figs. 1 and 2), although NIR and multicolor imaging were very effective in detecting the characteristic punctate and round hyper-reflective RPE lesions especially in milder forms of disease (Fig. 3). The total area and severity of irregular autofluorescence varied widely among the 10 patients. In 14 eyes out of 20 (70%), FAF showed a well-demarcated region of speckled autofluorescence with alternating hypo- and hyperautofluorescence, centred in the posterior pole and extending peripapillary (Fig. 1). Hyperautofluorescent vitelliform-like parafoveal lesions were seen in both eyes of 1 patient (patient 18) with a mild phenotype, whereas a very subtle stippled parafoveal hyperautofluorescence was noted in both eyes of the mildest case (patient 47). However, the multicolor and NIR findings for this case (patient 47) were more convincing (Fig. 3). In the most severe phenotype, bilateral diffuse areas of geographic atrophy throughout the posterior pole and periphery were noted (Fig. 1).
Fig. 1—Fundus autofluorescence images (A–T) and spectral domain optical coherence tomography (SD-OCT) B scans through the fovea (U, V, W, X, Y, Z, AA, BB, CC, DD, EE, FF, GG, HH, II, JJ, KK, LL, MM, NN) of the 10 affected patients. Note the spectrum of findings as illustrated with fundus autofluorescence (FAF). In the mildest presentation (A and B, patient 47), fundus autofluorescence shows only very subtle hyperautofluorescent stippling of the retinal pigment epithelium (RPE), but these alterations are more prominent with multicolor and near-infrared imaging (Fig. 3). A small corresponding hyper-reflective RPE lesion is noted with the SD-OCT B scan in the left eye. In patient 18 (C and D), scattered hyperautofluorescent and hyper-reflective vitelliform-like lesions are illustrated. With more significant toxicity, a speckled pattern of hypo- and hyperautofluorescent and hyper-reflective RPE lesions involving only the macula is shown (E and F, patient 10). With further progression, alterations are noted to extend around and nasal to the disc (G and H, I and J, patients 43 and 34, respectively). Well-demarcated areas of nummular or geographic hypoautofluorescent RPE atrophy are noted with more advanced toxicity (K–T, patients 39, 29, 22, 44, and 21). Corresponding OCT B scans illustrate patchy complete RPE and outer retinal atrophy. In the most severe case S and I (bottom row, patient 21), diffuse chorioretinal atrophy involving the posterior pole and periphery is noted. Corresponding SD-OCT imaging (MM and NN) illustrates diffuse RPE and outer retinal atrophy that corresponds with the nummular or geographic areas of well-demarcated hypoautofluorescent atrophy. Note the halo of peripapillary hypoautofluorescence in all 20 affected eyes.
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Fig. 2—Fundus color photography, fundus autofluorescence (FAF), en face optical coherence tomography (OCT), and corresponding spectral domain optical coherence tomography (SD-OCT) B scans of 5 presentations of pentosan polysulfate sodium (PPS)–associated maculopathy of varying severity. Patient 18 (A–D) represents a mild form of pentosan maculopathy with no signs of atrophy. The round orange lesions with multicolor reflectance match the hyperautofluorescent lesions on FAF, which correspond to the hyper-reflective lesions with en face OCT and focal retinal pigment epithelium (RPE) thickening with SD-OCT (red asterisk). No signs of atrophy are noted. The images for patients 10 (E–H) and 43 (I–L) illustrate a mild case with larger areas of involvement. The color photographs display pigment deposits that are more prominent and co-localize with hyperautofluorescent lesions with FAF. The hyperautofluorescent lesions correspond to hyper-reflective lesions with en face OCT and focal RPE thickening (red asterisk) with the cross-sectional OCT B scan. Note that the hypoautofluorescent FAF areas in this case fail to display evidence of atrophy with the matched OCT scans. The images for patients 39 (M–P) and 44 (Q–T) illustrate cases of moderate and severe severity, respectively. Atrophic lesions are well-demarcated with multicolor with baring of the choroidal vessels. A well-circumscribed round area of hypoautofluorescent atrophy is noted with FAF. This region co-localizes with a well-demarcated hyper-reflective lesion with en face OCT. SD-OCT illustrates a corresponding area of complete retinal pigment epithelial and outer retinal atrophy (CRORA) (red asterisk). Patient 44 displays similar atrophic lesions in the macula with FAF and OCT but also exhibits these atrophic lesions in the periphery (see Fig. 1Q and R).
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ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. hyperautofluorescent lesions on FAF and to the focal areas of hyper-reflective RPE thickening on SD-OCT. OCTA illustrated normal vascular perfusion at all segmentation levels except for decreased choriocapillaris perfusion corresponding to CRORA lesions in the moderate and severe patients. None of the affected patients presented with choroidal neovascularization. Spectralis NIR and multicolor photography (Fig. 3) illustrated characteristic round or punctate, orange hyper-reflective lesions that corresponded to focal RPE thickening with SD-OCT and focal hyperautofluorescence with FAF. These findings were especially helpful in detecting very mild cases as with patient 47 (Fig. 3A, E) for whom the FAF findings were not conclusive. Atrophy appeared as well-demarcated areas of increased transparency of the underlying choroid. Grading Severity in the Affected Cohort
Fig. 2 Continued.
The bilateral speckled pattern of hyper- and hypoautofluorescence extended past the macula to the disc in 12 out of 14 eyes (86%). Of these 12 eyes, the speckled pattern extended nasal to the disc in 4 (33%). In more advanced cases, atrophy was noted (12 eyes) as well circumscribed hypoautofluorescent perifoveal lesions that varied from multifocal lesions less than one-disc diameter in size (8 eyes, 67%) to larger areas of atrophy or diffuse atrophy, in severe cases, throughout the entire posterior segment (4 eyes, 33%) and into the periphery (Fig. 1). Additionally, all 20 eyes (100%) demonstrated peripapillary halos of hypoautofluorescence of varying diameter on FAF. Cross-sectional and en face SD-OCT illustrated focal areas of RPE thickening that co-localized with the hyperautofluorescent lesions on FAF (Fig. 2). The hypoautofluorescent lesions associated with the speckled pattern on FAF did not display any RPE or outer retinal abnormalities with corresponding OCT (Fig. 2). However, the well-demarcated hypoautofluorescent round lesions co-localized with CRORA5,6 on the cross-sectional and en face OCT (Fig. 2). Additional imaging modalities were used to characterize pathologic findings. On color fundus photography, abnormal pigmentary clumps were noted corresponding to the
The patients were graded based on the presence or absence of atrophy with FAF and OCT. Patients 10, 18, 34, 43, and 47 did not show evidence of well-demarcated areas of atrophy with FAF or CRORA with cross-sectional and en face OCT and were labeled as mild. Patients 22, 29, and 39 illustrated discrete lesions of atrophy with FAF and CRORA with OCT in the macula and were labeled as moderate. Patients 21 and 44 displayed diffuse atrophy with FAF throughout the posterior pole and periphery and were labeled as severe. Of note, all 10 patients exhibited symmetry regarding the severity grade between the 2 eyes (Fig. 1). Table 3 compares the duration, mean daily dose, and cumulative dose of PPS in the affected patients by severity grading. The sample sizes were too small to perform statistical comparisons; however, an overall trend was noted with increased duration of exposure, increased daily dose, and increased cumulative dose in patients with more severe disease. Specifically, the median duration of PPS intake was 16.0, 20.0, and 22.9 years in the mild, moderate, and severe groups, respectively. Similarly, median daily PPS dose was 300 mg versus 400 mg versus 555.2 mg in the mild, moderate, and severe groups, respectively. Median cumulative dosages were 2847.0, 3285.0, and 4015.3 g in the mild, moderate, and severe groups, respectively. However, it should be noted that some patients with high cumulative doses presented with a mild or moderate phenotype. Genetic Testing
Genetic testing performed in patient 21 yielded a heterozygous pathologic variant identified in the nephronophthisis 1 (NPHP1) allele. Additional variants of uncertain significance were identified in the CDH23, PCDH15, and SLC7A14
Table 3—Comparison of dosage parameters between patients with varying severity of disease Duration of PPS intake, median (range), y Mean daily PPS dose, median (range), mg Cumulative PPS dose, median (range), g
Mild (N = 5)
Moderate (N = 3)
Severe (N = 2)
16.0 (12.529.0) 300 (306.4600.0) 2847.0 (1752.05402.0)
20.0 (12.030.0) 400.0 (300.0593.8) 3285.0 (1533.04334.0)
22.9 (18.327.5) 555.2 (300.0600.0) 4015.3 (2007.56023.0)
PPS, pentosan polysulfate sodium.
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Fig. 3—Spectralis multicolor (A–D) and near-infrared reflectance (NIR) (E–H) photography in 4 mild cases of pentosan maculopathy. Patient 47 illustrates very subtle alterations with discrete punctate parafoveal hyper-reflective lesions in both eyes best appreciated with NIR. As severity worsens, the hyper-reflective spots on multicolor and NIR, which correspond with RPE thickening on SD-OCT, become more prominent in patients 18 (B and F), 10 (C and G), and 43 (D and H).
genes and were thought to be irrelevant to the patient’s notable retinal findings.
TAGEDH1DISCUSSIONTAGEDEN In this study, FAF proved to be an essential modality to identify and diagnose PPS-associated alterations that were consistent with the original features previously reported.3,4 A wellcircumscribed region of speckled hyper- and hypoautofluorescence was centred around the macula, often with extension
around the optic disc and even into the periphery. A peripapillary halo of hypoautofluorescence was noted in all affected eyes. The hyperautofluorescent lesions corresponded with focal areas of hyperpigmentation on color fundus photography and focal areas of hyper-reflective RPE thickening with cross-sectional and en face OCT. Of note, the associated hypoautofluorescent lesions did not co-localize with any notable abnormality with cross-sectional or en face OCT. More severe phenotypes, however, exhibited well-circumscribed parafoveal lesions of atrophy that displayed well-demarcated areas of CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
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ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. hypoautofluorescence with FAF and corresponding CRORA with cross-sectional and en face OCT. OCTA displayed normal perfusion within the retinal capillary system but reduced choriocapillaris flow corresponding to the CRORA lesions. There were no signs of choroidal neovascularization in any affected patients, although choroidal neovascularization was recently reported to complicate PPS-associated maculopathy.10 In the milder cases, NIR and multicolor imaging also proved valuable and displayed characteristic punctate or round parafoveal RPE lesions that were orange with multicolor and hyper-reflective with NIR (Fig. 3). This was especially helpful in illustrating findings in patient 47, the mildest case of our affected cohort. Although it may be argued that the findings in this case were not significant enough to conclude toxicity, we included this case in the affected cohort as the features were suggestive of a very early form of PPS-associated maculopathy that may be important to illustrate in this paper as more information is published and more is learned about this toxic disease. The findings noted with patient 18 further widened the spectrum of phenotypic disease. In this mild case, only a few vitelliform deposits were noted in a parafoveal and peripapillary distribution that could not be attributed to other causes of acquired vitelliform lesions such as reticular pseudo drusen or pachychoroid disease.1115 This patient was noted to have a very high cumulative PPS dosage (4745 g) and suggests that inherent anatomical and genetic considerations may have prevented a much more severe toxic presentation. At the other end of the spectrum, a diffuse, severely atrophic, chorioretinopathy, involving the posterior pole and periphery and resembling a choroidal dystrophy, such as choroideremia or lateonset retinal dystrophy (LORD syndrome), was noted (patient 21). Comprehensive genetic testing was unremarkable for any evidence of a choroidal dystrophy. Moreover, this patient was noted to have the highest cumulative dosage of PPS (6023 g) ever reported,3,4 which may explain the severe novel phenotype. Patient 21 was found to have a heterozygous mutation in NPHP1, a gene that encodes nephrocystin-1, a protein located at the base of the connecting cilium axoneme and suggested to be involved in actin- and microtubule-based sorting and transport,16 including transport between the inner and outer segments of photoreceptors.17 All known NPHP1 disorders (e.g., Senior Lokin syndrome and Joubert Syndrome) are autosomal recessive owing to homozygous mutations in NPHP1, and all documented cases have exhibited renal involvement with variable extrarenal manifestations.18 NPHP1 is unlikely to be causative in our patient who exhibited a heterozygous mutation and who lacked kidney and cerebellar involvement. Given the extremely high PPS dosage, it is possible that the retinal findings may be solely attributable to PPS toxicity. Alternatively, the heterozygous mutation may have established a genetic predisposition that alone would not cause disease, but in combination with a significant toxic drug exposure it could trigger severe retinal degeneration without affecting renal function. Genetic
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predisposition to a severe phenotype of hydroxychloroquine retinopathy has been previously reported.19 PPS inhibits growth factor signalling pathways, primarily fibroblast growth factor, platelet-derived growth factor, and epidermal growth factor, especially within RPE cells.20,21 Disruption of these pathways may injure the RPE and block the promotion of health maintenance and regeneration of the outer retina, which may be the mechanism by which PPS causes retinal toxicity.21 Pathways of RPE degeneration studied in age-related macular degeneration (AMD)2224 may parallel the spectrum of findings identified in this study of PPS-associated maculopathy. Disrupted photoreceptor turnover through a dysfunctional RPE, in a milder form of toxicity, leads to acquired vitelliform lesions (patient 18).1315 With more advanced disease, morphological alterations in the RPE develop, including focal RPE thickening (patients 10, 34, 43) and ultimately RPE atrophy (patients 22, 29, 39, 44), which may progress to involve the entire macula and even the periphery with more severe toxic exposures causing more profound loss of the RPE and inner choroid (patient 21). The reports of Pearce et al.3 and Hanif et al.4 are groundbreaking landmark studies that first identified an association of PPS treatment with a distinctive maculopathy that appears to be a very real association with important ramifications. This disorder can very easily masquerade as AMD or forms of macular dystrophy such as mitochondrial syndromes, and therefore chronic toxicity with progressive vision loss can be easily missed. It is important to note, however, that both of these studies were retrospective and analyzed patients who were symptomatic and who were ascertained because of other ophthalmological considerations indicating selection bias. Moreover, the authors relied on retinal imaging that was incomplete or unavailable and performed by other ophthalmologists not part of their study. In our cross-sectional study, patients were randomly ascertained and prospectively screened. Color fundus photography, SD-OCT, and FAF were performed in every patient. Detailed dosage exposure was also recorded. The prevalence of toxicity within this study cohort was noted to be 20%, which is remarkable. Further, not every patient with PPSassociated maculopathy presented with visual symptoms, indicating the importance of routine screening. Dosagerelated considerations are additionally important. No patients with cumulative dosages less than 1500 g were identified with toxicity in our study, whereas 31 out of 32 patients with PPS-associated maculopathy in prior studies3,4 presented with cumulative exposures greater than 500 g. Although not definitive, a dosage-related correlation was suggested in our study when considering the severity of the toxic retinopathy. Based on these findings, we would recommend that all patients starting PPS therapy should be referred to an ophthalmologist for baseline SD-OCT, NIR, and FAF testing. FAF and NIR are especially important and represent the gold-standard modalities to detect PPS-associated maculopathy. Annual SD-OCT, NIR, and FAF should be repeated especially as cumulative dosages approach or exceed 500 g.
ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. PPS prescribing doctors should be aware of the high risk of retinal toxicity and maculopathy as the cumulative dosages approach 1000 g or greater, especially 1500 g. Factors that may increase the risk of toxicity, such as AMD or genetic retinal dystrophies, should be weighed against the systemic benefit of the drug. Although average BMI was lower in the affected group, our study was not powered to detect a significant difference. With larger studies, more reliable conclusions may be made regarding dosage considerations as relates to the height and weight of the patient. The symptoms of IC can be especially burdensome, and discontinuation of PPS due to the risk of progressive vision loss must be weighed against the benefits of symptom relief, especially when alternative treatments have already been exhausted. Ophthalmologists should manage PPS-associated maculopathy on a case-by-case basis and approach the subject of PPS discontinuation with caution as patients may become distressed and distraught by the recommendation to discontinue PPS therapy. Open communication with the patient and his or her urologist prescribing the drug is essential. The 20% prevalence of PPS-associated maculopathy in this study captured from a sample size of 50 screened patients does not necessarily represent the true prevalence in the population at large. Although patients were randomly ascertained from a large university database, it is possible that those patients who agreed to be screened were more likely to exhibit toxicity. Therefore, we may have overestimated the true prevalence in the PPS population. Additional limitations included the lack of Early Treatment Diabetic Retinopathy Study visual acuity testing and the lack of genetic testing in all affected patients with PPS-associated maculopathy. The relevance of genetic testing in this patient population is undetermined but may provide guidance on a case-by-case basis. However, the phenotype of PPS-associated maculopathy appears to be distinctive, consistent, and readily identifiable although this study has broadened the spectrum of findings. PPS-treated patients may prove to be a unique population to study the interplay of genetic susceptibility and drug exposure.
TAGEDH1CONCLUSIONSTAGEDEN Our findings corroborate recent reports that prolonged consumption of PPS can lead to vision-altering changes in the macula with relatively unique findings with multimodal retinal imaging. FAF and NIR are important modalities for the detection and diagnosis of PPS-associated maculopathy. NIR displayed distinctive punctate or round hyper-reflective parafoveal lesions in milder forms of disease, whereas FAF illustrated a characteristic centrifugal speckled hypo- and hyperautofluorescence corresponding to RPE thickening with and without parafoveal nummular atrophy. A more widespread pattern of autofluorescent alterations or even a severe pattern of diffuse chorioretinal atrophy were appreciated with more significant toxic exposures. Our study randomly ascertained treated patients to determine the possible prevalence of associated maculopathy in the general
population with a history of PPS therapy. Patients on the medication may be at significant risk of macular toxicity, especially with dosages over 1500 g, and may need to discuss alternative therapies with their physicians with cumulative dosages greater than 1000 or 1500 g. We recommend an initial baseline eye examination to include multimodal retinal imaging including SD-OCT, NIR, and FAF with annual retinal imaging thereafter especially with cumulative dosages approaching or exceeding 500 g.
TAGEDH1SUPPLEMENTARY MATERIALSTAGEDEN Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jcjo.2019.12.001. TAGEDH1REFERENCESTAGEDEN 1. Giusto LL, Zahner PM, Shoskes DA. An evaluation of the pharmacotherapy for interstitial cystitis. Expert Opin Pharmacother. 2018;19: 1097–108. 2. Hanno PM, Erickson D, Moldwin R, Faraday MM, Association AU. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193:1545–53. 3. Pearce WA, Chen R, Jain N. Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium. Ophthalmology. 2018;125:1793–802. 4. Hanif A.M., Armenti S.T., Taylor S.C., et al. Phenotypic spectrum of pentosan polysulfate sodium-associated maculopathy: a multicenter study [E-pub ahead of print]. JAMA Ophthalmol. doi: 10.1001/ jamaophthalmol.2019.3392, Accessed 9/21/19. 5. Sadda SR, Guymer R, Holz FG, et al. Consensus definition for atrophy associated with age-related macular degeneration on OCT: classification of Atrophy Report 3. Ophthalmology. 2018;125:537–48. 6. Guymer R.H., Rosenfeld P.J., Curcio C.A., et al. Incomplete retinal pigment epithelial and outer retinal atrophy in age-related macular degeneration: classification of Atrophy Meeting Report 4 [E-pub ahead of print]. Ophthalmology. doi: 10.1016/j.ophtha.2019.09.035, Accessed 11/3/19. 7. Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125:369–90. 8. Holz FG, Bellman C, Staudt S, Sch€ utt F, V€olcker HE. Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2001;42:1051–6. 9. Nickel JC, Herschorn S, Whitmore KE, et al. Pentosan polysulfate sodium for treatment of interstitial cystitis/bladder pain syndrome: insights from a randomized, double-blind, placebo controlled study. J Urol. 2015;193:857–62. 10. Mishra K., Patel T.P., Singh M.S. Choroidal neovascularization associated with pentosan polysulfate toxicity [Epub ahead of print]. Ophthalmol Retina. doi: 10.1016/j.oret.2019.08.006, Accessed 10/30/19. 11. Dansingani KK, Balaratnasingam C, Klufas MA, Sarraf D, Freund KB. Optical coherence tomography angiography of shallow irregular pigment epithelial detachments in pachychoroid spectrum disease. Am J Ophthalmol. 2015;160:1243–54. e1242. 12. Rabiolo A, Sacconi R, Cicinelli MV, Querques L, Bandello F, Querques G. Spotlight on reticular pseudodrusen. Clin Ophthalmol. 2017;11:1707–18. 13. Freund KB, Laud K, Lima LH, Spaide RF, Zweifel S, Yannuzzi LA. Acquired vitelliform lesions: correlation of clinical findings and multiple imaging analyses. Retina. 2011;31:13–25. 14. Spaide RF. Deposition of yellow submacular material in central serous chorioretinopathy resembling adult-onset foveomacular vitelliform dystrophy. Retina. 2004;24:301–4. 15. Spaide R. Autofluorescence from the outer retina and subretinal space: hypothesis and review. Retina. 2008;28:5–35. 16. Mollet G, Silbermann F, Delous M, Salomon R, Antignac C, Saunier S. Characterization of the nephrocystin/nephrocystin-4 complex and subcellular localization of nephrocystin-4 to primary cilia and centrosomes. Hum Mol Genet. 2005;14:645–56. CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
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ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. 17. Jiang ST, Chiou YY, Wang E, et al. Essential role of nephrocystin in photoreceptor intraflagellar transport in mouse. Hum Mol Genet. 2009;18:1566–77. 18. Hoff S, Halbritter J, Epting D, et al. ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet. 2013;45:951–6. 19. Katsman D, Sanfilippo C, Sarraf D. Panretinal degeneration associated with long-term hydroxychloroquine use and heterozygous Ush2a mutation. Retin Cases Brief Rep. 2017;11(Suppl 1):S77–80. 20. Leschey KH, Hines J, Singer JH, Hackett SF, Campochiaro PA. Inhibition of growth factor effects in retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1991;32:1770–8. 21. Greenlee T, Hom G, Conti T, Babiuch AS, Singh R. Re: Pearce et al. pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium (Ophthalmology. 2018;125:1793802) Ophthalmology. 2019;126:e51. 22. Curcio CA. Soft drusen in age-related macular degeneration: biology and targeting via the oil spill strategies. Invest Ophthalmol Vis Sci. 2018;59:AMD160–81. 23. Balaratnasingam C, Messinger JD, Sloan KR, Yannuzzi LA, Freund KB, Curcio CA. Histologic and optical coherence tomographic correlates in drusenoid pigment epithelium detachment in age-related macular degeneration. Ophthalmology. 2017;124:644–56. 24. Balaratnasingam C, Yannuzzi LA, Curcio CA, et al. Associations between retinal pigment epithelium and drusen volume changes during the lifecycle of large drusenoid pigment epithelial detachments. Invest Ophthalmol Vis Sci. 2016;57:5479–89.
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Footnotes and Disclosure: Acknowledgements: This work was supported by the Research To Prevent Blindness, Inc (D.S.), and the Macula Foundation, Inc (D.S.). Dr. David Sarraf: Amgen (consultant), Bayer (consultant), Genentech (consultant, research), Heidelberg (research), Novartis (speaker), Optovue (consultant, research), Regeneron (research), and Topcon (research). From the *Retinal Disorders and Ophthalmic Genetics, Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA; y Division of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; zDepartment of Urology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA; xGreater Los Angeles VA Healthcare Center, Los Angeles, CA. Originally received Nov. 25, 2019. Final revision Dec. 10, 2019. Accepted Dec. 11, 2019. Correspondence to David Sarraf, MD, Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095. [email protected]
Pentosan-associated maculopathy: prevalence, screening guidelines, and spectrum of findings based on prospective multimodal analysis Derrick Wang, BA,* Adrian Au, MD,* Frederic Gunnemann, MD,* Assaf Hilely, MD,*,y Jackson Scharf, BS,* Khoi Tran, MD,* Michel Sun, MD, PhD,* Ja-Hong Kim, MD,z David Sarraf, MD*,x ABSTRACT 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.
Pentosan polysulfate sodium (PPS) is the only U.S. Food and Drug Administrationapproved oral medication for the management of the chronic bladder pain syndrome interstitial cystitis (IC).1,2 Recently, Pearce et al3 described a pigmentary maculopathy in patients who endorsed a prolonged history of PPS therapy. Features of this maculopathy included multifocal hypertrophic, vitelliform-like deposits at the level of the retinal pigment epithelium (RPE) with or without RPE atrophy in a parafoveal distribution.3,4 Given the recency of these findings, there is still much to be learned about this novel disorder. The true prevalence of PPS-associated maculopathy in the general population of patients taking pentosan is still unclear. There is also a lack of prospective analysis of patients using PPS with uniform multimodal retinal imaging including cross-sectional and en face spectral domain optical coherence tomography (SD-OCT), near-infrared reflectance (NIR), and fundus autofluorescence (FAF), which may be the most important modality for identification of this toxic condition. In this study, we describe the findings of a prospective analysis of PPS patients ascertained from a single large university database. The prevalence within
the study cohort, spectrum of phenotypic presentations, and the dose-related screening guidelines are presented.
TAGEDH1METHODSTAGEDEN This cross-sectional study received approval from the University of California, Los Angeles (UCLA), Institutional Review Board. It was conducted according to the tenets set forth by the Declaration of Helsinki. Information was gathered and secured in accordance with the Health Insurance Portability and Accountability Act. All data were de-identified and shared securely within the Stein Eye Institute. After Institutional Review Board approval was obtained, the UCLA electronic medical record was searched for all patients ever prescribed PPS between the months of March 2013 and October 2019. Key terms used in this large database search included “Elmiron 100 mg PO caps,” “Elmiron PO,” “pentosan polysulfate sodium 100 mg PO caps,” “pentosan polysulfate sodium PO,” and “pentosan polysulfate sodium POWD.” A total of 735 patients treated with PPS at UCLA were initially identified. The 735 patients were
Published by Elsevier Inc. on behalf of Canadian Ophthalmological Society. https://doi.org/10.1016/j.jcjo.2019.12.001 ISSN 0008-4182 CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
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ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. organized by date of first prescription. Of these 735, the first 440 patients were consecutively called by telephone to request participation in this study after verbal confirmation of current or previous use of PPS for any length of time. A total of 50 patients agreed to participate in the study. All patients were screened in the retina clinic of the senior author (D.S.). Upon arrival, patients were directed to fill out a questionnaire inquiring about ocular and medical history, smoking history, and medication history, including duration and daily dosage of PPS therapy and any changes in the regimen during the period of treatment. Visual symptoms, including details regarding the nature and timing of problems since starting PPS, were also queried. Patient demographic information, including date of birth, sex, identified race, height, and weight, was recorded. Body mass index (BMI) was calculated as weight in pounds divided by height in feet and inches for each patient screened. All 50 patients underwent complete eye examination and a standard multimodal retinal imaging protocol. Ocular examination included Snellen visual acuity testing, intraocular pressure measurement, and anterior segment and retinal evaluation including ophthalmoscopy of the posterior pole and periphery. Multimodal retinal imaging included color fundus photography of the posterior pole and periphery (Topcon 50DX; Topcon, Inc, Oakland, N,J & Optos California icg; Optos, Inc, Dunfermline, Scotland, UK), 30- and 50-degree FAF of the macula (Spectralis; Heidelberg Engineering, Inc, Heidelberg, Germany), ultra-widefield autofluorescence of the periphery (Optos California icg; Optos, Inc, Dunfermline, Scotland, UK), and multicolor and NIR (Spectralis; Heidelberg Engineering, Inc, Heidelberg, Germany). The wavelengths of autofluorescence were 488 nm (excitation filter) and 500 nm (barrier filter) for Spectralis and 532 nm (excitation filter) and 633 nm (barrier filter) for Optos. SD-OCT (Spectralis; Heidelberg Engineering, Inc, Heidelberg, Germany) of the macula was performed using a volume scan analysis of 25 scans (30° by 20° with B scans spaced 240 mm apart). OCT angiography (OCTA) and en face optical coherence tomography (OCT) (Solix & Avanti XR; Optovue, Inc, Fremont, CA) were also performed using the automated default segmentation protocol that included segmentation at the levels of the superficial and deep retinal capillary plexus and choriocapillaris. Co-localization of the FAF images with en face OCT scans was performed to determine structural associations of the autofluorescent patterns. Segmentation was aligned to the RPE for en face OCT co-localization analysis. The upper limit was set between the RPE and ellipsoid zone. The lower limit was set between the RPE and Bruch’s membrane. The thickness of the en face OCT slab was 20 mm. Areas of atrophy on OCT & FAF were defined according to previous publications.58 Defining criteria of complete RPE and outer retinal atrophy (CRORA) included a continuous band of hypertransmission of at least 250 mm in diameter in any lateral dimension, a continuous zone of attenuation or disruption of the RPE of at least 250 mm in diameter, and
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overlying photoreceptor degeneration.5,6 Atrophy on FAF was defined as a well-circumscribed round area of marked hypoautofluorescence of no specific minimal diameter.7,8 The severity of PPS-associated maculopathy was graded according to the presence or absence of atrophy with FAF and CRORA with OCT. Mild forms of PPS-associated maculopathy failed to show any evidence of frank atrophy with FAF, and hypoautofluorescent lesions on FAF failed to correspond to CRORA on OCT. Moderate forms of PPS-associated maculopathy illustrated well-demarcated areas of hypoautofluorescent RPE atrophy with FAF that co-localized with CRORA in the macula on OCT. Severe forms of PPSassociated maculopathy displayed more diffuse patterns of atrophy including CRORA in the posterior pole and hypoautofluorescent atrophy with FAF in the periphery. One patient underwent a Clinical Laboratory Improvement Amendmentscertified Invitae-Spark panel for commercial genetic testing. This panel evaluated 248 genes for variants associated with genetic disorders of inherited retinal dystrophies. A saliva sample was submitted for analysis. An expert grader (D.S.) evaluated every patient’s set of multimodal images to confirm presence or absence of retinal findings consistent with PPS-associated maculopathy based on prior publications.3,4 Statistical analyses were performed using R version 3.5.0 (www.r-project.org). Patient demographics, daily and cumulative dosages, BMI, and retinal findings on multimodal imaging were reported as medians, means, and standard deviations with interval variables or numerical counts and percentages with ordinal variables. Prevalence was calculated by the number of affected individuals over unaffected individuals. Snellen visual acuity was converted to logMAR for statistical analysis. Comparison of visual acuity was performed only on the right eye, which was chosen arbitrarily. The x2 test was performed for nominal variables (sex and tobacco use). The Wilcoxon signed-rank test was performed to compare the means of nonparametric interval variables (age, duration of PPS intake, daily PPS dose, cumulative PPS dose, BMI, weight, height, and visual acuity). p < 0.05 was considered statistically significant.
TAGEDH1RESULTSTAGEDEN Demographics and Description of the Total Cohort
A total of 50 patients (100 eyes) who reported previous or current use of PPS regardless of duration were consecutively screened for evidence of maculopathy (Table 1). Two affected patients (patients 21 and 22) were contacted and had already completed fundus photography, SD-OCT, and FAF with their retinal specialist, and therefore repeat imaging was not performed. Of the 50 patients, 46 (92%) were female and 43 (86%) self-reported as non-Hispanic Caucasian. Median age of this total cohort was 60 years (range 2393 years). Across the entire cohort, mean duration of PPS intake was 9.1 § 8.6 years, mean daily PPS dose was 330.4 § 214.3 mg, and cumulative PPS dose was 1228.4 § 1439.9 g
ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. Table 1—Demographics, dosage parameters, and visual acuity of total cohort, and unaffected and affected groups Age (average § STD, median) Sex
Male, n (%) Female, n (%)
Number of tobacco users (%) Average duration of PPS intake § STD in years (median) Mean daily PPS dose § STD in milligrams (median) Average cumulative PPS dose § STD in grams, (median) Average BMI § STD (median) Average weight § STD in pounds (median) Average height § STD in inches (median) Average visual acuity § STD in logMAR (median Snellen equivalent)
Total (N = 50)
Unaffected (N = 40)
Affected (N = 10)
57 § 17.3 (60) 4 (8.0) 46 (92.0) 13 (26.0) 9.1 § 8.6 (6.5) 330.4 § 214.3 (300) 1228.4 § 1439.9 (730.0) 23.6 § 5.2 (22.6) 140.0 § 34.1 (131.5) 64.4 § 3.0 (64) 0.2 § 0.4 (20/20)
55.5 § 17.8 (59) 3 (7.5) 37 (92.5) 11 (27.5) 6.3 § 6.6 (4.8) 301.8 § 222.9 (300) 691.7 § 706.6 (456.3) 24 § 5.5 (22.7) 143.0 § 35.1 (132.5) 64.7 § 2.6 (65) 0.1 § 0.3 (20/20)
63.2 § 14.7 (69.5) 1 (10.0) 9 (90.0) 2 (20.0) 20.3 § 6.6 (19.2) 444.8 § 128.5 (443.8) 3375.4 § 1650.0 (3066) 22.2 § 3.5 (22.4) 128.2 § 28.3 (124.5) 63.6 § 4.3 (62.5) 0.3 § 0.6 (20/20)
p 0.15 1.0 0.94 <0.001 <0.001 <0.001 0.57 0.24 0.19 0.29
STD, standard deviation; PPS, pentosan polysulfate sodium.
(Table 1). For reference, the recommended daily dosage of PPS is 300 mg.9 Mean BMI was 23.6 § 5.2, weight was 140.0 § 34.1 lbs, and height was 64.4 § 3.0 inches (Table 1). Average visual acuity at the time of screening was 0.2 § 0.3 (Snellen 20/31, Snellen median 20/20) across the entire cohort in both eyes. The majority of patients (48/50, 96%) reported IC as the indication for PPS therapy. The other 2 indications were irritable bowel syndrome (1/50, 2%) and pelvic pain syndrome (1/50, 2%) both in nonaffected patients. None of the patients reported any kidney or liver abnormalities. For detailed medical history for each of the 50 patients, please see Supplementary Table 1 (available online).
Demographics and Description of the Affected Cohort and Comparison with the Nonaffected Cohort
PPS-associated maculopathy was identified in 10 patients (20 eyes), whereas 40 patients (80 eyes) were noted to be normal with no evidence of pentosan maculopathy, resulting in a prevalence of 20% (i.e., 10/50) (Table 2). Of the 10 affected patients, 9 (90%) were female and 9 (90%) identified as
non-Hispanic Caucasian. Median age of the positive patients was 69.5 years (range 4176 years). Within the 10 affected patients with the characteristic maculopathy, a variety of associated visual complaints were reported. The most common symptom was nyctalopia or night blindness (n = 5, 50%) although mild cataract may be the etiology in 2 of these cases. One patient complained of distortion, 2 complained of blurry vision, and 2 were asymptomatic. In the affected patients, median Snellen visual acuity was 20/20 OD (range: 20/20hand motion) and 20/31 OS (range: 20/2020/60). The median intraocular pressures were 15 mm Hg OD (range 1116) and 15 mm Hg OS (range 918). On slit lamp examination, 6 patients were normal bilaterally, 3 had mild nuclear sclerotic cataracts, 1 showed asteroid hyalosis in the left eye, and 1 presented with bilateral Krukenberg’s spindles. On retinal examination, 6 patients demonstrated bilateral pigmentary maculopathy. Half of the eyes (10/20, 50%) showed evidence of bilateral RPE atrophy. No patients presented with heme or fluid in either eye. Comparison of the unaffected and affected patients was performed (Table 1). There was no statistically significant
Table 2—Body mass index (BMI), cumulative exposure, symptoms, Snellen visual acuity, anterior and posterior segment examination findings, and grading of disease severity of affected cases Patient No.
BMI
Cumulative Exposure (g)
Visual Symptoms
Visual Acuity
Intraocular Pressure (mm Hg)
Slit Lamp Exam
Fundus Exam
Severity Grading
47 18 10 43
25.4 23.1 24.3 22.1
1752 4745 2847 5402
None Distortion None Nyctalopia
20/20 OD 20/20 OS 20/40 OD 20/40 OS 20/20 OD 20/50 OS 20/25 OD 20/40 OS
16 OD 15 OS 12 OD 10 OS 11 OD 9 OS 13 OD 12 OS
Normal Normal Normal Normal
Mild Mild Mild Mild
34
19.2
1825
Nyctalopia
20/40 OD 20/30 OS
16 OD 18 OS
39
15.9
3285
Nyctalopia
20/20 OD 20/20 OS
15 OD 18 OS
Focal atrophy
Moderate
29
19.8
4334
Nyctalopia
20/20 OD 20/25 OS
15 OD 16 OS
20.9
1533
Blurry vision
20/20 OD 20/20 OS
15 OD 14 OS
44
28.5
2007.5
Blurry vision
20/30 OD 20/50 OS
16 OD 15 OS
21
22.65
6023
Nyctalopia
HM OD 20/60 OS
15 OD 16 OS
Normal
Parafoveal pigmentation, drusen Peripapillary atrophy, focal atrophy patches, macular granularity Parafoveal and peripapillary pigmentation, peripheral atrophy around arcades Extensive diffuse atrophy & reticular degeneration of the pigment epithelium
Moderate
22
Nuclear sclerotic 2 (OD) & nuclear sclerotic 1 (OS) cataracts Nuclear sclerotic 1 cataracts Dense asteroid hyalosis OS Nuclear sclerotic 1 cataracts, Krukenberg's spindles OU Normal
Normal Normal Parafoveal pigmentation Parafoveal and peripapillary pigmentation Parafoveal pigmentation, focal atrophy
Mild
Moderate
Severe
Severe
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ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. difference between groups in regard to age, sex, tobacco use, BMI, weight, height, or visual acuity (Table 1). However, when comparing duration of exposure, mean daily dose, and cumulative dose, the affected group was notable for significantly longer exposures and higher dosing. Specifically, the mean duration of PPS intake was 6.3 § 6.6 years (median: 4.8 years) in the unaffected group versus 20.3 § 6.6 years (median: 19.2 years, p < 0.001) in the affected group. The PPS-maculopathy group also exhibited a greater mean daily dose of 444.8 § 128.5 mg (median: 443.8 mg) versus 301.8 § 222.9 mg (median: 300 mg, p < 0.001) in the nonaffected group. The mean cumulative dose in the affected patient group was significantly greater at 3375.4 § 1650.0 g (median: 3066.0 g) versus 691.7 § 706.6 g (median: 456.3 g, p < 0.001) in the nonaffected group. Comparing ranges of cumulative dose between the affected and unaffected groups revealed overlap. The minimum cumulative dose at which PPS-associated maculopathy was identified was 1533 g. In the unaffected cohort, 5 patients (5/40, 12.5%) presented with greater cumulative doses: patient 3 (2336 g), patient 6 (3103 g), patient 15 (1643 g), patient 46 (1889 g), and patient 50 (1898 g).
Multimodal Retinal Imaging Findings of the Affected Cohort
In the eyes of the affected patients, wide-field FAF combined with SD-OCT best illustrated the PPS-induced macular findings (Figs. 1 and 2), although NIR and multicolor imaging were very effective in detecting the characteristic punctate and round hyper-reflective RPE lesions especially in milder forms of disease (Fig. 3). The total area and severity of irregular autofluorescence varied widely among the 10 patients. In 14 eyes out of 20 (70%), FAF showed a well-demarcated region of speckled autofluorescence with alternating hypo- and hyperautofluorescence, centred in the posterior pole and extending peripapillary (Fig. 1). Hyperautofluorescent vitelliform-like parafoveal lesions were seen in both eyes of 1 patient (patient 18) with a mild phenotype, whereas a very subtle stippled parafoveal hyperautofluorescence was noted in both eyes of the mildest case (patient 47). However, the multicolor and NIR findings for this case (patient 47) were more convincing (Fig. 3). In the most severe phenotype, bilateral diffuse areas of geographic atrophy throughout the posterior pole and periphery were noted (Fig. 1).
Fig. 1—Fundus autofluorescence images (A–T) and spectral domain optical coherence tomography (SD-OCT) B scans through the fovea (U, V, W, X, Y, Z, AA, BB, CC, DD, EE, FF, GG, HH, II, JJ, KK, LL, MM, NN) of the 10 affected patients. Note the spectrum of findings as illustrated with fundus autofluorescence (FAF). In the mildest presentation (A and B, patient 47), fundus autofluorescence shows only very subtle hyperautofluorescent stippling of the retinal pigment epithelium (RPE), but these alterations are more prominent with multicolor and near-infrared imaging (Fig. 3). A small corresponding hyper-reflective RPE lesion is noted with the SD-OCT B scan in the left eye. In patient 18 (C and D), scattered hyperautofluorescent and hyper-reflective vitelliform-like lesions are illustrated. With more significant toxicity, a speckled pattern of hypo- and hyperautofluorescent and hyper-reflective RPE lesions involving only the macula is shown (E and F, patient 10). With further progression, alterations are noted to extend around and nasal to the disc (G and H, I and J, patients 43 and 34, respectively). Well-demarcated areas of nummular or geographic hypoautofluorescent RPE atrophy are noted with more advanced toxicity (K–T, patients 39, 29, 22, 44, and 21). Corresponding OCT B scans illustrate patchy complete RPE and outer retinal atrophy. In the most severe case S and I (bottom row, patient 21), diffuse chorioretinal atrophy involving the posterior pole and periphery is noted. Corresponding SD-OCT imaging (MM and NN) illustrates diffuse RPE and outer retinal atrophy that corresponds with the nummular or geographic areas of well-demarcated hypoautofluorescent atrophy. Note the halo of peripapillary hypoautofluorescence in all 20 affected eyes.
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Fig. 2—Fundus color photography, fundus autofluorescence (FAF), en face optical coherence tomography (OCT), and corresponding spectral domain optical coherence tomography (SD-OCT) B scans of 5 presentations of pentosan polysulfate sodium (PPS)–associated maculopathy of varying severity. Patient 18 (A–D) represents a mild form of pentosan maculopathy with no signs of atrophy. The round orange lesions with multicolor reflectance match the hyperautofluorescent lesions on FAF, which correspond to the hyper-reflective lesions with en face OCT and focal retinal pigment epithelium (RPE) thickening with SD-OCT (red asterisk). No signs of atrophy are noted. The images for patients 10 (E–H) and 43 (I–L) illustrate a mild case with larger areas of involvement. The color photographs display pigment deposits that are more prominent and co-localize with hyperautofluorescent lesions with FAF. The hyperautofluorescent lesions correspond to hyper-reflective lesions with en face OCT and focal RPE thickening (red asterisk) with the cross-sectional OCT B scan. Note that the hypoautofluorescent FAF areas in this case fail to display evidence of atrophy with the matched OCT scans. The images for patients 39 (M–P) and 44 (Q–T) illustrate cases of moderate and severe severity, respectively. Atrophic lesions are well-demarcated with multicolor with baring of the choroidal vessels. A well-circumscribed round area of hypoautofluorescent atrophy is noted with FAF. This region co-localizes with a well-demarcated hyper-reflective lesion with en face OCT. SD-OCT illustrates a corresponding area of complete retinal pigment epithelial and outer retinal atrophy (CRORA) (red asterisk). Patient 44 displays similar atrophic lesions in the macula with FAF and OCT but also exhibits these atrophic lesions in the periphery (see Fig. 1Q and R).
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ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. hyperautofluorescent lesions on FAF and to the focal areas of hyper-reflective RPE thickening on SD-OCT. OCTA illustrated normal vascular perfusion at all segmentation levels except for decreased choriocapillaris perfusion corresponding to CRORA lesions in the moderate and severe patients. None of the affected patients presented with choroidal neovascularization. Spectralis NIR and multicolor photography (Fig. 3) illustrated characteristic round or punctate, orange hyper-reflective lesions that corresponded to focal RPE thickening with SD-OCT and focal hyperautofluorescence with FAF. These findings were especially helpful in detecting very mild cases as with patient 47 (Fig. 3A, E) for whom the FAF findings were not conclusive. Atrophy appeared as well-demarcated areas of increased transparency of the underlying choroid. Grading Severity in the Affected Cohort
Fig. 2 Continued.
The bilateral speckled pattern of hyper- and hypoautofluorescence extended past the macula to the disc in 12 out of 14 eyes (86%). Of these 12 eyes, the speckled pattern extended nasal to the disc in 4 (33%). In more advanced cases, atrophy was noted (12 eyes) as well circumscribed hypoautofluorescent perifoveal lesions that varied from multifocal lesions less than one-disc diameter in size (8 eyes, 67%) to larger areas of atrophy or diffuse atrophy, in severe cases, throughout the entire posterior segment (4 eyes, 33%) and into the periphery (Fig. 1). Additionally, all 20 eyes (100%) demonstrated peripapillary halos of hypoautofluorescence of varying diameter on FAF. Cross-sectional and en face SD-OCT illustrated focal areas of RPE thickening that co-localized with the hyperautofluorescent lesions on FAF (Fig. 2). The hypoautofluorescent lesions associated with the speckled pattern on FAF did not display any RPE or outer retinal abnormalities with corresponding OCT (Fig. 2). However, the well-demarcated hypoautofluorescent round lesions co-localized with CRORA5,6 on the cross-sectional and en face OCT (Fig. 2). Additional imaging modalities were used to characterize pathologic findings. On color fundus photography, abnormal pigmentary clumps were noted corresponding to the
The patients were graded based on the presence or absence of atrophy with FAF and OCT. Patients 10, 18, 34, 43, and 47 did not show evidence of well-demarcated areas of atrophy with FAF or CRORA with cross-sectional and en face OCT and were labeled as mild. Patients 22, 29, and 39 illustrated discrete lesions of atrophy with FAF and CRORA with OCT in the macula and were labeled as moderate. Patients 21 and 44 displayed diffuse atrophy with FAF throughout the posterior pole and periphery and were labeled as severe. Of note, all 10 patients exhibited symmetry regarding the severity grade between the 2 eyes (Fig. 1). Table 3 compares the duration, mean daily dose, and cumulative dose of PPS in the affected patients by severity grading. The sample sizes were too small to perform statistical comparisons; however, an overall trend was noted with increased duration of exposure, increased daily dose, and increased cumulative dose in patients with more severe disease. Specifically, the median duration of PPS intake was 16.0, 20.0, and 22.9 years in the mild, moderate, and severe groups, respectively. Similarly, median daily PPS dose was 300 mg versus 400 mg versus 555.2 mg in the mild, moderate, and severe groups, respectively. Median cumulative dosages were 2847.0, 3285.0, and 4015.3 g in the mild, moderate, and severe groups, respectively. However, it should be noted that some patients with high cumulative doses presented with a mild or moderate phenotype. Genetic Testing
Genetic testing performed in patient 21 yielded a heterozygous pathologic variant identified in the nephronophthisis 1 (NPHP1) allele. Additional variants of uncertain significance were identified in the CDH23, PCDH15, and SLC7A14
Table 3—Comparison of dosage parameters between patients with varying severity of disease Duration of PPS intake, median (range), y Mean daily PPS dose, median (range), mg Cumulative PPS dose, median (range), g
Mild (N = 5)
Moderate (N = 3)
Severe (N = 2)
16.0 (12.529.0) 300 (306.4600.0) 2847.0 (1752.05402.0)
20.0 (12.030.0) 400.0 (300.0593.8) 3285.0 (1533.04334.0)
22.9 (18.327.5) 555.2 (300.0600.0) 4015.3 (2007.56023.0)
PPS, pentosan polysulfate sodium.
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Fig. 3—Spectralis multicolor (A–D) and near-infrared reflectance (NIR) (E–H) photography in 4 mild cases of pentosan maculopathy. Patient 47 illustrates very subtle alterations with discrete punctate parafoveal hyper-reflective lesions in both eyes best appreciated with NIR. As severity worsens, the hyper-reflective spots on multicolor and NIR, which correspond with RPE thickening on SD-OCT, become more prominent in patients 18 (B and F), 10 (C and G), and 43 (D and H).
genes and were thought to be irrelevant to the patient’s notable retinal findings.
TAGEDH1DISCUSSIONTAGEDEN In this study, FAF proved to be an essential modality to identify and diagnose PPS-associated alterations that were consistent with the original features previously reported.3,4 A wellcircumscribed region of speckled hyper- and hypoautofluorescence was centred around the macula, often with extension
around the optic disc and even into the periphery. A peripapillary halo of hypoautofluorescence was noted in all affected eyes. The hyperautofluorescent lesions corresponded with focal areas of hyperpigmentation on color fundus photography and focal areas of hyper-reflective RPE thickening with cross-sectional and en face OCT. Of note, the associated hypoautofluorescent lesions did not co-localize with any notable abnormality with cross-sectional or en face OCT. More severe phenotypes, however, exhibited well-circumscribed parafoveal lesions of atrophy that displayed well-demarcated areas of CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
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ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. hypoautofluorescence with FAF and corresponding CRORA with cross-sectional and en face OCT. OCTA displayed normal perfusion within the retinal capillary system but reduced choriocapillaris flow corresponding to the CRORA lesions. There were no signs of choroidal neovascularization in any affected patients, although choroidal neovascularization was recently reported to complicate PPS-associated maculopathy.10 In the milder cases, NIR and multicolor imaging also proved valuable and displayed characteristic punctate or round parafoveal RPE lesions that were orange with multicolor and hyper-reflective with NIR (Fig. 3). This was especially helpful in illustrating findings in patient 47, the mildest case of our affected cohort. Although it may be argued that the findings in this case were not significant enough to conclude toxicity, we included this case in the affected cohort as the features were suggestive of a very early form of PPS-associated maculopathy that may be important to illustrate in this paper as more information is published and more is learned about this toxic disease. The findings noted with patient 18 further widened the spectrum of phenotypic disease. In this mild case, only a few vitelliform deposits were noted in a parafoveal and peripapillary distribution that could not be attributed to other causes of acquired vitelliform lesions such as reticular pseudo drusen or pachychoroid disease.1115 This patient was noted to have a very high cumulative PPS dosage (4745 g) and suggests that inherent anatomical and genetic considerations may have prevented a much more severe toxic presentation. At the other end of the spectrum, a diffuse, severely atrophic, chorioretinopathy, involving the posterior pole and periphery and resembling a choroidal dystrophy, such as choroideremia or lateonset retinal dystrophy (LORD syndrome), was noted (patient 21). Comprehensive genetic testing was unremarkable for any evidence of a choroidal dystrophy. Moreover, this patient was noted to have the highest cumulative dosage of PPS (6023 g) ever reported,3,4 which may explain the severe novel phenotype. Patient 21 was found to have a heterozygous mutation in NPHP1, a gene that encodes nephrocystin-1, a protein located at the base of the connecting cilium axoneme and suggested to be involved in actin- and microtubule-based sorting and transport,16 including transport between the inner and outer segments of photoreceptors.17 All known NPHP1 disorders (e.g., Senior Lokin syndrome and Joubert Syndrome) are autosomal recessive owing to homozygous mutations in NPHP1, and all documented cases have exhibited renal involvement with variable extrarenal manifestations.18 NPHP1 is unlikely to be causative in our patient who exhibited a heterozygous mutation and who lacked kidney and cerebellar involvement. Given the extremely high PPS dosage, it is possible that the retinal findings may be solely attributable to PPS toxicity. Alternatively, the heterozygous mutation may have established a genetic predisposition that alone would not cause disease, but in combination with a significant toxic drug exposure it could trigger severe retinal degeneration without affecting renal function. Genetic
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predisposition to a severe phenotype of hydroxychloroquine retinopathy has been previously reported.19 PPS inhibits growth factor signalling pathways, primarily fibroblast growth factor, platelet-derived growth factor, and epidermal growth factor, especially within RPE cells.20,21 Disruption of these pathways may injure the RPE and block the promotion of health maintenance and regeneration of the outer retina, which may be the mechanism by which PPS causes retinal toxicity.21 Pathways of RPE degeneration studied in age-related macular degeneration (AMD)2224 may parallel the spectrum of findings identified in this study of PPS-associated maculopathy. Disrupted photoreceptor turnover through a dysfunctional RPE, in a milder form of toxicity, leads to acquired vitelliform lesions (patient 18).1315 With more advanced disease, morphological alterations in the RPE develop, including focal RPE thickening (patients 10, 34, 43) and ultimately RPE atrophy (patients 22, 29, 39, 44), which may progress to involve the entire macula and even the periphery with more severe toxic exposures causing more profound loss of the RPE and inner choroid (patient 21). The reports of Pearce et al.3 and Hanif et al.4 are groundbreaking landmark studies that first identified an association of PPS treatment with a distinctive maculopathy that appears to be a very real association with important ramifications. This disorder can very easily masquerade as AMD or forms of macular dystrophy such as mitochondrial syndromes, and therefore chronic toxicity with progressive vision loss can be easily missed. It is important to note, however, that both of these studies were retrospective and analyzed patients who were symptomatic and who were ascertained because of other ophthalmological considerations indicating selection bias. Moreover, the authors relied on retinal imaging that was incomplete or unavailable and performed by other ophthalmologists not part of their study. In our cross-sectional study, patients were randomly ascertained and prospectively screened. Color fundus photography, SD-OCT, and FAF were performed in every patient. Detailed dosage exposure was also recorded. The prevalence of toxicity within this study cohort was noted to be 20%, which is remarkable. Further, not every patient with PPSassociated maculopathy presented with visual symptoms, indicating the importance of routine screening. Dosagerelated considerations are additionally important. No patients with cumulative dosages less than 1500 g were identified with toxicity in our study, whereas 31 out of 32 patients with PPS-associated maculopathy in prior studies3,4 presented with cumulative exposures greater than 500 g. Although not definitive, a dosage-related correlation was suggested in our study when considering the severity of the toxic retinopathy. Based on these findings, we would recommend that all patients starting PPS therapy should be referred to an ophthalmologist for baseline SD-OCT, NIR, and FAF testing. FAF and NIR are especially important and represent the gold-standard modalities to detect PPS-associated maculopathy. Annual SD-OCT, NIR, and FAF should be repeated especially as cumulative dosages approach or exceed 500 g.
ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. PPS prescribing doctors should be aware of the high risk of retinal toxicity and maculopathy as the cumulative dosages approach 1000 g or greater, especially 1500 g. Factors that may increase the risk of toxicity, such as AMD or genetic retinal dystrophies, should be weighed against the systemic benefit of the drug. Although average BMI was lower in the affected group, our study was not powered to detect a significant difference. With larger studies, more reliable conclusions may be made regarding dosage considerations as relates to the height and weight of the patient. The symptoms of IC can be especially burdensome, and discontinuation of PPS due to the risk of progressive vision loss must be weighed against the benefits of symptom relief, especially when alternative treatments have already been exhausted. Ophthalmologists should manage PPS-associated maculopathy on a case-by-case basis and approach the subject of PPS discontinuation with caution as patients may become distressed and distraught by the recommendation to discontinue PPS therapy. Open communication with the patient and his or her urologist prescribing the drug is essential. The 20% prevalence of PPS-associated maculopathy in this study captured from a sample size of 50 screened patients does not necessarily represent the true prevalence in the population at large. Although patients were randomly ascertained from a large university database, it is possible that those patients who agreed to be screened were more likely to exhibit toxicity. Therefore, we may have overestimated the true prevalence in the PPS population. Additional limitations included the lack of Early Treatment Diabetic Retinopathy Study visual acuity testing and the lack of genetic testing in all affected patients with PPS-associated maculopathy. The relevance of genetic testing in this patient population is undetermined but may provide guidance on a case-by-case basis. However, the phenotype of PPS-associated maculopathy appears to be distinctive, consistent, and readily identifiable although this study has broadened the spectrum of findings. PPS-treated patients may prove to be a unique population to study the interplay of genetic susceptibility and drug exposure.
TAGEDH1CONCLUSIONSTAGEDEN Our findings corroborate recent reports that prolonged consumption of PPS can lead to vision-altering changes in the macula with relatively unique findings with multimodal retinal imaging. FAF and NIR are important modalities for the detection and diagnosis of PPS-associated maculopathy. NIR displayed distinctive punctate or round hyper-reflective parafoveal lesions in milder forms of disease, whereas FAF illustrated a characteristic centrifugal speckled hypo- and hyperautofluorescence corresponding to RPE thickening with and without parafoveal nummular atrophy. A more widespread pattern of autofluorescent alterations or even a severe pattern of diffuse chorioretinal atrophy were appreciated with more significant toxic exposures. Our study randomly ascertained treated patients to determine the possible prevalence of associated maculopathy in the general
population with a history of PPS therapy. Patients on the medication may be at significant risk of macular toxicity, especially with dosages over 1500 g, and may need to discuss alternative therapies with their physicians with cumulative dosages greater than 1000 or 1500 g. We recommend an initial baseline eye examination to include multimodal retinal imaging including SD-OCT, NIR, and FAF with annual retinal imaging thereafter especially with cumulative dosages approaching or exceeding 500 g.
TAGEDH1SUPPLEMENTARY MATERIALSTAGEDEN Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jcjo.2019.12.001. TAGEDH1REFERENCESTAGEDEN 1. Giusto LL, Zahner PM, Shoskes DA. An evaluation of the pharmacotherapy for interstitial cystitis. Expert Opin Pharmacother. 2018;19: 1097–108. 2. Hanno PM, Erickson D, Moldwin R, Faraday MM, Association AU. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193:1545–53. 3. Pearce WA, Chen R, Jain N. Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium. Ophthalmology. 2018;125:1793–802. 4. Hanif A.M., Armenti S.T., Taylor S.C., et al. Phenotypic spectrum of pentosan polysulfate sodium-associated maculopathy: a multicenter study [E-pub ahead of print]. JAMA Ophthalmol. doi: 10.1001/ jamaophthalmol.2019.3392, Accessed 9/21/19. 5. Sadda SR, Guymer R, Holz FG, et al. Consensus definition for atrophy associated with age-related macular degeneration on OCT: classification of Atrophy Report 3. Ophthalmology. 2018;125:537–48. 6. Guymer R.H., Rosenfeld P.J., Curcio C.A., et al. Incomplete retinal pigment epithelial and outer retinal atrophy in age-related macular degeneration: classification of Atrophy Meeting Report 4 [E-pub ahead of print]. Ophthalmology. doi: 10.1016/j.ophtha.2019.09.035, Accessed 11/3/19. 7. Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125:369–90. 8. Holz FG, Bellman C, Staudt S, Sch€ utt F, V€olcker HE. Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2001;42:1051–6. 9. Nickel JC, Herschorn S, Whitmore KE, et al. Pentosan polysulfate sodium for treatment of interstitial cystitis/bladder pain syndrome: insights from a randomized, double-blind, placebo controlled study. J Urol. 2015;193:857–62. 10. Mishra K., Patel T.P., Singh M.S. Choroidal neovascularization associated with pentosan polysulfate toxicity [Epub ahead of print]. Ophthalmol Retina. doi: 10.1016/j.oret.2019.08.006, Accessed 10/30/19. 11. Dansingani KK, Balaratnasingam C, Klufas MA, Sarraf D, Freund KB. Optical coherence tomography angiography of shallow irregular pigment epithelial detachments in pachychoroid spectrum disease. Am J Ophthalmol. 2015;160:1243–54. e1242. 12. Rabiolo A, Sacconi R, Cicinelli MV, Querques L, Bandello F, Querques G. Spotlight on reticular pseudodrusen. Clin Ophthalmol. 2017;11:1707–18. 13. Freund KB, Laud K, Lima LH, Spaide RF, Zweifel S, Yannuzzi LA. Acquired vitelliform lesions: correlation of clinical findings and multiple imaging analyses. Retina. 2011;31:13–25. 14. Spaide RF. Deposition of yellow submacular material in central serous chorioretinopathy resembling adult-onset foveomacular vitelliform dystrophy. Retina. 2004;24:301–4. 15. Spaide R. Autofluorescence from the outer retina and subretinal space: hypothesis and review. Retina. 2008;28:5–35. 16. Mollet G, Silbermann F, Delous M, Salomon R, Antignac C, Saunier S. Characterization of the nephrocystin/nephrocystin-4 complex and subcellular localization of nephrocystin-4 to primary cilia and centrosomes. Hum Mol Genet. 2005;14:645–56. CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
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ARTICLE IN PRESS Pentosan-associated maculopathy—Wang et al. 17. Jiang ST, Chiou YY, Wang E, et al. Essential role of nephrocystin in photoreceptor intraflagellar transport in mouse. Hum Mol Genet. 2009;18:1566–77. 18. Hoff S, Halbritter J, Epting D, et al. ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet. 2013;45:951–6. 19. Katsman D, Sanfilippo C, Sarraf D. Panretinal degeneration associated with long-term hydroxychloroquine use and heterozygous Ush2a mutation. Retin Cases Brief Rep. 2017;11(Suppl 1):S77–80. 20. Leschey KH, Hines J, Singer JH, Hackett SF, Campochiaro PA. Inhibition of growth factor effects in retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1991;32:1770–8. 21. Greenlee T, Hom G, Conti T, Babiuch AS, Singh R. Re: Pearce et al. pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium (Ophthalmology. 2018;125:1793802) Ophthalmology. 2019;126:e51. 22. Curcio CA. Soft drusen in age-related macular degeneration: biology and targeting via the oil spill strategies. Invest Ophthalmol Vis Sci. 2018;59:AMD160–81. 23. Balaratnasingam C, Messinger JD, Sloan KR, Yannuzzi LA, Freund KB, Curcio CA. Histologic and optical coherence tomographic correlates in drusenoid pigment epithelium detachment in age-related macular degeneration. Ophthalmology. 2017;124:644–56. 24. Balaratnasingam C, Yannuzzi LA, Curcio CA, et al. Associations between retinal pigment epithelium and drusen volume changes during the lifecycle of large drusenoid pigment epithelial detachments. Invest Ophthalmol Vis Sci. 2016;57:5479–89.
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Footnotes and Disclosure: Acknowledgements: This work was supported by the Research To Prevent Blindness, Inc (D.S.), and the Macula Foundation, Inc (D.S.). Dr. David Sarraf: Amgen (consultant), Bayer (consultant), Genentech (consultant, research), Heidelberg (research), Novartis (speaker), Optovue (consultant, research), Regeneron (research), and Topcon (research). From the *Retinal Disorders and Ophthalmic Genetics, Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA; y Division of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; zDepartment of Urology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA; xGreater Los Angeles VA Healthcare Center, Los Angeles, CA. Originally received Nov. 25, 2019. Final revision Dec. 10, 2019. Accepted Dec. 11, 2019. Correspondence to David Sarraf, MD, Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095. [email protected]