Cystoid Macular Edema Arising 10 Years After Cessation of Pentosan Polysulfate Sodium Successfully Treated With Bevacizumab

Introduction

Pentosan polysulfate sodium (PPS) is a semisynthetic oral medication that is approved by the US Food and Drug Administration to treat interstitial cystitis (IC), a chronic, painful condition of the bladder and pelvic floor. ¹ Unfortunately, multiple recent studies have shown a link between PPS use and visually significant pigmentary retinopathy.^1–3

We report a case that emphasizes the importance of obtaining thorough medication and medical histories before establishing a diagnosis in patients with suspected early-onset AMD or retinal dystrophies and shows that PPS-associated maculopathy can progress for up to 10 years after cessation of PPS. This case also shows that in unilateral cases of CME induced by PPS-associated maculopathy, the fellow eye can sequentially develop CME within months. At present, the literature on the efficacy of antivascular endothelial growth factor (anti-VEGF) therapy for cystoid macular edema (CME) secondary to PPS-associated maculopathy is limited.^4,5

Case Report

A 57-year-old woman presented with new-onset metamorphopsia and blurry vision in the right eye. The left eye was asymptomatic. She had annual eye examinations since being diagnosed with AMD several years before due to the onset of drusen-like deposits and retinal pigment epithelium (RPE) mottling. The possibility of a retinal dystrophy was considered given the patient’s young age at diagnosis. The family medical and ocular histories were unremarkable, and genetic testing was deferred.

A previous examination showed paracentral macular RPE changes, most notably hyperpigmentation. Progressive outer retinal changes, including excrescences that appeared as focal hyperreflective nodules at the level of the RPE in both eyes on spectral-domain optical coherence tomography (SD-OCT), were originally mistaken to be drusen (Figure 1). CME had been absent for several years before and 2 years after the patient transferred care. Before the new symptoms, the best-corrected visual acuity had remained 20/20 OU.

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Figure 1.

Baseline hyperreflective paracentral retinal pigment epithelium (RPE) changes in the (A) right eye and (B) left eye seen on near-infrared reflectance imaging 2 years before symptom onset. Macular spectral-domain optical coherence tomography shows hyperreflective focal excrescences (arrowheads) at the level of the RPE in the (C) right eye and (D) left eye.

Soon after the onset of symptoms, a fundus examination and SD-OCT showed new CME in the right eye (Figure 2A). Fluorescein angiography (FA) showed a patchy pattern consistent with RPE injury and very subtle pinpoint leakage in the macula in both eyes without evidence of a choroidal neovascular membrane (Figure 3). An additional medical history showed the patient had a history of IC, necessitating 3 years of PPS (Elmiron, Janssen Pharmaceuticals) treatment, which was discontinued 10 years previously. The patient could not recall her daily dose; therefore, the cumulative dosage was unknown.

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Figure 2.

(A) Macular spectral-domain optical coherence tomography of the right eye shows new cystoid macular edema (CME) in the right eye at the first visit since the onset of symptoms. (B) The CME worsened after a 1-month trial of topical steroid and nonsteroidal antiinflammatory drug therapy. (C) Eight weeks later, the CME had completely resolved after 2 antivascular endothelial growth factor injections 4 weeks apart. (D) Subtle cystic changes developed 6 weeks after the third intravitreal injection.

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Figure 3.

(A) Early fluorescein angiography (FA) images show patchy hyperfluorescence and hypofluorescence resulting from macular retinal pigment epithelium changes in both eyes. Pinpoint leakage (arrows) was suspected in both eyes, more prevalent in the unaffected left eye. (B) Late FA images show staining. Significant leakage secondary to choroidal neovascular membrane suggestive of exudative ARMD is notably absent.

Fundus autofluorescence (FAF) was later performed and showed stark hyperautofluorescent and hypoautofluorescent patches throughout both maculae, consistent with PPS-associated maculopathy (Figure 4). Hypoautofluorescent peripapillary halo-like patterns in the absence of visible peripapillary atrophy further supported the diagnosis of PPS-associated maculopathy over AMD or hereditary macular dystrophies (Figure 4). ⁵

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Figure 4.

Fundus autofluorescence images show bilaterally symmetric, prominent hyperautofluorescent and hypoautofluorescent spots in both maculae. Small peripapillary hypoautofluorescent halos are seen beyond the margins of the nerves (disc margins demarcated by yellow lines). Peripapillary atrophy was not appreciated on fundus examination.

CME resulting from PPS-associated maculopathy has been successfully treated with topical nonsteroidal antiinflammatory drug (NSAIDs) and corticosteroids as well as topical and oral carbonic anhydrase inhibitors.^5,6 Given this reported success, the right eye was treated with a trial of topical prednisolone 3 times daily and bromfenac once daily for 1 month; however, there was no improvement in the symptoms and the CME had worsened, further threatening the fovea (Figure 2B). The patient had a series of 3 intravitreal injections of 1.25 mg/0.05 mL bevacizumab (Avastin, Genetech) (off-label use) spaced 4 weeks apart. The patient reported improvement in vision and complete resolution of the metamorphopsia after the second injection. OCT showed near complete resolution of the CME and a normal foveal contour 4 weeks after the second injection (Figure 2C). One month after the third injection, the patient developed small intraretinal cystic changes; however, no additional therapy was recommended because she remained asymptomatic (Figure 2D).

Five months after the onset of edema in the right eye, CME developed in the left eye to the extent seen in Figure 2A. Bevacizumab injections were given in the left eye, which led to resolution of the edema and improved vision.

Conclusions

Because of limited treatment options, PPS has been used extensively to treat bladder pain caused by IC. Recent studies, however, found a connection between PPS use and vision-threatening pigmentary maculopathy in more than 10% of patients with a cumulative PPS dose of 500 g to 999 g and in approximately 40% of patients with a cumulative intake greater than 1500 g.^1–3,5,7 It remains unclear how long visual compromise continues after cessation of the drug, with previous studies reporting progression up to 6 years after the drug is stopped. ⁶

Our patient developed changes in vision with alterations in retinal and RPE anatomy that appeared to be progressing 10 years after discontinuation of the PPS. Although the 3-year course she received was relatively short, Hanif et al ⁵ found a median duration of exposure of 15 years (range, 3-22 years) in a study of 35 patients with PPS-associated maculopathy.

Like many others with PPS-associated maculopathy, our patient was thought to have AMD or a retinal dystrophy, which delayed her diagnosis.^5,6,8,9 Progression of retinal degeneration despite cessation of the causative drug is seen with other medication-induced retinal toxicities, such as hydroxychloroquine toxicity. This further emphasizes the critical importance of early detection to limit retinal damage and subsequent vision loss. In addition, as in this case and others, retinal degradation induced by PPS might not manifest or generate symptoms until years after cessation of the drug, underscoring the need for continued close monitoring thereafter. ¹⁰

FAF appears to be the most useful diagnostic tool because it shows a densely speckled, hypoautofluorescent and hyperautofluorescent pattern throughout the macula and a unique hypoautofluorescent peripapillary halo that distinguishes PPS-associated maculopathy from hereditary maculopathies.^3,5,6,9 Near-infrared reflectance shows hyperreflective parafoveal lesions that are nonspecific. ³ Fundus photographs show variable degrees of pigmentary changes and interspersed yellow or orange deposits, which were confused for drusen in this case.^5,6 OCT shows nodular RPE thickening or excrescences that co-localize to hyperautofluorescent lesions on FAF and might dynamically evolve over time.^3,6 FA might show a spectrum of leakage patterns, including no leaking, pinpoint leaking (Figure 3A), or significant leaking. ⁴

Given that PPS-associated maculopathy was only recently recognized (in 2018), the literature describing treatment of CME secondary to PPS-associated maculopathy is limited. ¹ In Hanif et al’s ⁵ 2019 case series of 35 patients with PPS-associated maculopathy, CME was present in approximately 17% of patients. CME was treated successfully with topical carbonic anhydrase inhibitors and anti-VEGF agents, including bevacizumab and aflibercept. Subretinal and subtle intraretinal fluid secondary to CNV in the setting of PPS-associated maculopathy has also been shown to respond to anti-VEGF therapy. ¹¹

The case we describe further supports the limited literature regarding the efficacy of anti-VEGF therapy for the treatment of CME induced by PPS-associated maculopathy. This response to bevacizumab suggests VEGF, and therefore ischemia, are at least partially involved in the development or course of PPS-induced maculopathy. This suspicion is further supported by foveal avascular zone abnormalities, choriocapillaris flow voids, and choriocapillaris atrophy seen on OCT angiography of patients with PPS-associated maculopathy. ⁶

In conclusion, this case shows that PPS-associated maculopathy is often initially mistaken for AMD or a retinal dystrophy and that continued progression for up to 10 years after cessation of the medication is possible. Delayed onset of symptoms and phenotypically similar retinal findings can hinder the rendering of the appropriate diagnosis, especially when an accurately detailed medical history and medication history are not obtained. If unilateral CME develops, involvement of the fellow eye should be anticipated. In addition, patients with CME secondary to PPS-associated maculopathy that is not responsive to steroids or NSAIDs might benefit from anti-VEGF therapy.