Pentosan Polysulfate Maculopathy

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Pentosan polysulfate sodium (PPS) is the only FDA approved oral medication for the treatment of interstitial cystitis (IC). It has been used extensively to treat IC since its approval in 1996. Several recent studies have described a unique, progressive maculopathy associated in a dose-dependent manner with long term use of the medication. It often causes symptoms of prolonged dark adaptation and nyctalopia and may cause blurred vision. While visual acuity may initially remain intact, cystoid macular edema, macular neovascularization, and retinal pigment epithelium (RPE) atrophy may occur resulting in severe vision loss. Although its pathogenesis has not yet been definitively established, clinical imaging suggests that PPS maculopathy primarily impacts the RPE and the RPE-photoreceptor interface and results in a characteristic pattern of retinal imaging findings.

Disease Entity

Disease spectrum in pentosan polysulfate maculopathy shown via color fundus photography (top row), near infrared reflectance imaging (middle row), and fundus autofluorescent imaging (bottom row). Severity of cases increases going from left to right
Disease spectrum in pentosan polysulfate maculopathy shown via color fundus photography (top row), near infrared reflectance imaging (middle row), and fundus autofluorescent imaging (bottom row). Severity of cases increases going from left to right. Part 1 of 2 of this figure. Reprinted with permission from Elsevier from: Pearce WA, Chen R, Jain N. Pigmentary Maculopathy Associated with Chronic Exposure to Pentosan Polysulfate Sodium. Ophthalmology. 2018;125(11):1793-1802. doi:10.1016/j.ophtha.2018.04.026

Long-term use of pentosan polysulfate sodium (PPS) is strongly linked to a vision-threatening macular disease characterized by a unique constellation of retinal imaging findings.

Disease spectrum in pentosan polysulfate maculopathy shown via color fundus photography (top row), near infrared reflectance imaging (middle row), and fundus autofluorescent imaging (bottom row). Severity of cases increases going from left to right
Disease spectrum in pentosan polysulfate maculopathy shown via color fundus photography (top row), near infrared reflectance imaging (middle row), and fundus autofluorescent imaging (bottom row). Severity of cases increases going from left to right. Part 2 of 2 of this figure. Reprinted with permission from Elsevier from: Pearce WA, Chen R, Jain N. Pigmentary Maculopathy Associated with Chronic Exposure to Pentosan Polysulfate Sodium. Ophthalmology. 2018;125(11):1793-1802. doi:10.1016/j.ophtha.2018.04.026

Disease

Pentosan polysulfate sodium (trade name Elmiron, Janssen Pharmaceuticals, Titusville, NJ) is a semisynthetic sulfated polysaccharide that is the only FDA-approved oral therapy for interstitial cystitis (IC). Interstitial cystitis, or bladder pain syndrome, is a syndrome of urinary frequency, urgency, and chronic pelvic discomfort, without an otherwise identifiable cause. It is much more common in women and is estimated to impact over one million people in the United States.[1]

Pentosan polysulfate has been prescribed widely for IC in the US since its FDA approval in 1996, and was used for many years prior in an off-label fashion.[2] The American Urological Association currently recommends PPS as a second line therapy for IC after the failure of conservative management, and numerous international bodies recommend it as a first- or second-line agent.[1][3] Pentosan polysulfate is thought to protect the bladder lining from irritants by replacing disrupted glycosaminoglycans along the bladder urothelium.[4][5] A 2018 report first described a unique macular disease associated with long-term use of PPS in six patients.[6] Several subsequent studies have further characterized the disease and strengthened its dose-dependent association with PPS use.[7][8] Affected patients commonly experience difficulty reading, prolonged dark adaptation, and in some cases loss of visual acuity.[6][9][10] Retinal imaging findings suggest a primary insult to the retinal pigment epithelium (RPE) or RPE-photoreceptor interface.[6][9][10] Although most cases manifest disease in the posterior pole, some eyes have involvement of the far peripheral retina.[9][10] Pentosan polysulfate maculopathy may result in RPE and outer retinal atrophy, cystoid macular edema (CME), vitelliform maculopathy, and macular neovascularization (MNV).[9][10][11][12]

Risk Factors

The primary risk factor for development of PPS maculopathy is high cumulative PPS exposure. Several studies have suggested a dose-response relationship between the characteristic maculopathy and PPS exposure.[7][9][13][14] One study demonstrated PPS maculopathy prevalence rates of 12.7%, 30.0%, and 41.7% among cumulative exposure groups of 500—999 g, 1000-1500 g, and >1500 g, respectively.[7]

As of August 2020, there has only been one documented case of PPS-associated maculopathy in a patient with less than five years of exposure, and only four in patients with less than seven years of cumulative dosage at the standard daily dose (100 mg three times daily).[10] However, as screening programs become more widely implemented, it is likely that cases of early PPS maculopathy will be identified at lower exposures.

A study that broadly evaluated medical comorbidities and medications among patients with IC found that aside from PPS exposure, no covariate was associated with the presence of the characteristic maculopathy.[8] Although the medication is metabolized and excreted by the liver, spleen, and kidney, no links have yet been found to hepatic, renal, or splenic dysfunction.[4][10] No genetic associations have been found in analyses for genes linked to retinal disease.[6][9][10]

General Pathology

Multimodal retinal imaging indicates that PPS maculopathy is caused by a primary abnormality at the RPE or RPE-photoreceptor interface.[6][9][10] Characteristic findings in early disease include darkly pigmented nodular excrescences at the level of the RPE amidst yellowish subretinal deposits.[6][10] The pathology typically involves and centers around the fovea and affects both eyes symmetrically.[6][9][10] Cystoid macular edema, MNV, and RPE atrophy occur in some cases and can result in severe visual acuity loss. RPE atrophy appears to start in a parafoveal multifocal pattern and coalesce to involve the foveal center in severe cases.[10]

Pathophysiology

The pathophysiology of PPS maculopathy is not yet well understood. Pentosan polysulfate has wide-ranging biological activities including anticoagulant, anti-inflammatory, and fibrinolytic properties.[4] The backbone of the PPS molecule is similar to a glycosaminoglycan, which have myriad physiologic effects. Pentosan polysulfate also has a high negative charge which may lead to nonspecific interactions with positively charged molecules.

It is speculated that PPS causes a disruption in RPE-photoreceptor homeostasis leading to misprocessing of photoreceptor outer segments. The interphotoreceptor matrix, which supports the photoreceptor-RPE interface, is made up of glycosaminoglycans which PPS could disrupt owing to its similar structure.[15][16] Alternatively, some believe that long-term inhibition of fibroblast growth factor signaling may be responsible for PPS maculopathy. In vitro studies have found that PPS inhibits fibroblast growth factors that are an important part of retinal health maintenance.[17][18]

Murine research has demonstrated significant retinal functional deficits on electroretinography in mice that have been exposed to high levels of PPS.[19] Additional research is required to make definitive conclusions regarding disease pathogenesis.

Primary prevention

Avoidance of PPS therapy appears to be the only method for primary prevention of PPS maculopathy. However, IC can also carry a high symptom burden and some patients report significant benefit from PPS use. Prescribers should consider counseling patients regarding the risk of vision loss associated with PPS so that they can make an informed decision regarding using the medication. If they choose to take PPS, providers should prescribe the minimum effective dose and duration of treatment.

Diagnosis

While history and dilated fundus examination (DFE) can be suggestive of PPS maculopathy, multimodal retinal imaging, particularly fundus autofluorescence imaging, is helpful. In some cases, the clinician must integrate findings from the examination, fundus autofluorescence imaging, near infrared reflectance imaging, and optical coherence tomography to establish the diagnosis.

Screening

Although no formal screening guidelines have been released, ophthalmologists at the Emory Eye Center, where this condition was initially described, monitor patients taking PPS or diagnosed with PPS maculopathy annually with a comprehensive retinal evaluation including color fundus photography, FAF, OCT, and NIR imaging. Exams are continued for the duration of treatment or beyond if there is suspicion for potential maculopathy development. Although most documented cases have occurred after long-term exposure, there has been a reported case after only three years of PPS use and much is still unknown about this recently discovered condition.

Another group has recommend a baseline screening exam within 6 months of starting the drug and then annually as patients approach 500 g of cumulative exposure (approximately 4.6 years on the standard 300 mg daily dose).[9]

History

Providers should ask patients with suspected PPS maculopathy about the daily dose and duration of PPS intake. It may also be useful to ask about history of or ongoing tobacco use, although no such link has been established to date.

To gauge the functional impact of PPS maculopathy, it is useful to ask patients about difficulty adjusting to dim light, difficulty seeing at night, blurred vision, metamorphopsia and difficulty reading. Pentosan polysulfate maculopathy has also been identified in patients who are not reporting any visual symptoms.[9][10] Thus, a negative history for visual symptoms does not rule out a mild manifestation of the disease.

In order to frame discussions regarding PPS cessation, it is helpful to inquire about IC disease status. Last, it is helpful to obtain contact information for the PPS prescriber to facilitate discussions regarding discontinuation of PPS therapy.

Physical examination

Although exam findings may be more subtle than those on fundus imaging, comprehensive evaluation with DFE should be performed for a patient suspected of having PPS maculopathy.

Signs

Examination may reveal hyperpigmented macular spots and yellowish subretinal deposits in early disease, and patchy parafoveal RPE atrophy, or more widespread atrophy, in severe disease.[6][9][10][20] Some eyes may manifest CME or MNV.[10][11][12] A normal DFE does not rule out PPS maculopathy since patients often have manifestations of disease on imaging that are not readily apparent on examination.

Symptoms

Common symptoms of PPS maculopathy include prolonged dark adaptation, nyctalopia, and difficulty reading or blurred vision, often in the setting of normal BCVA.[6][9][10][11][20] Scotomata in the setting of RPE atrophy, and distorted vision have also been reported.[9][10][11][20] Severe vision loss can occur in the setting of CME, MNV, and/or RPE atrophy.[7][10][20] A comprehensive study of visual function in PPS maculopathy demonstrated Low Luminance Questionnaire scores to be among the lowest ever reported with this tool.[21]

Clinical diagnosis

Clinical diagnosis may be highly suggested in patients with characteristic symptoms, DFE, and history of extensive PPS use. However, multimodal retinal imaging is typically necessary to definitively diagnose PPS maculopathy.

Characteristic features of PPS maculopathy were defined in one study as the following: “(1) bilateral pathology centered on the fovea; (2) fundus photography revealing paracentral macular hyperpigmented spots, pale yellow deposits, and/or patchy retinal pigment epithelium atrophy; (3) a dense array of hyper- and hypoautofluorescent spots and reticular fundus autofluorescence imaging abnormalities; and (4) foci of nodular retinal pigment epithelium enlargement on OCT imaging corresponding to hyperreflectance on near infrared reflectance imaging.”[8]

Diagnostic procedures

Fundus photography, fundus autofluorescence imaging (FAF), optical coherence tomography (OCT), and near-infrared reflectance imaging (NIR) are useful imaging modalities to establish a diagnosis of PPS maculopathy. These same modalities are also useful when screening for the condition. Imaging findings are typically symmetric between both eyes.[9][10]

Multimodal imaging of macular pigment alterations in pentosan polysulfate maculopathy. Macular pigment clumps are visible in color fundus photography (A) and colocalize with hyperautofluorescent spots on fundus autofluorescence imaging (B) and hyperreflectant spots on near-infrared reflectance imaging (C). The lesions cast a shadow on the underlying choroid on ocular coherence tomography (D) and appear to be located in the retinal pigment epithelium. The locations of the scans in panel D correspond to the dotted lines in panel C in descending order.
Multimodal imaging of macular pigment alterations in pentosan polysulfate maculopathy. Macular pigment clumps are visible in color fundus photography (A) and colocalize with hyperautofluorescent spots on fundus autofluorescence imaging (B) and hyperreflectant spots on near-infrared reflectance imaging (C). The lesions cast a shadow on the underlying choroid on ocular coherence tomography (D) and appear to be located in the retinal pigment epithelium. The locations of the scans in panel D correspond to the dotted lines in panel C in descending order. Reprinted with permission from the American Medical Association from: Hanif AM, Armenti ST, Taylor SC, et al. Phenotypic Spectrum of Pentosan Polysulfate Sodium-Associated Maculopathy: A Multicenter Study. JAMA Ophthalmol. Published online September 5, 2019. doi:10.1001/jamaophthalmol.2019.3392

Color fundus photography typically shows more subtle manifestations compared to FAF. Hyperpigmented macular spots and deep yellowish subretinal deposits may be apparent, particularly in milder cases.[9][10][11][12] Patchy parafoveal RPE atrophy manifests in more advanced cases.[6][9][10][20]

Fundus autofluorescence imaging reveals a striking, densely packed array of hyper- and hypoautofluorescent spots typically centered on and involving the fovea.[6][9][10] Hyperautofluorescent spots colocalize with pigmented spots and yellow subretinal deposits apparent on color fundus photography.[6][9][10] In cases where the disease extends to the periapillary region, there is typically a hypoautofluorescent peripapillary halo.[9][10] RPE atrophy may also be noted in more severe cases, initially as multifocal parafoveal lesions, that ultimately coalesce and encroach on the foveal center. Widefield FAF imaging is helpful to elucidate the extent of involved tissue.[10]

Optical coherence tomography shows hyperreflective nodules at the level of the RPE that colocalize with macular pigment clumps on color fundus photography, hyperautofluorescence on FAF, and hyperreflectance on NIR imaging.[6][9][10] Unlike typical drusen or subretinal drusenoid deposits, these lesions appear to reside at the level of the RPE and project a shadow onto the underlying choroid.[10][22] These lesions may not be present on macular OCT in late-stage atrophic disease.[10] Although there may be ill-defined irregularity in the outer retinal bands, there is no clear OCT correlate for yellow macular deposits or the hypoautofluorescent component of FAF lesions.[9][10]

Near infrared reflectance imaging is another important imaging modality with prominent findings that may be present even in the absence of visible lesions in other imaging modalities.[9] Nodular hyperreflective lesions are visible on NIR that correspond to the pigmented lesions on color fundus photography and hyperreflective RPE excrescences on OCT.[6][9][10]

Some functional visual tests may also be useful in detecting visual dysfunction not apparent with BCVA testing alone. Dark adaptometry, perimetry, electroretinography, and visual function questionnaires such as the National Eye Institute Visual Function Questionnaire-39 and the Low Luminance Questionnaire have shown profound visual function deficits in PPS maculopathy patients that was not fully captured with BCVA testing.[6][10][21]

Laboratory test

There are no indicated laboratory tests for PPS maculopathy at this time.

Differential diagnosis

Most cases of pentosan polysulfate maculopathy that involve the peripapillary retina, demonstrate a hypoautofluorescent peripapillary ring (A). The autofluorescent signal is spared in many inherited macular dystrophies such as this dominant macular dystrophy associated with a variant of unknown significance in the ELOVL4 gene (B), another macular dystrophy associated with a disease-causing PRPH2 variant (C), and two disease-causing ABCA4 variants (D).
Most cases of pentosan polysulfate maculopathy that involve the peripapillary retina, demonstrate a hypoautofluorescent peripapillary ring (A). The autofluorescent signal is spared in many inherited macular dystrophies such as this dominant macular dystrophy associated with a variant of unknown significance in the ELOVL4 gene (B), another macular dystrophy associated with a disease-causing PRPH2 variant (C), and two disease-causing ABCA4 variants (D). Reprinted with permission from Elsevier from: Barnes AC, Hanif AM, Jain N. Pentosan polysulfate maculopathy versus inherited macular dystrophies: comparative assessment with multimodal imaging. Ophthalmol Retina. Published online May 21, 2020. doi:10.1016/j.oret.2020.05.008

The differential diagnosis for PPS maculopathy includes Age-related macular degeneration (AMD), macular dystrophies including pattern dystrophies, maternally inherited diabetes and deafness syndrome (MIDD), and pachychoroid pigment epitheliopathy. In most cases, it is possible, and clinically useful, to be able to differentiate these conditions without relying on the history of prior PPS exposure. Indeed, not all patients with macular lesions who take PPS have PPS maculopathy. Additionally, not all patients will disclose a past history of PPS use.

Age-related macular degeneration can be differentiated most readily by looking for the characteristic pattern of PPS maculopathy on FAF imaging, as described above.[22] Additionally, the hyperreflectant RPE lesions observed in earlier stages of PPS maculopathy are distinct from drusen and subretinal drusenoid deposits of AMD. In PPS maculopathy, these lesions appear to be at the level of the RPE and project a shadow onto the underlying choroid, and colocalize with highly hyperreflectant lesions on NIR imaging.[22] In one study comparing PPS maculopathy to AMD, there were no typical macular drusen in eyes with PPS maculopathy.[22]

Hereditary macular and pattern dystrophies typically have less densely-packed FAF lesions than PPS maculopathy and typically spare involvement of the autofluorescence signal in the peripapillary tissue.[23][24] This contrasts to the peripapillary hypoautofluorescent halo common in PPS maculopathy.[25] Another distinguishing characteristic of pattern dystrophies is that they are associated with mutations in a number of genes that are classically inherited in an autosomal dominant pattern.

Mitochondrial disorders such as MIDD can also cause a pigmentary maculopathy but the lesions characteristic of MIDD typically spare the fovea until late disease (unlike PPS maculopathy). Most cases with MIDD-associated macular changes have systemic manifestations such as deafness and diabetes mellitus.[26]

Pachychoroid diseases may present with similar macular changes as PPS maculopathy but characteristically have additional findings such as dilated choroidal vessels, choroidal hyperpermeability, RPE and neurosensory retinal detachments, and streaks from prior exudation on FAF imaging.[27] Pachychoroid diseases may also present asymmetrically between eyes while PPS maculopathy is typically symmetric.[10][27]

Management

There is currently no known treatment for PPS maculopathy. Primary prevention through avoidance or minimizing the cumulative exposure to PPS appears to be key to preventing the condition. Affected patients should undergo continued monitoring for treatable complications of PPS maculopathy such as CME and MNV, as outlined below.

General treatment

Prescribers of PPS should consider counseling patients regarding the risk of vision loss associated with PPS and have a discussion weighing risks and benefits of taking PPS and potential alternative therapies. If PPS is prescribed, providers should prescribe the minimum dose and duration necessary for disease management.

Fundus autofluorescence images of a pentosan polysulfate maculopathy patient with progressive atrophy at four (A) and eighteen (B) months after pentosan polysulfate cessation.
Fundus autofluorescence images of a pentosan polysulfate maculopathy patient with progressive atrophy at four (A) and eighteen (B) months after pentosan polysulfate cessation. Reprinted with permission from the American Medical Association from: Shah R, Simonett JM, Lyons RJ, Rao RC, Pennesi ME, Jain N. Disease Course in Patients With Pentosan Polysulfate Sodium-Associated Maculopathy After Drug Cessation. JAMA Ophthalmol. Published online July 9, 2020. doi:10.1001/jamaophthalmol.2020.2349

After a diagnosis of PPS maculopathy, patients are encouraged to work with their prescriber to transition to other IC therapies. After diagnosis, providers should consider monitoring patients annually with multimodal retinal imaging so that treatable vision-threatening sequelae may be addressed should they occur. Pentosan polysulfate maculopathy may progress after drug cessation.[20][28]

Medical therapy

There is no known treatment for PPS maculopathy itself. Affected individuals should consult with their ophthalmologist and PPS prescriber to discuss drug cessation and explore alternative treatments for IC.

Some vision-threatening complications of PPS maculopathy, including CME and MNV, can be treated pharmacologically. Cystoid macular edema can be treated with topical carbonic anhydrase inhibitors, corticosteroids, or nonsteroidal anti-inflammatory agents; oral acetazolamide; or intravitreal anti-VEGF injections. Macular neovascularization can also be treated with intravitreal anti-VEGF therapy.

Medical follow up

Ophthalmologists at the Emory Eye Center monitor patients taking PPS or diagnosed with PPS maculopathy annually with a comprehensive retinal evaluation including color fundus photography, FAF, OCT, and NIR imaging.

Another group recommends an initial exam within six months of initiating PPS and annual exams as the patient approaches 500 g cumulative exposure.[9]

Complications

Retinal pigment epithelium atrophy appears to be a manifestation of advanced PPS maculopathy.[9][10] It typically first develops as parafoveal multifocal atrophy that may coalesce over time and involve the foveal center.[10]

Leaking and non-leaking CME has been described in PPS maculopathy and has been successfully treated with both topical and intravitreal therapies described above.[10][12] Macular neovascularization has been reported in PPS maculopathy patients and has been successfully treated with intravitreal anti-VEGF injections.[10][11]

Prognosis

Although more longitudinal data is needed to explore the long term prognosis of this recently discovered condition, PPS maculopathy is not known to be reversible and may progress after drug cessation.[20][28] Eyes with RPE atrophy demonstrate progression of atrophy even after drug cessation.[20][28] These findings suggest that early detection is beneficial. Additionally, patients with PPS maculopathy should undergo continued monitoring for treatable complications including CME and MNV.


References

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