Pentosan Polysulfate Maculopathy (PPM) is a progressive pigmentary maculopathy that occurs with long-term use of sodium pentosan polysulfate (PPS), a treatment for interstitial cystitis (IC). It was first reported by Pearce et al. in 2018.
PPS is a semi-synthetic heparin-like glycosaminoglycan (GAG) compound sold under the brand name Elmiron in the United States, and over 1 million people suffering from IC take it long-term 1). The standard dose is 200 mg/day (divided into 2-3 doses per day).
Regarding the relationship between cumulative dose and prevalence, large-scale analyses have reported the following1).
| Cumulative dose | Prevalence |
|---|---|
| 500–999 g | 12.7% |
| 1000–1500 g | 30% |
| >1500 g | 41.7% |
The average duration of treatment in affected patients is reported as 15.0±5.7 years, with a mean cumulative dose of 1824±1042 g1). The median visual acuity at initial presentation is 20/25 (equivalent to decimal 0.8), and many cases already have visual dysfunction at the time of detection1).
PPS is a semi-synthetic glycosaminoglycan compound prescribed to relieve chronic pain and bladder discomfort in interstitial cystitis. In the United States, it is widely used under the brand name Elmiron, with a standard dose of 200 mg/day, often administered continuously over the long term.
In the early stages, there are often no symptoms, and the condition may be discovered incidentally during an examination. As the disease progresses, the following subjective symptoms appear.
Imaging findings characteristic of PPM are confirmed by multiple modalities.
FAF Findings
Dense speckled pattern: Speckles of mixed hyperfluorescence and hypofluorescence appear densely in the macula. This is a highly specific finding for PPM.
Peripapillary halo: A hypofluorescent band forms around the optic disc. Useful for differentiation from hereditary macular diseases.
Pseudopod-like extension: The lesion margin expands irregularly over time. This is an indicator of disease activity 1).
OCT and OCTA Findings
RPE nodules: Hyperreflective nodular changes at the level of the retinal pigment epithelium (RPE), casting a shadow on the underlying choroid.
Outer retinal tubulations (ORCs): Tubular structures occurring between the photoreceptor outer segments and the RPE1).
Choriocapillaris flow deficit: OCTA detects blood flow deficits in the choriocapillaris. This may be the earliest marker, appearing before other imaging abnormalities1)2).
Complication of type 3 MNV (macular neovascularization): The occurrence of type 3 MNV in PPM patients has been reported for the first time2). OCTA has shown hyperreflective foci (HRF) moving from the outer nuclear layer (ONL) to the inner nuclear layer (INL), followed by the appearance of flow signal2).
Multifocal electroretinography (mfERG): It can objectively evaluate macular dysfunction. Reduced amplitudes corresponding to the extent of the lesion are observed1).
The sole cause of PPM is long-term use of PPS. Dose-dependent toxicity is suggested, and cumulative dose is the greatest risk factor.
For the diagnosis of PPM, multimodal imaging evaluation is important. The Macula Society has published a screening protocol recommending assessment with fundus photography, FAF, SD-OCT, and multifocal electroretinography1).
The role of each test is described below.
| Test | Main Findings | Role |
|---|---|---|
| FAF | Dense speckled pattern | Most diagnostic |
| SD-OCT | RPE nodules / outer tubulation | Structural assessment |
| OCTA | Choriocapillaris defect | Earliest marker |
Differentiation from the following diseases is necessary.
A detailed history of PPS use (duration, daily dose, estimated cumulative dose) is essential for accurate diagnosis.
Currently, there is no fundamental treatment for PPM 1). The mainstay of treatment is discontinuation or tapering of PPS and symptomatic therapy for complications.
Anti-VEGF drug administration is effective for cases with type 3 MNV2).
Bousquet et al. reported a 72-year-old woman who developed type 3 MNV after 11 years of PPS use (cumulative dose 1205 g) and 1 year after discontinuing PPS. She received two intravitreal injections of aflibercept. Visual acuity improved from 20/60 to 20/30, and regression of MNV was confirmed2).
PPM lesions are irreversible, and cases of progression even after drug discontinuation have been reported1)2). Since early detection and discontinuation may delay progression, regular screening and early intervention are important.
The exact pathogenesis of PPM remains largely unknown, but several mechanisms involving GAG-like structures of PPS have been proposed.
Disruption of the interphotoreceptor matrix by GAG-like structures: PPS has a structure similar to sulfated GAGs, accumulating in the retinal extracellular matrix and disrupting it. The interphotoreceptor matrix (IPM), essential for maintaining photoreceptor outer segments, is impaired, leading to photoreceptor degeneration1).
Inhibition of fibroblast growth factor (FGF): PPS may bind to and inhibit FGF, a heparin-binding growth factor, thereby impairing signaling necessary for cell maintenance in the RPE and choriocapillaris1).
Damage to the choriocapillaris: PPS impairs perfusion of the choriocapillaris, reducing nutrient and oxygen supply to the RPE and photoreceptors. Flow deficits observed on OCTA reflect this choroidal microcirculatory disturbance1)2).
Mechanism of type 3 MNV: It is speculated that RPE damaged by PPS loses its compensatory function locally, inducing inward neovascularization (type 3 MNV) from the deep retinal capillary plexus. The process observed on OCTA, where HRF moves from the ONL to the INL and then a flow signal appears, suggests the growth process of new blood vessels 2).
Pinto AM et al. observed a 13-year long-term course and first recorded the persistent progression of pseudopodial pattern on FAF 1). Visual acuity decreased from 20/25 to 20/100 over 13 years, and it was confirmed that lesions persisted and progressed even after discontinuation of PPS.
Quantification of flow deficit in the choriocapillaris using OCTA is attracting attention as an early diagnostic marker.
Bousquet et al. recorded that flow deficit in the choriocapillaris existed even before the onset of type 3 MNV, showing that OCTA could be the earliest marker of structural changes 2). This suggests the possibility of predicting progression to MNV in advance.
The Macula Society established screening guidelines in 2019 1). Research continues on more accurate screening methods, such as OCT quantification and application of AI for image analysis.
