Pentosan Polysulfate Maculopathy

Etiology

Studies agree that the duration of PPS use, which correlates strongly with cumulative exposure to PPS, might be the most important risk factor for developing PPSM.[9][10] Although PPSM has been seen in a patient with only 325 g and 2.25 years of exposure, most patients develop the disease years later.[11] Specifically, a 2022 review averaging 9 studies calculated an average of 15.0 ± 5.7 years of exposure and a cumulative exposure of 1824 ± 1042 g, data which were corroborated in a subsequent large review.[12] One of these studies noted a prevalence of toxicity of 16% among all affected patients versus a prevalence of 40% in those with cumulative dosages greater than 1000 g and 55% in those with a cumulative dose greater than 1500 g.[5]

These studies included patients from the time of PPSM diagnosis, not when they become symptomatic, so the onset of the disease is likely earlier.[4] When these patients were categorized by disease severity, there was an association between severity, duration of use, and cumulative dose, but not a daily dose of PPS.[5] This association was also borne out in a large-scale study of insurance records, which showed an increased risk of PPSM among those users with more than 3 years of exposure to PPS compared with those with less than 3 years (hazard ratio of 9.5 vs 2.2).[10]

The daily dose and dose per unit of body weight are also not infrequently discussed as potential enablers of toxicity. One study found a higher mean daily dose among affected patients (445 vs 302 g).[9] This finding has been corroborated in a survey study in which patients on 100 mg of PPS for 15 years were less likely to report maculopathy than the patients on 500 mg for a median intake of 5 years.[13] The BMI of affected patients may be on the upper end of normal (24.6 kg/m) but has also been reported to be closer to the middle of the normal range (23.2 kg/m).[12][14]

Epidemiology

Patients with PPSM are predominantly White (93%) and female (90%), with a mean age of 62.2 ± 13.2 years.[4] The prevalence of PPSM among PPS users is difficult to gauge due to differing study designs, varying durations of drug use, differing cumulative (and perhaps daily) doses, mischaracterization of affected patients as possibly having other maculopathies, and the fact that subtle signs and symptoms of the disease may be missed at a point when rigid screening protocols have not yet been widely adopted.

Notwithstanding these limitations, the prevalence of PPSM among those who have used PPS ranges from 0.7% to 2.4% and 3.4% in large-scale retrospective studies from insurance claims databases; however, these studies likely underestimate the true prevalence of PPSM because patients would have to have been diagnosed with another retinal disease, and length of follow-up in the databases limits the ability to find an association between PPS and a retinal disorder.[10][14][15]

Among larger prospective screening studies on known PPS users, the prevalence is estimated to be between 16.5% and  23.1%, although these may overestimate the true prevalence because of selection bias.[5][8]

Pathophysiology

PPS has been proposed to cause this characteristic maculopathy by direct toxicity to either the retinal pigment epithelium (RPE) or the choroid, although other mechanisms have been proposed. RPE toxicity is thought to be due to PPS interfering with the interaction of the retina's extracellular matrix (ECM) or its regulators, notably fibroblast growth factor (FGF). Choroid toxicity is postulated due to changes in the choroidal vasculature, specifically the choriocapillaris. These findings are perhaps best supported by imaging, which consistently finds a primary abnormality in these layers, as well as the finding of progression despite drug cessation.[4][6][16]

The ECM in the retina includes the interphotoreceptor matrix (IPM). This area is responsible for intracellular communication, the delivery of signaling molecules, nutrients, and metabolism, maintenance of retina adhesion, photoreceptor alignment, and the transport regulation of oxygen. These processes are predominantly controlled by the IPM's large glycosylated proteins, including chondroitin sulfate, dermatan sulfate, SPACR, and SPACRCAN.[17][18][19]

PPS has been shown to interact with cartilage proteoglycans in experimental animal models of arthritis, leading to its approval as a disease-modifying antirheumatic agent for veterinarians.[2] In infectious arthritis, PPS has been shown to be associated with decreased levels of ADAMTs5 and TIMP-3 and stable levels of aggrecan, collagen I, and II.[2] The ECM and IPM also contain complement factor H[18]; PPS has been shown to inhibit the alternative and classical pathways of complement activation and could have a harmful effect via this pathway as well.[2] Due to its structural similarity to these glycosylated proteins, PPS could displace the normal IPM constituents, similar to its effect in the bladder urothelium.

One additional component of the ECM and IPM is the fibroblast growth factors (FGFs) that bind to heparin and heparan sulfate.[20] PPS has been shown to inhibit the FGF-1, -2, and -4 signaling pathways, which play an important role in animal models of the organization and development of the retina, as well as maintenance of retinal health and regeneration.[21]

When FGF signaling is inhibited in transgenic zebrafish, the RPE layer thickens significantly as the cells grow to contact the outer segments of the photoreceptors.[22] In humans, certain chemotherapeutic agents target FGF receptors (FGFRs), including erdafitinib (pan-FGFR inhibitor) and pemigatinib (FGFR 1-3), both of which have been shown to induce an increase in reflectivity and thickening of the ellipsoid and interdigitation zones, with subsequent subretinal fluid (SRF) and serous retinal detachment.[23][24][25][26] SRF from chemotherapeutic targeting starts an average of 21 days after starting the medication. Conversely, SRF will often resolve without discontinuation of PPS. Additionally, in one case report, there were no changes to the choroidal vasculature [24][27]

More recent research using optical coherence tomography–angiography (OCT-A) to characterize choroidal vasculature in PPS-exposed patients who have no other findings of PPSM has shown increased vascular flow deficits within the choriocapillaris and decreased choroidal stroma in the deeper Haller and Sattler layers, leading to an increased choroidal vascular index (CVI). (CVI corresponds to the ratio between the choroidal luminal area and the luminal and stromal areas.) As the authors point out, this could be due to the choriocapillaris being a secondary target of PPSM or a secondary effect of the disrupted RPE.[5][28] 

The fact that these flow voids are detectable in patients without other stigmata of the disease lends credence to the choriocapillaris being a primary site of injury, as ischemic changes would only be expected to progress. Further, the evidence that visual acuity is spared despite these changes in the choriocapillaris flow may also support this argument.[7]

Other proposals for the pathogenesis of PPSM include mitochondrial dysfunction (based on phenotypic similarity) and the fact that there may be an undefined common cause of interstitial cystitis, making the maculopathy unrelated to PPS exposure.[1][29][30]

In sum, the ECM of the RPE and the choroidal vasculature contain numerous constituents that have either been shown to be affected by PPS or have theoretical interactions based on the structure of PPS. Therefore, the pathogenesis of PPSM is likely located in this area.[21]

History and Physical

Patients with PPSM will report a history of chronic use of PPS, which they may have already discontinued. If they are unable to report the use of the medication, they may also report having used a drug to help with bladder pain.

Although patients can be asymptomatic, they may also present with the following symptoms in order of decreasing frequency: decreased visual acuity, nyctalopia, metamorphopsia, paracentral scotoma, and delayed dark adaptation.[7][11] These symptoms are generally accepted as having a gradual onset. However, one case report described a patient who transitioned from asymptomatic and without retinal findings to having developed advanced PPSM within 2 years.[31]

Regarding visual acuity, the decrease experienced by patients is typically mild, with many studies reporting an average of 20/25 unless the patchy areas of the atrophic retina coalesce into the central fovea.[4][5][32] However, measures of visual acuity alone fail to characterize the visual disability caused by PPSM. Patient-reported outcomes on the National Eye Institute Visual Functioning Questionnaire (NEI VFQ-39) reflect that patients with moderate and advanced PPSM have worse function than those with intermediate age-related macular degeneration (AMD). Additionally, results on the Low Luminance Questionnaire reflect especially low subjective scores on driving, dim lighting, and extreme lighting.[32]

Delayed dark adaptation has also been studied objectively. Although many patients were found to have an increased rod intercept time, the wide variability of the results caused the test to have a low sensitivity for detecting PPSM.[32]

Patients are unaffected by decreased contrast sensitivity until late in the disease state.[32]

Evaluation

Anterior segment examination is predominantly within normal limits for patients of this age.[5] Fundus examination findings can be subtle and are primarily characterized as densely-packed bilateral paracentral hyperpigmented spots with surrounding yellow subretinal deposits with mottled RPE atrophy.[11][33] Most of these spots are bilateral (97.3%) and confined to the posterior pole; however, wide-field imaging has also shown that 36% of patients had changes in the peripheral retina.[6][12][6]

The pattern is most striking on autofluorescence, which shows a typically well-circumscribed area of small, densely-packed hyper- and hypoautofluorescent spots.[11][34] Fundus autofluorescence (FAF) also discloses that 100% of eyes have a peripapillary hypoautofluorescent halo.[5]

On OCT, the colocalized yellowish pigment on fundus examination and the hyperautofluorescent lesions correspond to nodular RPE abnormalities and excrescences, which cast a shadow onto the underlying choroid (thereby differentiating them from drusen).[4][11] With time, these areas of excrescences and conglomerations change; specifically, overlying retinal layers will progressively thin, and there will be associated RPE atrophy.[6][7][8][11] Cystoid macular edema (CME) occurs less frequently (between 4.2% and 12.9% of patients), as do neovascular membranes (1.4% to 17.6% of patients) and subfoveal vitelliform deposits.[35]

Near-infrared reflectance (NIR), co-acquired with OCT, is often highly effective in showing the characteristic lesions in mild forms of the disease, including when FAF findings are inconclusive.[12] Specifically, similar symmetrical hyperreflectant spots centered on the macula may be seen on NIR, whereas the FAF does not show these lesions. This difference may be due to NIR utilizing a longer wavelength of light (820 nm) than FAF (480 nm), penetrating more avidly into deeper retinal layers.[36] The critical implication of this finding is that patients who are unable to access a center with fundus autofluorescence capabilities can still be screened if OCT is used.

On OCT-A, PPSM has many characteristic findings that may hint at the ultimate pathophysiology of the disease. PPSM is associated with abnormal foveal avascular zone (FAZ) configurations and decreased choriocapillaris perfusion in patients with later stages of the disease. These areas of decreased perfusion were shown to have a flow void average of 54%, compared with 14% in non-PPSM patients, and they correspond to areas of outer retinal atrophy.[5][7]

A separate analysis of the stroma on OCT-A found a decreased stromal choroidal area with a preserved stromal luminal area, yielding an increased choroidal vascularity index. These changes on OCT-A may be utilized to detect patients with forme fruste PPSM, as increased flow voids were found in 15 patients with greater than 1000 g of PPS exposure who had no other findings on retinal imaging.[28] Further, it can help differentiate the condition from AMD, in which the choroidal vascularity index increases.[5] Importantly, OCT-A can also identify patients with choroidal neovascular membranes.[12][37]

When tested on electroretinography (ERG), patients can have nonspecific responses ranging from normal to mild attenuation of amplitude in code and rod responses with variable delay in response.[38] Similarly, multifocal ERG will reflect mild-to-severe attenuation of response amplitude.[6][34] Electro-oculograms reflect predominantly normal Arden ratios, though dark adaptometry is frequently found to be prolonged.[7][11][32]

Multiple studies have included genetic testing for patients with PPSM to rule out other maculopathies. Although none have found clear associations, some wonder if there may be a genetic predisposition to having a more severe phenotype.[5][7][39] For example, a patient in one study had an NPHP1 mutation and severe phenotype, and another had a family history of AMD and a variant of undetermined significance in the RP1 gene who presented with geographic atrophy and count fingers vision.[7][9] Other studies have reported multiple variants of uncertain significance, including ABCA4, ADAM9, IMPG2, MPZ, and TIMP3.[6]

Based on these results, Barnes and colleagues proposed 6 diagnostic criteria:[33]

1. Macular hyperpigmented spots with yellow-orange deposits and patchy RPE atrophy on fundus photography
2. Densely packed clusters of hyper- and hypoautofluorescent areas within the posterior pole on FAF
3. Focal thickening of the RPE with hyperreflectance on NIR
4. The peripapillary hypoautofluorescent halo
5. Maximum size of the hyperautofluorescent spots of 2 venule widths.
6. Absence of typical drusen

Further, based on their work, Wang and colleagues proposed the following guidelines for defining disease severity:[9]

1. Mild: Speckled pattern on FAF without well-demarcated atrophic lesions on FAF and no evidence of complete RPE and outer retinal atrophy
2. Moderate: Well-demarcated, nummular, and colocalized lesions with RPE and outer retinal atrophy; no central foveal involvement
3. Severe: Well-demarcated lesions with associated hypoautofluorescent atrophy with RPE and outer retinal atrophy, which involves the central fovea

Hanif and colleagues proposed a similar classification of severity:[6]

1. Disease within the vascular arcades and without areas of atrophy
2. Disease extending to the vascular arcades but not more than 2  disc diameters beyond or the presence of noncentral atrophy.
3. Disease that extends more than 2  disc diameters beyond the temporal arcades or the presence of central foveal atrophy.

Additionally, Wang et al found a correlation between disease severity and cumulative dosage; however, the sample size was too small to draw any conclusions.[5]

Treatment / Management

There is no known treatment for PPSM; therefore, primary prevention is imperative with medication avoidance or using the lowest effective dose if necessary. The sight-threatening sequelae of PPSM can be treated with common medications already used to address those conditions. For example, patients with cystoid macular edema have been successfully treated with carbonic anhydrase inhibitors and anti–vascular endothelial growth factor (VEGF) drugs, and patients with choroidal neovascular membranes have been treated with intravitreal anti-VEGF medications.[37]

Differential Diagnosis

The differential diagnosis of PPSM and the primary methods of differentiating it from these conditions include:

AMD

PPSM and AMD are characterized by patients with similar demographics and pigmentary macular changes, which can progress to geographic atrophy. The 2 entities can be differentiated via multimodal imaging and identification of the typical pattern of PPSM.[40]

Specifically, hyperpigmented macular spots with yellow-orange deposits, which are at the level of the RPE and not below, along with dense packing of hyper- and hypoautofluorescent spots on FAF (especially with a peripapillary autofluorescent halo) best describe PPSM. On the other hand, AMD can be identified by drusen, which is below the RPE. In one study comparing these diagnoses, no macular drusen were found in eyes diagnosed with PPS. In contrast, RPEE pigmentary clumps were more frequently found in AMD eyes of patients with prior PPS exposure.[40] 

Pattern Dystrophy

When differentiating PPSM from other pattern dystrophies, the same framework from above is used; however, special attention is paid to three features in patients with borderline imaging.[33] First, the peripapillary hypoautofluorescent halo is extremely useful for differentiating from the ABCA4-retinopathies; however, it is less so when the disease has not yet progressed to encompassing the optic nerve. Second, the density of abnormalities in PPSM is significantly higher than what is seen in hereditary maculopathies. Third, PPSM can involve (but does not necessarily have to) the central fovea early in the disease course.[33]

Inquiring about the family history or performing genetic testing can be useful in cases that are not elucidated by these three findings.

Mitochondrial Dystrophy

There is a phenotypic overlap between PPSM and mitochondrial retinopathies, including reticulated-appearing fundus, peripapillary atrophy, and nyctalopia. One difference that may be seen between these diseases is that PPSM does not necessarily spare the fovea early in the disease, whereas mitochondrial illnesses will. Further, mitochondrial illnesses often have systemic manifestations not seen in PPSM, such as muscle weakness (eg, cardiomyopathy).[41]

Prognosis

PPSM is a progressive maculopathy that leads to areas of RPE atrophy that can decrease visual acuity, causing legal blindness. Other visually debilitating symptoms include nyctalopia, metamorphopsia, a paracentral scotoma, and delayed dark adaptation.[4] The disease may progress despite discontinuation; however, cessation may help slow or reverse the disease.[7][42][43][44][45]

Complications

In addition to decreased visual acuity from RPE atrophy, the sight-threatening sequelae of PPSM include CME, subfoveal vitelliform deposits, and macular neovascular membranes.[12][35][37][46]