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Retinal Disease Mimicking Age-Related Macular Degeneration

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A recent study has reported a link between prolonged exposure to pentosan polysulfate sodium (PPS), the only FDA-approved oral medication for the treatment of interstitial cystitis and retinal damage. Sold under the brand name Elmiron, it is an effective, well-established treatment for bladder infections and is widely prescribed. The first clinical trial testing the therapeutic efficacy of PPS on interstitial cystitis was in 1987, with initial use in the US in 1996.

Interstitial cystitis (IC) or bladder pain syndrome (BPS) is a poorly defined chronic clinical disease distinguished by abdominal pain, frequent urination, and an urgency to urinate.1 Patients report pressure and pain in the bladder area with persistent urinary tract symptoms lasting for more than 6 weeks. There is no infection or other clear obstruction causing the discomfort. The patient can experience poor quality of life with difficulty sleeping, sexual dysfunction, stress, and depression.2 Stress increases symptoms of urination urgency and bladder pain in patients with IC/BPS.2,3

The exact cause of IC/BPS is uncertain, but some theories include: defects in the bladder tissue, presence of inflammatory mast cells, bladder damage, and the body’s immune system attacking the bladder. Diagnosis is made by eliminating any other cause for the symptoms and only then is treatment initiated.4

Pentosan polysulfate sodium is a semi-synthetic analogue of biologic glycosaminoglycans and performs like an anticoagulant to thin the blood. Its mechanism of action is not completely understood in the treatment of IC/BPS but the consensus seems to be that it may form a protective coating over the bladder tissue by binding to the epithelial lining.5 It can take more than 3 months before patients notice an improvement in their symptoms, and ongoing treatment with PPS is often necessary.1 Prolonged therapy has been prescribed for decades with no known ocular toxicity previously reported. It is estimated that more than 1 million people in the US have IC/BPS and, with Elmiron being the only oral treatment available, there is the potential for hundreds of thousands of people to have had long-term exposure to PPS. 

Pearce et al. described a potential vision threatening complication with chronic use of PPS.6 Six patients presented with a similar retinopathy primarily affecting the macula. The patients involved reported symptoms of prolonged dark adaptation and blurry vision, and imaging was suggestive of retinal pigment epithelium (RPE) damage.6 On fundus examination these patients demonstrated subtle macular changes, and fundus autofluorescence imaging of the posterior pole revealed abnormalities.6 It is not yet understood how varied PPS exposure length, dosage, and susceptibility may have influenced the outcome.

These findings prompted Ophthalmologists at Kaiser Permanente, California to look at their population of patients. They examined their entire database (4.3 million) and found 140 patients who had taken an average of 5,000 pills over the course of 15 years. Of these patients, 91 came in for a retinal examination. Twenty-two of the 91 patients showed obvious signs of drug toxicity.7

Shah et al. also performed a retrospective study evaluating all patients with IC/PBS seen at the Emory Eye Center over a 4-year period. They identified 80 patients with prior exposure to PPS and, of these, 14 had signs of maculopathy.8 The researchers commented that their findings implicate PPS as a causative drug for macular disease, but larger human trials are needed to decisively establish the connection.8 

The documented maculopathy has a consistent clinical presentation confirmed in the largest retrospective case series of 35 patients with a confirmed diagnosis of PPS-associated maculopathy.9 The data were obtained from four institutions and the median PPS intake duration was 14.5 years. The median cumulative level per kilogram of body mass was 24.7 g/kg.9 Color fundus photography revealed paracentral pigment clumps with yellow subretinal deposits. Fundus autofluorescence exhibited a densely packed pattern of hyper- and hypo-autofluorescent spots at the macula and optical coherence tomography demonstrated nodular lesions at the RPE level corresponding to these macular spots. In a small number of cases, longitudinal evaluation showed extension of the disease peripherally with pigmented macular spots progressing to RPE atrophy over time.9 These clinical presentations see PPS toxicity masquerading as age-related macular degeneration. 

The potential adverse visual effects of PPS must be considered before prescribing long-term therapy. A screening protocol will likely arise, similar to that currently used for hydroxychloroquine toxicity investigations. Dosing strategies should be implemented to prescribe the lowest necessary dose for symptom control. Baseline visual examination with imaging and yearly follow up will likely become protocol.8,10 For IC/BPS patients with comorbid macular disease, PPS may not be a recommended therapeutic option and, if patients are diagnosed with PPS maculopathy, drug cessation would be advisable. Without fully understanding the mechanism of action of PPS, it is difficult to predict if visual symptoms will persist and even progress after drug cessation.8 

Ongoing clinical trials and retrospective studies will enhance our knowledge of the effects of PPS on the retina and help formulate screening protocols to reduce vision-threatening implications.

References

1. Van Ophoven A, Vonde K, Koch W, Auerbach G, Maag K. Efficacy of pentosan polysulfate for the treatment of interstitial cystitis/bladder pain syndrome: Results of a systematic review of randomized controlled trials. Curr Med Res Opin. 2019;35(9):1495-1503. doi: 10.1080/03007995.2019.1586401.

2. Lutgendorf SK, Kreder KJ, Rothrock NE, Ratiff TL, Zimmerman B. Stress and symptomatology in patients with interstitial cystitis: A laboratory stress model. J Urol. 2000;164:1265–1269.  

3. Koziol JA, Clark DC, Gittes RF, Tan EM. The natural history of interstitial cystitis: A survey of 374 patients. J Urol. 1993;149:465–469.

4. What is interstitial cystitis(ic)/bladder pain syndrome? Urology Care Foundation. https://www.urologyhealth.org/urologic-conditions/interstitial-cystitis. 2019.

5. Hanno PM, Erickson D, Moldwin R, Faraday MM. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Jurol. 2015;193:5:1545-1553.

6. Pearce WA, Chen R, Jain N. Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium. Ophthalmology. 2018;125(11):1793–802. doi: 10.1016/j.ophtha.2018.04.026

7. Hanif AM, Jain N. Clinical pearls for a new condition: Pentosan polysulfate therapy, a common treatment for interstitial cystitis, has been associated with a maculopathy. Rev of Ophthal. 2019.

8. Shah R, Jain N. Pentosan polysulfate maculopathy. Frequently asked questions about a newly described vision-threatening condition. Ret Phys. 2019.

9. Hanif A, Taylor S, Armenti S, et al. Expanded clinical spectrum of pentosan polysulfate sodium-associated pigmentary maculopathy. Paper presented at: Association for Research in Vision and Ophthalmology; April 30, 2019; Vancouver, BC, Canada.

10. Ferguson TJ, Geraets RL, Barker MA. Chronic use of pentosan polysulfate sodium associated with risk of vision-threatening disease. Int Urogy J. 2019;30:337–338. doi: 10.1007/s00192-018-3850-9.

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