Case of the Month

Edited by Robert N. Johnson, MD

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Case #126

December, 2019

Presented by:

Caleb Ng,  MD

A 57 year-old female referred for distortion and decreased vision

Case of the Month Listing

Figures 1A and B: Color fundus photographs of the right and left eye. Note the areas of pigment mottling encircling the right fovea, and more subtle pigment changes in the left eye. The optic nerve and vessels are normal.

Case History:

A 57 year-old Caucasian female patient with presented for evaluation of mild distortion of central vision that had been present for 10 years, but significantly worsened over the last 2 years. She was most symptomatic when trying to read. She also reported decreased vision when transitioning from light to dark settings.

 

On examination, best corrected visual acuity was 20/20-2 and 20/25-2 in right and left eyes, respectively. Intraocular pressure was 13 and 15. Anterior segment exam was unremarkable. Posterior segment exam of the right eye revealed a circular area of RPE clumping in the fovea and subtle areas of retinal pigment epithelium (RPE) atrophy. The left eye similar revealed granular RPE disruption, but in a more speckled pattern. (Figures 1A and B). Fluorescein angiography of both eyes revealed mottled hyper- and hypofluorescence in both macula without evidence of leakage (Figures 2A-D). Fundus autofluorescence of both eyes revealed areas of increased autofluorescence in the right macula corresponding to the circular area of pigment clumps. (Figure 3A and inset). In the left macula, there was multiple dot-like areas of reduced autofluorescence in the macula (Figure 3B). OCT studies showed the areas of pigment clumping and hyperreflectivity in the outer retinal layers in the right eye (Figure 4A).

Figures 2A-D: Fluorescein angiogram of the right and left eyes. Mottled areas of hyperfluorescence are present in both eyes, more prominently in the right eye (Figures 2A and B). No leakage is present in the late phases (Figures 2C and D).

Figures 3A and B): Fundus autofluorescence of the right eye and left eye. The areas of increased hyperfluorescence in the right eye correspond to the pigment clumping. Dot-like areas of reduced hyperfluorescence are present in the left eye.

Figures 4A and B: SD-OCT of the right and left macula. Hyperreflective areas overlying the RPE clumps are noted in the outer retina of the right eye (Figure A).

What is your Diagnosis?

Differential Diagnosis

  • Pattern Dystrophy
  • Age-Related Macular Degeneration
  • Doyne honeycomb retinal dystrophy (malattia leventinese)
  • Drug toxicity

 

Additional History and Diagnosis

The patient revealed a 20 year history of interstitial cystitis, initially treated with 2 courses of intravesical pentosan polysulfate sodium (PPS) and then changed to oral PPS for approximately 20 years. On recent follow up with her urologist, patient was advised to cease use of PPS and follow up with retinal specialist regarding her visual symptoms. Patient was diagnosed with pentosan polysulfate sodium maculopathy.

 

Discussion

Interstitial cystitis (IC) is a chronic, incurable condition that predominantly affects women and is in the spectrum of diseases known as painful bladder syndrome. It manifests as bladder pain or pressure, or pelvic pain. This condition is thought to arise from aberrant innervation of the bladder, resulting in smaller threshold for contraction and voiding.1 In the early 1990’s PPS was discovered to significantly decrease symptoms compared to placebo without any significant adverse reactions.2,3 The treatment is postulated to coat the lining of the bladder, reducing irritation and cellular permeability. PPS proceeded to obtain FDA approval in 1996 and has since been utilized extensively to treat IC without any safety concerns for decades. However, Jain et al published a case series in 2018 of 6 patients with unique pigmentary retinopathy noted in the setting of chronic oral PPS exposure.4 These patients shared findings of paracentral hyperpigmentation of the RPE with surrounding array of vitelliform-like deposits on fundus exam, with extensive macular changes on autofluorescence.4 A more recent presentation on larger series of 35 confirmed PPS-associated maculopathy patients is revealing possible trends in clinical features.5 (Table) The authors note that given the recent recognition of this entity, the observed findings likely reflect relatively advanced disease, and does not characterize incipient disease. The mechanism of chronic PPS exposure induced maculopathy is yet to be elucidated. A recent paper suggested that PPS may interfere with retinal fibroblast growth factor signaling.6

In a recent presentation of a series of 91 patients that had taken PPS for over 15 years (and at least 5000 pills) observed toxicity rose with the amount of drug consumed. Investigators noted the rate of toxicity of those taking 500 to 1000 grams was 11% and that number jumped to 42% when patients were taking 1500 grams or more.7 It was also noted that the late-stage damage can mimic advanced dry atrophic macular degeneration and result in permanent vision loss.

 

At this time, official screening and dosing recommendations are unavailable. However, when PPS use is necessary, the available evidence suggests the use of the lowest effective dose for the shortest possible duration. Asymptomatic patients with chronic PPS exposure may benefit from baseline examination with imaging (fundus photos, FAF, and OCT) and serial exams with fundus imaging.

Summary of Findings in 35 Patients with PPS Maculopathy

  • Median Age: 60 years (range 37-79 years)
  • Median Duration of PPS Intake: 14.5 years (range 3-22 years)
  • Median Duration of Visual Symptoms: 4 years (range 1-9 years)
  • Color Fundus Photos:
    • Bilateral, symmetric pathology (100%)
    • Centered on and involving fovea (100%)
    • Spots of hyperpigmentation (50%)
  • Fundus Autofluorescence:
    • Dense pattern of hyper- and hypoautofluorescent spots (100%)
    • Well circumscribed region of disease (55%)
    • RPE atrophy >⅓ disc diameter in size (40%)
    • Center-involving atrophy (9%)
  • Ocular Coherence Tomography
    • Discrete lesions of RPE thickening (100%)
    • Ill-defined irregularity in outer retinal bands (100%)

References:

 

  1. Interstitial Cystitis. Mayo Clinic. www.mayoclinic.org/diseases-conditions/interstitial-cystitis/symptoms-causes/syc-20354357. Accessed October 22, 2019
  2. Mulholland SG, Sant GR, Hanno P, Staskin DR, Parsons L. Pentosan polysulfate sodium for therapy of interstitial cystitis: A double-blind placebo-controlled clinical study. Urology. 1990 Jun 1;35(6):552-8.
  3. Parsons CL, Benson G, Childs SJ, Hanno P, Sant GR, Webster G. A quantitatively controlled method to study prospectively interstitial cystitis and demonstrate the efficacy of pentosanpolysulfate. The Journal of urology. 1993 Sep 1;150(3):845-8
  4. Pearce WA, Chen R, Jain N. Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium. Ophthalmology. 2018 Nov 1;125(11):1793-802.
  5. Li AL, Jain N, Yu Y, VanderBeek BL. Association of macular disease with long-term use of pentosan polysulfate sodium: findings from a large U.S. national insurance database. May 1, 2019. Association for Research in Vision and Ophthalmology. Vancouver, BC.
  6. Greenlee T, Horn G, Conti T, Babiuch AS, and Singh R: Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium. Ophthalmology Letters to the Editor. 2019: 7 Page e51.
  7. Vora, Robin. Prevalence of Maculopathy Associated with Pentosan Polysulfate Therapy in Kaiser Permanente Northern California. AAO Presentation, 2019

Comments or Questions

Interstitial cystitis (IC) is a chronic, incurable condition that predominantly affects women and is in the spectrum of diseases known as painful bladder syndrome. It manifests as bladder pain or pressure, or pelvic pain. This condition is thought to arise from aberrant innervation of the bladder, resulting in smaller threshold for contraction and voiding. In the early 1990’s PPS was discovered to significantly decrease symptoms compared to placebo without any significant adverse reactions. The treatment is postulated to coat the lining of the bladder, reducing irritation and cellular permeability. PPS proceeded to obtain FDA approval in 1996 and has since been utilized extensively to treat IC without any safety concerns for decades. However, Jain et al published a case series in 2018 of 6 patients with unique pigmentary retinopathy noted in the setting of chronic oral PPS exposure. These patients shared findings of paracentral hyperpigmentation of the RPE with surrounding array of vitelliform-like deposits on fundus exam, with extensive macular changes on autofluorescence. A more recent presentation on larger series of 35 confirmed PPS-associated maculopathy patients is revealing possible trends in clinical features. (Table) The authors note that given the recent recognition of this entity, the observed findings likely reflect relatively advanced disease, and does not characterize incipient disease. The mechanism of chronic PPS exposure induced maculopathy is yet to be elucidated. A recent paper suggested that PPS may interfere with retinal fibroblast growth factor signaling.

In a recent presentation of a series of 91 patients that had taken PPS for over 15 years (and at least 5000 pills) observed toxicity rose with the amount of drug consumed. Investigators noted the rate of toxicity of those taking 500 to 1000 grams was 11% and that number jumped to 42% when patients were taking 1500 grams or more. It was also noted that the late-stage damage can mimic advanced dry atrophic macular degeneration and result in permanent vision loss.