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Pentosan maculopathy

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Title: Pentosan maculopathy

Author (s): Ivan Cardenas, BS, Nnana Amakiri, MD, Akbar Shakoor, MD, Eileen Hwang, MD, PhD

Date: 10/23/2023

Keywords/Main Subjects: Pentosan maculopathy, AMD, drug toxicity, pentosan polysulfate sodium, interstitial cystitis

Diagnosis: Pentosan Maculopathy

Case Report:

This is a case of a 68-year-old woman with a three-year history of progressing drusen, diagnosed with age-related macular degeneration (AMD) by an outside ophthalmology office. She was referred to the Moran Eye Center for further workup due to the persistent progression of her findings, and an increasing suspicion of medication toxicity. She had a history of interstitial cystitis diagnosed approximately 27 years prior to her presentation, for which she started treatment with pentosan polysulfate sodium (pentosan). She did not have any other ocular conditions or surgeries and no family history of ocular disease. Other than her interstitial cystitis, she had a history of muscular dystrophy, hypertension, hyperlipidemia, and myocardial infarction. Besides pentosan, she was taking AREDS vitamins, estradiol, gabapentin, and amitriptyline.

Her exam demonstrated a visual acuity of 20/30 in both eyes, physiologic intraocular pressure, and a slit lamp exam without significant abnormalities. Dilated fundus exam and color fundus imaging demonstrated hypopigmentation of the retinal pigment epithelium in the central macula and mild peripapillary atrophy bilaterally (Figure 1). Humphrey visual field showed a paracentral defect in the left eye and central defect in the right eye (Figure 2). On optical coherence tomography (OCT), there was ellipsoid zone (EZ) disruption bilaterally, with multifocal hyperreflective retinal pigment epithelial (RPE) lesions (Figure 3). On fundus autofluorescence imaging, the macula showed a densely packed array of hyperautofluorescent and hypoautofluorescent spots (Figure 4A and 4B) and the optic nerve showed a ring of hypoautofluorescence, which correlated with the peripapillary atrophy seen on color fundus imaging (Figure 4C and 4D). Infrared imaging of the macula showed hyperreflective punctate lesions scattered throughout the macula (Figure 5).

She lacked the classic findings seen in AMD or pattern dystrophies, and due to the unique characteristics found in her workup in the setting of possible medication toxicity, she was diagnosed with pentosan maculopathy. After informed consent and shared decision making, the decision was made to cease the medication. She continues to be followed for evidence of progression, given the possibility of disease progression after cessation of the drug. She also has remained under close care by her urologist, due to worsening of the pain associated with her interstitial cystitis.

Discussion:

Pentosan maculopathy is a rare ocular condition caused by use of pentosan polysulfate sodium, a drug approved by the FDA in 1996 for the treatment of interstitial cystitis. Ocular toxicity of pentosan was first described in a 6-patient cohort in 2018.1 One study found ocular toxicity in 20% of patients who had a cumulative dose of pentosan greater than 500g (equivalent to 4.5 years at the standard dose).2  Pentosan toxicity preferentially impacts the macula and is believed to be a result of cumulative exposure to the drug.3,4,5 It commonly presents with blurred vision, difficulty with dim lighting and/or dark adaptation, and difficulty reading, though visual acuity is generally preserved in early maculopathy. While the exact mechanism of its impact on the retina is unknown, ongoing case reports and studies in mice suggest possible disruption of the glycosaminoglycans in the RPE-photoreceptor interface, as well as possible fibroblast growth factor signal inhibition or choriocapillaris injury.6,7,8,9

The patient described here was initially misdiagnosed with dry AMD, which highlights the importance of asking AMD patients about their medical history, and particularly their medications. Without this information, the etiology can easily be missed and may lead to progression of the condition. While this patient’s findings were consistent with pentosan maculopathy, different forms of maculopathies were considered, such as AMD with geographic atrophy, hereditary maculopathies, or pattern dystrophies. The diagnosis of pentosan maculopathy was reinforced through distinct imaging characteristics seen on OCT and fundus autofluorescence. The OCT of our patient showed multifocal hyperreflective retinal pigment epithelial lesions with posterior shadowing (Figure 3) characteristic of pentosan maculopathy.  These lesions are distinct from the drusen seen in dry AMD, which are less hyperreflective, and located under the retinal pigment epithelium rather than intrinsic to the retinal pigment epithelium (Figure 6).3 The autofluorescence images of our patient demonstrate a densely packed array of hyperautofluorescent and hypoautofluorescent spots involving the posterior pole (Figure 4).3 While pattern dystrophies may also be characterized by hyper- and hypoautofluorescent patches, lines and spots (Figure 7),10,11,12 the pattern of autofluorescence in pentosan maculopathy is more densely clustered (Figure 4).

Beyond OCT and autofluorescence, near infrared imaging has also been used as an imaging modality for the disease, where it has been proposed for mild cases where it demonstrates parafoveal hyperreflective punctate lesions as was seen in our case (Figure 5).3,13 Advanced pentosan maculopathy may result in retinal pigment epithelium atrophy (Figure 8), although our case was early in its course without atrophy.4,9 In one study, RPE atrophy which extended into the fovea was used as a criteria for severe pentosan maculopathy, and was associated with very poor visual acuity.9 Studies have also reported peripapillary halos1,3,9,13,, defined as a circumferential ring of hypoautofluorescence surrounding the optic nerve in the absence of peripapillary atrophy. While our case did demonstrate a ring of hypoautofluorescence, it was consistent with the peripapillary atrophy seen on color fundus imaging so was not described as a halo. Peripapillary atrophy typically results in hypoautofluorescence surrounding the optic nerve14, but the atrophy can be distinguished from the halo by hypopigmentation on color fundus photos or examination.15,16 These peripapillary halos have been noted even in mild cases, and are not typically seen in other retinal conditions.3,9 Taken together, this constellation of findings is unique to pentosan maculopathy and provided us with the necessary evidence to diagnose the condition.

Many experts agree on the importance of comprehensive eye exams to screen patients for signs of pentosan maculopathy. Research publications emphasize that these exams should include multimodal imaging, especially autofluorescence,1,4,17 given the high specificity of autofluorescence findings. Conflicting guidelines exist for when screening exams should begin. Some researchers have recommended beginning screening eye exams after a cumulative dose of 500g.3 On the other hand, the American Urogynecologic Society has recommended baseline evaluation followed by annual screening starting after five years,18 and the manufacturer of Elmiron, the brand name for pentosan, recommends baseline evaluation within 6 months of initiation and periodic evaluation.19 While stopping this drug gives the best chance of vision preservation, it may worsen the interstitial cystitis as was seen in our patient’s case. It may also continue to progress after cessation, although there are no current estimates on how long the progression may continue.20,21 When addressing toxicities and systemic illnesses impacting the retina, it is imperative to engage in multidisciplinary discussions among healthcare providers and actively involve patients in shared decision-making to ascertain the most optimal treatment approach.

Figures

Figure 1. Color fundus images of right eye (A) and left eye (B) showing hypopigmentation of the retinal pigment epithelium in the central macula and mild peripapillary atrophy bilaterally.

Figure 2. Central 10-2 Humphrey Visual Field showing central defects in the right eye (A) and paracentral defects in the left eye (B).

Figure 3. Optical coherence tomography (OCT) of the right eye (A) and left eye (B) showing features characteristic of early pentosan maculopathy.

Figure 4. Fundus autofluorescence of the macula in the right eye (A) and left eye (B) showing characteristic features of pentosan maculopathy, specifically densely packed array of hyperautofluorescent and hypoautofluorescent spots. Autofluorescence of the optic nerve of the right eye (C) and left eye (D) showing a circumferential ring of hypoautofluorescence consistent with areas of peripapillary atrophy seen on color fundus imaging.

Figure 5. Near infrared reflectance imaging of the right eye (A) and left eye (B) showing hyperreflective punctate lesions scattered throughout macula.

Figure 6. OCT findings of intermediate dry AMD showing drusen, which are hyperreflective deposits beneath the retinal pigment epithelium.

Figure 7. Autofluorescence image of butterfly pattern dystrophy showing linear patterns of hyperautofluorescence on a hypoautofluorescent background (A). Autofluorescence image of adult foveomacular vitelliform dystrophy showing a round hyperautofluorescent spot within the fovea (B).

Figure 8. Images from a patient with severe pentosan maculopathy and count fingers vision in both eyes due to retinal pigment epithelium atrophy involving the fovea.  Optical coherence tomography shows loss of the outer retina and retinal pigment epithelium, and thin choroid (A, B).  Color fundus photographs show that the hypopigmentation due to atrophy involves most of the macula (C, D).

 

References

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