Man presents with decreased vision in left eye
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A 64-year-old man was referred to the New England Eye Center for evaluation of decreased vision in his left eye.
Two weeks before presentation, the patient was comparing vision in his two eyes and noticed his left eye vision was blurrier compared with the right. He presented to his local ophthalmologist who on dilated exam found retinal pigment epithelium (RPE) changes bilaterally. The patient denied any other ocular symptoms including pain, double vision, light sensitivity, distortion, flashes and floaters.
The patient’s ocular history was notable for quiescent proliferative diabetic retinopathy status post 360° of panretinal photocoagulation (PRP) in both eyes 25 years prior, as well as pseudophakia in both eyes. He was not on any ophthalmic medications. His medical history included type 1 diabetes (diagnosed when he was 6 years old), hypothyroidism, interstitial cystitis and chronic sciatica status post lumbar spinal fusion several years prior. His medications included insulin, amitriptyline, levothyroxine, simvastatin, gabapentin, marshmallow root capsule and multivitamins. His family history was significant for type 1 diabetes in his father and heart disease in his two brothers. There was no known family history of ocular disease. He was an electrical engineer, never smoked and drank alcohol only socially. His only known allergy was to contrast dye (hives/rash). His review of systems was unremarkable.
Examination
Visual acuity without correction was 20/30 in the right eye and 20/100 in the left eye, with no improvement with pinhole in either eye. Pupils were equal in size and briskly reactive to light with no afferent pupillary defect. IOP was 15 mm Hg in both eyes. Extraocular motility and confrontation visual fields were full. With Ishihara color plates, color vision was full in the right eye; however, the patient was not able to identify the control plate or any subsequent color plates with the left eye. External exam showed normal lids and adnexa. Anterior segment exam of both eyes was unremarkable, only notable for centered posterior chamber IOLs. Posterior segment exam demonstrated clear vitreous, pink and healthy optic nerves with cup-to-disc ratios of 0.2, vessels with normal caliber, and PRP scars 360° in the periphery in both eyes. Both maculas demonstrated subtle paracentral hyperpigmented spots and yellowish subretinal macular deposits, more pronounced in the left eye (Figure 1).
Source: Kate V. Dennett, MD, and Shilpa J. Desai, MD
Humphrey visual field testing 30-2 showed central scotomas in both eyes (Figure 2). OCT of the maculas demonstrated focal, discrete nodules of hyperreflectivity at the level of the RPE, which co-localized with the hyperpigmented spots on fundus exam, with outer retinal atrophy (Figure 3). Fundus autofluorescence (FAF) showed well-circumscribed central patches of speckled hyperautofluorescent and hypoautofluorescent spots, more so in the left eye than the right eye (Figure 4).
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Decreased vision
The differential diagnosis for bilateral pigmentary retinopathy with outer retinal atrophy has three main categories: degenerative etiologies, hereditary dystrophies and toxic/metabolic causes.
The degenerative category includes age-related macular degeneration. Clinical manifestations include drusen (one of the earliest signs) and focal hyperpigmentation at the level of the RPE, similar to the changes seen in this patient, and can progress into geographic atrophy/hypopigmentation from severe RPE atrophy. Patients are typically older adults, with associated risks including family history and environmental factors such as smoking and obesity. Pachychoroid pigment epitheliopathy presents with features similar to this patient’s findings, including RPE drusen-like deposits and FAF findings of granular and mixed stippled hyper/hypoautofluorescence. However, the patient’s choroid does not appear abnormally thick on OCT.
Hereditary dystrophies include Stargardt disease, which is the most common macular dystrophy, and pattern dystrophy such as adult-onset foveomacular dystrophy. The clinical phenotype of Stargardt disease can be variable, but classically the macula has a “beaten bronze” appearance caused by RPE atrophy. FAF of the macula typically shows hypoautofluorescence with surrounding hyperautofluorescent spots, which may appear similar to the patient’s FAF findings. Adult-onset foveomacular dystrophy usually presents in middle age with minimal impact on central vision until later in the disease course. On exam, the oval-shaped vitelliform macular lesion is typically mildly elevated and hyperautofluorescent on FAF. This patient had no known family history of ocular disease. Maternally inherited diabetes and deafness was also in the differential because the patient had type 1 diabetes; however, he denied any hearing loss, which typically precedes visual changes in this disease.
In terms of a toxic or metabolic etiology, both hydroxychloroquine and pentosan polysulfate sodium (PPS) toxicity may produce a maculopathy similar to this patient with irregularity in macular pigmentation. However, OCT of hydroxychloroquine maculopathy typically shows a loss of the ellipsoid zone in addition to outer retinal thinning, producing the classic “flying saucer” sign, which was not present in this patient. The patient also denied any previous hydroxychloroquine use.
Further history
Upon further questioning, the patient reported having recently discontinued PPS, which he had been taking for interstitial cystitis for a total of 4 years. His cumulative drug dose intake was calculated to be approximately 256 g. He self-discontinued the medication 1 week before presentation, as he had heard of a potential association between the medication and visual symptoms.
Discussion
Elmiron (pentosan polysulfate sodium, Janssen Pharmaceuticals) is currently the only FDA-approved medication for treatment of interstitial cystitis. Chronic use of PPS has recently been linked to a vision-threatening toxic maculopathy, first reported in 2018. The exact mechanism by which PPS causes retinal toxicity is unknown; however, PPS inhibits growth factor signaling pathways within RPE cells, likely preventing them from proper maintenance and regeneration, ultimately causing injury.
Presenting symptoms may include blurry vision (particularly at near), prolonged dark adaptation and metamorphopsia. Visual acuity is often preserved until fovea-involving severe disease. Patients may be asymptomatic, which highlights the importance of routine screening for patients taking PPS.
PPS-associated maculopathy presents with clinical features that are similar to other pigmentary maculopathies, including AMD and pattern dystrophy, and is often misdiagnosed. The primary ocular manifestation of PPS-associated maculopathy is bilateral, multifocal, vitelliform-like pigmentary deposits in the retina, specifically in a distribution around the fovea. These changes may be subtle in the early period, sometimes interspersed with yellow- or orange-colored deposits. In later phases, there may be patchy RPE atrophy with or without the characteristic hyperpigmented spots. It has been associated with cystoid macular edema and choroidal neovascularization as well. Multimodal ophthalmic imaging including FAF and OCT serves to highlight these characteristic retinal changes, especially early in the disease when changes may be subtle on exam.
Several reports have found that clinical features of PPS-associated maculopathy may persist and even continue to progress after discontinuation, making it a potential long-term threat to central vision. The duration of PPS ingestion and total cumulative dose may also play a role in the risk of developing maculopathy. Wang and colleagues found that a cumulative dose of greater than 1,500 g places the patient at significant risk for retinal toxicity. As such, the authors developed preliminary recommendations for dose-related screening guidelines: initial baseline dilated exam including color fundus photos, OCT and FAF; annual dilated exam with retinal imaging, especially with cumulative doses approaching or exceeding 500 g; and discussing the lowest dose/duration of PPS necessary, with caution in prescribing the medication for patients with previously diagnosed macular disease. As this distinct, newly described condition continues to be investigated, it is imperative to screen patients using PPS and have clear discussions regarding the risk for potential vision loss.
- References:
- Hanif AM, et al. JAMA Ophthalmol. 2019;doi:10.1001/jamaophthalmol.2019.3392.
- Huckfeldt RM, et al. Ophthalmic Surg Lasers Imaging Retina. 2019;doi:10.3928/23258160-20191009-10.
- Pearce WA, et al. Ophthalmology. 2018;doi:10.1016/j.ophtha.2018.04.026.
- Shah R, et al. JAMA Ophthalmol. 2020;doi:10.1001/jamaophthalmol.2020.2349.
- Vora RA, et al. Ophthalmology. 2020;doi:10.1016/j.ophtha.2020.01.017.
- Wang D, et al. Can J Ophthalmol. 2020;doi:10.1016/j.jcjo.2019.12.001.
- For more information:
- Kate V. Dennett, MD, and Shilpa J. Desai, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Christine Benador-Shen, MD, and Malgorzata Dymerska Peterson, MD. They can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.