A Case of Declining Night Vision

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Tony Stork* is a 55-year-old soft­ware sales representative who, over the course of two years, was having a harder time stargazing at night with his wife. He also had difficulty visually adapting to different light conditions when he moved from an outdoor to an indoor environment. He had never had vision problems before, so he decided to see an eye specialist.

He initially consulted a general ophthalmologist who—based on an initial examination and the above symptoms —concluded that Mr. Stork had degenerative retinal drusen consistent with age-related macular degeneration (AMD) in both eyes. He was referred to our retina clinic.

We Get a Look

History. Mr. Stork had no relevant medical or surgical history. He had not experienced any peripheral visual field loss, photopsias, or eye pain. Notably, he told us that his paternal grandmother, his father, an aunt, and a cousin all had a history of presumed retinitis pigmentosa (RP), but he did not know whether they had undergone confirmatory genetic testing.

Exam. Mr. Stork’s best-corrected VA was 20/20 in both eyes, and his IOPs were normal. The anterior seg­ment exam was normal, apart from 1+ nuclear sclerotic cataracts in both eyes.

The posterior segment exam of both eyes demonstrated symmetric, fine yellow-white drusen-like deposits in the temporal macula and midperiphery, with patchy areas of retinal pigment epithelium (RPE) atrophy in the temporal midperiphery (Fig. 1A).

Imaging. Mr. Stork’s age, which was on the younger side for AMD, along with the clinical findings prompted us to pursue further inves­tigations. OCT showed parafoveal ellipsoid zone and RPE disruption with subretinal deposits (Fig. 1B). Fundus autofluores­cence (FAF) demonstrated well-defined scalloped areas of RPE atrophy consistent with the clinical exam, which had revealed symmetric hy­popigmented deposits along the temporal midperiphery (Fig. 2).

WE GET A LOOK. (1A) Magnified widefield fundus image, right eye, demonstrates fine yellow-white drusen-like deposits in the temporal macula and midperiphery, with patchy areas of RPE atrophy in the temporal midperiphery (asterisk). (1B) OCT of the right eye demonstrates parafoveal ellipsoid zone and RPE disruption with subretinal deposits. The left eye, not pictured, had symmetric findings.

FAF. Fundus autofluorescence of the right (2A) and left (2B) eyes demonstrates temporal hyperautofluorescence with scalloped areas of patchy hypoautofluorescence (asterisk) corresponding to the RPE atrophy seen on the exam.

Differential Diagnosis

When examining a middle-aged patient with new-onset nyctalopia and hypopigmented midperipheral RPE changes in the absence of intraoc­ular inflammation, the clinician should consider the following:

• paraneoplastic- or nonparaneoplas­tic-associated autoimmune retinopathy,
• vitamin A deficiency,
• outer retinal inflammatory condi­tions such as acute zonal occult outer retinopathy, or
• inherited retinal diseases, including late-onset retinal degeneration (L-ORD), RP, and fleck-related retinal dystrophies (e.g., Stargardt disease, fundus albipunctatus, or retinitis punctata albescens).

Mr. Stork had not experienced photopsias and had no history of ma­lignancy. Although cancer-associated retinopathies can affect both eyes, the symmetry and the strong dominant family history of nyctalopia pointed toward an inherited retinal disease. In addition, the appearance of the fundus on FAF was not suggestive of an auto­immune retinopathy, which can present with a parafoveal hyperautofluorescent ring.¹ The patient was younger than is usual for advanced AMD. Vitamin A deficiency seemed unlikely, given that he had no history of bowel surgery, had normal conjunctivae, and said that he ate a diet of meat and vegetables.

Our Diagnosis and Confirmatory Testing

The characteristic symmetric, tempo­ral macular findings and nyctalopia led us to strongly suspect a diagnosis of L-ORD. Electroretinogram testing demonstrated significantly attenuated scotopic responses with prolonged implicit times and slightly reduced photopic responses. Confirmatory genetic testing was positive for a com­mon mutation in the C1QTNF5 gene, p.S163R, which is consistent with a diagnosis of L-ORD.²

Discussion

Pathogenesis. The exact pathogenesis of L-ORD is unknown. The C1QT­NF5 gene on chromosome 11 encodes complement component 1q and tumor necrosis factor–related protein 5 and is expressed in the RPE, ciliary process­es, and lens epithelium.³ Postmortem exams demonstrate thick, lipid-rich de­posits between the RPE and the Bruch membrane; these deposits may act as a barrier to nutrients.^4,5 Increased deposit thickness and loss of photoreceptors have been correlated.⁵ Electrophysiol­ogy shows that rod-specific functions are the first to be compromised, with subsequent cone dysfunction.⁴

Typical presentations. L-ORD patients begin to report ophthalmic symptoms, such as progressive nycta­lopia, at approximately 50 to 60 years of age.² Clinical exams may initially ap­pear normal; as the disease progresses, fine yellow-white drusen-like deposits appear in the midperiphery. These de­posits form atrophic areas that spread throughout the retina, eventually leading to loss of central and peripheral vision, choroidal neovascularization (CNV), and pigmentary retinopathy.^2,6 Long an­terior zonule insertions, early cataracts, and peripupillary iris transillumination deficits may also be present.⁷

The early midperipheral changes may often be missed on clinical exam, and this case highlights the importance of FAF in demonstrating the character­istic pattern in the beginning stages of L-ORD.

Management. No specific treat­ment is available; reports of vitamin A supplementation to slow progression are scant.³ Affected patients should be monitored for the development of secondary CNV, which would then warrant treatment.² Because of the autosomal dominant inheritance pattern of L-ORD, genetic counseling and, when appropriate, family planning counseling should be provided.

Our Patient

Mr. Stork continues follow-up to monitor for CNV. He was counseled to discuss his diagnosis with those of his relatives who had a history of pre­sumed RP, and they were offered exams to determine whether their diagnoses were more consistent with L-ORD.

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* Patient name is fictitious.

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1 Lima LH et al. Retina. 2012;32(7):1385-1394.

2 Crawford CM et al. Adv Ophthalmol Vis Syst. 2017;6(4):107-108.

3 Ayyagari R et al. Invest Ophthalmol Vis Sci. 2005;46(9):3363-3371.

4 Papastavrou VT et al. Can J Ophthalmol. 2015;50(2):112–118.

5 Milam AH et al. Ophthalmology. 2000;107(12):2256-2266.

6 NIH. Genetic and Rare Diseases Information Center. https://rarediseases.info.nih.gov/diseases/4357/late-onset-retinal-degeneration. Accessed April 14, 2022.

7 Subrayan V et al. Am J Ophthalmol. 2005;140(6):1127-1129.

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Further reading. Agerwal et al. Late-Onset Retinal Macular Degenera­tion: An Entity Not to Be Overlooked. Retina Cases Brief Rep. 2010;4(3):257-261.

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Dr. Hamdan is a research assistant, and Dr. Mammo and Dr. Srivastava are vitreoretinal surgery and uveitis specialists. All are at the Cole Eye Institute, Cleveland Clinic in Cleveland. Relevant financial disclosures: None.

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