That’s not AMD: Mimickers of age-related macular degeneration

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Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss in older adults. Early diagnosis and differentiation from other retinal conditions are crucial for providing optimal care and preventing further vision loss. Several retinal diseases can present with similar clinical features and symptoms of both wet and dry AMD. This article explores key AMD mimickers and provides practical insights for accurate diagnosis and differentiation.

Best vitelliform macular dystrophy

Figure 1a. Best Disease. Optical coherence tomography shows atrophy of the outer retina, loss of inner segment/outer segment line, and choroidal hypertransmission defect. (Images courtesy of Pamela Rath, MD)

Figure 1b. Fundus autofluorescence highlights hypoautofluorescence due to retinal pigment epithelium loss, surrounded by a hyperautofluorescent border. (Images courtesy of Pamela Rath, MD)

Best vitelliform macular dystrophy, or Best disease, presents bilaterally with macular changes classically described as an egg yolk appearance (Figure 1). These round yellow lesions have well-defined borders and typically develop in early childhood. Over time, the lesions change through multiple stages, including the pseudohypopyon stage in which the yellow deposits move down, usually occurring during puberty, and then the vitelliruptive (scrambled egg) stage when vision often begins to decline, ultimately leading to the atrophic stage.¹ The atrophy that forms can be mistaken for geographic atrophy secondary to AMD. Additionally, choroidal neovascularization (CNV) can develop, which can be misdiagnosed as wet AMD.

Best disease can be differentiated from AMD by the earlier age of onset and more uniform and smooth appearance of the lesion compared with the irregular lesions seen in AMD and the lack of drusen in Best. As the disease is often transmitted in an autosomal dominant fashion with variable penetrance, a history of low vision in a middle-aged family member may be helpful. On optical coherence tomography (OCT), Best lesions show vitelliform material accumulation between the retinal pigment epithelium (RPE) and ellipsoid zone, whereas drusen in AMD develop between the RPE and Bruch membrane.¹

Stargardt disease

Figure 2a. Stargardt Disease. Optical coherence tomography shows atrophy of the outer retina, choroidal hypertransmission defect, and hyperreflective material in the outer retina consistent with lipofuscin. (Images courtesy of Srinivas Kondapalli, MD)

Figure 2b. Fundus autofluorescence shows bull’s eye maculopathy (hypoautofluorescent macula surrounded by a hyperautofluorescent ring). (Images courtesy of Srinivas Kondapalli, MD)

Stargardt is an autosomal recessive inherited retinal disease that can present as either early onset (childhood) or late onset (adult). The heterogeneous nature of Stargardt results in varying severities of clinical appearance (RPE changes, pigmentary changes, pisciform flecks, beaten bronze appearance of macula, foveal thinning, etc) and visual symptoms. The late-onset form can be misdiagnosed as AMD as the yellow flecks can be mistaken for drusen (Figure 2). Drusen in AMD are found within the macula, whereas Stargardt flecks can extend throughout the posterior pole and often spare the macula.²

Imaging can also help differentiate late-onset Stargardt and AMD. On OCT, Stargardt flecks appear as a thickened RPE, whereas AMD drusen occur between RPE and the Bruch membrane. On fundus autofluorescence (FAF), flecks show a strong hyperautofluorescence (remember, pisciform means fish-like; just like fish scales, which are often shiny, these flecks appear bright) whereas drusen are hypoautofluorescent or only mildly hyperautofluorescent.²

Chronic central serous chorioretinopathy

Figure 3. Chronic Central Serous Chorioretinopathy. Optical coherence tomography shows separation of the neurosensory retina at the macula and thickened choroid. (Images courtesy of Srinivas Kondapalli, MD)

Central serous chorioretinopathy (CSCR) is defined by the separation of the neurosensory retina at the macula, with the buildup of serous fluid between the photoreceptors and RPE (Figure 3).³ CSCR is generally an acute, self-limiting disease occurring most frequently in men aged 30 to 50 years, and is often associated with stress, corticosteroid use, or hormonal changes. Chronic cases of CSCR can occur in about 15% of patients, which can lead to RPE atrophy and CNV. The chronic cases are more likely to develop in older patients, potentially leading to a misdiagnosis of AMD.³

Several differentiating characteristics can be appreciated by utilizing imaging. In chronic CSCR, the choroid becomes thicker, whereas in both dry and wet AMD, the choroid becomes thinner. On FAF, RPE atrophy from chronic CSCR can appear granular with areas of punctate hyperautofluorescence within the hypoautofluorescent area of atrophy.⁴ In contrast, RPE atrophy from GA secondary to AMD is hypoautofluorescent within the area of atrophy and often has a hyperautofluorescent border.

Macular telangiectasia type 2

Macular telangiectasia type 2 (MacTel) is a bilateral neurodegenerative disease due to dysfunction and depletion of Müeller glial cells. Like AMD, MacTel affects the central retina, and early retinal changes may be subtle on clinical examination. In advanced stages of MacTel, atrophy and scarring may occur, which may be confused for GA secondary to AMD, and CNV can also develop, leading to a potential misdiagnosis of wet AMD.⁵

Figure 4a. Macular Telangiectasia Type 2. Optical coherence tomography shows retinal cavitation, ellipsoid zone loss, and inner limiting membrane drape. (Images courtesy of Srinivas Kondapalli, MD)

Figure 4b. Macular Telangiectasia Type 2. Fundus autofluorescence shows hypoautofluorescence consistent with loss of macular pigment and telangiectatic vessels. (Images courtesy of Srinivas Kondapalli, MD)

On clinical exam, patients with MacTel may present with crystalline deposits, parafoveal retinal graying, and telangiectatic vessels (Figure 4). Increased parafoveal hyperautofluorescence due to loss of macular pigment is an early sign of MacTel on FAF and in contrast to the hypoautofluorescence seen with drusen and GA or hyperautofluorescence due to lipofuscin accumulation in degenerating RPE. On OCT, ellipsoid zone loss beginning temporal to the fovea may be observed, as well as retinal cavitations and an inner limiting membrane drape. FA shows characteristic late-stage leakage from telangiectatic vessels.⁵

Conclusion

Optometrists must recognize and differentiate AMD from other retinal conditions that may mimic its presentation. A thorough clinical examination, complemented by advanced imaging techniques, is essential for accurate diagnosis and appropriate management. Early recognition of AMD mimickers can ensure that patients receive the most effective treatment for their condition, potentially preserving their vision and quality of life. By keeping these mimicking conditions in mind, optometrists can provide better patient outcomes through precise diagnosis and timely referrals when needed.

References:

1. Tripathy K, Salini B. Best disease. In: StatPearls [Internet]. Updated August 25, 2023. StatPearls Publishing; January 2024. https://www.ncbi.nlm.nih.gov/books/NBK537290/

2. Kohli P, Tripathy K, Kaur K. Stargardt disease. In: StatPearls [Internet]. Updated January 8, 2024. StatPearls Publishing; January 2024. https://www.ncbi.nlm.nih.gov/books/NBK587351/

3. Sartini F, Figus M, Nardi M, Casini G, Posarelli C. Non-resolving, recurrent and chronic central serous chorioretinopathy: available treatment options. Eye (Lond). 2019;33(7):1035-1043. doi:10.1038/s41433-019-0381-7

4. Zola M, Chatziralli I, Menon D, Schwartz R, Hykin P, Sivaprasad S. Evolution of fundus autofluorescence patterns over time in patients with chronic central serous chorioretinopathy. Acta Ophthalmol. 2018;96(7):e835-e839. doi:10.1111/aos.13742

5. Kedarisetti KC, Narayanan R, Stewart MW, Reddy Gurram N, Khanani AM. Macular telangiectasia type 2: a comprehensive review. Clin Ophthalmol. 2022;16:3297-3309. doi:10.2147/OPTH.S373538