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QUESTION

WHAT ARE THE AGE-RELATED MACULAR DEGENERATION LOOK-ALIKES? DO I TREAT THEM ANY DIFFERENTLY?

Kaivon Pakzad-Vaezi, MD
Kathryn L. Pepple, MD, PhD

The majority of clinical practice adheres to the classic medical aphorism, “When you hear hoof beats, think of horses not zebras.” However, not every patient presenting with macular drusen, pigmentary changes, or areas of retinal pigment epithelium (RPE) atrophy carries the straightforward diagnosis of non-neovascular (or dry) age-related macular degeneration (AMD). Detecting zebras in the herd affords the clinician an opportunity to identify and treat systemic disease, neoplasia, or a genetic mutation with multigenerational implications.

Suspicion for an AMD look-alike should be spurred when typical signs of AMD are detected at an earlier age than expected or in association with specific clinical patterns. Variations in the typical signs (ie, drusen, pigmentary change, RPE atrophy) that should tip you off to an atypical case are listed in Table 3-1. When clinical suspicion for atypical AMD is high, increased attention should be paid to the clinical history, including age of presentation, initial fundus changes, the degree of visual acuity loss, and especially to subtle or pronounced nyctalopia. The review of systems should probe for problems with hearing, diabetes, renal disease, or skin problems. A history of current or prior steroid use should be elicited. The family history is also informative and will often identify relatives carrying a diagnosis of early onset AMD, unexplained visual loss and blindness, or occasionally nyctalopia. In some cases, examination of accompanying family members can be revealing. It is unusual for the diagnosis of an AMD mimic to be made solely with dilated fundus examination. Common ancillary tests including fundus photography, fundus autofluorescence (FAF), and optical coherence tomography (OCT) are complementary modalities used in developing the initial differential diagnosis. Ultimately, electroretinography (ERG) and/or electrooculograms (EOG) may be required in association with genetic testing to clarify the diagnosis.

We first characterize the drusen based on OCT and FAF appearance. The typical drusen of AMD include macular yellow-white, round-ovoid elevations of various sizes and number in the macula in people over 55 years of age.1 OCT morphology can vary, but common AMD-related drusen demonstrate hyperreflective elevations at the level of the RPE with mixed FAF.² Small (< 63 μm) macular drusen in the absence of other findings are thought to reflect normal aging changes and do not require work-up or treatment.³ Likewise, peripheral drusen are a common finding in the elderly and, in the absence of macular drusen, are not included in current AMD classifications.³ It is also rare that they suggest pathology that requires additional evaluation.

Cuticular drusen (Figure 3-1) are associated most often with typical AMD, but they are also the most common drusen type associated with MPGN II.² They are identified by their prolate shape on OCT, “sawtooth” profile, and are hypoautofluorescent on FAF.² MPGN II is typically diagnosed between the ages of 5 to 15 years, with vision loss occurring as a late complication; however, in the correct clinical context, renal function tests and urinalysis should be considered as part of the evaluation of cuticular drusen in a young person.

Subretinal drusenoid deposits (SDD) (Figure 3-2) refer to hyperreflective material located between the retina and RPE instead of at or below the level of the RPE on OCT. They are often hypoautofluorescent, but occasionally may be hyperautofluorescent and, in these cases, are particularly suggestive of an inherited dystrophy.² They are occasionally present along with typical drusen in patients with AMD; however, a predominance of SDD suggests alternative diagnoses, such as an inherited retinal dystrophy or vitamin A deficiency. Vitamin A deficiency can produce anterior segment changes and ERG abnormalities and can be easily screened with a blood test. If confirmed, supplementation can produce dramatic recovery.⁴ Taking a history of nyctalopia is particularly helpful in these cases. Examples of genetic dystrophies that cause SDD include dominant drusen (EFEMP1), Sorsby fundus dystrophy (TIMP3), MPGN II, North Carolina macular dystrophy (Grades I and II), pseudoxanthoma elasticum (ABCC6), and LORD (C1QTNF5).^2,5 Diagnostic clues include dominant inheritance (EFEMP1, TIMP3, C1QTNF5), early nyctalopia and ERG changes (TIMP3, C1QTNF5), aggressive choroidal neovascularization (CNV; TIMP3), angioid streaks (ABCC6), long anterior lens zonules and scalloped peripheral atrophic changes (C1QTNF5), and renal disease (MPGN II).

When the lesions look more like flecks on OCT and FAF, a new set of different diagnoses are prompted. Flecks are differentiated from drusen by the lack of uniform round-oval, dome-shaped appearance, the distribution, and the usually yellow/vitelliform appearance. While drusen tend to stain on FA, flecks demonstrate blockage from lipofuscin, or variable window defect if adjacent RPE has degenerated.⁶ We find FAF to be the most helpful in not only demonstrating hyperautofluorescence of the flecks, but also to reveal more extensive fundus involvement than appreciated clinically. Stargardt disease (fundus flavimaculatus, ABCA4-retinopathy) (Figure 3-3) is the prototype fleck dystrophy. It often presents in childhood with decreased central vision, although adult-onset cases are well-described.⁷ An autosomal recessive inheritance pattern may be elicited, and we recommend baseline ERG for prognostication⁸ as well as avoidance of high-dose vitamin A supplementation.⁹ The classic dark choroid on FA is rare with modern fundus cameras, and, as such, we reserve FA solely to rule out CNV. Pattern dystrophy (Figure 3-4), which can also present with flecks and can be difficult to differentiate clinically from ABCA4-retinopathy, often presents in mid- or late-life as atypical AMD. Multiple patterns of vitelliform flecks have previously been described clinically.⁶ In the era of molecular genetics, most of these are recognized as an autosomal dominant-inherited defect in PRPH2.¹⁰ Many patients are asymptomatic and this may only be detected on routine ocular exam. Armed with a strong family history of AMD, they often present erroneously, taking Age-Related Eye Disease Study (AREDS) formulations. Clues for diagnosis include traditional patterns (ie, butterfly, reticular, multifocal, pulverulentus),⁶ usually a paucity of drusen, and/or symmetric central vitelliform lesions that are hyperautofluorescent as in adult vitelliform macular dystrophy (AVMD). Symptomatically, these patients present for 2 main reasons: expanding RPE atrophy or CNV. Of note, a partially collapsed vitelliform lesion can mimic subretinal fluid; clues to rule out CNV can be appreciated on FA, indocyanine green, previous OCT, or a typical vitelliform lesion in the other eye. Finally, one should remember that flecks can accompany such systemic conditions as MIDD, pseudoxanthoma elasticum (ABCC6), Alport syndrome, and myotonic dystrophy.⁶ Appropriate questioning and examination should therefore be prompted.

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