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Retinal Physician

Article

Dry AMD Masquerade Syndromes

The authors present examples of pattern and cone-rod dystrophies, and maculopathies associated with medication toxicity or systemic disorders, which can resemble dry AMD.

Retinal Physician January 1, 2017

The prevalence of nonexudative age-related macular degeneration (AMD) will dramatically increase with an aging population. By the year 2020, an estimated 196 million people globally will have AMD and 11 million will have significant vision loss.1 Whenever cases present with atypical features, ophthalmologists should consider other diagnoses, as numerous retinal diseases have overlapping features with dry AMD. In this article, we present examples of pattern and cone-rod dystrophies, and maculopathies associated with medication toxicity or systemic disorders, all of which were referred to a retina clinic for assessment of dry AMD. These cases were ultimately diagnosed as other pathologies with the aid of ancillary testing. They all can be considered “Dry AMD-masquerade syndromes.”

CASES

Cuticular Drusen (Basal Laminar Drusen)

Related

A diagnosis of cuticular drusen (Figure 1) was originally considered distinct from AMD, with a more favorable prognosis, but more recently it has been considered a subtype of AMD. Despite numerous clinical and histological similarities, important differentiating features exist. On fundus examination, cuticular drusen are small (25-75 microns), yellow-white and nodular. Macular OCT demonstrates these drusen to be blunted, triangular-shaped and below the RPE, giving a saw-tooth pattern.2 FA strikingly reveals innumerable hyperfluorescent drusen that significantly outnumber the drusen noted clinically, yielding the characteristic “stars-in-the-sky” appearance during the early arteriovenous phase.2 Interestingly, on FAF, these drusen are hypoautofluorescent when very small, but also present with a hypoautofluorescent center surrounded by a ring of hyperautofluorescence.2 Overall, the frequency of choroidal neovascularization seen with this AMD subtype ranges from 4% to 56% depending on the study.3-5 One-third of patients can develop geographic atrophy.6 In patients with early-onset, extensive cuticular drusen, a rare complement mutation is associated with an increased risk of developing choroidal neovascularization and type II membranoproliferative glomerulonephritis.4,7,8 Close ocular and systemic monitoring is warranted.

Figure 1. This 52-year-old female was referred with a 4 month history of progressive blurring of central vision and metamorphopsia from her left eye (LE). Visual acuity (VA) measured 20/20 both eyes (BE) and fundus examination revealed bilateral macular retinal pigment epithelial (RPE) mottling with patches of atrophy in the nasal macula (Figure A). Macular OCT demonstrated areas of outer retinal segment and RPE atrophy and fine sub-RPE drusen BE (Figure B). Fundus autofluorescence (FAF) vividly demonstrated innumerable, punctate hyperautofluorescent lesions significantly outnumbering the drusen noted clinically, which is characteristic for this disorder. There were also patches of hypoautofluorescence correlating to RPE atrophy (Figure C). With the aid of multimodal imaging, a diagnosis of cuticular drusen with RPE atrophy was made. In addition to the examples from this case, in another case, a classic appearance is depicted on fluorescein angiography (FA), on which these numerous punctate drusen stain discretely, resulting in a “stars-in-the-sky” appearance (Figure D)
Figure 1. This 52-year-old female was referred with a 4 month history of progressive blurring of central vision and metamorphopsia from her left eye (LE). Visual acuity (VA) measured 20/20 both eyes (BE) and fundus examination revealed bilateral macular retinal pigment epithelial (RPE) mottling with patches of atrophy in the nasal macula (Figure A). Macular OCT demonstrated areas of outer retinal segment and RPE atrophy and fine sub-RPE drusen BE (Figure B). Fundus autofluorescence (FAF) vividly demonstrated innumerable, punctate hyperautofluorescent lesions significantly outnumbering the drusen noted clinically, which is characteristic for this disorder. There were also patches of hypoautofluorescence correlating to RPE atrophy (Figure C). With the aid of multimodal imaging, a diagnosis of cuticular drusen with RPE atrophy was made. In addition to the examples from this case, in another case, a classic appearance is depicted on fluorescein angiography (FA), on which these numerous punctate drusen stain discretely, resulting in a “stars-in-the-sky” appearance (Figure D)

Peter Bracha, MD, is a resident and Thomas A. Ciulla, MD, MBA is on the clinical faculty at Indiana University Dept. of Ophthalmology in Indianapolis. Neither author reports any financial interests in products mentioned in this article. Dr Ciulla can be reached via e-mail at thomasciulla@gmail.com.

Gass first classified pattern dystrophies, which represent a group of autosomal dominant maculopathies involving pigmentary abnormalities.9 They generally carry a more favorable prognosis than AMD.

Multifocal Pattern Dystrophy Simulating Fundus Flavimaculatus

Multifocal pattern dystrophy simulating fundus flavimaculatus (Figure 2) is one of five main pattern dystrophy categories that Gass classified.9 Patients develop mild-to-moderate visual disturbances in midlife which progress to severe vision loss in up to 50% of patients after the age 70 due to atrophy of the RPE-photoreceptor complex and/or development of choroidal neovascularization.10 Early in the course of the disease, patients have nonspecific pigmentary changes.4 Subsequently, they develop a variable number of irregularly shaped and/or elgongated, yellow-white flecks throughout the posterior pole and around retinal vascular arcades.10 FA reveals staining of these lesions and FAF demonstrates significantly increased autofluorescence of the flecks with a small, adjacent zone of decreased autofluorescence.10 Macular OCT shows moderately reflective deposits just anterior to the ellipsoid zone.11 Most patients have an abnormal electrooculogram and 50% have an abnormal ERG.10 Genetic testing can reveal a peripherin/RDS mutation but other mutations have been associated with this pathology.10

Figure 2. This 38-year-old, asymptomatic male was referred for bilateral maculopathy. VA measured 20/20 BE. Fundus examination revealed numerous elongated yellow flecks that were hyperautofluorescent on FAF (Figures A and B). FA identified early, mild choroidal silence and staining of the yellow flecks (Figure C). Considering the excellent VA and lack of beaten bronze fundus appearance, Stargardt’s disease was ruled out and the diagnosis of multifocal pattern dystrophy simulating fundus flavimaculatus was made.
Figure 2. This 38-year-old, asymptomatic male was referred for bilateral maculopathy. VA measured 20/20 BE. Fundus examination revealed numerous elongated yellow flecks that were hyperautofluorescent on FAF (Figures A and B). FA identified early, mild choroidal silence and staining of the yellow flecks (Figure C). Considering the excellent VA and lack of beaten bronze fundus appearance, Stargardt’s disease was ruled out and the diagnosis of multifocal pattern dystrophy simulating fundus flavimaculatus was made.

Adult-Onset Foveomacular Vitelliform Dystrophy

Adult-onset foveomacular vitelliform dystrophy (Figure 3), another pattern dystrophy, typically presents with mild visual disturbances between 30 and 50 years of age.12 Vitelliform lesions are hyperautofluorescent on FAF and hypofluorescent on early FA frames with later staining.13,14 Macular OCT reveals a dome-shaped hyperreflective area between the RPE and ellipsoid zone.12,15 Genetic testing classically identifies a mutation in the peripherin 2 (PRPH2) gene, but other genetic mutations have been associated.13

Figure 3. This 85-year-old, glaucomatous female was referred with a one-month history of bilateral blurring of central vision. VA measured 20/200 RE and 20/30 LE and fundus examination revealed bilateral yellow foveal lesions with pigment clumping (Figure A). FA demonstrated central blocking defects in early frames without staining or leakage (Figure B). Red-free photographs provided great contrast of the lesions (Figure C). Her findings and symptoms were consistent with adult-onset foveomacular vitelliform dystrophy.
Figure 3. This 85-year-old, glaucomatous female was referred with a one-month history of bilateral blurring of central vision. VA measured 20/200 RE and 20/30 LE and fundus examination revealed bilateral yellow foveal lesions with pigment clumping (Figure A). FA demonstrated central blocking defects in early frames without staining or leakage (Figure B). Red-free photographs provided great contrast of the lesions (Figure C). Her findings and symptoms were consistent with adult-onset foveomacular vitelliform dystrophy.

Cone-rod dystrophy

Cone-rod dystrophy (Figure 4) typically presents during childhood with poor VA and severe color-vision loss.16 Fundus appearance can range from normal to a bull’s eye maculopathy with temporal pallor of the optic nerve.16 Goldman visual fields reveal a central scotoma.16 Full-field ERG, which is necessary for diagnosis, demonstrates progressively deteriorating cone amplitudes with comparatively normal rod amplitudes.16

Figure 4. This 78-year-old male was referred with a one- year history of progressive, bilateral central blurring. VA measured 20/40 RE and count fingers LE. Fundus examination revealed bilateral generalized RPE atrophy with optic nerve pallor LE, and FA demonstrated staining in a bull’s eye pattern (Figures A and C). Macular OCT identified bilateral outer retinal and RPE atrophy, and an epiretinal membrane RE (Figure B). The patient denied a history of hydroxychloroquine or chloroquine use. Cone-rod dystrophy was suspected and then confirmed when ERG showed a broadly diminished wave-form that was worse under photopic conditions.
Figure 4. This 78-year-old male was referred with a one- year history of progressive, bilateral central blurring. VA measured 20/40 RE and count fingers LE. Fundus examination revealed bilateral generalized RPE atrophy with optic nerve pallor LE, and FA demonstrated staining in a bull’s eye pattern (Figures A and C). Macular OCT identified bilateral outer retinal and RPE atrophy, and an epiretinal membrane RE (Figure B). The patient denied a history of hydroxychloroquine or chloroquine use. Cone-rod dystrophy was suspected and then confirmed when ERG showed a broadly diminished wave-form that was worse under photopic conditions.

Hydroxychloroquine Toxicity

Hydroxychloroquine is used for many rheumatologic disorders. The toxicity risk is very low in patients who consume less than 5.0 mg/kg of real body weight and who have been on therapy for less than 10 years.17 When toxicity develops (Figure 5), patients frequently complain of nyctalopia and paracentral scotomas. This paracentral scotoma can be identified and tracked with visual fields, the most sensitive of which is a 10-2 Humphrey visual field. Early in the course of the disease, fundus appearance is normal and in later stages a bull’s eye maculopathy develops. Macular OCT reveals a loss of the external limiting membrane, disruption of the ellipsoid zone, parafoveal thinning of the outer nuclear layer, and RPE damage.18 On multifocal ERG, paracentral, central or generalized amplitude reductions develop.19 FAF findings vary depending on disease severity: early pathology highlights a paracentral ring of increased autofluorescence; moderate severity shows a paracentral mottled hypoautofluorescence with an adjacent hyperautofluorescence; and advanced disease reveals a complete central loss of autofluorescence.19

Figure 5. This 65-year-old female was referred with a 2-month history of bilateral blurring of central vision. VA measured 20/30 RE and 20/20 LE. Fundus examination revealed a bilateral bull’s eye pattern of RPE changes and FAF demonstrated a bilateral ring of hypoautofluorescence surrounded by a ring of hyperautofluorescence (Figures A and C). Macular OCT identified parafoveal ellipsoid zone loss along with generalized retinal thinning (Figure B). After additional questioning regarding her current and past medications, she endorsed a 20-year history of hydroxychloroquine use that was stopped several years prior to presentation. Despite no hydroxychloroquine use for a number of years, this patient most likely demonstrated symptomatic progression of hydroxychloroquine toxicity.
Figure 5. This 65-year-old female was referred with a 2-month history of bilateral blurring of central vision. VA measured 20/30 RE and 20/20 LE. Fundus examination revealed a bilateral bull’s eye pattern of RPE changes and FAF demonstrated a bilateral ring of hypoautofluorescence surrounded by a ring of hyperautofluorescence (Figures A and C). Macular OCT identified parafoveal ellipsoid zone loss along with generalized retinal thinning (Figure B). After additional questioning regarding her current and past medications, she endorsed a 20-year history of hydroxychloroquine use that was stopped several years prior to presentation. Despite no hydroxychloroquine use for a number of years, this patient most likely demonstrated symptomatic progression of hydroxychloroquine toxicity.

Cancer-Associated Retinopathy

Cancer associated retinopathy (Figure 6) typically presents with subacute vision loss over weeks to months.20 Symptoms vary depending on the degree of rod and cone involvement; patients frequently present with symptoms of shimmering or flickering lights.20 On clinical examination, patients show a normal appearing fundus early in the course of the disease, but with progression, they develop retinal arteriolar attenuation, retinal pigment epithelial mottling and optic disc pallor.20,21 Goldman visual field testing can identify a generalized depression or a central, paracentral, arcuate or ring scotoma.22 ERG is a sensitive diagnostic test early in the course of disease and demonstrates a depression of a- and b-waves on either phototopic and/or scotopic conditions depending on the degree of rod or cone involvement.22 FAF can reveal abnormal hyperautofluorescence surrounding a parafoveal region of normal autofluorescence.23 Macular OCT shows a loss of outer retinal complex components.23 Immunohistochemistry can identify antiretinal antibodies, most common of which are antirecoverin and anti-alpha-enolase antibodies.20

Figure 6. This 71-year-old male was referred with nyctalopia and with subacute blurring of central vision bilaterally. VA measured 20/50 RE and 20/40 LE and fundus examination revealed parafoveal RPE mottling (Figure A). Macular OCT identified a generalized irregularity of the ellipsoid zone (Figure B). FA revealed staining of the RPE mottling only (Figure C). ERG was consistent with rod > cone dysfunction.
Figure 6. This 71-year-old male was referred with nyctalopia and with subacute blurring of central vision bilaterally. VA measured 20/50 RE and 20/40 LE and fundus examination revealed parafoveal RPE mottling (Figure A). Macular OCT identified a generalized irregularity of the ellipsoid zone (Figure B). FA revealed staining of the RPE mottling only (Figure C). ERG was consistent with rod > cone dysfunction.

Myotonic Dystrophy

The classic ocular finding in myotonic dystrophy is the “Christmas tree cataract,” a posterior subcapsular, red and green, iridescent opacification of the lens. Patients can present with other ophthalmic findings including ocular hypotony and pigmentary retinopathy (Figure 7) that can be confused for AMD.24,25 The pathognomonic systemic feature is muscle weakness and myotonia of the distal legs, hands, neck and face.26 Fundus examination can reveal butterfly-shaped macular pigmentary changes, peripheral reticular pigmentation and peripheral polygonal-shaped atrophy.27 FAF of the macular pigmentary changes demonstrates a branching linear pattern of mixed hyper- and hypoautofluorescence.28 Macular OCT of these changes identifies patches of inderdigitation zone hyperreflectivity and ellipsoid zone hyporeflectivity.28

Figure 7. This 43-year-woman with a history of myotonic dystrophy was referred with blurring of central vision LE. VA measured 20/30 LE. Fundus examination revealed mild pigmentary changes in the macula (top left), corroborated on red-free fundus photography (top right). FA demonstrated patchy staining of the RPE mottling on early and late frames (bottom left and right respectively). These findings were consistent with myotonic dystrophy with pattern dystrophy of the macula.
Figure 7. This 43-year-woman with a history of myotonic dystrophy was referred with blurring of central vision LE. VA measured 20/30 LE. Fundus examination revealed mild pigmentary changes in the macula (top left), corroborated on red-free fundus photography (top right). FA demonstrated patchy staining of the RPE mottling on early and late frames (bottom left and right respectively). These findings were consistent with myotonic dystrophy with pattern dystrophy of the macula.

CONCLUSION

Despite the prevalence of dry AMD, it is important for ophthalmologists to consider less common diseases and multi-modal imaging to arrive at the correct diagnosis. As demonstrated in this series, numerous pathologies have overlapping features with dry AMD, including pattern dystrophies, cone-rod dystrophies, medication toxicities, and systemic disorders associated with maculopathies. Other common disorders with overlapping features of dry AMD include inactive central serous retinopathy and other “pachychoroid”-related maculopathies, particularly in older patients, as these entities can cause macular pigmentary changes. Historical and exam features that raise suspicion of “Dry AMD-masquerade syndromes” include younger age, suspect medications and systemic disorders, family history, highly symmetric macular pathology and lack of typical drusen. Cuticular drusen and flecks, as demonstrated above, as well as dominant drusen (Malattia Leventinese), and even crystalline retinopathies such as tamoxifen maculopathy, could mimic drusen. Ancillary testing with red-free photography, FA, FAF, macular OCT and ERG can be helpful in further characterizing the retinal pathology. Newer techniques such as OCT with enhanced depth imaging can be used to demonstrate thickened choroid, which is characteristic of central serous retinopathy and other “pachychoroid”-related maculopathies. In the future, genetic testing will become commonplace, and will further delineate many of these maculopathies. RP

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