History of present illness
We present a case of a 60-year-old healthy female patient with an unremarkable past ocular history referred for evaluation of fundus abnormalities in both eyes. She reports that her vision has been stable for several years and denies blurry vision, scotomata, floaters, photopsias, metamorphopsia, dyschromatopsia, or nyctalopia. Her family history was unremarkable for any ophthalmic conditions. She has no history of substance use and takes no medications.
Ocular examination findings
Visual acuity with correction was 20/20 in the right eye and 20/25 in the left eye. Intraocular pressure was normal. Her pupils were briskly reactive to light, equal, and without relative afferent pupillary defect. Extraocular motility and visual fields with confrontation were full. Slit lamp examination was only significant for early nuclear sclerotic cataract and mild asteroid hyalosis in both eyes. Dilated fundus examination revealed bilateral parafoveal concentric atrophy.
Imaging
Fundus photography of both eyes illustrated symmetrical parafoveal atrophy in a bull’s eye pattern ( Fig. 18.1 ). Optical coherence tomography (OCT) of both eyes showed preserved foveal contour; parafoveal attenuation of the outer retina and shoddy loss and attenuation of the ellipsoid zone (EZ). There is focal and irregular parafoveal thickening of the retinal pigment epithelium (RPE) ( Fig. 18.2 ). Fundus autofluorescence (FAF) of both eyes demonstrated parafoveal patchy areas of hypo- and hyperautofluorescence ( Fig. 18.3 ).
Questions to ask
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Does the patient have a family history of vision problems? This symmetrical pattern of atrophy can be seen in several inherited macular dystrophies such as Stargardt disease, central areolar choroidal dystrophy (CACD), benign concentric annular macular dystrophy, and cone dystrophy.
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Patient reports no known family history of eye conditions.
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What medications is the patient currently taking or has used in the past? Parafoveal outer retinal atrophy can be seen in chloroquine and hydroxychloroquine toxicity.
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Patient denies current or past use of medications associated with retinal toxicity.
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Assessment
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This is a case of a 60-year-old woman with no visual symptoms, no past ocular history, and a negative family history who presents with incidental findings of bilateral, symmetrical parafoveal outer retinal atrophy noted on fundus examination, OCT, and FAF.
Differential diagnosis
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Central areolar choroidal dystrophy (CACD)
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Stargardt disease
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Medication-associated toxicity (e.g., chloroquine, hydroxychloroquine, pentosan polysulfate)
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Benign concentric annular macular dystrophy
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Cone or cone-rod dystrophy
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North Carolina macular dystrophy (NCMD)
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Pattern dystrophy of the retinal pigment epithelium
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Best disease (vitelliform macular dystrophy)
Working diagnosis
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CACD
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Clinical diagnosis was made based on fundus findings of well-demarcated, concentric area of parafoveal atrophy in the absence of other history, examination, or imaging findings that would be characteristic of other etiologies.
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However, given the phenotypic variation of this entity and overlapping features with other conditions on the differential diagnosis, genetic testing was performed for diagnostic confirmation.
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Multimodal testing and results
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Fundus photography
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The macula reveals a bilateral, symmetrical, well-circumscribed area of parafoveal atrophy with visualization of underlying choroidal vessels and sclera in advanced cases. ,
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OCT
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As noted in our patient, OCT changes of the outer retina predominate and progress in four stages.
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Stage 1 is characterized by focal parafoveal areas of disruption of RPE and EZ anatomy.
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Stage 2 progresses to outer nuclear layer thinning with early external limiting membrane irregularity. Additionally, focal elongation of the photoreceptor outer segments can be observed.
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Stage 3 progresses to complete absence of outer retinal layers and RPE atrophy correlating to hypoautofluorescence on FAF.
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Stage 4 is characterized by progression of total outer retinal layer and RPE loss involving the fovea. Outer retinal tubulations extending from the photoreceptor layer can be seen at the borders of atrophy in the majority of cases.
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FAF
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FAF changes also progress in four stages.
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Stage 1 shows focal areas of hyperautofluorescence.
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Stage 2 shows speckled or patchy areas of hyper- and hypoautofluorescence as noted in our patient ( Fig. 18.3 ).
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Stages 3 and 4 reveal more confluent areas of RPE and outer retinal atrophy that are non-foveal-involving and foveal-involving, respectively.
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Fluorescein angiography (FA)
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FA may show early-phase hyperfluorescence corresponding to a window defect. If RPE atrophy is incomplete, a speckled pattern of hyperfluorescence can be visualized. In late-phase images, discrete areas of hyperfluorescence may be seen at the edge of the central lesion corresponding to incomplete choriocapillaris atrophy. ,
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Indocyanine green angiography
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Two distinct phenotypes have been described. The first demonstrates hyperfluorescence in the early phase and normofluorescence in the late phase. The second phenotype shows hypofluorescence in the early phase and normofluorescence with pinpoint areas of leakage within the atrophic lesion in the late phase.
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Electroretinography (ERG)
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In full-field ERG, mildly decreased cone b-wave amplitude and prolonged b-wave implicit time are the main abnormalities observed; these may extend beyond the area of central atrophy.
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Of note, multifocal ERG can be helpful in detecting macular dysfunction in cases of CACD that only involve a small central area, and will typically show lower P1/N1 amplitudes and delayed P1/N1 implicit times.
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OCT angiography
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An increase in the avascular zone can be seen at the superficial capillary plexus (SCP) and deep capillary plexus. Microaneurysms, vascular loops, and intraretinal microvascular abnormalities, especially in the SCP, can be seen in earlier disease stages. Widespread impaired vascular perfusion may be seen in later disease stages.
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Genetic testing
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Our patient carried a p.Arg142Trp mutation in the PRPH2 or peripherin/RDS gene, which leads to a CACD phenotype.
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In most cases, CACD is inherited in an autosomal dominant fashion.
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Five identified PRPH2 mutations can cause autosomal dominant CACD, although significant intrafamilial variation in penetrance and expressivity has been observed. Macular changes typically begin in early adulthood and may progress in the fourth or fifth decade of life. This feature is highlighted by our patient, who presents with no vision symptoms, excellent visual acuity, and relatively mild disease despite her older age.
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Miscellaneous
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Visual field testing: central scotoma corresponding to areas of atrophy; normal peripheral field.
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Color vision: Farnsworth Panel–D15 testing with disturbances affecting the blue axis.
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Management
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At this time there is no treatment for CACD, thus our patient was observed.
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After genetic testing, it is important to counsel the patient on the autosomal dominant inheritance pattern of this disease for the purposes of family planning. Screening of other family members should also be considered, especially because of phenotypic heterogeneity.
Follow-up care
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Patients can be followed annually once diagnosis is confirmed
Algorithm 18.1 : Algorithm for differential diagnosis for bull’s eye maculopathy
This algorithm ( Algorithm 18.1 ) highlights the most common genetic defects and characteristic clinical or imaging findings.
