History of present illness
A 63-year-old female patient was referred for evaluation of atypical drusen in both eyes. She reported normal central vision in both eyes. Her past medical history included hypothyroidism, hypertension, and hypercholesterolemia.
Ophthalmic examination findings
Visual acuity was 20/16 without correction in each eye. Intraocular pressures were normal. External and anterior segment examination showed mild nuclear sclerotic cataracts. Dilated fundus examination demonstrated an extensive interlacing network of yellowish deposits, including some punctate lesions, involving the maculae (with relative sparing nasally) and extending beyond the arcades (particularly temporally and superotemporally) in both eyes, as well as large, soft drusen in the temporal macula of the left eye ( Figs. 22.1 and 22.2 ).
Imaging
Optical coherence tomography (OCT) showed that the interlacing network in both eyes consisted of multiple lesions of hyperreflective material above the retinal pigment epithelium (RPE) ( Fig. 22.3 ). Some lesions comprised mounds of hyperreflective material that altered the ellipsoid zone (EZ), whereas others were conical and broke through the EZ. Soft drusen were also observed in some B-scans, comprising nonconical lesions of hyperreflective material below the RPE layer. Fundus autofluorescence (FAF) imaging revealed an extensive interlacing network (i.e., a reticular appearance) in both eyes comprising hypoautofluorescent lesions surrounded by areas of hyperautofluorescence ( Fig. 22.4 ). A similar appearance was observed on near-infrared reflectance (NIR) imaging ( Fig. 22.5 ).
Questions to ask
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Does the patient have slow dark adaptation? Reticular pseudodrusen (RPD) are typically accompanied by prolonged dark adaptation.
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Dark adaptation was highly prolonged. The patient admitted to her vision taking many minutes to adapt to the low light conditions of a movie theatre and described the phenomenon of afterimages of bright lights persisting sometimes for several hours.
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Is the patient known to have age-related macular degeneration (AMD)? RPD are observed most commonly in AMD.
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Yes
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Is there a family history of inherited retinal disease (particularly Sorsby fundus dystrophy, late-onset retinal degeneration, fundus albipunctatus, or retinitis punctata albescens)? RPD can be observed in these conditions.
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No
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Does the patient have systemic features of pseudoxanthoma elasticum (e.g., characteristic skin lesions, intermittent claudication, coronary artery disease, or gastrointestinal bleeding)? RPD can also be observed in this condition.
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No
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Could the patient have vitamin A deficiency (e.g., from dietary deprivation, gastrointestinal conditions, or liver disease), which has been linked to RPD?
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No
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Related to AMD, questions on smoking history and oral supplement use are appropriate.
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The patient had never smoked cigarettes and took Age Related Eye Disease Study (AREDS2) supplements.
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Assessment
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This 63-year-old female patient had extensive RPD in both eyes and no apparent monogenic retinal disease or systemic condition as a potential cause. Other findings of AMD were present.
Differential diagnosis
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RPD should be distinguished from other retinal deposits, including soft drusen, cuticular drusen, RPE pigmentary abnormalities, and flecks
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AMD is the most common cause of RPD
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RPD can also be seen in some monogenic retinal diseases:
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Sorsby fundus dystrophy ( TIMP3 mutations)
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Late-onset retinal degeneration (LOLD) ( CTRP5 mutations)
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Fundus albipunctatus ( RDH5 mutations)
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Retinitis punctata albescens ( RLBP1 or RDH5 mutations)
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Pseudoxanthoma elasticum
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Vitamin A deficiency
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Extensive macular atrophy with pseudodrusen
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Otherwise normal retina (i.e., with RPD as either an aging phenomenon or an isolated feature in atypical AMD)
Working diagnosis
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Intermediate AMD with extensive RPD in both eyes
Multimodal testing and results
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Color fundus photography (CFP) ( Fig. 22.1 )
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Often poorly visualized. If apparent, typically observed as (1) a network of faint interlacing ribbons, (2) more discrete dot-like deposits, and/or (3) moderately confluent globules in the midperiphery.
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OCT ( Fig. 22.3 )
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Lesions of hyperreflective material above the RPE layer.
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Often considered in three or four stages: stage 1, diffuse granular hyperreflective material; stage 2, mounds of hyperreflective material that alter the EZ; stage 3, conical lesions of hyperreflective material that break through the EZ ; and stage 4, hyperreflective lesions fading into the inner retinal layers.
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Proposed as the base modality for defining RPD, given high sensitivity and specificity, and ability to determine their subretinal location.
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FAF ( Fig. 22.4 )
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Interlacing network comprising hypoautofluorescent lesions, sometimes with a “target” appearance (i.e., a central area of isoautofluorescence encased by a halo of hypoautofluorescence), surrounded by areas of hyperautofluorescence
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NIR ( Fig. 22.5 )
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Similar appearance to FAF
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High sensitivity and specificity for detecting RPD
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Deep learning algorithms have been trained to detect RPD presence automatically from FAF and/or CFP images ,
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Dark adaptation
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RPD presence in AMD is strongly associated with very slow dark adaptation
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Genetic testing
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RPD presence in AMD is strongly associated with a high AMD polygenic risk score and is preferentially associated with risk variants at ARMS2/HTRA1 rather than CFH
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Management
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The management of a patient with RPD is guided by the parent condition.
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In this case of a patient with intermediate AMD, management comprised recommendations for daily AREDS2 oral supplement use, home monitoring for symptoms of progression (using an Amsler grid or other home monitoring program), avoidance of smoking, and a healthy diet (Mediterranean pattern).
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RPD presence in AMD might make eyes inappropriate for subthreshold nanosecond laser (SNL) treatment. In post hoc analyses of one randomized controlled trial of SNL for eyes with intermediate AMD, RPD presence appeared to be a strong factor in predicting a negative response (i.e., increased risk of progression to late AMD or nascent geographical atrophy).
Follow-up care
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Follow-up is guided by the parent condition. For AMD, this is determined by the disease stage; for example, every 6 to 24 months for early AMD and every 6 to 18 months for intermediate disease.
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However, RPD presence in AMD is associated with increased risk of progression to late disease, particularly geographical atrophy, type 3 neovascular AMD, and isolated outer retinal atrophy. , Therefore our patient was recommended for repeat evaluation and multimodal imaging at least every 6 months. As always, prompt evaluation is required for any new symptoms.
Algorithm 22.1 : Algorithm for workup of reticular pseudodrusen: staging and differential diagnosis of their parent condition
