Collaborative Case #004: The Elephant in the Room

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Case Presentation

A patient who had been followed for several years presented for an unscheduled visit with complaints of recent decline in VA OU. At the examination, the patient was diagnosed with neovascular age-related macular degeneration (AMD) OS (BCVA at presentation was 20/60). He was subsequently managed with a series of intravitreal anti-VEGF agents, resulting in stable 20/60 BCVA over the next several visits. His left eye (Figure 1) had demonstrated pigmentary and drusen changes over the years with small, demarcated areas of depigmentation, but he maintained 20/40 VA with no evidence of neovascularization. In addition to his ophthalmic condition, he was also being treated for elevated blood lipids, systemic hypertension, and early dementia.

Figure 1. Color fundus photograph of the left eye of a patient who developed neovascular AMD changes in the fellow eye. Note the pigmentary changes, drusen, and geographic atrophy in the macula.

This patient has advanced AMD, geographic atrophy [GA] OD and wet AMD OS in both eyes, with a poor prognosis for maintaining 20/40 vision in his left eye. Advanced GA is a slowly progressive disease that although initially may not affect vision or may only show minimal effects of BCVA, it will eventually result in permeant severe vision loss. This example highlights the devastating effects of both wet and dry AMD. Although an established treatment option has been in place for his right eye, only recently have we had FDA-approved treatment options for the clinical presentation of the left eye.

Figure 2. Color fundus photograph of patient’s right eye 3 years after baseline examination (top right). Note progression of GA and regression of drusen pattern. Corresponding OCT (top left). Enhanced depth mode for imaging has highlighted visibility of the choroid and emphasizes the loss of RPE. Despite treatment, outer retinal laminations are indistinct. Color fundus photograph of patient's left eye 3 years after baseline examination (lower right). Note progression of GA and regression of drusen pattern. Corresponding OCT (lower left). Vitreomacular traction has altered the inner retinal architecture. Although the resolution is poor, the enhanced visibility of the choroid emphasizes the loss of RPE. Additionally, large and small drusen are imaged.

All of the above should be considered to minimize the risk of developing or progression of AMD in general, including GA. The patient in Figure 1 was recommend the full slate of items in the above question and followed until the time of his death. Unfortunately, until recently the yoke of GA was inescapable. Another example of GA progression is shown in Figure 2. This patient was followed over the course of 8 years with significant progression of the clinical picture as well as visual performance, which was asymmetric. Based on genetic testing, this patient was recommended a specific nutritional supplement formulation, but his condition progressed much faster in his left eye (20/200 at the most recent visit) than in his right eye (20/25).

Figure 3. Color fundus photographs of the left eye of the patient in Figure 2 who was followed over 6 years (chronologically captured at 2-year intervals) whose visual acuity declined to 20/200 over the period of management. It is difficult to appreciate the extent of subtle outer retinal changes using color fundus photography alone.

DISCUSSION

GA is often regarded as the red-headed stepchild of AMD as there were few to no specific management options to retard its progression.² Recently the retinal pigment epithelium (RPE) has been implicated in the pathogenesis of AMD with potential targeted therapies.³ Although compounds such as elamipretide and photobiomodulation are not FDA-approved, their promise is on the horizon.^4,5 As of this writing, there are at least a dozen candidate treatments listed on the clinical trials.gov website.⁶

Previous guidance regarding the management of dry AMD, including GA, comes from analysis of more than 14,000 eyes enrolled in the AREDS studies. Not surprisingly, saturated fats, mono-saturated fats, and oleic acid were associated with risk for progression and should therefore be avoided. Among the protective dietary items were antioxidant vitamins, a host of minerals, eicosapentaenoic acid and docosahexaenoic acid (aka omega-3 polyunsaturated fatty acids).^7,8 Any patient with a family history of macular degeneration should be considered at risk for developing AMD. In the presence of any early indication of AMD (eg, small drusen, pigmentary alterations) or even the suspicion of beginning GA at clinical evaluation should undergo further testing, such as fundus autofluorescence (FAF) or OCT to determine if any indication of GA is present. Patients demonstrating the presence of drusen, subretinal drusenoid deposits or loss of RPE should be monitored closely for progression. Of note as progression of GA occurs, drusen may regress. In the second patient reported here, the color fundus photographs demonstrate the regression of drusen with the enlargement of GA territories.

Recently, the FDA has granted approval for a complement inhibitor pegcetacoplan (Syfovre, Apellis Pharmaceuticals) injected intravitreally to slow GA lesion growth rate of GA secondary to AMD. This likely represents the first step in the journey to enhanced treatment strategies for GA. The significance of this is that now there is a specific treatment for GA beyond lifestyle, nutritional and supplement recommendations. Another promising candidate is avacincaptad pegol, which completed clinical trials (GATHER) and has been submitted for FDA approval. These treatment options may slow the progression of the disease.

Initially, GA is characterized by well-delineated orange round lesions near the macula. The VA will not be affected, but other visual disturbances, such as night driving difficulties, problems reading, and contrast sensitivity may ensue. Enormous strides have been made in retinal imaging over the past two decades. The refinement of widefield imaging and the introduction of optical coherence tomography angiography (OCTA) have enhanced the ability to diagnose retinal vascular disease processes earlier, which has led to more precise monitoring, especially given contemporary treatment options.

Diagnostic Modalities

The development and maturity of fundus autofluorescence (FAF) and OCT has offered new insights into outer retinal patho-anatomy and especially the early indicators of GA. The confluence of OCT and FAF may offer the earliest indication of GA.^12-15 Particular attention should be paid to the outer retina/RPE interface using high-resolution OCT (spectral domain SD-OCT) and using results from FAF when available concurrently. In their absence, clinicians may invoke other avenues to find specific changes that affect performance in early AMD and GA specifically. These will include low luminance visual acuity and dark adaptation time measurement.^16,17

FAF: hypoAF of atrophic lesion will be denoted with associated presence of hyperAF surrounding the lesion. Specific FAF patterns may be associated with increased risk of progression.
OCT: choroidal hypertransmission with be seen in association with GA lesions. In addition, overlying photoreceptor degeneration is seen as attenuation of RPE/photoreceptor integrity line.

With evolving technology comes novel terminology. Given the pathogenesis of AMD originating at the level of the RPE, descriptive terms such as incomplete and complete outer retinal atrophy (iCORA and CORA, respectively) have been established.^9-11 The terms nascent GA and iCORA have emerged as equivalent clinical descriptors.^11-14 Considering the anatomic changes occurring early in the disease process, it makes sense that looking for these hallmarks on these respective technologies will be significant for identifying early GA beyond documentation with color fundus photography.

KEY TAKEAWAYS

GA is a slow, progressive disease, and even though it presents in the advanced stage of the disease, it may not be initially associated with decreased vision and therefore may go undiagnosed.
The advent of FAF and OCT may help to better clinically diagnose early findings associated with GA.
New treatment options may help slow the progression of GA, thereby aiding in slowing too the progression towards devastating vision loss.

Leo Semes, OD

- Professor Emeritus, University of Alabama at Birmingham School of Optometry

leopsemes@gmail.com

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ABOUT THIS SERIES

On the path from initial diagnosis to severe disease management, patients may encounter a number of eye care providers. The Collaborative Care Case Series was developed, with guidance from William Trattler, MD, and Diana Shechtman, OD, FAAO, to challenge clinicians' understanding of diagnostic and treatment conventions and advance knowledge of all eye care providers along the continuum.

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