Updates on Geographic Atrophy: Diagnostic techniques and emerging therapies
Age-related macular degeneration (AMD) is a progressive eye condition that predominantly affects individuals over the age of 50, gradually leading to central vision loss. As one of the leading causes of vision impairment among older adults, AMD primarily targets the macula, the central portion of the retina responsible for sharp and detailed vision. Early detection and timely management are crucial in mitigating the impact of AMD on visual function. Diagnostic tools play a pivotal role in assessing the severity and progression of the disease, aiding healthcare professionals in formulating effective treatment strategies. From advanced imaging techniques such as optical coherence tomography (OCT) to functional tests like fundus autofluorescence, the array of diagnostic equipment utilized in AMD management ensures a comprehensive understanding of the condition, facilitating personalized and targeted interventions for patients.
Age-related macular degeneration (AMD) is a multifaceted eye disease characterized by progressive damage to the macula. The condition is broadly classified into two main types: dry AMD and wet AMD. Dry AMD, accounting for the majority of cases, involves the gradual accumulation of drusen, yellow deposits beneath the retina, leading to a slow deterioration of central vision over time. In contrast, wet AMD is characterized by the growth of abnormal blood vessels beneath the macula, which can leak fluid or blood, causing rapid and severe vision loss. Both types of AMD undergo distinct stages of progression. Early AMD may exhibit minimal symptoms, with the presence of drusen as the primary indicator. Intermediate AMD is marked by increased drusen size and potential pigment changes in the retina. Advanced AMD manifests as severe vision impairment, either due to extensive geographic atrophy in the case of dry AMD or choroidal neovascularization in wet AMD. Understanding these stages and classifications is pivotal for timely diagnosis, appropriate intervention, and effective management of AMD to preserve visual function and enhance the quality of life for affected individuals.
Geographic atrophy as seen in fundus autofluorescence imaging
Geographic atrophy (GA) is a severe and vision-threatening manifestation of dry age-related macular degeneration (AMD). Characterized by the progressive loss of retinal pigment epithelium (RPE) cells and photoreceptors in the macular region, GA leads to the formation of distinct, well-defined areas of atrophy. These atrophic patches result in the loss of central vision and can significantly impact a person's ability to perform daily tasks that require detailed and sharp vision, such as reading and recognizing faces. Unlike the more common drusen-associated early and intermediate stages of dry AMD, geographic atrophy represents an advanced and irreversible stage of the disease. On OCT, geographic atrophy is defined as a zone of RPE loss/ attenuation and overlying PR degeneration >/250 um in diameter with homogenous choroidal hyper-transmission. The natural progression of the condition varies depending on the initial involvement at presentation. Progression typically involves 2.5 years from the first appearance until foveal involvement in most cases. However, extrafoveal and multifocal lesions progress at faster rates. Patients with geographic atrophy may experience reduced dark adaptation and contrast sensitivity as well as paracentral scotomas. Acuity is not generally affected until geographic atrophy invades the center of the fovea, however even non-central geographic atrophy may cause significant difficulties with tasks such as reading, facial recognition, and mobility. The progression of geographic atrophy can negatively impact a patient's life by creating social isolation, increased risk of falls, depression and anxiety.
Geographic atrophy depicted on OCT
A multimodal imaging approach is optimal for detecting and managing geographic atrophy over time. Diagnostic techniques such as color fundus photography, fundus autofluorescence, near-infrared reflectance, and OCT can be used in tandem to track progression of geographic atrophy. Color fundus photography involves capturing detailed, high-resolution color images of the retina, allowing healthcare professionals to visualize and document changes in the macular region. In the context of GA, color fundus photography helps identify characteristic features such as well-defined areas of depigmentation and atrophy. A sharply demarcated circular area of RPE depigmentation with underlying exposed choroidal blood vessels is indicative of GA with this imaging technique. However, color fundus photography is ineffective at detecting early geographic atrophy and is not an ideal way to track its enlargement over time. Fundus autofluorescence (FAF) imaging is a valuable diagnostic tool in the evaluation of macular degeneration. By capturing the natural fluorescence emitted by lipofuscin in the retinal pigment epithelium, FAF images provide crucial insights into the health and integrity of the macula, aiding in the identification of key pathological changes associated with geographic atrophy. This form of imaging is more sensitive for GA detection than color fundus photography. On fundus autofluorescence, geographic atrophy will appear dark (hypo-autofluorescent) and will be well demarcated. The degree of surrounding hyper-autofluorescence seen on this imaging can provide a prognostic value in predicting geographic atrophy progression. Similarly, geographic atrophy appears hypo-autofluorescent or dark on near-infrared reflectance imaging as well. OCT (Optical Coherence Tomography) is instrumental in diagnosing geographic atrophy in macular degeneration by providing detailed cross-sectional images of the retina. It enables clinicians to visualize the distinct features of atrophy, such as thinning of the retinal layers and loss of retinal pigment epithelium, allowing for precise measurement and monitoring of the extent and progression of geographic atrophy. High-risk OCT biomarkers for future geographic atrophy (GA) development include features such as nascent GA characterized by incomplete retinal pigment epithelium and outer retinal atrophy, subsidence of the inner nuclear layer and outer plexiform layer, descent of the external limiting membrane, loss of external limiting membrane and/or photoreceptor ellipsoid zone, hyporeflective wedges, intraretinal hyperreflective foci, drusen with hyporeflective cores, and collapse of drusenoid pigment epithelial detachment. These biomarkers collectively signify impending GA and provide crucial insights into the structural changes associated with the progression of macular degeneration. In addition, OCT-A can be utilized to monitor choriocapillaris flow which may indicate faster GA enlargement in cases where greater flow impairment is seen surrounding the GA lesions.
Complement inhibition therapy emerges as a promising avenue in the management of geographic atrophy (GA). While it represents a significant stride in the field, it is important to note that the treatment, which involves inhibiting complement factors, serves to slow the progression of GA rather than entirely halting its enlargement. Administered through intravitreal injections on a monthly or bi-monthly basis, this therapeutic approach aims to address the underlying mechanisms contributing to GA, offering hope in the quest to manage and mitigate the impact of this vision-threatening condition. Complement inhibition therapy for geographic atrophy (GA) involves intravitreal injection of agents such as pegcetocoplan (C3 inhibitor) and avacincaptad pegol (ACP, C5 inhibitor). Pegcetocoplan, FDA approved in February 2023, demonstrated a 20% reduction in GA growth over 24 months in combined data from DERBY and OAKS phase 3 trials, with preservation of visual acuity in extrafoveal lesions. Avacincaptad pegol, approved in August 2023, showed a 35.4% reduction in GA area in Gather 1 and a 17.7% reduction in GA growth in Gather 2, along with a 56% reduction in the risk of vision loss over the first 12 months of treatment in combined data analysis. However, both therapies pose a dose-dependent increased risk for progression to neovascular AMD and have reported cases of post-approval intraocular inflammation.
Referral considerations for macular degeneration are crucial in determining the potential benefits of complement inhibition therapy. Patients most likely to benefit from such treatment include those with extrafoveal geographic atrophy (GA), especially those showing progression over time or exhibiting surrounding hyper autofluorescence in fundus autofluorescence (FAF). Additionally, individuals with central-involving GA in the fellow eye may also benefit. It is important to send documentation of progression along with the referral. Patients motivated to undergo intravitreal injections at least every other month and those with sufficient life expectancy to experience a benefit from the treatment are also prime candidates. On the other hand, those less likely to benefit include individuals with neovascular or exudative AMD, a history of anti-VEGF treatment in the affected eye (though fellow eye cases are acceptable), disciform macular scars, extensive central-involving GA with poor acuity, stable GA lesions without surrounding hyper autofluorescence, RPE atrophy from other causes, and the presence of confounding diseases limiting best-corrected visual acuity (BCVA), such as end-stage glaucoma. Understanding these referral considerations is vital for optimizing patient outcomes and tailoring treatment approaches to individual needs.
The complex landscape of age-related macular degeneration (AMD) demands a comprehensive understanding of its stages, classifications, and diagnostic methodologies for effective management. From early detection to advanced imaging techniques, the array of diagnostic equipment available ensures a personalized and targeted approach to interventions. Geographic atrophy (GA) stands out as a particularly challenging manifestation, necessitating a multimodal imaging approach for accurate diagnosis and monitoring. As we delve into the realm of complement inhibition therapy, the latest strides in treatment bring hope for slowing the progression of GA, but with careful consideration of patient selection and potential risks. The importance of thoughtful referral considerations underscores the need for individualized care, aligning treatment strategies with the unique characteristics of each patient. As research and innovation continue to shape the field, a holistic approach serves as a foundation for optimizing outcomes and improving the quality of life for those affected by geographic atrophy.
Learn more about this topic in our upcoming CE event on Thursday, January 25, 2024 with Dr. Carolyn Matcher.
Written by Dr. Hannah Alegado, O.D.
Topic and information courtesy of Dr. Carolyn Matcher’s course: “Imaging Techniques and Emerging Therapies for Geographic Atrophy”
