How Lesion Patterns Shape Vision Loss in Age-Related Macular Degeneration
Imagine your central vision slowly fading, with blind spots expanding like spilled ink across the page when you try to read, recognize faces, or see fine details.
This is the reality for millions living with geographic atrophy (GA), an advanced form of age-related macular degeneration (AMD). What many patients—and even some clinicians—don't realize is that not all GA progresses equally. The pattern of lesions, specifically whether they appear as single (unifocal) or multiple (multifocal) areas of damage, significantly influences how quickly vision deteriorates. Recent research has revealed that multifocal GA progresses 46% faster than unifocal GA, making this distinction critical for prognosis and future treatments 2 5 .
People affected worldwide by geographic atrophy
Progression of multifocal GA compared to unifocal GA
Steady, linear progression pattern for both GA types
Key Insight: The macula, a tiny area at the center of our retina, is responsible for our sharp, detailed vision. When geographic atrophy sets in, the delicate tissues of the macula—including photoreceptors, retinal pigment epithelium, and choriocapillaris—waste away, creating permanent blind spots that gradually enlarge over time 2 .
Age-related macular degeneration exists on a spectrum, progressing through early, intermediate, and late stages. Geographic atrophy represents the advanced "dry" form of AMD, distinct from the "wet" form characterized by leaking blood vessels. While treatments exist for wet AMD, until recently, there were no approved therapies to slow GA progression, making understanding its natural course particularly important 3 .
In GA, the damage isn't random. The disease specifically targets the retinal pigment epithelium (RPE), a layer of cells that acts as a supportive foundation for photoreceptors (the light-sensing cells of the retina) and a filtration system for the underlying choroid blood supply. When these RPE cells die, the photoreceptors they support also perish, leading to irreversible vision loss 3 .
| Characteristic | Unifocal GA | Multifocal GA |
|---|---|---|
| Definition | Single continuous area of atrophy | Two or more separate areas of atrophy |
| Appearance | One distinct lesion | Multiple discrete lesions |
| Progression Rate | Slower (0.136 mm/year) | Faster (0.199 mm/year) |
| Typical Baseline Size | Often larger at detection | Often smaller individual lesions |
| Clinical Significance | More predictable expansion | 46.3% faster progression rate |
The classification of GA into unifocal and multifocal types isn't merely descriptive—it reflects fundamental differences in disease behavior. Unifocal GA presents as a single, continuous area of atrophy, while multifocal GA features multiple separate lesions that may eventually merge 2 . This distinction matters because, as we'll explore, these different patterns progress at markedly different rates.
For years, ophthalmologists debated whether unifocal and multifocal GA represented different disease stages or distinct progression patterns. Some studies reported comparable growth rates between the two types, while others suggested significant differences. This confusion stemmed from relatively small studies with short follow-up periods, making it difficult to draw firm conclusions 2 .
This uncertainty was resolved when researchers combined data from multiple studies in a comprehensive meta-analysis that included 3,489 eyes from 3,001 patients across 12 independent studies. This large-scale analysis revealed several critical findings that have reshaped our understanding of GA progression 2 5 .
3,489 eyes from 3,001 patients across 12 independent studies
The most striking discovery was that multifocal GA progresses significantly faster than unifocal GA. When researchers measured the growth of what they called the "effective radius" (a way to standardize measurement of irregularly shaped lesions), multifocal GA expanded at 0.199 mm/year compared to 0.136 mm/year for unifocal GA—a 46.3% difference 2 5 .
Perhaps even more importantly, the research demonstrated that GA growth follows a steady, linear pattern over approximately seven years for both types. This finding was significant because it suggested that GA progression is predictable and follows consistent patterns, making it possible to forecast future vision loss and potentially measure treatment effectiveness accurately 2 .
Perimeter-Driven Hypothesis: The most insightful discovery came when researchers identified why multifocal GA progresses faster. They proposed that growth rate depends on total lesion perimeter—the combined length of all edges of the atrophy where damaged and healthy tissue meet. Think of a single large circle compared to several smaller circles that together have the same total area—the smaller circles will have a much greater combined perimeter. In multifocal GA, multiple small lesions create more "fronts" from which the atrophy can expand, accelerating the overall progression 2 8 .
The pivotal 2020 meta-analysis published in Ophthalmology Retina represented a watershed moment in GA research. This comprehensive study didn't simply collect existing data—it employed sophisticated statistical methods to reconcile apparently conflicting findings from earlier research and establish clear principles of GA progression 2 5 .
The researchers systematically searched five major literature databases up to May 2019, identifying 2,312 records. After rigorous screening, they included 12 studies that met their strict criteria: these studies classified treatment-naïve GA patients based on lesion focality and reported GA lesion sizes on at least two occasions at least six months apart 2 .
The team faced a significant challenge—different studies had enrolled patients at different stages of GA progression, creating the appearance of widely varying initial lesion sizes. To address this, they introduced an innovative statistical approach using "horizontal translation factors" that effectively aligned the datasets as if all patients had been followed from the very beginning of their disease 2 .
Using random effects models (which account for variability between studies), the researchers analyzed both the area and effective radius growth rates. They also performed subgroup analyses to determine if different imaging modalities (color fundus photography, fundus autofluorescence, or optical coherence tomography) affected the measured growth rates 2 .
| Lesion Type | Growth Rate (mm/year) | Comparative Rate |
|---|---|---|
| Unifocal GA | 0.136 ± 0.008 | Baseline |
| Multifocal GA | 0.199 ± 0.012 | 46.3% faster |
The researchers discovered that when unifocal and multifocal GA lesions with the same total baseline area were compared, they grew at vastly different rates, with multifocal GA progressing approximately 1.46 times faster. However, this difference disappeared when they accounted for the different baseline total perimeters between the groups, strongly supporting the perimeter-driven growth hypothesis 2 .
Additionally, the study demonstrated that GA growth rates were consistent across different imaging modalities (color fundus photography, fundus autofluorescence, and optical coherence tomography). This finding was particularly important because it confirmed that results from studies using different imaging techniques could be reliably compared and combined 2 .
Understanding GA progression relies on sophisticated imaging technologies that allow researchers to visualize and measure minute changes in retinal structure over time. These tools have revolutionized our ability to track disease progression and identify biomarkers that predict future outcomes.
Represents one of the earliest methods for documenting AMD and GA. GA appears as sharply demarcated areas that highlight increased visibility of the underlying choroidal vessels. While widely available and cost-effective, CFP offers limited resolution for detecting early changes 3 .
Has become a fundamental imaging modality for GA. This technique uses the natural fluorescence of lipofuscin—a pigment that accumulates in RPE cells—to create detailed images of the retina. Areas of GA appear dark or hypoautofluorescent because the RPE cells (and their lipofuscin) have disappeared 3 .
| Biomarker | What It Reveals | Prognostic Significance |
|---|---|---|
| Hyperreflective Foci | Inflammatory activity in retina | Associated with accelerated local progression 3 9 |
| Incomplete RPE and Outer Retinal Atrophy (iRORA) | Early atrophic changes | High risk (HR: 9.42) for progression to complete GA 9 |
| Non-neovascular Subretinal Fluid | Fluid accumulation without leaking blood vessels | Novel predictor of progression to GA 9 |
| Thick Basal Lamina Deposits | Abnormal deposits beneath RPE | Leads to earlier atrophy development (1.26 vs. 2.15 years) 6 |
| Choriocapillaris Flow Impairment | Reduced blood flow in underlying choroid | Directly correlated with GA growth rate |
| Tool Category | Specific Examples | Function in GA Research |
|---|---|---|
| Imaging Devices | Confocal Scanning Laser Ophthalmoscope, Spectral-domain OCT, Swept-source OCT | High-resolution retinal imaging and measurement of structural changes |
| Analysis Software | RegionFinder, AI-based segmentation algorithms | Semi-automated quantification of atrophy area and progression |
| Statistical Tools | Random effects models, Horizontal translation factors, Multivariate linear mixed-effects regression | Harmonizing data from multiple studies and accounting for variability |
| Classification Systems | CAM Criteria (Classification of Atrophy Meetings), Complete RPE and Outer Retinal Atrophy (cRORA) definition | Standardized identification and measurement of atrophic lesions |
The distinction between unifocal and multifocal geographic atrophy represents more than an academic classification—it provides crucial prognostic information that helps clinicians give patients more accurate expectations about their visual future. The understanding that multifocal GA progresses significantly faster than unifocal lesions, and that this difference stems from the total lesion perimeter, represents a fundamental advance in ophthalmology 2 5 .
This knowledge comes at a pivotal time, as the first treatments for GA have recently emerged. Understanding differential progression patterns allows clinicians to identify which patients may benefit from more aggressive monitoring and earlier intervention. Furthermore, clinical trials can use this information to stratify patients more effectively, ensuring that treatment groups are balanced for this important prognostic factor .
Recently approved complement inhibitors and drugs in development aim to slow the progression of GA by targeting the underlying inflammatory processes that drive the disease. Understanding different progression patterns will be essential for evaluating the effectiveness of these treatments across different GA subtypes .
As we identify more biomarkers—from both imaging and fluid samples—we move closer to personalized prognosis and treatment selection. A current research project is even investigating how blood and fecal biomarkers respond to lifestyle changes in AMD patients, potentially offering new ways to slow progression through modifiable factors 7 9 .
Final Perspective: For the millions living with or at risk for geographic atrophy, these advances offer hope. While GA remains a serious condition that causes irreversible vision loss, our growing understanding of its progression patterns means we can better predict its course, identify those at greatest risk, and develop more effective strategies to preserve vision. The silent progression in our eyes is becoming increasingly visible to science, bringing us closer to the day when we can not just predict but prevent the expansion of these blinding lesions.