Age-Related Macular Degeneration

Overview

Age-related macular degeneration is a progressive disorder affecting the macula that represents an increasingly important public health issue due to aging populations and increased longevity.¹ It is a leading cause of visual impairment in patients aged 50 and older, with an estimated 200 million people affected worldwide and a projected 288 million by 2040.² The disease affects individuals older than 55 years and threatens high-acuity central vision required for important tasks such as reading, driving, and recognizing faces.¹ Advanced AMD, including neovascular AMD (wet) and geographic atrophy (late dry), is associated with substantial, progressive visual impairment.³

Epidemiology & Risk Factors

The main risk factor for AMD is advancing age.⁴ In patients over age 75, there is a 25% risk of early AMD and an 8% risk of late AMD.⁴ With aging populations in many countries, more than 20% might have the disorder.³ The number of cases is expected to increase because of the aging population.⁴

Major risk factors include:

• Cigarette smoking³
• Nutritional factors³
• Cardiovascular diseases³
• Genetic markers, including genes regulating complement, lipid, angiogenic, and extracellular matrix pathways³

Some studies have suggested a declining prevalence of AMD, perhaps due to reduced exposure to modifiable risk factors.³

Pathophysiology

Retinal aging that contributes to AMD pathogenesis is characterized by multiple pathologic processes.⁵ Key features include:

• Accumulation of drusen deposits⁵
• Alteration in the composition of Bruch's membrane and extracellular matrix⁵
• Vascular inflammation and dysregulation⁵
• Mitochondrial dysfunction⁵
• Accumulation of reactive oxygen species (ROS)⁵
• Retinal pigment epithelium (RPE) cell senescence⁵

The understanding of underlying mechanistic pathways continues to evolve, with multiple pathways implicated in disease development and progression.¹

Clinical Presentation

The severity of vision loss in AMD ranges from mild to severe.⁴ Patients experience progressive impairment of central high-acuity vision, which interferes with activities requiring fine visual detail such as reading, driving, and recognizing faces.¹ Advanced AMD is associated with substantial, progressive visual impairment.³ Physicians should be aware of the symptoms to refer appropriately for ophthalmologic evaluation, as early detection can be helpful to prevent disease progression.⁴

Exam Findings

Diagnosis of AMD requires a dilated fundus examination.⁴ Accurate diagnosis combines clinical examination and investigations.³ Key diagnostic modalities include:

• Retinal photography³
• Angiography³
• Optical coherence tomography³

Advances in retinal imaging have identified biomarkers of progression to late AMD.¹

Classification

AMD is classified based on stage of progression and subtype. Advanced or late AMD includes two major forms:

• Neovascular AMD (wet): characterized by abnormal blood vessel growth³
• Geographic atrophy (late dry/atrophic AMD): characterized by progressive atrophy of the retinal pigment epithelium^3,1

The disease also encompasses early and intermediate stages characterized by drusen and pigmentary changes.¹

Differential Diagnosis

• Other causes of central vision loss in older adults
• Diabetic macular edema
• Retinal vein occlusion
• Central serous chorioretinopathy
• Macular hole
• Epiretinal membrane
• Other macular dystrophies

Management

Dietary Supplementation

Dietary anti-oxidant supplementation slows progression of disease.³

Neovascular AMD Treatment

Treatment for neovascular AMD incorporates intraocular injections of anti-VEGF agents, occasionally combined with other modalities.³ The advent of anti-VEGF therapy has revolutionized the treatment of neovascular AMD.⁶ Evidence suggests that two commonly used anti-VEGF therapies, ranibizumab and bevacizumab, have similar efficacy, but possible differences in systemic safety are difficult to assess.³ New treatments for neovascular AMD offer potentially longer-lasting effects.¹

Dry AMD/Geographic Atrophy Treatment

Dry AMD is being investigated for possible therapeutic options.⁶ Therapeutic categories undergoing clinical trials include complement pathway inhibitors, visual cycle modulators, reduction of toxic byproducts, antioxidative therapy, neuroprotective agents, laser therapy, surgical options, gene therapy, stem cell therapy, and miscellaneous treatments.⁶ Two intravitreal anti-complement factors (pegcetacoplan and avacincaptad pegol) have recently shown phase 3 clinical trial evidence of a reduction in the growth of geographic atrophy.⁶ Progress is being made towards a treatment for atrophic late AMD.¹

Future Directions

Future treatments include inhibition of other angiogenic factors, and regenerative and topical therapies.³ An effective intervention to slow progression in the earlier stages of disease, or to prevent late AMD development remains elusive.¹

Complications

Advanced AMD is associated with substantial, progressive visual impairment.³ The disease threatens central high-acuity vision required for important tasks such as reading, driving, and recognizing faces.¹ AMD is a leading cause of blindness worldwide.^3,2 Vision loss severity ranges from mild to severe, with advanced stages causing significant functional disability.⁴

Clinical Pearls

• AMD primarily affects individuals older than 55 years, with risk increasing substantially after age 75^1,4
• Dilated fundus examination is required for diagnosis, but should be supplemented with imaging including optical coherence tomography^4,3
• Early detection can help prevent disease progression, emphasizing the importance of timely referral⁴
• Advances in retinal imaging have identified biomarkers that predict progression to late AMD¹
• Some studies suggest declining prevalence possibly due to reduced exposure to modifiable risk factors such as smoking³
• Anti-VEGF therapy has transformed outcomes in neovascular AMD, with newer agents offering potentially longer duration of action^1,6

Common Pitfalls

• Failing to obtain dilated fundus examination in older patients with visual complaints, leading to delayed diagnosis⁴
• Not recognizing that visual impairment in AMD is progressive and can range from mild to severe, affecting patient counseling and expectations⁴
• Overlooking modifiable risk factors such as smoking and nutritional deficiencies that may influence disease progression³
• Not referring patients with early or intermediate AMD for specialized ophthalmologic evaluation and consideration of dietary supplementation^4,3
• Assuming no treatment options exist for dry AMD, when complement inhibitors have recently shown efficacy in geographic atrophy⁶
• Delaying anti-VEGF treatment in neovascular AMD, which can result in irreversible vision loss³