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Macular Diseases

NON-EXUDATIVE (DRY) AGE-RELATED MACULAR DEGENERATION

Jordan D. Deaner, MD and Allen C. Ho, MD, FACS

• Constitutes 85% to 90% of age-related macular degeneration (AMD). Drusen are the hallmark lesions, however retinal pigment epithelial (RPE) hyperpigmentation and atrophy may also be present.
  
• Oxidative stress is the suspected disease mechanism, resulting in photoreceptor toxicity, lipofuscin accumulation in RPE, drusen formation, and choriocapillaris atrophy.

• Drusen size: small (< 63 μm), intermediate (63 to 124 μm), large (> 124 μm)—for reference, retinal veins at optic disc margin are approximately 125 μm in diameter
  
• Drusenoid pigment epithelial detachments (PED) may arise from coalesced drusen (> 350 μm)
  
• RPE granularity or stippling—RPE (geographic) atrophy (Figure 1-1A)

Staging of AMD as Defined by the Age-Related Eye Disease Study

• Early AMD: many small drusen or few (< 10) intermediate drusen; risk of progression to advanced AMD is 1.3% over the 5-year period in the Age-Related Eye Disease Study (AREDS)
  
• Intermediate AMD: 10 or more intermediate drusen, a single large druse; risk of progression to advanced AMD is 18%
  
• Advanced AMD: presence of either geographic atrophy (GA) or choroidal neovascularization (CNV)

• Optical coherence tomography (OCT): focal sub-RPE deposits correlate to drusen; loss of RPE and associated outer retinal structures correlate to GA (Figure 1-1B)
  
• OCT angiography (OCT-A): This dye-less imaging modality can identify CNV in a noninvasive manner.
  
• Fluorescein angiography (FA): Drusen typically show early blocking and late staining, but no leakage; GA presents as a transmission window defect without leakage; CNV will show leakage.
  
• Fundus autofluorescence (FAF): Drusen are classically hyperautofluorescent due to over-accumulation of lipofuscin within RPE cells, while GA appears as marked hypo-autofluorescence. Increased autofluorescence at borders of GA is associated with increased rate of progression.

• Patients need to be educated on symptoms of CNV development including acute metamorphopsia, decreased vision, paracentral, or central scotoma.
  
  
  
  • Eyes with large soft drusen or RPE hyperpigmentation are at higher risk for development of CNV.
    
  • Home monitoring for CNV with either Amsler grid or a digital system such as ForeSeeHome which is approved by the Food and Drug Administration (FDA)
  
  
• Address modifiable risk factors such as healthy diet (leafy dark green vegetables and omega-3 fatty acids) and smoking cessation (most important modifiable risk factor)
  
• Low vision consultation for severe visual impairment
  
• Dietary supplementation
  
  
  
  • Original AREDS formula, recommended for patients with intermediate AMD or worse,1 showed a 25% risk reduction in progression to advanced AMD over a 5-year period and 19% risk reduction of moderate vision loss. This benefit continued at 10 years with 44% placebo vs 34% supplement patients with advanced AMD (27% risk reduction).
    
  • AREDS II study2 showed the addition of lutein and zeaxanthin, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), or both, did not yield any additional risk reduction. However, lutein and zeaxanthin replaced beta carotene due to an increased risk of lung cancer in former smokers who took beta carotene.
    
  • AREDS II formula: 500 mg vitamin C, 400 IU vitamin E, 10 mg lutein, 2 mg zeaxanthin, 80 mg zinc, 2 mg copper

WET AGE-RELATED MACULAR DEGENERATION

Priya Sharma Vakharia, MD and Chirag P. Shah, MD, MPH

• CNV typically develops in eyes with pre-existing dry AMD, which can lead to permanent visual impairment if not treated.
  
• Associated with older age, family history, genetics, and smoking; may also be associated with obesity and cardiovascular disease

Signs and Symptoms

Metamorphopsia, decreased vision, or scotoma

Exam Findings

Subretinal and/or intraretinal fluid, subretinal and/or intraretinal hemorrhage, gray membrane, lipid exudates, fibrovascular pigment epithelial detachment, associated with pre-existing drusen, atrophy, and retinal pigment epithelium changes (Figures 1-2A, 1-3A, and 1-3C)

• OCT: reveals presence of a CNV complex with intraretinal or subretinal fluid (Figures 1-3B and 1-3D)
  
• FA: Shows early hyperfluorescence and late leakage in the area of the CNV (Figure 1-2B). This can be associated with a classic or occult appearance.
  
• Indocyanine green angiography: Ancillary test to visualize the CNV complex, particularly helpful for occult CNV, polypoidal lesions, or when hemorrhage is present. Visualization is enhanced because indocyanine green is highly protein-bound and a longer wavelength is used.
  
• OCT angiography: noninvasive method of angiography which can reveal the CNV

Differential Diagnosis

Central serous chorioretinopathy, polypoidal choroidal vasculopathy, myopic CNV, idiopathic CNV, pattern dystrophy, vitelliform dystrophy, ocular histoplasmosis syndrome, angioid streaks and associated CNV, macular telangiectasia, chorioretinitis

Management

• Intravitreal anti-vascular endothelial growth factor (VEGF) injections decrease drive for abnormal blood vessel growth and reduce leakage from CNV.
  
  
  
  • Current standard of care with several different anti-VEGF medications currently available
    
    
    
    • Ranibizumab: Recombinant humanized monoclonal antibody fragment to VEGF. FDA-approved for treatment of wet AMD, based on results of pivotal ANCHOR and MARINA trials.^5,6
      
    • Bevacizumab: Full-length humanized anti-VEGF antibody that is used off-label to treat macular degeneration. Was shown to be noninferior to ranibizumab in the Comparison of AMD Treatment Trials (CATT).7
      
    • Aflibercept: Fusion protein consisting of VEGF receptors 1 and 2 fused to Fc portion of IgG. FDA-approved for treatment of wet AMD; noninferior to ranibizumab in pivotal VIEW1 and VIEW2 trials.⁴
      
    • Brolucizumab: Humanized single-chain antibody fragment that binds all isoforms of VEGF-A. FDA-approved for treatment of wet AMD: noninferior to aflibercept in pivotal HARRIER and HAWK trials.³
      
    • Pegaptanib: Modified oligonucleotide which binds with and inactivates extracellular VEGF. First anti-VEGF therapy to be FDA-approved for wet AMD, demonstrating efficacy in the VISION trial.⁸ Rarely used due to development of more effective drugs.
    
    
  • Treatment paradigms for injections
    
    
    
    • Monthly or fixed-interval dosing (based on landmark clinical trials)
      
    • Pro re nata (PRN): As needed when clinical or diagnostic evidence of activity, such as hemorrhage, macular edema on OCT or decreased vision. This method requires strict monthly monitoring to ensure no disease activity.
      
    • Treat-and-extend: injection at each visit but gradual lengthening of treatment intervals until signs of exudation are noted; interval is then shortened.
  
  
• Laser photocoagulation: causes local destruction of CNV
  
  
  
  • Limited efficacy and can have significant visual sequalae since retina overlying CNV is also damaged; rarely used in anti-VEGF era except occasionally for extrafoveal CNV
  
  
• Photodynamic therapy (PDT): FDA-approved treatment that involves injecting a photosensitive chemical (verteporfin) and activating it over CNV using a 689 nm laser in an attempt to selectively induce CNV regression without damaging overlying retina
  
  
  
  • Demonstrated to slow progression compared to natural history, but inferior to anti-VEGF therapy and is now rarely employed as monotherapy but may be used in combination with anti-VEGF for treatment resistant cases and is particularly helpful in polypoidal choroidal vasculopathy
  
  
• Pars plana vitrectomy (PPV)
  
  
  
  • With subretinal TPA: may be used in patients with thick submacular hemorrhage involving the fovea to liquefy and displace the hemorrhage
    
  • With extraction of CNV: largely historical and rarely used due to overall lack of efficacy and advent of anti-VEGF treatment

EPIRETINAL MEMBRANE (MACULAR PUCKER)

Sundeep K. Kasi, MD

• Growth of fibrocellular tissue on surface of retina causing disruption and wrinkling of macular contour
  
• Most frequently age-related and due in part to vitreous detachment, but must look for retinal tears, prior ocular surgery, and history of vein occlusion, inflammation or trauma
  
• Affects 2% of patients > 50 years old and 20% of patients > 75 years old. Ten to twenty percent bilateral but often asymmetric.

Signs and Symptoms

Decreased vision, distortion, metamorphopsia, and/or macropsia

Reflective sheen over macula with effacement of foveal light reflex, retinal striae and thickening with membranous tissue in more advanced cases (Figure 1-4A)

Testing

• Amsler grid: distortion of lines with waviness, slanting, or bending
  
• OCT: reflective material on superficial retina with wrinkling or flattening of macular contour, retinal thickening, cystoid or schisis changes (Figure 1-4B)
  
• FA: can show hyperfluorescence indicating leakage from edema due to the traction exerted on retinal vessels

Differential Diagnosis

Macular edema, vitreomacular traction (VMT), lamellar macular hole

Management

• No treatment indicated when patient is asymptomatic, but continued semi-annual or annual monitoring is advised to detect progression
  
• PPV with membrane peeling; internal limiting membrane (ILM) peeling is optional and studies have shown mixed results in terms of effect on vision and recurrence rate. It is particularly effective for patients with significant metamorphopsia.

FULL-THICKNESS MACULAR HOLE

M. Ali Khan, MD

• Foveal defect involving all neural retinal layers, spanning from ILM to RPE
  
• Most cases are idiopathic (due to abnormal vitreo-foveal traction); secondary causes include trauma and pathologic myopia
  
• Prevalence: Ranges from 0.2 to 3.3 in 1000. Risk factors: female gender and older age (sixth decade of life or greater).
  
• Classification systems
  
  
  
  • Gass classification (exam-based, not imaging based): Stage 1 (impending hole), Stage 2 (small, < 400 µm defect), Stage 3 (large, > 400 µm defect), Stage 4 (full defect with associated complete posterior vitreous detachment)
    
  • International Vitreomacular Traction Study Group (IVTS)⁹ classification (spectral domain-OCT [SD-OCT] based system). Full-thickness macular hole are classified by the following:
    
    
    
    • Size based on minimum hole diameter: small (≤ 250 um), medium (> 250 but ≤ 400 um), or large (> 400 um)
      
    • Status of vitreous: with or without VMT

Signs and Symptoms

Decreased central vision, metamorphopsia, and/or a central blind spot (scotoma); vision: near normal to severely reduced depending on size and duration

Exam Findings

Round, red-based appearing lesion at foveal center (Figure 1-5A), concurrent epiretinal membrane (ERM) may be present, Watzke-Allen sign: patient’s description of discontinuity in center of thin slit beam centered over hole on fundoscopy

OCT: current standard for diagnosis shows a full-thickness defect from ILM to RPE seen on at least one B-scan image; hole width (in microns) is measured at narrowest linear hole diameter; hole edges often appear rounded and may have cystic changes (Figure 1-5B)

• Treatment options
  
  
  
  • Vitrectomy surgery (most common method of repair) with single surgery anatomic closure of hole is typically achieved in ~90% of initial cases. ILM peeling has been associated with improved hole closure rates and lower rates of reopening. Face-down positioning is common, though requirement and duration of positioning is a subject of debate; additional surgical maneuvers (use of silicone oil, ILM flaps, etc.) may be utilized in special cases.
    
  • Pharmacologic vitreolysis with intravitreal ocriplasmin
    
    
    
    • Microplasmin for Intravitreal Injection—Traction Release without Surgical Treatment (MIVI-TRUST) studies10 revealed improved macular hole closure rates with ocriplasmin vs vehicle injection (40.6% vs 10.6%, P < .001). Smaller hole size was strongly associated with treatment success.
    
    
  • Pneumatic vitreolysis: Intravitreal injection of air or gas bubble. Small retrospective series have noted closure rates for small macular holes between 50% to 100%. Further data is necessary to refine rates. Available data suggests improved results with longer acting (C3F8) gas.
  
  
• Larger size and longer duration are associated with poor outcomes and observation may be appropriate in chronic cases with poor prognosis.

VITREOMACULAR TRACTION

M. Ali Khan, MD

Characterized by abnormal vitreous adhesion to the macula resulting in anatomic distortion of fovea. The anatomic alteration differentiates VMT from vitreomacular adhesion (VMA).

• Classification system
  
  
  
  • IVT classification⁹ (SD-OCT based system)
    
    
    
    • All of the following 3 features must be present on at least one B-scan ultrasound: (1) partial perifoveal vitreous detachment, (2) vitreous adhesion to macula within a 3-mm radius of fovea, (3) associated distortion of the fovea but without full-thickness defect
      
    • VMT can be further categorized by size of VMA (focal [≤ 1500 μm] or broad [> 1500 μm]) and presence or absence of concurrent macular disease

Signs and Symptoms

Decreased central vision, metamorphopsia, and/or a central blind spot (scotoma)

Exam Findings

Macular schisis, subretinal fluid, and cystic changes; concurrent ERM and other macular disease may be present

Testing

• OCT: standard for diagnosis with IVTS classification system; features such as loss of foveal contour, macular schisis, subretinal fluid, and pseudocysts may be present (Figure 1-6)

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