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OCT-A in Wet AMD: Latest Studies (2025-2026)

🔬 Top 2026 Studies

1. AI-Based Treatment Response Assessment via Paired OCT-A (April 2026)

• AI-based analysis of paired OCTA scans outperformed experienced human graders in characterizing treatment response
• The model characterized macular neovascularization (MNV) vascular remodeling and fluid resolution
• Potential applications include: optimizing retreatment intervals, identifying early recurrence, prognosticating future therapeutic needs, and guiding personalized therapy (which eyes respond best to which agents)
• Authors argued this approach could reduce subjectivity in monitoring and support large-scale longitudinal studies

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2. Systematic Review: OCT-A-Based MNV Assessment in nAMD - Standardization Gap (May 2026)

• OCTA provides detailed, noninvasive MNV visualization but methodological heterogeneity is a major barrier to clinical utility
• MNV subtypes documented: Type 1 (5,059 eyes), Type 2 (973 eyes), Type 3 (321 eyes), mixed (138 eyes)
• Devices used: spectral-domain (86 studies, most commonly RTVue XR Avanti) vs. swept-source (64 studies, most commonly PLEX Elite 9000)
• Common scan sizes: 3x3 mm and 6x6 mm - but segmentation strategies showed marked heterogeneity, with frequent manual corrections needed
• Only a minority of studies addressed projection artifact correction
• Bottom line: Standardized imaging/analytical protocols are urgently needed for reproducible biomarker development in AMD management

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3. Pachychoroid Neovasculopathy vs. nAMD - OCT-A Multimodal Differentiation (March 2026)

• Pachychoroid neovasculopathy (PNV) is frequently misdiagnosed as nAMD, particularly in patients >50 years
• Multimodal imaging (including OCT-A) is essential for differentiation, as treatment strategy differs significantly
• PNV typically presents as type 1 choroidal neovascularization and requires different management than CNV secondary to AMD

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📊 High-Quality Supporting Evidence (2025)

4. Macular Atrophy in nAMD - Systematic Review & Meta-Analysis

• 23 studies, 3,013 eyes in meta-analysis
• Pooled 24-month macular atrophy incidence: 29% (95% CI 20-38%) under anti-VEGF therapy
• Type 3 MNV had highest atrophy rate: 49% at 24 months
• OCT, FAF, and multimodal imaging used for atrophy detection; highlights OCT-A's role in follow-up

5. Advancing OCT-A to the Clinic - Comprehensive Review

• Reviews OCTA quantification metrics for AMD, diabetic retinopathy, and glaucoma
• Covers capillary dropout, microaneurysms, neovascularization detection
• Discusses the role of OCTA in diagnostics, staging, and treatment response evaluation

6. En Face Structural OCT in nAMD - Clinical Practice Review

• Reviews structural en-face OCT utility alongside OCT-A in both neovascular and non-neovascular AMD
• Focuses on practical clinical workflow integration

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🏥 Conference Highlights: Retina World Congress 2026 (May 14-17, Fort Lauderdale)

• Investigational OCTA Devices showed promise in assessing peripheral diabetic retinal disease (Schlottmann MD)
• Home OCT monitoring for nAMD (Protocol AO trial data) was a major discussion point - AI-driven home OCT can reliably track wet AMD disease activity
• OTX-TKI (SOL-1 data) demonstrated superiority over aflibercept in wet AMD, presented at CTS 2026

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Key Themes Across 2026 Literature

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🔴 AGE-RELATED MACULAR DEGENERATION (AMD)

A Complete Ophthalmology Presentation — Basic to Advanced

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📌 SLIDE 1 — TITLE & OVERVIEW

┌─────────────────────────────────────────────────────────────────┐
│                                                                   │
│   AGE-RELATED MACULAR DEGENERATION                               │
│                     AMD                                          │
│                                                                   │
│   "The Silent Thief of Central Vision"                          │
│                                                                   │
│   ● Epidemiology & Burden                                        │
│   ● Anatomy of the Macula                                        │
│   ● Classification & Staging                                     │
│   ● Pathogenesis — Dry & Wet                                     │
│   ● Risk Factors & Genetics                                      │
│   ● Clinical Features & Investigations                           │
│   ● OCT & OCT-A — Advanced Imaging                               │
│   ● Management — Dry & Wet AMD                                   │
│   ● Emerging Therapies & Gene Therapy                            │
│   ● Monitoring & Prognosis                                       │
│                                                                   │
└─────────────────────────────────────────────────────────────────┘

---

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📌 SLIDE 2 — EPIDEMIOLOGY & GLOBAL BURDEN

Key Facts

• Leading cause of irreversible central vision loss in adults >55 in developed countries
• Prevalence doubles with each decade after age 55
• Predominantly affects industrialized nations
• 90% = dry AMD | 10% = wet AMD (but accounts for 90% of AMD-related blindness)
• Peripheral vision is preserved throughout — only central vision is affected
• "Individuals can walk down a street without difficulty but cannot recognize facial features" — Harrison's 22E

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📌 SLIDE 3 — ANATOMY OF THE MACULA

CROSS-SECTION OF THE MACULA (Kanski's Fig. 14.1 / Ryan's Ch. 65)

VITREOUS
    ↓
┌─────────────────────────────────────────────────────────┐
│  INNER LIMITING MEMBRANE (ILM)                          │
├─────────────────────────────────────────────────────────┤
│  NERVE FIBER LAYER (NFL)                                │
├─────────────────────────────────────────────────────────┤
│  GANGLION CELL LAYER (GCL)                              │
├─────────────────────────────────────────────────────────┤
│  INNER PLEXIFORM LAYER (IPL)                            │
├─────────────────────────────────────────────────────────┤
│  INNER NUCLEAR LAYER (INL)                              │
├─────────────────────────────────────────────────────────┤
│  OUTER PLEXIFORM LAYER (OPL) / Henle Fiber Layer (HFL) │
├─────────────────────────────────────────────────────────┤
│  OUTER NUCLEAR LAYER (ONL) — Photoreceptor nuclei       │
├─────────────────────────────────────────────────────────┤
│  EXTERNAL LIMITING MEMBRANE (ELM)                       │
├─────────────────────────────────────────────────────────┤
│  PHOTORECEPTORS — Rods (periphery) & Cones (fovea)      │
│     Ellipsoid Zone (EZ) — inner segments                │
│     Interdigitation Zone (IZ) — outer segments/RPE      │
├─────────────────────────────────────────────────────────┤
│  RETINAL PIGMENT EPITHELIUM (RPE)  ←── KEY TARGET       │
│     RPE basement membrane (RPE-BL)                      │
├─────────────────────────────────────────────────────────┤
│  BRUCH'S MEMBRANE (5 layers):                           │
│     • RPE basement membrane (inner)                     │
│     • Inner collagenous zone (ICZ)                      │
│     • Elastic layer                                     │
│     • Outer collagenous zone (OCZ)                      │
│     • Choriocapillaris basement membrane (outer)        │
├─────────────────────────────────────────────────────────┤
│  CHORIOCAPILLARIS ← Sole blood supply to outer retina   │
├─────────────────────────────────────────────────────────┤
│  CHOROID (Haller's & Sattler's layers)                  │
└─────────────────────────────────────────────────────────┘
    ↓
SCLERA

The Critical Triad in AMD

RPE + Bruch's Membrane + Choriocapillaris = Outer Retinal Neurovascular Unit Disruption of any one component → photoreceptor damage → central vision loss

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📌 SLIDE 4 — CLASSIFICATION & STAGING (AREDS System)

┌─────────────────────────────────────────────────────────────────────┐
│                     AMD CLASSIFICATION                              │
│              (AREDS Simplified Scale & Clinical Grading)            │
└─────────────────────────────────────────────────────────────────────┘

┌──────────────┬──────────────────────────────┬─────────┬───────────┐
│ STAGE        │ FEATURES                     │ DRUSEN  │ RISK/5yr  │
├──────────────┼──────────────────────────────┼─────────┼───────────┤
│ NO AMD       │ Normal macula                │ None or │ <0.5%     │
│              │                              │ small   │           │
├──────────────┼──────────────────────────────┼─────────┼───────────┤
│ EARLY AMD    │ Small/medium drusen          │ <125 μm │ 0.5–1%    │
│              │ No pigment change            │         │           │
├──────────────┼──────────────────────────────┼─────────┼───────────┤
│ INTERMEDIATE │ Large drusen ≥125 μm         │ ≥125 μm │ ~13–18%   │
│ AMD          │ OR pigment changes           │ soft    │ (bilateral│
│              │ May have subtle visual loss  │ drusen  │ +pigment: │
│              │                              │         │ ~50%)     │
├──────────────┼──────────────────────────────┼─────────┼───────────┤
│ LATE AMD     │ Geographic atrophy           │ Present │ ~50%      │
│ — DRY (GA)   │ Well-demarcated RPE loss     │         │           │
│              │ Visible choroidal vessels    │         │           │
├──────────────┼──────────────────────────────┼─────────┼───────────┤
│ LATE AMD     │ Choroidal neovascularization │ Usually │ URGENT    │
│ — WET (nAMD) │ SRF, hemorrhage, exudate    │ present │ anti-VEGF │
│              │ Acute central visual loss    │         │           │
└──────────────┴──────────────────────────────┴─────────┴───────────┘

AREDS Simplified Risk Score (Kanski Ch. 14 / Ryan's Ch. 66)

• Large drusen (≥125 μm)
• Pigmentary abnormality (hyper or hypo)

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📌 SLIDE 5 — DRY AMD PATHOGENESIS FLOWCHART

╔══════════════════════════════════════════════════════════════╗
║  DRY AMD PATHOGENESIS — MOLECULAR CASCADE                   ║
╚══════════════════════════════════════════════════════════════╝

AGING + GENETIC SUSCEPTIBILITY (CFH Y402H, ARMS2/HTRA1)
    + OXIDATIVE STRESS (SMOKING, LIGHT EXPOSURE)
                         │
                         ▼
         ┌─────────────────────────────┐
         │   IMPAIRED RPE FUNCTION     │
         │  ↑ Lipofuscin in RPE cells  │
         │  (A2E = phototoxic toxin)   │
         └─────────────┬───────────────┘
                       │
                       ▼
         ┌─────────────────────────────────────────┐
         │   BRUCH'S MEMBRANE CHANGES              │
         │  • Lipoprotein secretion by RPE →       │
         │    accumulates in sub-RPE space         │
         │  • Thickening, calcification            │
         │  • Lipid peroxidation (DHA, linolenic)  │
         └─────────────┬───────────────────────────┘
                       │
                       ▼
         ┌─────────────────────────────────────────┐
         │   DRUSEN FORMATION                      │
         │  Hard → Soft → Confluent                │
         │  Contents: ApoB lipoproteins,           │
         │  vitronectin, complement proteins,      │
         │  esterified & unesterified cholesterol  │
         └─────────────┬───────────────────────────┘
                       │
                       ▼
         ┌─────────────────────────────────────────┐
         │   COMPLEMENT ACTIVATION                 │
         │  CFH variants → ↓ regulation of C3      │
         │  C3 → C3a + C3b → C5 → C5a + C5b-9    │
         │  MAC (membrane attack complex) formed   │
         └─────────────┬───────────────────────────┘
                       │
                       ▼
         ┌─────────────────────────────────────────┐
         │   CHRONIC SUBCLINICAL INFLAMMATION      │
         │  RPE cell stress → senescence           │
         │  Pyroptotic cell death (NLRP3)         │
         └─────────────┬───────────────────────────┘
                       │
                       ▼
         ┌─────────────────────────────────────────┐
         │   GEOGRAPHIC ATROPHY (GA)               │
         │  RPE + choriocapillaris + photoreceptors│
         │  → Well-defined area of atrophy         │
         │  → Central scotoma, legal blindness     │
         └─────────────────────────────────────────┘

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📌 SLIDE 6 — WET AMD PATHOGENESIS FLOWCHART

╔══════════════════════════════════════════════════════════════╗
║  WET AMD PATHOGENESIS — ANGIOGENIC CASCADE                  ║
╚══════════════════════════════════════════════════════════════╝

HYPOXIA / OXIDATIVE STRESS in RPE (from drusen/GA)
                         │
                         ▼
              ┌──────────────────────┐
              │  ↑ VEGF-A expression │
              │  + Angiopoietin-2    │
              │  (destabilizes BV)   │
              └──────────┬───────────┘
                         │
                         ▼
              ┌──────────────────────────────────────┐
              │  Binds VEGFR-1 / VEGFR-2 on          │
              │  choriocapillaris endothelial cells   │
              └──────────┬───────────────────────────┘
                         │
            ┌────────────┴────────────┐
            ▼                         ▼
   ANGIOGENESIS                PERMEABILITY ↑
  (New vessel sprouting)      (Fluid leakage into
  CNV growth                   subretinal/intraretinal
  through Bruch's              space: SRF, IRF, PED)
  membrane
            │                         │
            └────────────┬────────────┘
                         ▼
          ┌─────────────────────────────────────┐
          │   MACULAR NEOVASCULARIZATION (MNV)  │
          │   Type 1 / Type 2 / Type 3          │
          └──────────────┬──────────────────────┘
                         │
                         ▼
          ┌─────────────────────────────────────┐
          │   COMPLICATIONS                     │
          │  • Subretinal hemorrhage            │
          │  • RPE tears                        │
          │  • Macular atrophy (MA)             │
          │  • Disciform scar (end-stage)       │
          │  → IRREVERSIBLE CENTRAL VISION LOSS │
          └─────────────────────────────────────┘

FARICIMAB DUAL MECHANISM (NEW 2022):
Anti-VEGF-A  +  Anti-Ang-2
    ↓                ↓
Block CNV     Stabilize vessels
    └────────┬────────┘
             ▼
    Superior vascular stability
    → Extended dosing Q12–16 weeks

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📌 SLIDE 7 — DRUSEN IN DETAIL (Ryan's Ch. 65-66 + Kanski Ch. 14)

Types of Drusen

⭐ NEW: Subretinal Drusenoid Deposits (SDD) — Key Gap Finding

SOFT DRUSEN vs. SUBRETINAL DRUSENOID DEPOSITS (Ryan's Ch. 65, Table 65.2)

Feature              Soft Drusen/BLinD          Subretinal Drusenoid Deposits
─────────────────────────────────────────────────────────────────────────────
Location             Sub-RPE (external to BM)   SUBRETINAL (above RPE apical)
Lipids               Esterified + unesterified  Unesterified cholesterol ONLY
                     cholesterol                (no oil red-O binding)
FAF appearance       Hyperautofluorescent       HYPOautofluorescent
Complement           C5b-9 localized            C1q localized to SDD, not drusen
Associated MNV type  Type 1 (sub-RPE)           Type 3 (intraretinal origin) ← KEY
Follow rod topography Follows CONES (subfoveal) Follows RODS (perifoveal ring)
Impact of laser      Improved (↓ progression)   WORSENED (↑ progression) ← KEY
Mendelian disorders  Sorsby, Doyne, etc.        AMD-specific
─────────────────────────────────────────────────────────────────────────────

Clinical significance: SDD/reticular pseudodrusen predict faster GA progression and Type 3 MNV. They are best seen on infrared reflectance and swept-source OCT — often missed on color fundus photography alone.

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📌 SLIDE 8 — RISK FACTORS

Non-Modifiable

Modifiable

Ocular Risk Factors

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📌 SLIDE 9 — GENETICS OF AMD (Ryan's Ch. 64 + Thompson & Thompson)

         GENETIC ARCHITECTURE OF AMD
    AMD is POLYGENIC and MULTIFACTORIAL
         GWAS identified >40 susceptibility loci

Genetic Model

  Genetic susceptibility          Environmental exposure
  (CFH + ARMS2 variants)    ×    (Smoking + Diet + Age)
               ↓
        Clinical AMD phenotype
  (Type/severity/age of onset)

KEY: Smoking + high BMI + CFH risk genotype = COMPOUNDED risk
     → Earlier onset of advanced AMD (especially Type 3 MNV)

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📌 SLIDE 10 — CLINICAL FEATURES

DRY AMD — Symptoms

• Gradual, insidious loss of central vision (months to years)
• Metamorphopsia (Amsler grid distortion)
• Difficulty reading, face recognition, watching TV
• Often asymptomatic in early/intermediate stages
• Vision often better in bright light (pupil constriction improves optics)
• Peripheral vision always preserved
• Delayed dark adaptation (rod function impaired early) — functional biomarker

DRY AMD — Signs (Chronological Order per Kanski)

1. Numerous intermediate-large soft drusen
   ↓
2. Focal hyper- and/or hypopigmentation of RPE
   ↓
3. Drusenoid PED (confluent large soft drusen)
   ↓
4. Drusen calcification (glistening white nodules)
   ↓
5. Drusen regression/fading (↓ autofluorescence)
   ↓
6. GEOGRAPHIC ATROPHY (GA):
   • Well-defined, sharply demarcated RPE depigmentation
   • Visible choroidal vessels beneath (bare choroid)
   • Central or perifoveal distribution
   • Horseshoe-shaped → bull's-eye → foveal involvement
   • Average growth rate: 1.78 mm²/year (square root transformed)

WET AMD — Symptoms (URGENT PRESENTATION)

• Sudden onset central or paracentral scotoma
• Acute metamorphopsia — lines appear wavy/distorted
• Photopsias (flashes) in central visual field
• Rapid, profound central visual loss (hours to days)

WET AMD — Signs (Kanski + Ryan's Ch. 67)

CRITICAL SIGNS:
 ● Drusen + subretinal fluid (SRF)        ← most common
 ● Intraretinal fluid (IRF) / cystoid macular edema
 ● Pigment epithelial detachment (PED):
     - Serous PED (smooth dome; optically empty on OCT)
     - Fibrovascular PED (irregular, hyperreflective)
     - Drusenoid PED (homogeneous; no SRF)
     - Haemorrhagic PED (dark red; underlying MNV or PCV)
 ● Subretinal/intraretinal haemorrhage
 ● Lipid exudates (hard exudates)
 ● Subretinal fibrosis (disciform scar — end stage)
 ● RPE tears (rip at edge of PED)

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📌 SLIDE 11 — MNV TYPES & CLASSIFICATION (Ryan's Ch. 67 + Kanski)

╔═══════════════════════════════════════════════════════════════════╗
║         MACULAR NEOVASCULARIZATION — ANATOMIC CLASSIFICATION     ║
╚═══════════════════════════════════════════════════════════════════╝

⭐ NEW: Non-Exudative (Quiescent) Type 1 MNV — Key Gap Finding

Ryan's Ch. 67: Grossniklaus & Green (1998) proposed that Type 1 MNV may be biologically protective — the neovascular complex may recapitulate morphology of native choriocapillaris, supporting hypoxic/micronutrient-insufficient outer retinal cells. Histological evidence: outer retinal cells overlying non-exudative MNV remain intact; neovessels have fenestrations from hypoxic RPE-secreted VEGF. Non-exudative MNV should not automatically trigger treatment — decision based on presence of exudation.

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📌 SLIDE 12 — POLYPOIDAL CHOROIDAL VASCULOPATHY (PCV)

Key Features (Kanski Ch. 14 + Ryan's Ch. 67)

• Aberrant inner choroidal vessel network terminating in polypoidal dilations
• Predominantly in Asian and African populations (PCV accounts for 25–50% of "wet AMD" in Asians vs. 8–13% in Whites)
• Patient: often >50 years, female, no classical drusen
• May represent Type 1 MNV subtype (aneurysmal MNV1) or pachychoroid neovasculopathy spectrum

Diagnostic Criteria

Treatment

• PDT + anti-VEGF combination is superior to anti-VEGF monotherapy for polyp closure
• EVEREST II trial: Combination PDT + ranibizumab achieved 69.3% complete polyp regression vs. 34.7% monotherapy
• Anti-VEGF monotherapy (faricimab/aflibercept) can control exudation but incomplete polyp regression

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📌 SLIDE 13 — INVESTIGATIONS & IMAGING

╔══════════════════════════════════════════════════════════════════╗
║            INVESTIGATION PATHWAY FOR SUSPECTED AMD               ║
╚══════════════════════════════════════════════════════════════════╝

PATIENT WITH SUSPECTED AMD
         │
         ▼
1. BEST CORRECTED VISUAL ACUITY (BCVA) — ETDRS/Snellen
         │
         ▼
2. AMSLER GRID — 10° central field (both eyes separately)
   → Metamorphopsia = URGENT wet AMD flag
         │
         ▼
3. SLIT-LAMP BIOMICROSCOPY + DILATED FUNDUS EXAMINATION
   (90D / 78D lens — grade drusen, RPE changes)
         │
         ▼
4. OCT (Optical Coherence Tomography) — MANDATORY
   [SRF, IRF, drusen volume, PED, ellipsoid zone status]
         │
    ┌────┴─────┐
    ▼           ▼
DRY AMD       WET AMD SUSPECTED
    │               │
    ▼               ▼
FAF (Fundus      FFA (Fluorescein Angiography)
Autofluorescence) → Classic vs occult CNV
→ GA extent,        → Leakage pattern
  RPE viability
    │               │
    ▼               ▼
Document,      OCT-A (non-invasive MNV mapping)
monitor        ± ICGA (if PCV suspected)

Imaging Modalities — Reference Table (Kanski Ch. 14 / Ryan's Ch. 67)

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📌 SLIDE 14 — OCT IN AMD: DETAILED GUIDE

Key OCT Findings in Dry AMD

Key OCT Findings in Wet AMD

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📌 SLIDE 15 — OCT-A IN AMD ⭐ (KEY NEW CONTENT — Ryan's Ch. 67 + Kanski + Novarese 2026)

Technical Principle (Kanski, line 2933)

"OCT-A detects red blood cell movement within microvasculature using serial OCT B-scans at the same retinal position. Differences between scans generate detectable contrast as red cells move. A 2D map of microcirculation within retinal/choroidal layers is created."

OCT-A Advantages over FFA

• Non-invasive (no dye injection)
• Simultaneous structural + vascular information
• Choroidal visualization without ICGA
• Quantification of MNV area and morphology
• Detects non-exudative (quiescent) MNV invisible on FFA

OCT-A Appearances by MNV Type (Ryan's Ch. 67)

TYPE 1 MNV (sub-RPE slab):
 ┌─────────────────────────────────────────────────────┐
 │  GLOMERULUS or MEDUSA shape (tangled vessel loops)  │
 │  Often smaller on OCT-A than FFA-based estimate     │
 │  (FFA dye leakage artificially enlarges lesion)     │
 │  Detectable as quiescent/non-exudative MNV          │
 └─────────────────────────────────────────────────────┘

TYPE 2 MNV (outer retina slab):
 ┌─────────────────────────────────────────────────────┐
 │  Fine, immature, indistinct vessel network above RPE│
 │  Corresponds to classic CNV on FFA                  │
 │  Associated with SHRM on structural OCT             │
 └─────────────────────────────────────────────────────┘

TYPE 3 MNV (intraretinal slab):
 ┌─────────────────────────────────────────────────────┐
 │  TUFT-LIKE focal intraretinal capillary network     │
 │  Nascent Type 3 = intraretinal hyperreflective foci │
 │     WITH flow signal                                │
 │  Confirmed by B-scan overlay showing lesion         │
 └─────────────────────────────────────────────────────┘

Five OCT-A Features of ACTIVE MNV (Ryan's Ch. 67)

Choriocapillaris on OCT-A in nAMD ⭐

• Characteristic "dark halo" (ring-shaped choriocapillaris hypoperfusion) surrounding MNV
• Flow deficit greater in concentric rings around Type 1 MNV
• Pathogenesis: ischemia, mechanical compression, or "steal phenomenon"
• Prognostic: larger CC flow deficits → worse visual outcomes

Standardization Gap (Novarese et al. 2026, PMID 42107776)

Systematic review of 155 studies, 9,025 patients: marked heterogeneity in devices (SD-OCT vs SS-OCT), scan sizes (3×3 vs 6×6 mm), segmentation, binarization, artifact correction. Standardized protocols urgently needed for reproducible MNV biomarker development.

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📌 SLIDE 16 — FAF PATTERNS IN GA — JUNCTIONAL ZONE ⭐ (Kanski + Ryan's Ch. 66)

FAF Classification at GA Margin (Junctional Zone)

┌─────────────────────────────────────────────────────────────────┐
│   Is there any INCREASED FAF at the junctional zone?           │
└──────────────┬───────────────────┬──────────────────────────────┘
               │YES                │NO
               ▼                   ▼
     Configuration?           NONE pattern
     (adjacent to GA margin)  → SLOW progression rate
               │
    ┌──────────┼─────────────────────────────────┐
    ▼          ▼               ▼                 ▼
  FOCAL     BANDED         PATCHY            DIFFUSE
  (small    (almost        (individual       (increased FAF
  spots)    continuous     large spots)      elsewhere too)
            ring)
   ↑             ↑               ↑                 ↑
  SLOW         SLOW           INTERMEDIATE      FASTEST
  progression  progression    progression       PROGRESSION
                                                RATE

Subtypes of DIFFUSE Pattern (fastest progression)

Clinical key: Diffuse FAF at junctional zone = highest risk of rapid GA expansion. Used in clinical trials (OAKS, DERBY, GATHER1/2) as secondary endpoint.

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📌 SLIDE 17 — DRY AMD MANAGEMENT FLOWCHART

╔═════════════════════════════════════════════════════════════════╗
║              DRY AMD MANAGEMENT PATHWAY                         ║
╚═════════════════════════════════════════════════════════════════╝

EARLY DRY AMD (small/medium drusen, no central symptoms)
         │
         ▼
┌──────────────────────────────────┐
│   LIFESTYLE MODIFICATION         │
│  ● STOP SMOKING ← MOST IMPORTANT│
│  ● Mediterranean diet            │
│  ● UV-blocking sunglasses        │
│  ● Control BP, BS, lipids        │
│  ● Regular aerobic exercise      │
└──────────────┬───────────────────┘
               │
               ▼
INTERMEDIATE DRY AMD (large drusen ≥125 μm OR pigment changes)
               │
               ▼
┌──────────────────────────────────────────────────────────┐
│   AREDS2 SUPPLEMENTS (daily oral)                        │
│                                                          │
│  Vitamin C         500 mg                                │
│  Vitamin E         400 IU                                │
│  Lutein            10 mg   ← replaces beta-carotene      │
│  Zeaxanthin         2 mg   ← replaces beta-carotene      │
│  Zinc oxide        80 mg                                 │
│  Cupric oxide       2 mg   (prevents zinc-induced anemia)│
│                                                          │
│  ⚠ AVOID beta-carotene in smokers/ex-smokers             │
│    → 28% increased lung cancer risk (ATBC/CARET trials) │
└──────────────┬───────────────────────────────────────────┘
               │
               ▼
┌──────────────────────────────────┐
│   HOME MONITORING                │
│  Daily Amsler grid               │
│  ± ForeseeHome PHP device        │
│  NEW: AI-driven home OCT ←2026  │
│  Any new metamorphopsia →        │
│  URGENT CLINIC REVIEW (same week)│
└──────────────┬───────────────────┘
               │
               ▼
ADVANCED DRY AMD — GEOGRAPHIC ATROPHY
               │
               ▼
┌────────────────────────────────────────────────────────────────┐
│   COMPLEMENT INHIBITORS (FDA APPROVED 2023)                    │
│                                                                │
│  Pegcetacoplan (Syfovre, Apellis)                             │
│  • C3 inhibitor (intravitreal)                                │
│  • Monthly or every-other-month injection                     │
│  • OAKS trial: ~22% (monthly) / 18% (EOM) reduction in GA    │
│    growth vs. sham at 24 months                               │
│  • ⚠ Increased risk of exudative conversion in treated eyes  │
│                                                                │
│  Avacincaptad pegol (Izervay, Iveric Bio/Astellas)           │
│  • C5 inhibitor (intravitreal)                                │
│  • Monthly injection                                          │
│  • GATHER2: 14.5% reduction in GA growth; foveal sparing     │
│    preserved                                                  │
│  • FDA approved August 2023                                   │
└──────────────┬─────────────────────────────────────────────────┘
               │
               ▼
┌──────────────────────────────────┐
│  LOW VISION REHABILITATION       │
│  Magnification aids              │
│  Eccentric fixation training     │
│  Electronic magnifiers           │
│  Psychological support           │
│  Macular Society registration    │
└──────────────────────────────────┘

AREDS Trial Summary

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📌 SLIDE 18 — WET AMD MANAGEMENT FLOWCHART

╔═══════════════════════════════════════════════════════════════╗
║           WET AMD MANAGEMENT — TREAT-AND-EXTEND              ║
╚═══════════════════════════════════════════════════════════════╝

STEP 1: CONFIRM WET AMD
OCT (SRF/IRF/PED) + BCVA + FFA/OCT-A
         │
         ▼
STEP 2: LOADING PHASE — 3 MONTHLY IVT INJECTIONS
(Faricimab 6 mg OR Aflibercept 8 mg first-line — 2025 guidelines)
         │
         ▼
STEP 3: ASSESS RESPONSE ON OCT AT EACH VISIT
         │
    ┌────┴──────────────────────────────┐
    ▼                                    ▼
MACULA DRY (no SRF/IRF)           FLUID PRESENT (SRF or IRF)
    │                                    │
    ▼                                    ▼
EXTEND interval +2 weeks          MAINTAIN or SHORTEN -2 weeks
(Q6w→Q8w→Q10w→Q12w→Q16w)         Re-assess next visit
    │
    └──────────────────────────────────┐
                                       ▼
                    PERSISTENT FLUID at maximum interval (Q4w)
                                       │
                                       ▼
                         SWITCH anti-VEGF agent
                    (e.g., ranibizumab → faricimab →
                           aflibercept 8 mg)
                                       │
                                       ▼
                    REASSESS after 3 injections of new agent

TREATMENT GOALS:
 ● Anatomically dry macula on OCT (no SRF, ideally no IRF)
 ● Maintain or improve BCVA
 ● Reduce injection burden while maintaining disease control

---

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📌 SLIDE 19 — ANTI-VEGF AGENTS (Complete Reference)

Currently Approved Agents (2025)

Molecular Comparison

MOLECULAR SIZE (smallest → largest):
  brolucizumab (26 kDa) < ranibizumab (48 kDa) < aflibercept (97 kDa) < bevacizumab (149 kDa)

MOLAR DOSE (relative to aflibercept):
  brolucizumab: 11× > ranibizumab: ~5× > aflibercept: 1× > bevacizumab: ~1×

OCULAR HALF-LIFE:
  faricimab/brolucizumab > aflibercept (9d) > ranibizumab (7d) > bevacizumab

Landmark Trial Results

---

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📌 SLIDE 20 — ANTI-VEGF MECHANISM & ANG-2 PATHWAY ⭐

╔══════════════════════════════════════════════════════════════╗
║         VEGF + ANGIOPOIETIN SIGNALING IN AMD                ║
╚══════════════════════════════════════════════════════════════╝

NORMAL STATE:
Pericytes → constitutively release ANG-1 → binds TIE-2
→ vascular stability, anti-inflammatory, survival signaling

AMD/HYPOXIA STATE:
↑ ANG-2 (released from Weibel-Palade bodies on inflammation)
→ ANG-2 competes with ANG-1 at TIE-2
→ TIE-2 signaling blocked
→ Pericyte detachment + vessel destabilization
→ SENSITIZES endothelium to VEGF-A effects

  ANG-2         +       VEGF-A
    │                       │
    ▼                       ▼
TIE-2 blocked         VEGFR-1/VEGFR-2
(destabilization)      (angiogenesis + permeability)
    │                       │
    └───────────┬───────────┘
                ▼
       CNV GROWTH + FLUID LEAK

FARICIMAB:
 Blocks ANG-2   +   Blocks VEGF-A
     │                   │
     ▼                   ▼
TIE-2 re-activated  CNV halted
(vessel stability)  (fluid resolved)
     │
     ▼
LONGER TREATMENT INTERVALS (Q16w) vs single anti-VEGF

---

---

📌 SLIDE 21 — PDT & THERMAL LASER (Historical + Current Role)

Photodynamic Therapy (PDT) — Verteporfin

Thermal Laser Photocoagulation

• Thermal destruction of well-defined extrafoveal classic CNV (Type 2)
• Rarely used today; MPS (Macular Photocoagulation Study) showed benefit only for classic extrafoveal CNV
• Risk: scotoma at treatment site; CNV recurrence

---

---

📌 SLIDE 22 — COMPLICATIONS OF ANTI-VEGF THERAPY

Ocular Complications

Macular Atrophy — Three Mechanisms (Ryan's Ch. 67)

1. Natural progression of concomitant DRY AMD (ongoing complement damage)
   +
2. MNV regression → fibrocellular replacement → contraction → photoreceptor loss
   +
3. Interference with basal RPE nutrition (anti-VEGF suppresses VEGF-dependent
   choriocapillaris fenestrations → RPE hypoxia)

---

---

📌 SLIDE 23 — GEOGRAPHIC ATROPHY: TREATMENT TRIALS (2023–2025)

Rationale: CFH/CFI genetic variants → insufficient complement regulation → excess C3/C5 activation → RPE destruction → GA progression. Blocking C3 (upstream, broader) or C5 (downstream, more specific) slows this cascade.

---

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📌 SLIDE 24 — GENE THERAPY PIPELINE (2025)

╔═══════════════════════════════════════════════════════════════════╗
║    GENE THERAPY FOR AMD — CONCEPT                                 ║
║    Single IVT injection of AAV vector → transfects retinal cells  ║
║    → Continuous therapeutic protein production                    ║
║    → ELIMINATES monthly injection burden                          ║
╚═══════════════════════════════════════════════════════════════════╝

If successful: One injection every 2–5 years vs. current 6–12 injections per year

---

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📌 SLIDE 25 — EMERGING THERAPIES (Non-Gene, 2025)

---

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📌 SLIDE 26 — 2026 LATEST EVIDENCE ⭐ (AI + OCT-A)

Top 2026 Studies on OCT-A in Wet AMD

1. AI-Based Treatment Response via Paired OCT-A (Morsy et al., Sci Rep 2026)

AI analysis of paired OCTA scans (pre- and post-treatment) outperformed experienced human graders in characterizing nAMD treatment response. AI quantified MNV vascular remodeling + fluid resolution. Potential to optimize retreatment intervals, detect early recurrence, enable personalized therapy.

2. Systematic Review: OCT-A MNV Standardization (Novarese et al., Ophthalmol Retina 2026, PMID 42107776)

155 studies, 9,025 patients. Marked heterogeneity in devices, scan protocols, segmentation, binarization, artifact correction. Standardized protocols urgently needed.

3. Pachychoroid Neovasculopathy Spectrum (Lingardo et al., Graefes 2026)

PNV frequently misdiagnosed as nAMD. Multimodal OCT-A essential to differentiate. Treatment strategy differs significantly from AMD-associated CNV.

4. Macular Atrophy Meta-Analysis (Berni et al., Ophthalmol Retina 2025, PMID 39842718)

23 studies, 3,013 eyes. Pooled 24-month MA incidence: 29%. Type 3 MNV: 49%. Low certainty of evidence highlights need for better OCT-A biomarkers.

---

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📌 SLIDE 27 — DIFFERENTIAL DIAGNOSIS

---

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📌 SLIDE 28 — MONITORING PROTOCOL

Home Monitoring Devices

---

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📌 SLIDE 29 — PROGNOSIS

Predictors of Poor Visual Outcome (Kanski Ch. 14 / Ryan's Ch. 67)

1. Late presentation (>6 weeks from symptom onset)
2. Large subretinal hemorrhage (>4 disc areas)
3. Subfoveal CNV at baseline
4. Subretinal fibrosis / disciform scar
5. Poor anti-VEGF response after 3 loading doses
6. Development of macular atrophy
7. Intraretinal hyperreflective foci at baseline (strongest predictor of MA)

---

---

📌 SLIDE 30 — KEY MNEMONICS & REVISION SUMMARY

DRUSEN Mnemonic

D — Deposits (extracellular between RPE and Bruch's) R — Risk: size matters (>125 μm = high risk) U — Unesterified cholesterol (SDD) vs. esterified (soft drusen) S — Soft → GA; SDD → Type 3 MNV E — Early AMD: small drusen only = low risk N — Neovascular risk: large + bilateral + pigment = 50% in 5 years

ANTI-VEGF Mnemonic — "PReBFA"

P egaptanib → 2004 → VEGF165 only R anibizumab → 2006 → MARINA/ANCHOR e Bevacizumab → off-label → CATT F libercept (Afl 2 mg) → 2011 → VIEW 1&2 A fli 8 mg + Brolucizumab → 2023/2019 → PULSAR/HAWK Faricimab → 2022 → TENAYA/LUCERNE → dual VEGF+Ang-2

OCT-A Activity: 5 Features — "SCAPH"

S ea-fan/medusa morphology C apillaries numerous + small A nastomoses present P eripheral arcade at terminus H alo (perilesional dark halo on CC slab)

GA FAF Progression — BPDNF (slowest to fastest)

None → Focal → Banded → Patchy → Diffuse ← fastest

---

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📌 SLIDE 31 — LOW VISION REHABILITATION

Optical Aids

• High-plus reading glasses (up to +20D)
• Hand/stand magnifiers
• Binoculars for distance viewing

Electronic Aids

• Video magnifiers (CCTV systems)
• E-readers with adjustable font size
• Screen-reading software (iOS VoiceOver, Android TalkBack)
• Smartphones with AI scene description

Rehabilitative Training

• Eccentric fixation training — using parafoveal/peripheral retina for tasks previously performed by fovea
• Orientation and mobility training
• Kitchen and daily living adaptations (high-contrast utensils, improved lighting)
• Implantable Miniature Telescope (IMT) — 2.2–2.7× magnification; for bilateral advanced AMD with stable disciform scar; Phase 3 trial: 67% gained ≥3 lines vs 13% fellow eye

Psychological Support

• Depression is common (up to 30% of AMD patients with severe visual loss)
• CBT, peer support groups, Macular Society
• Legal registration as visually impaired; DVLA/DMV driving regulations

---

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📌 SLIDE 32 — SOURCES & REFERENCES

STANDARD TEXTBOOK SOURCES:
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
1. Kanski's Clinical Ophthalmology, 10th Ed (2023, Elsevier)
   Ch. 14 — Macular Degeneration (pp. 580–620)

2. Ryan's Retina, 3rd Edition — Chapters 64, 65, 66, 67, 68:
   Ch.64: Epidemiology & Risk Factors (Seddon, Sobrin, Davoudi)
   Ch.65: Pathogenesis (Curcio, Spaide)
   Ch.66: Non-Neovascular AMD & GA (Chaikitmongkol, Bressler)
   Ch.67: Neovascular AMD (Borrelli, Soueid, Querques)
   Ch.68: Pharmacotherapy of AMD (Budoff, Leung, Kaiser, Dugel)

3. Wills Eye Manual, 7th Edition — Sections 11.16 & 11.17
4. Goodman & Gilman's Pharmacological Basis, Ch. 74
5. Harrison's Principles of Internal Medicine, 22nd Ed, Ch. 391

KEY CLINICAL TRIALS:
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
AREDS (2001), AREDS2 (2013), MARINA (2006), ANCHOR (2006),
CATT (2011), VIEW 1&2 (2012), HAWK/HARRIER (2019),
TENAYA/LUCERNE (2022), PULSAR (2023), OAKS/DERBY (2023),
GATHER1/2 (2021–23), AVONELLE-X (2025), SOL-1 (2026)

2025–2026 LITERATURE:
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
• Morsy et al. Sci Rep 16:15405 (2026) — AI + paired OCTA
• Novarese et al. Ophthalmol Retina (2026) PMID 42107776
  — OCT-A standardization systematic review
• Berni et al. Ophthalmol Retina (2025) PMID 39842718
  — Macular atrophy meta-analysis
• Lingardo et al. Graefes (2026) PMID 41385093
  — Pachychoroid neovasculopathy spectrum
• Hormel & Jia. Taiwan J Ophthalmol (2025) PMID 40995309
  — Advancing OCTA to clinic

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📌 ADDITIONAL FINDINGS NOTE (Gap Additions from Ryan's + Kanski)

The following topics were absent from prior presentations and are now integrated above:

1. ✅ Subretinal drusenoid deposits (SDD/reticular pseudodrusen) — Slide 7 — distinct entity from soft drusen; unesterified cholesterol only; follows rod topography; associated with Type 3 MNV; worsened by laser; detected on NIR reflectance + SS-OCT
2. ✅ Non-exudative (quiescent) Type 1 MNV — Slide 11 — may be biologically protective; does not automatically require treatment
3. ✅ OCT-A technical principle + limitation — Slide 15 — flow, not vessel walls; too slow/fast flow undetected (Kanski only)
4. ✅ Five OCT-A features of MNV activity (SCAPH) — Slide 15 — sea-fan, capillaries, anastomoses, peripheral arcade, halo
5. ✅ Choriocapillaris dark halo on OCT-A — Slide 15 — ring-shaped hypoperfusion; prognostic
6. ✅ FAF junctional zone patterns — Slide 16 — None/Focal/Banded/Patchy/Diffuse; Diffuse = fastest GA progression
7. ✅ Drusenoid PED — Slide 7 — confluent soft drusen; 75% → GA; 25% → MNV by 10 years; homogeneous on OCT; no SRF
8. ✅ BlamD vs. BLinD histopathology — Slide 14 — BlamD internal to RPE-BL; BLinD external; OCT cannot reliably distinguish
9. ✅ Outer retinal tubulation (ORT) — Slide 14 — hyperreflective ring around hyporeflective tubule; degenerate cones + Muller cells; distinct from cystoid spaces
10. ✅ RPE tears — Slide 22 — predictors: PED height >400 μm; scrolled RPE on OCT; bare Bruch's membrane
11. ✅ PCV as pachychoroid / Type 1 aneurysmal MNV — Slide 12 — ICGA gold standard; PDT+anti-VEGF combination
12. ✅ Macular atrophy mechanisms (3 pathways) — Slide 22 — complement damage + fibrosis + anti-VEGF on CC fenestrations
13. ✅ Angiopoietin/TIE-2 biology — Slide 20 — full Ang-1/Ang-2/TIE-2 mechanism rationale for faricimab
14. ✅ Port Delivery System (PDS) — Slide 25 — refillable scleral implant; 13-month median refill interval
15. ✅ AREDS simplified 4-point risk score — Slide 4 — 0 to 50% 5-year risk; validated clinical tool
16. ✅ SRF patterns in non-nAMD (3 patterns) — Slide 14 — SRF above drusenoid PED crest; drape over drusen; SRF in crypts

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What's on the card (A4 Landscape, 4-column layout):

---

What's in the flowchart (A4 Portrait, print-ready):

HEADER BAND (navy + gold accent)
│
├── STEP 1: Confirm nAMD
│   Side panel: OCT criteria, BCVA, FFA/OCT-A, ICGA if PCV
│
├── STEP 2: Select First-Line Agent
│   Side panel: ★ Faricimab 6mg (Q16w) · Afl 8mg (Q16w)
│              Alternatives: Afl 2mg, Ranibizumab, Bevacizumab
│              ⚠ Brolucizumab vasculitis warning
│
├── STEP 3: Loading Phase
│   3 × monthly IVT injections
│
├── STEP 4: OCT Assessment at Every Visit
│   Side panel: DRY / tolerant SRF / active IRF definitions
│
├── ◆ DIAMOND 1: MACULA DRY on OCT?
│   ├── YES ✔ → EXTEND +2 weeks (Q4→Q6→Q8→Q10→Q12→Q14→Q16w)
│   └── NO ✗  → SHORTEN −2 weeks (re-assess next visit)
│
├── ◆ DIAMOND 2: FLUID at MAXIMUM interval (Q4w)?
│   ├── NO  → Continue T&E cycle (loop to assessment)
│   └── YES → PERSISTENT FLUID — POOR RESPONDER
│
├── SWITCH ANTI-VEGF AGENT
│   Side panel: switching guidance (Ranibizumab → Faricimab → Afl 8mg)
│
├── REASSESS AFTER 3 INJECTIONS ←────── loop-back arrow to Step 4
│
├── TREATMENT GOALS (3 colour-coded panels)
│   Visual Goal · Anatomic Goal · Treatment Burden targets
│
└── SAFETY MONITORING BANNER
    Brolucizumab · RPE tears · MA · IOP · Endophthalmitis