Drusen, geographic atrophy and neovascular phenotypes

Morphologic Classification of Drusen

Drusen represent focal accumulations of acellular extracellular material located beneath the neurosensory retina, historically localized between the basement membrane of the RPE and the inner collagenous zone of Bruch membrane (sub-RPE deposits):

1. Hard Drusen

• Small ($<63\,\mu\text{m}$ in diameter), discrete, nodular, round lesions with crisp, well-demarcated margins.
• Represent compact, dense hyaline lipid-protein deposits.
• Found universally in the aging population; asymptomatic and carry a minimal standalone risk of progression to choroidal neovascularisation unless accompanied by large confluent drusen.

2. Soft Drusen

• Large (typically $\ge 125\,\mu\text{m}$), pale yellow-white, dome-shaped mounds with indistinct, hazy, confluent boundaries.
• Reflect localized dome-like elevations where continuous sheets of neutral lipid and vesicular membranous debris detach the RPE from Bruch membrane (basal linear deposits).
• Tend to coalesce over time, forming large drusenoid pigment epithelial detachments (drusenoid PEDs).
• Represent the single most important clinical risk factor for progression to geographic atrophy and neovascular AMD.

3. Cuticular Drusen (Basal Laminar Drusen)

• Plentiful, tiny ($25-75\,\mu\text{m}$), uniform, triangular or nodular sub-RPE excrescences composed of packed basement membrane collagen.
• On funduscopy, they appear as a dense "carpet" of yellow punctate lesions across the macula.
• Angiographic Hallmark: On fluorescein angiography (FA), cuticular drusen produce a characteristic "stars in the sky" (or "milky way") appearance, demonstrating early, crisp punctate hyperfluorescent transmission window defects that persist into late frames without significant dye leakage.
• Complication: Predisposed to developing vitelliform-like exudative macular detachments in middle age.

4. Reticular Pseudodrusen (Subretinal Drusenoid Debris - SDD)

• Unlike conventional drusen which accumulate underneath the RPE, reticular pseudodrusen accumulate above the RPE in the subretinal space, between the apical RPE membrane and the photoreceptor inner/outer segment junctions.
• Imaging Characteristics: Often difficult to distinguish on standard colour fundus photography, appearing as a subtle, interlacing, ribbon-like yellowish network in the superior macula. They are visualised with exquisite sensitivity on near-infrared reflectance (NIR) (appearing as hyporeflective grouped spots surrounded by hyperreflective halos), blue light fundus autofluorescence (FAF), and cross-sectional SD-OCT (conical mounds of hyperreflective debris breaching the ellipsoid zone).
• Prognostic Significance: Reticular pseudodrusen represent a potent, independent risk factor for rapid progression to geographic atrophy and the development of Type 3 macular neovascularisation (RAP).

Geographic Atrophy and Complement Inhibitors

Geographic atrophy is advanced non-neovascular AMD with loss of outer retina and RPE. OCT demonstrates loss of outer-retinal structures and hypertransmission; autofluorescence helps map lesion extent. Record foveal involvement, progression and functional difficulties. Care includes smoking cessation, visual rehabilitation, counselling, and surveillance for neovascular conversion; supplements do not regenerate an atrophic fovea.

Pegcetacoplan inhibits C3 and avacincaptad pegol inhibits C5. Their trials measured slowing of lesion growth rather than recovery of lost vision. Risks include repeated-injection complications and neovascular conversion; inflammation/vasculitis concerns differ between products. Trial efficacy does not itself confer authorisation.

For the European context, EMA confirmed refusal of Syfovre (pegcetacoplan) on 19 September 2024 and the Commission refused authorisation on 16 December 2024. The Izelvay (avacincaptad pegol) application was withdrawn on 24 October 2024. US brand approval should not be described as routine EU availability. See EMA Syfovre and EMA Izelvay. Regulatory status should be rechecked before clinical use.

Neovascular AMD (nAMD): Classification & Multimodal Phenotypes

Neovascular (exudative or "wet") AMD is characterized by the pathologic sprouting of fragile, immature capillary networks from the choroid or retina that breach normal anatomic barriers, accompanied by vascular hyperpermeability, lipid exudation, and subretinal haemorrhage. Modern classification divides macular neovascularisation (MNV) into four distinct entities:

1. Type 1 MNV (Occult Neovascularisation)

• Anatomic Location: The neovascular complex originates from the choriocapillaris and proliferates strictly underneath the retinal pigment epithelium (sub-RPE space), above Bruch membrane and below the RPE.
• Morphology: Commonly presents as a fibrovascular pigment epithelial detachment (fibrovascular PED) or shallow irregular PED on SD-OCT (the "double-layer sign").
• Fluorescein Angiography (FA): Lacks early, crisp vascular borders. Appears as stippled, mottled hyperfluorescence in the mid-transit phase with irregular, late-phase pin-point staining or poorly demarcated sub-RPE dye pooling ("leakage of undetermined source").

2. Type 2 MNV (Classic Neovascularisation)

• Anatomic Location: The neovascular fronds penetrate through Bruch membrane AND the RPE layer, arborizing within the subretinal space (above the RPE, beneath the neurosensory retina).
• Morphology: Presents on SD-OCT as a hyperreflective, well-demarcated subretinal mass resting on the apical surface of an intact or disrupted RPE band, accompanied by adjacent subretinal and intraretinal fluid.
• Fluorescein Angiography (FA): Exhibits classic early, bright, lacy, cartwheel-pattern hyperfluorescence with well-delineated margins, followed in late phases by profuse, diffuse dye extravasation that completely obscures the lesion boundaries.

3. Type 3 MNV (Retinal Angiomatous Proliferation - RAP)

• Anatomic Location: Angiogenesis originates within the deep capillary plexus of the neurosensory retina (intraretinal neovascularisation), subsequently growing downward into the subretinal space to establish chorio-retinal anastomoses.
• Morphology: Clinically presents with superficial intraretinal flame/blot haemorrhages, localized cystoid macular oedema, and a high association with reticular pseudodrusen in elderly Caucasian females. Frequently advances through three stages: Stage 1 (intraretinal), Stage 2 (subretinal extension), and Stage 3 (choroidal anastomosis with vascularised PED). Rapidly bilateral in $>50\%$ of patients within 3 years.

4. Polypoidal Choroidal Vasculopathy (PCV)

• Anatomic Location: Considered an aneurysmal variant of Type 1 MNV or a primary manifestation of the pachychoroid disease spectrum. Originates in the inner choroidal vasculature.
• characteristic Features: Characterized by an extensive branching vascular network (BVN) terminating in orange-red, nodular, aneurysmal polypoidal vascular ectasias.
• Clinical Presentation: Characteristically affects younger patients, men, and individuals of East Asian and African ancestry. Presents with recurrent, massive subretinal haemorrhages, vitreous haemorrhage, and large serosanguineous PEDs with relatively preserved visual acuity in early stages.
• Diagnostic Imaging: Indocyanine green angiography (ICGA) is the reference method for demonstrating aneurysmal lesions and the branching network, with early nodular hypercyanescence and sometimes a hypofluorescent halo. OCT features such as sharp-peaked PEDs and sub-RPE ring-like lesions can support a clinical diagnosis when ICGA is unavailable. Integrate the imaging and haemorrhagic phenotype when planning anti-VEGF therapy and selected PDT.