What is the role of Optical Coherence Tomography (OCT) biomarkers in diagnosing and monitoring Neovascular Age-related Macular Degeneration (NAMD) in a patient with a history of diabetic macular edema?

OCT Biomarkers in Neovascular Age-Related Macular Degeneration

Spectral-domain OCT (SD-OCT) or swept-source OCT (SS-OCT) volume scans (6×6 mm with scan spacing ≤120 μm) must be performed at every visit for patients with neovascular AMD to assess disease activity and guide anti-VEGF treatment decisions. 1, 2

Essential OCT Protocol for NAMD

Baseline and Follow-Up Imaging Requirements

• SD-OCT or SS-OCT volume scans are mandatory at every clinical visit for neovascular AMD patients, with scan dimensions of at least 6×6 mm and maximum distance between scans not exceeding 120 μm 1

• The American Academy of Ophthalmology designates OCT as a Class "R" recommendation (must be performed) for establishing diagnosis, detecting early progression signs, monitoring disease activity, and evaluating neovascularization in neovascular AMD 2

• OCT provides cross-sectional morphology of the retina, retinal pigment epithelium, and choroid with near-histological detail, allowing precise repositioning of subsequent scans for longitudinal comparison 2

Complementary Imaging at Baseline and Selected Visits

• Fluorescein angiography (FA) and fundus autofluorescence (FAF) are recommended at baseline, approximately every 6 months during follow-up, and at final outcome assessment 1

• Near-infrared reflectance and color fundus photography should be performed at visits when FA or FAF is conducted to enhance interpretation 1

• Indocyanine green angiography is optional at baseline, with the decision to include it reflecting regional prevalence of specific neovascularization subtypes such as polypoidal choroidal vasculopathy or retinal-choroidal anastomosis 1

Critical OCT Biomarkers for Treatment Decisions

Fluid Compartmentalization: The Primary Treatment Trigger

Retinal fluid assessment represents the most clinically significant OCT biomarker, with intraretinal fluid (IRF) specifically associated with poor visual outcomes and requiring immediate treatment intensification. 3, 4

• Intraretinal fluid (IRF) indicates active disease with breakdown of the blood-retinal barrier and carries the strongest negative prognostic value for visual acuity outcomes 5, 3, 6

• Subretinal fluid (SRF) represents fluid accumulation between the neurosensory retina and RPE, with prognostic significance varying based on volume and persistence 5, 3, 6

• Sub-RPE fluid (also termed pigment epithelial detachment fluid) indicates fluid beneath the retinal pigment epithelium and often signifies type 1 neovascularization 5, 6

• OCT must be performed at each visit to assess for persistent or recurrent fluid in any compartment, as this directly determines whether to continue current treatment intervals or intensify therapy 7, 3

Structural Biomarkers Indicating Disease Severity

• Ellipsoid zone (EZ) integrity: Disruption or loss of the ellipsoid zone on OCT correlates with photoreceptor damage and predicts worse visual outcomes, making it a critical prognostic marker 5, 6

• Hyperreflective foci (HRF): These represent lipid-laden macrophages or RPE migration and indicate chronic inflammatory activity; higher numbers correlate with worse visual prognosis 5, 3, 6

• Subretinal hyperreflective material (SHRM): This biomarker consists of fibrin, blood, and inflammatory cells; its presence and texture changes predict treatment response, with baseline SHRM characteristics distinguishing super-responders from non-responders 5, 4, 6

• Outer retinal tubulations (ORT): These degenerative structures indicate chronic photoreceptor loss and typically appear in areas of geographic atrophy or longstanding neovascular disease 5, 6

Choroidal and Sub-RPE Biomarkers

• Hyporeflective prechoroidal cleft: This space between the RPE and choroid may indicate type 1 neovascularization and has implications for treatment response 5, 6

• Double-layer sign: Visualization of two distinct hyperreflective lines in the sub-RPE space suggests type 1 neovascular membrane and can be detected without dye-based angiography 5, 6

• Subretinal drusenoid deposits (SDD): Also called reticular pseudodrusen, these appear as hyperreflective deposits above the RPE and indicate increased risk for geographic atrophy development 6

OCT Angiography: Emerging but Not Yet Standard

• OCT-A enables detailed characterization of neovascularization in AMD through depth-resolved, noninvasive visualization of blood flow based on motion contrast 1

• OCT-A can detect non-exudative type 1 neovascularization and analyze different choroidal layers at atrophic lesion borders 1

• However, OCT-A remains exploratory and optional in clinical protocols, as data are still forthcoming regarding its ability to influence treatment decisions compared to established modalities 1

Quantitative OCT Metrics and Their Limitations

Central Retinal Thickness: Historical but Insufficient

• Central point thickness (CPT) or central foveal thickness (CFT) decreases on average following anti-VEGF treatment, with reductions observed as early as Day 7 after the first injection 8

• Critical limitation: CPT/CFT data alone do not provide information useful for influencing treatment decisions or predicting final visual acuity results 8

• Retinal thickness must be interpreted alongside qualitative fluid assessment rather than used as an isolated metric 8, 3

Advanced Radiomic Features: Research Frontier

• Texture-based radiomic features extracted from fluid, SHRM, and different retinal compartments can distinguish super-responders (patients achieving and maintaining fluid resolution) from non-super responders with cross-validated AUC of 0.75 using baseline features alone 4

• Delta-texture features (changes between baseline and month 3) yield AUC of 0.78, and combining baseline OCT features, delta-texture features, and clinical parameters achieves AUC of 0.81 4

• These radiomic approaches remain investigational and require machine learning classifiers not yet integrated into clinical practice 4

Special Considerations for Diabetic Macular Edema History

In patients with both neovascular AMD and prior diabetic macular edema, OCT interpretation requires heightened vigilance for IRF, as these patients may have pre-existing inner retinal structural damage that complicates fluid assessment. 9

• OCT has become the single most important diagnostic and prognostic tool in DME management, providing quantitative assessment that enables earlier detection and more targeted therapeutic approaches 9

• Spectral-domain OCT provides superior pathophysiologic understanding of macular edema patterns, which is relevant when distinguishing AMD-related fluid from residual DME-related changes 9

• The presence of hyperreflective foci may be more prevalent in patients with diabetic history, potentially confounding interpretation of AMD disease activity 5, 9

Common Pitfalls in OCT Interpretation

• Automated segmentation is imperfect and device-dependent, with lack of industrial standards between manufacturers requiring manual verification of fluid detection 2

• Limited field of view compared to fundus photography means peripheral lesions may be missed; OCT captures only the scanned area 2

• Image quality dependence: Poor signal strength from media opacities or patient fixation issues can render OCT uninterpretable, necessitating repeat imaging 2

• Atrophy boundary definition remains controversial, particularly distinguishing complete RPE and outer retinal atrophy from incomplete forms 2

• Three-dimensional datasets require complex software for analysis and substantially longer reading times compared to two-dimensional imaging 2