Glaucoma is a progressive optic neuropathy characterized by the degeneration of retinal ganglion cells (RGCs) and their axons, leading to irreversible visual field (VF) loss if untreated. With an estimated 80 million individuals affected worldwide, glaucoma constitutes the second leading cause of blindness globally, imposing a substantial burden on public health systems and individual quality of life.

The fundamental challenge in glaucoma management lies in the temporal disconnect between structural and functional damage. By the time conventional standard automated perimetry (SAP) reliably detects VF defects, it is estimated that up to 25–40% of retinal ganglion cells may already be irreversibly lost within the affected region — a phenomenon described as the "structure-function gap." This delay in functional detection renders standard perimetry a suboptimal sole monitoring tool, particularly in patients with early-to-moderate glaucoma.

Spectral-domain optical coherence tomography (SD-OCT) has emerged as a transformative non-invasive imaging modality capable of quantifying the thickness of the peripapillary retinal nerve fiber layer (RNFL), macular ganglion cell complex (GCC), and optic nerve head (ONH) morphology with micrometer-level resolution. The biological rationale for its superior early detection capability rests on the premise that axonal loss and ganglion cell thinning are upstream events in the glaucomatous cascade, preceding the functional consequences measurable by psychophysical tests.

Multiple cross-sectional studies have demonstrated that OCT parameters — most notably inferior and superior RNFL thickness, GCL+ thickness, and rim area — discriminate glaucomatous from normal eyes with high accuracy. However, the longitudinal evidence specifically addressing how far in advance of VF loss OCT-based changes emerge, and which combination of parameters maximizes the diagnostic lead time in a prospective clinical setting, remains insufficiently characterised.

This prospective longitudinal cohort study was designed to address these critical clinical questions by systematically evaluating the temporal relationship between OCT-detected structural changes and subsequent VF deterioration, determining the diagnostic accuracy of individual and combined OCT indices, and identifying specific structural parameters that serve as the most reliable early biomarkers of progressive glaucomatous damage.

This prospective, single-centre longitudinal cohort study was conducted at the Glaucoma Service of the Dr. VRK Women's Medical College, Teaching Hospital from June 2023 to December 2025. The study adhered to the tenets of the Declaration of Helsinki and received approval from the Institutional Ethics Committee. Written informed consent was obtained from all participants prior to enrolment. 2.2 Participants A total of 244 eyes from 244 participants were enrolled across three groups: (1) confirmed primary open-angle glaucoma (POAG) — 124 eyes; (2) ocular hypertension (OHT) — 68 eyes; and (3) healthy control subjects — 52 eyes. Inclusion criteria for the glaucoma group required: open anterior chamber angle on gonioscopy; glaucomatous optic disc changes (cup-to-disc ratio ≥ 0.65, vertical asymmetry ≥ 0.2, or neuroretinal rim thinning); reproducible VF defects on SAP (at least two reliable consecutive tests); and intraocular pressure (IOP) > 21 mmHg at diagnosis or on treatment. OHT subjects had IOP > 21 mmHg on ≥ 2 measurements with normal VF and optic disc appearance. Controls had IOP ≤ 21 mmHg, normal optic discs, and no ocular disease. Exclusion criteria included: best-corrected visual acuity (BCVA) worse than 0.5 LogMAR; spherical equivalent refractive error outside −6.00 to +3.00 D; media opacity precluding image acquisition; prior intraocular surgery; secondary glaucomas; neurological conditions affecting the visual pathway; and unreliable SAP results (fixation loss >20%, false positive or false negative error >15%). 2.3 OCT Imaging Protocol All participants underwent SD-OCT imaging using the Cirrus HD-OCT 5000 platform (Carl Zeiss Meditec, Dublin, CA, USA) with software version 10.0.1. The optic disc cube 200×200 scan was used to acquire peripapillary RNFL thickness maps, and the macular cube 512×128 scan was used to derive ganglion cell and inner plexiform layer (GCIPL) data. All scans with signal strength < 7/10 or exhibiting motion artifacts were excluded and repeated. The following parameters were extracted at each visit: global average RNFL, superior and inferior quadrant RNFL, clock-hour RNFL sectors, GCL+ average and minimum, rim area, vertical cup-to-disc ratio, and cup volume. Lamina cribrosa depth was measured using enhanced depth imaging (EDI) mode. Imaging was performed at 6-month intervals throughout the study period, yielding a minimum of 5 serial OCT examinations per participant. RNFL progression analysis was performed using the Guided Progression Analysis (GPA) software, with trend-based and event-based outputs evaluated. Annual RNFL loss rate was calculated by linear regression of all available data points. 2.4 Visual Field Assessment Standard automated perimetry was performed using the Humphrey Field Analyzer 3 (Carl Zeiss Meditec) with the SITA-Standard 24-2 algorithm at 6-month intervals, concurrent with OCT examinations. VF progression was defined by the Glaucoma Progression Analysis (GPA) algorithm as "likely progression" based on three or more locations showing significant pattern deviation change on three consecutive reliable tests, or by a mean deviation (MD) decline of ≥ −1.0 dB/year with p < 0.05 on trend analysis over at least 4 tests. 2.5 Statistical Analysis Statistical analyses were performed using SPSS version 28.0 (IBM Corp., Armonk, NY) and R version 4.3.1. Receiver operating characteristic (ROC) curves were constructed for each OCT parameter individually and in combination, with areas under the curve (AUC) compared using the DeLong method. Optimal cut-off values were determined using the Youden index. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated at optimal cut-offs. Lead time advantage was defined as the interval between first OCT-detected structural change and first confirmed VF progression. Multivariate binary logistic regression was employed to identify independent OCT predictors of subsequent VF loss, adjusting for age, IOP, baseline RNFL thickness, and follow-up duration. A p-value < 0.05 was considered statistically significant throughout.

3.1 Baseline Characteristics

Table 1 summarises the baseline demographic and clinical characteristics of all three study groups. There were no statistically significant differences among groups in age, sex distribution, or BCVA (p > 0.05 for all). As expected, mean baseline IOP was significantly higher in the OHT group (26.2 ± 3.8 mmHg) compared to controls (14.3 ± 2.2 mmHg; p < 0.001). Cup-to-disc ratio was highest in the glaucoma group (0.72 ± 0.11). Positive family history of glaucoma was most prevalent in the glaucoma group (41.9%).

Table 1. Baseline Demographic and Clinical Characteristics of Study Participants

SD: standard deviation; IOP: intraocular pressure; BCVA: best-corrected visual acuity; Hx: history.

3.2 OCT Structural Parameters in Progressors vs. Non-Progressors

Among the 124 glaucoma eyes, 58 (46.8%) demonstrated confirmed structural progression on OCT during the follow-up period (progressors). Table 2 presents the comparison of key OCT parameters between progressors and non-progressors. All measured parameters showed statistically significant differences (p ≤ 0.003). Inferior RNFL thickness was most markedly reduced in progressors (66.7 ± 12.1 µm vs. 93.8 ± 10.4 µm; mean difference −27.1 µm; p < 0.001). Annual RNFL loss rate was substantially higher in progressors (−2.14 ± 0.72 µm/year vs. −0.48 ± 0.31 µm/year; p < 0.001). Lamina cribrosa depth was significantly greater in progressing eyes (427 ± 52 µm vs. 381 ± 44 µm; p = 0.003).

Table 2. Comparison of OCT Parameters Between Progressors and Non-Progressors

RNFL: retinal nerve fiber layer; GCL+: ganglion cell and inner plexiform layer complex; µm: micrometres; yr: year.

3.3 Diagnostic Performance of OCT Parameters

Table 3 summarises the ROC-derived diagnostic performance metrics for individual and combined OCT parameters for detecting glaucoma progression. The combined OCT index — incorporating global RNFL, inferior RNFL, GCL+ average, and rim area — achieved the highest AUC of 0.96 (95% CI: 0.93–0.99), with sensitivity of 92.6% and specificity of 94.3%. Among individual parameters, inferior RNFL achieved the highest single-parameter AUC (0.93; sensitivity 87.9%, specificity 90.1%). All OCT parameters significantly outperformed VF mean deviation in diagnostic accuracy (VF MD AUC = 0.82; p < 0.001 for all comparisons by DeLong test).

Table 3. Diagnostic Performance of OCT Parameters for Detection of Glaucoma Progression

AUC: area under the ROC curve; CI: confidence interval; PPV: positive predictive value; NPV: negative predictive value; VF: visual field; MD: mean deviation.

3.4 Lead Time Advantage of OCT Over Visual Field Testing

Table 4 quantifies the temporal lead time by which each OCT parameter detected progression relative to VF-confirmed deterioration. The combined OCT index provided the greatest lead time advantage of 34.6 months (95% CI: 29.2–40.0 months). Inferior RNFL thinning alone detected progression a mean of 31.2 months before VF loss (95% CI: 25.9–36.5 months). Global RNFL and GCL+ thinning provided lead times of 26.4 and 22.8 months, respectively. In multivariate analysis, an annual RNFL loss rate ≥ 2.0 µm/year was the strongest independent predictor of subsequent VF progression (OR = 4.87; 95% CI: 2.94–8.07; p < 0.001).

Table 4. Lead Time Advantage of OCT-Based Structural Detection Over Visual Field Progression

VF: visual field; MD: mean deviation; CI: confidence interval. Lead time is the interval between first OCT-detected change and confirmed VF progression.

The findings of this prospective longitudinal cohort study firmly support the hypothesis that SD-OCT-based structural parameters reliably detect glaucoma progression substantially earlier than conventional standard automated perimetry. The mean lead time advantage of up to 34.6 months conferred by the combined OCT index has profound implications for clinical practice: it represents a therapeutic window of nearly three years during which treatment escalation could be initiated, potentially preserving functional vision that would otherwise be irreversibly lost.

The biological underpinning of this temporal precedence is well established. Axonal degeneration of RGC fibres — directly reflected in RNFL thinning — and somatic RGC loss — quantified through GCL+ measurements — are the primary structural substrates of glaucoma. The psychophysical response captured by SAP requires a critical mass of functional neurons to reveal a statistically significant defect, creating the inherent lag described as the "structure-function gap." Our findings extend prior cross-sectional observations into longitudinal evidence demonstrating that this gap averages approximately 2.5–3 years across clinically meaningful OCT parameters.

The superior performance of inferior RNFL thickness among individual parameters (AUC 0.93) aligns with the known vulnerability of the inferior arcuate bundle — the Bjerum arcuate region — in glaucoma. This sector's predilection for early damage has been attributed to multiple factors including larger axon diameter (conferring earlier susceptibility to mechanical deformation), reduced axonal transport capacity, and the biomechanical stress concentration at the inferior pole of the lamina cribrosa. Our finding of significantly greater lamina cribrosa depth in progressing eyes corroborates this structural vulnerability hypothesis and suggests that posterior laminar displacement may serve as an additional prognostic marker.

The combined OCT index — aggregating global RNFL, inferior RNFL, GCL+ average, and rim area — achieved an AUC of 0.96, which represents near-optimal diagnostic performance. This composite approach capitalises on the partial independence of individual structural measurements: RNFL assesses axonal integrity at the level of the optic disc, while GCL+ reflects somatic ganglion cell status in the macula — two anatomically distinct but pathogenetically linked compartments. The additive diagnostic yield of combining these parameters has practical clinical implications, supporting the current recommendation to acquire both peripapillary and macular OCT scans routinely.

The annual RNFL loss rate emerged as the most powerful independent predictor of subsequent VF progression in multivariate analysis (OR = 4.87 per µm/year exceeding 2.0 µm threshold). This finding is clinically actionable: it suggests that a rate-based threshold of ≥ 2.0 µm/year on trend-based RNFL analysis should trigger clinical review and consideration of treatment optimisation, even in the absence of detectable VF change. This rate-based approach is philosophically aligned with the principle of treating structural damage aggressively in the pre-perimetric phase, particularly in young patients where lifetime cumulative damage risk is highest.

Several limitations warrant acknowledgement. The study enrolled participants from a single tertiary referral centre, which may introduce selection bias towards more severe or treatment-refractory disease. The use of a single OCT platform (Cirrus HD-OCT) limits generalisability to other platforms, although the fundamental parameters studied are platform-analogous. The definition of VF progression, while consensus-aligned, remains heterogeneous across studies, complicating direct inter-study comparisons. Furthermore, artefacts from floor effects in advanced glaucoma may have influenced RNFL measurements in a subset of participants with more severe baseline damage.

Future directions should include multi-centre validation of the combined OCT index across diverse ethnic cohorts — given documented differences in normative RNFL thickness distributions between Asian, African, and European populations — as well as head-to-head comparisons with swept-source OCT and OCT-angiography parameters. The integration of artificial intelligence–based progression detection algorithms into the OCT workflow represents a particularly promising avenue for improving both sensitivity and clinician efficiency.

This prospective longitudinal study demonstrates with high statistical confidence that SD-OCT structural parameters — individually and especially in combination — detect glaucoma progression a mean of 22–35 months earlier than standard automated perimetry. The combined OCT index provides exceptional diagnostic accuracy (AUC = 0.96) and should be incorporated into routine glaucoma monitoring protocols as the primary progression biomarker. An annual RNFL loss rate of ≥ 2.0 µm/year constitutes a critical clinical threshold warranting therapeutic reassessment. Widespread adoption of OCT-guided, rate-based monitoring strategies has the potential to transform the management paradigm for glaucoma — shifting intervention from a reactive functional model to a proactive structural preservation strategy, thereby reducing the global burden of glaucomatous blindness.

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