Identification of prognastic factors for development and progression of prolifative diabetic retinopathy

Abstract

Introduction
Proliferative diabetic retinopathy (PDR) occurs when new retinal blood vessels develop in an attempt to replace capillaries damaged by hyperglycaemia in diabetes, which is referred to as ‘capillary nonperfusion’. The new vessels, however, are fragile and can rupture, resulting in severe sight-threatening complications such as vitreous haemorrhage and tractional retinal detachment. These complications can lead to total visual loss despite the availability of treatments. This PhD project was devised to advance knowledge of the condition and, in particular, the reasons for the variable rate in progression to PDR amongst people with diabetes, the impact of capillary nonperfusion on visual function, and the effect of baseline presenting characteristics and type of laser panretinal photocoagulation (PRP) performed on the clinical outcomes of patients treated for PDR.

Methods
To this effect, the thesis comprises three components.
A systematic review and meta-analysis synthesised current evidence, based on published literature on prognostic factors associated with the development and progression of PDR (Chapter 2).
A prospective, longitudinal, observational cohort study investigated the relationship between retinal sensitivity deficit and retinal perfusion, its relationship with duration of diabetes, and changes in retinal sensitivity deficit over time (Chapter 3).
A retrospective analysis of clinical data explored the effects of baseline characteristics and laser type performed on anatomical and visual outcomes in people with PDR undergoing PRP (Chapter 4).

Results
The Cochrane prognosis review revealed higher glycated haemoglobin (HbA1c) levels (adjusted OR ranged from 1.11 [95% CI 0.93 to 1.32] to 2.10 [95% CI 1.64 to 2.69]) and more advanced stages of retinopathy (adjusted OR ranged from 1.38 [95% CI 1.29 to 1.48] to 12.40 [95% CI 5.31 to 28.98]) to be independent prognostic factors for the development of PDR. There was also a moderate level of evidence to suggest some markers of renal disease, for instance, albumin creatinine ratio (adjusted HR ranged from 1.22 [95% CI 1.20 to 1.78] to 6.65 [95% CI 3.92 to 11.29]) and estimated glomerular filtration rate (adjusted HR ranged from 2.55 [95% CI 1.22 to 5.35] to 4.22 [95% CI 1.27 to 14.07]) were associated with increased risk of developing PDR, and that gender is not likely to increase the risk of developing PDR (adjusted HR ranged from 0.92 [95% CI 0.71 to 1.19] to 1.08 [95% CI 0.94 to 1.22]).

The prospective, longitudinal cohort, observational study included 44 eyes (2449 retinal points) of 44 adult patients (aged >18 years) with type 1 (T1D) or type 2 (T2D) and moderate to very severe non-proliferative diabetic retinopathy (NPDR) or PDR with at least one eye naïve to treatment, and no other retinal disorders. Twenty-seven eyes (1439 retinal points) were included in the follow-up analysis at one year and 12 eyes (545 retinal points) at two years. There was substantial evidence indicating that mean retinal sensitivity deficit was reduced in nonperfused (12.2 dB, 95%CI 11.1 – 13.2, p < 0.001) compared with perfused retinal areas (6.6 dB, 95%CI 5.1 – 8.2, p < 0.001). There was no relationship between retinal sensitivity deficit in perfused and nonperfused retinal areas, nor mean retinal sensitivity deficit, and duration of diabetes. Retinal ischaemic index was, however, statistically significantly associated with duration of diabetes, but not mean retinal sensitivity deficit in multivariable regression analyses correcting for age, gender, DR severity at baseline, and HbA1c. The change in retinal sensitivity in perfused and nonperfused areas from baseline to one-year follow-up and from one- to two-year follow-up, although statistically significant, may not be clinically meaningful.

The retrospective clinical study determined that people receiving multi-spot pattern laser had a statistically significantly delayed stabilisation (HR: 0.57, p = 0.020) and increased risk of progression (HR: 1.87, p = 0.045) compared to those receiving single spot standard laser. Among other potential predictors in multivariable regression analysis, only vitreous haemorrhage and fibrosis or traction at baseline increased the risk of progression (HR: 1.58, p = 0.047; and HR: 4.29, p ≤ 0.001, respectively). Baseline characteristics and type of laser had no statistically significant effect on visual outcomes.

Conclusion
Maintaining adequate glucose control, even when more severe stages of DR are present, is likely to reduce the risk of progression to PDR and its sight-threatening complications, and should be pursued.
Retinal sensitivity is reduced in people with moderate to severe NPDR and PDR, even in regions of perfused tissue. However, the rate of functional loss appears to be relatively gradual, providing an opportunity for therapeutic interventions.
Clinicians should be aware of the potentially reduced effectiveness of multi-spot pattern laser, when compared with standard single spot laser, for treating PDR. These findings should be considered when selecting laser treatment, planning surveillance, and counselling patients with PDR undergoing PRP.

Thesis is embargoed until 31 July 2025.

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Belfast Association for the Blind
Supervisor	Noemi Lois (Supervisor), Ruth Hogg (Supervisor) & John Lawrenson (Supervisor)