43 Photocoagulation for sight threatening diabetic retinopathy

Background

Definition

Sight threatening diabetic retinopathy takes two forms (see Box 43.1). Diabetic macular oedema involves thickening of the central retina (macula) associated with microvascular abnormalities caused by diabetes. There may be related deposition of lipid exudates, or cystic change at the centre of the macula. Proliferative diabetic retinopathy involves new blood vessels arising from the optic disc (new vessels disc, NVD), or from retinal vessels (new vessels elsewhere, NVE). These may give rise to haemorrhage into the vitreous gel, or retinal detachment.

Incidence/prevalence

In a probability sample of a Wisconsin population, the tenyear incidence of diabetic macular oedema was 14–25%,1 and that of proliferative retinopathy 10–30%.2 (See Table 43.1.)

Aetiology

In diabetic macular oedema hyperglycaemia causes injury to retinal microvasculature. Resulting leakage through or between retinal capillary endothelial cells results in extracellular fluid accumulation, retinal thickening and impaired function. Intracellular fluid accumulation and leakage through the retinal pigment epithelium may also contribute.

In proliferative diabetic retinopathy hyperglycaemiainduced changes to blood elements, vessel walls and flow causes occlusion of retinal capillaries. Enhanced production of growth factors by ischaemic retina appears to cause retinal capillary endothelial cell proliferation and new vessel formation.

Risk factors

Risk factors for more rapid retinopathy progression include longer duration of diabetes, type 1 and insulin treated type 2 diabetes, certain ethnicities, male sex, poor

glycaemic or tightened glycaemic control, hypertension, renal dysfunction, pregnancy, and possibly cataract surgery, as well as specific ophthalmoscopic signs (see Box 43.2).

Prognosis

Diabetic retinopathy is the commonest cause of blindness in the working population of the western world and the commonest cause of preventable blindness in the UK. Prior to the advent of photocoagulation, the prognosis for vision was very poor.

Questions

1In patients with proliferative diabetic retinopathy, does photocoagulation reduce the risk of visual loss?

2In patients with diabetic macular oedema, does photocoagulation reduce the risk of visual loss?

3In patients with diabetic retinopathy that has not reached the high risk proliferative stage, does photocoagulation (early treatment) reduce the risk of visual loss?

4Does photocoagulation technique affect treatment outcome?

All randomised controlled trials found have been included. Smaller trials superseded by larger, better controlled trials were excluded.3,4

Question

In patients with proliferative diabetic retinopathy, does photocoagulation reduce the risk of visual loss?

The evidence

One large (n = 1758) multi-centre RCT of high quality, the Diabetic Retinopathy Study (DRS), was identified.5 Patients with severe non-proliferative (NPDR) or proliferative diabetic retinopathy (PDR) in both eyes were included. Patients with visual acuity 6/30, those who had undergone

prior photocoagulation, and those in which photocoagulation was not possible, were excluded. One eye of each patient was assigned randomly to scatter (panretinal) photocoagulation, and the other to indefinite

deferral of photocoagulation. The principal outcome variable was development of severe visual loss (visual acuity ≤ 1·5/60 on two successive visits). Severe visual loss occurred in 26% of untreated versus 12% of treated eyes

with “high risk proliferative retinopathy” in two years (number needed to treat (NNT) 8, 95% CI 5–18).

Comment

This study established the benefit of panretinal photocoagulation for proliferative diabetic retinopathy. Quantum treatments were applied to eyes at specific high risk disease thresholds. Titrating the amount of treatment to the risk of visual loss might be equally valid.

Questions

In patients with diabetic macular oedema, does photocoagulation reduce the risk of visual loss?

In patients with diabetic retinopathy that has not reached the high risk proliferative stage, does photocoagulation (early treatment) reduce the risk of visual loss?

The evidence

One large (n = 3711) high quality multi-centre RCT, the Early Treatment Diabetic Retinopathy Study (ETDRS) was identified.6 Patients with diabetic retinopathy in both eyes having either no macular oedema and more severe non-proliferative or early proliferative retinopathy and visual acuity 6/12 or macular oedema and mild, moderate or severe non-proliferative retinopathy or early proliferative retinopathy, and visual acuity 6/60 were included. Patients with high risk proliferative retinopathy or other significant ocular disease were excluded. One eye of each patient was assigned randomly to early photocoagulation and the other to deferral of photocoagulation until high risk proliferative retinopathy developed. Eyes selected for photocoagulation received one of four combinations of focal (macular) laser therapy or mild/full scatter (panretinal) laser therapy. The principal outcome variables were the development of severe visual loss (visual acuity ≤ 1·5/60 on two successive visits) and moderate visual loss (loss of ≥ three lines of visual acuity). Moderate visual loss occurred in 12% of treated eyes with clinically significant diabetic macular oedema versus 24% of untreated eyes in three years (NNT 9, 95% CI 6–16).

The five-year risk of severe visual loss was 2·6% in the early treatment group versus 3·7% in the deferred treatment group; a difference of borderline significance (P = 0·035 versus the chosen significance level of 0·01; NNT 86, 95% CI 51–275). Early treatment was also associated with a higher incidence of adverse effects. Subgroup analysis suggests, however, that early treatment may be more beneficial in patients with type 2 diabetes.7

Comment

This study established the benefits of macular laser therapy for diabetic macular oedema. Clinical examination does, however, underestimate the incidence of retinal thickening. Better recognition of thickening, for example, using optical coherence tomography, might improve the effectiveness of laser therapy, and less destructive treatment, for example, using micropulse laser, might reduce adverse effects.

“Early treatment” photocoagulation of eyes with retinopathy that has not yet reached the high risk proliferative stage cannot be unequivocally recommended on the basis of the ETDRS findings. In addition, randomisation categories did not include eyes with high risk proliferative retinopathy and clinically significant macular oedema. A non-randomised study suggested that results comparable to the ETDRS can be achieved by immediate application of focal and one fraction of scatter, followed two to four weeks later by the second fraction of scatter.8

Question

Does photocoagulation technique affect treatment outcome?

The evidence

Xenon-arc versus argon laser photocoagulation

One large (n = 1758) multi-centre RCT of high quality, the Diabetic Retinopathy Study (DRS),5 and three small (n = 15–63) RCTs were identified.9–11 Eyes were randomised to treatment in the DRS and were further randomised to xenon arc or argon laser photocoagulation; in the other studies, eyes with proliferative diabetic retinopathy were randomised to argon or xenon treatment. There was no significant difference in therapeutic benefit between xenon and argon treatment in any of the studies. In the DRS, a persistent treatment-related loss of one to four lines of visual acuity was encountered in 9·3% of argon treated eyes and 19·1% of xenon treated eyes, and severe visual field loss in 7% and 41% of eyes, respectively (number needed to harm (NNH) 11 and 3, respectively).

Comment

Xenon treatment is now rarely used.

Laser wavelength

One large (n = 696) high quality multi-centre RCT, the Krypton Argon Regression Neovascularisation Study (KARNS),12 and 11 other smaller RCTs (n = 8–210) were

identified.13–23 Eyes with proliferative retinopathy (10 studies) or macular oedema (two studies) and clear media were included. People with significant vitreous haemorrhage in eyes with proliferative retinopathy were excluded. In the KARNS and three other studies14,21,23 eyes were randomised to argon blue-green or krypton red panretinal photocoagulation. Other comparisons included argon bluegreen versus diode infrared15,19 dye orange20 and dye orange or dye yellow17; argon green versus krypton red23; argon green versus diode infrared22; dye yellow versus dye red13; and frequency-doubled Nd:YAG yellow-green versus argon green.16 The principal outcome variables included regression of neovascularisation/macular oedema, visual acuity, visual fields. No difference in therapeutic effect, visual acuity or adverse effect was encountered in any study.

Comment

Wavelength appears not to be a critical treatment parameter for either macular or panretinal laser.

Laser delivery parameters

Pattern of laser application

Two small RCTs (n = 40, 42) were identified.24,25 The inclusion criterion was proliferative diabetic retinopathy. Interventions studied were peripheral versus more central panretinal photocoagulation. Neither study showed a difference between techniques in regression of neovascularisation or visual acuity. One study26 showed greater field loss with more central photocoagulation, the other did not. One study27 showed more tendency for macular oedema with more central photocoagulation, the other study did not examine this.

Burn characteristics

Two small RCTs were identified (n = 12,34).26,28 The inclusion criterion was proliferative diabetic retinopathy. Intervention was long duration versus short duration burns, intense versus light. No difference between techniques in therapeutic effect was demonstrated. Intense laser had more adverse effect on visual field than light.

Comment

The practice of applying intense laser has grown less common, which limits the relevance of the older studies on pattern of laser delivery to current practice.

Temporal distribution of laser application

Two small (n = 35, 50) but well-controlled RCTs were identified.27,29 One study divided laser application over several

visits (fractionation), the other applied early retreatment to eyes in which high risk retinopathy did not regress within three weeks. Principal outcome variables were regression of neovascularisation and visual acuity. Neither treatment strategy affected regression of neovascularisation or visual acuity.

Comment

The ETDRS data show a higher rate of early visual loss in eyes randomised to immediate panretinal photocoagulation when compared to the deferral group, especially in eyes randomised to full compared to mild panretinal photocoagulation. Although the ETDRS study cohort did not include eyes with high risk proliferative retinopathy, its data are used by some to justify fractionation of the treatment of high risk eyes.

Summary

Panretinal photocoagulation for high risk proliferative diabetic retinopathy and macular laser therapy for diabetic macular oedema reduce visual loss, and the technique of photocoagulation appears to have relatively little effect on these benefits. Early photocoagulation, before the development of high risk proliferative retinopathy reduces slightly the rate of visual loss, but rates are in any case low and there are significant adverse effects of treatment.

Implications for practice

To reduce the risk of visual loss, laser therapy is indicated for macular oedema when it meets the definition of clinical significance and for proliferative disease when it meets the definition of high risk retinopathy.

Implications for research

Any trial of novel therapy for treating diabetic retinopathy should involve comparison of its risks and benefits with laser treatment applied according to the recommendations of the Diabetic Retinopathy and Early Treatment retinopathy study.

Reference

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