Diabetes is a significant cause of sight loss in industrialised countries. Diabetic macular oedema (DME) is the most common cause of visual impairment in the diabetic population. Visual impairment in DME results from disruption of the inner blood-retinal barrier, increased vascular permeability and exudation of serous fluid and lipid into the central retina (the macula). Within the past 30 years treatment for DME has evolved. Focal laser photocoagulation was established as an evidence-based standard treatment to maintain vision in DME. Intravitreal injections of corticosteroid, and particularly anti-vascular endothelial growth factor (anti-VEGF), have shown promise in not only maintaining, but also improving, vision in DME. These treatments are increasingly used either as standalone treatment or as adjunct treatment with laser.

Who gets DME?

DME can occur at any stage of diabetic retinopathy (DR). The estimated global prevalence of DME amongst diabetics is 6.8%, with approximately 21 million patients worldwide affected.¹ DME is more common in patients with type 1 diabetes, longer histories of diabetes, elevated HbA1c, hypertension and hypercholesterolaemia. Management of these associated risk factors is beneficial in preventing and halting progression.¹

What changes occur in DME?

DME occurs as a result of increased permeability of the inner blood-retina barrier (BRB). Advanced glycation end products (AGEs) accumulate and activate inflammatory mediations. The resulting endothelial cell death leads to free passage of fluid into the retina. Fluid leaks from abnormal vasculature – microaneurysms, dilated retinal capillaries and intraretinal microvascular abnormalities (IRMAs). Serous fluid and lipid exudation may appear as hard exudates and large accumulations within the retina can distort central vision. 

Macular ischaemia often coexists with DME. It is characterised by loss of capillaries within the macula, which can be seen on fluorescein angiography (FFA). There is currently no treatment for macular ischaemia. 

How is DME diagnosed?

DME should be suspected in all diabetic patients who describe distortions in central vision. To establish the diagnosis patients should have a dilated fundus examination supplemented by optical coherence tomography (OCT) and FFA. The Early Treatment of Diabetic Retinopathy Study (ETDRS)² defined standard treatment for DME for the past 25 years. The ETDRS defined clinically significant macular oedema (CSME) as retinal thickening present at or within 500 microns of the fovea, hard exudates if associated with macular thickening within 500 microns of the fovea or thickening greater than 1,500 microns within 1,500 microns of the fovea.

A national screening programme for DR is being developed. Patients are screened annually by digital fundus photography, and the photographs visually inspected to identify DR and maculopathy. Where there is evidence of maculopathy, DME may coexist and such patients are reviewed within 12-16 weeks by an ophthalmologist. 

Is DME treatable?

Primary prevention

Associated risk factors should be assessed and optimised. Glycaemic control should be reinforced with a HbA1C target of 6.5%. Blood pressure should be maintained at 140/80 mmHg or lower. A lipid-lowering agent should also be considered to target a total serum cholesterol of 4.0 mmol/l or LDL of 2.0 mmol/l. 

There are a number of treatments which have demonstrated efficacy in maintaining, and in some cases improving, vision. 

Focal laser photocoagulation

In the ETDRS study,² focal laser was compared with observation to treat DME. Laser-treated patients had a 50% reduction in moderate vision loss (from 24-12% of eyes) compared to observed patients at three-year follow-up. The ETDRS conclusion was that all eyes with ‘clinically significant macular oedema’ (CSME, defined above) should undergo focal laser. CSME was since used in many trials as a standard criteria for treatment in DME, but recent studies use central macular thickening as the treatment criteria. There are three main theories regarding the effect of retinal laser: a reduction in retinal oxygen demand via elimination of oxygen-requiring photoreceptors; reduced retinal capillaries with resultant reduced leakage; and restoration of outer BRB. It must be noted that laser treatment acted to halt progression in 50% of patients but did not result in any improvement in visual acuity (VA). 

Corticosteroid treatment

Inflammation plays a significant role in the pathology of DME. The Diabetic Retinopathy Clinical Research Network³ compared the used of intravitreal triamcinolone (1mg or 4mg) with the standard macular laser. VA was modestly improved and loss of vision was reduced in the steroid treatment groups; however, these patients had a significantly higher risk of developing cataract and glaucoma. Extended release intravitreal implants of fluocinolone acetonide are now available for the treatment of DME. While these implants have shown efficacy in reducing DME over an extended period of up to two years, the device has two important steroid-related side-effects: cataract and glaucoma, requiring surgery in 90% and 34% of patients respectively at four years.⁴

Long-term studies are awaited to further assess the long-term risk-benefit of these implants, but they may be useful in patients who have already undergone cataract surgery and who are refractory to other DME treatments.

Anti-VEGF agents

VEGF is a potent angiogenic and vascular permeability factor and is a key molecular target in DME. Recent data from the DRCRnet studies support the use of ranibizumab, an anti-VEGF antibody, in the treatment of DME.³ In this large multi-centre clinical trial patients with reduced vision from central foveal edema were treated with intravitreal ranibizumab with deferred laser or intravitreal ranibizumab with prompt laser. This was compared with standard laser management. 

Patients in both ranibizumab groups showed significant improvement and preservation of vision and reduced macular thickness when compared with laser alone. There was no significant difference between the prompt and deferred laser groups. There was no increased risk of glaucoma or cataract associated with this treatment. The treatment regimen required 13 intravitreal injections in the first year; however, this decreased to a median number of two to three in the second year. These results have established anti-VEGF treatment as a mainstay in the treatment of DME; however, this will have significant implications on the provision of services.

Conclusions 

The management of DME is undergoing change, and the optimal combination and timing of laser and/or intravitreal treatments has not yet been defined. The previous standard therapy of focal/grid laser photocoagulation acted, at best, to retain vision with many patients losing vision. It is important that patients be aware that laser photocoagulation is a preventative measure against progression of the disease to the severe irreversible end of the diabetic eye spectrum. Intravitreal ranibizumab (Lucentis) was licensed for use in DME in May 2011. Anti-VEGF treatment is a unique, novel treatment offering a potential improvement in vision. 

Current evidence supports the use of monthly ranibizumab therapy as a first-line treatment in cases of DME with central macular involvement with reduced vision. Intravitreal therapy should be supplemented with prompt or deferred laser treatment as necessary. Laser treatment alone is recommended for CSME without central foveal involvement or when no vision loss has occurred. Patients who have undergone cataract surgery do equally as well with intravitreal triamcinolone treatment. 

However the side-effect of raised intraocular pressure requiring intervention may limit this. The combination of laser photocoagulation and intravitreal showed no superiority to intravitreal treatment alone at two years. These recommendations are based on randomised controlled trials of one to two years duration and may require alteration as long-term ranibizumab data become available and as additional therapeutic agents become available. 

References

1. Yau JW, Rogers SL, Kawasaki R et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012; 35(3): 556-564 
2. Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Ophthalmology 1987; 94: 761-774
3. Elman MJ, Bressler NM, Diabetic Retinopathy Clinical Search Network et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011; 118(4): 609-614
4. Pearson PA, Cornstock TL, Ip M et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology 2011; 118(8): 1580-1587