The current-care toolbox for DME

Know your technologies, especially OCT. As for drug therapies, you’ll need to be intimate with the Big Three.

By Michael P. Hood, MD and Jorge I. Calzada, MD

As diabetes rates^* climb in the United States, referrals to ophthalmologists to screen for diabetic retinopathy have become a major part of our clinical practice. Uncontrolled diabetes causes microvascular damage throughout the body, and in the eye can lead to an array of abnormalities, including macular edema and neovascularization. Diabetic macular edema (DME) is caused by increased capillary permeability, which often results in a significant decrease in visual acuity. With so many things to consider when evaluating and treating patients with DME, it is important that physicians have an up-to-date algorithm to guide their decision-making.

Historically, clinically significant diabetic macular edema (CSME) was diagnosed following the criteria set forth in the Early Treatment Diabetic Retinopathy Study (ETDRS).¹ It is important to remember that CSME in this study was determined through the use of stereo contact lens biomicroscopy or stereo photography. For years after its publication, the ETDRS guided the way ophthalmologists diagnose and treat diabetic retinopathy.

Retinal leakage from microaneurysms superior to the fovea.
COURTESY JORGE I. CALZADA, MD

Since the advents of high-resolution optical coherence tomography (OCT) and anti-VEGF agents, however, most retina specialists have altered their approach to diabetic eye disease. While a meticulous exam must still be performed on all patients, OCT has become the most reliable way to identify DME, and it often detects macular edema that is not apparent on physical exam. Although it is not required in most cases, fluorescein angiography can also aid in diagnosis of DME by confirming active capillary leakage in the foveal and juxtafoveal regions, and by determining the pattern of leakage.

We have included a logical flowchart approach for the management of diabetic macular edema (see treatment algorithm on page 78). True, this flowchart is based on evidence-based medicine, but we recognize it is also steeped in the personal experience of the authors, and that other authorities may recommend a different approach.

Diagnosis

The first step in management is the diagnosis of DME. This will require clinical examination and optical coherence tomography. With that information, the clinician can determine if the macular edema is focal or diffuse. For our purposes we define focal edema as edema that occupies one quadrant or less of the macular area. Macular thickness maps generated from raster OCT scans can demonstrate the pattern and extent of the edema, but should not be used as a basis for the treatment algorithm. Only by evaluating all the OCT scans can a physician make an informed judgment on the macular anatomy. Thickness maps can have artifacts from inadequate segmentation of the retina, namely decentration from the fovea, so misinterpreting retinal atrophy and missing coexisting pathologies could occur when using these maps.

The role of fluorescein angiography in the management of DME has diminished greatly with the advent of modern Fourier domain OCT. Actually, making a macular edema diagnosis does not require angiographic evidence or confirmation. The value of angiography lies in the following:

1. Determining if the leakage is due to a blood-retinal barrier breakdown (which is associated with diffuse macular edema) or from discrete microaneurysms

2. Evaluating the presence of peripheral nonperfusion and neovascularization

3. Evaluating for coexisting retinal vasculopathies or their diagnoses.

Treatment

In the presence of focal DME, the angiography can help guide the clinician in the planning of laser therapy by directing the laser to leaking microaneurysms. Since laser therapy, even when successful, can lag months behind anti-VEGF therapy in clinical improvement, we recommend starting therapy with anti-VEGF therapy whenever the foveal region is involved. Focal laser therapy can be deferred until the foveal edema subsides (to control recurrence) or even while undergoing anti-VEGF therapy. Focal edema that does not involve the fovea may be treated successfully by using focal laser treatment on the leaking microaneurysms.² But, just a few patients present with edema without foveal involvement.

Treatment algorithm for diabetic macular edema
COURTESY JORGE I. CALZADA, MD

Diffuse DME, regardless of the presence of foveal involvement, is usually best treated with anti-VEGF therapy.^3-10 As a general rule, bevacizumab (Avastin, Genentech) is less potent than ranibizumab (Lucentis, Genentech) or aflibercept (Eylea, Regeneron). Aflibercept seems to be more potent in improving diabetic macular edema than ranibizumab. Any of the three agents could be used as a starting therapy for DME, based on severity of disease, availability, insurance or cost. Agents can always be changed in the course of management if the treating physician feels that the potency is insufficient to treat an individual patient or if the clinical response diminishes over time. The DRCR.net Protocol T showed that if a patient has center-involving DME and the presenting visual acuity is approximately 20/40 or better, there was no statistical difference in visual improvement between aflibercept, ranibizumab, and bevacizumab. However, if the presenting vision is about 20/50 or worse, consider aflibercept, as it’s been shown to be superior in visual acuity gains at one year after treatment initiation.⁹

If the patient shows no improvement after the first injection, most retina specialists will continue treating with monthly intravitreal anti-VEGF agents for about three more consecutive visits before considering other treatment modalities.

Most patients will demonstrate and maintain significant improvement with continued monthly anti-VEGF therapy. Often the biggest challenge with chronic therapy over 6-12 months is not the lack of efficacy of the medication, but the reluctance of patients to continue with monthly or near monthly injections. If there is a co-existing epimacular membrane, surgical peel of the membrane with or without internal limiting membrane (ILM) peel can decrease the need for further anti-VEGF injections.

When no epimacular membrane exists but the need for chronic therapy does — or when there is incomplete resolution of DME — the surgeon can consider other treatment modalities.

Wide-angle angiography can determine the presence and location of retinal nonperfusion due to capillary closure. Panretinal photocoagulation laser directed to the areas of nonperfusion may decrease the production of VEGF due to ischemic retina and decrease in turn the need or intensity of anti-VEGF therapy.¹¹ Given the potential complications of steroid glaucoma and cataract formation associated with intravitreal steroids, we reserve this modality as a third-line therapy.^12,13 Finally, if all other modalities have been attempted or are not feasible for the patient, performing a pars plana vitrectomy with peeling of the internal limiting membrane (even in the absence of an epimacular membrane) could improve or control chronic DME.¹⁴

Conclusion

Fortunately, most cases of DME do not require treatment escalation beyond second-line therapy. When initiating treatment with an anti-VEGF agent, physicians must educate their patients on the importance of having close, reliable follow-up as to ensure an optimal outcome. Patients also benefit from knowing that, while frequent injections per month may be required during the initiation phase of treatment. Once the edema resolves, most will not need more than four to six injections per year. It is also vital to ensure that patients have close follow-up with their primary care physicians or endocrinologists to improve their glycemic control. By doing this, patients will not only decrease the risk of progression of their diabetic retinopathy, but more importantly, will decrease the significant morbidity and mortality associated with uncontrolled hyperglycemia. OM

REFERENCES

About the Authors
	Dr. Hood is completing his vitreoretinal surgery fellowship at the Charles Retina Institute in Memphis, Tenn. He is also an instructor at the Hamilton Eye Institute of the University of Tennessee. Contact Dr. Hood at miphood@gmail.com.
	Dr. Calzada is a vitreoretinal surgeon and President of Charles Retina Institute in Memphis, Tenn. He specializes in macular diseases, complex retinal detachment repair and pediatric retina surgery.
	Disclosures: Dr. Hood has no financial relationships to disclose.
	Dr. Calzada has financial relationships with AbbVie, Alcon, Genentech and Regeneron.