Diabetic macular edema treatment guidelines in India: IJO (Part 1)

A large variety of therapeutic strategies are now available to manage DME: macular laser photocoagulation, intravitreal pharmacotherapy (anti-VEGF and steroids), and surgical intervention. Diverse approaches may be required to treat DME depending on the location, type, and associated morbidities and complications.

A set of guidelines was developed to standardize the treatment options to avoid variations in the management of DME. A consensus from a Delphi survey and evidence base from randomized controlled trials were used to inform best practices in India. Considerations were given to out-of-pocket expenses incurred for the treatment and the compliance required for optimal treatment benefit. This review by Giridhar S and team discussed the management of DME in different situations such as noncenter-involving macular edema (NCI-DME), center-involving macular edema (CI-DME), DME with other associated ocular problems, and DME with systemic comorbidities.

Evaluation of a patient with DME

A detailed ophthalmic examination should include the following information:

A. Ocular and systemic history

B. Visual acuity (LogMAR or ETDRS chart) for distance and near vision

C. Fundus examination (with 90D/78D/Indirect Ophthalmoscopy)

D. Color fundus photography (posterior pole and 4‑field or wide‑field)

E. Fundus fluorescein angiography (FFA) at baseline to provide the overall and macular capillary nonperfusion (CNP)

F. Optical coherence tomography (OCT)

G. Optional - Optical coherence tomography angiography (OCTA) may be done to rule out macular ischemia.

Management of noncenter‑i n v o l v i n g m a c u l a r edema (NCI‑DME)

• Treatment naïve NCI‑DME

Any DME not involving the fovea is classified as NCI‑DME. On OCT, the retinal thickening involves any 1 or more of the noncentral fields on the ETDRS grid. Retinal thickening is defined as above the threshold (>320 µm) and central subfield thickness (CST) of less than normal +2 SD (machine‑specific). This subgroup of patients can present with good visual acuity. However, the progression of NCI-DME to CI-DME in the first year is generally low (14%). Systemic factors such as hyperglycemia, hyperlipidemia, and hypertension are risk factors for progression to CI-DME.

Treatment for naïve NCI-DME:

• NCI‑DME with good vision (6/6‑6/9) can be observed with monthly follow-up

• NCI‑DME with BCVA <6/9 attributed to macular edema can be treated with macular laser if it meets the CSME criteria. Focal laser is performed targeting leaking microaneurysms shown on FFA in areas of thickening between 500–3000 µm from the center of macula

Conventional argon laser is absorbed by the melanin pigments in RPE, leading to protein denaturation and atrophy. However, intense whitening of the retinal burns is best avoided. In subthreshold micropulse laser, energy is delivered in many repetitive short impulses. The laser power is set at a low level so that it does not form any visible lesion on the retina.

Clinical signs with poor visual prognosis that coexist with DME include subfoveal plaque, fibrosis and macular pigmentary changes, and these should be recorded and prognosis explained to the patient. Macular laser is unlikely to benefit in these situations and should only be done with caution.

NCI‑DME after intravitreal injections for CI‑DME

Patients may have persistent NCI-DME after treating CI-DME with anti-VEGFs or steroid therapy. BCVA plays an important role in decision-making.

1. In eyes with BCVA of 6/9 or better, it is best to observe the patients on a 2 monthly basis. The follow-up can gradually be increased to a maximum of 4 months if vision stays stable and there is no progression to CI-DME.
2. In eyes with BCVA worse than 6/9, macular laser (focal/ grid laser) may be considered if it meets CSME criteria. These patients can then be followed up after a month with the follow-up interval then doubled to a maximum of 4 months. Those who fail to respond to macular laser can be planned for a repeat treatment with anti-VEGFs.
3. A plaque of hard exudates may deposit at the macula, close to the fovea, which carries a poor prognosis, and this should be explained to the patient before embarking on any therapy. Intravitreal steroids (triamcinolone acetonide or dexamethasone) have been reported as an option to reduce the exudates, but its effects are equivocal. Potential risk of glaucoma and cataract (in phakic eyes) should be assessed prior to steroid injection. In the absence of macular thickening, repeat injection of anti-VEGF for persistent exudates may resolve the exudates, but improvement ofvision is unlikely. These patients should be evaluated for control of systemic status especially serum lipids and treated with lipid-lowering drugs as per the advice of the physician.

Management of center‑involving diabetic macular edema (CI‑DME)

Treatment of naïve CI‑DME

Intravitreal injections (IVI) of anti‑VEGF agents are the first line of treatment for naïve CI-DME. Multiple clinical trials have demonstrated that anti‑VEGF therapy is more effective in improving vision in CI-DME than macular laser treatment, supplanting it as the first‑line therapy for CI‑DME. The standard doses for the IVI anti-VEGF pharmacotherapies are ranibizumab (Lucentis/Accentrix/biosimilar) – 0.5 mg/0.05 ml, bevacizumab (Avastin) – 1.25 mg/0.05 ml, and aflibercept (Eylea) – 2 mg/0.05 ml).

The Diabetic Retinopathy Clinical Research Network(DRCR) protocol for CI-DME starts with monthly IVI for 4–6 months initially and then allows for holding on treatment if there is no improvement in vision or central subfield thickness, or if 6/6 Snellen vision and/orthe resolution of DME has been achieved.

Anti-VEGF treatment can be resumed if there is a worsening vision or CST on subsequent visits. If on consecutive visits, treatment is not required, the follow‑up interval is doubled up to 4 months. This approach has been demonstrated to reduce the number of injections while delivering excellent VA gains.

Treatment is deferred when vision has improved to 6/6 and the OCT has become normal (normal foveal contour with reduction of retinal thickening at the macula, regression of the neurosensory detachment, and disappearance of cystic spaces in the neurosensory retina). An alternative approach to reducing the injection burden is a treat-and-extend regimen, wherein the interval between visits is adjusted based on the treatment response.

Stopping anti‑VEGF therapy

No further improvement is defined as a <10% decrease in the central subfield thickness on OCT and a <1 line improvement in VA on the Snellen chart after the last injection, and in the opinion of the treating ophthalmologist, no further benefit can be expected with additional treatment. In eyes with vision better than or equal to 6/7.5 and persistent DME, treatment can be withdrawn and the patients kept under observation, reinstituting treatment if DME recurs.

Recurrent DME

In eyes that develop recurrent DME after complete resolution following multiple anti-VEGF injections, it is preferable to continue the same treatment if vision continues to improve with a progressive decrease in CST.

Nonresponders to anti‑VEGF therapy

The most common reason for nonresponse to anti-VEGF therapy is due to inadequate treatment as per the above protocol. In eyes with persistent DME and VA <6/12, a different anti‑VEGF may be considered. If the patient has been on bevacizumab, a switch to ranibizumab or aflibercept is recommended; if on ranibizumab, a switch to aflibercept is advised.

Intraocular steroids, preferably implants, can be considered in some situations and patients who have persistent DME despite anti‑VEGF therapy might benefit from this treatment. The DRCR.net Protocol I and Protocol T have demonstrated the percentage of patients who continue to have macular edema after six months of treatment.

Switching to intravitreal steroids can be considered in the following situations:

1. Responding to anti‑VEGFs but difficult to maintain frequent follow-up visits

2. Pseudophakic patients who have reached a plateau – persistent intraretinal fluid (IRF)/VA <6/12

3. Persistent edema and needing cataract surgery

4. Occurrence of systemic vascular event while on anti-VEGFs

5. Associated features such as extensive hard exudates and presence of hyperreflective dots on OCT

6. Eyes post vitrectomy

Additional laser photocoagulation to treat persistent edema (considered after 4–6 injections) may also be considered for the following:

1. Persistent CSME with visible microaneurysms

2. If a switch to steroid is not possible (glaucoma/young phakic patient), grid +/− focal laser may be applied to areas of retinal thickening

Role of vitrectomy in DME

Patients with recalcitrant DME may benefit from vitrectomy surgery. These include DME with predominantly vitreomacular traction or tractional epiretinal membrane (ERM) or a taut posterior hyaloid. Through the removal of adherent posterior hyaloid, vitreomacular traction (VMT), and ERM, the anteroposterior and tangential traction is released, resulting in better oxygenation to the inner retina, which may improve capillary blood flow in the perifoveal area and reduce hypoxia-induced VEGF drive.

In addition, histamine, VEGF, and free radicals have been shown to be decreased in the preretinal space after vitrectomy. An attached vitreous also has an adverse effect on the clinical response of DME. However, vitrectomy may result only in structural improvement with nonsignificant visual improvement.

There is little evidence to support vitrectomy as a treatment for DME in the absence of vitreomacular traction and laser; anti-VEGFs or steroids should be considered as the treatment of choice.

Control of systemic risk factors

Strict glycemic and blood pressure control remains the hallmark of prevention and progression of DME. It is also important to assess the renal status and refer to a physician for adequate control.

Glitazones and underlying hematological disorders, such as idiopathic thrombocytopenic purpura or multiple myeloma, can also result in persistent DME. Reevaluation of the systemic status especially hypertension, anemia, and renal status in patients with bilateral neurosensory detachments at the fovea unresponsive to treatment is recommended.

A rapidly progressing DR or a bilateral central retinal vein occlusion may be due to blood dyscrasias, and a complete hemogram with peripheral blood smear is also recommended.

Source: Giridhar S, Verma L, Rajendran A, Bhende M, Goyal M, Ramasamy K, et al. Diabetic macular edema treatment guidelines in India: All India Ophthalmological Society Diabetic Retinopathy Task Force and Vitreoretinal Society of India consensus statement. Indian J Ophthalmol 2021;69:3076-86.