Diabetic macular edema treatment guidelines in India: IJO (Part 2)

Proliferative diabetic retinopathy (PDR) with DME

Both PDR and DME are distinct patterns of retinal microvascular features that reflect small‑vessel disease. Among patients with T2DM, the presence of DME in PDR can be associated with an increased risk of incident cardiovascular disease.

Treatment naïve PDR should be treated with pan-retinal photocoagulation (PRP). In the presence of extra macular traction, PRP should be done 2DD away from the traction and DME treated as per standard protocol. In the presence of vision-threatening traction, vitrectomy is indicated in addition to PRP. The presence of traction, threatening, or involving fovea is an indication for surgery. One must assess the extent of traction and vascularity of the proliferation as anti-VEGFs in such situations should be avoided as it can lead to worsening of traction or Crunch syndrome.

In presence of a vitreous hemorrhage, where the view of the retina is compromised, a B Scan should be done to rule out traction at the macula. In presence of traction, a vitrectomy is indicated. In absence of traction, PRP should be done to the extent and area possible. Anti-VEGFs can be used to treat DME and may prevent re-bleed from neovascularization elsewhere in the eye. Nonresolving vitreous hemorrhage requires vitrectomy. The renal status should be evaluated in eyes with sudden onset of bullous or exudative retinal detachment post PRP.

DME in pseudophakic eyes

Macular edema (ME) may be secondary to many retinal diseases. Therefore, before treatment is initiated, it is necessary to differentiate DME from pseudophakic cystoid macular edema (PCME)/Irvin–Gass syndrome.

By performing an OCT before cataract surgery in eyes with suspected DME, one can anticipate DME or progression of DME following surgery. On FFA, pseudophakic edema will show a diffuse petaloid type of leakage with disc leakage, with the absence of microaneurysms and hard exudates around the edema. The presence of hard exudates, microaneurysms, or DR in the other eye strongly favor DME.

In the presence of DME with no component of Irvine–Gass syndrome, treatment with anti-VEGFs can be initiated for CI-DME. First-line treatment with topical or subtenon's steroids is recommended for pseudophakic edema. In the presence of both DME and Irvine–Gass syndrome topical nonsteroidal anti‑inflammatory drugs (NSAIDs) should be used followed by anti-VEGFs. In nonresponders who have already been treated with anti-VEGFs (after 3–6 injections), it is reasonable to switch to steroids.

DME during pregnancy

With the increase in the prevalence of T2DM in the younger age group and increasing gestational age worldwide, there is a proportional increase in the number of pregnant women with diabetes. The prevalence of DR in early pregnancy in T2DM is estimated at 14%. While gestational diabetes is not associated with an increased risk of developing DR, those with undiagnosed T2DM may present with DR during or after pregnancy.

All pregnant women should be screened for DR every trimester during pregnancy. If DR has progressed in the third trimester, monitoring should be continued in the postnatal period up to 12months. Communication and close collaboration between obstetricians and ophthalmologists is mandatory. Counseling regarding the effect of pregnancy on DR should ideally be initiated before pregnancy.

DME has been reported to spontaneously regress post-partum. Therefore, a period of close observation may be reasonable. However, if there is a progressive deterioration of vision, the use of intravitreal steroids, particularly dexamethasone implants, is recommended. However, the patients should be fully informed about the possibility of cataract associated with the use of steroid implants.

PDR in pregnant women must always be treated, given the risk of progression and the difficulties faced with multiple visits. Treatment should ideally be started before the onset of pregnancy, especially for severe NPDR and PDR and therefore stabilized prior to conception. The use of IVI anti-VEGFs in pregnancy is not recommended because of potential effects on developing embryos or fetus. It is therefore recommended that women should wait at least 3 months after the last intravitreal injection before conceiving.

DME in type I diabetes

Although DME is considered to be more prevalent in T2DM, the Diabetes Control and Complications Trial (DCCT) reported that 27% of the individuals with type 1 diabetes (T1DM) developed DME within 9 years of onset of diabetes.

Management of DME in T1DM is similar to that in T2DM; however, they need more frequent and regular monitoring by the diabetologist/endocrinologist for glycemic control. Puberty is a well-known risk factor for DR in T1DM, and DR and DMEcan progress rapidly during pregnancy especially in T1DM.

Data from the DCCT showed that severity of retinopathy was associated with increased triglycerides and inversely associated with high-density lipoprotein (HDL) in T1DM. Higher serum lipids have also been shown to be associated with an increased risk of CSME and retinal hard exudates in T1DM.

Diabetic ketoacidosis (DKA) in T1DM may present with bilateral DME aggravated by fluid overload that resolves without any active ocular intervention. Therefore, systemic evaluation is very important in those with T1DM presenting with DME. The use of IVI of anti-VEGFs in children is limited and most reports are on the management of retinopathy of prematurity. Anti-VEGFs are well tolerated in this group; however, compliance is more challenging than in adults, and extra efforts should be made to counsel these patients.

DME in vitrectomized eyes

Eyes with macular edema after vitrectomy are likely to have poorer initial VA, thinner central macular thickness, greater prevalence of PDR, prior treatments as laser photocoagulation or other treatments for DME, prior cataract surgery, and longer duration of diabetes. Considering these factors, treatment for DME in a vitrectomized eye is challenging. Studies suggest secretion of type II procollagen and a lack of high molecular weight hyaluronan following pars plana vitrectomy. The pharmacokinetic parameters of IVI of anti-VEGFs may hence be affected as the ambience of the vitreous cavity is altered.

Intravitreal steroids are effective in these eyes. Intravitreal dexamethasone implant has also been shown to have similar efficacy in both vitrectomized and nonvitrectomized eyes. In pseudophakic eyes with CI-DMI, intravitreal steroids can be considered as the first choice in suitable cases. Fluocinolone implant (Ileuvin) has also been shown to be effective in vitrectomized eyes.

Based on current evidence, both anti-VEGFs and steroids have their role in the treatment of DME in vitrectomized eyes

DME in the presence of macular ischemia

Ischemic maculopathy may also explain poor vision despite adequate treatment for associated DME. An enlarged foveal avascular zone (FAZ) or irregular margin of FAZ on FFA are well‑defined signs of macular ischemia. However, the best parameter to assess macular ischemia on OCT-A is unclear. Macular laser photocoagulation should be avoided in eyes with diabetic macular ischemia. These eyes should be treated with anti-VEGFs or steroids for the associated DME.

DME in glaucomatous eyes

The management of DME in eyes with established glaucoma or those being treated for ocular hypertension or steroid responders should preferably be carried out with either macular laser or anti-VEGFs. Intraocular pressure (IOP) should be monitored regularly after each intravitreal injection and preoperative IOP-lowering agents should be used to prevent spikes in pressure. The use of steroids should be avoided in these patients. If necessary, augmentation of anti-glaucoma medications may be needed.

DME with cataract

Visually disabling cataract can coexist with DME. Where possible, DME should be stabilized before cataract surgery. Patients should be counseled on the visual outcome following cataract surgery as the vision may not be as good as those without DR. In some cases, complete resolution of DME may not be achieved, and it is advisable to progress with concurrent or post-cataract surgery IVI anti-VEGFs or steroid therapy. In the presence of clinically significant cataracts with poor view of the fundus and preexisting DME, surgery can be planned along with IVI anti-VEGFs or steroids.

Treatment can also be planned 2 weeks after surgery and subsequent protocol continued. Postoperative topical NSAIDs are also recommended to prevent pseudophakic macular edema. NdYAG laser capsulotomy may also be required during the course of therapy for DME and no extra precautions need be taken. However, visual prognosis must be explained.

DME with optic nerve abnormalities

Optic nerve abnormalities may rarely complicate the clinical picture of DME. DME can coexist with diabetic papillopathy or anterior ischemic optic neuropathy (AION). Diabetic papillopathy is usually not associated with visual field defects and afferent pupillary defects; it has a milder visual loss and invariably resolves spontaneously with good diabetic control and results in negligible residual visual debilitation.

Malignant hypertension-associated disc edema could be discerned with a blood pressure assessment. FFA plays an important role in differentiating AION from diabetic papillopathy with AION showing early disc hypofluorescence due to hypoperfusion with late leakage around the affected segment. In contrast, a very early disc leakage that increases with time is seen in diabetic papillopathy. FFA will also show other features of DR. Treatment should be based on the primary underlying cause.

DME with mixed retinopathy

Hypertension is one of the commonest comorbidities associated with diabetes, and hypertensive retinopathy can often coexist with DR and has inspired the term "mixed retinopathy." Elevated blood pressure is an independent risk factor for both development and subsequent progression of DR. Macular star exudates is a classic feature seen in hypertensive retinopathy. Malignant hypertension is evidenced by disc edema with peripapillary hemorrhages and edema. It is of paramount importance to differentiate mixed retinopathy from other vascular diseases such as central retinal vein occlusion and ocular ischemic syndrome. Prompt control of hypertension should be advised by all ophthalmologists.

DME with lattice degenerations

Retinal detachment is a rare complication of intravitreal injections. The vitreous in diabetic patients undergo structural changes and enzymatic vitreolysis. Both IVI anti-VEGFs and increasing age are risk factors for posterior vitreous detachment. Therefore, careful examination of the periphery and prophylactic treatment of any lesions that could predispose to retinal detachment is advisable. The interval between laser prophylaxis and anti-VEGFs should ideally be 3 weeks.

Blepharitis and external eye infection

People with diabetes are more susceptible to any infection, including ocular infection. The presence of blepharitis was shown to be a significant risk factor for endophthalmitis following intravitreal injections. Therefore, it is recommended that any active external infection including blepharitis should be treated prior to anti-VEGF therapy. In addition, eyelid checks before the injection, avoidance of subconjunctival anesthesia, and administration of povidone-iodine and topical antibiotics immediately after intravitreal injection are important steps to avoid endophthalmitis.

Managing DME in patients with other systemic problems

DME and dyslipidemia

Increased levels of total cholesterol, triglycerides, and low-density lipoproteins, as well as low high-density lipoproteins, have been implicated in the pathogenesis of DME. These observations led to studies testing lipid‑lowering drugs such as fenofibrate and simvastatin in reducing the severity of DME and progression of DR. The beneficial effects of fenofibrate on DR progression and incidence of treatable DME were observed in people with normal lipid levels, suggesting that the effects of fenofibrate may not be due to the lipid‑lowering effects of the drug. Lipid-lowering therapy has also been shown to reduce the severity and foveal migration of hard exudates in DME. The beneficial role of lipid‑lowering drugs in the management of DME and DR is emerging from real-world scenario studies

DME and anemia

Anemia has been indicated as an independent factor for the early progression of diabetes-related complications and is considered to worsen DME. Studies have shown that hemoglobin levels of <12 g/dL result in doubling the risk of DR. The majority of patients with anemia have an underlying renal dysfunction, which affects the production of erythropoietin (EPO). EPO enhances the function of the blood–retinal barrier, increases oxygenation, and protects against the damaging effects of VEGF, and may also have a neuroprotective role in the retina. Treatment with subcutaneous EPO injections has been shown to improve DME. However, EPO may also have an aggravating role as it has been shown to be important in the angiogenic processes in DR, especially at the proliferative stage. Additionally, anti‑VEGF injections may be required in presence of center-involving DME.

DME and renal disease

The association between DR and renal disease has been extensively studied, including the influence of nephropathy on treatment outcomes in DME. The hallmark of established diabetic nephropathy is persistent albuminuria (category A3, severely increased) with coexisting DR, with no evidence of alternative kidney disease.

In TIDM, a clinical diagnosis of diabetic kidney disease can be made when there is persistent moderate (A2) or severe (A3) albuminuria or a persistent reduction in estimated glomerular filtration rate (eGFR) to60 mL/min/1.73 m2, occurring at least 5 years after the onset of diabetes. DR will also be present in over 95% of cases. Albuminuria does not have to be present to make a diagnosis providing eGFR is persistently<60 mL/min/1.73 m2 .

DME with cardiovascular disease (CVD)

DME and DR are associated with increased risk of incident CVD, which includes coronary heart disease, stroke, or death from cardiovascular causes. Persons with DME or PDR were more likely to have incident CVD and fatal CVD compared with those without DME or PDR. Treatment with anti-VEGFs should not be initiated if a patient had a stroke (cerebrovascular accidents) or myocardial infarction within the previous 3 months; PRP or steroid treatments should be considered in these patients. However, if the event occurred more than 3 months previously treatment with anti-VEGFs can be initiated. However, if systemic risks of thromboembolic phenomenon are significant, it is best to consult a physician first.

DME in patients with hypertension

The presence of neurosensory detachment and retinal thinning on OCT and fluctuations in central retinal thickness indicate associated poor blood pressure control. Renal disease-associated hypertension and anemia need to be controlled prior to considering intravitreal anti-VEGFs. It is preferable to avoid anti-VEGF in uncontrolled hypertension. Risk of vascular events increases if blood pressure is >180/110 mm Hg. While the risk of vision loss is particularly high if anti-VEGF agents are avoided for too long, it is preferable to defer any intravitreal injection until control of blood pressure; in addition, patients and physicians should be advised on the urgency to initiate treatment for DME. In eyes with DME that respond favorably to anti-VEGF agents, controlling blood pressure can have a further beneficial effect and hence should be encouraged.

DME in patients with uncontrolled diabetes

Poor glycemic control is an independent marker for the progression of DR and DME. Strict glycemic control is useful at any stage of DR. Poor or fluctuating glycemic control can alter the compliance of regular monthly intravitreal injections. Other systemic comorbidities in people with diabetes, such as diabetic kidney disease, uncontrolled hypertension, and cardiovascular disease, can also affect the adherence to follow‑ups following anti-VEGFs.

DME is preventable to some extent, and there is a need to optimize the control of systemic factors, including hyperglycemia, hyperlipidemia, and blood pressure. Thus, the care should be done holistically by a multidisciplinary team with the physician or an endocrinologist, internal medicine specialist or primary care physician being the center of a patient's care. There have been significant advances in the management of DME. However, DME management remains suboptimal in many patients with diabetes. The recommendations given are based on expert evaluation, and current evidence and aim to help guide the optimal choice of treatment and regimen for DME in India. Though anti‑VEGFs are the first line of management, coexisting ocular diseases and associated comorbidities may alter the management strategy.

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.