Macular Edema in Diabetes 

Updated: Sep 07, 2018
Author: Emmanouil Mavrikakis, MD, PhD; Chief Editor: Andrew A Dahl, MD, FACS 

Overview

Practice Essentials

Macular edema in diabetes, defined as retinal thickening within 2 disc diameters of the center of the macula, results from retinal microvascular changes that compromise the blood-retinal barrier, causing leakage of plasma constituents into the surrounding retina and, consequently, retinal edema.[1]

Focal edema is associated with hard exudate rings caused by leakage from microaneurysms. Diffuse edema is caused by leakage from microaneurysms, retinal capillaries, and arterioles.

Diabetes is the leading cause of new blindness in the United States, with clinically significant macular edema (CSME) contributing greatly to this vision loss.

Signs and symptoms

The following findings indicate the presence of clinically significant macular edema (CSME), as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS):

  • Retinal thickening within 500 µm of the center of the fovea

  • Hard, yellow exudates within 500 µm of the center of the fovea with adjacent retinal thickening

  • At least 1 disc area of retinal thickening, any part of which is within 1 disc diameter of the center of the fovea

See Clinical Presentation for more detail.

Diagnosis

Diabetic macular edema (DME) is diagnosed by funduscopic examination. The following studies can also be performed, to provide information for treatment and follow-up:

  • Optical coherence tomography (OCT): Captures reflected light from retinal structures to create a cross-sectional image of the retina, which is comparable to histologic sections as seen with a light microscope; it can demonstrate 3 basic structural changes of the retina from diabetic macular edema: retinal swelling, cystoid edema, and serous retinal detachment

  • Fluorescein angiography: Distinguishes and localizes areas of focal versus diffuse leakage, thereby guiding the placement of laser photocoagulation

  • Color stereo fundus photographs: Can be used to evaluate long-term changes in the retina

Visual acuity should also be measured. Although it does not aid in the diagnosis of CSME—initially, at least, patients may have a visual acuity of 20/20—it is an important parameter in following the progression of macular edema.

Laboratory studies

  • Protein levels: Proteinuria is a good marker for the development of diabetic retinopathy; thus, patients with diabetic nephropathy should be observed more closely

  • Lipid and triglyceride levels: Elevated triglyceride and lipid levels increase the risk of retinopathy, while normalization of lipid levels reduces retinal leakage and deposition of exudates

See Workup for more detail.

Management

Pharmacologic treatment

Intravitreal treatments for macular edema include the following:

  • Triamcinolone acetonide: Significantly reduces macular edema and improves visual acuity, particularly when the macular edema is pronounced[2, 3, 4]

  • Ranibizumab: Recombinant humanized antibody fragment that is active against all isoforms of vascular endothelial growth factor (VEGF) ̶ A (a protein that causes breakdown of the blood-retina barrier)

  • Fluocinolone intravitreal implant: Significant improvement in visual acuity maintained for 36 months

Laser treatment

Laser photocoagulation is a well-proven therapy to reduce the risk of vision loss from diabetic macular edema. Treatments include the following:

  • Focal treatment: Addresses leaking microaneurysms

  • Grid pattern photocoagulation: Used for diffuse leakage

See Treatment and Medication for more detail.

Background

The Early Treatment Diabetic Retinopathy Study (ETDRS) set the guidelines for the treatment of diabetic macular edema (DME). Since that time, the standard of treatment for diabetic macular edema has been glycemic control as demonstrated by the Diabetes Control and Complications Trial (DCCT), optimal blood pressure control as demonstrated by the United Kingdom Prospective Diabetes Study (UKPDS), and macular focal/grid laser photocoagulation.

In ETDRS, laser photocoagulation reduced the risk of moderate visual loss from diabetic macular edema by 50% (from 24% to 12% 3 years after initiation of treatment).[1] Nevertheless, some patients suffer permanent visual loss even after intensive treatment.

Over the past few years, research has started to focus on the use of anti-vascular endothelial growth factor (VEGF) therapy to treat DME. As new and promising treatment options emerge, these treatments will need to be reevaluated.

It is imperative for patients with diabetes to understand that a healthy lifestyle and compliance with medical care can greatly reduce the development and progression of complications of their disease, in the eyes as well as other organs.

For patient education information, see the Diabetes Center, as well as Diabetic Eye Disease.

For further clinical information, see the Medscape Reference articles Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, and Diabetic Retinopathy.

Pathophysiology

Diabetic macular edema results from retinal microvascular changes. Thickening of the basement membrane and reduction in the number of pericytes are believed to lead to increased permeability and incompetence of the retinal vasculature. This compromise of the blood-retinal barrier leads to the leakage of plasma constituents into the surrounding retina, with subsequent retinal edema.[1] Hypoxia produced by this mechanism can also stimulate the production of vascular endothelial growth factor (VEGF). There is evidence that VEGF is up-regulated in diabetic macular edema and proliferative diabetic retinopathy.[5]

A study suggests that the pathogenesis of diabetic macular edema is not only related to VEGF dependency but also to other inflammatory and angiogenic cytokine levels that can be suppressed by corticosteroids.[6]

Epidemiology

Diabetes is the leading cause of new blindness in the United States, and clinically significant macular edema (CSME) contributes greatly to this vision loss. In the absence of ophthalmologic treatment, persons with diabetes have a 25-30% risk of moderate vision loss. With treatment, the risk drops by 50%. According to 2007 data, 23.6 million people in the United States have diabetes, but only 17.9 million have been diagnosed.[7] . About 50% of those with diagnosed diabetes do not receive appropriate eye care. The World Health Organization estimates that worldwide, more than 150 million people have diabetes.

Although diabetes is more common in Hispanics, African Americans, and Native Americans than in whites, no data describe a greater risk of developing macular edema among diabetic patients of any one racial group. Likewise, no data describe a difference in risk of diabetic macular edema between the sexes.

Diabetic retinopathy, not specifically diabetic macular edema, generally occurs in persons older than 40 years. It rarely occurs before puberty.

 

Presentation

History

Specific inquiry should be made into risk factors for the development of diabetic retinopathy. These include the type of diabetes, the duration, and the degree of control. After 20 years of disease, nearly all patients with type 1 and 60% of patients with type 2 diabetes have some degree of retinopathy. The risk increases with the duration of disease. Hence, diabetic retinopathy is more likely to be present in patients older than 40 years.

The Diabetes Control and Complications Trial (DCCT) clearly demonstrated that tighter control of blood sugar is associated with reduced incidence of diabetic retinopathy. Glycosylated hemoglobin [HbA1c] should be less than 7%.

Proteinuria is a good marker for the development of diabetic retinopathy; thus, patients with diabetic nephropathy should be observed more closely. Elevated blood pressure increases the risk of retinopathy; patients with diabetes and hypertension may develop diabetic retinopathy with superimposed hypertensive retinopathy. Elevated triglyceride and lipid levels increase the risk of retinopathy, while normalization of lipid levels reduces retinal leakage and deposition of exudates.

Finally, diabetic retinopathy can progress rapidly in pregnant women, especially those with preexisting diabetic retinopathy.

Physical Examination

Funduscopy under stereopsis and high magnification should be performed on every patient with diabetes to assess for diabetic macular edema (DME) and diabetic retinopathy. An indirect ophthalmoscope does not provide adequate magnification for the diagnosis of diabetic macular edema.

Diabetic macular edema is defined as retinal thickening within 2 disc diameters of the center of the macula. Focal edema is associated with hard exudate rings resulting from leakage from microaneurysms. Diffuse edema results from breakdown of the blood-retinal barrier with leakage from microaneurysms, retinal capillaries, and arterioles.

Clinically significant macular edema (CSME), as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS), exists with any of the following findings:

  • Retinal thickening within 500 µm of the center of the fovea

  • Hard, yellow exudates within 500 µm of the center of the fovea with adjacent retinal thickening

  • At least 1 disc area of retinal thickening, any part of which is within 1 disc diameter of the center of the fovea

Visual acuity should also be measured. Although visual acuity does not aid in the diagnosis of CSME—initially, at least, patients may have a visual acuity of 20/20—it is an important parameter in following the progression of CSME.

The status of the posterior hyaloid should also be determined. In CSME, the posterior hyaloid is detached, taut, and thickened.

 

DDx

Diagnostic Considerations

Other problems to be considered in patients with possible diabetic macular edema (DME) include the following:

  • Cystoid macular edema

  • Hypotonic retinopathy

  • Macular pucker

  • Epinephrine use in aphakia

Differential Diagnoses

 

Workup

Approach Considerations

Diagnosis of diabetic macular edema (DME) is made by funduscopic examination. However, other studies can provide valuable information for guiding treatment and for long-term follow-up.

Optical coherence tomography (OCT) captures reflected light from retinal structures to create a cross-sectional image of the retina, which is comparable to histologic sections as seen with a light microscope. OCT has been able to demonstrate a moderate correlation between retinal thickness and best-corrected visual acuity, and it has been able to demonstrate 3 basic structural changes of the retina from diabetic macular edema: retinal swelling, cystoid edema, and serous retinal detachment.

OCT is not currently required to establish a diagnosis and is not prescribed by current practice guidelines; however, OCT has gained widespread acceptance as an additional modality to help identify and evaluate macular pathology.[8] Quantitative measurement of macular thickness and subjective analysis of the foveal architecture allow a precise and reproducible way to monitor macular edema.

Fluorescein angiography does not aid in the diagnosis of clinically significant macular edema (CSME) but should be performed if treatment of CSME is being considered. Fluorescein angiography distinguishes and localizes areas of focal versus diffuse leakage, thereby guiding the placement of laser photocoagulation. The proximity of the leakage to the foveal avascular zone should be noted.

Color stereo fundus photographs provide an opportunity to evaluate long-term changes in the retina.

 

Treatment

Approach Considerations

As with all complications of diabetes, successful management of macular edema requires good control of the diabetes itself.

The Early Treatment Diabetic Retinopathy Study (ETDRS) was the first study to provide a treatment paradigm in this disease using laser therapy to reduce moderate vision loss in patients with clinically significant macular edema by approximately 50%.[9] Although prevention of vision loss is important, visual improvement would be preferable.

Over the past few years, research has started to focus on the use to anti–vascular endothelial growth factor (VEGF) therapy to treat diabetic macular edema (DME). As new and promising treatment options emerge and prospective data begin to mount, it is becoming clearer that anti-VEGF therapy will play an increasing role in the treatment of DME.

A variety of intravitreal medications are currently available, with others under study. Pars plana vitrectomy may also be beneficial.

Medical treatment should focus on optimizing glycemic and hypertensive control and lowering lipid levels. Optimal control of diabetes, blood pressure, and lipids has been shown to positively impact diabetic retinopathy.[10] These issues are best managed by primary care physicians and internists.

Patients should receive follow-up care according to standard practice guidelines. See the American Academy of Ophthalmology Preferred Practice Pattern for Diabetic Retinopathy.

For more information, see the Medscape Reference topics Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, and Diabetic Retinopathy.

Intravitreal Treatment

Intravitreal corticosteroids

Triamcinolone acetonide

Intravitreal triamcinolone acetonide (IVTA) has been shown to significantly reduce macular edema and to improve visual acuity, particularly when the macular edema is pronounced.[2, 3, 4] Action is maximal at 1 week, lasting 3-6 months.

Some studies advocate IVTA as primary therapy, whereas others label it as adjunctive therapy to macular photocoagulation.[11]

Patients should be counseled about the risk (30-40%) of increased intraocular pressure, which usually can be medically controlled. Other adverse effects include a less than 1% chance of retinal detachment, cataract, and endophthalmitis.

Dexamethasone

In July 2014, the FDA approved dexamethasone intravitreal implant (Ozurdex) for diabetic macular edema in patients who are pseudophakic or are phakic and scheduled for cataract surgery.[12] This indication was expanded to include the general DME patient population in September 2014.[13] Approval was based on 2 randomized, multicenter, masked, placebo-controlled, phase III clinical trials with identical protocols. Data from 1048 patients were pooled for analysis. The percentage of patients with ≥15-letter improvement in best-corrected visual acuity (BCVA) from baseline was greater with dexamethasone intravitreal implant 0.7 mg (22.2%) than with placebo implant (12%).[14]

Fluocinolone acetonide

A long-acting fluocinolone intravitreal implant (Iluvien) was approved by the FDA in September 2014 for the treatment of diabetic macular edema in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. Iluvien consists of tiny, cylindrical tube containing fluocinolone acetonide that is implanted in the back of the eye via a 25-gauge needle and that releases submicrogram levels of the drug for 36 months. Possible adverse reactions to the implant include increased ocular pressure and cataract development.[15]

Approval was based on clinical trial data from the Fluocinolone Acetonide for Macular Edema (FAME) studies that showed that, at month 24 after receiving the fluocinolone implant (releases 0.2 mcg/day), 28.7% of patients (P = 0.002) experienced an improvement from baseline in their best corrected visual acuity of 15 letters or more on the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart. Patients treated with the implant experienced a statistically significant improvement in visual acuity compared to the control group by week 3 of follow-up and maintained a statistically significant advantage over the control through completion of the trial at month 36.[16]

Intravitreal anti-VEGF agents

Vascular endothelial growth factor (VEGF) increases retinal vascular permeability, causes breakdown of the blood-retina barrier, and results in retina edema. VEGF is up-regulated in diabetic retinopathy. Currently available anti-VEGF agents in the United States include pegaptanib sodium, ranibizumab, aflibercept, and bevacizumab. Bevacizumab is not commercially available as an intravitreal injection.

Pegaptanib sodium is a pegylated aptamer directed against the VEGF-A165 isoform. It was the first FDA-approved ophthalmologic anti-VEGF agent for the treatment of choroidal neovascularization (CNV) from age-related macular degeneration (ARMD). In a phase 2 prospective clinical trial, it appeared to improve anatomic and visual outcome in patients with diabetic macular edema.[17] Phase 3 trials of pegaptanib sodium for diabetic macular edema are being conducted.

Ranibizumab is a recombinant humanized antibody fragment that is active against all isoforms of VEGF-A. Intravitreal ranibizumab is FDA approved for the treatment of exudative ARMD. In the RESOLVE study (phase 2, placebo-controlled, randomized, multicenter study), 151 patients were randomized 1:1:1 to ranibizumab monotherapy at a dose of 0.3 mg or 0.5 mg or sham treatment. Rescue laser photocoagulation treatment was offered with persistent disease activity after 3 months. Patients received an initial treatment of 3 consecutive monthly injections and were followed monthly with an as-necessary regimen from month 3 to month 12. At month 12, a mean increase in best corrected visual acuity (BCVA) of 11.8 letters in the 0.3-mg group and of 8.8 letters in the 0.5-mg group was noted, as compared with a reduction in BCVA of -1.4 letters in the sham group.[18]

In the READ-2 study (phase 2, randomized multicenter study), 126 patients were randomized 1:1:1 to receive 0.5 mg of ranibizumab, focal/grid laser coagulation, or a combination of ranibizumab and laser. At month 6, the mean gain in BCVA was significantly greater in the ranibizumab monotherapy group, with +7.2 letters, compared with the laser monotherapy group, who lost -0.4 letters and the combination treatment group, gaining only +3.8 letters.[19]

In the RESTORE study (phase 3, laser-controlled, randomized, multicenter study), 345 patients were randomized 1:1:1 to 0.5 mg ranibizumab plus sham laser, 0.5 mg ranibizumab plus active laser, or sham injections with active laser. A treatment initiation phase included 3 consecutive monthly intravitreal injections of either ranibizumab or sham. Subsequently, an as-necessary regimen was followed from month 3 to month 12. The mean change in BCVA from baseline to months 1-12 was +6.1 letters in the ranibizumab monotherapy group, +5.9 letters in the group receiving combination therapy with ranibizumab and laser, and +0.8 letters in the laser alone group.[20]

The Diabetic Retinopathy Clinical Research Network performed a phase 3 randomized multicenter trial randomizing 854 eyes to sham injection plus prompt laser, ranibizumab injection plus prompt laser, ranibizumab injection plus deferred laser, or 4-mg triamcinolone injection plus prompt laser. The 1-year mean change in BCVA was significantly greater in the group receiving ranibizumab plus prompt/deferred laser, with +9 letters, compared with triamcinolone or sham treatment plus laser, with +4 and +3 letters, respectively. In pseudophakic eyes, intravitreal triamcinolone injection plus prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation.[21] The expanded 2-year results are similar to the 1-year results and reinforce the conclusion that ranibizumab should be considered for patients with diabetic macular edema.[22]

Three-year results of this trial were reported in 2012, suggesting that focal/grid laser treatment at the initiation of intravitreal ranibizumab is not better, and may be worse, for vision outcomes than deferring laser treatment for at least 24 weeks in patients with DME involving the fovea and with vision impairment.[23]

The FDA approved ranibizumab (Lucentis) for diabetic macular edema in August 2012. Approval was based on the phase III trials, RIDE and RISE, 2 identically designed, parallel, double-blind, 3-year clinical trials, which were placebo-treatment–controlled for 24 months. A total of 759 patients were randomized into 3 groups to receive monthly treatment with 0.3 mg ranibizumab (n=250), 0.5 mg ranibizumab (n=252), or placebo injection (control group, n=257). Results showed subjects who received 0.3 mg ranibizumab experienced significant, early (day 7), and sustained (24 months) improvements in vision (P< .01).[24]

The following are results from the RIDE and RISE trials:

  • More patients who received ranibizumab were able to read at least 3 additional lines (15 letters) on the eye chart at 24 months (RIDE, 34% in the 0.3-mg group vs 12% in the control group; RISE, 45% in the 0.3-mg group vs 18% in the control group)

  • The ranibizumab group had average vision gains exceeding 2 lines (10 letters) on the eye chart at 24 months (RIDE, 10.9 letters in the 0.3-mg group vs 2.3 letters in the control group; RISE, 12.5 letters in the 0.3-mg group vs 2.6 letters in the control group)

  • Significant gains in average vision were observed 7 days after the first treatment

  • The ranibizumab group was significantly more likely to maintain their vision (lose < 15 letters on the eye chart) at 24 months (RIDE, 98% in the 0.3-mg group vs 92% in the control group; RISE, 98% in the 0.3-mg group vs 90% in the control group)

  • Vision improvements observed with ranibizumab treatment at 24 months were maintained with continued treatment through 36 months

The FDA approved aflibercept for diabetic macular edema in August 2014. It was previously approved for neovascular age-related macular degeneration and macular edema. Approval for DME was based on 2 studies (VISTADME and VIVIDDME) comparing aflibercept with macular laser photocoagulation, in which patients treated with aflibercept were able to read, on average, 2 additional lines on an eye chart, while control patients showed no improvement.[25]

Bevacizumab is a full-length recombinant humanized antibody that is active against all isoforms of VEGF-A. It is FDA approved as an adjunctive systemic treatment for metastatic colorectal cancer. Small, nonrandomized pilot studies have documented some efficacy against diffuse diabetic macular edema. The Diabetic Retinopathy Clinical Research Network conducted a phase 2, prospective, randomized, multicenter clinical trial to determine the safety and possible benefits of this agent. They concluded that intravitreal bevacizumab can reduce diabetic macular edema in some eyes, but the study was not designed to determine whether the treatment was beneficial.[17] A phase 3 trial would be needed for that purpose.

The intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT) study also recently released 12-month data. This is a prospective, single-center, randomized, 2-year trial, enrolling 80 patients with center-involving clinically significant macular edema (CSME) who had received at least 1 prior macular laser treatment, to compare the efficacy of repeated intravitreal bevacizumab with 4 monthly modified macular laser treatments. The mean change in ETDRS visual acuity at 12 months in the laser group was -0.5 letters, while the bevacizumab group gained a mean of 8 letters during the same period.[26] At 24 months the mean change in ETDRS visual acuity was a gain of 8.6 letters for the bevacizumab group compared to a mean loss of 0.5 letters for the macular laser therapy group.[27]

In 2015, the Diabetic Retinopathy Clinical Research (DRCR) Network reported the results of a randomized clinical trial to compare relative changes in visual acuity following 1 year of intravitreal injections of anti-VEGF agents aflibercept, bevacizumab, and ranibizumab for the treatment of diabetic macular edema involving the center of the macula (Protocol T). The mean change in visual acuity at 1 year was greater with aflibercept (+13.3) than bevacizumab (+9.7) or ranibizumab (+11.2). However, this was not clinically significant. The greater overall effect was driven by eyes with initial visual acuity of 20/50 or worse. Mean visual acuity letter score improvement in this subgroup was +18.9 for aflibercept, +11.8 for bevacizumab, and +14.2 for ranibizumab (P values: aflibercept-bevacizumab, < 0.001; aflibercept-ranibizumab = 0.003; ranibizumab-bevacizumab = 0.21). For eyes with and initial visual acuity of 20/32 to 20/40, the mean change was +8.0 for aflibercept, +7.5 for bevacizumab, and +8.3 for ranibizumab (P values: >0.50 for each pairwise comparison). In conclusion, in eyes with decreased visual acuity due to diabetic macular edema, all 3 agents, on average, substantially improved VA. However, the relative effect depends on initial visual acuity. When initial visual acuity loss was mild, there was no apparent differences among the 3 treatment groups. However, the worse the initial visual acuity, the greater the relative advantage of aflibercept over the other two agents.[28]

In 2016, the DRCR Network reported the 2-year results of Protocol T. Overall, at 2 years, aflibercept improved vision more than bevacizumab, but a difference between ranibizumab and aflibercept in terms of outcome was not identified. In eyes with baseline vision of 20/32-20/40, all three agents improved vision similarly. However, in eyes with baseline vision of 20/50 or more, the benefit of aflibercept over ranibizumab was no longer statistically significantly different, while bevacizumab remained inferior.[29]

Laser Treatments

Laser photocoagulation is a well-proven therapy to reduce the risk of vision loss from diabetic macular edema. The Diabetic Retinopathy Clinical Research Network reported results from a multicenter, randomized clinical trial comparing focal/grid laser photocoagulation and intravitreal triamcinolone for the treatment of diabetic macular edema. They concluded that over a 2-year period, focal/grid laser photocoagulation is more effective and has fewer adverse effects than 1- or 4-mg doses of preservative-free intravitreal triamcinolone for most patients with diabetic macular edema.[30]

Studies on all other surgical modalities have been limited in the number of patients and the scope of disease being treated; therefore, these procedures have limited use and questionable efficacy.

The goal of macular laser treatment is to reduce progression of diabetic macular edema; significant visual improvement is uncommon. Photocoagulation has been shown to reduce the risk of moderate visual loss from diabetic macular edema by 50%, from 24% to 12%, 3 years after initiation of treatment.[9]

Laser treatment is most effective when initiated before visual acuity is lost from diabetic macular edema; this emphasizes the need for diligent monitoring and follow-up care.

Laser treatment of diabetic macular edema should precede panretinal photocoagulation (PRP) by at least 6 weeks because the use of PRP before laser treatment may worsen diabetic macular edema. PRP should not be delayed in patients with very severe nonproliferative diabetic retinopathy or high-risk proliferative diabetic retinopathy.

Laser treatment is directed toward areas of leakage that have been identified by examination (areas of retinal thickening) or by fluorescein angiography. The laser produces burns 50-100 µm in diameter. Focal treatment addresses leaking microaneurysms. Grid pattern photocoagulation is used for diffuse leakage. Argon green, krypton yellow, and 532 frequency up-converted diode lasers are used to treat focal lesions. Scatter laser photocoagulation involves placement of multiple argon blue-green or green or krypton red laser burns.

Lesions amenable to laser treatment include the following:

  • Focal leaks greater than 500 µm from the foveal center that are believed to cause retinal thickening or hard exudates

  • Focal leaks 300-500 µm from the foveal center that are causing retinal thickening and hard exudates and have persisted after a first treatment in a patient with visual acuity of less than 20/40, provided that treatment will not destroy the perifoveal capillary network

  • Areas of diffuse leakage: microaneurysms, intraretinal microvascular abnormality (IRMA), or diffusely leaking macular capillary bed

  • Thickened avascular zones, other than the normal foveal avascular zone

It is important to avoid the foveal avascular zone.

Macular thickness and the need for retreatment

In patients with diabetic macular edema, a significant association exists between higher central macular thickness at baseline and the need for at least 3 treatments with a combination of IVTA and laser photocoagulation, according to a study by O’Day et al. In a post-hoc analysis derived from a prospective, randomized, double-blind, placebo-controlled trial (42 patients/42 eyes), the investigators found that half of the study’s patients required 3 or more IVTA/laser treatments, with macular thickness being the only baseline characteristic significantly associated with the number of treatments received.[31]

Day and colleagues suggested that as a result of requiring more treatments, patients with high baseline thickness may be at greater risk for intraocular pressure increase, progression of cataract, and steroid-associated adverse events.

Future Therapies

VEGF Trap-Eye is a soluble VEGF receptor fusion protein that binds all forms of VEGF-A and related placental growth factor (PGF). When administered as a single 4 mg intravitreal injection in a phase 1 study, a marked decrease in central retinal thickness and mean macular volume was noted.

Retisert,[32] a steroid implant (fluocinolone acetonide), was evaluated in patients with diabetic macular edema with good results, but its adverse effect profile was cause for concern (90% of patients developed cataracts, and 40% required glaucoma surgery within 3 y).

Pars Plana Vitrectomy

Many studies suggest that vitreomacular traction or the vitreous itself may play a role in increased retinal vascular permeability.[33, 34] Removal of the vitreous or relief of vitreous traction with vitrectomy may, in some patients, be followed by resolution of macular edema and corresponding visual rehabilitation. However, this treatment may be applicable only to a specific subset of eyes with diabetic macular edema.

Patients with refractory clinically significant macular edema (CSME) and a taut posterior hyaloid face who have not responded to macular laser treatment may benefit from a vitrectomy, with possible significant improvement in visual acuity.[33]

In eyes with diffuse diabetic macular edema without posterior vitreous detachment, vitrectomy with posterior vitreous detachment may be effective in resolving the diabetic macular edema and may lead to an increase in visual acuity.[34]

Complications

Adverse effects and complications of laser use are related mostly to either misdirected light or excessive energy, both of which are generally preventable with operator familiarity with standard treatment parameters.

Subretinal fibrosis is a vision-threatening condition, which occurred in 2% of eyes with diabetic macular edema in the Early Treatment Diabetic Retinopathy Study (ETDRS).[35] Subretinal fibrosis is an elevated mound or flat sheet of grey or white tissue deep to the retina at or near the center of the macula. On fluorescein angiography, this lesion is hyperfluorescent in the capillary phase with persistence into the late phase and diffusion of dye. Subretinal fibrosis is associated most strongly with very severe hard exudates. It also is associated with a poor lipid profile. A previously proposed association with laser treatment has not been demonstrated in studies. The prognosis for patients with this complication is poor; subretinal fibrosis is generally refractive to focal laser therapy.

Residual massive foveal hard exudates may remain after the resolution of diabetic macular edema and may be associated with profound and irreversible vision loss. In one study, aspiration of hard exudates following a small retinotomy and serous neurosensory detachment resulted in an increase of visual acuity in 5 of 7 patients.[36]

 

Medication

Medication Summary

As with all complications of diabetes, successful management of macular edema requires good control of the diabetes itself. A variety of intravitreal medications are currently available, with others under study. Medical treatment should focus on optimizing glycemic and hypertensive control and lowering lipid levels.

Corticosteroids, Ophthalmic

Class Summary

Corticosteroids such as triamcinolone have anti-inflammatory effects and can be used for the treatment of diabetic macular edema.

Triamcinolone acetonide (Triesence)

Triamcinolone is a synthetic corticosteroid with anti-inflammatory effects. It is indicated for several ophthalmic diseases such as ocular inflammatory conditions and visualization during vitrectomy. Intravitreal triamcinolone is also being used in the treatment of diabetic macular edema.

Dexamethasone intravitreal implant (Ozurdex)

Dexamethasone intravitreal implant is indicated for the treatment of diabetic macular edema.

Fluocinolone intravitreal implant (Iluvien)

Corticosteroids are thought to act by inhibition of phospholipase A2 via induction of inhibitory proteins collectively called lipocortins; it is postulated that these proteins control biosynthesis of potent mediators of inflammation (eg, prostaglandins, leukotrienes) by inhibiting release of the common precursor, arachidonic acid. It is indicated for diabetic macular edema in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure.

Anti-VEGF Agents

Class Summary

Vascular endothelial growth factor (VEGF) increases retinal vascular permeability, causes breakdown of the blood-retina barrier, and results in retina edema. VEGF is up-regulated in diabetic retinopathy. Currently available anti-VEGF agents in the United States include pegaptanib sodium, ranibizumab, aflibercept, and bevacizumab. Bevacizumab is not commercially available as an intravitreal injection.

Ranibizumab (Lucentis)

Ranibizumab is a recombinant humanized antibody fragment that is active against all isoforms of VEGF-A. Intravitreal ranibizumab is FDA approved for the treatment of diabetic macular edema, exudative ARMD, and macular edema caused by retinal vein occlusion.

Aflibercept intravitreal (Eylea)

Aflibercept binds and prevents activation of vascular endothelial growth factors (VEGF-A) and placental growth factor (PIGF). It is approved for AMD, macular edema, and diabetic macular edema.

Pegaptanib (Macugen)

Pegaptanib sodium is a pegylated aptamer directed against the VEGF-A165 isoform. It was the first FDA-approved ophthalmologic anti-VEGF agent for the treatment of choroidal neovascularization (CNV) from age-related macular degeneration (ARMD).

Bevacizumab (Avastin)

Bevacizumab is a full-length recombinant humanized antibody that is active against all isoforms of VEGF-A. It is FDA approved as an adjunctive systemic treatment for metastatic colorectal cancer. Currently, a specific ophthalmic product is not available for intravitreal administration.