|SYMPOSIUM - DIABETIC RETINOPATHY UPDATE
|Year : 2014 | Volume
| Issue : 1 | Page : 26-34
Current trends in the treatment of diabetic macular edema
Sofia Theodoropoulou1, Ahmed Sallam2
1 Department of Ophthalmology, Gloucestershire Hospitals, NHS Foundation Trust, Gloucester, United Kingdom
2 Department of Ophthalmology, Gloucestershire Hospitals, NHS Foundation Trust, Gloucester, UK; Department of Ophthalmology, Ain Shams University, Cairo, Egypt
|Date of Web Publication||3-Mar-2015|
Dr. Ahmed Sallam
Department of Ophthalmology, Gloucestershire Hospitals, NHS Foundation Trust, Gloucester, UK
Source of Support: None, Conflict of Interest: None
Since the introduction of focal/grid macular laser over 25 years ago and until recently, laser photocoagulation has been the standard of care in the treatment of diabetic macular edema (DME). Whilst laser photocoagulation was shown to halve the risk of moderate visual loss over 3 years, from 24% to 12%, only < 5% of patients achieves better visual acuity. Within the last 5 years, the use of intravitreal corticosteroids and intravitreal anti-vascular endothelial growth factor (VEGF) agents have come into clinical practice for the management of DME and several recent randomized clinical trials have shown superior effectiveness of anti-VEGF treatments compared to conventional macular laser. The introduction of depot steroid injections as flucinolone acetoinde has also lead to a current increase in interest in the use of intravitreal corticosteroids for DME treatment. In this review, we discuss the ocular treatment options currently available for the treatment of DME, mainly focusing on macular laser as well as intravitreal anti-VEGF and corticosteroid treatments.
Keywords: Diabetes, laser, macular edema, ranibizumab
|How to cite this article:|
Theodoropoulou S, Sallam A. Current trends in the treatment of diabetic macular edema. Egypt Retina J 2014;2:26-34
| Introduction|| |
Many countries have experienced a rise in obesity rates over the past two decades. Obesity carries many health-related implications, including an increased risk for diabetes mellitus, which affects an estimated 6.3% of the US population and 4% of the worldwide population.  Diabetes often affects the small vasculature of end organs, including the eye. Diabetic retinopathy (DR) affects about one half of patients with diabetes and is one of the leading causes of vision loss and blindness among working-age people. 
Diabetic macular edema (DME) results from pathologic capillary permeability related to overexpression of vascular endothelial growth factor (VEGF) and other cytokine mediators.  This leads to accumulation of fluid and exudate at the macula and is the most common cause of visual impairment in DR. The Diabetes Control and Complications Trial (DCCT) reported that 27% of Type I diabetic patients develop DME within 9 years of onset.  An even higher incidence of DME has been reported in older patients with Type II diabetes. 
Up until recently, argon laser photocoagulation has been the mainstay of treatment for macular edema since the publication of the results of the Early Treatment DR Study (ETDRS), which showed an approximate 50% reduction in the rate of moderate vision loss at 3 years following laser photocoagulation compared to no treatment. However, for patients with center-involving macular edema, the risk of moderate vision loss at 3 years remained 15% with treatment.  Both DCCT and United Kingdom Prospective Diabetes Study have demonstrated that tight glycemic and blood pressure control decrease the risk of microvascular complications of Type I and Type II diabetes, respectively, including DR and vision loss. ,,,, Whilst a more intensive blood pressure and blood sugar control have currently become the standard of care (SOC), recent studies from the DR Clinical Research Network (DRCR.net) indicate that even with the guidelines of tight glycemic and blood pressure control, 12-13% of patients with fovea-involving DME who undergo focal/grid laser lose 10 or more ETDRS letters after 2-3 years of follow-up.  Additionally, with a baseline median vision of 20/50 to 20/63, only 36 to 44% of patients gained 10 or more ETDRS letters after 2-3 years. ,,
Within the last 5 years, the use of intravitreal corticosteroids and intravitreal anti-VEGF agents have come into clinical practice for the management of DME and several recent randomized clinical trials have shown superior effectiveness of anti-VEGF treatments compared to conventional macular laser. ,, The introduction of depot steroid injections as flucinolone acetoinde has also lead to a current increase in interest in the use of intravitreal corticosteroids for DME treatment. , In this review, we discuss the ocular treatment options currently available for the treatment of DME, mainly focusing on macular laser as well as intravitreal anti-VEGF and corticosteroid treatments.
| Current Treatment Options for Diabetic Macular edema|| |
Since the introduction of focal/grid macular laser over 25 years ago and until recently, laser photocoagulation has been the SOC in the treatment of DME.  The mechanisms of action of focal/grid laser are still not well understood. Microaneurysms, the sources of leakage in DME, are targeted by the laser, and hemoglobin in the microaneurysms absorbs the laser energy. This promotes thrombosis within the microaneurysm, halting further leakage. Applying laser spots to the retinal pigment epithelium (RPE) may also stimulate the outer blood retinal barrier, and this may compensate for the pathological increase in permeability of the inner blood retinal barrier in DR. In general, green wavelength is employed as this wavelength is readily absorbed by hemoglobin, which has the advantage of improved uptake when photocoagulating microaneurysms. Other wavelengths have also been utilized; while they may be advantageous in specific cases, there is no evidence that the choice of wavelength impacts visual outcomes. In practice, macular photocoagulation in eyes with DME begins with identifying the areas of retinal thickening and leakage. Fluorescein angiography can be utilized as an adjunct to determine the points of leakage, previously lasered areas as well as areas of capillary nonperfusion. Conventional macular laser involves placement of light, small (50-100 um) laser burns only within thickened areas of the macula (modified grid), including direct (focal) treatment of microaneurysms using laser spots scattered approximately two to three burn widths apart within other areas of edema not accounted for by microaneurysms. There is no clinical benefit usually from re-treating thickened macular areas that has been lasered previously. The foveal avascular zone (FAZ) is generally avoided to prevent central scotomas but areas of nonperfusion that are not continuous with the FAZ can be treated to decrease the VEFG drive for the macular edema.
The advantages of photocoagulation have been made clear by the ETDRS, in which laser photocoagulation was shown to halve the risk of moderate visual loss over 3 years, from 24% to 12%.  However, only a small percentage of patients (<5%) achieved better visual acuity.  Macular photocoagulation is also not suitable for foveal involving macular edema and in eyes with significant foveal ischaemia and FAZ disruption. There is also no clinical benefit usually from re-treating thickened macular areas that has been adequately lasered previously [Figure 1]. While macular laser is associated with a low risk of adverse events, potential complications include paracentral scotomas, lateral creep of juxtafoveal laser scars into the fovea, accidental foveal photocoagulation, subfoveal fibrosis, and choroidal neovascularization at the sites of laser scars. In addition, there can be residual massive hard exudates after the resolution of edema, and patients often experience colour vision impairment. ,
|Figure 1: Colour fundus photograph of a patient with diabetic macular edema that has been refractory to grid macular laser treatment. This patient was treated before anti-vascular endothelial growth factor agents were available|
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Macular laser for DME is likely to continue to be part of the management of DME in selected subset of patients as those with nonfoveal involving macular edema. This would be of particular importance in the developing world, owing to the lower cost of laser treatment and the less intensive management requirements compared to newer intravitreal therapeutics. While it previously was used as a monotherapy, focal/grid laser could also be used in conjunction with anti-VEGF therapy, typically when nonfoveal involving DME persists and is not continuing to improve after repeat anti-VEGF therapy.
Subthreshold diode-laser micropulse technology
Newer laser technologies include subthreshold diode-laser micropulse technology , and selective retina therapy (SRT).  These modalities aim at minimizing retinal photoreceptor damage while mainly targeting the RPE. Micropulse diode (810 nm) laser treatment is a low-intensity procedure that is administered via high-density distribution in both pathologically involved and uninvolved areas of the retina. In this technique, laser emission is divided into a "train" of short, repetitive pulses that persist for 0.1-0.5 s. The "on" time is the duration of each micropulse (typically 100-300 μs) and the "off" time (1700-1900 μs) is the interval between successive micropulses. This "off" time allows for heat dissipation, which decreases collateral damage and confines treatment to the RPE.  This is in stark contrast to conventional continuous wave laser, where the same magnitude of energy is delivered throughout the entire exposure cycle ranges from 0.1 to 0.5 s.
Subthreshold micropulse diode laser photocoagulation is designed to target the RPE melanocytes while avoiding photoreceptor damage. The term "subthreshold" refers to photocoagulation that does not produce visible intraretinal damage or ophthalmically visible scarring either during or after treatment. In fact, burns are undetectable not only on clinical examination, but also on intravenous fluorescein angiography (and fundus autofluorescene). Intensity of subthreshold treatment can vary from no lesion produced to microscopic destruction of the RPE and photoreceptor outer segment structures.  Micropulse laser can be delivered directly over areas of edema, including the central fovea. The effect of the laser is slow and may require several months to obtain the desired result. However, the effects of the micropulse laser treatment appear longer lasting than anti-VEGF therapy alone.
A recent randomized clinical trial demonstrated superior results for the primary endpoint of visual acuity for high-density subthreshold diode-laser micropulse photocoagulation compared to standard modified ETDRS laser at 1 year.  Encouraging results have also been reported for SRT,  but this treatment modality has not been directly compared to focal/grid laser. Further Phase II/III studies are underway to evaluate these treatment modalities. ,
Intravitreal anti-vascular endothelial growth factor therapy
Inhibition of VEGF has become a topic of interest in recent years in the area of neovascular age-related macular degeneration. The properties of VEGF, and the consequences of its inhibition, suggest a pivotal role for this approach in the management of DME. In the pathophysiologic cascade leading to DME, chronic hyperglycemia leads to oxidative damage to endothelial cells as well as to an inflammatory response. The ensuing ischemia results in overexpression of a number of growth factors, including VEGF as well as insulin-like growth factor-1, angiopoeitin-1 and -2, stromal-derived factor-1, fibroblast growth factor-2, and tumor necrosis factor (TNF).  Synergistically, these growth factors mediate angiogenesis, protease production, endothelial cell proliferation, migration, and tube formation. TNF-alpha (TNF-α) and VEGF play a role in the early stages of angiogenesis, with TNF-α promoting leukocyte adhesion and VEGF promoting leukostasis, resulting in ischemia. VEGF also increases vascular permeability by relaxing endothelial cell junctions, which increases permeability and leakage. Blockade of all involved growth factors will likely be necessary to completely suppress the detrimental effects of ischemia, but even isolated blockade of VEGF was shown to have beneficial effects on DME. ,
Pegaptanib sodium (Macugen ® , Eyetech Pharmaceuticals, Melville, NY/Pfizer, New York, NY) is an anti-VEGF aptamer, that binds to and blocks the effects of VEGF-165, one isoform of the VEGF family of molecules. The drug is approved by the US Food and Drug Administration (FDA) for the treatment of neovascular age-related macular degeneration, and it has been studied in a Phase II trial for DME.  In that study, 172 subjects with DME were randomized to receive a series of three intravitreal injections of pegaptanib (at entry and then 6 weeks apart) in one of three doses, or a sham injection, and were followed for 36 weeks. Additional injections or photocoagulation were permitted every 6 weeks through the end of the study. At the 36 weeks mark, mean visual acuity had improved to 20/50 in the pegaptanib 0.3 mg group (the dose that was approved by the FDA) versus only 20/63 in the sham group (P = 0.04). Mean central retinal thickness decreased by 68 μm in the 0.3 mg group, whereas it increased by 4 μm only in the sham group (P = 0.02). In addition, photocoagulation was required in 25% of the 0.3 mg group compared with 48% of the sham group (P = 0.04).
Ranibizumab (Lucentis™, Genentech, San Francisco, CA, USA) is an antibody fragment that also binds and blocks the effects of VEGF. Unlike pegaptanib, ranibizumab binds and inhibits all isoforms of VEGF. Ranibizumab is currently the main anti-VEGF treatment used for treatment of DME and is approved by the FDA. The UK National Institute for Health and Care Excellence (NICE) has also recommended ranibizumab as an option for treating visual impairment due to DME only if associated with a central retinal thickness of at least 400 um [Figure 2]. Several randomized control studies have evaluated ranibizumab as a treatment option for patients with DME and these include:
|Figure 2: Fluorescein angiogram and optical coherence tomography of another patient with mild foveal involving diabetic macular edema|
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The study on "safety and efficacy of ranibizumab in DME" (RESOLVE study)  is a Phase II, placebo-controlled, randomized, multicenter study. In that study, 151 patients were randomized 1:1:1 to ranibizumab monotherapy at a dose of 0.3 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 three consecutive monthly injections and were followed monthly with an as-necessary regimen from month 3 to 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.
The ranibizumab for edema of the macula in diabetes-2 study  is a Phase II, randomized multicenter study with 126 patients randomized 1:1:1 to receive 0.5 mg of ranibizumab, focal/grid laser coagulation, or a combination of ranibizumab and laser. At month 36, the mean gain in BCVA was significantly greater in the ranibizumab monotherapy group, with +10.3 letters, compared with the laser monotherapy group, who lost-1.6 letters and the combination treatment group, gaining only +2 letters.
In the RESTORE study, ranibizumab monotherapy or combined with laser versus laser monotherapy for DME, , a Phase III, 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. At months 12, mean change in BCVA 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.
RIDE and RISE studies  are two identically designed, parallel, double-blind, 3 years clinical trials, which were placebo-treatment-controlled for 24 months. A total of 759 patients were randomized into three 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 < 0.01). Results from the RIDE and RISE trials also showed that more patients who received ranibizumab were able to read at least three additional lines (15 ETDRS letters) (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). Furthermore, the ranibizumab group had average vision gains exceeding two lines (10 letters) 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). The data published from both studies showed that vision improvements observed with ranibizumab treatment at 24 months were maintained with continued treatment through 36 months.
Bevacizumab (Avastin ® , Genentech, San Francisco, CA, USA) is the full antibody from which ranibizumab is derived. This anti-VEGF molecule is FDA approved for systemic treatment of metastatic colon cancer, but not for any ophthalmic indications. Its use in conditions such as age-related macular degeneration, DR, and DME is currently off-label. The use of bevacizumab for the treatment of DME has been investigated by several studies. ,,, The intravitreal bevacizumab or laser therapy in the management of DME study  was a prospective, single-center, randomized, 2 years study of 80 patients with center-involving DME who had received at least one prior macular laser treatment. The study aimed to compare the efficacy of repeated intravitreal bevacizumab with 4 monthly modified macular laser treatments. Results of this study were not very much different from those obtained with ranibizumab treatment indicating that compared to laser where most patients did not gain vision, anti-VEGF inhibition is associated with significant visual gain. 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. Similar results were seen at 24 months where 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.
Another anti-VEGF agent that has been developed for intravitreal injection is aflibercept (Eylea, VEGF trap eye, BAY86-5321) and can be administered bimonthly. Aflibercept consists of the VEGF binding portions of the human VEGFR-1 and -2 fused to the Fc portion of the human immunoglobulin-G1. In addition to having high affinity to all isoforms of VEGF-A, it also binds to placental growth factor, which is known to potentiate the angiogenic action of VEGF.  Recent data from 2 controlled, randomized, Phase III trials (VISTA and VIVID) showed that intravitreal aflibercept use in a dose of 2 mg/0.05 ml was associated significant superiority in functional and anatomic endpoints over macular laser, with similar efficacy in the monthly (2q4) and bimonthly (2q8) treated groups. Mean BCVA gains from baseline to week 52 in the aflibercept 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 vs. 0.2 letters in VISTA, and 10.5 and 10.7 vs. 1.2 letters in VIVID. 
KH902 (Kanghong Biotech, Chengdu, China) is a similar molecule that incorporates different domains from the VEGFR-1 and 2 and is currently in Phase I/II trials for DME.  AAV2-sFLT01 (Genzyme, Cambridge, MA, USA) is a replication deficient Adenovirus expressing VEGFR-1. It offers the possibility of more sustained VEGF blockade. It is currently in Phase I safety trial in patients with neovascular age-related macular degeneration. 
Vascular endothelial growth factor inhibition represents an important component of DME therapy in the future. Improvements in drug delivery will be necessary in order to avoid repeated intravitreal injections and the cumulative risk of endophthalmitis associated with this route of administration. Such improvements may also reduce the risk of systemic adverse events, as intraocular anti-VEGF treatment has been associated with a slightly elevated risk of nonocular hemorrhage and stroke. 
| Intravitreal Corticosteroids|| |
There is a growing body of evidence to indicate that inflammation plays a significant role in the development of DME. ,, Given the role of inflammation in the pathogenesis of DME, steroids have more recently been utilized for the treatment of DME. It is also possible that their mode of action in DME may be also mediated through their ability to inhibit the expression of VEGF.
Intravitreal triamcinolone acetonide
Two recent randomized controlled trials by the DRCR.net have investigated the use of intravitreal triamcinolone in the treatment of DME [Figure 3]. ,,,, In the first of these two studies, the use of focal/grid laser was compared to treatment with 1 or 4 mg of intravitreal triamcinolone, with retreatment possible every 4 months in each arm of the study. At the 4 months follow-up, the triamcinolone arms showed superiority in terms of visual acuity, at 1 year laser and intravitreal triamcinolone treatments appeared equivalent and at the 2 years primary endpoint, laser was found to be superior to either of the intravitreal steroid arms and these results were held after 3 years of follow-up. ,,
|Figure 3: Intravitreal triamcinolone acetonide injection in a pseudophakic patient with diabetic macular edema|
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In the second of these trials, focal/grid laser alone was compared to 4 mg of intravitreal triamcinolone plus laser. The study also included two additional arms utilizing intravitreal ranibizumab. Similar to the previous study, the triamcinolone plus laser arm showed superiority compared to laser alone in terms of visual acuity at 24 weeks follow-up. However, at 1 and 2 years, all treatments appeared fairly equivalent in terms of visual acuity outcome, but with increased rates of cataract and elevated intraocular pressure (IOP) in the triamcinolone plus laser group. , In the subgroup of patients who were pseudophakic at baseline, the triamcinolone plus laser arm appeared superior to the laser alone treatment and equivalent to the treatment arms that included anti-VEGF therapy. However, these eyes were more likely to have additional follow-up visits for management of increased IOP.
Fluocinolone acetonide (FAc) intravitreal inserts are nonbiodegradable cylindrical tubes of polymer loaded with 190 μg FAc that are currently available for insertion into the vitreous cavity through a 25-gauge needle in an outpatient setting. Inserts provide sustained delivery of FAc in the eye for up to 36 months. ,,
A prospective, multicenter, randomized, controlled clinical trial investigated the role of the FAc implant in DME patients.  To be eligible, patients had to meet the following criteria: At least one disc area of DME involving the fovea, at least one previous macular laser treatment 3 or more months prior to enrollment, and visual acuity between 20 and 68 ETDRS letters. One hundred ninety-seven patients were enrolled and randomized in a 2:1 ratio to receive either the 0.59 mg implant or SOC therapy consisting of repeat macular laser or observation at the investigator's discretion. At 12 months, there was little difference in visual acuity levels between eyes that received the implant and eyes that received SOC treatment. Though the results were not statistically significant, more implanted eyes lost 3 or more lines of vision compared to the SOC group. This was probably due to steroid-induced lens opacities that typically develop in this time frame. At 24 months and 36, and presumably after any necessary cataract surgery, visual acuity was significantly better in implanted eyes than in eyes receiving SOC therapy. At 24 months, 27.6% of implanted eyes versus only 8.7% of SOC eyes had gained three or more lines of vision (P = 0.002), and at 36 months such a gain was seen in 27.6% of implanted eyes versus 14.5% of SOC eyes (P = 0.038). , Resolution of central macular edema occurred in 60.3% of implanted eyes versus 21.3% of SOC eyes at 12 months (P < 0.0001). By 24 months, central macular edema resolution was 49.0% in implanted eyes and 29.8% in SOC eyes (P = 0.0295), and by 36 months central macular edema resolution was 51.2% in implanted eyes compared with 37.7% in SOC eyes (P = 0.070).
Through the first 36 months, 59.1% of implanted eyes versus 5.8% of control eyes had IOP elevation of 30 mm Hg or greater at any time. Glaucoma filtration surgery was required in 29.1% of implanted eyes. Ninety-five percent of implanted phakic eyes required cataract extraction by 36 months, compared with 18.5% of control eyes.  Other side effects included, retinal detachment which was observed in 2.4% of implanted eyes, and endophthalmitis occurred in 1.6% of implanted eyes compared with 0% for both parameters in SOC eyes. Explantation of the device was required in 9.4% of eyes; 50% of explanations were performed to manage elevated IOP.
The FAME study is another controlled trial that investigated the use of FAc in DME.  Subjects with persistent DME despite at least one macular laser treatment were randomized 1:2:2 to sham injection (n = 185), 0.2 μg/day insert which is the currently licensed implant dose (n = 375), or 0.5 μg/day insert (n = 393). At month 36, the percentage of patients who gained ≥ 15 in letter score was 28.7% (low-dose) and 27.8% (high-dose) in the FAc insert groups compared with 18.9% in the sham group. Almost all phakic patients in the FAc insert groups developed cataract, but their visual benefit after cataract surgery was similar to that in pseudophakic patients. Around 40% of eyes treated with the 0.2 ΅ g/day insert required IOP lowering medications. The incidence of incisional glaucoma surgery at month 36 was 4.8% in the low-dose group and 8.1% in the high-dose insert group.
Intravitreal FAc was recently granted approval in the UK by NICE but only for DME in pseudpakaic eyes that is not responsive to SOC. It has also been approved in other different countries in Europe for treatment of DME but is still not approved for this indication in the US.
Dexamethasone intravitreal implant
Dexamethasone intravitreal implant (Ozurdex) is another sustained-release formulation of corticosteroid that has been approved by both FDA and NICE for the treatment of macular edema due to retinal vein occlusion. Recent studies have also shown the benefit of Ozurdex in treating DME and the drug has recently been approved by FDA for diabetic macular oedema in eyes that are or will be rendered pseudophakic. , In one study, a subgroup analysis of 171 eyes with persistent DME of ≥90 days that were treated with either 0.7 or 0.35 mg of Ozurdex showed better visual acuity (improvement of 10 letters or more), decreased central foveal thickness (CFT) and decreased leakage on fluorescein angiogram at 90 days compared to observation. Both the 0.7 mg and 0.35 mg groups had IOP elevation, but the rate was lower than what was reported for intravitreal triamcinolone acetonide.  The MEAD study is a Phase III randomized controlled trial of patients with DME that received treatment with Ozurdex.  Subjects were randomized (1:1:1) to study treatment with 0.7 mg implant, which is the currently marketed product, 0.35 mg implant, or sham procedure. Patients who met re-treatment eligibility criteria were retreated no more often than every 6 months. At 3 years, the percentage of patients who gained ≥15 in letter score was 22.2% (0.7 mg group) and 18.4% (0.35 mg) compared with12% in the sham group. For patients receiving the 0.7 mg implant, IOP was elevated in about one third of eyes but in most cases it was possible to control the increase in IOP with topical treatment and only a small proportionate of eyes required glaucoma surgery (0.3%). Cataract surgery was undertaken in nearly 60% of eyes during the 3 years study period in the 0.7 mg implant group compared to 7% in the sham group. 
Dexamethasone intravitreal implant may present a good alternative option in the treatment of patients with chronic DME, who require repeated monthly injection of anti-VEGF agents, as it allows an extended interval between injections. The drug can also be of benefit in patients who had previous vitrectomy as unlike anti-VEGFs, the pharmacokinteics of Ozurdex is not significantly altered by vitrectomy surgery [Figure 4].
|Figure 4: Operative photograph of intravitreal dexamethasone implant (Ozurdex) administered after pars plana vitrectomy surgery. Note the posterior location of implant which is usually seen in vitrectomized eyes|
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| Vitrectomy|| |
Initially advocated for clearing media opacities and relieving retinal traction in eyes with advanced DR, vitrectomy techniques have advanced in the last decade, leading to more extended indications in diabetics. ,, Vitrectomy for DME was first described in a group of 10 patients with presumed vitreomacular traction due to taut posterior hyaloids, nine of whom achieved improved vision.  Currently, DME with vitreomacular traction remains the main indication for vitrectomy surgery in DME [Figure 5]. The role of vitrectomy for this type of DME was recently investigated by the DRCR.net in a small, prospective cohort study of 87 eyes. All eyes underwent vitrectomy, with removal of membranes at the surgeon's discretion. At 6 months postoperatively, VA improved by more than two lines in 38% of eyes and worsened by two lines or more in 22% of eyes. The mean decrease in macular thickness on OCT was 160 μm, with 43% of patients having macular thickness of <250 μm. 
|Figure 5: Fluorescein angiogram and optical coherence tomography scan of a patient with diabetic macular edema and vitreomacular traction. Patient was treated with pars plana vitrectomy|
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Encouraged by improvement in eyes with vitreomacular traction, some authors have advocated vitrectomy for treatment of chronic DME in the absence of vitreomacular traction. ,, In aggregate, these studies report excellent thinning of the macula, which compares favorably with that achieved by anti-VEGF treatment. ,,, However, because visual acuity results vary from one study to another and the vision improvement is not well defined, the role of vitrectomy surgery in DME eyes without vitreomacular traction remains controversial.
Vitrectomy surgery is not without complications. ,, These include, cataract formation as well as other less common postoperative problems of retinal detachment, vitreous hemorrhage and glaucoma. In addition, an important practical point to consider when operating on DME eyes is that vitrectomy surgery significantly shortens the half-life of subsequent anti-VEGF therapy. 
| Conclusion|| |
Macular (focal/modified grid) laser still has a role in our practice for cases with clinically significant DME that does not involve the fovea whereas anti-VEGF agents are currently the standard treatment for centre-involving DME and in those with nonfoveal involving DME that has failed laser treatment. In our hands, pseudophakic patients, particularly those who has had previous vitrectomy surgery, require repeat anti-VEGF injections or has an unstable cardiovascular disease are good candidates for intravitreal steroids treatment. As regards, the role of vitrectomy surgery for DME, in our practice, we only consider surgery in patients with DME that is associated with clinical or OCT evidence of vitreomacular traction. Finally, it is worth mentioning that wide field angiography can be of help in patients with persistent DME to help localize and treat peripheral areas of capillary nonperfusion with laser in an attempt to decrease possible VEGF drive for the edema.
New pharmaceutical treatments that may become approved in the future as well as a more complete understanding of the role of selective photocoagulation of non-perfused retinal regions using wide field angiography, is likely to translate into continued visual benefit and a decreased treatment burden for DME patients.
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